Photodynamic therapy illuminator and photodynamic therapy methods

Abstract

A method of treating non-melanoma skin cancer or a precancerous skin condition in a patient is provided. The method includes applying to a lesion on the patient a topical composition including 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; incubating the topical composition on the lesion; and illuminating the lesion with a blue light source.

Description

PHOTODYNAMIC THERAPY ILLUMINATOR ANDPHOTODYNAMIC THERAPY METHODSCROSS-REFERENCE TO RELATED PATENT APPLICATIONS[00011 This application claims the benefit of and priority to U.S. Application No. 63 / 780,137, filed on March 28, 2025, U.S. Application No. 63 / 694,159, filed on September 12, 2024, and U.S. Application No. 63 / 643,794, filed on May 7, 2024, the entire disclosures of which are hereby incorporated by reference herein.TECHNICAL FIELD[0002[ The present disclosure relates generally to a photodynamic therapy illuminator and methods of using a photodynamic therapy illuminator for providing photodynamic therapy.BACKGROUND

[0003] Photodynamic therapy (PDT), photodynamic diagnosis (PD), and / or photochemotherapy are generally used to treat and / or diagnose disorders in or near the skin or other tissues, such as those in a body cavity. For example, PDT or PD may be used for treatment and / or diagnosis of actinic keratosis of the scalp or facial areas of a patient. In addition, PDT and PD may be used for treatment and / or diagnosis of other indications (e.g., acne, warts, psoriasis, photo-damaged skin) and other areas of the patient (e.g., the extremities).

[0004] During one form of PDT or PD, a patient is first administered a photoactivatable agent or a precursor of a photoactivatable agent that accumulates in the tissue to be treated or diagnosed. The area in which the photoactivatable agent is administered is then exposed to visible light, which causes chemical and / or biological changes in the agent. These changes allow the agent to then selectively locate, destroy, or alter the target tissue while, at the same time, causing only mild and reversible damage to other tissues in the treatment area. One example of a precursor of a photoactivatable agent is 5-aminolevulinic acid (“ALA”), which is commonly used in PDT of actinic keratosis. As they are used here, the terms ALA or 5-aminolevulinic acid refer to ALA itself, precursors thereof and pharmaceutically acceptable salts of the same.SUMMARY

[0005] Provided herein according to one aspect of the present disclosure is a method of treating non-melanoma skin cancer or a precancerous skin condition in a patient in need thereof, the method comprising:(i) applying to a lesion on the patient, a topical composition comprising 5 -aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source.|0006| In at least one embodiment, the non-melanoma skin cancer is basal cell carcinoma, cutaneous squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, or sebaceous carcinoma.

[0007] In at least one embodiment, the cutaneous squamous cell carcinoma is invasive squamous cell carcinoma (SCCI), clear-cell squamous cell carcinoma, spindle cell squamous cell carcinoma (sarcomatoid SCC), squamous cell carcinoma with single cell infiltrates, de novo squamous cell carcinoma, verrucous carcinoma, or lymphoepithelioma-like carcinoma of the skin (LELCS).

[0008] In at least one embodiment, the precancerous skin condition is actinic cheilitis, squamous cell carcinoma in situ (isSCC), leukoplakia, keratocanthoma, or lentigo maligna. In at least one embodiment, the precancerous skin condition is isSCC.

[0009] In at least one embodiment, the lesion is located on the head, neck, torso, arm, leg, hand, or foot. In at least one embodiment, the lesion is located on an organ or an internal cavity, such as a bladder or a cervix, or on the genitalia.

[0010] In at least one embodiment, the isSCC is facial isSCC.(0011 ] In at least one embodiment, the method further comprises occluding the lesion during the incubating step and prior to illuminating the lesion with the light source. In at least one embodiment, occluding the lesion comprises applying a light-blocking occlusive dressing to the lesion. In at least one embodiment, occluding the lesion comprises applying a transparent film dressing to the lesion. In at least one embodiment, occluding the lesion comprises applying a low density polyethylene barrier to the lesion.

[0012] In at least one embodiment, the method further comprises applying a secondary barrier over the lesion that is occluded, wherein the secondary barrier comprises foil or elastic material.10013] In at least one embodiment, the method further comprises cleaning the lesion after the incubating step and prior to the illuminating step.

[0014] In at least one embodiment, the method further comprises heating the lesion either (1) after the incubating step and before the illuminating step or (2) during the illuminating step.

[0015] In at least one embodiment, the method further comprises heating the lesion during the incubating step.

[0016] Provided herein in another aspect is a method of treating cutaneous T-cell lymphoma, non-small cell lung cancer, esophageal cancer, cervical cancer, bladder cancer, or mucosal cancer, Kaposi sarcoma, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia in a patient in need thereof, the method comprising:(i) applying to a lesion on the patient, a topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source.

[0017] In at least one embodiment, the mucosal cancer is located in the gastrointestinal tract or urogenital area.

[0018] In at least one embodiment, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is in a stored form of a dry solid prior to administration to the patient.

[0019] In at least one embodiment, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of about 1% w / w to about 30% w / w. In certain embodiments, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of about 20% w / w.

[0020] In at least one embodiment, the at least one pharmaceutically acceptable excipient comprises at least one selected from a group consisting of a penetration enhancer and a chelating agent.

[0021] In at least one embodiment, the penetration enhancer is selected from a group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, glycol derivatives, glycerides, azones, polysorbates, macrogolglycerides, polyethylene glycol derivatives, ethoxylated ether derivatives, bile salts, and sulfated glycosaminoglycan, or a combination of any two or more thereof. In at least one embodiment, the penetration enhancer is selected from a group consisting of propylene glycol, polyethylene glycol, and 2- (2-ethoxyethoxy)ethanol. In at least one embodiment, the penetration enhancer is present in the topical composition in an amount of about 2% w / w to about 50% w / w.

[0022] In at least one embodiment, the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof. In some embodiments, the chelating agent is present in the topical composition in an amount of about 0.1% w / w about to 0.25% w / w.

[0023] In at least one embodiment, the at least one pharmaceutically acceptable excipient further comprises an anti-foaming agent. In at least one embodiment, the anti-foaming agent is cyclomethicone.

[0024] In at least one embodiment, the incubating step is performed for a period of about 15 minutes to about 24 hours.

[0025] In at least one embodiment, the blue light source delivers blue light at about 10 J / cm2. In at least one embodiment, the blue light source delivers blue light at an irradiance density of approximately 10 mW / cm2.

[0026] In at least one embodiment, the blue light source delivers blue light at about 20 J / cm2. In at least one embodiment, the blue light source delivers blue light at an irradiance density of approximately 20 mW / cm2.

[0027] In at least one embodiment, the method further comprises applying an optical clarifying agent to the lesion prior to the illuminating step. In at least one embodiment, the optical clarifying agent is a skin moisturizer.

[0028] In at least one embodiment, the method further comprises evaluating a sample of the lesion in a cell-based test prior to applying the topical composition. In some embodiments, the cell-based test is a histopathology test.

[0029] In at least one embodiment, the patient has previously been treated for the cancer or precancerous condition. In some embodiments, the patient is refractory to previous treatment.

[0030] In at least one embodiment, the patient has not been previously treated with other therapy for the cancer or precancerous condition.[0031 J In at least one embodiment, the blue light source is an illuminating panel for providing photodynamic therapy to a treatment surface, the panel comprising: a housing; a plurality of light sources coupled to the housing arranged in an array; and at least one air circulator disposed within the housing, the at least one air circulator disposed within the housing and configured to provide airflow (e.g., cooling airflow) to the treatment surface, wherein the at least one air circulator comprises: an air circulation device; and a plenum defining an air passageway toward the treatment surface; wherein the plenum comprises: a base portion configured to couple to the air circulation device;a conduit extending from the base portion, the conduit terminating at the treatment array surface, wherein a terminal end of the conduit defines an outlet for providing the cooling airflow.

[0032] In at least one embodiment, the conduit terminates above the plurality of light sources within the treatment array surface.[ 00331 In at least one embodiment, the at least one air circulator comprises a first air circulator and a second air circulator. In at least one embodiment, the outlet of the first air circulator is disposed within an upper portion of the panel and the outlet of the second air circulator is disposed within a lower portion of the panel.

[0034] In at least one embodiment, the plurality of light sources are light emitting diodes (LEDs).

[0035] In at least one embodiment, the air circulation device is a fan.

[0036] In at least one embodiment, the conduit forms a hook shape.

[0037] In at least one embodiment, the outlet is structured to have a v-shape.

[0038] In at least one embodiment, the conduit is structured such that a width of the conduit decreases from the base portion to the outlet to cause acceleration of the cooling airflow.

[0039] In at least one embodiment, the air circulator is operably coupled to a controller, the controller configured to operate the air circulator in a plurality of operational modes.

[0040] In at least one embodiment, wherein the blue light source is an illuminator for providing photodynamic therapy to a treatment surface, the illuminator comprising: a treatment array comprising a plurality of panels, wherein each of the plurality of panels comprises a plurality of light sources; and wherein at least one panel of the plurality of panels comprises at least one air circulator, the at least one air circulator configured to provide airflow to the treatment surface; and wherein the at least one air circulator comprises:an air circulation device; and a plenum defining an air passageway toward the treatment surface; wherein the plenum comprises: a base portion configured to couple to the air circulation device; a conduit extending from the base portion, the conduit terminating at a surface within the one panel comprising the plurality of light sources, and wherein a terminal end of the conduit defines an outlet for providing the cooling airflow.

[0041] In at least one embodiment, the plurality of panels comprises five panels. In at least one embodiment, the at least one panel is a panel disposed centrally within the five panels.

[0042] In at least one embodiment, the at least one panel further comprises at least one handle, the at least one handle structured to facilitate positioning of the treatment array.

[0043] In at least one embodiment, the illuminator further comprises: a base; and an adjustable arm coupled to the base and the treatment array, the arm comprising: a first portion extending from the base; and a second portion coupled to the first portion, the second portion in a direction substantially perpendicular to the first portion.

[0044] In at least one embodiment, the first portion is structured to be vertically adjustable relative to the base.

[0045] In at least one embodiment, the second portion comprises a first section and a second section, the second section being structured to rotate relative to the first section. In at least one embodiment, the second section is coupled to the treatment array at a second joint, the second joint comprising at least one of a tilting mechanism or a rotating mechanism to facilitate positioning of the treatment array relative to the treatment surface. In at least one embodiment, at least one of the tilting mechanism or the rotating mechanism comprises a torque insert to enable locking a position of the treatment array.

[0046] In at least one embodiment, the treatment surface is located on at least one of a patient’s head, upper extremities, lower extremities, torso, or back.

[0047] In at least one embodiment, 5-aminolevulinic acid is the sole active agent administered to the patient.

[0048] Provided herein in another aspect is a method of treating cutaneous squamous cell carcinoma in situ comprising delivering a dose of blue light of approximately 20 J / cm2at approximately 20 mW / cm2.[00491 Provided herein in another aspect is a method of treating cutaneous squamous cell carcinoma in situ, comprising:(i) applying a topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, to a cutaneous squamous cell carcinoma in situ lesion;(ii) incubating the topical composition on the lesion for approximately 18 hours to approximately 24 hours; and(iii) illuminating, with an illuminator, the lesion for an illumination period of approximately 16 minutes and 40 seconds with a dose of blue light of approximately 20 J / cm2at approximately 20 mW / cm2.

[0050] In at least one embodiment, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of approximately 20% w / w.

[0051] In at least one embodiment, steps (i)-(iii) are performed in a first treatment session, and the method further comprises repeating steps (i)-(iii) in a second treatment session, the second treatment session being approximately 25 days to approximately 31 days after the first treatment session.BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The disclosure will become more fully understood from the following detailed description, taken in conjunction with the accompanying figures, wherein like reference numerals refer to like elements, in which:

[0053] FIG. l is a front perspective view of an illuminator, according to at least one embodiment.

[0054] FIG. 2 is a back perspective view of the illuminator of FIG. 1, according to at least one embodiment.

[0055] FIG. 3 is a side perspective view of the illuminator of FIG. 1 in a collapsed configuration, according to at least one embodiment.

[0056] FIG. 4 is another side perspective view of the illuminator of FIG. 1, according to at least one embodiment.

[0057] FIG. 5 is another side perspective view of the illuminator of FIG. 4, according to at least one embodiment.

[0058] FIG. 6A is a front perspective view of illuminating panels of the illuminator of FIG. 1, according to at least one embodiment.

[0059] FIG. 6B is a partially exploded front view of the illuminating panels of FIG. 6A, according to at least one embodiment.

[0060] FIG. 6C is a rear view of the illuminating panels of FIG. 6A, according to at least one embodiment.

[0061] FIG. 7A is a side cross-sectional view of the illuminating panels of FIG. 6A, according to at least one embodiment.

[0062] FIG. 7B is a side cross-sectional view of the illuminating panels of FIG. 6A taken along line B-B of FIG. 6A near a top portion of the panels, according to at least one embodiment.

[0063] FIG. 8 A is a front cross-sectional view taken along line A-A of FIG. 4 of an illuminating panel of the illuminator in FIG. 1, according to at last one embodiment.

[0064] FIGS. 8B-8D are alternate front cross-sectional view of the illuminating panel of FIG. 8A, illustrating components of an air circulator therein, according to at least one embodiment.

[0065] FIG. 8E is a front perspective view of a plenum within the air circulator of the illuminating panel of FIGS 8A-8D, according to at least one embodiment.

[0066] FIG. 9 is a front view of a control interface of the illuminator of FIG. 1, according to at least one embodiment.

[0067] FIG. 10 is a front view of a power switch of the illuminator of FIG. 1, according to at least one embodiment.

[0068] FIG. 11 A is a front view of a control lock interface of the illuminator of FIG. 1, according to at least one embodiment.

[0069] FIGS. 1 IB-11C are front views of a switch within the control lock interface of FIG.11 A, according to at least one embodiment.

[0070] FIGS. 12A-12B are side views of the illuminator of FIG. 1 showing a treatment arm in each of a stowed position and a treatment position, according to at least one embodiment.

[0071] FIG. 13 is a front perspective view of a panel control joint of the illuminator of FIG.1, according to at least one embodiment.

[0072] FIGS. 14A-14B are top views of panels within the illuminator of FIG. 1 illustrating the panels in first and second swiveled positions, according to at least one embodiment.

[0073] FIGS. 15-16 are back views of panels within the illuminator of FIG. 1 illustrating a panel control joint, according to at least one embodiment.

[0074] FIG. 17 is a back view of panels within the illuminator of FIG. 1, according to at least one embodiment.

[0075] FIG. 18 is a side view of the panels of FIG. 17, according to at least one embodiment.

[0076] FIG. 19 is a graphical representation of photon efficiency adjusted light dose versus depth for red and blue light.

[0077] FIGS. 20A-20F depict imaging of facial squamous cell carcinoma in situ (isSCC) in three patients before (Visit 1 : FIGS. 20A, 20C, 20E) and after (Visit 10: FIGS. 20B, 20D, 20F) treatment using aminolevulinic acid with photodynamic therapy (ALA-PDT). For FIGS. 20A, 20C, and 20E, the lesion is within the square marked by 4 dots on the patient’s skin. After treatment, the lesion is completely or nearly completely invisible to the naked eye.DETAILED DESCRIPTION

[0078] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments can be utilized, and other changes can be made, without departing from the spirit or scope of the subject matter presented here. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the figures, can be arranged, substituted, combined, and designed in a wide variety of different configurations, all of which are contemplated and made part of this disclosure.

[0079] The present disclosure pertains at least in part to a photodynamic therapy (PDT) illuminator and methods of using the photodynamic therapy illuminator for providing photodynamic therapy.

[0080] Photodynamic therapy may be carried out using certain compositions, such as ALA, in connection with illuminators. Such compositions and / or illuminators (as well as methods of treatment, dressings, and other details) are disclosed, for example, in (i) U.S. Patent No. 5,954,703 to Golub, issued on September 21, 1999, (ii) U.S. Patent No. 6,223,071 to Lundahl et al., issued on April 24, 2001, (iii) U.S. Patent No. 10,814,114 to Boyajian et al., issued on October 27, 2020, (iv) U.S. Patent No. 10,589,122 to Boyajian et al., issued on March 17, 2020, (v) U.S. Patent No. 11,446,512 to Boyajian et al, issued September 20, 2022, (vi) U.S. Patent No. 11,179,574 to Boyajian et al., issued on November 23, 2021, (vii) U.S. Patent No. 10,603,508 to Boyajian et al., issued on March 31, 2020, (viii) U.S. Patent No. 10,357,567 to Lundahl et al., issued on July 23, 2019, (ix) U.S. Patent Application Publication No.2020 / 0261580 to Willey, published on August 20, 2020, (x) U.S. Patent Application Publication No. 2023 / 0145771 to Boyajian etal., published on May 11, 2023, (xi) U.S. Patent Application Publication No. 2023 / 0131170 to Sanghvi et al., published on April 27, 2023, and (xii) U.S. Provisional Application No. 63 / 579,195 filed August 28, 2023 and PCT Application PCT / IB2024 / 058331 filed August 28, 2024 (having associated publication WO 2025 / 046471), both to Lundahl. The entire contents of the foregoing patents and / or patent applications are incorporated herein by reference for background information and the compositions, illuminators, devices, dressings, methods of treatment, processes and techniques relating to photodynamic therapy and diagnosis disclosed therein.

[0081] Nonmelanoma skin cancer (NMSC) is the most common form of cancer, with cutaneous squamous cell carcinoma (SCC) accounting for 20% of all skin cancers. Although less prevalent than basal cell carcinoma (BCC), SCC carries a significant risk of metastasis and mortality and a poor prognosis. The incidence of SCC continues to rise, as observed in the Rochester Epidemiology Project conducted by the Mayo Clinic, which reported a 263% increase in the incidence of SCC between studies spanning the years 1976 to 1984 and 2000 to 2010. Ultraviolet radiation exposure is the primary risk factor for developing SCC; other risk factors include advanced age, fair skin, carcinogen exposure, chronic inflammation, and immunosuppression. SCC often arises from precancerous lesions, including actinic keratoses (AKs) and SCC in situ (isSCC), also known as Bowen disease. isSCC is a common superficial cutaneous malignancy with a reported rate of progression to invasive SCC of 3% to 5%. Treatment of isSCC can mitigate or prevent such progression.

[0082] Histopathological examination is the mainstay for the diagnosis of SCC, with certain histological features, such as poor differentiation, tumor depth greater than approximately 2 mm, and perineural invasion, indicating a higher risk for recurrence and metastasis. The gold standard for the treatment of SCC is Mohs micrographic surgery (MMS) or surgical excision. MMS is indicated for high-risk SCC and SCC located in the head, neck, or genital region. For low-risk SCC or isSCC, standard excision with 4- to 6-mm clinical margins of normalappearing skin is recommended, as per National Comprehensive Cancer Network guidelines. Nonsurgical treatment options for isSCC include radiation therapy, topical chemotherapy,electrocoagulation, cryosurgery, and photodynamic therapy (PDT). Systemic chemotherapy is reserved for advanced SCC.

[0083] PDT has emerged as an effective and cosmetically favorable treatment for many dermatologic conditions, including AKs, BCC, isSCC, and warts. It involves the application of a photosensitizing agent, such as aminolevulinic acid (ALA) or methyl aminolevulinate (MAL), which converts to its active form, protoporphyrin IX (PpIX), upon illumination. Activated PpIX generates reactive oxygen species, selectively destroying neoplastic cells. ALA-PDT using a 20% 5-ALA solution with blue light (LEVULAN® KERASTICK® with BLU-U® Illuminator, Sun Pharmaceutical Industries, Inc.) is approved in the United States for the treatment of minimally to moderately thick AKs on the face, scalp, and upper extremities.Exemplary Illuminator Devices

[0084] As described herein, an illuminator is provided to emit light from at least one light source to treat a patient. The light source can comprise at least one light emitting diode (LED) or at least one array of LEDs, or a plurality of LED arrays, for example. As described herein, the light source delivers blue light. The blue light can be at wavelengths at or above 400 nanometers (nm), for example, about 430 nm, about 420 nm or, for example, 417 nm. However, the light source can also emit visible light in other ranges of the spectrum, such as in the green and / or red ranges between 400 and 700 nm, for example, about 625 nm to 640 nm or, for example, 635 nm. For example, the light source can also emit light having wavelengths of 510 nm, 540 nm, 575 nm, 630 nm, or 635 nm. In addition, the light source can be configured to emit light continuously or the light source can be configured to flash one or more individual LEDs on and off based on a predetermined interval. Furthermore, the light source can be configured such that only one wavelength of light (e.g., blue) is emitted. Alternatively, the light source can be configured such that two or more wavelengths of light are emitted from the arrays. For example, the light source can be configured to alternately emit blue light and red light for treatment purposes. In at least one embodiment, the light source can also emit red light having wavelengths of 570 to 670 nm. In at least oneembodiment, the light source is configured to emit blue light of two or more wavelengths. In at least one alternative embodiment, the light source can emit red light.

[0085] The total light dose (J / cm2) is equal to irradiance (mW / cm2) multiplied by time (seconds). An additional parameter to be controlled for delivery of an appropriate treatment light dose is exposure time (among other parameters which may be controlled to influence treatment). This may be accomplished by a timer, which can appropriately control the electrical power supplied to the light source, and which can be set by a healthcare provider. In at least one embodiment, blue light is delivered at a dose of about 20 J / cm2. In at least one embodiment, blue light is applied at an intensity of 20 mW / cm2for 1000 seconds to provide a dose of about 20 J / cm2.

[0086] Referring generally to the figures, an illuminator for providing PDT is shown. In at least one embodiment, the illuminator is a blue light PDT illuminator. In at least one embodiment, the illuminator is configured for use with aminolevulinic acid HC1 (ALA) (e.g., Levulan® Kerastick® for Topical Solution, 20%).

[0087] In at least one embodiment, the illuminator is configured to facilitate treatment of minimally to moderately thick actinic keratoses (AK) of the face, scalp, and / or upper extremities. In other embodiments, the illuminator is configured to facilitate PDT of the body. In at least one embodiment, the illuminator is configured to treat one or more dermatological indications. In at least one embodiment, the illuminator is configured to treat moderate inflammatory acne vulgaris. In at least one embodiment, the illuminator is configured for use at a 10 mW / cm2power setting to deliver 10 J / cm2. In at least one embodiment, the illuminator is structured to provide a power output of up to 50 mW / cm2. In at least one embodiment, the illuminator is structured to provide a range of power outputs and maintain a compact footprint in clinical settings.

[0088] The following describes at least one embodiment and various exemplary non-limiting parameters thereof. In at least one embodiment, the illuminator can have a power input of 120V, 60 Hz, and 5 Amps. In at least one embodiment, the illuminator can be structured to have a footprint comprised of a light unit and base having a fixed width in a closed position (e.g., a flat array shape), and a depth that is larger in an open position (a deployed position,e.g., a U-shaped array) than in the closed position. For example, a footprint of the illuminator including its light unit and base can have a width between about 20 inches and about 30 inches in both the open and closed positions. A depth thereof can be between about 40 inches and about 50 inches in an open position, and about 25 inches to about 30 inches in a closed position. A height thereof can be between about 40 inches (as a minimum height) and about 75 inches (as a maximum height). For example, in a non-limiting embodiment, the width can be about 21 inches when open or closed, a depth can be about 41 inches when open or about 27 inches when closed, and the height can be about 41 inches as a minimum height or about 67 inches as a maximum height. The overall dimensions of the light unit can be about 20 to about 35 inches in width in an opened position and between about 15 to about 25 inches in width in a closed position. The overall dimensions of the light unit can be about 2 to about 5 inches in depth in an open position and about 10 inches to about 15 inches in depth in a closed position, and about 15 inches to about 25 inches in height. For example, the overall dimensions of the light unit can include a width of about 30 inches ± 0.5 inches (e.g., about 29.5 inches) in an open position and about 18 inches in a closed position. Similarly, dimensions of the light unit can include a depth of about 4 ± 0.5 inches (e.g., about 3.5 inches) in an open position and about 12 ± 0.5 inches (e.g., about 12.5 inches) in a closed position, and a height of about 20 inches. Further, in at least one embodiment, the weight of the illuminator can be between about 100-130 lbs., e.g., about 115 lbs. The illuminator can be configured to operate at a temperature between about 20 to about 30° C (68 to about 86° F), a pressure of about 101 kPa, and a relative humidity (RH%) of about 0% to about 95% (non-condensing). The illuminator can have an exemplary power output of 10 mW / cm2+ 10% which can be outputted when treating certain conditions and / or in connection with or without the use of certain topical compositions (e.g., for use with Levulan® Kerastick®).The illuminator can have an exemplary power output of about 10 or 20 mW / cm2+10% which can be outputted when treating certain conditions and / or in connection with or without the use of certain topical compositions (e.g., for performing light-alone treatment of acne). The output wavelength can be, for example, 417 nm ± 5 nm with an output uniformity of about 30%. The exemplary illuminator can be configured to provide a light dose under a timer setting of about 16 minutes and 40 seconds to deliver a light dose of 10 J / cm2at 10mW / cm2or a timer setting of 8 minutes, 20 seconds to deliver 10 J / cm2at 20 mW / cm2, where these or other timings can be set as default timer settings.

[0089] Turning now to the figures and referring specifically to FIGS. 1-2, an illuminator 10 for providing PDT is shown, according to at least one embodiment. As shown, the illuminator includes a base 15 supported by a plurality of wheels 20 (e.g., four wheels). In at least one embodiment, the plurality of wheels 20 include locking casters. The illuminator 10 further includes a treatment array 25, where the treatment array 25 is configured to emit light to a treatment surface for providing PDT. As shown, the treatment array 25 is connected to the base 15 via an adjustable arm 30. As shown, the illuminator 10 can be structured such that the treatment array 25 includes five panels 35, where each of the panels 35 is configured to provide light to a treatment surface.

[0098] As shown, the illuminator 10 also includes a control panel 50 disposed on the base, the control panel 50 including one or more user interfaces to enable control of the illuminator 10. The user interface 50 can allow the user and / or the patient to tailor aspects of treatment, such as by controlling one or more air circulation units 40 (e.g., one or more fans) or to control turning the illuminator 10 on and off. The one or more air circulation units 40 can alleviate patient discomfort and / or pain during or after treatment. The illuminator 10 can also include at least one handle 45 coupled to the base 15, where the handle 45 can be used to facilitate moving or other displacement of the illuminator 10 (e.g., during transport of the illuminator 10 through a clinical setting).[00911 In at least one embodiment, the illuminator 10 is configured such that it can be used for patient treatment when it is in an expanded configuration, such as shown in FIGS. 1-2. To preserve space within a clinical setting and / or to facilitate ease of transport of the illuminator 10, the illuminator 10 can be rearranged to be in a collapsed configuration, such as shown in FIG. 3.[00921 As shown in FIGS. 4-5, the adjustable arm 30 of the illuminator 10 is coupled to a top portion of the base 15. The adjustable arm 30 includes a first portion 55 and a second portion 60, the first portion 50 being structured as a vertical post extending from the top portion of the base 15 in a direction substantially parallel to a long axis of the base 15. As shown, thesecond portion 60 includes a horizontal bracket extending in a direction that is substantially perpendicular to the first portion 55. The second portion 60 can include a first section 75 and a second section 80 coupled to the first section 75. As shown in FIGS. 4 and 5, the first section 75 is coupled to the first portion 55 at a first end. The first section 75 is further coupled to the second section 80 at a second end. Accordingly, the first portion 55 and the second portion 60 facilitate adjustment of the treatment array in both the horizontal and vertical directions (i.e., relative to the base 15).

[0093] As shown in FIGS. 4-5, the adjustable arm 30 can include one or more joints such that the arm 30 (and thus the treatment array 25) can pivot relative to the base 15 to facilitate ease of adjusting the treatment array 25, and to enable collapsing the illuminator 10 for storage. In at least one embodiment, the second portion 60 can include one or more joints such that a distal end of the second portion 60 can rotate or pivot relative to a proximate end of the second portion 60 (i.e., the end adjacent the first portion 55). For example, as shown in FIGS. 4 and 5, the first section 75 is coupled to the second section 80 at a hinged joint 67, which enable the second section 80 to rotate relative to the first section 75. In at least one embodiment, the first portion 55 can translate relative to the base such that an overall height of the illuminator 10 can be adjusted to facilitate treatment of a patient. For example, in at least one embodiment, the first portion 55 can be adjusted relative to the base 15 such that it extends or retracts telescopically relative to the base 15. In at least one embodiment, the illuminator 10 includes one or more locking mechanisms to lock the first portion 55 at one or more height settings.

[0094] As described above, the treatment array 25 can include five panels 35, as shown in FIG. 6A, to facilitate encircling or otherwise surrounding a treatment area. It should be noted, however, that in at least one embodiment, the treatment array 25 can be configured to include any number of panels 35. In at least one embodiment, the treatment array 25 is structured to provide a uniform distribution of blue light to one or more areas of a patient’s skin (e.g., face, scalp, upper extremities, etc.). In at least one embodiment, each of the panels 35 within the treatment array 25 includes a housing 77 and a plurality of light sources 85 coupled to the housing 77, the plurality of light sources 85 defining a treatment array 25 surface for providing PDT.

[0095] In at least one embodiment, the light sources 85 include a plurality of light emitting diodes (LEDs) 96 (shown in FIG. 7B). As shown in FIG. 6A, the panels 35 are connected to each other via nested hinges disposed between adjacent edges of each of the panels 35, which are described in greater detail below. Each of the hinges are structured such that a distance between light-emitting edges of each of the panels 35 is minimized. In at least one embodiment, the panels 35 are covered by a protective shield. In at least one embodiment, the protective shield can be a plastic. In at least one embodiment the protective shield is heat, chemical, and / or impact resistant. In at least one embodiment, each of the panels 35 and / or each of the light sources 85 are individually controllable such that each panel 35 (and each light source 85 therein) or each light source 85 can be selectively controlled to provide a specific light output and light distribution.

[0096] In at least one embodiment, at least one of the panels 35 can include one or more air circulation units 40 coupled thereto. For example, as shown, at least one of the panels 35 can include one or more air circulation units 40 disposed within and coupled to the housing 77 behind the light sources 85 (i.e., behind the treatment array 25 surface). Although the figures show the center panel 35 having two air circulation units 40, any one or more of the panels 35 within the treatment array 25 can include one or more air circulation units 40. In at least one embodiment, the one or more air circulation units 40 are configured to direct airflow (e.g., cooling airflow) to the treatment surface on the patient to improve patient comfort during PDT. As shown in FIG. 6 A, at least one of the panels 35 can include one or more handles 87 to facilitate positioning of the treatment array 25. As shown in FIG. 6 A, the center panel 35 can include two handles 87, where a first handle 87 is disposed on an upper portion of the center panel 35 and a second handle 87 is disposed on a lower portion of the center panel 35. In at least one embodiment, the first and second handles 87 extend from upper and lower edges, respectively, of the center panel 35. In other embodiments, the handles 87 can be attached or formed on any portion of the center panel 35. For example, in at least one embodiment, the handles 87 can be disposed on a side of the center panel 35 opposite the light sources. In other embodiments, panels adjacent to or spaced from the center panel can include one or more handles 87.

[0097] As shown in FIG. 6B, and as described above, the panels 35 can be structured to include a housing 77 (i.e., a back portion) and a front portion 79, where the front portion 79 is structured to couple to the housing 77. In at least one embodiment, the front portion 79 can be structured to include the plurality of light sources 85. In other embodiments, the front portion 79 can be disposed in front of the light sources 85 and structured to enable light to from the light sources 85 to pass therethrough. In at least one embodiment, the front portion 79 of each panel 35 includes a diffusive layer 93, structured to diffuse light (i.e., scatter or soften light) from the plurality of light sources. The diffusive layer 93 can be a film, an inlay, or an overlay. In at least one embodiment, the diffusive layer 93 can be formed by a separate component that is selectively couplable and removable relative to the front portion 79 for each panel 35.

[0098] As described above, the adjustable arm 30 includes a first portion 55 and a second portion 60, the first portion 50 being structured as a vertical post extending from the top portion of the base 15 in a direction substantially parallel to a long axis of the base 15. The second portion 60 includes a horizontal bracket extending in a direction that is substantially perpendicular to the first portion 55, where the second portion 60 includes a first section 75 and a second section 80 coupled to the first section 75. As shown, the second section 80 is structured to couple to the treatment array 25 at a joint 65. Specifically, as shown in FIG. 6C, the joint 65 can include a plate 86, which is structured to be received within a mount 83 (or recess) disposed within the housing 77 of a center panel 35 of the treatment array 25. The plate 86 can be structured to rotate relative to the housing 77 to enable rotation and adjustment of the treatment array 25 during PDT. In at least one embodiment, the joint 65 can also include an insert 91, which can be disposed between the plate 86 and the mount 83. The insert 91 can be structured to reduce friction between the plate 86 and the mount 83 during rotation or other movement of the arm 30 and / or the treatment array 25. In at least one embodiment, the insert 91 can be a synthetic material (e.g., nylon). In other embodiments, the insert 91 can include one or more other plastic components structured to reduce friction at the joint 65. As shown in FIG. 6C, the joint 65 can also include a bracket 88, which is structured to couple to the second section 80.

[0099] FIGS. 7A-7B illustrate side cross-sectional views of the center panel 35 of the treatment array 25 taken long line B-B of FIG. 6A. As shown, the panel 35 includes two air circulation units 40, each having at least one curved plenum 100 that defines an air passageway that is oriented toward a treatment surface of the patient. In at least one embodiment, the panel 35 can include a first air circulation unit (air circulator) 40 disposed within an upper portion of the panel 35 and a second air circulation unit 40 disposed within a bottom portion of the panel 35. As shown, the at least one plenum 100 defines an outlet 90 that is angled relative to the illuminating surface of the panel 35 (i.e., the surface of the panel 35 including the light sources 85) such that air flowing from the air circulation unit 40 is received by the patient within the treatment area. In at least one embodiment, the one or more air circulation units 40 can be configured to operate during or after illumination. In at least one embodiment, each air circulation unit 40 includes one or more air circulation devices. In at least one embodiment, the one or more air circulation devices can include one or more fans, blowers, or other mechanisms for causing airflow.[0100| As shown in FIGS. 7A-7B, the plenum 100 is disposed within the panel 35 behind the surface of the panel 35 including the light sources 85. The plenum 100 includes a body having a base portion 115, which is configured to couple to an air circulation device 110. The air circulation device 110 is structured to draw air through an inlet 95 disposed on a back surface of the panel 35 (i.e., on the surface opposite the surface including the light sources 85). The plenum 100 further includes a conduit 105 that extends from the base portion 115 and forms the outlet 90. As shown, the conduit 105 can be structured to have a generally curved or hook shape such that the conduit extends upward toward an upper portion of the panel 35 and curves such that a terminal end of the of the conduit 105, which forms the outlet 90, terminates at a surface of the panel 35 containing the light sources 85 (i.e., the treatment array 25 surface). That is, the outlet 90 can be structured such that it is formed within the treatment array 25 surface. For example, the conduit 105 can be structured to terminate adjacent (e.g., above) the light sources 85 on the surface of the panel 35 containing said light sources 85. In at least one embodiment, the plenum 100 can be structured to facilitate acceleration of air flow through the plenum. As shown in FIG. 7B, the conduit 105 can include a transition region 117 within which a width of the conduit 105 decreases to force air through the outlet 90.

[0101] FIGS. 8A-8D show front cross-sectional views of the center panel of the treatment array taken along line A- A of FIG. 4, according to at least one embodiment. As shown, the center panel 35 can include a first outlet and a second outlet, where each outlet is fluidly coupled to at least one plenum 100 defining airflow pathways from the panel 35 toward a treatment surface of the patient. As shown, in at least one embodiment, the center panel 35 can include a first air circulation unit 40 (i.e., including a first fan) configured to provide airflow through the first outlet 90, and a second air circulation unit 40 (i.e., including a second fan) configured to provide airflow through the second outlet 90.101021 In at least one embodiment, the first outlet 90 can be defined by a first plenum 100 and the second outlet 90 can be defined by a second plenum 100. In at least one embodiment, each air circulation unit 40 can be structured such that the air circulation device 110 is at least partially nested with a portion of the plenum 100. For example, in at least one embodiment and as shown in the figures, the air circulation device 110 of the first air circulation unit 40 can be disposed within the first plenum 100 and the second air circulation unit 40 can be disposed within the second plenum 100. As illustrated in FIG. 8 A, a first air circulation unit 40 can be disposed within an upper portion 120 of the panel 35 and a second air circulation unit 40 can be disposed within a lower portion 122 of the panel. It should be noted that although the figures show the air circulation units 40 and plenums 100 being disposed within or near upper and lower portions of the center panel 35, in at least one embodiment, the panel 35 can be structured such that air can flow along the sides, from the center, or from any other portion of the panel 35.

[0103] In at least one embodiment, such as shown in FIGS. 8B-8D, each plenum 100 can be structured such that the base portion 115 is configured to house an air circulation device 110 (e.g., a fan) and the conduit 105 defines an airflow pathway out from the panel 35. As shown, the base portion 115 can be configured to fit over the air circulation device 110 such that the air circulation device 110 fits within the base portion 115. As shown in FIGS. 8A-8D, the base portion 115 can have a generally rectangular shape. In other embodiments, the base portion 115 can have a shape corresponding to a shape of the air circulation device 110.

[0104] The plenum 100 can be fixed within the panel 35 (e.g., to the housing 77) via one or more fasteners 130. As shown in FIGS. 8B-8D, the base portion 115 can be coupled to a portion of the panel 35 and / or the air circulation device 110 via the one or more fasteners 130. In at least one embodiment, such as shown in FIG. 8E, the base portion 115 can include a plurality of apertures 133 disposed along a perimeter of the base portion 115 structured to receive corresponding fasteners 130. Although the figures show the base portion 115 including four apertures 133 and four fasteners 130, in at least one embodiment, the base portion 115 can include any number of apertures 133 for receiving a corresponding number of fasteners 130.

[0105] In at least one embodiment, the plenum 100 can be formed to have a shape that facilitates targeted air flow to a treatment area on a patient. As described above, and as shown in FIG. 8 E, the conduit 105 of the plenum 100 is curved to direct airflow both toward the upper portion 120 (or lower portion 122) and a front surface of the panel 35 containing the light sources 85. The conduit 105 also includes the transition region 117 in which a width of the conduit 105 decreases or tapers from the base portion 115 to the outlet 90 to facilitate airflow acceleration toward the outlet 90. In addition, the terminal end 135 of the conduit 105 can be structured to target airflow to a treatment area on a patient. As shown in FIG. 8E, the terminal end 135 of the conduit 105 can be formed to have a flattened v-shape (an inverted triangle wherein the vertex is at a lower most point) such that air is directed downward and toward a centerline of the panel 35 (i.e., a cross-section of the conduit 105 at the outlet 90 forms the v-shape).

[0106] In at least one embodiment, and as described above, the base 15 includes a control unit (controller) 50, as shown in FIG. 9. In at least one embodiment, the control unit 50 can include a built-in power output monitoring and diagnostic system, which illuminates an indicator light 207 to inform the user of the system’s status. In at least one embodiment, the control unit 50 includes a system timer used to set the light dose delivered to the patient via the light sources 85 within the panels 35. As illustrated in FIG. 9, the control unit 50 can include a power button 205, configured to power the illuminator 10 (and the treatment array 25) on and off. In at least one embodiment, the system power button 205 is used to load apre-programed treatment cycle. As shown in FIG. 9, the control unit 50 can be configured such that the indicator light 207 surrounds the power button 205.

[0107] The control unit 50 can include a user interface 200 having one or more controls (e.g., buttons, levers, knobs, etc.) to control an energy level of the illuminator 10 (i.e., an energy level of the light sources 85 within the panels 35 of the treatment array 25). For example, as shown in FIG. 9, the control unit 50 can include a level button 210, which can be pressed by a user to control a power level (e.g., 10 mW, 20, mW, etc.) of the light sources 85 within the panels 35 of the treatment array 25. In at least one embodiment, control unit 50 can automatically load a 10 mW power level at initial power up (i.e., when the illuminator 10 is powered on) and can reset to a 10 mW power level after the completion of any treatment cycle (i.e., after a dose of light is provided to a treatment surface on a patient by the light sources 85 within the panels 35 of the treatment array 25).

[0108] In at least one embodiment, the control unit 50 of the illuminator 10 can include a display 230. In at least one embodiment, the display 230 is configured to provide a visual display indicating a power level of the illuminator 10. For example, as shown in FIG. 9, the display 230 can be configured to provide a visual display of 16:40 when the control unit 50 is used to set the illuminator 10 to a 10 mW power level. In at least one embodiment, the display of 16:40 corresponds to a treatment time of approximately 16 minutes and 40 seconds. Although the figures and above description indicate a treatment time of approximately 16:40 to be associated with a set 10 mW power level, in at least one embodiment, the illuminator 10 can be controlled by the control unit 50 to carry out PDT for any selected amount of time for a given power level. In at least one embodiment, the illuminator 10 can be controlled by the control unit 50 to operate at a lower power level and at a high power level. In at least one embodiment, the low power level can correspond to a power level of approximately 10 mW. In at least one embodiment, the high power level can correspond to a power level of approximately 20 mW. In at least one embodiment, the level button 210 can be used to select either the low power level or the high power level. The power level can be increased incrementally.

[0109] For example, a 20 mW power level setting can be selected on the control unit 50 by pressing the level button 210, which can change the visual display provided by the display 230. In at least one embodiment, the display 230 can be configured to provide a visual display of 8:20 when the control unit 50 is used to set the illuminator 10 to a 20 mW power level. In at least one embodiment, the display of 8:20 corresponds to a treatment time of approximately 8 minutes and 20 seconds. Although the figures and above description indicate a treatment time of 8:20 to be associated with a set 20 mW power level, in at least one embodiment, the illuminator 10 can be controlled by the control unit 50 to carry out PDT for any selected amount of time for a given power level.

[0110] It should be noted that in at least one embodiment, the control unit 50 can include or comprise at least one controller, where the at least one controller is configured to include a processor and a non-transitory computer readable medium (e.g., a memory device) having computer-readable instructions stored thereon that, when executed by the processor, cause the at least one controller to carry out one or more operations. In at least one embodiment, the at least one controller is a computing device (e.g., a microcomputer, microcontroller, or microprocessor). In other embodiments, the at least one controller is configured as part of a data cloud computing system configured to receive commands from a user control device and / or remote computing device.[01111 In at least one embodiment, the power button 205 can also be used as a status indicator of the illuminator 10. For example, in at least one embodiment, the power button 205 can include or be disposed adjacent to the indicator light 207. As shown in FIG. 9, the indicator light 207 can be structured as a ring light surrounding the power button 205. In at least one embodiment, the indicator light 207 can be configured to display a first color to indicate a first operational state of the illuminator 10 and a second color to indicate a second operational state of the illuminator 10. In at least one embodiment, the first operational state can be a normal operational state and the second operational state can be an abnormal operational state (e.g., a fault condition).(0112] In at least one embodiment, the first color can be a blue hue, where the indicator light207 emits a blue light to indicate a normal operation. In other embodiments, the second colorcan be an amber hue, where the indicator light 207 emits an amber light to indicate an abnormal condition (e.g., a fault condition). In at least one embodiment, the first color and / or the second color can be any suitable color (e.g., red, green, yellow, pink, purple, orange, to enable a user to distinguish between the first condition and the second condition. In yet other embodiments, the indicator light 207 can be configured to flash at different frequencies to indicate the first condition, the second condition, and / or any other condition. For example, the indicator light 207 can be configured to emit a steady light to indicate the first condition and emit a flashing light to indicate the second condition. In at least one embodiment, the user interface 200 of the control unit 50 is configured to control starting, stopping, and / or pausing of a treatment cycle (i.e., a dose of light or a series of light doses being provided to a treatment surface on a patient by the light sources 85 within the panels 35 of the treatment array 25). In at least one embodiment, the control unit 50 is configured to pause the treatment cycle responsive to depression of the power button 205. In other embodiments, pressing the power button 205 while the treatment cycle is paused can cancel the treatment cycle and clear the time displayed on the display 230. In at least one embodiment, and as described above, the control unit 50 can be configured to control power levels of the illuminator 10. For example, in at least one embodiment, the level button 210 can be used to toggle between power settings. As described above, the illuminator 10 can be configured to operate at a first or a second power level. The first power level can be approximately 10 mW and the second power level can be approximately 20 mW. Accordingly, in at least one embodiment, the level button 210 can be configured to toggle between approximately 10 mW and approximately 20 mW.

[0114] In at least one embodiment, the power level can be selected via toggling the level button 210 following depression of the power button 205, where selecting a power level with the button 210 can cause the control unit 50 to load a pre-programmed treatment cycle. For example, selecting the first power level can cause the control unit 50 to load a first treatment cycle and selecting the second power level can cause the control unit 50 to load a second treatment cycle.

[0115] In at least one embodiment, each of the pre-programmed treatment cycles can be characterized by a power level of the light sources 85 in addition to a duration of treatment. Accordingly, in at least one embodiment, the control unit 50 can include a system timer (i.e., a timer controlling illumination of the light sources 85 within the treatment array 25) that is configured to automatically set a time period to provide light (via the treatment array 25) to the treatment area based on the power level selected via the level button 210. In at least one embodiment, the control unit 50 can include a second visual display 235, which is configured to indicate which power level is selected by the level button 210. For example, in at least one embodiment, the power level selected will be displayed within the display 235 as “10” or “20” to indicate an approximately 10 mW power level or an approximately 20 mW power level, respectively. In at least one embodiment, the second display 235 can be disposed above the level button 210. In at least one embodiment, the system timer within the control unit 50 is configured to set a first time period corresponding to a first power level (e.g., approximately 10 mW) and a second time period corresponding to a second power level (e.g., approximately 20 mW). In at least one embodiment, the first time period is greater than the second time period, or vice versa. In other embodiments, the set time period is greater at lower power levels and higher at lower power levels.|01l6| The user interface 200 of the control unit 50 can also include one or more controls (e.g., buttons, levers, knobs, etc.) to control cooling operations of the illuminator 10. For example, as shown in FIG. 9, the control unit 50 can include a fan button 220, which can be pressed by a user to control operation of the at least one air circulation unit 40 within the at least one panel 35 (e.g., the center panel). In at least one embodiment, each of the air circulation units 40 can be operated to be in off, low, medium, or high modes, as controlled by the fan button 220. In at least one embodiment, the one or more air circulation units 40 can automatically shut off when the system timer reaches zero during a treatment (i.e., when the control unit 50 determines that the set time period has lapsed).

[0117] The user interface 200 of the control unit 50 can also include one or more controls (e.g., buttons, levers, knobs, etc.) to control the system timer. As described above, the timer within the control unit 50 sets a period of time for carrying out PDT by the illuminator 10. As shown in FIG. 9, the control unit 50 can include a toggle button 215, which can be pressed bya user to increase or decrease a treatment time — thus increasing or decreasing the period of time set by the system timer. In at least one embodiment, a maximum treatment time can be set to 30 minutes. In at least one embodiment, the period of time set by the system timer can correspond to an exposure time (i.e., exposure of the patient to blue light) and / or to automatically turn off the light sources 85 within the treatment array 25 after the set exposure time has elapsed. In at least one embodiment, the toggle button 215 can include an “up” arrow and a “down” arrow. In at least one embodiment, depressing the “up” arrow can increase the set period of time and depressing the “down” arrow can decrease the set period of time. In at least one embodiment, when the toggle button 215 is first depressed, the “up” and “down” buttons can change the output (i.e., the reading) on the display 230 at a first speed (e.g., slowly). If the “up” or “down” arrows of the toggle button 215 remain depressed, the control unit 50 can cause the display 230 can change at a second speed that is faster than the first speed. In at least one embodiment, depressing and releasing the “up” and “down” arrows of the toggle button 215 can adjust the set time period by small increments (e.g., 30 seconds, 1 minute, 2 minutes, 5 minutes, etc.) as shown on the display 230.

[0118] As described above, the user interface 200 of the control unit 50 can also include one or more controls (e.g., buttons, levers, knobs, etc.) to control the start and / or stop of PDT provided by the illuminator 10. For example, as shown in FIG. 9, the control unit 50 can include a start / stop button 225, which can be pressed by the user to start or stop illumination (and thus PDT) by the illuminator 10. Finally, as shown in FIG. 9 and as described above, the illuminator 10 can include one or more visual displays, which can be configured to provide one or more visual indicators of a level of treatment, a time for treatment, and / or a mode associated with the one or more air circulation units. For example, as described previously, the user interface 200 of the control unit 50 can include a first display 230 and a second display 235. In at least one embodiment, the display 230 can be a four-digit LED display or a display having a different number of digits. In at least one embodiment, the display 230 can show the set period of time on the system timer of the control unit 50 by displaying an amount of remaining time in treatment in minutes and seconds. In other embodiments, prior to the start of treatment, the display 230 can show an amount of set exposure time, which can correspond to the set period of time.

[0119] In at least one embodiment, pressing the start / stop button 225 while the treatment cycle is active (i.e., while the illuminator 10 is carrying out PDT) can cause the treatment cycle to pause. In at least one embodiment, pausing treatment can cause the light sources 85 within the treatment array 25 to turn off and the system timer to stop counting down the set period of time. In at least one embodiment, the indicator light 207 can flash (e.g., flash a blue color) while the treatment cycle is paused. In at least one embodiment, the control unit 50 can cause the illuminator 10 to automatically return to a standby mode if the treatment cycle is paused for greater than a threshold period of time (e.g., approximately 10 minutes). In at least one embodiment, pressing the start / stop button 225 while the treatment cycle is paused can cause the treatment cycle to resume. In at least one embodiment, when the treatment cycle is resumed after the start / stop button 225 is pressed, the light sources 85 within the treatment array 25 can re-illuminate, the control unit 50 can cause the system timer to resume counting down, and the indicator light 207 can emit a steady light (e.g., steady blue light, a steady red light). In at least one embodiment, the indicator light 207 can emit variable, e.g., intermittent light. In at least one embodiment, when the illuminator 10 is in an active treatment cycle, the treatment array 25 provides steady illumination to the treatment area of a patient. In other embodiments, the illuminator 10 is in an active treatment cycle, the treatment array 25 provides variable or intermittent light to the treatment area of the patient.

[0120] In at least one embodiment, the illuminator 10 can also include a main power switch 255 disposed on a bottom portion 253 of the base 15, as shown in FIG. 10. In at least one embodiment, the main power switch 255 can be configured to control power to the illuminator 10. In at least one embodiment, the main power switch 255 can be configured as a circuit breaker and can release when an over-current situation is sensed. For example, if the control unit 50 or a sensor operably coupled to the main power switch 255 detects an overcurrent situation, in which a current supplied or drawn by the treatment array 25 exceeds a predetermined threshold current, the main power switch 255 can cut off power to the illuminator 10. In at least one embodiment, pressing the power button 205 with the main power switch 255 activated (i.e., on) will cause the control unit 50 to toggle to load and or clear a treatment cycle for the illuminator 10.

[0121] As shown in FIG. 10, the bottom portion 253 of the base 15 of the illuminator 10 can include a visual indicator 260 that displays an activation state of the main power switch 255. For example, the indicator 260 may include a light source that emits light when the main power switch 255 is activated. The indicator 260 may emit no light when the main power switch 255 is inactivated (i.e., off). In other embodiments, the indicator 260 can emit light having a first color when the main power switch 255 is activated. The indicator 260 can then emit light having a second color when the main power switch 255 is inactivated but the illuminator 10 remains connected to a power supply (e.g., via power cord 265).|0122| In at least one embodiment, the illuminator 10 can include one or more mechanisms to facilitate locking a position of the arm 30 relative to the base 15. As shown in FIGS. 11 A- C, the base 15 can include a first lock 270 (“column lock”), which can be structured to lock a vertical position of the first portion 55 (“column”) of the arm 30. For example, as shown in FIG. 1 IB, when the first lock 270 is in an open position, the first portion 55 of the arm 30 can be freely translated in the vertical direction relative to the base 15. When the first portion 55 of the arm 30 is positioned, the first lock 270 can be switched to a locked position to prevent further movement of the first portion 55 of the arm 30. In at least one embodiment, the first lock 270 can include a column slide 275, where the column slide 275 is configured to slide within a slot 280 between the locked position and the unlocked position. As shown in FIG.1 IB, when the column slide 275 is in the unlocked position, the column slide 275 may be at a first end (e.g., top end) of the slot 280. Similarly, as shown in FIG. 11C, when the column slide 275 is in the locked position, the column slide 275 may be at a second (e.g., bottom end) of the slot 280. In at least one embodiment, the first lock 270 can include a visual indicator within the slot 280, as shown in FIGS. 1 IB-11C. For example, the slot 280 can display a first indicator (e.g., green, unlocked lock symbol) when the column slide 275 is in the unlocked position and display a second indicator (e.g., red, locked lock symbol) when the column slide 275 is in the locked position.

[0123] In at least one embodiment, the first portion 55 of the arm can be configured such that it can move upward relative to the base 15 even when the first lock 270 is in the locked position (i.e., until a maximum extension height is reached). In at least one embodiment, thecolumn slide 275 can include a button with one or more visual indicators to indicate to a user when the first lock is in an open or locked position.

[0124] As described above, the second portion 60 of the adjustable arm 30 can include at least one joint 87 to control rotation of the second section 80 (i.e., forming the distal end of the arm 30) relative to the first section 75 (i.e., forming the proximal end of the arm 30 adjacent to the first portion 55). As shown in FIGS. 12A-12B, the at least one joint 87 can include a depressible release button 300. In at least one embodiment, when the release button 300 is depressed, the second section 80 (which forms the distal end of the second portion 60) can rotate relative to the first section 75 (which forms the proximal end of the second portion 60) about the joint 87 to adjust a position of the arm 30. In at least one embodiment, the first section 75 and the second section 80 are approximately equal in length such that the release button 300 is disposed at a midpoint between the distal and proximal ends of the second portion 60. In at least one embodiment, the release button 300 can be pressed by a user to facilitate collapsing of the arm 30 such that the illuminator 10 can be stored. In at least one embodiment, the second portion 60 is configured to transition from a collapsed position when an angle 305 between the first section 75 and the second section 80 (i.e., an angle between the distal and proximal ends of the second section) is approximately 90 degrees, to a fully extended position when the angle 305 between the first section 75 and the second section 80 is approximately 180 degrees (i.e., when the distal and proximal ends of the second section 60 are axially aligned).

[0125] In at least one embodiment, the second portion 60 is configured to automatically lock at each of the collapsed position and the fully extended position. For example, the joint 87 is configured to prevent movement of the second section 80 relative to the first section 75 when the angle 305 is 90 degrees, and / or when the angle 305 is approximately 180 degrees. In other embodiments, the joint 87 is configured such that movement between the second section 80 and the first section 75 is permitted only when the button 300 is depressed, thereby allowing selective positioning between the first and second sections 75, 80 when the angle 305 is any angle between approximately 90 degrees and approximately 180 degrees. In yet other embodiments, the joint 87 is configured such that movement between the first and secondsections, 75, 80 freely permitted when the angle 305 is between approximately 90 degrees and approximately 180 degrees.

[0126] In at least one embodiment, and as shown in FIGS. 13 and 14A-14B, the illuminator 10 can include a tilting mechanism 310 within or near the joint 65, which is formed between the treatment array 25 and the arm 30. In at least one embodiment, the tilting mechanism 310 can enable tilting of the treatment array 25 relative to the arm 30. In at least one embodiment, the treatment array 25 can be tilted relative to the arm 30 up to approximately 90 degrees from a when the illuminator is in the collapsed position (i.e., when the center panel 35 of the treatment array 25 is facing the floor). The tilting mechanism 310 can facilitate positioning of the treatment array 25 relative to a treatment area on a patient to enable precise treatment. In at least one embodiment, the tilting mechanism 310 can include one or more torque inserts 320, controllable via one or more corresponding handles or knobs 315. In at least one embodiment, the structure of the torque inserts 320 and the knobs 315 can eliminate the need for an additional, separate lock to secure a tilted position of the treatment array 25 relative to the arm 30. For example, the treatment array 25 can be loosened via the knobs 315, which reduce torque applied by the inserts 320, to enable the treatment array 25 to move (i.e., tilt) relative to the arm 30. Once the treatment array 25 is adjusted relative to the arm 30 to a desired position, the knobs 315 can be used to tighten the torque inserts 320 to lock the position of the treatment array 25 relative to the arm. In at least one embodiment, the torque inserts 320 can hold the treatment array 25 at any position relative to the arm 30 through a 180 degree range of motion. In at least one embodiment, the range of motion can be represented by the arrows 325 and 327 shown in FIGS. 14A-14B.

[0127] In at least one embodiment, the illuminator 10 can additionally or alternatively include a rotating mechanism 330 disposed within or near the joint 65 to facilitate rotation of the treatment array 25 relative to the adjustable arm 30, as shown in FIGS. 15-16. In at least one embodiment, the rotating mechanism 25 can include one or more hinges 335 (e.g., formed with the bracket 88), which enable rotation of the treatment array 25 about a long axis defined by the second section 80. In at least one embodiment, the treatment array 25 can be rotated up to approximately 90 degrees from when the illuminator 10 is in the collapsed position (i.e., when the center panel of the treatment array is aligned with a long axis of thearm). For example, the array can be rotated up to ± 45°, 60°, 75°, 80°, 85°, or 90°. The rotating mechanism 330 can facilitate positioning of the treatment array 25 relative to a patient to enable precise treatment. In at least one embodiment, the rotating mechanism 330 can include two detent positions at the ends of the travel (i.e., located at 0 degrees and 90 degrees) to lock the treatment array 25 into position (relative to the arm 30) that is suitable for PDT of a treatment area on a patient. In at least one embodiment, the treatment array 25 can include two position indicators 340 located on a back surface of the center panel 35 (i.e., on a back surface of the housing of the panel 35) that align with one or more indicator marks 345 disposed on (e.g., engraved) into a back plate 343 coupled to the back surface of the panel 35. Accordingly, when the treatment array 25 is at the limit of travel relative to the arm 30, the position indicators 340 can align with the indicators 345.

[0128] As shown in FIGS. 17 and 18, the panels 35 are connected via nested hinges 350 that facilitate adjustment of each panel 35 relative to another, adjacent panel 35. In at least one embodiment, the hinges 250 can include torque inserts that maintain a position of each panel 35 without locks (i.e., without a separate locking mechanism). In at least one embodiment, the hinges 250 can include one or more indicators 355 to facilitate alignment. For example, as shown in FIG. 18, the portion of the hinge 350 coupled to a first panel 35 and the portion of the hinge 350 coupled to a second panel 35 can each include a visual indicator 355, where alignment of the visual indicators 355 of each portion of the hinge 350 can indicate a predetermined alignment of the first panel 35 and the second panel 35. In at least one embodiment, the hinges 350 can include one or more stops to limit rotation of the panels 35. As described above, the hinges 350 are nested in that each hinge 350 for each panel 35 is at least partially nested with an adjacent hinge 350 for an adjacent panel 35 such that a distance between light sources 85 in adjacent panels 35 is minimized. By minimizing the distance between the light sources 35 in adjacent panels 35, the treatment array 10 can provide a uniform illumination during PDT.Variations of Illuminator Devices10129] In various embodiments, an illuminator for use in PDT treatment methods can have similar or different characteristics as the illuminator 10. In at least one embodiment, theilluminator can include fewer panels and / or light sources as compared to the illuminator 10. In other embodiments, the illuminator can include more panels and / or light sources as compared to the illuminator 10. In yet other embodiments, the illuminator can be structured to include a singular treatment array than can be customizable in size and / or operation based on a desired treatment protocol.

[0130] As noted above, the illuminator can be configured for PDT in conjunction with the application of one or more photosensitizers, such as ALA, to a treatment surface / area on a patient. In at least one embodiment, and as described in further detail below, the ALA can be applied to the treatment surface / area using one or more applicators (e.g., a wand). The applicator can include at least one reservoir (e.g., an ampule) for containing the ALA and a distribution portion (e.g., a point applicator) for topically applying the ALA to the surface. In at least one embodiment, the illuminator can be integrated with the applicator to facilitate streamlined treatment. For example, in at least one embodiment, the applicator can be structured such that the distribution portion includes one or more light sources configured to provide a dose of red and / or blue light to the treatment area, and / or light of a different wavelength. In at least one embodiment, the one or more light sources can be included within one or more panels. In at least one embodiment, the one or more light sources can be individually mounted LEDs. In at least one embodiment, the illuminator can be a portable “table-top” or “standalone” illuminator having a plurality of panels that can be assembled on an elevated surface, e.g., a surface on which a patient may be lying down, and which is not assembled to a separate stand extending from ground height.(0131 ] In various embodiments, the illuminator can be configured to be adapted to a particular patient and / or treatment area. For example, in at least one embodiment, the illuminator can be structured to include one or more light sources that can be reconfigurable to conform to a particular patient and / or treatment area. In at least one embodiment, the one or more light sources can be disposed on or embedded within at least one substrate, where the at least one substrate can be restructured or reformed to have a shape that resembles, conforms, or otherwise complements a shape or topographical aspect of the treatment area. For example, in at least one embodiment, the at least one substrate can be mesh-like,structured to be reformable so as to resemble or conform to the treatment area or a contour thereof.

[0132] In yet other embodiments, the illuminator can have a unitary treatment array configured to have a curved shape so as to surround a patient and / or treatment area. The treatment array can be pivotably or rotationally coupled to an adjustable arm such that the treatment array (and light sources contained therein) can be adjusted to provide uniform illumination to the treatment area. In at least one embodiment, the adjustable arm can be adjusted in both vertical and horizontal directions.

[0133] In various embodiments, the illuminator can be configured to operate at approximately 120V. In other embodiments, the illuminator can operate at voltages greater than (e.g., 130V, 150V, 200V, etc.) or less than 120V (e.g., 110V, 90V, 50V, etc.). In at least one embodiment, a frequency of the power to the illuminator can be approximately 60 Hz. In other embodiments, the power frequency can be less than 60Hz (e.g., 10Hz, 20Hz, 40Hz, etc.) or greater than 60Hz (e.g., 70Hz, 90Hz, 100Hz, etc.). In various embodiments, power to the illuminator can be delivered at a current of approximately 5 Amps. In other embodiments, the current can be greater than (e.g., 10 Amps, 20 Amps, 30 Amps, etc.) or less than 5 Amps (e.g., 1 Amps, 2 Amps, 4 Amps, etc.).

[0134] In at least one embodiment, a footprint (i.e., including the treatment array and coupled base) can be structured to be about 53-54 cm in width. In yet other embodiments, the footprint can be greater than or less than 53 cm. In other embodiments, the footprint can be greater than or less than 54 cm. In some embodiments, a depth of the illuminator footprint can be between 69 and 105 cm. In other embodiments, the depth of the illuminator footprint can be less than 60 cm or greater than 105 cm. In other embodiments, a height of the illuminator footprint can be between 105 cm and 171 cm. In yet other embodiments, the height of the illuminator footprint can be greater than 171 cm or less than 105 cm. In some embodiments, the illuminator can have a weight of approximately 52-53 kg. In other embodiments, the weight can be less than 52 kg or greater than 53 kg. In various embodiments, the illuminator can be structured to operate within a temperature range of approximately 20 - 30° C. In other embodiments, the illuminator can be structured to operateat temperatures lower than 20° C or greater than 30° C. In various embodiments, the illuminator is structured to output light at a wavelength of approximately 417 nm ± 5 nm. In yet other embodiments, the illuminator is structured to output light at a wavelength that is less than or greater to 417 nm.101351 In various embodiments, the control unit of the illuminator can be configured to include a microprocessor regulator with software framework drivers that are programmed to control an input set operational parameter to a specified tolerance. In some embodiments, the input set operational parameter is a temperature. In other embodiments, the input set operational parameter is a power output. In yet other embodiments, the input set operational parameter is a wavelength. In some embodiments, the control unit can be configured to operate the illuminator at the input set operational parameter based on one or more feedback loops based on corresponding reference data sets.Exemplary Treatment Techniques

[0136] One or more treatment methods can be implemented for using the illuminator in accordance with any of the embodiments described above. In various implementations, the illuminator can be powered on using a main power switch. A power button within a control unit (i.e., a control unit configured to control operation of the illuminator) can then be utilized to load a treatment cycle. A power level button (or other selector) can be used (e.g., pressed, turned, switched, etc.) to select a power level and to cause the selected power level and / or treatment time to be indicated within at least one display on the illuminator. For example, in various implementations, the power level button can be pressed until a “10” is illuminated in a display to indicate a selected power level of lOmW and / or “16:40” can be displayed to indicate a treatment time is 16 minutes and 40 seconds. After setting the power level using one or more selectors disposed on / within the illuminator, it can be verified (e.g., by a user) that the at least one display on the illuminator (i.e., the timer display) is active and the illuminator is in a normal operational state. For example, to verify the power level, it can be verified that the at least one display corresponds to the selected power level (i.e., by displaying a set time corresponding to the power level). In some embodiments, the illuminator can include one or more indicators (e.g., lights) to indicate a normal operationalstate of the illuminator. In some embodiments, eye protection can be positioned on the patient prior to initiating treatment of the patient using the illuminator.

[0137] Prior to initiating treatment, the patient can be placed in an upright, sitting position and the illuminator can be positioned relative to the patient. In various implementations, the specific positioning of the illuminator can depend on the location of the treatment area and the lesions to be treated therein. In various implementations, the treatment array can be repositioned from a collapsed (i.e., stowed) position by into a locked treatment position. In at least one embodiment, the treatment array can be rotated, pivoted, or otherwise reconfigured so as to surround a treatment area. For example, in some implementations, the treatment array can form a “U” shape. In at least one embodiment, an adjustable arm coupled to the treatment array can be unlocked and adjusted to a specific height. Tilt and rotation of the treatment array can be adjusted using one or more tilt / rotation mechanisms to optimize a position of the treatment array relative to the treatment area.

[0138] In at least one embodiment, a position of the illuminator and the treatment array can vary based on the location of the treatment surface. For example, in at least one embodiment, the illuminator can be positioned such that it surrounds a patient’s head and the surface area to be treated (i.e., the treatment surface) is disposed between approximately 2 inches and approximately 4 inches from the surfaces of panels containing light sources (i.e., the treatment array surface). In at least one embodiment, the patient’s nose be positioned to be within approximately 2 inches from the treatment array surface. In at least one embodiment, the patient’s forehead and cheeks should be within approximately 4 inches from the treatment array surface. In yet other embodiments, the sides of the patient’s face and the patient’s ears can be positioned to be within approximately 2 inches from the treatment array surface. In at least one embodiment, the surface to be treated can be approximately 4.3 inches, approximately 4.4 inches, approximately 4.5 inches, approximately 4.6 inches, approximately 4.7 inches, approximately 4.8 inches, or approximately 4.9 inches from the treatment array 25 surface. In at least one embodiment, the surface to be treated can be approximately 4.9 inches ± 0.6 inches from the treatment array surface.

[0139] In carrying out the above method, the user of the illuminator can verify that the set power level of the illuminator is correctly indicated on the at least one display of the illuminator. If the user of the illuminator determines the at least one display does not indicate the desired power level and / or the desired treatment time, the power level button and / or a time select button (or other selector) can be respectively used to adjust the power level and the treatment time. In various implementations, a user can continue to use (e.g., depress, rotate, switch, etc.) the power level button (or selector) and / or the time select button (or selector) button until the at least one display correctly reflects the selected settings for a given treatment cycle. In various implementations, a user can ensure that all personnel in the treatment room (e.g., patient, medical care practitioners and associates, etc.) are wearing appropriate eye protection. Treatment can commence responsive to depression (or other selection) of a start / stop selector (e.g., button) on the illuminator. During treatment, the user of the illuminator can verify that the system timer is counting down (i.e., by verifying the time shown in the at least one display is counting down), and that PDT is in progress (e.g., by verifying appropriate indicators indicate accordingly). In at least one embodiment, at the end of the treatment (i.e., when the set period of time has lapsed), the system timer within the control unit can automatically turn off the light sources within the treatment array to stop PDT.

[0140] In various implementations, following treatment, the user of the illuminator can remove the patient from the illuminator (i.e., reposition the patient such that the treatment area is not surrounded by the treatment array) and remove the patient’s eye protection. In various implementations where the illuminator is used in a clinical setting for PDT treatment of multiple patients in series, when the user is finished treating patients for the day, the user can place the treatment array in a stowed / collapsed position to protect the illuminator and to minimize the storage footprint. The user can then turn off the main power switch of the illuminator.

[0141] It should be noted that although the preceding description indicates the illuminator can be used to provide treatment at a power level of lOmW and / or for a treatment time of 16 minutes and 40 seconds, the illuminator can be used at various other power levels for other treatment times. For example, in other embodiments, the illuminator can be used to providetreatment at a power level of 20mW and / or for a treatment time of 8 minutes and 20 seconds. In various embodiments, the power level of the illuminator can be set to 20mW. In other embodiments, the power level can be greater than 20mW. In yet other embodiments, the power level can be less than lOmW. In various embodiments, the power level can be between lOmW and 20mW (e.g., 11, 12, 13, 14, 15, 16, 17, 18, or 19mW). In some embodiments, the control unit of the illuminator can be used to adjust or tune the power level and / or treatment time at the start or prior to the start of treatment. In some embodiments, the control unit of the illuminator can be used to adjust or tune the power level and / or treatment time during treatment. In various embodiments, the treatment time can be less than 8 minutes. In some embodiments, the treatment time can be greater than 8 minutes. In other embodiments, the treatment time can be between 8 and 16 minutes. In yet other embodiments, the treatment time can be greater than 16 minutes.

[0142] In various implementations PDT methods can be employed using the illuminator 10. Accordingly, in some implementations, the illuminator 10 can be powered on using the main power switch 255. The power button 205 within the control unit 50 can then be pressed to load a treatment cycle. The power level button 210 can be pressed to select a power level and to cause the selected power level to be indicated within the display 235 and / or the display 230. For example, the power level button 210 can be pressed until “10” is illuminated in the display 235 above the button 210 and the display 230 reads “16:40” to indicate a power level of 10 mW is selected and the treatment time is 16 minutes and 40 seconds. After setting the power level using the power level button 210, it can be verified (e.g., by a user) that the display 230 (i.e., the timer display) is active and the illuminator 10 is in a normal operational state. For example, to verify the power level, it can be verified that the display 230 corresponds to the selected power level (i.e., by displaying a set time corresponding to the power level), and the indicator light 207 indicates a normal operational state of the illuminator 207 (e.g., by emitting a solid blue light). In some implementations, eye protection can be positioned on the patient prior to initiating treatment of the patient using the illuminator 10.

[0143] Prior to initiating treatment, the patient can be placed in an upright, sitting position and the illuminator 10 can be positioned relative to the patient. In various implementations,the specific positioning of the illuminator 10 can depend on the location of the treatment area and the lesions to be treated therein. In various implementations, the treatment array 25 can be repositioned from the collapsed (i.e., stowed) position by pressing the release button 300 on the arm 30 and raising the arm 30 into a locked treatment position. In at least one embodiment, the treatment array 25 can be rotated such that the treatment array 25 forms a “U” shape (i.e., the panels 35 are arranged in a “U” shape) for treatment. In at least one embodiment, the first portion 55 of the arm 30 can be unlocked and adjusted to a specific height by sliding the column slide 275 into the locked position after the desired treatment height (i.e., a height defined between a surface of the panels 35 containing the light sources 85 and the treatment surface) is attained. Tilt and rotation of the treatment array can be adjusted using the tilt mechanism 310 and rotation mechanism 330, respectively, to optimize a position of the treatment array 25 relative to the treatment area.

[0144] In at least one embodiment, a position of the illuminator 10 and the treatment array 25 can vary based on the location of the treatment surface. For example, in at least one embodiment, the illuminator 10 can be positioned such that it surrounds a patient’s head and the surface area to be treated (i.e., the treatment surface) is disposed between approximately 2 inches and approximately 4 inches from the surfaces of the panels 35 containing the light sources 85 (i.e., the treatment array surface). In at least one embodiment, the patient’s nose should be no closer than approximately 2 inches from the treatment array 25 surface. In at least one embodiment, the patient’s forehead and cheeks should be no further than approximately 4 inches from the treatment array 25 surface. In yet other embodiments, the sides of the patient’s face and the patient’s ears should be no closer than approximately 2 inches from the treatment array 25 surface. In at least one embodiment, the surface to be treated can be approximately 4.3 inches, approximately 4.4 inches, approximately 4.5 inches, approximately 4.6 inches, approximately 4.7 inches, approximately 4.8 inches, or approximately 4.9 inches from the treatment array 25 surface. In at least one embodiment, the surface to be treated can be approximately 4.9 inches ± 0.6 inches from the treatment array 25 surface.

[0145] In carrying out the above method, the user of the illuminator 10 can verify that the set power level of the illuminator 10 is correctly indicated in the display 230 and / or the display235. For example, if the desired power level is 10 mW, the user can verify the display 235 indicates a “10” and the display 230 indicates a treatment time of 16 minutes 40 seconds (or any other selected period of time). If the user of the illuminator 10 determines the display 230 and / or the display 235 do not indicate the desired power level and / or the desired treatment time, the power level button 210 and / or the time select button 215 can be respectively used to adjust the power level (i.e., to 10 mW) and the treatment time. In various implementations, a user can continue to depress the power level button 210 and / or the time select button 215 button until the display 230 and / or the display 235 correspond to the selected settings for a given treatment cycle. In various implementations, a user can ensure that all personnel in the treatment room (e.g., patient, medical care practitioners and associates, etc.) are wearing appropriate eye protection. Treatment can commence responsive to depression of the start / stop button 225 on the illuminator 10. During treatment, the user of the illuminator 10 can verify that the system timer is counting down (i.e., by verifying the time shown in the display 230 is counting down), and that PDT is in progress (e.g., by verifying the indicator light 207 emits a flashing blue light). In at least one embodiment, at the end of the treatment (i.e., when the set period of time has lapsed), the system timer within the control unit 50 can automatically turn off the light sources 85 within the treatment array 25 to stop PDT.10146] In various implementations, following treatment, the user of the illuminator 10 can remove the patient from the illuminator 10 (i.e., reposition the patient such that the treatment area is not surrounded by the treatment array 25) and remove the patient’s eye protection. In various implementations where the illuminator 10 is used in a clinical setting for PDT treatment of multiple patients in series, when the user is finished treating patients for the day, the user can place the treatment array 25 and arm 30 into the stowed / collapsed position to protect the illuminator 10 and to minimize the storage footprint. The user can then turn off the main power switch 255 at the base 15 of the illuminator.

[0147] In at least one embodiment, to treat the scalp, the methods outlined above can be adapted such that the illuminator (in accordance with any of the embodiments discussed herein) is positioned above a patient’s scalp. In at least one embodiment, to treat the patient’s upper extremities, the illuminator can be positioned to illuminate the patient’s extremities. In various implementations, the illuminator can be positioned relative to the patient’s upperextremities so the entire surface area to be treated (i.e., the entire treatment surface) lies between 2 inches and 4 inches from the treatment array surface. Accordingly, the patient’s upper extremities can be positioned such that the treatment surface (on the patient’s upper extremities) is no closer than 2 inches from the treatment array surface and no further than 4 inches from the treatment array surface. As noted above, in at least one embodiment, the surface to be treated can be approximately 4.3 inches, approximately 4.4 inches, approximately 4.5 inches, approximately 4.6 inches, approximately 4.7 inches, approximately 4.8 inches, or approximately 4.9 inches from the treatment array surface.101481 To treat acne, the above methods outlined above can be adapted by operating the illuminator at a lOmW or a 20mW power level (or at any power level lower than lOmW, greater than 20mW, or between 10mW-20mW). In at least one embodiment, operation of the illuminator can be adapted to treat skin disorders including, but not limited to, lesions, actinic keratoses, acne, basal cell carcinoma, squamous cell carcinoma, melanoma, oral leukoplakia, and actinic cheilitis. In at least one embodiment, operation of the illuminator can be adapted to provide PDT to treat skin disorders on treatment surfaces disposed on a patient’s head, face, upper extremities, torso, back, lower extremities, neck, tongue, or elsewhere on the patient’s body.

[0149] In at least one embodiment, the illuminator can be configured to provide blue light to a top 1-1.5 mm of a patient’s skin within the treatment area to avoid patient discomfort. By operating the illuminator such that light from the light sources provides blue light (or red light) to the top 1-1.5 mm of the patient’s skin, pain perceived by the patient can be minimized as a patient’s pain receptors can be approximately 3-4 mm below the skin surface. Thus, effects (i.e., pain, discomfort) associated with PDT can be alleviated by reducing light penetration levels by the treatment array within the treatment surface. Moreover, by limiting penetration of PDT as provided by the treatment array can reduce activation of protoporphyrin IX (PPIX) disposed within non-target dermal tissue below the treatment surface. By reducing activation of the PPIX, pain can be minimized as accumulation of PPIX is limited.

[0150] In at least one embodiment, the control unit of the illuminator (in accordance with any of the embodiments disclosed herein) can be configured to carry out one or more predetermined treatment protocols based on input from a user. For example, in at least one embodiment, the user can program the control unit to cause the treatment array to provide illumination at a first power level for a first time period and at a second power level for a second time period. For example, in at least one embodiment, the control unit can cause the treatment array to carry out illumination at a first power level of 20 mW for 8 minutes and 20 seconds, and a second power level of 10 mW for 16 minutes and 40 seconds.10.1511 In at least one embodiment, the illuminator (in accordance with any of the embodiments disclosed herein) can be configured to provide red light (or blue light) to the treatment surface. In at least one embodiment, the illuminator can be operated such that the treatment array can selectively provide blue light or red light to the treatment surface. For example, in at least one embodiment, the control unit can cause the treatment array to provide a first dose of red light or blue light for a first time period, and then subsequently provide a second dose of red light or blue light for a second time period.

[0152] As discussed above, the illuminator (in accordance with any of the embodiments disclosed herein) can be configured to provide blue light to the treatment surface, which can treat a variety of skin conditions while reducing penetration depth as compared to red light, as shown in FIG. 19. In particular, because penetration of light into a patient’s skin is wavelength dependent, blue light (which has a shorter wavelength) has a lower penetration depth as compared to red light (which has a longer wavelength). Accordingly, by adjusting a dose of blue light provided by the illuminator, the treatment area can be treated with greater efficiency as less energy may be needed for treatment (e.g., caused by reduced treatment time), and patient discomfort can be reduced with reduced penetration depth. In various implementations, using the illuminator to provide blue light at doses of 10 J / cm2or 20 J / cm2, or any dose between 10 J / cm2and 20 J / cm2(e.g., 11, 12, 13, 14, 15, 16, 17, 18, or 19 J / cm2) is effective to treat lesions. In other embodiments, the illuminator can be operated to provide a dose less than 10 J / cm2or greater than 20 J / cm2. For example, in various implementations, providing blue light at a dose of 20 mW / cm2for one thousand (1,000) seconds (i.e., a dose of 20 J / cm2) can treat a variety of skin conditions, including lesions having a thickness ofapproximately 2.5 mm. In contrast, with red light, treatment at penetration depths of approximately 2.5 mm (e.g., at the bottom of a 2.5 mm thick actinic keratotic lesion) may necessitate approximately 37.5 J / cm2of red light. Thus, as appreciated from FIG. 19, blue light at a dose of approximately 10 J / cm2was surprisingly found to yield approximately a 25% more effective dose at a penetration depth of approximately 1 mm (e.g., at the bottom of a 1 mm thick actinic keratotic lesion) as compared to red light. In some implementations, the effective dose of blue light as compared to red light can be approximately the same at a penetration depth of about 1.5 mm.Pulse Dye Laser Mediated Methods10153] As described herein, photodynamic therapy (PDT), photodynamic diagnosis (PD), or photochemotherapy are generally used to treat and / or diagnose various diseases and / or disorders relating to the skin or other tissues (e.g., tissues within a body cavity). As described above, PDT can include administering photoactivatable agents and exposing a patient to photoactivating light to activate the agents and convert them to their cytotoxic form, to destroy cells associated with a disease or disorder of the skin. For example, photodynamic therapy or photodynamic diagnosis may be used for treatment or diagnosis of acne, warts, psoriasis, photo-damaged skin, cancer, actinic keratosis and many other conditions. Such treatment may encompass different areas of a patient (e.g., the legs or portions of the arms including the forearms, the back, the abdomen, the chest, or another portion of a body such as face or neck). PDT using ultraviolet (UV) or blue light can be used to treat, among other indications, mild to moderate acne (i.e., due to anti-inflammatory effects on skin cells).

[0154] In various implementations, PDT methods can include use of a pulse dye laser in combination with aminolevulinic acid photodynamic therapy to treat and / or diagnose several types of diseases or disorders relating to the skin or other tissues. According to one aspect of the present disclosure, a method of performing photodynamic therapy includes applying, to the skin of a patient, a topical composition. The topical composition includes 5- aminolevulinic acid (ALA) hydrochloride, and a vehicle comprising at least one penetration enhancer to enhance accumulation of protoporphyrin IX (PpIX) in the skin. The method canfurther include incubating the topical composition and, following incubation, applying, to the skin, a pulse dye laser for at least a first time period.

[0155] In various implementations, the PDT method includes treatment of a skin condition by applying a 20% w / w ALA HC1 topical solution to a lesion (and adjacent skin). The method can further include covering the treatment area (i.e., lesion and adjacent skin) with a bandage or occlusive layer and incubating the treatment area for a period of time. In some implementations, a pulse dye laser (PDL) and blue light illumination (BLU-U®; 10 J / cm2 for 16 minutes and 40 seconds) can then be administered to the treatment area. Patients can undergo ALA-PDL-PDT treatment during a single treatment session or over multiple sessions spanning a period of time of 7-60 days. In various implementations, patients can receive least two ALA-PDL-PDT treatment sessions separated by a 30-day period. In various implementations, the PDL can be administered with a pulse duration of approximately 0.45 millisecond and a fluence of 13 J / cm2.

[0156] The term “incubation time” or “incubation” can refer to the time period from a time when a drug (such as ALA) is applied until a time when illumination occurs. For example, the incubation time may be an interval from when a drug is applied (e.g., topically) until the commencement of deliberate exposure to targeted illumination by an illuminator (e.g., as opposed to ambient illumination). As will be understood by one of skill in the art, incubation may occur in the dark (most common). However, incubation may also occur in the presence of light, including daylight (e.g., so-called painless PDT). Incubation, whether in the dark or under light exposure, may take place with or without heat.

[0157] In some implementations, the skin of the patient intended to be treated (i.e., the treatment area) is exposed to a pulse dye laser and light during a first and second time period. In various embodiments, the first time period is a period immediately after completion of an incubation time or after a small lag time post completion of incubation time. In some embodiments, the second time period is a period after the first time period (i.e., after exposure of pulse dye laser during the first time period), where in the second time period the skin is exposed to a light from a light source. In some embodiments, the skin is exposed to a blue light during the second time period. In some embodiments, the skin is exposed to redlight during the second time period. In some embodiments, heat is also applied during the second time period.

[0158] In various implementations, a method of treating a patient includes topical application of a 20% ALA HC1 to a treatment area (e.g., a lesion and the adjacent skin). Following topical application, the treatment area can be covered with an occlusive covering (e.g., bandage) and incubated for a period of time. In various embodiments, the period of time is between approximately 18 hours and approximately 24 hours. After incubation, the treatment area can be treated with a pulse dye laser (e.g., at a pulse duration of 0.45 millisecond and a fluence of 13 J / cm2) and blue light illumination (BLU-U®; 10 J / cm2for 16 minutes and 40 seconds. Patients can undergo two ALA-PDL-PDT treatment sessions separated by a 30-day period.

[0159] In various implementations, treatment of the skin using PDL can be carried out using an illuminator (e.g., the illuminator 10). In at least one embodiment, the pharmaceutical composition is a solution comprising 20% 5-aminolevulinic acid HC1. In at least one embodiment, the light emitted by the illuminator has a wavelength of between about 400 to about 450 nm. In at least one embodiment, a suitable dose of light is about 6-15 J / cm2. In at least one embodiment, the pharmaceutical composition is a nanoemulsion comprising 10% 5- aminolevulinic acid HC1. In at least one embodiment, the light emitted by the illuminator can have a wavelength of between about 620 to about 640 nm. In some embodiments, the wavelength is approximately 630 nm. In one embodiment, the dose of light is about 37 J / cm2. In various embodiments, heat can be applied to the treatment area during and / or after incubation.

[0160] In certain embodiments, as described above, the treatment area can be covered with a bandage or occlusive layer. In certain embodiments, the occlusive layer is low density polyethylene. In at least one embodiment, the ALA may be covered, following its application to the treatment surface, by a material having a degree of occlusion of 65% or more, a material having a degree of occlusion of 75% or more, or 85% or more, or another material. Such material may be provided in order to retain moisture in the tissue and thus improvepenetration of the ALA. The low-density polyethylene may be characterized by a density of approximately 0.917 g / cm3to approximately 0.930 g / cm3.

[0161] As described above, in at least one embodiment, treatment may be carried out on heat- treated skin. To heat the skin, a heating element (e.g., a heat source) may be provided that is separate from or integrated with an illuminator. The heat source may be used to heat the region to be treated. According to at least one embodiment, a method of treatment includes warming up an illuminator (e.g., the illuminator 10) so as to cause heat to be emitted from the illuminator, and exposing a treatment site to the illuminator. Heating is believed to increase the rate of porphyrin production in the skin. In particular, the heat accelerates the conversion of ALA to porphyrin (e.g., photoactivatable porphyrin or proto porphyrin). In at least one embodiment, by heating the skin as described herein, the rate of porphyrin production in the skin is increased by about 10%, about 20%, about 30%, about 40%, or about 50% or more. In at least one embodiment, the rate of porphyrin production in the skin is increased by about 50% or more by heating the skin for about five minutes followed by heating and a light dose for about eight minutes. For example, in some instances, the amount of PpIX in skin can approximately double with the application of heat to the treatment area compared to when no heat is applied to the treatment area.

[0012] For example, in at least one embodiment, the LEDs of an illuminator (e.g., the illuminator 10) can emit light for photodynamic treatment of skin. In particular, the LEDs may emit blue light for carrying out PDT of acne, NMSC, AK, or DSAP on heat-treated skin (e.g., skin that is previously or concurrently heated). In at least one embodiment, the skin may be treated by applying 20% ALA solution and delivering a light dose of about 10 J / cm2of light at 410 to 450 nm, while heating or otherwise maintaining a surface of the patient to be treated (a treatment surface, skin surface, etc.) at a temperature of about 40°C.|0163[ For example, in at least one embodiment, the LEDs of an illuminator (e.g., the illuminator 10) emit light for photodynamic treatment of skin. In particular, the LEDs may emit red light for carrying out PDT of acne, NMSC, AK, or DSAP on heat-treated skin (e.g., skin that is previously or concurrently heated). In at least one embodiment, the skin may be treated by applying 10% ALA gel and delivering a light dose of about 37 J / cm2of light at 630nm for approximately one hour, while heating or otherwise maintaining a surface of the patient to be treated (a treatment surface, skin surface, etc.) at a temperature of about 40°C.

[0164] In at least one embodiment, by heating the skin as described herein, a reduction in incubation time needed for ALA may be achieved. In at least one embodiment, the incubation period may be drastically reduced. For example, the incubation period may be reduced to less than about 20 minutes, about 30 minutes, about 45 minutes or about 1 hour. A significant quantity of porphyrins is produced after about 20 minutes of incubation of 20% ALA gel or solution on skin heated to about 40°C, with even a greater quantity produced after about 30 minutes. The quantity of porphyrins produced after 60 minutes incubation of 20% ALA gel or solution without a pulse dye laser or heat treatment is smaller than for either 20 or 30 minutes with PDL or heat.

[0015] As described above, at least one aspect of the present disclosure relates to a method for photodynamically treating a surface of a patient (and optionally occluding the patient’s skin as part of the treatment). In various implementations, a patient may be treated using PDT and / or PDL to treat skin cancer (e.g., non-melanoma skin cancer (NMSC), squamous cell carcinoma, nodular basal cell carcinoma, recurrent nodular basal cell carcinoma, infiltrative basal cell carcinoma, multi-focal basal cell carcinoma), warts, psoriasis, or other dermatological conditions.

[0166] For example, a method of treating skin cancer selected from non-melanoma skin cancer (NMSC), squamous cell carcinoma, nodular basal cell carcinoma, recurrent nodular basal cell carcinoma, infiltrative basal cell carcinoma, multi-focal basal cell carcinoma in a subject in need thereof may be carried out, including (i) applying topical ALA HC1 solution or gel to the affected skin; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14 - 24 hours; (iii) applying a pulse dye laser to an affected area of the subject’s skin for a sufficient time; and (iv) administering light (e.g., blue light) to the affected area to treat the cancer. In at least one embodiment, the skin cancer is non-melanoma skin cancer (NMSC). In at least one embodiment, the skin cancer is squamous cell carcinoma. In at least one embodiment, the squamous cell carcinoma is a cutaneous in situ squamous cell carcinoma. In at least one embodiment, the skin cancer isnodular basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma. In at least one embodiment, the skin cancer is infiltrative basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma multi-focal basal cell carcinoma.101.671 Additionally, in various implementations, a method of treating skin cancer in a patient can include (i) applying topical ALA HC1 solution or gel to the affected skin; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14 - 24 hours; (iii) applying a pulse dye laser to an affected area of the subject’s skin for 0.25 - 75 millisecond at a fluence of 8-22 J / cm2; and (iv) administering blue light to the affected area for 16 minutes and 40 seconds at 10 J / cm2light dose to treat the cancer. In at least one embodiment, the skin cancer is non-melanoma skin cancer (NMSC). In at least one embodiment, the skin cancer is squamous cell carcinoma. In at least one embodiment, the squamous cell carcinoma is a cutaneous in situ squamous cell carcinoma. In at least one embodiment, the skin cancer is nodular basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma. In at least one embodiment, the skin cancer is infiltrative basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma multi-focal basal cell carcinoma.

[0168] In at least one implementation, a method of treating skin cancer in a patient can include (i) applying topical ALA HC1 solution or gel to the affected skin; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 18 - 24 hours; (iii) applying a pulse dye laser to an affected area of the subject’s skin for 0.45 millisecond at a fluence of 13 J / cm2; and (iv) administering blue light illumination (e.g., using a BLU-U® device, Sun Pharmaceutical Industries, Inc., Princeton, NJ, or other illuminator) to the affected area for 16 minutes and 40 seconds at 10 J / cm2light dose to treat the cancer. In at least one embodiment, the skin cancer is non-melanoma skin cancer (NMSC). In at least one embodiment, the skin cancer is squamous cell carcinoma. In at least one embodiment, the squamous cell carcinoma is a cutaneous in situ squamous cell carcinoma. In at least one embodiment, the skin cancer is nodular basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma. In at least one embodiment, the skin cancer is infiltrative basal cell carcinoma. In at least oneembodiment, the skin cancer is recurrent nodular basal cell carcinoma multi-focal basal cell carcinoma.

[0169] In various implementations, a method of treating skin cancer in a patient can include (i) applying topical ALA HC1 20% solution to the affected skin; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14- 24 hours; (iii) applying a pulse dye laser to an affected area of the subject’s skin for 0.25 - 75 millisecond at a fluence of 8-22 J / cm2; and (iv) administering blue light to the affected area for 16 minutes and 40 seconds at 10 J / cm2light dose to treat the cancer. In at least one embodiment, the skin cancer is non-melanoma skin cancer (NMSC). In at least one embodiment, the skin cancer is squamous cell carcinoma. In at least one embodiment, the squamous cell carcinoma is a cutaneous in situ squamous cell carcinoma. In at least one embodiment, the skin cancer is nodular basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma. In at least one embodiment, the skin cancer is infiltrative basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma multi-focal basal cell carcinoma.[0170| In various implementations, a method of treating skin cancer in a patient can include (i) applying topical ALA HC1 solution or gel to the affected skin; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14- 24 hours; (iii) applying a pulse dye laser to an affected area of the subject’s skin for 0.25 - 75 millisecond at a fluence of 8-22 J / cm2; and (iv) administering red light to the affected area to treat the cancer. In at least one embodiment, the skin cancer is non-melanoma skin cancer (NMSC). In at least one embodiment, the skin cancer is squamous cell carcinoma. In at least one embodiment, the squamous cell carcinoma is a cutaneous in situ squamous cell carcinoma. In at least one embodiment, the skin cancer is nodular basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma. In at least one embodiment, the skin cancer is infiltrative basal cell carcinoma. In at least one embodiment, the skin cancer is recurrent nodular basal cell carcinoma multi-focal basal cell carcinoma.

[0171] In various embodiments, implementation of the above methods can cause a reduction in cancer lesion size for a patient having cancer. In at least one embodiment, the reduction persists for a period of at least three months. In exemplary embodiments, treatment results in a reduction in cancer lesion severity. In at least one embodiment, the side effects of treatment are reduced relative to a method that does not include a pulse dye laser treatment of the skin.

[0172] In at least one embodiment, a method is provided for treating non-melanoma skin cancers (NMSCs) of the face. The method includes applying heat to achieve a skin temperature of between about 38°C and about 42°C; applying a therapeutically effective amount of the composition to the affected area; incubating the pharmaceutical composition for less than about 24 hours; applying a pulse dye laser to the affected skin, and administering a suitable dose of light (e.g., red light) to the area. In at least one aspect of above embodiments, the incubation time is up to 24 hours, less than 24 hours, or less than 20 hours, or less than 18 hours, or less than 14 hours, with or without heating. In at least one embodiment, the incubation time is about 18 hours to about 24 hours (e.g., about 18, 19, 20, 21, 22, 23, or 24 hours, including any value therebetween). In at least one embodiment, the incubation time is about 15 minutes to about 24 hours (e.g., about 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes, including any value therebetween; or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, including any value therebetween). In at least one embodiment, the ALA is incubated simultaneously with application of PDL to the skin or within a few seconds (e.g., within about 0.5 seconds to about 5 seconds) or minutes (e.g., within about 1 minute to about 15 minutes) prior to PDL treatment of the skin, or after PDL treatment of the skin has commenced. The following discussion sets forth illustrative examples of how treating a disease or disorder of the skin may be carried out using an exemplary illuminator, e.g., for performing photodynamic therapy, in combination with a pulse dye laser.

[0173] The PDT and PDL methods outlined above have been implemented and demonstrated experimentally. In at least one such experiment, twenty (20) patients with clinically observable and biopsy-confirmed isSCC on the face were recruited. A diagnostic biopsy was performed within 6 months of recruitment, and the lesion was not previously treated. Onlylesions with a diameter of 0.4 cm - 1.3 cm were considered for the study, and patients with infiltrative, severe metaplastic, or recurrent isSCC were excluded.

[0174] Treatment consisted of topical application of ALA HC1, 20% topical solution to the lesion and the adjacent skin. The treated area was covered with a bandage and incubated for 18 - 24 hours. A pulse dye laser (pulse duration: 0.45 millisecond, fluence: 13 J / cm2) and blue light illumination (BLU-U®; 10 J / cm2for 16 minutes and 40 seconds) were administered. Patients each underwent two ALA-PDL-PDT treatment sessions separated by a 30-day period.

[0175] Surgical excision of the legions was performed 4-6 weeks after the second treatment for histopathological assessment. Clinical clearance (CC) of the skin lesion, defined as no clinically visible lesion remaining at the site, was evaluated at regular patient follow-up visits. Lesions were assessed for pigmentation (hyperpigmentation, hypopigmentation, depigmentation) by the investigator at each office visit. Tolerability was assessed using the local skin reaction scale and lesion site pain scale. Local skin reactions (LSRs) were evaluated at every visit and recorded on a 6-parameter scale including erythema, flaking / scaling, crusting, swelling, vesiculation / pustulation, and erosion / ulceration. Responses to each parameter were scored by the investigator on a scale from 0 (not present) to 4 (high severity). Lesion site pain was collected from the patients within 15 minutes after each blue light illumination. The patient reported the pain score on a 10-centimeter visual analog scale (VAS) that ranged from 0 (no pain) to 10 (worst pain possible).| 0176| The primary endpoint of the noted experiment was determined based on the proportion of patients who achieved histological clearance of isSCC at the end of treatment (EOT). The secondary endpoint was determined based on the proportion of patients with CC of the skin lesion.

[0177] As noted above, twenty patients with Fitzpatrick skin type II or III and a mean age of 70.7 years (age range: 45-87) fulfilled the inclusion and exclusion criteria and were enrolled in the study — all of whom completed the study. None of the participants discontinued the study prematurely. There were 12 (60%) male and 8 (40%) female patients. The locations of the isSCCs were as follows: 3 (15%) on the left cheek and / or ear, 10 (50%) on the right cheekand / or ear, 1 (5%) on the central face (nose, upper labial), and 6 (30%) on the forehead (upper eyebrow, glabellar region). Overall, 5 (25%) lesions were located on the left face, one (5%) at the mid-face, and 14 (70%) were located on the right face. The mean diameter was 0.655 cm (range: 0.5-1.2 cm, standard deviation [SD] : 0.20).|0178| Overall, 17 / 20 patients (85%) achieved the primary endpoint of histological clearance at EOT / surgical excision. Two of the patients with residual isSCC had untreated skip lesions present to which the treatment failure was attributed. Excluding patients with skip lesions, the histological clearance rate after treatment was 17 / 18 (94%). Clinical clearance was observed before surgical excision in 13 patients (65%). Four patients (20%) achieved CC as of day 15; 4 patients (20%) as of day 29, 2 patients (10%) as of day 44, and 3 patients (15%) as of day 58. For reference, the second blue light illumination occurred on day 30, and surgical excision occurred on day 58 (± 9 days; range, 4-6 weeks after the second treatment). No patients had any lesional pigmentation changes throughout the study.

[0179] Median lesion skin reactions (LSRs) peaked within 1 week after each PDT and blue light treatment (visits 3 and 7; see Table 1). LSRs steadily decreased thereafter. Erythema and scaling were the most frequent LSRs. Of note, LSR values were higher at visit 1 (pretreatment) than at visit 10. Images obtained during visit 1 (pre-treatment) and visit 10 (posttreatment) illustrate the successful clearance of isSCC with ALA-PDL-PDT in the setting of decreasing erythema and scaling.Table 1: Median local skin reaction scores for the lesion areas (end of treatment is denoted by “EOT” and treatment is denoted by “Tx”)|0180| The mean pain score recorded by patients on the VAS within 15 minutes after each blue light illumination was 2.95 (range, 0-10; SD, 2.97). The majority of patients (n = 13, 65%) did not report any adverse events (AEs) throughout the study period. None of the reported AEs were serious. None of the AEs were considered by the investigators to be related to the study treatment, and treatment administration was not altered due to any of the reported AEs. None of the patients withdrew from the study for any reason.101.811 According to the present method, PDL was used to activate the photosensitizer before PDT. Efficacy observed may be attributed in part to study design elements including diameter <2.0 cm, incubation time >4 hours, and lesions located on the face. Histological analysis revealed treatment failure in 3 patients. One of these patients had a multifocal isSCC on the left inferior lateral malar cheek, and treatment failure may be attributable to failure to treat the peripheral margins of the lesion during PDT, leaving behind residual isSCC. Another treatment failure occurred on the right superior ear helix, where treatment ineffectiveness may be attributable to the crumpled surface of the helix.Methods and Uses

[0182] In one aspect, provided herein is a method of treating cancer or a precancerous condition in a patient in need thereof, the method comprising, consisting essentially of, or consisting of:(i) applying to a lesion on the patient, a topical composition comprising, consisting essentially of, or consisting of 5 -aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).In such methods, the lesion is caused by the cancer or the precancerous condition.

[0183] The cancer includes, but is not limited to, non-melanoma skin cancer, cutaneous T- cell lymphoma, non-small cell lung cancer, esophageal cancer, cervical cancer, bladder cancer, Kaposi sarcoma, and mucosal cancer. The precancerous condition includes, but is not limited to precancerous skin conditions, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia.

[0184] In another aspect, provided herein is a method of treating non-melanoma skin cancer or a precancerous skin condition in a patient in need thereof, the method comprising, consisting essentially of, or consisting of:(i) applying to a lesion on the patient, a topical composition comprising, consisting essentially of, or consisting of 5 -aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).In such methods, the lesion is caused by the non-melanoma skin cancer or the precancerous skin condition.

[0185] In another aspect, provided herein is a method of treating non-melanoma skin cancer or a precancerous skin condition in a patient in need thereof, the method comprising, consisting essentially of, or consisting of:(i) applying to a lesion on the patient, a topical composition comprising, consisting essentially of, or consisting of 5 -aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).In such methods, the lesion is caused by the non-melanoma skin cancer or the precancerous skin condition.

[0186] In another aspect, provided herein is a method of treating non-melanoma skin cancer in a patient in need thereof, the method comprising, consisting essentially of, or consisting of:(i) applying to a lesion on the patient, a topical composition comprising, consisting essentially of, or consisting of 5 -aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).In such methods, the lesion is caused by the non-melanoma skin cancer.

[0187] In another aspect, provided herein is a method of treating a precancerous skin condition in a patient in need thereof, the method comprising, consisting essentially of, or consisting of:(i) applying to a lesion on the patient, a topical composition comprising, consisting essentially of, or consisting of 5 -aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source (e.g., a blue light source, a red light source, or another light source or any combination thereof) .In such methods, the lesion is caused by the precancerous skin condition.

[0188] Non-melanoma skin cancer includes, but is not limited to, basal cell carcinoma, cutaneous squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, or sebaceous carcinoma. Cutaneous squamous cell carcinoma includes, but is not limited to, invasive squamous cell carcinoma (SCCI), clear-cell squamous cell carcinoma, spindle cell squamous cell carcinoma (sarcomatoid SCC), squamous cell carcinoma with single cell infiltrates, de novo squamous cell carcinoma (including but not limited to Marjolin ulcers), verrucous carcinoma, or lymphoepithelioma-like carcinoma of the skin (LELCS).

[0189] In at least one embodiment, the basal cell carcinoma involves genetic mutations of one or more of PTCHI, PTCH2, BAP1, MC1R, CYFIP2, HOXB5, PTPN3, MARCKSL1, CDC2, LRP1B, IL-6, SOCS3, TGM3, a Hedgehog signaling gene (SHH, SMO, GLI1, GLI2,GL3), a DNA repair gene, P53, or associated with basal cell nevus syndrome. In at least one embodiment, the cutaneous squamous cell carcinoma involves genetic mutations of one or more of a DNA repair gene, ALK, CD20, CDK1, SOCS3, LRP1B, TCF4, or P53. In at least one embodiment, the cutaneous squamous cell carcinoma is associated with oculocutaneous albinism, epidermolysis bullosa, or Fanconi anemia. Merkel cell carcinoma (Mcc), which includes Mcc associated with Merkel cell polyomavirus infection, may have cancer cells with integrated Mcc DNA or Mcc having a mutated T Antigen gene.

[0190] The precancerous skin condition includes, but is not limited to, actinic keratosis, actinic cheilitis, squamous cell carcinoma in situ (isSCC), leukoplakia, keratocanthoma, or lentigo maligna. In at least one embodiment, the precancerous skin condition is actinic cheilitis, squamous cell carcinoma in situ (isSCC), leukoplakia, keratocanthoma, or lentigo maligna. In at least one embodiment, the precancerous skin condition is squamous cell carcinoma in situ (isSCC).

[0191] In at least one embodiment, the lesion is located on the head (including, but not limited to, the face, chin, and / or scalp) neck, torso (including, but not limited to, the chest, trunk, buttocks, back, and / or abdomen), arm, leg, hand, or foot. In at least one embodiment, the lesion is located on the face. In at least one embodiment, the lesion is located on an organ or an internal cavity, such as a bladder or a cervix, or on the genitalia.

[0192] In various implementations, use of ALA with PDT (ALA-PDT) can be used to effectively treat isSCC. Accordingly, in at least one embodiment, the precancerous skin condition is isSCC. In some further embodiments, the isSCC is facial isSCC.[ 0193 [ In another aspect, provided herein is a method of treating cutaneous T-cell lymphoma, non-small cell lung cancer, esophageal cancer, bladder cancer, mucosal cancer, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia in a patient in need thereof, the method comprising, consisting essentially of, or consisting of:(i) applying to a lesion on the patient, a topical composition comprising, consisting essentially of, or consisting of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).In such methods, the lesion is caused by the cutaneous T-cell lymphoma, the non-small cell lung cancer, the esophageal cancer, the bladder cancer, the Kaposi sarcoma, the mucosal cancer, the Barrett esophagus, the cervical dysplasia, or the cervical intraepithelial neoplasia.

[0194] In at least one embodiment, the mucosal cancer is located in the gastrointestinal tract or urogenital area. In at least one embodiment, the lesion is in a body cavity with mucous membranes, such as but not limited to the ears, nostrils, mouth, throat, stomach, genitals, or anal cavity. In at least one embodiment, the lesion is located in the esophagus, lungs, stomach, intestines, bladder, or uterus.

[0195] In at least one embodiment, a method of treating bladder cancer further comprises administering Bacillus Calmette-Guerin (BCG) to the patient.

[0196] In at least one embodiment, the method further comprises evaluating a sample of the lesion in a cell-based test prior to applying the topical composition. In at least one embodiment, the cell-based test is a histopathology test.

[0197] In at least one embodiment, the lesion is about 0.4 cm to about 1.3 cm in diameter. This includes about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, or 1.3 cm, or any value therebetween, in diameter. Facial lesions ranging from approximately 0.4 cm to approximately 1.3 cm in diameter can be treated using ALA-PDT methods according to the present disclosure.(0198] In at least one embodiment, the patient is has previously been treated for the cancer or precancerous condition. In at least one embodiment, the patient is refractory to previous treatment.

[0019] In at least one embodiment, the patient has not been previously treated with other therapy for the cancer or precancerous condition.

[0200] A method of ALA-PDT to treat isSCC can include debriding each lesion prior to applying ALA. Accordingly, in at least one embodiment, the methods described herein(regardless of condition to be treated) further comprise debriding the lesion prior to applying the topical composition. For example, each lesion can be debrided using a 4 inch x 4 inch gauze pad.

[0201] The methods described herein include applying a topical composition comprising 5- aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, to the lesion. The method can include applying ALA (e.g., LEVU AN®) to each lesion and skin adjacent thereto.

[0202] The methods described herein can also include incubating the lesions, after ALA application, for a predetermined period of time. In at least one embodiment, the incubating step is performed for a period of about 15 minutes to about 24 hours. This includes about 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes, or any value therebetween; and also includes about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, or 24 hours, or any value therebetween. In at least one embodiment, the incubating step is performed for a period of about 18 hours to about 24 hours. In at least one embodiment, ALA 20% topical solution is applied to each lesion and adjacent skin and incubated for approximately 18 hours to approximately 24 hours.]0203[ The period of time for the incubation step can be reduced by use of a 5-ALA- containing topical composition comprising a penetration enhancer and / or use of an illuminator with a power level of 20 mW / cm2(20 J / cm2). Accordingly, in at least one embodiment, an exemplary method for reducing incubation time (e.g., while treating any of the conditions described herein) includes (i) applying, to a treatment area, a topical composition comprising 5-ALA, or a pharmaceutically acceptable salt thereof, and a penetration enhancer according to any of the embodiments set forth herein, and / or (ii) illuminating the treatment area with a photodynamic therapy device (e.g., an illuminator) to deliver a light dose of about 20 J / cm2at 20 mW / cm2. The incubation time can be reduced from a first period to a second period shorter than a first period by at least a given amount. The first period can be, for example, a period of about 24 hours or more. The reduced period can be a period of about 5 hours or less, about 4 hours or less, about 3.5 hours or less, about 3hours or less, about 2 hours or less, about 1 hour or less, about 45 minutes or less, about 30 minutes or less, or about 15 minutes. The penetration enhancer can be selected from a group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, glycol derivatives, glycerides, azones, polysorbates, macrogolglycerides, polyethylene glycol derivatives, ethoxylated ether derivatives, bile salts, and sulfated glycosaminoglycan, or a combination of any two or more thereof. In at least one embodiment, the penetration enhancer is selected from a group consisting of propylene glycol, polyethylene glycol, and 2- (2-ethoxyethoxy)ethanol. In at least one embodiment, the penetration enhancer is present in the topical composition in an amount of about 2% w / w to about 50% w / w.

[0204] In at least one embodiment, a method of reducing incubation time includes (i) applying, to a treatment area, a topical composition comprising 5-ALA, or a pharmaceutically acceptable salt thereof, and a penetration enhancer according to any of the embodiments set forth herein, and / or (ii) illuminating the treatment area with a photodynamic therapy device (e.g., an illuminator) to deliver a light dose of about 20 J / cm2at 20 mW / cm2, while at least one of (i) or (ii) is performed while optionally actively circulating air, e.g., through an air circulator, so that air is directed to the patient. In at least one embodiment, incubation time is reduced by (i) applying, to a treatment area, a topical composition comprising 5-ALA, or a pharmaceutically acceptable salt thereof, and a penetration enhancer according to any of the embodiments set forth herein, and / or (ii) illuminating the treatment area with a photodynamic therapy device (e.g., an illuminator) to deliver a light dose of about 20 J / cm2at 20 mW / cm2, while at least one of (i) or (ii) is performed while optionally applying heat to the treatment area and / or under occlusion. In at least one embodiment, heating can be applied while air is circulated to the patient by an air circulator.

[0205] In at least one embodiment, a method of reducing incubation time includes (i) applying, to a treatment area, a topical composition comprising 5-ALA, or a pharmaceutically acceptable salt thereof, and a penetration enhancer selected from a group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, glycol derivatives, glycerides, azones, polysorbates, macrogolglycerides, polyethylene glycol derivatives, ethoxylated ether derivatives, bile salts, and sulfated glycosaminoglycan, or a combination of any two or more thereof; and / or (ii) illuminating the treatment area with aphotodynamic therapy device (e.g., an illuminator) to deliver a light dose of about 20 J / cm2at 20 mW / cm2, while at least one of (i) or (ii) is performed while optionally actively circulating air, e.g., through an air circulator, so that air is directed to the patient. In at least one embodiment, incubation time is reduced by (i) applying, to a treatment area, a topical composition comprising 5-ALA, or a pharmaceutically acceptable salt thereof, and a penetration enhancer selected from a group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, glycol derivatives, glycerides, azones, polysorbates, macrogolglycerides, polyethylene glycol derivatives, ethoxylated ether derivatives, bile salts, and sulfated glycosaminoglycan, or a combination of any two or more thereof; and / or (ii) illuminating the treatment area with a photodynamic therapy device (e.g., an illuminator) to deliver a light dose of about 20 J / cm2at 20 mW / cm2, while at least one of (i) or (ii) is performed while optionally applying heat to the treatment area and / or under occlusion. In at least one embodiment, heating can be applied while air is circulated to the patient by an air circulator.[0206| In at least one embodiment, incubation time is reduced by (i) applying, to a treatment area, a topical composition comprising 5-ALA, or a pharmaceutically acceptable salt thereof, and a penetration enhancer selected from a group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and / or (ii) illuminating the treatment area with a photodynamic therapy device (e.g., an illuminator) to deliver a light dose of about 20 J / cm2at 20 mW / cm2, while at least one of (i) or (ii) is performed while optionally actively circulating air, e.g., through an air circulator, so that air is directed to the patient. In at least one embodiment, incubation time is reduced by (i) applying, to a treatment area, a topical composition comprising 5-ALA, or a pharmaceutically acceptable salt thereof, and a penetration enhancer selected from a group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and / or (ii) illuminating the treatment area with a photodynamic therapy device (e.g., an illuminator) to deliver a light dose of about 20 J / cm2at 20 mW / cm2, while at least one of (i) or (ii) is performed while optionally applying heat to the treatment area. In at least one embodiment, heating can be applied while air is circulated to the patient by an air circulator. In at least one embodiment, the treatment area is occluded during incubation, as discussed in more detail below.

[0207] In at least one embodiment, the method further comprises occluding the lesion during the incubating step and prior to illuminating the lesion with the light source. In at least one embodiment, occluding the lesion comprises applying a light-blocking occlusive dressing or a moisture protecting occlusion dressing to the lesion. In at least one embodiment, occluding the lesion comprises applying a light-blocking occlusive dressing. In at least one embodiment, occluding the lesion comprises applying a moisture protecting occlusion dressing to the lesion. In at least one embodiment, the light-blocking occlusive dressing can be opaque or transparent. In particular, in at least one embodiment, occluding the lesion comprises applying a transparent film dressing to the lesion. A non-limiting example of a transparent film dressing is a low-density polyethylene barrier. Accordingly, in at least one embodiment, occluding the lesion comprises applying a low density polyethylene barrier to the lesion. The low density polyethylene may be characterized by a density of about 0.917 g / cm3to about 0.930 g / cm3. In at least one embodiment, the method further comprises applying a secondary barrier over the lesion that is occluded, wherein the secondary barrier comprises foil or elastic material. In at least one embodiment, the method further comprises cleaning the lesion after the incubating step and prior to the illuminating step.

[0208] In at least one embodiment, the method further comprises heating the lesion either (1) after the incubating step and before the illuminating step or (2) during the illuminating step. In at least one embodiment, the method further comprises heating the lesion after the incubating step and before the illuminating step. In at least one embodiment, the method further comprises heating the lesion during the illuminating step. In at least one embodiment, the method further comprises heating lesion during the incubating step. In at least one embodiment, the method comprises heating the lesion after the incubating step and before the illuminating step and further heating during the illuminating step. In at least one embodiment, the lesion is heated to a surface temperature of greater than about 37 °C. In at least one embodiment, the lesion is heated to a surface temperature of greater than about 40

[0209] A heating element may be used as a heat source for heating the lesion. In at least one embodiment, the methods described herein include warming up an illuminator so as to cause heat to be emitted from the illuminator, and exposing a treatment site (i.e., the lesion to which5-aminolevulinic acid has been applied) to the illuminator. The heat accelerates the conversion of the 5-aminolevulinic acid to porphyrin (e.g., photosensitive porphyrin or proto porphyrin). The relationship between temperature exposure and 5-aminolevulinic acid conversion is non-linear, and the enzymatic pathways responsible for the conversion are highly sensitive to temperature. In at least one embodiment, increasing the temperature of tissue by approximately 2 °C approximately doubles the rate of production of protoporphyrin IX (PpIX).

[0210] In at least one embodiment, the heat source is an infrared quartz heater. In at least one embodiment, the heat source comprises frame mounted resistance tape heaters or a plurality of heaters, including at least one selected from the group including IR LEDs, resistance cartridge heaters, positive temperature coefficient heaters, or IR quartz heaters. The heat may be deliberately generated and directed towards the area to be treated, as opposed to ambient heat in the clinical setting or by-product heat from one or more operating mechanisms of the illuminator.10211 [ In at least one embodiment, by heating the skin as described herein, a reduction in incubation time needed for 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, may be achieved. A significant quantity of porphyrins is produced after about 20 minutes of incubation of 20% 5-aminolevulinic acid gel on skin heated to about 40 °C, with even a greater quantity produced after about 30 minutes. The quantity of porphyrins produced after about 60 minutes incubation of 20% 5-aminolevulinic acid gel without heat is smaller than for either about 20 or about 30 minutes with heat.

[0212] In at least one embodiment, the method further comprises applying an optical clarifying agent to the lesion prior to the illuminating step. Non-limiting examples of optical clarifying agents include skin moisturizers, e.g., moisturizers containing EDTA.

[0013] The method can include providing at least one dose of blue light via the illuminator 10 for a predetermined period of time. In at least one embodiment, the illuminating was performed for about 500 to about 1200 seconds. This includes about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, or 1200 seconds, including any value therebetween. In at least one embodiment, the illuminating was performed for about 1000seconds. In at least one embodiment, each lesion is treated using blue light therapy for a period of 16 minutes and 40 seconds at a power level of approximately 20 mW / cm2(20 J / cm2) (i.e., corresponding to a power level of “20 mW” as described herein). In at least one embodiment, each lesion is treated using blue light therapy for a period of 16 minutes and 40 seconds at a power level of approximately 10 mW / cm2(10 J / cm2).

[0214] Photodynamic therapy sessions may be repeated about every 4 to about every 6 weeks. In various implementations of the methods described herein, ALA-PDT can be repeated such that patients receive treatment at a first time point and at a second time point following the first time point. In at least one embodiment, each lesion (and thus each patient) is treated twice using ALA-PDT, where a second treatment can be carried out at approximately 28 days (± 3 days) following a first treatment.[0215J In various implementations, efficacy of ALA-PDT can be determined using various histopathological assessments.

[0216] In a study involving 32 patients with biopsy-confirmed facial isSCC (see Example 1), the isSCC was treated according to an ALA-PDT method described herein. Lesions of approximately 0.4 cm to approximately 1.3 cm in diameter were included. In accordance with the techniques described herein, the lesion was debrided with a 4 x 4 gauze and ALA 20% topical solution was applied to the lesion and adjacent skin, and incubated for 18-24 hours, followed by blue light therapy for 16 minutes 40 seconds at 20 J / cm2at 20 mW / cm2. Patients underwent two treatments with ALA-PDT spaced 28 + 3 days apart. An area corresponding to each original legion was excised from corresponding patients following the second treatment for histopathological assessment. In various implementations, determination of ALA-PDT efficacy can be measured by a degree of clearance of isSCC from the area of skin. In other implementations, determination of ALA-PDT efficacy can be measured based on a degree of clearance of each lesion from the area of skin. In the above-described study, a primary efficacy endpoint was the degree of clearance of isSCC (i.e., where greatest efficacy corresponded to complete histological absence of isSCC) and a secondary efficacy endpoint was the degree of clearance of each lesion (i.e., where greatest efficacy corresponded to complete absence of lesions).

[0217] In various implementations of ALA-PDT methods, safety assessments can be carried out before, during, and / or after each treatment. In the study described above, safety assessments were carried out approximately 15 minutes after each of the first treatment and the second treatment. Although two patients did not complete the study, at the conclusion of the study, it was determined that ALA-PDT treatment using a blue light dose of 20 J / cm2was effective in treating isSCC. In the study, no residual isSCC was detected in 100% of the patients who completed both the first treatment and the second treatment. In addition, clinical clearance of each lesion was achieved in 100% of the patients who completed both the first treatment and the second treatment. The average median and standard deviation of immediate post-treatment pain scores during the study was 2.56 ± 2.15 on the visual analog (VAS) scale. Accordingly, as reflected in the described study, ALA-PDT with an illuminator as described herein can provide effective and tolerable treatment for isSCC on the face, among other skin conditions.[02181 Thus, according to the present disclosure, a method of treating cutaneous squamous cell carcinoma in situ is provided. The method includes applying a topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, to a cutaneous squamous cell carcinoma lesion. The method further includes incubating the topical composition on the lesion for a first treatment period. The method additionally includes illuminating, with an illuminator, the lesion for an illumination period with blue light. In certain implementations, red light may be applied in lieu of or in addition to blue light. For example, a red light dose of 37.5 J / cm2at 630 nm may be applied, e.g., for ten minutes. Accordingly, in at least one embodiment, the method comprises applying to a lesion on the patient, a topical composition comprising, consisting essentially of, or consisting of 5- aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a non-sterile topical formulation of 10% 5- aminolevulinic acid hydrochloride (equaling 7.8% of free acid) in a gel-matrix with nanoemulsion); and illuminating the lesion with a red light source.10219] Treatment sessions in which 5-ALA is applied prior to illumination may be repeated (i.e., ALA-PDT as described above). For example, a treatment session may be carried outonce after an initial treatment session (for a total of 2 or more treatment sessions), or multiple times after an initial treatment session (for a total of 3 or more treatment sessions).

[0220] The techniques described herein include, but are not limited to, performing photodynamic therapy using the following methods, according to any of the disclosed embodiments herein:(i) a method of treating squamous cell carcinoma in situ (isSCC);(ii) a method of treating facial squamous cell carcinoma in situ (isSCC);(iii) a method of treating squamous cell carcinoma in situ (isSCC), the method comprising topically applying 5-aminolevulinic acid or a pharmaceutically acceptable salt thereof to a lesion; incubating the lesion for approximately 24 hours; and applying blue light to the lesion following incubation;(iv) a method of using an illuminator for providing photodynamic therapy; or(v) a method of treating a patient, the method comprising applying 5- aminolevulinic acid to the patient’s skin and applying blue light to the skin using an illuminator.[0221 | In another aspect, provided herein is a topical composition comprising, consisting essentially of, or consisting of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in a method of treating cancer or a precancerous condition, the method comprising, consisting essentially of, or consisting of:(i) applying the topical composition to a lesion on the patient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).

[0222] In another aspect, provided herein is a topical composition comprising, consisting essentially of, or consisting of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in a method of treating non-melanoma skin cancer or a precancerous skin condition (e.g., isSCC), the method comprising, consisting essentially of, or consisting of:(i) applying the topical composition to a lesion on the patient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).

[0223] In another aspect, provided herein is a topical composition comprising, consisting essentially of, or consisting of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in a method of treating cutaneous T-cell lymphoma, non-small cell lung cancer, esophageal cancer, bladder cancer, Kaposi sarcoma, mucosal cancer, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia, the method comprising, consisting essentially of, or consisting of(i) applying the topical composition to a lesion on the patient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).

[0224] In another aspect, provided herein is a use of a topical composition comprising, consisting essentially of, or consisting of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for a method of treating cancer or a precancerous condition, the method comprising, consisting essentially of, or consisting of(i) applying the topical composition to a lesion on the patient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).

[0225] In another aspect, provided herein is a use of a topical composition comprising, consisting essentially of, or consisting of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for a method of treating non-melanoma skin cancer or a precancerous skin condition (e.g., isSCC), the method comprising, consisting essentially of, or consisting of(i) applying the topical composition to a lesion on the patient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).

[0226] In another aspect, provided herein is a use of a topical composition comprising, consisting essentially of, or consisting of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for a method of treating cutaneous T-cell lymphoma, non-small cell lung cancer, esophageal cancer, bladder cancer, Kaposi sarcoma, mucosal cancer, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia, the method comprising, consisting essentially of, or consisting of(i) applying the topical composition to a lesion on the patient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a light source (e.g., a blue light source, a red light source, or another light source or any combination thereof).Topical Compositions with 5-Aminolevulinic Acid

[0227] In at least one embodiment, treatment is performed using a topical composition applied to the treatment surface, and 5-aminolevulinic acid or the pharmaceutically acceptable salt thereof is present in the topical composition in an amount of about 1% w / w to about 70% w / w. This includes an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% w / w, or any value therebetween. In at least one embodiment, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of about 1% w / w to about 30% w / w. In at least one embodiment, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of about 20% w / w.

[0228] About 78 mg to 708 mg of 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is administered to the patient prior to or during illumination with the illuminator. This includes administration of about 78 mg, about 100 mg, about 156 mg, about 200 mg, about 234 mg, about 300 mg, about 354 mg, about 400 mg, about 468 mg, about 546 mg, about 624 mg or about 708 mg, or any value therebetween.

[0229] In at least one embodiment, the at least one pharmaceutically acceptable excipient comprises at least one selected from a group consisting of a penetration enhancer and a chelating agent. In at least one embodiment, the at least one pharmaceutically acceptable excipient comprises a penetration enhancer. In at least one embodiment, the at least one pharmaceutically acceptable excipient comprises a chelating agent. In at least one embodiment, the at least one pharmaceutically acceptable excipient comprises a penetration enhancer and a chelating agent.(0230] Non-limiting examples of a penetration enhancer include dialkyl derivatives of acetamide and formamide (such as dimethyl acetamide or dimethyl formamide), pyrrolidone derivatives (such as N-methyl-2-pyrrolidone), fatty acids (such as oleic acid), glycol derivatives (such as propylene glycol), glycerides, azones (such as laurocapram or 1-n- dodecyl-azacycloheptan-2-one), polysorbates (such as TWEEN® (polysorbate) 80, Croda International PLC, Snaith, UK), macrogolglycerides (such as stearoyl macrogolglycerides, oleoyl macrogolglycerides, lauroyi macrogolglycerides, capryl-caproyl macrogolglycerides), polyethylene glycol derivatives (such as polyethylene glycol 400), ethoxylated ether derivatives (such as diethyleneglycol monoethyl or diethyleneglycol monomethyl ether), bile salts, sulfated glycosaminoglycan, and any combination of two or more thereof. In at least one embodiment, the penetration enhancer is selected from a group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol (TRANSCUTOL®, Gattefosse SA, Saint-Priest, France).

[0231] In at least one embodiment, the penetration enhancer is present in the topical composition in an amount of about 2% w / w to about 50% w / w. This includes an amount of about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50% w / w, or any value therebetween. In at least one embodiment, the penetration enhancer is present in the topical composition in an amount of about 10% w / w to about 50% w / w, or about 20% w / w to about 40% w / w.

[0232] In at least one embodiment, the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof. Non-limiting examples of the pharmaceutically acceptable salt include disodium edetate, disodium edetate dehydrate, trisodium edetate, di-potassium edetate, dipotassium edetate dehydrate, edetate calcium disodium, diethylenetriamine pentaacetic acid, and organic acid such as citric acid, fumaric acid, malic acid, lactic acid and glycolic acid. In at least one embodiment, the chelating agent is disodium edetate.

[0233] In at least one embodiment, the chelating agent is present in the topical composition in an amount of about 0.01% w / w about to 2% w / w. This includes an amount of about 0.01%, 0.05%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.4%, 0.5%, 0.75%, 0.80%, 0.90%, 1.0%, 1.1%, 1.2%, 1.25%, 1.4%, 1.5%, 1.75%, 1.80%, 1.90% or 2.0% w / w, or any value therebetween. In at least one embodiment, the chelating agent is present in the topical composition in an amount of about 0.1% w / w about to 0.25% w / w.

[0234] In at least one embodiment, the at least one pharmaceutically acceptable excipient further comprises an anti-foaming agent. In at least one embodiment, the anti-foaming agent is cyclomethicone. The anti-foaming agent may be present in the topical composition in an amount of about 0.2% w / w to about 1.0% w / w. This includes about 0.2%, 0.25%, 0.4%, 0.5%, 0.75%, 0.80%, 0.90%, or 1.0% w / w, or any value therebetween. In at least one embodiment, the anti-foaming agent is present in the topical composition in an amount of about 0.5% w / w.

[0235] The topical composition can be prepared by simple admixture of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, with the vehicle. The vehicle can be prepared by mixing of permeation enhancer (if present), chelating agent (if present), antifoaming agent (if present), and other inactive ingredients (if present) in any order.Preferably, the vehicle can be prepared by adding the ingredients in the following order: to purified water, chelating agent is added and mixed well. To this, solvent such as ethyl alcohol is added, then propylene glycol is added, then polyethylene glycol 400, then isopropyl alcohol, then TRANSCUTOL®, and then Laureth-4 is added. The vehicle is mixed after addition of each ingredient. Finally, an anti-foaming agent such as cyclomethicone is added to obtain the final mixture. It has been surprisingly discovered that the order of addition in this order prevents precipitation of the chelating agent, such as EDTA.

[0236] In at least one embodiment, the topical composition further comprises one or more other inactive ingredients that are conventionally used in given product types. The inactive ingredients may be selected from alcohol, isopropyl alcohol, polyethylene glycol, propylene glycol, glycerine, diethylene glycol monoethyl ether or purified water or combinations thereof. The inactive ingredients may comprise a surfactant or a wetting agent and / or a humectant. The surfactant or wetting agent may be selected from the group consisting of laureth-4, sodium lauryl sulphate, sodium dodecyl sulfate, ammonium lauryl sulphate or sodium octech-l / deceth-1 sulfate thereof. The humectant may be selected from the group consisting of polyethylene glycol, propylene glycol, hyaluronic acid or glycerin thereof.

[0237] In at least one embodiment, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is in a stored form of a dry solid prior to administration to the patient. In at least one embodiment, essentially anhydrous 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is admixed with the vehicle just prior to its use. The anhydrous 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, may be, for example, the hydrochloride salt of 5-aminolevulinic acid, an endogenous 5-carbon aminoketone. In at least one embodiment, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is contained in powderized form inside a first ampule. A second ampule contains a solution vehicle. The first and second ampules are contained inside a plastic applicator. The first and second ampules may be crushed, e.g., by applying finger pressure, or inside a device configured to exert pressure on the ampules. Once the ampules are crushed, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, formerly contained in the first ampule contacts the solution formerly contained in the second ampule, and dissolves in the solution vehicle. The applicator in which the ampules wereprovided may be shaken so as to disperse and dissolve the powdered 5 -aminolevulinic acid, or the pharmaceutically acceptable salt thereof, in the solution vehicle. Once combined, the resulting solution is applied to the patient within 2 hours of preparation. In at least one embodiment, the applicator can contain two pairs of ampules, e.g., a pair of ampules containing 5-aminolevulinic acid and a pair of ampoules containing the solution vehicle.

[0238] In at least one embodiment, the 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, is provided in a composition such as a ready-to-use solution or a reconstituted powder for solution, gel, cream or lotion formulation. The 5-aminolevulinic acid admixture may be topically applied to a region of skin e.g., lesion) using a point applicator to control dispersion of the 5-aminolevulinic acid admixture so as to achieve a substantially uniform wetting of the region of skin with the 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, by contacting the 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, with the surface of the region of skin. The term “substantial,” or “substantially” as used herein, may refer to any value which lies within the range as defined by a variation of up to ± 10% from the average value. However, in other embodiments, the 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, may be applied digitally (i.e., by first disposing the 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, on the gloved fingertips of a practitioner, who then dabs the 5- aminolevulinic acid, or a pharmaceutically acceptable salt thereof, on the region to be treated), or with a tool such as a spatula, a swab, a gauze pad, or a bandage.

[0239] The topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, can be applied directly to lesions to be treated at the region of skin and to a margin beyond the lesions (such as approximately 5 mm or less than approximately 5 mm, e.g., approximately 2-4 mm). Alternatively, the topical composition can be administered to affected areas, without applying the 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, to healthy tissue not containing lesions and / or areas away from the lesions.(0240] In at least one embodiment, the topical composition containing 5-aminolevulinic acid is LEVULAN® (DUSA Pharmaceuticals, Billerica, MA), a topical formulation of 20% 5-aminolevulinic acid hydrochloride, which may be administered via a KERASTICK® applicator (DUSA Pharmaceuticals, Billerica, MA). In at least one embodiment, about 354 mg of 5-aminolevulinic acid hydrochloride as a dry solid is mixed with a solution vehicle to produce the topical formulation which is administered to the patient. In at least one embodiment, the composition is AMELUZ® (Biofrontera AG, Leverkusen, Germany), a non-sterile topical formulation of 10% 5-aminolevulinic acid hydrochloride (equaling 7.8% of free acid) in a gel-matrix with nanoemulsion. In at least one embodiment, about one gram (100 mg) of 5-aminolevulinic acid hydrochloride gel is administered (equivalent to 78 mg of aminolevulinic acid). In at least one embodiment, about two grams (200 mg) of 5- aminolevulinic acid hydrochloride gel is administered (equivalent to 156 mg of aminolevulinic acid). In at least one embodiment, about three gram (300 mg) of 5- aminolevulinic acid hydrochloride gel is administered (equivalent to 234 mg of aminolevulinic acid). In at least one embodiment, about six grams (600 mg) of 5- aminolevulinic acid hydrochloride gel is administered (equivalent to 468 mg of aminolevulinic acid). The composition can be a composition as set forth in (i) U.S. Patent Application Publication No. 2023 / 0131170 to Sanghvi et al. and / or (ii) U.S. Patent Application Serial No. 63 / 579,195 to Lundahl and PCT Application PCT / IB2024 / 058331 (having associated publication WO 2025 / 046471). The entire contents of the foregoing patent applications are incorporated herein by reference for background information and the compositions, methods of treatment, processes and techniques relating to photodynamic therapy and diagnosis disclosed therein.

[0241] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of:(i) at least one penetration enhancer, and(ii) at least one chelating agent.

[0242] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of:a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of:(i) at least one penetration enhancer,(ii) at least one chelating agent, and(iii) optionally, an antifoaming agent.

[0243] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of:(i) at least one penetration enhancer selected from a group consisting of glycol derivatives, polyethylene glycol derivatives, ethoxylated ether derivatives,(ii) ethylenediaminetetraacetic acid (EDTA) or its pharmaceutically acceptable salts thereof, and(iii) optionally, an antifoaming agent.

[0244] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, b) propylene glycol, c) EDTA or its pharmaceutically acceptable salt, and d) optionally, an antifoaming agent.

[0245] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle,wherein the vehicle comprises, consists essentially of, or consists of:(i) propylene glycol,(ii) EDTA and pharmaceutically acceptable salts, and(iii) optionally, an antifoaming agent.

[0246] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of:(i) propylene glycol,(ii) 2-(2-ethoxyethoxy)ethanol, and(iii) disodium edetate, and(iv) optionally, an antifoaming agent.

[0247] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of:(i) propylene glycol in an amount in the range of about 10% w / w to about 50 % l i,(ii) 2-(2-ethoxyethoxy)ethanol in an amount in the range of about 2 % w / w to about 50 % w / w, and(iii) disodium edetate, and(iv) optionally, an antifoaming agent.

[0248] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid in an amount of 20% w / w of the composition,b) propylene glycol in an amount of 20% to 40% w / w of the composition, and c) EDTA in an amount of 0.1% to 0.5% w / w of the composition.

[0249] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in an amount of 1-30 % w / w, b) propylene glycol in an amount in the range of about 10 % w / w to about 50 % w / w, c) 2-(2-ethoxyethoxy)ethanol in an amount in the range of about 2% w / w to about 50 % w / w, and d) disodium edetate.

[0250] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, b) ethanol, c) laureth-4 d) polyethylene glycol, e) isopropyl alcohol, f) propylene glycol, g) 2-(2-ethoxyethoxy)ethanol, h) edetate di sodium, i) cyclomethicone, and j) purified water.

[0251] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of:(i) ethanol,(ii) laureth-4,(iii) polyethylene glycol,(iv) isopropyl alcohol,(v) propylene glycol,(vi) 2-(2-ethoxyethoxy)ethanol,(vii) edetate disodium,(viii) cyclomethicone, and purified water.

[0252] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in an amount of 20 % w / w, b) ethanol in an amount of 10 to 15 % w / w of the composition, c) laureth-4 in an amount of 5 to 10% w / w of the composition, d) polyethylene glycol in an amount of 1 to 5 % w / w of the composition, e) isopropyl alcohol in an amount of 2 to 4 % w / w of the composition, f) propylene glycol in an amount of 20 to 40 % w / w of the composition, g) 2-(2-ethoxyethoxy)ethanol in an amount of 2 to 4% w / w of the composition, h) edetate disodium in an amount of 0.1 to 0.25 % w / w of the composition, i) cyclomethicone in an amount of 0.2 to 0.5 % w / w of the composition, and j) purified water.

[0253] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of(i) ethanol in an amount of 10 to 15 % w / w of the composition,(ii) laureth-4 in an amount of 5 to 10% w / w of the composition,(iii) polyethylene glycol in an amount of 1 to 5 % w / w of the composition,(iv) isopropyl alcohol in an amount of 2 to 4 % w / w of the composition,(v) propylene glycol in an amount of 20 to 40 % w / w of the composition,(vi) 2-(2-ethoxyethoxy)ethanol in an amount of 2 to 4% w / w of the composition,(vii) edetate disodium in an amount of 0.1 to 0.25 % w / w of the composition, and(viii) cyclomethicone in an amount of 0.2 to 0.5 % w / w of the composition.

[0254] In at least one embodiment, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, in the form of a dry solid, and b) a vehicle, wherein the vehicle comprises, consists essentially of, or consists of:(i) ethanol in an amount of 10 to 15 % w / w of the composition,(ii) laureth-4 in an amount of 5 to 10% w / w of the composition,(iii) polyethylene glycol in an amount of 1 to 5 % w / w of the composition,(iv) isopropyl alcohol in an amount of 2 to 4 % w / w of the composition,(v) propylene glycol in an amount of 20 to 40 % w / w of the composition,(vi) 2-(2-ethoxyethoxy)ethanol in an amount of 2 to 4% w / w of the composition,(vii) edetate disodium in an amount of 0.1 to 0.25 % w / w of the composition, and(viii) cyclomethicone in an amount of 0.2 to 0.5 % w / w of the composition, and(ix) purified water.

[0255] In at least one embodiment, 5-aminolevulinic acid or a pharmaceutically acceptable salt thereof is the sole active agent administered to the patient. In other words, in at least one embodiment, the methods described herein do not administer any other active agent to the patient other than 5-aminolevulinic acid or a pharmaceutically acceptable salt thereof. Accordingly, in at least one embodiment, 5-aminolevulinic acid or a pharmaceutically acceptable salt thereof is the sole active agent in the topical composition.-n-Examples

[0256] Example 1. Treatment of human patients with facial squamous cell carcinoma in situ (isSCC)

[0257] The effectiveness, safety, and tolerability of aminolevulinic acid photodynamic therapy (ALA-PDT) for the treatment of patients with facial isSCC was evaluated.

[0258] Adult patients with histologically confirmed facial isSCC were enrolled in the study. Histological diagnosis of the lesions had been performed within 6 months of screening. Only lesions measuring 0.4 cm to 1.3 cm in diameter were included. Patients with nodular basal cell carcinoma, superficial basal cell carcinoma, other non-SCC tumors, severe squamous metaplasia, infiltrative desmoplastic or micronodular growth patterns on biopsy, or a history of recurrence of the target isSCC were excluded.

[0259] Prior to the application of 20% ALA hydrochloric acid (HC1), lesions were gently abraded using 4 x 4 gauze and wiped with alcohol wipes. Following lesion preparation, 20% ALA HC1 was applied topically to the lesion and approximately 5 mm of the surrounding area. The treated area was then occluded with a bandage and incubated for 24 hours, during which patients were instructed to keep the treatment area dry and avoid direct sunlight. After the 24-hour incubation period, patients underwent PDT using blue light (BLU-U®) at an irradiance of 10 mW / cm2, delivering a total fluence of 10 J / cm2for 16 minutes and 40 seconds. Each patient received 2 ALA-PDT sessions, administered 28 (± 3) days apart.

[0260] Eight weeks after the second treatment, the lesions were surgically excised for histopathological analysis by a board-certified dermatopathologist. Lesion size and eventual complete clinical clearance (CC), defined as no clinically visible lesion at the site, were assessed by the investigator at each visit. Pigmentation changes at the lesion site (hyperpigmentation, hypopigmentation, and depigmentation) were evaluated at each visit by the investigator on a scale of 0 (none) to 3 (severe). Tolerability of the treatment was evaluated at each visit from local skin reactions (LSRs) on a scale of 0 (not present) to 4 (high severity) for erythema, flaking / scaling, crusting, swelling, vesiculation / pustulation, and erosion / ulceration. Patients also rated pain at the treatment site within 15 minutes after eachALA application and blue light illumination using a 10-cm visual analog scale (VAS) that ranged from 0 (no pain) to 10 (worst pain possible).

[0261] Outcomes. The primary endpoint of the study was the proportion of patients achieving complete histological clearance of isSCC at the end of treatment (EOT). The secondary endpoints were the proportion of patients with CC of the treated lesion as measured by investigator assessment and the aesthetic appearance of the treated lesion as reflected by LSR scores.Results

[0262] Thirty-two patients with a mean (range) age of 75 (54-95) years and Fitzpatrick skin type I, II, or III were enrolled. Two patients did not complete the study. Among the 30 patients who completed the study, 20 (67%) were male and 10 (33%) were female. The locations of the isSCC lesions were as follows: 7 (23.3%) on the left cheek or temple, 10 (33.3%) on the right cheek or temple, and 13 (43.3%) on the forehead (glabellar region or eyebrow). Overall, 15 (50%) lesions were located on the left side of the face and 15 (50%) on the right; none were located in the midface. The mean lesion diameter was 0.73 cm (range, 0.4-1.2 cm; standard deviation [SD], 0.20 cm). The mean lesion width was 0.59 cm (range, 0.4-1.1 cm; SD, 0.19 cm).

[0263] All patients who completed the study (n = 30) achieved complete histological clearance of the treated isSCC lesion at EOT / surgical excision. Clinical clearance (CC) was also observed in all patients prior to surgical excision (FIGS. 20A-20F). One (3.3%) patient achieved CC by Day 27, 12 (40%) by Day 49, another 12 (40%) by Day 58, and the remaining 5 (16.7%) by Day 69. For context, the second blue light illumination occurred on Day 29, and surgical excision was performed on Day 58 (± 7 days after the second treatment).

[0264] Almost all patients (29 / 30 [96.7%]) exhibited no changes in lesion pigmentation. One patient experienced mild hyperpigmentation 14 days after the first blue light treatment, which was resolved by the following visit 14 days later.

[0265] Erythema and flaking / scaling were the most common LSRs. Mean LSR scores for erythema and erosion / ulceration peaked on the day of each blue light treatment, one day after ALA application (Visits 3 and 6; Table 1), whereas mean LSR scores for flaking / scaling peaked within 2 weeks after each blue light treatment. LSRs steadily decreased thereafter. Mean LSR scores were higher at Visit 1 (pretreatment) than at Visit 10 (EOT).Table 1. Mean local skin reaction scores for the lesion areasVisit Erythema Flaking / Crusting Swelling Vesiculation / Erosion / _ scaling _ pustulation ulcerationVisit 1 (pre-TX) 2.1 1.0 0.1 0 0 0Visit 3 (1X1) 2.9 0.1 0 0 0 0.9Visit 4 (FUl) 2.0 1.2 0.1 0 0 0Visit 5 (pre-TX) 1.8 0.6 0 0 0 0Visit 6 (TX2) 2.9 0.1 0.1 0 0 0.8Visit 7 (FU2) 1.8 0.7 0.1 0 0 0Visit 8 (FU3) 1.6 0.1 0 0 0 0Visit 9 (FU4) 1.4 0.1 0 0 0 0Visit 10 (EOT) 1.2 0 0 0 0 0EOT, end of treatment; FU, follow-up; TX, treatment

[0266] The mean pain score recorded by patients on the VAS within 15 minutes of each ALA application and each blue light treatment was 2.71 (range, 0-9; SD, 2.27).

[0267] The treatment was well tolerated, with the majority of patients (28 / 30 [93.3%]) experiencing no adverse events (AEs). Reported AEs in 2 patients were not considered treatment related by the investigators, nor did they influence treatment administration or study outcomes.

[0268] The study described herein used ALA-PDT with blue light to treat relatively small (mean dimensions, 0.73 x 0.5 cm) isSCC lesions located on the face after a 24-hour ALA incubation period. All patients achieved CC before eventual confirmation of histologicalclearance by the end of the treatment period. The data described herein suggest that clinical and histological clearance can be achieved with a nonsurgical approach, in contrast to the current gold standard of surgical treatment for isSCC.

[0269] The study described herein demonstrated that ALA-PDT is an effective, safe, and well-tolerated treatment strategy for facial isSCC. This approach surprisingly and unexpectedly achieved 100% clinical and histological clearance with minimal AEs and excellent cosmetic outcomes, reinforcing its viability as a noninvasive alternative to traditional surgical methods. ALA-PDT offers patients a well-tolerated and effective treatment option, particularly for lesions on cosmetically sensitive areas such as the face.

[0270] Example 2. Treatment of human patients with squamous cell carcinoma in situ (isSCC)

[0271] Adult patients with histologically confirmed isSCC are enrolled in the study.Histological diagnosis of the lesions is performed within 6 months of screening. Only lesions measuring 0.4 cm to 1.3 cm in diameter are included. Patients with nodular basal cell carcinoma, superficial basal cell carcinoma, other non-SCC tumors, severe squamous metaplasia, infiltrative desmoplastic or micronodular growth patterns on biopsy, or a history of recurrence of the target isSCC are excluded. One cohort of patients is treatment-naive, whereas another cohort of patients is refractory to prior treatment.

[0272] Prior to the application of 20% ALA hydrochloric acid (HC1), lesions are gently abraded using 4 x 4 gauze and wiped with alcohol wipes. Following lesion preparation, a composition containing 20% ALA HC1 (as described herein) is applied topically to the lesion and approximately 5 mm of the surrounding area. Such compositions may consist of (a) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, edetate disodium, cyclomethicone, and purified water; or (b) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, and purified water. The treated area is then occluded with a bandage and incubated for up to 24 hours, during which patients are instructed to keep the treatment area dry and avoid direct sunlight. After the 24- hour incubation period, patients undergo PDT using blue light at an irradiance of (a) 10 mW / cm2, delivering a total fluence of 10 J / cm2for 16 minutes and 40 seconds or (b) 20mW / cm2, delivering a total fluence of 20 J / cm2for 16 minutes and 40 seconds. Each patient receives at least two ALA-PDT sessions, administered 28 (± 3) days apart.

[0273] Eight weeks after the second treatment, the lesions are surgically excised for histopathological analysis by a board-certified dermatopathologist. Lesion size and eventual complete clinical clearance (CC), defined as no clinically visible lesion at the site, are assessed by the investigator at each visit. Pigmentation changes at the lesion site (hyperpigmentation, hypopigmentation, and depigmentation) are evaluated at each visit by the investigator on a scale of 0 (none) to 3 (severe). Tolerability of the treatment is evaluated at each visit from local skin reactions (LSRs) on a scale of 0 (not present) to 4 (high severity) for erythema, flaking / scaling, crusting, swelling, vesiculation / pustulation, and erosion / ulceration. Patients also rate pain at the treatment site within 15 minutes after each ALA application and blue light illumination using a 10-cm visual analog scale (VAS) that ranged from 0 (no pain) to 10 (worst pain possible).

[0274] The primary endpoint of the study is the proportion of patients achieving complete histological clearance of isSCC at the end of treatment (EOT). The secondary endpoints are the proportion of patients with CC of the treated lesion as measured by investigator assessment and the aesthetic appearance of the treated lesion as reflected by LSR scores.

[0275] Patients are expected to achieve clinical and histological clearance with minimal adverse effects and excellent cosmetic outcomes.

[0276] Example 3. Treatment of human patients with basal cell carcinoma, cutaneous squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, or sebaceous carcinoma

[0277] Adult patients with histologically confirmed basal cell carcinoma, cutaneous squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, or sebaceous carcinoma are enrolled in the study. Histological diagnosis of the lesions is performed within 6 months of screening. Only lesions measuring 0.4 cm to 1.3 cm in diameter are included. One cohort of patients is treatment-naive, whereas another cohort of patients is refractory to prior treatment.(0278] Prior to the application of 20% ALA hydrochloric acid (HC1), lesions are gently abraded using 4 x 4 gauze and wiped with alcohol wipes. Following lesion preparation, a composition containing 20% ALA HC1 (as described herein) is applied topically to the lesion and approximately 5 mm of the surrounding area. Such compositions may consist of (a) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, edetate disodium, cyclomethicone, and purified water; or (b) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, and purified water. The treated area is then occluded with a bandage and incubated for up to 24 hours, during which patients are instructed to keep the treatment area dry and avoid direct sunlight. After the 24- hour incubation period, patients undergo PDT using blue light at an irradiance of (a) 10 mW / cm2, delivering a total fluence of 10 J / cm2for 16 minutes and 40 seconds or (b) 20 mW / cm2, delivering a total fluence of 20 J / cm2for 16 minutes and 40 seconds. Each patient receives at least 2 ALA-PDT sessions, administered 28 (± 3) days apart.[02791 Eight weeks after the second treatment, the lesions are surgically excised for histopathological analysis by a board-certified dermatopathologist. Lesion size and eventual complete clinical clearance (CC), defined as no clinically visible lesion at the site, are assessed by the investigator at each visit. Pigmentation changes at the lesion site (hyperpigmentation, hypopigmentation, and depigmentation) are evaluated at each visit by the investigator on a scale of 0 (none) to 3 (severe). Tolerability of the treatment is evaluated at each visit from local skin reactions (LSRs) on a scale of 0 (not present) to 4 (high severity) for erythema, flaking / scaling, crusting, swelling, vesiculation / pustulation, and erosion / ulceration. Patients also rate pain at the treatment site within 15 minutes after each ALA application and blue light illumination using a 10-cm visual analog scale (VAS) that ranged from 0 (no pain) to 10 (worst pain possible).

[0280] The primary endpoint of the study is the proportion of patients achieving complete histological clearance of the cancer at the end of treatment (EOT). The secondary endpoints are the proportion of patients with CC of the treated lesion as measured by investigator assessment and the aesthetic appearance of the treated lesion as reflected by LSR scores.(0281 ] Patients are expected to achieve clinical and histological clearance with minimal adverse effects and excellent cosmetic outcomes.

[0282] Example 4. Treatment of human patients with actinic cheilitis, leukoplakia, keratocanthoma, or lentigo maligna

[0283] Adult patients with histologically confirmed actinic cheilitis, leukoplakia, keratocanthoma, or lentigo maligna are enrolled in the study. Histological diagnosis of the lesions is performed within 6 months of screening. Only lesions measuring 0.4 cm to 1.3 cm in diameter are included. One cohort of patients is treatment-naive, whereas another cohort of patients is refractory to prior treatment.

[0284] Prior to the application of 20% ALA hydrochloric acid (HC1), lesions are gently abraded using 4 x 4 gauze and wiped with alcohol wipes. Following lesion preparation, a composition containing 20% ALA HC1 (as described herein) is applied topically to the lesion and approximately 5 mm of the surrounding area. Such compositions may consist of (a) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, edetate disodium, cyclomethicone, and purified water; or (b) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, and purified water. The treated area is then occluded with a bandage and incubated for up to 24 hours, during which patients are instructed to keep the treatment area dry and avoid direct sunlight. After the 24- hour incubation period, patients undergo PDT using blue light at an irradiance of (a) 10 mW / cm2, delivering a total fluence of 10 J / cm2for 16 minutes and 40 seconds or (b) 20 mW / cm2, delivering a total fluence of 20 J / cm2for 16 minutes and 40 seconds. Each patient receives at least 2 ALA-PDT sessions, administered 28 (± 3) days apart.

[0285] Eight weeks after the second treatment, the lesions are surgically excised for histopathological analysis by a board-certified dermatopathologist. Lesion size and eventual complete clinical clearance (CC), defined as no clinically visible lesion at the site, are assessed by the investigator at each visit. Pigmentation changes at the lesion site (hyperpigmentation, hypopigmentation, and depigmentation) are evaluated at each visit by the investigator on a scale of 0 (none) to 3 (severe). Tolerability of the treatment is evaluated at each visit from local skin reactions (LSRs) on a scale of 0 (not present) to 4 (high severity)for erythema, flaking / scaling, crusting, swelling, vesiculation / pustulation, and erosion / ulceration. Patients also rate pain at the treatment site within 15 minutes after each ALA application and blue light illumination using a 10-cm visual analog scale (VAS) that ranged from 0 (no pain) to 10 (worst pain possible).

[0286] The primary endpoint of the study is the proportion of patients achieving complete histological clearance of the precancerous condition at the end of treatment (EOT). The secondary endpoints are the proportion of patients with CC of the treated lesion as measured by investigator assessment and the aesthetic appearance of the treated lesion as reflected by LSR scores.

[0287] Patients are expected to achieve clinical and histological clearance with minimal adverse effects and excellent cosmetic outcomes.

[0288] Example 5. Treatment of human patients with cutaneous T-cell lymphoma, nonsmall cell lung cancer, esophageal cancer, cervical cancer, bladder cancer, Kaposi sarcoma, mucosal cancer, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia

[0289] Adult patients with histologically confirmed cutaneous T-cell lymphoma, non-small cell lung cancer, esophageal cancer, cervical cancer, bladder cancer, Kaposi sarcoma, mucosal cancer, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia are enrolled in the study. Histological diagnosis of the lesions is performed within 6 months of screening. Only lesions measuring 0.4 cm to 1.3 cm in diameter are included. One cohort of patients is treatment-naive, whereas another cohort of patients is refractory to prior treatment.

[0290] Prior to the application of 20% ALA hydrochloric acid (HC1), lesions are gently abraded as needed. Following lesion preparation, a composition containing 20% ALA HC1 (as described herein) is applied topically to the lesion and approximately 5 mm of the surrounding area. Such compositions may consist of (a) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, edetate disodium, cyclomethicone, and purified water; or (b) 20% ALA HC1, ethanol, laureth-4, polyethylene glycol, isopropyl alcohol, and purified water. The treated area is then occludedas needed and incubated for up to 24 hours. After a 24-hour incubation period, patients undergo PDT using blue light at an irradiance of (a) 10 mW / cm2, delivering a total fluence of 10 J / cm2for 16 minutes and 40 seconds or (b) 20 mW / cm2, delivering a total fluence of 20 J / cm2for 16 minutes and 40 seconds. Each patient receives at least 2 ALA-PDT sessions, administered 28 (± 3) days apart. Patients with bladder cancer may undergo concurrent BCG treatment.

[0291] Eight weeks after the second treatment, the lesions are surgically excised for histopathological analysis. Lesion size and eventual complete clinical clearance (CC), defined as no clinically visible lesion at the site, are assessed by the investigator at each visit. Pigmentation changes at the lesion site (hyperpigmentation, hypopigmentation, and depigmentation) are evaluated at each visit by the investigator on a scale of 0 (none) to 3 (severe). Tolerability of the treatment is evaluated at each visit on a scale of 0 (not present) to 4 (high severity) for erythema, flaking / scaling, crusting, swelling, vesiculation / pustulation, and erosion / ulceration. Patients also rate pain at the treatment site within 15 minutes after each ALA application and blue light illumination using a 10-cm visual analog scale (VAS) that ranged from 0 (no pain) to 10 (worst pain possible).

[0292] The primary endpoint of the study is the proportion of patients achieving complete histological clearance of the cancer or precancerous condition at the end of treatment (EOT). The secondary endpoints are the proportion of patients with CC of the treated lesion as measured by investigator assessment and the aesthetic appearance of the treated lesion as reflected by LSR scores.

[0293] Patients are expected to achieve clinical and histological clearance with minimal adverse effects and excellent cosmetic outcomes.

[0294] Certain Embodiments

[0295] Paragraph AL An illuminating panel for providing photodynamic therapy to a treatment surface, the panel comprising: a housing;a plurality of light sources coupled to the housing and disposed within a treatment array surface; and at least one air circulation unit disposed within the housing, the at least one air circulation unit disposed within the housing and configured to provide a cooling airflow to the treatment surface, wherein the at least one air circulation unit comprises: an air circulation device; and a plenum defining an air passageway toward the treatment surface; wherein the plenum comprises: a base portion configured to couple to the air circulation device; a conduit extending from the base portion, the conduit terminating at the treatment array surface, wherein a terminal end of the conduit defines an outlet for providing the cooling airflow.

[0296] Paragraph A2. The illuminating panel of Paragraph Al, wherein the conduit terminates above the plurality of light sources within the treatment array surface.

[0297] Paragraph A3. The illuminating panel of Paragraph Al, wherein the at least one air circulation unit comprises a first air circulation unit and a second air circulation unit.

[0298] Paragraph A4. The illuminating panel of Paragraph A3, wherein the outlet of the first air circulation unit is disposed within an upper portion of the panel and the outlet of the second air circulation unit is disposed within a lower portion of the panel.

[0299] Paragraph A5. The illuminating panel of Paragraph Al, wherein the plurality of light sources are light emitting diodes (LEDs).

[0300] Paragraph A6. The illuminating panel of Paragraph Al, wherein the air circulation device is a fan.

[0301] Paragraph A7. The illuminating panel of Paragraph Al, wherein the conduit forms a hook shape.

[0302] Paragraph A8. The illuminating panel of Paragraph Al, wherein the outlet is structured to have a v-shape (i.e., an inverted triangle having its apex at a relatively lowermost point).

[0303] Paragraph A9. The illuminating panel of Paragraph Al, wherein the conduit is structured such that a width of the conduit decreases from the base portion to the outlet to cause acceleration of the cooling airflow.

[0304] Paragraph A10. The illuminating panel of Paragraph Al, wherein the air circulation unit is operably coupled to a controller, the controller configured to operate the air circulation unit in a plurality of operational modes.

[0305] Paragraph Al 1. An illuminator for providing photodynamic therapy to a treatment surface, the illuminator comprising: a treatment array comprising a plurality of panels, wherein each of the plurality of panels comprises a plurality of light sources, wherein at least one panel of the plurality of panels comprises at least one air circulation unit, the at least one air circulation unit configured to provide a cooling airflow to the treatment surface; and wherein the at least one air circulation unit comprises: an air circulation device; and a plenum defining an air passageway toward the treatment surface; wherein the plenum comprises: a base portion configured to couple to the air circulation device; a conduit extending from the base portion, the conduit terminating at a surface within the one panel comprising the plurality of light sources, and wherein a terminal end of the conduit defines an outlet for providing the cooling airflow.

[0036] Paragraph A12. The illuminator of Paragraph Al l, wherein the plurality of panels comprises five panels.

[0307] Paragraph A13. The illuminator of Paragraph A12, wherein the at least one panel is a panel disposed centrally within the five panels.

[0308] Paragraph A14. The illuminator of Paragraph Al l, wherein the at least one panel further comprises at least one handle, the at least one handle structured to facilitate positioning of the treatment array.

[0309] Paragraph A15. The illuminator of Paragraph Al l, further comprising: a base; and an adjustable arm coupled to the base and the treatment array, the arm comprising: a first portion extending from the base; and a second portion coupled to the first portion, the second portion in a direction substantially perpendicular to the first portion.

[0310] Paragraph A16. The illuminator of Paragraph A15, wherein the first portion is structured to be vertically adjustable relative to the base.

[0311] Paragraph Al 7. The illuminator of Paragraph Al 5, wherein the second portion comprises a first section and a second section, the second section being structured to rotate relative to the first section.]0312[ Paragraph A18. The illuminator of Paragraph A17, wherein the second section is coupled to the treatment array at a second joint, the second joint comprising at least one of a tilting mechanism or a rotating mechanism to facilitate positioning of the treatment array relative to the treatment surface.

[0313] Paragraph A19. The illuminator of Paragraph A18, wherein at least one of the tilting mechanism or the rotating mechanism comprises a torque insert to enable locking a position of the treatment array.

[0314] Paragraph A20. The illuminator of Paragraph Al l, wherein the treatment surface is located on at least one of a patient’s head, upper extremities, lower extremities, torso, or back.

[0315] Paragraph A21. A method of treating cutaneous squamous cell carcinoma in situ comprising treatment with the illuminator according to any of the embodiments described herein.

[0316] Paragraph A22. A method of treating cutaneous squamous cell carcinoma in situ comprising delivering a dose of blue light of approximately 20 J / cm2at approximately 20 mW / cm2.

[0317] Paragraph A23. A method of treating cutaneous squamous cell carcinoma in situ, comprising:(i) applying a topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, to a cutaneous squamous cell carcinoma in situ lesion;(ii) incubating the topical composition on the lesion for approximately 18 hours to approximately 24 hours; and(iii) illuminating, with an illuminator, the lesion for an illumination period of approximately 16 minutes and 40 seconds with a dose of blue light of approximately 20 J / cm2at approximately 20 mW / cm2.

[0318] Paragraph A24. The method of Paragraph A23, wherein the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of approximately 20% w / w.

[0319] Paragraph A25. The method of Paragraph A23, wherein steps (i)-(iii) are performed in a first treatment session, and the method further comprises repeating steps (i)-(iii) in a second treatment session, the second treatment session being approximately 25 days to approximately 31 days after the first treatment session.

[0320] Paragraph Bl. A method of treating squamous cell carcinoma in situ (isSCC) according to any of the disclosed embodiments herein.

[0321] Paragraph B2. A method of treating facial squamous cell carcinoma in situ (isSCC) according to any of the disclosed embodiments herein.

[0322] Paragraph B3. A method of treating squamous cell carcinoma in situ (isSCC) according to any of the disclosed embodiments herein, the method comprising topically applying 5-aminolevulinic acid or a pharmaceutically acceptable salt thereof to a lesion;incubating the lesion for approximately 24 hours; and applying blue light to the lesion following incubation.

[0323] Paragraph B4. A method of using an illuminator for providing photodynamic therapy according to any of the disclosed embodiments herein.

[0324] Paragraph B5. A method of treating a patient according to any of the disclosed embodiments herein, the method comprising applying 5-aminolevulinic acid to the patient’s skin and applying blue light to the skin using an illuminator.

[0325] Paragraph B6: A method of reducing incubation time during photodynamic therapy according to any of the disclosed embodiments herein.

[0326] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0327] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to beunderstood that this disclosure is not limited to particular methods, illuminators, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0328] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.[0329 j Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination. Moreover, the disclosure also contemplates that in at least one embodiment, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a composition comprises components A, B and C (or A, B, and / or C), it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0330] All numerical designations, e.g., temperature, time, concentration, and weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of plus or minus 10%, or alternatively 5%, or alternatively 2.5%. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about” or “approximately.” As used herein, terms such as “about,” “approximately” and “substantially” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. Given the context in which it is used, “about,” “approximately,” “substantially” and similar terms can mean up to plus or minus 10%, or alternatively 5%, or alternatively 2.5%, of the particular value.

[0331] As used herein and in the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well as well as the singular form, unless the context clearly indicates otherwise.]0332[ Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0333] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0334] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

WHAT IS CLAIMED IS:

1. A method of treating non-melanoma skin cancer or a precancerous skin condition in a patient in need thereof, the method comprising:(i) applying to a lesion on the patient, a topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source.

2. The method of claim 1, wherein the non-melanoma skin cancer is basal cell carcinoma, cutaneous squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, or sebaceous carcinoma.

3. The method of claim 2, wherein the cutaneous squamous cell carcinoma is invasive squamous cell carcinoma (SCCI), clear-cell squamous cell carcinoma, spindle cell squamous cell carcinoma (sarcomatoid SCC), squamous cell carcinoma with single cell infiltrates, de novo squamous cell carcinoma, verrucous carcinoma, or lymphoepithelioma-like carcinoma of the skin (LELCS).

4. The method of claim 1, wherein the precancerous skin condition is actinic cheilitis, squamous cell carcinoma in situ (isSCC), leukoplakia, keratocanthoma, or lentigo maligna.

5. The method of claim 4, wherein the precancerous skin condition is isSCC.

6. The method of any one of claims 1-5, wherein the lesion is located on the head, neck, torso, arm, leg, hand, or foot.

7. The method of claim 5, wherein the isSCC is facial isSCC.

8. The method of any one of claims 1-7, further comprising occluding the lesion during the incubating step and prior to illuminating the lesion with the light source.

9. The method of claim 8, wherein occluding the lesion comprises applying a lightblocking occlusive dressing to the lesion.

10. The method of claim 8, wherein occluding the lesion comprises applying a transparent film dressing to the lesion.

11. The method of claim 8, wherein occluding the lesion comprises applying a low density polyethylene barrier to the lesion.

12. The method of any of claims 8-11, further comprising applying a secondary barrier over the lesion that is occluded, wherein the secondary barrier comprises foil or elastic material.

13. The method of any one of claims 1-12, further comprising cleaning the lesion after the incubating step and prior to the illuminating step.

14. The method of any one of claims 1-13, further comprising heating the lesion either (1) after the incubating step and before the illuminating step or (2) during the illuminating step.

15. The method of any one of claims 1-14, further comprising heating the lesion during the incubating step.

16. A method of treating cutaneous T-cell lymphoma, non-small cell lung cancer, esophageal cancer, cervical cancer, bladder cancer, mucosal cancer, Kaposi sarcoma, Barrett esophagus, cervical dysplasia, or cervical intraepithelial neoplasia in a patient in need thereof, the method comprising:(i) applying to a lesion on the patient, a topical composition comprising 5 -aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(ii) incubating the topical composition on the lesion; and(iii) illuminating the lesion with a blue light source.

17. The method of claim 16, wherein the mucosal cancer is located in the gastrointestinal tract or urogenital area.

18. The method of any one of claims 1-17, wherein the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is in a stored form of a dry solid prior to administration to the patient.

19. The method of any one of claims 1-18, wherein the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of about 1% w / w to about 30% w / w.

20. The method of claim 19, wherein the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of about 20% w / w.

21. The method of any one of claims 1-20, wherein the at least one pharmaceutically acceptable excipient comprises at least one selected from a group consisting of a penetration enhancer and a chelating agent.

22. The method of claim 21, wherein the penetration enhancer is selected from a group consisting of dialkyl derivatives of acetamide and formamide, pyrrolidone derivatives, fatty acids, glycol derivatives, glycerides, azones, polysorbates, macrogolglycerides, polyethylene glycol derivatives, ethoxylated ether derivatives, bile salts, and sulfated glycosaminoglycan, or a combination of any two or more thereof.

23. The method of claim 21, wherein the penetration enhancer is selected from a group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol.

24. The method of any one of claims 21-23, wherein the penetration enhancer is present in the topical composition in an amount of about 2% w / w to about 50% w / w.

25. The method of any one of claims 21-24, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 21-25, wherein the chelating agent is present in the topical composition in an amount of about 0.1% w / w about to 0.25% w / w.

27. The method of any one of claims 21-26, wherein the at least one pharmaceutically acceptable excipient further comprises an anti-foaming agent.

28. The method of claim 27, wherein the anti-foaming agent is cyclomethicone.

29. The method of any one of claims 1-28, wherein the incubating step is performed for a period of about 15 minutes to about 24 hours.

30. The method of any one of claims 1-29, wherein the blue light source delivers blue light at about 10 J / cm2.

31. The method of any one of claims 1-30, wherein the blue light source delivers blue light at an irradiance density of approximately 10 mW / cm2.

32. The method of any one of claims 1-29, wherein the blue light source delivers blue light at about 20 J / cm2.

33. The method of any one of claims 1-29 or claim 32, wherein the blue light source delivers blue light at an irradiance density of approximately 20 mW / cm2.

34. The method of any one of claims 1-33, further comprising applying an optical clarifying agent to the lesion prior to the illuminating step.

35. The method of claim 34, wherein the optical clarifying agent is a skin moisturizer.

36. The method of any one of claims 1-35, further comprising evaluating a sample of the lesion in a cell-based test prior to applying the topical composition.

37. The method of claim 36, wherein the cell-based test is a histopathology test.

38. The method of any one of claims 1-37, wherein the patient has previously been treated for the cancer or precancerous condition.

39. The method of claim 38, wherein the patient is refractory to previous treatment.

40. The method of any one of claims 1-37, wherein the patient has not been previously treated with other therapy for the cancer or precancerous condition.

41. The method of any one of claims 1-40, wherein the blue light source is an illuminating panel for providing photodynamic therapy to a treatment surface, the panel comprising:a housing; a plurality of light sources coupled to the housing arranged in an array; and at least one air circulator disposed within the housing, the at least one air circulator disposed within the housing and configured to provide a cooling airflow to the treatment surface, wherein the at least one air circulator comprises: an air circulation device; and a plenum defining an air passageway toward the treatment surface; wherein the plenum comprises: a base portion configured to couple to the air circulation device; a conduit extending from the base portion, the conduit terminating at the treatment array surface, wherein a terminal end of the conduit defines an outlet for providing the cooling airflow.

42. The method of claim 41, wherein the conduit terminates above the plurality of light sources within the treatment array surface.

43. The method of claim 41, wherein the at least one air circulator comprises a first air circulator and a second air circulator.

44. The method of claim 43, wherein the outlet of the first air circulator is disposed within an upper portion of the panel and the outlet of the second air circulator is disposed within a lower portion of the panel.

45. The method of claim 41, wherein the plurality of light sources are light emitting diodes (LEDs).

46. The method of claim 41, wherein the air circulation device is a fan.

47. The method of claim 41, wherein the conduit forms a hook shape.

48. The method of claim 41, wherein the outlet is structured to have a v-shape.

49. The method of claim 41, wherein the conduit is structured such that a width of the conduit decreases from the base portion to the outlet to cause acceleration of the cooling airflow.

50. The method of claim 41, wherein the air circulator is operably coupled to a controller, the controller configured to operate the air circulator in a plurality of operational modes.

51. The method of any one of claims 1-40, wherein the blue light source is an illuminator for providing photodynamic therapy to a treatment surface, the illuminator comprising: a treatment array comprising a plurality of panels, wherein each of the plurality of panels comprises a plurality of light sources; and wherein at least one panel of the plurality of panels comprises at least one air circulator, the at least one air circulator configured to provide a cooling airflow to the treatment surface; and wherein the at least one air circulator comprises: an air circulation device; and a plenum defining an air passageway toward the treatment surface; wherein the plenum comprises: a base portion configured to couple to the air circulation device; a conduit extending from the base portion, the conduit terminating at a surface within the one panel comprising the plurality of light sources, and wherein a terminal end of the conduit defines an outlet for providing the cooling airflow.

52. The method of claim 51, wherein the plurality of panels comprises five panels.

53. The method of claim 52, wherein the at least one panel is a panel disposed centrally within the five panels.

54. The method of claim 51, wherein the at least one panel further comprises at least one handle, the at least one handle structured to facilitate positioning of the treatment array.

55. The method of claim 51, wherein the illuminator further comprises: a base; and an adjustable arm coupled to the base and the treatment array, the arm comprising: a first portion extending from the base; and a second portion coupled to the first portion, the second portion in a direction substantially perpendicular to the first portion.

56. The method of claim 55, wherein the first portion is structured to be vertically adjustable relative to the base.

57. The method of claim 55, wherein the second portion comprises a first section and a second section, the second section being structured to rotate relative to the first section.

58. The method of claim 55, wherein the second section is coupled to the treatment array at a second joint, the second joint comprising at least one of a tilting mechanism or a rotating mechanism to facilitate positioning of the treatment array relative to the treatment surface.

59. The method of claim 58, wherein at least one of the tilting mechanism or the rotating mechanism comprises a torque insert to enable locking a position of the treatment array.

60. The method of claim 51, wherein the treatment surface is located on at least one of a patient’s head, upper extremities, lower extremities, torso, or back.

61. The method of any one of claims 1-60, wherein 5-aminolevulinic acid is the sole active agent administered to the patient.

62. A method of treating cutaneous squamous cell carcinoma in situ comprising delivering a dose of blue light of approximately 20 J / cm2at approximately 20 mW / cm2.

63. A method of treating cutaneous squamous cell carcinoma in situ, comprising:(i) applying a topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, to a cutaneous squamous cell carcinoma in situ lesion;(ii) incubating the topical composition on the lesion for approximately 18 hours to approximately 24 hours; and(iii) illuminating, with an illuminator, the lesion for an illumination period of approximately 16 minutes and 40 seconds with a dose of blue light of approximately 20 J / cm2at approximately 20 mW / cm2.

64. The method of claim 63, wherein the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is present in the topical composition in an amount of approximately 20% w / w.

65. The method of claim 63, wherein steps (i)-(iii) are performed in a first treatment session, and the method further comprises repeating steps (i)-(iii) in a second treatment session, the second treatment session being approximately 25 days to approximately 31 days after the first treatment session.

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