Photodynamic therapy in combination with an hedgehog pathway inhibitor for use in treating non-melanoma skin cancer

Abstract

A method of treating non-melanoma skin cancer in a patient in need thereof is provided. The method includes administering a hedgehog pathway inhibitor to the patient and applying to a region of skin on the patient, a topical composition comprising 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The method further includes incubating the topical composition on the region of skin; and illuminating the region of skin with a light source at an irradiance density of 20 mW / cm2.

Description

PHOTODYNAMIC THERAPY IN COMBINATION WITH AN HEDGEHOG PATHWAY INHIBITOR FOR USE IN TREATING NON-MELANOMA SKIN CANCERCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 579,195, filed August 28, 2023, the entire contents of which are incorporated herein by reference.FIELD

[0002] The present disclosure relates generally to methods of treating non-melanoma skin cancer.BACKGROUND

[0003] Non-melanoma skin cancer (NMSC) refers to a group of cancers that develop in the upper layers of the skin and includes all types of skin cancers that are not melanoma, including keratinocyte carcinomas. Two common types of non-melanoma skin cancer are basal cell carcinoma and squamous cell carcinoma. Basal cell carcinoma accounts for about 75% of skin cancers, whereas squamous cell carcinoma accounts for about 25% of skin cancers.

[0004] Photodynamic therapy (PDT), photodynamic diagnosis (PD), or photochemotherapy is generally used to treat and / or diagnose several types of ailments in or near the skin or other tissues, such as those in a body cavity. For example, photodynamic therapy or photodynamic diagnosis may be used for treatment or diagnosis of actinic keratosis of the upper extremities (e.g., the dorsal surface of the hand or forearms), scalp or facial areas of a patient. In addition, such techniques may be used for treatment and diagnosis of other indications (e.g., acne, warts, psoriasis, photo-damaged skin, cancer) and other areas of the patient (e.g., the legs or portions of the arms other than the forearms).

[0005] During one form of photodynamic therapy, a patient is first administered a photoactivatable agent or a precursor of a photoactivatable agent that accumulates in the tissue tobe treated. 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 at most only mild and reversible alteration or damage to other tissues in the treatment area. One example of a precursor of a photoactivatable agent is 5-aminolevulinic acid, a 5- aminoketone compound of Formula I below:(Formula 1)

[0006] 5-aminolevulinic acid is commonly used in photodynamic therapy of actinic keratosis, among other conditions. Photosensitization, following application of a topical composition (e.g., a topical solution or emulsion or nanoemulsion) containing 5-aminolevulinic acid, occurs through the metabolic conversion of aminolevulinic acid to protoporphyrin IX (PpIX). PpIX is a photosensitizer which accumulates in the skin. 5-aminolevulinic acid, which is formed from succinyl CoA and glycine in the first step of heme synthesis, is to a limited extent able to penetrate the skin and lead to a localized build-up of PpIX; since the action of ferrochelatase (the metallating enzyme) is the rate limiting step in heme synthesis, an excess of 5-aminolevulinic acid leads to accumulation of PpIX, the photosensitizing agent. When exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a photodynamic reaction, resulting in a cytotoxic process dependent upon the simultaneous presence of oxygen. The absorption of light results in an excited state of porphyrin molecules, and subsequent spin transfer from photoreactive porphyrins to molecular oxygen generates singlet oxygen, which can further react to form superoxide and hydroxyl radicals. In the case where 5-aminolevulinic acid is used to treat actinic keratosis, since the skin bearing actinic keratitis lesions is more readily penetrated by 5-aminolevulinic acid than healthy skin, these changes allow the PpIX to then selectively locate, destroy, or alter the target tissue while, at thesame time, causing at most only mild and reversible damage to other tissues in the treatment area.

[0007] There is a need in the art for improved methods to treat non-melanoma skin cancer. The present disclosure satisfies this need.SUMMARY

[0008] Provided herein in one aspect is a method of treating non-melanoma skin cancer in a patient in need thereof, the method comprising administering a hedgehog pathway inhibitor to the patient; applying to a region of skin on the patient, a topical composition comprising 5- aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; incubating the topical composition on the region of skin; and illuminating the region of skin with a light source at an irradiance density of approximately 20 mW / cm2.

[0009] In some embodiments, the non-melanoma skin cancer is basal cell carcinoma or squamous cell carcinoma.

[0010] In some embodiments, 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.

[0011] In some embodiments, 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.

[0012] In some 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.

[0013] In some embodiments, the at least one pharmaceutically acceptable excipient comprises at least one selected from a group consisting of a penetration enhancer and a chelating agent.

[0014] In some embodiments, 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.

[0015] In some embodiments, the penetration enhancer is selected from a group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol.

[0016] In some embodiments, the penetration enhancer is present in the topical composition in an amount of about 2% w / w to about 50% w / w.

[0017] In some embodiments, the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

[0018] 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.

[0019] In some embodiments, the at least one pharmaceutically acceptable excipient further comprises an anti-foaming agent.

[0020] In some embodiments, the anti-foaming agent is cyclomethicone.

[0021] In some embodiments, the incubating step is performed for a period of about 15 minutes to about 10 hours.

[0022] In some embodiments, the method further comprises occluding the region of skin during the incubating step and prior to illuminating the region of skin with the light source.

[0023] In some embodiments, occluding the region comprises applying a light-blocking occlusive dressing to the region.

[0024] In some embodiments, occluding the region comprises applying a transparent film dressing to the region.

[0025] In some embodiments, occluding the region comprises applying a low density polyethylene barrier to the lesion.

[0026] In some embodiments, the method further comprises applying a secondary barrier over the region that is occluded, wherein the secondary barrier comprises foil or elastic material.

[0027] In some embodiments, the method further comprises cleaning the region of skin after the incubating step and prior to the illuminating step.

[0028] In some embodiments, the method further comprises heating the region of skin either (1) after the incubating step and before the illuminating step or (2) during the illuminating step.

[0029] In some embodiments, the method further comprises heating the region of skin during the incubating step.

[0030] In some embodiments, the light source delivers blue light.

[0031] In some embodiments, the light source delivers red light.

[0032] In some embodiments, the blue light is delivered at about 20 J / cm2.

[0033] In some embodiments, the hedgehog pathway inhibitor is sonidegib or vismodegib.

[0034] In some embodiments, the hedgehog pathway inhibitor is daily administered for about 6 weeks to 8 weeks prior to applying the topical composition.

[0035] In some embodiments, the hedgehog pathway inhibitor is daily administered for about 3 months to about 6 months prior to applying the topical composition.

[0036] In some embodiments, the hedgehog pathway inhibitor is daily administered until one or more side effects symptoms appear in the patient and prior to applying the topical composition.

[0037] In some embodiments, the one or more side effect symptoms comprise hair loss, change in taste, tiredness, nausea, diarrhea, weight loss, decreased appetite, vomiting, abdominal pain, itching, and headache.

[0038] In some embodiments, the method further comprises applying an optical clarifying agent to the region of skin prior to the illuminating step.

[0039] In some embodiments, the optical clarifying agent is a skin moisturizer.

[0040] In some embodiments, steps (ii)-(iv) are repeated about every 4 to about every 6 weeks.

[0041] In some embodiments, steps (ii)-(iv) are repeated about every 4 weeks to about every 6 weeks until side effect symptoms from step (i) subside from the patient.

[0042] In some embodiments, the method is repeated continuously.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Features, aspects, and advantages of the present disclosure will become apparent from the following description and the accompanying exemplary embodiments shown in the drawings, which are briefly described below.

[0044] FIGS. 1A-1B show top views of a main body of an illuminator according to an exemplary embodiment.

[0045] FIGS. 2A-2B show perspective views of the main body of the illuminator of FIGS. 1A- 1B.

[0046] FIGS. 3A-3B show detailed views of the hinges of the main body of the illuminator ofFIGS. 1A-1B.

[0047] FIG. 4 shows a perspective view of the illuminator having the main body of FIGS. 1A- 1B mounted to a stand.

[0048] FIG. 5 shows a schematic view illustrating an addressable configuration of LEDs mounted on the main body of the illuminator of FIGS. 1 A-1B.

[0049] FIG. 6 shows a schematic view illustrating widths and lengths of individual panels of the main body of the illuminator of FIGS. 1 A-1B.

[0050] FIGS. 7A and 7B illustrate an illuminator according to an embodiment.

[0051] FIG. 7C illustrates an illuminator according to an embodiment.

[0052] FIG. 7D illustrates an illuminator according to an embodiment, in which heat is emitted to a control volume, e.g., a cubic volume.

[0053] FIG. 7E depicts a control volume according to an embodiment.

[0054] FIG. 7F is a perspective view showing a configuration according to an embodiment.

[0055] FIG. 8 shows a front view of an illuminator system according to an exemplary embodiment.

[0056] FIG. 9 shows a top perspective view of the illuminator system of FIG. 8.

[0057] FIG. 10 shows a front perspective view of the illuminator system of FIG. 8.

[0058] FIG. 11 shows a rear view of the illuminator system of FIG. 8.

[0059] FIG. 12 shows a front perspective view of the illuminator system of FIG. 8.

[0060] FIG. 13 shows a top perspective view of a mounting mechanism of the illuminator system of FIG. 8.

[0061] FIG. 14 shows a side perspective view of a panel of the illuminator system of FIG. 8.

[0062] FIG. 15A shows a side view of an illuminator of the illuminator system of FIG. 8.

[0063] FIG. 15B shows a side view of an illuminator of the illuminator system of FIG. 8.

[0064] FIG. 16 shows a back view of an illuminator of the illuminator system of FIG. 8.

[0065] FIG. 17 shows a back view of an illuminator of the illuminator system of FIG. 8.

[0066] FIG. 18 shows a front view of the illuminator system of FIG. 8 in a stored position.

[0067] FIG. 19 shows a perspective view of the illuminator system of FIG. 8 in a stored position.

[0068] FIG. 20 shows a top view of a panel of the illuminator system of FIG. 8.

[0069] FIG. 21 shows a front view of an interface panel of the illuminator system of FIG. 8.

[0070] FIG. 22 shows a front view of a main power switch of the illuminator system of FIG. 8.

[0071] FIG. 23 shows a front view of a vertical column lock of the illuminator system of FIG.8.

[0072] FIG. 24 shows a front view of an arm lock of the illuminator system of FIG. 8.

[0073] FIG. 25 shows a cross-sectional side view of a panel of the illuminator system of FIG.8.

[0074] FIG. 26 shows a perspective view of a fan plenum of a panel of the illuminator system of FIG. S ►

[0075] FIG. 27 shows a detailed cross-sectional view of a fan plenum of the illuminator system of FIG. S

[0076] FIG. 28 shows a detailed cross-sectional view of a fan plenum of the illuminator system of FIG. 8.

[0077] FIG. 29 shows a detailed cross-sectional view of a fan plenum of the illuminator system of FIG. 8.

[0078] FIG. 30 shows a touch screen of the illuminator system of FIG. 8.

[0079] FIG. 31 shows a schematic diagram of a controller of the illuminator system of FIG. 8.DETAILED DESCRIPTION

[0080] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s).

[0081] The use of the terms “a” and “an” and “the” and similar references in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0082] Provided herein is a method to treat non-melanoma skin cancer in a patient in need thereof, the method comprising undergoing a first treatment regimen wherein a hedgehogpathway inhibitor is daily administered to the patient for a period of about 6 to about 8 weeks, or until one or more side effect symptoms appear; and subsequently undergoing a second treatment regimen, wherein the patient undergoes photodynamic therapy.

[0083] More particularly, in one aspect, presented herein is a method of treating non-melanoma skin cancer in a patient in need thereof, the method comprising:(i) administering a hedgehog pathway inhibitor to the patient;(ii) applying to a region of skin on the patient, a topical composition comprising 5- aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(iii) incubating the topical composition on the region of skin; and(iv) illuminating the region of skin with a light source at an irradiance density of 20 mW / cm2.

[0084] In some embodiments, the non-melanoma skin cancer is basal cell carcinoma or squamous cell carcinoma. In some embodiments, the non-melanoma skin cancer is basal cell carcinoma. In some embodiments, the non-melanoma skin cancer is squamous cell carcinoma. In some embodiments, the non-melanoma skin cancer is squamous cell carcinoma in situ. In some embodiments, the patient is diagnosed with or is suffering from xeroderma pigmentosum.Hedgehog Pathway Inhibitor

[0085] As used herein, a hedgehog pathway inhibitor is administered to a patient only after the patient’s bone plates have fused, which may be confirmed by x-ray. In some embodiments, the patient is about 14 to about 16 years old, or older. In some embodiments, the patient is an adult (i.e., at least 18 years old).

[0086] In some embodiments, the hedgehog pathway inhibitor is selected from a group consisting of sonidegib, vismodegib, glasdegib, taladegib, saridegib, and BMS-833923. In some embodiments, the hedgehog pathway inhibitor is sonidegib or vismodegib. In someembodiments, the hedgehog pathway inhibitor is sonidegib. In some embodiments, the hedgehog pathway inhibitor is vismodegib.

[0087] Sonidegib (available as 0D0MZ0®, Sun Pharmaceutical Industries Ltd., Mumbai, India) may be administered orally to the patient. In some embodiments, about 200 mg of sonidegib is administered daily to the patient.

[0088] Vismodegib (available as Erivedge®, Genentech, Inc., South San Francisco, CA) may be administered orally to the patient. In some embodiments, about 150 mg of vismodegib is administered daily to the patient.

[0089] In some embodiments, the hedgehog pathway inhibitor is daily administered for about 6 weeks to about 8 weeks prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 6 weeks prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 7 weeks prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 8 weeks prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 3 months to about 6 months prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 3 months prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 4 months prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 5 months prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered for about 6 months prior to applying the topical composition. In some embodiments, the hedgehog pathway inhibitor is daily administered until one or more side effect symptoms appear and prior to applying the topical composition. In some embodiments, the one or more side effect symptoms comprise hair loss, change in taste, tiredness, nausea, diarrhea, weight loss, decreased appetite, vomiting, abdominal pain, itching, and headache.Topical Compositions with 5-Aminolevulinic Acid

[0090] In some embodiments, 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 70% w / w. This includes an amount of about 1%, 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%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% w / w, or any value therebetween. In some embodiments, 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 some 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.

[0091] In some embodiments, 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 some embodiments, 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 some embodiments, 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 were provided 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 some embodiments, 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.

[0092] About 78 mg to 708 mg of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, is administered to the patient prior to the incubating and illuminating steps. 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 of 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, or any value therebetween.

[0093] In some embodiments, 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 some embodiments, the at least one pharmaceutically acceptable excipient comprises a penetration enhancer. In some embodiments, the at least one pharmaceutically acceptable excipient comprises a chelating agent. In some embodiments, the at least one pharmaceutically acceptable excipient comprises a penetration enhancer and a chelating agent.

[0094] 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 some embodiments, 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).

[0095] In some embodiments, 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 some embodiments, 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.

[0096] In some embodiments, 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, dipotassium 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 some embodiments, the chelating agent is disodium edetate.

[0097] In some embodiments, 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 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.

[0098] In some embodiments, the at least one pharmaceutically acceptable excipient further comprises an anti-foaming agent. In some embodiments, 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 some embodiments, the antifoaming agent is present in the topical composition in an amount of about 0.5% w / w.

[0099] 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 bymixing of permeation enhancer (if present), chelating agent (if present), anti-foaming 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 antifoaming 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.

[0100] In some embodiments, 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.

[0101] In some embodiments, 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 the region of skin 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 saltthereof, 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.

[0102] 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 about 5 mm or less than about 5 mm, e.g., about 2 to about 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.

[0103] In some embodiments, the 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 some embodiments, 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 some embodiments, 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 some embodiments, about one gram (100 mg) of 5-aminolevulinic acid hydrochloride gel is administered (equivalent to 78 mg of aminolevulinic acid). In some embodiments, about two grams (200 mg) of 5-aminolevulinic acid hydrochloride gel is administered (equivalent to 156 mg of aminolevulinic acid). In some embodiments, about three gram (300 mg) of 5-aminolevulinic acid hydrochloride gel is administered (equivalent to 234 mg of aminolevulinic acid). In some embodiments, about six grams (600 mg) of 5-aminolevulinic acid hydrochloride gel is administered (equivalent to 468 mg of aminolevulinic acid).

[0104] In some embodiments, 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 or consists of:(i) at least one penetration enhancer, and(ii) at least one chelating agent.

[0105] In some embodiments, 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 or consists of:(i) at least one penetration enhancer,(ii) at least one chelating agent, and(iii) optionally, an antifoaming agent.

[0106] In some embodiments, 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 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.

[0107] In some embodiments, 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.

[0108] In some embodiments, 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 or consists of:(i) propylene glycol,(ii) EDTA and pharmaceutically acceptable salts, and(iii) optionally, an antifoaming agent.

[0109] In some embodiments, 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 or consists of:(i) propylene glycol,(ii) 2-(2-ethoxyethoxy)ethanol, and(iii) disodium edetate, and(iv) optionally, an antifoaming agent.

[0110] In some embodiments, 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 or consists of:(i) propylene glycol in an amount in the range of about 10% w / w to about 50 % w / w,(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.

[0111] In some embodiments, the topical composition comprises, consists essentially of, or consists of: a) 5-aminolevulinic acid, or a pharmaceutically acceptable salt thereof, b) propylene glycol, c) 2-(2-ethoxyethoxy)ethanol, and d) disodium edetate.

[0112] In some embodiments, 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.

[0113] In some embodiments, 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.

[0114] In some embodiments, 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 disodium, i) cyclomethicone, and j) purified water.

[0115] In some embodiments, 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 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(ix) purified water.

[0116] In some embodiments, 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, andj) purified water.

[0117] In some embodiments, 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 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.

[0118] In some embodiments, the composition containing 5-aminolevulinic acid is a composition disclosed in U.S. Patent Application Serial No. 17 / 968,931 filed October 19, 2022 or U.S. Provisional Patent Application Serial No. 63 / 422,877 which are incorporated by reference herein in their entireties for the compositions, compounds and formulae disclosed therein.Methods of Treatment

[0119] The region of skin on the patient may be located anywhere on the patient, including upper extremities (e.g., the dorsal surface of the hands, upper arms or forearms), neck, scalp or facial areas (e.g., nose, forehead, cheeks, tongue) and other areas of the patient (e.g., the genital region or the legs or feet, or portions of the arms other than the forearms).

[0120] In some embodiments, the incubating step is performed for a period of about 15 minutes to about 10 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, or 10 hours, or any value therebetween.

[0121] In some embodiments, the method further comprises occluding the region of skin during the incubating step and prior to illuminating the region of skin with the light source. In some embodiments, occluding the region comprises applying a light-blocking occlusive dressing or a moisture protecting occlusion dressing to the region. In some embodiments, occluding the region comprises applying a light-blocking occlusive dressing. In some embodiments, occluding the region comprises applying a moisture protecting occlusion dressing to the region. In some embodiments, the light-blocking occlusive dressing can be opaque or transparent. In particular, in some embodiments, occluding the region comprises applying a transparent film dressing to the region. A non-limiting example of a transparent film dressing is a low-density polyethylene barrier. Accordingly, in some embodiments, occluding the region 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 some embodiments, the method further comprises applying a secondary barrier over the region that is occluded, wherein the secondary barrier comprises foil or elastic material.

[0122] In some embodiments, the method further comprises cleaning the region of skin after the incubating step and prior to the illuminating step.

[0123] In some embodiments, the method further comprises heating the region of skin either (1) after the incubating step and before the illuminating step or (2) during the illuminating step. In some embodiments, the method further comprises heating the region of skin after the incubating step and before the illuminating step. In some embodiments, the method further comprises heating the region of skin during the illuminating step. In some embodiments, the method further comprises heating the region of skin during the incubating step. In some embodiments, the method comprises heating the region of skin after the incubating step and before the illuminating step and further heating during the illuminating step.

[0124] In some embodiments, the skin is heated to a surface temperature of greater than about 37 °C. In some embodiments, the skin is heated to a surface temperature of greater than about 40 °C.

[0125] A heating element may be used as a heat source for heating the region of skin. In some embodiments, 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 region of skin to which 5-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 some embodiments, increasing the temperature of tissue by approximately 2 °C approximately doubles the rate of production of protoporphyrin IX (PpIX).

[0126] In a non-limiting example, the 5-aminolevulinic acid, or the pharmaceutically acceptable salt thereof, is applied to a region of skin on the patient. Next, the heating element is activated to apply heat to the patient's skin at the region of skin for a first treatment period for a thermal soak, which may be about 20 to about 30 minutes, for example. During the heating, the region of skin may or may not be occluded. In other words, the region of skin may be heated while being occluded. Following the first treatment period, light may be applied for a secondtreatment period, e.g., about 8 to about 15 minutes. In some embodiments, total thermal soak, corresponding to exposure to heat, may be from about 1 minute to about 90 minutes.

[0127] In some embodiments, the heat source is an infrared quartz heater. In some embodiments, 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.

[0128] In some embodiments, 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.

[0129] In some embodiments, the illuminator may be provided with a fan or other air distributor which provides a gentle flow of air (e.g., a laminar or other generally even flow) tangential to the skin surface, which may reduce sensation of pain.

[0130] In some embodiments, the method further comprises applying an optical clarifying agent to the region of skin prior to the illuminating step. Non-limiting examples of optical clarifying agents include skin moisturizers, e.g., moisturizers containing EDTA.

[0131] In some embodiments, steps (ii)-(iv) are repeated about every 4 to about every 6 weeks. In some embodiments, steps (ii)-(iv) are repeated about every 4 weeks. In some embodiments, steps (ii)-(iv) are repeated about every 5 weeks. In some embodiments, steps (ii)-(iv) are repeated about every 6 weeks. In some embodiments, steps (ii)-(iv) are repeated about every 4 to about every 6 weeks until side effect symptoms from step (i) subside from the patient. Steps (ii)-(iv) may be repeated 1, 2, 3, 4, or 5 times or more. In some embodiments, after steps (ii)-(iv) have been repeated, step (i) is repeated 1 time before steps (ii)-(iv) are repeated 1, 2, 3, 4, or 5 times or more. In some embodiments, after steps (ii)-(iv) have been repeated, step (i) is repeated 90 to 180 times (e.g., daily administration for about 3 months to about 6 months) before steps (ii)-(iv) are repeated 1, 2, 3, 4, or 5 times or more. In some embodiments, after steps (ii)-(iv) have been repeated, step (i) is repeated daily until one or more side effect symptoms appear in the patient and before steps (ii)-(iv) are repeated until the one or more side effect symptoms have subsided. In some embodiments, the method of treatment is repeated continuously. In some embodiments, the method of treatment is repeated for about 12 months to about 24 months, about 12 months to about 36 months, about 12 months to about 48 months, or about 12 months to about 60 months, or more. This includes about 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, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 months, and any value therebetween.Light Sources

[0132] The light source may be lasers, dye lasers pumped by argon or metal vapor lasers and frequency-doubled Nd:YAG lasers. The light source may be a non- laser source such as, but not limited to, tungsten filament, xenon arc, metal halide and fluorescent lamps halogen bulbs, LED light delivery, or direct sunlight.

[0133] In some embodiments, the light source has a power output that is uniform in intensity and color. Illuminators, such as those disclosed in U.S. Patent Nos. 10,589,122, 8,758,418; 8,216,289; 8,030,836; 7,723,910; 7,190,109; 6,709,446; and 6,223,071 and U.S. Published Patent Application No. 2023 / 0145771, and U.S. Provisional Application No. 63 / 643,794 filed May 7, 2024, which are incorporated by reference in their entireties for the techniques, methods, compositions, and devices related to PDT and PD, and particularly the illuminator constructions therein, are typically used to provide the proper uniformity of light for treatment purposes. These devices generally include a light source (e.g., a fluorescent tube, LED or LED array), coupling elements that direct, filter or otherwise conduct emitted light so that it arrives at itsintended target in a usable form, and a control system that starts and stops the production of light when necessary. In some embodiments, the light source includes a plurality of LEDs, e.g., in an array.

[0134] In some embodiments, the light source delivers blue light. The blue light may be at wavelengths at or above 400 nanometers (nm), for example, about 430 nm, about 420 nm or, for example, 417 nm. However, the LED may 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 LED may also emit light having wavelengths of 510 nm, 540 nm, 575 nm, 630 nm, or 635 nm. In addition, the LED may be configured to emit light continuously or the LED may be configured to flash the diodes on and off based on a predetermined interval. Furthermore, the LED may be configured such that only one wavelength of light (e.g., blue) is emitted. Alternatively, the LED may be configured such that two or more wavelengths of light are emitted from the arrays. For example, the LED may be configured to alternately emit blue light and red light for treatment purposes. In some embodiments, the LED arrays may also emit red light having wavelengths of 570 to 670 nm.

[0135] Since 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 the correct 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 some embodiments, blue light is delivered at a dose of about 20 J / cm2. In some embodiments, blue light is applied at an intensity of 20 mW / cm2for 1000 seconds to provide a dose of about 20 J / cm2.Exemplary Illuminators

[0136] FIGS. 1A-1B and 2A-2B illustrate an embodiment of a configurable illuminator according to the present disclosure. The illuminator includes a main body 100, which preferablyhas five individual panels 10a- lOe, each of which are connected in a rotatable manner via nested hinges 50. Each panel contains an array of light emitting diodes (LED) 60, which may be configured in an evenly spaced pattern across the face of the panel. The number of individual LEDs arranged in a given array is not particularly limited. Alternatively, other types of light sources may be used, such as fluorescent or halogen lamps.

[0137] Preferably, each LED array 60 extends as far to the edges as possible. In addition, the LED arrays 60 are preferably dimensioned to provide an overall lighted area for a given treatment area based on a range from the 5th percentile of corresponding sizes of female subjects to the 95th percentile of corresponding sizes of male subjects for that particular treatment area. The LED arrays 60 emit light at an appropriate wavelength according to the intended treatment or to activate the particular photoactivatable agent used in treatment or diagnosis. For example, when ALA is used as a precursor of a photoactivatable agent for the treatment of actinic keratosis, the LED arrays 60 preferably emit blue light having wavelengths at or above 400 nanometers (nm), for example, about 430 nm, about 420 nm or, for example, 417 nm. However, the LED arrays 60 may 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 LED arrays 60 may also emit light having wavelengths of 510 nm, 540 nm, 575 nm, 630 nm, or 635 nm. In addition, the LED arrays 60 may be configured to emit light continuously or the LED arrays 60 may be configured to flash the diodes on and off based on a predetermined interval. Furthermore, the LED arrays 60 may be configured such that only one wavelength of light (e.g., blue) is emitted. Alternatively, the LED arrays 60 may be configured such that two or more wavelengths of light are emitted from the arrays. For example, the LED arrays 60 may be configured to alternately emit blue light and red light for treatment purposes.

[0138] As shown in FIGS. 1A-1B and 2A-2B, the five panels 10a- lOe can include panels of different widths relative to one another. In particular, in certain embodiments, three panels 10a, 10c, lOe are configured to have wider widths, while two panels 10b, lOd have smaller, narrower widths, each of the narrower widths of the two panels 10b, lOd being less than each of the widerwidths of the three panels 10a, 10c, lOe. In some embodiments, the wider widths of the three larger panels 10a, 10c, lOe are approximately equal. In other embodiments, the wider widths of the three larger panels 10a, 10c, lOe are different relative to one another. In addition, the narrower widths of the two panels 10b, lOd may be approximately equal or may be different relative to one another. The panels are further arranged in an alternating configuration, with the narrower panels (e.g., 10b) positioned in between two wider panels (e.g., 10a, 10c). As shown in FIG. 6, in some embodiments, the narrower panels 10b, lOd are configured to have a width that is about 30% to 60% less than the width of the wider panels 10a, 10c, lOe. In other embodiments, the narrower panels 10b, lOd are configured to have a width that is about 30% to 50% less than the width of the wider panels 10a, 10c, lOe.

[0139] As shown in FIGS. 1A-1B and 2A-2B, the panels 10a- lOe are rotatably connected by hinges 50. The hinges 50 may take the form of nested hinges, which may include hinges that substantially reduce or eliminate optical dead spaces. As shown in FIGS. 2A-2B, on at least one side of a panel, a tab 23 may extend out from both the top and bottom of the panel. The tabs 23 are configured such that a side of an adjacent panel may be received between the tabs 23, as shown in FIG. 2A. Thus, as seen in FIGS. 2A-2B and 6, the height of the adjacent panel (e.g., panel 10a) is slightly smaller than the height of the tabbed panel (e.g., panel 10b) into which the adjacent panel is received. As shown in FIG. 6, the middle panel (i.e., panel 10c) is preferably configured as having the largest height, such that it is tabbed on both sides and may receive the sides of adjacent panels on each side. As seen in FIGS. 1A-1B, each of the tabs 23 further includes an opening to receive a bolt to connect adjacent panels together.

[0140] The panels 10a- lOe may be arranged such that side panels can move so as to expand a total footprint or coverage area of the panels 10a- lOe, and may be configured to extend to portions of a patient such as the patient’s chest or stomach. In at least one embodiment, at least one of the panels 10a- lOe may be arranged such that at least one of the panels is provided in a flat or folded (bent or angled, for example) arrangement. The panels may be moved in a continuously variable manner. In at least one embodiment, one or more of the panels is provided with one or more detent mechanisms to retain the one or more panels in a desired position. Theone or more detent mechanisms may be provided with the one or more panels such that the movement of the panels is restrained by the detent mechanisms to achieve a plurality of distinct panel configurations for treatment, in which the panels are kept in a specific position while a patient is being treated. The panels may be arranged relative to each other so as to achieve one or more particular configurations of the illuminator. In at least one embodiment, the panels may be arranged relative to each other such that the illuminator achieves at least one of a curved, flat or folded configuration, for example.

[0141] As shown in further detail in FIGS. 3A-3B, between the tabs 23 are the nested hinges 50, which are mounted to the inner side surfaces of adjacent panels (e.g., 10a, 10b) to allow for rotation of the panels. A flange 51 of the hinge 50 is mounted to the inner side surface of a panel via bolts 53. The inner side surface of a panel may include a recess in which the flange 51 may be placed. The inner side surface of the panel may also include an additional recess to accommodate the joint of the hinge 50 such that the joint of the hinge 50 becomes substantially flush with an outer front surface of the panel. Such configurations may allow for the outside vertical edges of adjoining panels to be positioned closer to one another. By spacing the vertical edges of adjoining panels closer, optical dead spaces may be further reduced or eliminated. In addition, the hinges 50 together with the tabs 23 may reduce the number of pinch points present in the system.

[0142] As shown in FIGS. 1A-1B, the main body 100 of the illuminator may include a mounting head 40. The mounting head 40 may allow for the main body 100 to be mounted to a movable stand 80, which is shown in FIG. 4, to allow a user to easily move the main body 100 to the appropriate treatment position. The stand 80 includes a base 81 and a vertical pillar 82. The base 81 may further include wheels 87 at its bottom in order to allow the user to horizontally move the illuminator to an appropriate position. The wheels 87 may include locks, such that the stand 80 is prevented from further horizontal movement once positioned. In addition, the vertical pillar 82 may be attached to the base 81 at a pivot point 83. The pivot point 83 allows the vertical pillar 82 to be rotated to increase the range of positioning for the illuminator. At a top end, the vertical pillar 82 includes a connecting arm 85, which may serve as a mountingstructure for the main body 100. The connecting arm 85 includes a hinge point 86 such that the main body 100 can be moved vertically relative to the stand 80. The vertical pillar 82 may also be configured as a telescopic structure, such that the user can change the height of the vertical pillar 82. This allows for an increased range of vertical movement for the main body 100, which can allow the user to position the main body 100 at lower portions of a treatment area, such as a patient’s legs or feet. The stand 80 may also include a stabilization arm 84. Once the stand 80 and main body 100 is positioned, the stabilization arm 84 may be attached to the main body 100 to prevent unwanted movement of the main body 100 during treatment. As further shown in FIG. 4, a controller and power supply 90 is mounted to the stand 80 in order to supply electrical power to the main body 100 and allow the user to control the main body 100 for treatment purposes. Alternatively, the controller and power supply 90 may be directly mounted to the main body 100. In order to provide a cooling system for the LED arrays 60, one or more fans 70 may be mounted onto each of the panels, as shown in FIG. 4.

[0143] At least one controller (also referred to as a control unit) is also connected to the panels to regulate power to the lights to achieve the required uniformity and intensity for the target treatment. In at least one embodiment, the controller may also control output of a heat source 160 discussed in more detail below. In at least one embodiment, there may be a plurality of controllers controlling at least one dynamic process, e.g., controlling output(s) of one or more of: one or more light sources, one or more heat sources, and / or one or more air sources (such as a fan), in any combination. For example, separate controllers or integrated controllers may be provided for respectively controlling the output of LED arrays 60 and the heat source 160. In at least one embodiment, a first controller may control both light and heat sources, and a second controller may control an air source, for example.

[0144] The controller may be implemented as hardware, software, or a combination of both, such as a memory device storing a computer program and a processor to execute the program. Alternatively, each panel may have a dedicated controller to regulate power to the individual LED array on a given panel to allow for more particular calibration of the illuminator, which may further enhance uniformity and increase efficiency. Under Lambert’s cosine law, lightintensity at a given point on a “Lambertian” surface (such as skin) is directly proportional to the cosine of the angle between the incoming ray of light and the normal to the surface. Thus, a ray of light that is directed to the front of a curved surface (e.g., a head of a patient) will arrive in a substantially perpendicular manner to that area and will result in 100% absorbance. However, a ray of light that arrives at a side edge of the curved surface will arrive in a substantially parallel manner. According to Lambert’s cosine law, the intensity, and thus absorption, of the light at the side edge will approach zero, making treatment at that area ineffective. Thus, a “fall off’ of light exposure tends to occur at the edges of a curved surface. In addition, “fall off’ increases as the distance between the light source and the point on the surface increases.

[0145] Configuring an illuminator to conform to the curved surface (e.g., a U-shaped configuration designed to “wrap around” the curvature of the surface) aids in reducing this effect and increases overall uniformity. However, to sufficiently increase uniformity, the light source should be larger relative to the target treatment area in order to fully encompass the body part to be treated and also provide light from all angles to any target point on the treatment area. In order to increase the uniformity of light exposure to the treatment area while maintaining a practical size of the illuminator, the LED arrays 60 may be individually configured to increase the intensity of light emitting from certain diodes to compensate for this fall-off effect.

[0146] An example in which the LED arrays 60 may be individually configured is shown in FIG. 5. Here, the LED arrays 60 are divided into three general areas, which may be described as “addressable strings.” Areas 1, 3, and 5 correspond to an addressable string configuration that may be included in the wider panels 10a, 10c, and lOe, while areas 2, 4, and 6 correspond to an addressable string configuration that may be included in the narrower panels 10b and lOd. The current to each area is adjusted in order to adjust the intensity of light emitting from each of the areas. For example, a higher current may be supplied to areas 1 and 2 than the current supplied to areas 3 and 4 such that areas 1 and 2 emit a higher intensity of light than areas 3 and 4. Similarly, a higher current may be supplied to areas 3 and 4 than the current supplied to areas 5 and 6. Thus, a higher intensity of light is emitted overall from the edges, which may allow for a reduction in any fall-off effect. Alternatively, the illuminator may be configured to adjust eachindividual diode present in a given LED array 60, allowing for an even greater calibration effect (that is, fine tuning).

[0147] Furthermore, by using either pre-programmed settings or sensors to detect the curvature of the surface to be treated, the LED arrays 60 can be individually configured to emit more intense light to only those areas that require it. Additionally, pre-programmed sensors can be used to detect the orientation of one or more panels (e.g., whether a panel is curved or folded flat) and may be used to configure the LED arrays 60 to emit more or less intense light in areas that require it. In particular, in at least one embodiment, at least one sensor detects an orientation of at least one panel and provides detection information (a detection result) to the controller. The sensors may include one or more encoders, such as one or more angle encoders, which are provided at one or more locations on the panels. In at least one embodiment, at least one sensor is a microswitch configured to sense a position of at least one panel. In some embodiments, a plurality of sensors may include an encoder, a microswitch, or combinations thereof. The sensors are communicated with the controller and are configured to provide information about the panel orientation, such as an angle at which a panel is disposed, to the controller. The controller then controls the intensity of light in accordance with a detection result. In at least one embodiment, a plurality of sensors provides information to the controller so that the controller may carry out a determination as to whether the illuminator has a configuration that is one of a plurality of preset configurations. For example, the controller may store, in a memory, information relating to one or more preset configurations (e.g., for a bent illuminator, a flat illuminator, etc.).

[0148] When the controller receives information transmitted from the sensors, the controller may compare the sensed information to the preset configurations to determine a match between the sensed information and one or more preset configurations. The controller may further store a protocol for altering intensity which is executed upon determining a match between the sensed information and the preset configuration. For example, if the illuminator is detected to be a curved illuminator, the controller implements a light intensity output which is correlated to the preset protocol for a curved illuminator. The controller may further compare an existingintensity to an intensity associated with a particular configuration and determine whether the intensity should be adjusted. This allows for an increase in uniformity of light exposure in an efficient manner as power output and / or light intensity is increased to only certain diodes, in accordance with need. In at least one embodiment, a plurality of preset configurations may be presented to a clinician or practitioner, e.g., on a touch screen, who may then select the preset configuration corresponding to the physical arrangement of the illuminator in the clinical environment.

[0149] The addressable strings of the LED arrays 60 may also include varying amounts of individual diodes mounted within the particular area. For example, for the wider panels 10a, 10c, and lOe, 12 diodes may be mounted in each of areas 1, while 9 diodes may be mounted in each of areas 3, and 41 diodes may be mounted in area 5, resulting in a total of 83 individual diodes included within each of the wider panels 10a, 10c, and lOe. For the narrower panels 10b and lOd, 8 diodes may be mounted in each of areas 2, while 9 diodes may be mounted in each of areas 4, and 23 diodes may be mounted in area 6, resulting in a total of 57 individual diodes included within each of the narrower panels 10b and lOd. However, the number and arrangement of diodes included within each of the LED arrays 60 is not particularly limited. For example, the wider panels 10a, 10c, and lOe may each contain a total amount of diodes that ranges from about 80 diodes to about 350 diodes. Similarly, the narrower panels 10b and lOd may each contain a total amount of diodes that ranges from about 50 diodes to about 250 diodes. By varying the arrangement of the diodes within each of the addressable strings of the LED arrays 60, power output and / or the intensity of light emitted from a given array may be better controlled and fine-tuned.

[0150] In addition, individually regulating power to the LED arrays 60 can also contribute to the reduction or elimination of the optical dead spaces that may otherwise occur at the hinge points. Specifically, power output and / or the emitted light intensity may be increased close to the edges of the array that are closest to the nested hinges to compensate for the lack of light emitting from the meeting point of panels. The narrower panels 10b, lOd are also preferably operated at a higher power level and / or at a higher emitted light intensity compared to the widerpanels 10a, 10c, lOe in order to provide additional fill-in light. Furthermore, individual power regulation may aid in compensating for manufacturing variance that can occur in individual diodes. Finally, by fine-tuning each array 60, the panels can be easily deployed for other applications as each array is specifically configurable to address the lighting needs of the specific application.

[0151] The illuminator may further include a timer, which can indicate to the user the appropriate length of exposure time for the particular treatment. The illuminator may also be programmed with pre-stored light dosing parameters to allow the user to select a desired treatment type. The pre-stored parameters may include, for example, pre-stored settings for exposure time, light intensity, and outputted wavelength. Based on the selected treatment, the illuminator is automatically configured to provide the correct lighting dosage by being supplied with the appropriate power output to achieve the required uniformity for the treatment. Alternatively, the illuminator can be provided with sensors that detect the size of the treatment area positioned in front of the illuminator. The sensors then determine the correct light dosing parameters based on the sensed treatment area. The illuminator may also further include actuators and may be programmed to be moved automatically depending on the selected treatment. Once a treatment is selected, the illuminator may be automatically positioned into the proper configuration by the actuators without requiring the user to move the system by hand. Alternatively, the sensors may detect the adjusted position of the illuminator manually set by the user. The detected position of the illuminator may then be used to indicate the intended treatment area. Correct light dosing parameters for the specific treatment area may then be provided based on the detected position set by the user.

[0152] The illuminator of the present disclosure allows for an infinite amount of configurations that can be adapted for the targeted treatment area. The configurations may range from a flatplane emitter (as shown in FIGS. IB and 2B) to a substantially U-shaped configuration (as shown in FIGS. 1A and 2A). The adjustable illuminator may also be configured such that the two end panels 10a, lOe can be pulled back relative to the three middle panels 10b, 10c, lOd, such that a smaller U-shaped configuration may be created by the middle panels. Thus, theadjustable illuminator allows for the treatment of additional areas of a patient’s body. In other words, not only can the adjustable illuminator effectively deliver a uniform light intensity to traditional surfaces such as the face or scalp, but the adjustable illuminator can also provide a device that can easily be configured to treat other portions of a patient’s body, in particular, those having smaller curved surfaces, such as the arms and legs. Moreover, the adjustable illuminator may also be easily positioned to deliver a uniform light intensity to larger treatment areas, such as the back or chest.

[0153] As described above, the narrower panels 10b, lOd are dimensioned such that the panels act as “lighted hinges.” Thus, when the wider panels 10a, 10c, lOe are adjusted into the desired form, the illuminator “bends” at the narrower panels 10b, lOd, where traditionally the “bend” would occur substantially at the hinge itself. Thus, instead of an unlighted “bent” portion as would occur in the conventional illuminator, the present illuminator provides a “bent” portion that is also configured to emit light, thereby helping to reduce optical dead space without requiring large amounts of power differentiation among the light sources of each panel to provide the required fill-in light. The effects of this configuration were verified with evaluation of the light uniformity measured with a cosine response detector, which mimics the response of a patient’s skin to the incident of light at a distance of two inches. Total light dose, in terms of J / cm2, was measured based on emitted irradiance (W / cm2) over time (in seconds).

[0154] The light output uniformity produced by the illuminator shown in FIGS. 1-8 is enhanced across the patient’s face and exhibits little to no deviation from the light output measured in the center of the patient’s face to the light output measured at the edges of the patient’s face. Total light doses of about 10 J / cm2are provided across all regions of the face, including the center of the face (for example, the patient’s nose), the patient’s check areas, and the outer boundaries of the patient’s cheek areas, such as the ears and forehead. Moreover, total light dose drops off minimally at the extreme outer boundaries of the patient’s face. In one embodiment, the measured output over an active emitting area (over the entire active emitting area) is within 60% of the measured maximum (over the entire active emitting area) measured with a cosine response detector over all operation distances. More preferably, the measuredoutput over the emitting area is within 70% of the measured maximum over a distance of two and four inches. Even more preferably, the measured output over the emitting area is within about 80% of the measured maximum over a distance of two and four inches.

[0155] While certain embodiments described above relate to an illuminator comprising a plurality of panels, other embodiments may include an arcuate illuminator without individual rectilinear panels. For example, in at least one embodiment, the illuminator may be constructed of at least one curvilinear member. Further, the arcuate illuminator may have substantially curved portions extending from a substantially flat portion provided between the substantially curved portion. The patient’s face may be positioned so as to be opposed to the substantially flat portion, such that at least three sides of the patient’s head are surrounded by the illuminator. For example, the patient’s face may be directly opposed to a first portion of the illuminator, while the left and right sides of the patient’s head may be opposed to second and third portions, respectively.

[0156] FIGS. 7A and 7B illustrate an apparatus according to an embodiment of the present disclosure. The apparatus is an illuminator including certain components shown, for example, in FIGS. 2A-2B. The illuminator can be configured to be positioned at a distance of between about 5 cm to about 10 cm from the surface of the patient to be treated, e.g., about 5 cm to about 8 cm from the surface to be treated. The illuminator includes a frame 150 into which panels 10a- lOe are assembled. In addition to the panels 10a- lOe, a heat source (heating element) 160 is assembled in the frame 150. For example, as shown in FIG. 7B, the heat source 160 may be sandwiched between panels 10b, lOd and positioned at least partially behind panel 10c. The heat source 160 may include curved terminal portions 162, 164 which project beyond the panels, such that at least a portion of the heat source is not obstructed by the panels and is directly exposed to the patient. In at least one embodiment, the heat source 160 may be an infrared quartz heater. Together the panels lOa-lOe, frame 150, and portions 162, 164 create a partially enclosed space which retains a bath of warm air into which a portion of the patient (e.g., the patient’s head) may be immersed.

[0157] In at least one embodiment, the heat source 160 may comprise frame mounted resistance tape heaters. In at least one embodiment, the heat source 160 may comprise 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, as mentioned above. In at least one embodiment, the IR quartz heater is relatively responsive and produces a sufficient heat output, and may be readily controlled, e.g., by a controller 77, which may be a proportional integral derivative (PID) controller. Further, the IR quartz heater is relatively compact and may be integrated into the frame 150 without requiring enlargement of the frame 150.

[0158] The heat source 160 may be equipped with at least one controller ( a control unit), such as the controller 77 to heat output to the target treatment. The control unit may be a controller implemented as hardware, software, or a combination of both, such as a memory device storing a computer program and a processor to execute the program. In at least one embodiment, the heat source 160 is controlled by a PID controller with monitoring and over / under temperature limit control. In some embodiments, the controller may further include one or more of an input / output (I / O) expansion module and a data logging and field communications access module. The controller may be a microprocessor regulator with software framework drivers programmed to control an input set temperature to a specified tolerance based on feedback from a reference control thermistor 170 discussed below. In at least one embodiment, the heat source is configured to output sufficient heat to reach a predetermined skin or tissue temperature target, e.g., about 40 °C ± 2 °C.

[0159] FIG. 7C illustrates an illuminator according to an embodiment. In at least one embodiment, the illuminator further includes one or more thermistors. The thermistors may be integrated into the illuminator or provided in a kit including a suite of diagnostic tools. In at least one embodiment, a negative temperature coefficient or a positive temperature coefficient thermistor may be provided as a reference control thermistor 170 disposed on or near the heat source 160. In at least one embodiment, the thermistor 170 may be arranged at a portion of the heat source 160 proximate to an upper portion of panel 10c. A temperature measured by thereference control thermistor 170 may be compared to a temperature measured at the exposed skin of the patient, e.g., by a temperature probe placed on the patient’s forehead, such as a contact thermocouple. In some embodiments, one or more thermocouples may be used to ascertain a relationship between the skin temperature (thermocouple temperature) and a temperature sensed by thermistor 170 (a control temperature or thermistor temperature).

[0160] In particular, the one or more thermocouples may be used to ascertain a relationship between skin temperature and control temperatures when the illuminator is originally manufactured, or when a first diagnosis is carried out. For example, a reference or control temperature may be set based on experimentally derived data, and a reference or control temperature against which the thermocouple temperature is compared may be temperature value from a table stored in a memory of a control unit connected to the illuminator. In at least one embodiment, the thermistor may be a programmable thermistor in which one or more temperature values are stored, and after the thermistor is programmed, it may be used to regulate the heat output of heat source 160. The comparison of temperatures may be carried out at one or more locations across the exposed skin of the patient. For example, by carrying out temperature measurement at a plurality of locations across the patient’s face, a thermal map of the patient’s face may be constructed. A thermal mapping may be performed before and after treatment. Further, the results of the thermal mapping may be compared, e.g., to a user’s needs as articulated in a treatment or clinical plan. The results of a patient’s thermal mapping may be compared to one or more other patient’s thermal mapping data.

[0161] In at least one embodiment, the heat source 160 may be used in conjunction with fans 70. For example, the fans 70 may be operated to circulate cooling air through the system. Further, cool air or room temperature air, which travels along a path indicated by arrows labeled ‘C’ in FIG. 7C, may be directed toward a heat exchanger in the heat source 160. The heat exchanger heats the cool air. The heated air, which travels along a path indicated by arrows labeled ‘H’ in FIG. 7C, may be blown at relatively gentle flow rates. In at least one embodiment, the fans 70 are controlled by a controller to provide an air speed of about 3-6 knots and a volumetric flow rate of 14 cubic feet per minute (CFM). In some embodiments, the fan speedmay be constant or variable. In at least one embodiment, a controller (which may be a controller that controls at least one of the LEDs 60 or heat source 160) controls the fans 70. The controller may control the output of one or more of fans 70 by varying the revolutions per minute (RPM) of fans 70, for example. The heated air may be blown by fans 70 toward the face of the patient, e.g., from a top and bottom of the heat source 160. The air flow creates a bath or pocket of heated air which substantially arounds the patient’s skin, such that the patient’s face, for example, may be enveloped in warm air. The thermodynamic behavior of the system may allow for controlling the disparity between the temperature at the patient’s skin (measured with the contact thermocouple) and the temperature measured by the thermistor, so as to be within about 15 °C, for example. In at least one embodiment, the surface of the patient’s skin (e.g., their facial skin) attains a stable temperature within five minutes of when the heat from the heat source 160 is emitted.

[0162] Control of the thermodynamic transfer behavior allows for the air that is being blown and the heat output by the heat source to be modulated in accordance with a desired heating effect of the skin. In at least one embodiment, a desired raise in skin temperature (e.g., by 2 °C) may be achieved by determining a rise in air temperature and a corresponding time period. That is, the controller may be programmed to determine how high and for how long the temperature should be raised in order to heat a patient’s skin to a desired level. Further, in at least one embodiment, the controller may also make such a determination with respect to air speed and / or volumetric flow rate. Such determinations by the controller may be made with reference to one or more maps stored in the memory of the controller. For example, one such map is a map correlating the temperature of thermistor 170 to a rise in skin temperature. Another such map is a map correlating the thermistor temperature to the air speed and the volumetric flow rate of the air. The air speed and volumetric flow rate themselves vary at least in part based on the configuration of heat source 160, and more particularly, how the curved portions (plenums) 162, 164 are structured and arranged. In at least one embodiment, the one or more maps stored in memory may correlate one or more of the thermistor temperature, a desired skin temperature, a volumetric flow rate, an air speed, and an air temperature to each other. The controller mayreference information from one or more such maps to carry out a precise control of skin temperature. The system may be provided with a plurality of sensors for sensing temperature at a plurality of locations, and the controller may reference the aforementioned maps containing data from such sensors to control the heat source 160 at one or more locations. Further, by taking into account information from the thermal heat maps, heating of the skin at multiple points may be controlled in accordance with a treatment plan. In one embodiment, the use of such map allows the desired skin temperature to be obtained without directly measuring the skin temperature by one or more temperature sensors on the skin, for example.

[0163] FIG. 7D illustrates an illuminator according to an embodiment, in which heat is emitted to a control volume, e.g., a cubic volume. In at least one embodiment, the heat source 160 may emit heat to a treatment target, such as a target within a cubic volume 172 as shown in FIG. 7D. The cubic volume 172 may have a total height of 6”, and the temperature may be measured at a plurality of points in the x, y and z directions of the cubic volume 172. For example, the temperature may be sensed at 3” from a center panel 10c, where a predetermined treatment target is disposed at a center of the cubic volume 172. FIG. 7E depicts the cubic volume 172 wherein a treatment target is a patient’s nose, centered in the volume. FIG. 7F is a perspective view showing an exemplary positioning of a patient with respect to the heat source 160 and illuminator.

[0164] In some embodiments, temperature may be measured at any or all of a plurality of nodes so as to construct a thermal map. In at least one embodiment, the data may be recorded every minute, or at a different predetermined time interval. In at least one embodiment, the cubic volume 172 is established as a measurement framework. Measurements of temperature (and measurements of distance from one or more of panels 10) may be taken at one or more of the nodes and compared, for example, to the temperature taken at the thermistor 170. In this manner, the positioning of the patient may be controlled with respect to the illuminator to ensure that the total acceptable light dose is achieved.

[0165] In at least one embodiment, the heat source 160 may be warmed up for about fiveminutes, and the patient may then be exposed to light from light source 60 and heat from heat source 160 for about 10 minutes. In at least one embodiment, selected forced convection may be used, as it may have fewer instabilities and narrower variation in temperature over a heated target. Further, in at least one embodiment, an indirect heat application may be employed, such that the patient's skin does not directly contact the heat source 160. Rather, heat is emitted at a distance from the patient’s skin, and the controller determines a proposed emission pattern based on the results of a comparison between a plurality of temperature measurements taken at nodes of the control volume 172 to a temperature measurement taken by thermistor 170.

[0166] In at least one embodiment, the controller may turn the heat source 160 on or off through firmware that takes feedback from the temperature of thermistor 170 and has a firmware setting of ± 1 degree. In at least one further embodiment, a non-contact infrared (IR) sensor, such as a laser infrared sensor, may be used to detect skin temperature and supply the sensed skin temperature data to the controller. The input from the non-contact IR sensor may be provided in one or more maps stored in the controller, as further data indicative of skin temperature. In at least one embodiment, during an initial warm-up period (e.g., about five minutes), when the heat source 160 is beginning to warm up, the system is not yet at a steady state where it can be controlled to deliver a desired output, but is in a transient state. The non-contact IR sensor may allow for the patient’s skin temperature to be detected and for the detection result to be compared to skin temperature values for a plurality of patients. Such skin temperature data may be data derived from a sample population and stored in a map in the controller. If a given patient’s skin temperature is colder than an average skin temperature, the controller may accelerate heating up of the heat source 160 in order to promote warming up of the patient’s skin in a more efficient manner. Alternatively, if the patient’s skin temperature is comparable to or warmer than the average skin temperature, the warm-up process may not be accelerated, but may continue normally.

[0167] In at least one embodiment, a high skin or tissue temperature was between about 40.3 - 42.6 °C, with an average skin temperature of 41.3 °C. Thermal testing was conducted with application of only light or heat, or both light and heat, at 10 mW / cm2and 20 mW / cm2. Thermaltesting indicated that light itself did not appear to influence the temperature of skin on the patient’s face, when the heat was on.

[0168] FIGS. 8-31 illustrate at least one embodiment of a configurable illuminator, shown as illuminator system 1105. The illuminator system 1105 may include at least some of the same or similar features as the illuminator described above with reference to FIGS. 1-7F. The illuminator system 1105 may be arranged with a folding apparatus designed to allow maneuverability and reconfigurability of illuminator panels. In at least one embodiment, the illuminator system 1105 is adjustable via a post. The post is supported by a hydraulic cylinder according to at least one embodiment. The hydraulic cylinder allows raising and / or lowering with manual force applied by a user’s digit(s) and / or hands. The cylinder is optionally outfitted with a valve to lock the cylinder in position. Other constructions may be utilized, e.g., instead of a hydraulic cylinder, a spring may be used.

[0169] For example, in at least one embodiment, the illuminator system 1105 is provided with a vertical post which are optionally provided with one or more supports arms. The one or more support arms are configured to support illuminator panel(s) whose height is adjustable. The post may be pushed down into a body of the illuminator system 1105 or pulled up out of the illuminator system 1105. The illuminator system 1105 may be provided with one or more air cylinders (with at least one check valve and / or at least one spring) to allow the post to be moved with minimal force (e.g., finger pressure). These aspects allow the illuminator system 1105 to be readily maneuverable and usable under various conditions.

[0170] In at least one embodiment, the illuminator system 1105 uses a ducting arrangement to draw air in via an air distributor (e.g., a fan) at the back of an illuminator panel and output the air via a J-shaped ducting arrangement such that the air gently flows (for example, a laminar flow or similar even, uniform flow) substantially parallel to the front surface (the surface that emits light) of a panel and substantially tangentially to the skin surface. A controller allows a healthcare provider or the patient to control the fan speed at different speeds (for example, slow and fast) in accordance with an observation of the healthcare provider and / or a desire expressed by thepatient. The air may be room temperature air (for example about 68 °F to about 75 °F or about 65 °F to about 72 °F).

[0171] In particular, whether or not the skin is pre-heated as described above, the flowing air is nonetheless cooler than the treatment surface. The temperature is significantly lower than body temperature, and thus feels cooling to the patient. The air may also be cooled below room temperature, in at least one embodiment. The air flow may provide evaporative cooling that reduces the perception or sensation of pain. The air speed can be, for example, about 3 to about 6 knots, e.g., about 3 knots, about 4 knots, about 5 knots or about 6 knots. Such air distributors may have an air flow rate of about 7.5 CFM to about 12 CFM, about 14 CFM, about 5 CFM to about 15 CFM or about 5 CFM to about 20 CFM. Enhancing patient comfort in this manner may influence the willingness of a patient to complete a course of treatment, among other benefits.

[0172] The illuminator system 1105 may be equipped with a thermal management system having additional components beyond those described above. For example, additional air distributors may direct waste heat away from electronic components to the external environment.

[0173] Further, in at least one embodiment, the illuminator system 1105 can be provided with sensors that detect the size of the treatment area positioned in front of the illuminator. In at least one embodiment, information from the sensors can be used (e.g., by a controller) determine the correct light dosing parameters based on the sensed treatment area. In at least one embodiment, the sensors are configured to detect the adjusted position of the illuminator manually set by the user. The detected position of the illuminator may then be used to indicate the intended treatment area. Appropriate light dosing parameters for the specific treatment area may be provided based on the detected position set by the user.

[0174] Referring to FIGS. 8-11, at least one embodiment of a configurable illuminator system 1105 is illustrated. Illuminator system 1105 includes an illuminator 1100. The illuminator 1100 comprises a plurality of panels 110. The panels 110 may be the same as or similar to the panels 10. The panels 110 are provided with LEDs 160 (e.g., similar to or same as LEDs 60) that areused to emit light for photodynamic therapy for treatment of diseases and disorders of the skin (which may be defined as a multi-layer organ including the epidermis, dermis and subcutaneous tissue, and further including mucous membranes contiguous with the outer skin). The skin to be treated may be, for example, on the surface of the head, face, scalp, ears, tongue, neck, arms, legs, torso, genitals, hands or feet, or elsewhere.

[0175] The illuminator 1100 preferably has five panels 110 (namely, panels HOa-l lOe). The panels 110 may vary in size. For example, a first panel 110a may be a first size, a second panel 110b may be a second size, a third panel 110c may be a third size, a fourth panel HOd may be the second size, and a fifth panel I lOe may be the first size. In at least one alternative embodiment, the panels may be of equivalent size.

[0176] In conventional illuminators, the panels are equally sized by width and length and are typically driven at the same power level. The panels are further joined at their edges. Owing to this construction, light is not emitted from a “gap” between the light sources. The lack of light emitting from such areas, together with the uniform supply of power to the panels, can cause optical “dead space” in certain portions of the target treatment area. These portions, in turn, receive less overall light, resulting in a lower dose of treatment in those portions. In some instances, the dose of treatment can be lowered by as much as a factor of five when compared with those areas receiving a desired amount of light.

[0177] At least one embodiment of the present disclosure includes a plurality of panels 110, wherein at least one panel 110 is of a different width than the other panels. This panel is positioned between two other panels and, in a way, acts as a “lighted hinge” to provide enough “fill-in” light to reduce or eliminate the optical dead spaces when the panels are bent into a certain configuration. Preferably, five panels in total may provide for a desirable increase in the total size of possible treatment areas. Two of the panels (e.g., panels 110b and HOd in FIG. 9) are preferably of a smaller width than the other three larger panels (e.g., panels 110a, 110c and I lOe in FIG. 9). The panels are positioned in an alternating manner such that each of thesmaller-width panels is situated in between two of the three larger panels to allow for both adjustability and increased uniformity.

[0178] In at least one embodiment, each panel 110 contains an array of light emitting diodes (LEDs) 160, which may be configured in an evenly or unevenly spaced pattern across a face of the panel 110. In at least one embodiment, three adjacent panels may be illuminated (e.g., the three inner panels) and two panels may be non-illuminated for a given period, such that illumination may be carried out with a small number of panels than the total number of panels present in the illuminator 1100. The number of individual LEDs arranged in a given array is not particularly limited. The panels 110 are configured to uniformly illuminate a treatment surface of a patient via the LEDs. Thus, a substantially homogenous distribution of light may be imparted to the treatment surface.

[0179] Preferably, the LEDs may be distributed across a plurality of arrays, where each array of LEDs 160 extends as far to the edges of the panels 110 as possible. In addition, the arrays of LEDs 160 are preferably dimensioned to provide an overall lighted area for a given treatment area based on a range from the 5th percentile of corresponding sizes of female subjects to the 95th percentile of corresponding sizes of male subjects for that particular treatment area. The LEDs 160 emit light at an appropriate wavelength according to the intended treatment or to activate the particular photoactivatable agent used in treatment or diagnosis. For example, when ALA is used as a precursor of a photoactivatable agent for the treatment of AK, the LEDs 160 preferably emit blue light having wavelengths at or above 400 nanometers (nm), for example, about 430 nm, about 420 nm or, for example, 417 nm. However, the LEDs 160 may 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 LEDs 160 may also emit light having wavelengths of 510 nm, 540 nm, 575 nm, 630 nm, or 635 nm. In addition, the LEDs 160 may be configured to emit light continuously or may be configured to flash the diodes on and off based on a predetermined interval. Furthermore, the LEDs 160 may be configured such that only one wavelength of light (e.g., blue) is emitted. Alternatively, the LEDs 160 may be configured such that two or more wavelengths of light areemitted from the arrays. For example, the LEDs 160 may be configured to alternately emit blue light and red light.

[0180] In at least one embodiment, the LEDs 160 on each of the panels 110 are individually configurable to provide specific power output to certain areas on the panels 10 to compensate for decreased uniformity. For example, the power outputted to each individual diode in an array of LEDs 160 may be individually adjusted. In more detail, the LED arrays may be divided into three general areas, which may be described as “addressable strings.” The current to each area is adjusted in order to adjust the intensity of light emitting from each of the areas. For example, a higher current may be supplied to a given area associated with a particular string or strings, so that it produces a higher intensity of light than another area associated with another string or other strings. Alternatively or in addition, the LEDs 160 may be operated at a higher power level.

[0181] In addition, individually regulating power to the LEDs 160 can contribute to the reduction or elimination of optical dead spaces that may otherwise occur where typical illuminator panels are connected. Specifically, power output and / or the emitted light intensity may be increased close to the edges of arrays of LEDs 160 to compensate for the lack of light emitting from an area where neighboring panels meet or adjoin. The narrower panels 110b, 1 lOd are preferably operated at a higher power level and / or at a higher emitted light intensity compared to the wider panels 110a, 110c, I lOe in order to provide additional “fill-in” light. In this manner, the LEDs 160 are controllable such that a higher intensity of light is emitted overall from the edges of the panels 110, which may allow for a reduction in any fall-off effect. Thus, such a configuration provides a more uniform illumination output than one in which power and / or intensity are equal across all panels. In at least one embodiment, the illuminator 1100 may be configured to adjust each individual diode present in a given LED array, allowing for further calibration.

[0182] In at least one alternative embodiment, other types of light sources may be used, such as fluorescent or halogen lamps, instead of or in addition to LEDs 160.

[0183] In at least one embodiment, each panel 110 contains at least one vent 168. The vent 168 may be configured to actively (e.g., push / pull) or passively (e.g., provide a path) expel air from the panel 110. In at least one embodiment, the panel 110 may include a plurality of vents 168. For example, the panel 110 may include a first vent 168 and a second vent 168. The first vent maybe disposed at or proximate to a first end of the panel 110, and the second vent 168 may be disposed at or proximate to a second end of the panel 110. Each panel 110 may also contain at least one fan 170. The fan 170 may be configured to draw air into the panel 110 or to expel air from inside the panel 110. A fan 170 may be disposed on a back side of the panel 110. The fan 170 may be disposed at a central location of the panel 110. In at least one embodiment, a panel 110 includes a plurality of fans 170. For example, panel 110c includes a first fan 170 disposed proximate a first end of the panel 110c and a second fan 170 disposed proximate a second end of the panel 110c.

[0184] Each panel 10 may contain a distance sensor 111. The distance sensor 111 may detect a distance between the panel 110 and a treatment surface (an affected area) disposed in front of the panel 110. The distance sensor 111 may be automatically turned on when the associated panel 110 is turned on. Detecting the distance between the panel 110 and the treatment surface can facilitate individual adjustment of each panel 110 such that each panel 110 is at a desired distance from the treatment surface.

[0185] As shown in FIG. 13, in at least one embodiment, the panels 110 may be coupled together via a hinge 158 or other adjustable connection point to facilitate movement of the panels 110 with respect to each other. For example, the panels 110 may be connected in a rotatable manner via nested hinges 158. The illuminator 1100 may be configured to fold and unfold via the hinges 158 depending on use. For example, the panels 110 can be in an unfolded (e.g., flat) arrangement when treating areas such as a back, chest or abdomen of a patient. The panels 110 can be in a folded (e.g., U-shaped) arrangement, when treating areas such as a face, scalp, arm, or leg. For example, the outermost panels 110 may face each other (at least in part). The panels 110 can also be in a folded arrangement when in a stowed position. For example, the panels 110 may be wrapped around at least a portion of the illuminator system 1105 (e.g., the verticalcolumn 182) when the illuminator 1100 is not in use. The hinges 158 may include torque inserts to maintain a position of the panels 10 without using an additional lock. The hinges 158 may also include hard stops that prevent the panels 110 of the illuminator 1100 from having an undesired configuration. For example, the hinges 158 may prevent the panels 110 from being fully unfolded (e.g., flat), or from bending beyond the flat configuration (e.g., a U-shape in an opposite direction).

[0186] As shown in FIG. 10, the illuminator system 1105 may include a moveable stand 180. The movable stand 180 may simplify movement of the illuminator system 1105 between various locations and orientations. For example, the moveable stand 180 may include a vertical column 182 coupled to a base 181. The vertical column 182 may extend perpendicular to the base 181. The base 181 may provide support for the vertical column 182 and other components of the illuminator system 105 that are coupled with the vertical column 182. The base 181 may be movable. For example, the base 181 may include a plurality of wheels, shown as casters 187. For example, the base 181 may include four casters 187. The casters 187 may facilitate rolling of the illuminator system 1105 from a first location to a second location, or from a first orientation to a second orientation.

[0187] As shown in FIG. 10, in at least one embodiment, the illuminator system 1105 includes one or more hooks 183. For example, the illuminator may include a first hook 183a and a second hook 183b. The first hook 183a and the second hook 183b may be disposed on a first side of the vertical column 182. The first hook 183a may be disposed above the second hook 183b. The hooks 183 may be rotatably coupled with the vertical column 182. The illuminator system 1105 may also include a handle 184 (e.g., a stabilization arm). The handle 184 may be disposed around three sides of the vertical column 182. For example, the handle 184 may extend from a first side of the vertical column 182, wrap around a second side of the vertical column 182, and connect to the vertical column 182 via a third side of the vertical column 182. Apart from a first and second connection point disposed on the first and third side of the vertical column 182, the handle 184 may be spaced apart from the vertical column 182.

[0188] As shown, for example, in FIGS. 8-11, the illuminator system 1105 may further comprise an extension member 186. The extension member 186 may be partially disposed within the vertical column 182. The vertical column 182 and the extension member 186 may be configured as a telescoping structure wherein the extension member 186 can extend or slide into the vertical column 182 and extend or slide vertically out of the vertical column 182 between different positions. The extension member 186 may be configured to adjust a height of the illuminator 1100. For example, when the extension member 186 is in a retracted position (a low position) and a majority of the extension member 186 is generally disposed in the vertical column 182, as shown in FIGS. 8-9, the illuminator is in a low position. Conversely, when the extension member 186 is in an extended position (an expanded position, or an elevated position) and a majority thereof is disposed generally outside of the vertical column 182, as shown in FIGS. 8-9, the illuminator 1100 is in a high (raised or elevated) position. The different positions may be based on a use of the illuminator 1100, taking into account one or more of: (i) patient characteristics (e.g., a relatively shorter versus a relatively taller person), (ii) patient orientation (e.g., a standing versus sitting position) or (iii) location of an area to be treated (e.g., the back versus the forearms). The position of the extension member 186 may be adjusted either manually or automatically (e.g., by power). The extension member 186 may be configured to maintain any position between a top position (e.g., fully extended) and a bottom position (e.g., fully retracted).

[0189] As seen in FIG. 9, a top of the extension member 186 may be coupled with or be integral with (e.g., for a single component) a connecting arm 185. The connecting arm 185 extends horizontally from the top of the extension member 186. The connecting arm 185 is configured to move with the extension member 186 as the extension member 186 moves relative to the vertical column 182 (e.g., as the extension member 186 moves into or out of the vertical column 182). The connecting arm 185 can include a material of sufficient strength to support other components of the illuminator system 1105 (e.g., the illuminator 1100).

[0190] The connecting arm 185 has a joint, shown as pivot point 189. The pivot point 189 divides the connecting arm 185 into two portions, a first portion and a second portion. The firstportion can be a stationary portion 197 and the second portion can be a movable portion 198. The movable portion 198 can extend from an end of the stationary portion 197. The movable portion 198 is rotatably coupled with the stationary portion 197. For example, the movable portion 198 can pivot around the pivot point 189. For example, the movable portion 198 can rotate vertically about the pivot point 189. In at least one embodiment, the movable portion 198 rotates about 190 degrees around the pivot point 189 (so as to be rotatable within a range from 0° to about 90°).

[0191] For example, the stationary portion 197 may define a horizontal plane. The movable portion 198 may rotate between a horizontal position (e.g., parallel with the stationary portion197 and disposed in the horizontal plate) and a vertically downward position (e.g., perpendicular to the stationary portion 197 and extending downward)). The horizontal position may be a use position or treatment position. The vertically downward position may be a stowed position. In at least one embodiment, the movable portion 198 may rotate about up to 180 degrees around the pivot point 189 (e.g., in a range from about zero to 180 degrees). For example, movable portion198 may rotate between the vertically downward position and a vertically upward position (e.g., perpendicular to the stationary portion 197 and extending upward). The vertically upward position may be a use position or treatment position. The movable portion 198 may also be configured to remain at any other angle relative to the stationary portion 197.

[0192] In at least one embodiment, the illuminator system 1105 includes an arm lock 122, as shown in FIG. 8 and FIG. 24, among others. The movable portion 198 may be folded into a vertical position, for example, when the illuminator system 1105 is not in use or is being stored. The movable portion 198 may be rotated into a horizontal position, for example, when the illuminator system 1105 is being used for treatment. The arm lock 122 may be disposed at a location where the movable portion 198 couples with the stationary portion 197. For example, the arm lock 122 may be disposed at the pivot point 189. The pivot point 189 may be disposed approximate to a midpoint of the connecting arm 185 such that the arm lock 122 may be disposed approximate to the midpoint of the connecting arm 185. The arm lock 122 may be activated when no force is applied. To unlock or release the movable portion 198, the arm lock122 may be depressed. The arm lock 122 may automatically lock the movable portion 198 in a position when the movable portion 198 reaches the use position or the fully stowed position.

[0193] The connecting arm 185 is configured to support the illuminator 1100 at the various positions described herein. The movable portion 198 is coupled with the illuminator 1100 via a mounting mechanism 140, as shown in FIG. 11, FIG. 12 and FIG. 13. The mounting mechanism 140 may include a bracket 142 coupled with the movable portion 198. The bracket 142 defines a first rotational axis, shown as bracket axis 144. The bracket 142 may extend from a first side of the movable portion 198. For example, the bracket 142 may extend from a bottom side of the movable portion 198 when the movable portion 1198 is in a horizontal position. The mounting mechanism 140 may further include a plate 146. The plate 146 couples with at least one of the plurality of panels 110 of the illuminator 1100. The plate 146 preferably couples with a central panel (e.g., panel 110c) of the illuminator 1100. The plate 146 is preferably positioned at a central location of the backside of the panel 110. The plate 146 defines a second rotational axis, shown as plate axis 148. The plate axis 148 maybe perpendicular, or substantially perpendicular, to the bracket axis 144.

[0194] In at least one embodiment, the plate 146 includes at least one projection 150. The projection 150 extends from the plate 146 to couple with the bracket 142. In at least one embodiment, the plate 146 includes two projections 150. Coupling the plate 146 with the bracket 142 via the projections 150 facilitates securing of the illuminator 1100 to the movable stand 180. The projections 150 are rotatably coupled with the bracket 142 such that the projections 150 and the plate 146 can rotate about the bracket axis 144. With the illuminator 100 coupled with the plate 146, the illuminator 1100 can rotate about the bracket axis 144. For example, the illuminator can tilt about ± 90 degrees from a stowed position (e.g., with the center panel 110 facing the floor). The bracket 142 may utilize one or more torque inserts that are capable of holding the illuminator 1100 at any position without an additional lock. The movable portion 198 may remain stationary while the illuminator 1100 rotates or tilts.

[0195] As shown in FIG. 14, the illuminator 1100 may rotate or tilt about the bracket axis 144. Rotation about the bracket axis may facilitate placement of the illuminator 1100 for treatment. For example, the illuminator 1100 may be rotated about the bracket axis 144 such that the illuminator 1100 is disposed below the connecting arm 185 (e.g., a stowed or neutral position) with the movable portion 198 in a horizontal position. In such an embodiment, the panels 110 may be facing toward a floor (or ground) where the illuminator system 1105 sits. The central panel 110 of the illuminator may be oriented horizontally.

[0196] The illuminator 1100 may be rotated about the bracket axis 144 such that the illuminator 1100 is disposed on a side of the connecting arm 185. For example, the illuminator 1100 may be rotated about 90 degrees such that the panels 110 face toward a wall. In such an embodiment, the central panel 110 of the illuminator may be oriented vertically. The illuminator 1100 can rotate about 90 degrees (e.g., in a range from about zero degrees up to about 90 degrees) to either the left or right side of the movable portion 198, as shown by the arrows of FIG. 14. As such, the illuminator 1100 can rotate approximately up to 180 degrees around the bracket axis 144 (e.g., in a range from about zero to 180 degrees). The one or more torque inserts can hold the illuminator 1100 at any position through the permitted 180 degree range of motion.

[0197] The plate 146 may be rotatably coupled to the panel 110 such that the panel 110, and the other panels 110 of the illuminator 1100 can rotate about the plate axis 148 relative to the plate 146. For example, as shown in FIGS. 12 and 13, the illuminator 1100 may rotate about 90 degrees from a stowed or neutral position (e.g., the center panel 110 is aligned with the stationary portion 197 of the connecting arm 185). In at least one embodiment, the mounting mechanism 140 includes a positioning guide 152 on the plate 146 and a position indicator 154 on the panel 110. The positioning guide 152 indicates the rotation range of the illuminator 1100 (e.g., about 90 degrees). The position indicator 154 indicates where within the rotation range the illuminator 1100 is currently positioned. For example, as shown in FIG. 13, the positioning guide 152 may indicate that the illuminator 1100 can rotate as long as the position indicator 154 aligns with a portion of the positioning guide 152. As the illuminator 1100 rotates, the positionindicator 154 may travel around the positioning guide 152. When the position indicator 154 reaches an end of the positioning guide 152, the mounting mechanism 140 may prevent the illuminator 1100 from rotating any further in that direction. For example, the mounting mechanism 140 may have a detent at each end of the positioning guide 152 to lock the illuminator 1100 into position. The position of the illuminator 1100 may be locked into a position for treatment when the position indicator 154 aligns with an end of the positioning guide 152.

[0198] The illuminator 1100 can rotate such that the position indicator 154 moves from a first position aligned with a first end of the positioning guide 152 to a second position aligned with a second end of the positioning guide 152. The movement between the first position and the second position can include a rotation of the illuminator 1100 of about 90 degrees. To move between the first and second positions, the illuminator 1100 can move about 90 degrees to the left (e.g., clockwise) or 90 degrees to the right (e.g., counterclockwise). The illuminator 1100 may also move to any intermediate position disposed between the first and second ends of the positioning guide 152. The illuminator 1100 is configured to remain at any desired angle during operation. For example, the position indicator 153 may be disposed between the first and second ends of the positioning guide 152 when the illuminator 1100 is being used.

[0199] As apparent from FIG. 15 A, FIG. 15B, FIG. 16, FIG. 17, FIG. 18, FIG. 19 and FIG. 20, the illuminator 1100 may rotate about both the bracket axis 144 and the plate axis 148 regardless of the position of the movable portion 198 of the connecting arm 185 or the height of the extension member 186. For example, in FIG. 15 A, the extension member 186 is in a low (retracted) position, the movable portion 198 of the connecting arm 185 is in a horizontal position, the illuminator 1100 is rotated about the bracket axis 144 such that the illuminator 1100 is disposed on a left side of the connecting arm 185, and the illuminator 1100 is rotate such that the panels HOa-l lOe are disposed in a horizontal orientation. In FIG. 15B, the extension member 186 is the same low position, movable portion 198 is in the same horizontal position, and the panels 110a- 1 lOe are still oriented in the same horizontal orientation, but the illuminator 1100 is rotated about the bracket axis 144 in the opposite direction such that the illuminator 1100is disposed on a right side of the connecting arm 185. For example, the illuminator 1100 rotated under the connecting arm 185 to switch from the left side to the right side. The same movements can be made when the extension member 186 is extended from, and not fully disposed in, the vertical column 182.

[0200] In FIG. 16, the illuminator 1100 is still disposed on the right side of the connecting arm 185 (as viewed from the right of the figure), but the illuminator 1100 is rotated about the plate axis 148 such that the panels HOa-l lOe are disposed in a vertical orientation. In FIG. 17, the movable portion 198 is oriented vertically and the illuminator 1100 may still rotate about either the plate axis 148 or the bracket axis 144 to a desired orientation. The orientation of the panels 110 with respect to each other can also be modified in any position. For example, with the movable portion 198 in the vertical position, the panels 110 may move between a flat configuration and a folded configuration. For example, FIG. 17 shows the movable portion 198 in a vertical position with the panels 110 in a flat configuration. FIGS. 18 and 19 show the movable portion 198 still in the vertical position, but with the panels 110 in a folded configuration. FIG. 20 shows the movable portion 198 in a horizontal position with the panels 110 in a folded configuration.

[0201] The components of the illuminator system 1105 described herein facilitate movement of the illuminator 1100 to provide uniform light to a desired treatment area. The illuminator 1100 can move between a fully stowed position and various operational positions, and various intermediate positions in between. In the fully stowed position, (i) the extension member 186 is in its lowest position (e.g., a majority of the extension member 186 is disposed in the vertical column 182), (ii) the movable portion 198 of the connecting arm 185 is in a vertically downward position (perpendicular to the stationary portion 197), and (iii) the central panel 110 of the illuminator 1100 is aligned with the movable portion 198 (e.g., vertical and at the neutral position relative to both the bracket axis 144 and the plate axis 148). Further, when the illuminator 100 is fully stowed, the panels 110 of the illuminator 1100 are configured to be maintained in a U-shaped arrangement and to surround at least a portion of the vertical column182. The panels 110 of the illuminator 1100 are foldable within the contours of the base 181 and the vertical column 182.

[0202] In at least one embodiment, an operational position includes the extension member 186 extending at least partially from the vertical column 182 (the vertical column lock 121 can lock the vertical column 182 at any height), the movable portion 198 of the connecting arm 185 being horizontal and parallel with the stationary portion 197, the illuminator 1100 disposed at any orientation relative to the bracket axis 144 and the plate axis 148, and the panels 110 of the illuminator 1100 in any configuration to provide light to the desired treatment area. Regarding the plate axis 148, the illuminator 1100 may be substantially parallel with the movable portion 198 of the connecting arm 185 or may rotate about 90 degrees to be substantially perpendicular to the movable portion 198. The illuminator 100 may also be at any angle between about 0 and about 90 degrees with respect to the plate axis 148. Regarding the bracket axis 144, the illuminator 1100 may be in the neutral position and be in the same vertical plane as the stationary portion 197 of the connecting arm 185, or may either (i) rotate up to about 90 degrees (e.g., in a range from about zero to 90 degrees) in a first direction to be disposed on a first side of the movable portion 198 (out of the plane of the stationary portion 197) or (ii) rotate up to about 90 degrees (e.g., in a range from about zero to 90 degrees) in a second direction to be disposed on a second side of the movable portion 198 (also out of the plane of the stationary portion 197).

[0203] Referring now to FIG. 22, illuminator system 1105 includes a main power switch 196. The main power switch 196 may control when power is supplied to the illuminator system 1105. The main power switch 196 may be a two-position rocker switch that can toggle between two positions. For example, a first position can activate (e.g., turn on power to) the illuminator system 1105 and the second position can deactivate (e.g., disconnect all electrical components of) the illuminator system 1105. The first position can place the illuminator system 1105 in a stand-by mode. At least one emitter (e.g., an LED 160) may be disposed adjacent to the main power switch 196. The emitter is configured to provide illumination when the illuminator system 1105 is in the stand-by mode. The main power switch 196 may be located on the base 181 adjacent to a socket for a removable power cord (e.g., a medical grade power cord).

[0204] As shown in FIG. 23, the illuminator system 1105 includes a vertical column lock 121. The vertical column lock 121 may be disposed below the handle 184. The vertical column lock 121 may be moved between a first position and a second position. The first position may be an up position that unlocks the vertical column 182 such that the extension member 186 can move in and out of the vertical column 182 and the height of the illuminator 1100 can be adjusted. A bezel adjacent to the vertical column lock 121 may be a first predetermined color (e.g., green or another color) when the vertical column lock 121 is in the up position to indicate the vertical column 182 is unlocked. The second position may be a down position that locks the vertical column 182 such that the extension member 186 is fixed at its current position. The bezel adjacent to the vertical column lock 121 may be a second predetermined color (e.g., red or another color) when the vertical column lock 121 is in the down position to indicate the vertical column 182 is locked.

[0205] As shown in FIG. 8 and FIG. 21, the illuminator system 1105 may include an interface panel 190. The interface panel 190 may be supported by the vertical column 182. The interface panel 190 may be coupled with the vertical column 182 and may be removable from the vertical column 182. The interface panel 190 may include any number of buttons, switches, or other control mechanisms that control aspects of the illuminator system 1105. For example, the interface panel 190 may include a power button 191a and a status indicator 191b. The power button 191a may control a setting of the illuminator system 1105. For example, the power button 191a may load one of two pre-programmed treatment cycles to the illuminator system 1105. For example, the last treatment cycle used (e.g., lOmW or 20mW) may be loaded and a time is displayed (e.g., 16:40 or 8:20).

[0206] The status indicator 191b may indicate a status of the illuminator system 1105. For example, different colors or frequencies of the status indicator 191b may have different meanings. For example, a first color (e.g., blue) may indicate a first status (e.g., normal operation) and a second color (e.g., amber) may indicate a second status (e.g., fault condition). A flashing first color may indicate a third status and a solid first color may indicate a fourth status. Actuating the power button 191a (e.g., pressing the button) at predetermined times maycause predetermined actions. For example, pressing the power button 191a while a treatment cycle is “paused” may cancel the treatment cycle to clear the time displayed. Pressing the power button 191a with a main power switch 196 (described in more detail below) activated may toggle to load or clear a treatment cycle for the illuminator system 1105.

[0207] The status indicator 191b may include an array of LEDs disposed around the power button 191a (e.g., in an annular pattern or a different pattern). The status indicator 191b displays a status of the illuminator system 1105. In at least one embodiment, at a beginning of a treatment, the status indicator 191b may illuminate a steady blue (or another color) to indicate that control electronics of the illuminator system 1105 are functioning normally and that associated software is ready for use. The status indicator 191b may change from the steady blue to a slow flashing blue (or another color) when the illuminator system 1105 is placed into a pause mode. In at least one embodiment, another color or other colors may be used. The status indicator 191b may return to a steady blue when the cycle resumes. The status indicator 191b may illuminate a steady amber or flashing amber (or another color) if a fault condition is detected (i.e., in response to detecting a fault).

[0208] The interface panel 190 may include time adjuster 192. For example, the time adjuster 192 may be a button configured to control a treatment time of the panels 110 (e.g., the time the illuminator is activated). A maximum treatment time may be predetermined. For example, a maximum treatment time may be set at thirty minutes. The time adjuster 192 may be used to adjust an exposure time manually or automatically turn off the LEDs of the panels 110 after a set exposure time has lapsed. The time adjuster 192 may include an up button 192a and a down button 192b to increase or decrease the time, respectively. When first depressed, the up button 192a and the down button 192b change a displayed reading relatively slowly (e.g., within a first predetermined time period, such as over fifteen seconds, etc.). When the up button 192a or the down button 192b remain depressed, the displayed reading changes more quickly (e.g., within a second predetermined time period that is shorter than the first time period, e.g., within five seconds). Depressing and releasing the up and down buttons 192a, 192b quickly allows for anadjustment to the displayed time. For example, each depression may adjust the time by a given interval (e.g., by one second).

[0209] The interface panel 190 may include a level adjuster 193. For example, the level adjuster 193 may be a button configured to adjust an intensity or power setting (e.g., power level) of the illuminator 1100. For example, the level adjuster 193 may switch the power between two settings (e.g., lOmW and 20m W). The power level may be selected after pressing the power button and status indicator 191 to load one of the pre-programmed cycles. The time adjuster 192 may automatically set the correct time for the power level selected. The power level selected may be displayed above the level adjuster 193. For example, the lOmW setting may be displayed as “10” and the 20mW setting may be displayed as “20.”

[0210] The interface panel 190 may include a comfort adjuster (comfort controller, patient settings controller) 194. For example, the comfort adjuster 194 may be a button or other interface configured to control a patient comfort fan. For example, the comfort adjuster 194 may be a button or other interface configured to switch a setting of a fan between off, low, and high. The patient comfort fan may be controllable by the healthcare provider or patient upon pressing the power button and status indicator 191 to load the treatment cycle. The comfort adjuster 194 can be used to cycle through the three settings. The patient cooling fans may automatically shut off when a cycle timer reaches zero during treatment.

[0211] The interface panel 190 may include a start / stop button 195. For example, the start / stop button may be configured to initiate the programmed treatment cycle, pause an active treatment cycle, or restart a paused treatment cycle. Pressing the start / stop button 195 while the treatment cycle is active may cause one or more of the following: (i) pausing or cessation of the treatment cycle, (ii) switching off of LEDs, and (iii) terminating a count-down performed by the timer. The power button and status indicator 191 may flash a predetermined color to indicate that the system is paused. The illuminator system 1105 may automatically return to stand-by mode when left paused for a predetermined time or more. For example, the illuminator system 1105 may automatically return to stand-by mode if left paused for over 5 minutes. Pressing the start / stopbutton 195 while the system is paused may cause the treatment cycle to resume, the LEDs 160 to illuminate, and the timer to resume counting down. The power button and status indicator 191 may display a steady predetermined color to indicate normal operating status (e.g., a steady blue color, or another color).

[0212] As shown in FIG. 30, the illuminator system 1105 may include a touch screen 1200. The touch screen 1200 may be a part of the interface panel 190, the controller 1115, or some other independent device (e.g., a user device). The touch screen 1200 may allow a user to control, monitor, and adjust settings of the illuminator system 1105. For example, the touch screen 1200 may include at least one of the power button 191a, the status indicator 191b, the time adjuster 192, the lever adjuster 193, the comfort adjuster 194, and / or the start / stop button 195. The touch screen 1200 may include additional features (e.g., buttons, displays, notifications, etc.) for a user to monitor and control the settings.

[0213] For example, the touch screen 1200 may provide a heat controller 1201 to control the heat directed to the patient for pain management. The touch screen 1200 may provide a notification window 1202 to provide notifications or alerts to the user. The touch screen 1200 may provide a time indicator 1203. The time indicator 1203 may display a time remaining for the treatment. The time displayed on the time indicator 1203 may change as time progresses and may change as adjusted via the time adjuster 192. In at least one embodiment, the remaining exposure time is displayed in minutes and seconds. Prior to pushing the start / stop button 195, the exposure time indicator displays the amount of exposure time set. When the start / stop button 195 is pressed, the exposure time indicator 1203 counts down the amount of exposure time remaining. The exposure time indicator 1203 may turn off automatically when the display reaches zero. The interface panel 190 may include some or all of these additional features, even if the interface panel 190 does not include the touch screen 1200.

[0214] The illuminator system 1105 may include one or more sensors 1110. In at least one embodiment, the illuminator system 1105 may include a sensor 1110 configured to detect a size of a treatment area of a patient. In at least one embodiment, the illuminator system 1105 mayinclude a sensor 1110 configured to detect a position of the illuminator 1100. The position of the illuminator 1100 may include the height of the extension member 186, the orientation of the illuminator 1100 (e.g., vertical, horizontal, to the right or left of the connecting arm 185), or the configuration of the panels 110 (e.g., U-shaped, flat, etc.). The position of the illuminator 1100 and the size of the treatment area can be used to determine the correct light dosing parameters for the treatment. The sensor 1110 can be disposed on any component of the illuminator system 1105. For example, a sensor 1110 may be disposed on the vertical column 182, a panel 110, and / or the connecting arm 185, among others. The sensor 1110 can be any type of sensor configured to detect data indicative of the position of the illuminator.

[0215] The illuminator system 1105 may include a controller 1115. As shown in FIG. 31, the controller 1115 may be configured to monitor and control various components of the illuminator system 1105. For example, the controller 1115 may be configured to control the heat source currents to accommodate differing tissue geometries and to provide differing power levels, including varying the current over time to modulate a patient’s pain tolerance. The variation in current may be in response to input from sensors such as a distance sensor or a sensor that indicates the relative position of the panels.

[0216] In at least one embodiment, the controller 1115 may also be configured to transition the illuminator system 1105 between a curved geometry and a flat geometry and maintain uniformity and power throughout the transition. The controller 1115 may also include a processing circuit 1116. The processing circuit 1116 may include a processor 1117 and a memory 1118. The memory 1118 (e.g., storage device) may include one or more devices (e.g., RAM, EPROM, optical disk storage, magnetic disk storage flash memory, hard disk storage, or any other medium) for storing data and / or computer code for completing or facilitating the various processes and functions described in the present disclosure. The memory 1118 may be or include transitory memory or non-transitory memory and may include any type of information structure for supporting the various activities and information structures described in the present disclosure.

[0217] According to at least one embodiment, the memory 1118 is communicably connected with the processor 1117 and includes computer code for executing (e.g., by the processor 1117) the processes described herein. The processor 1117 may be a general purpose single-chip or multi-chip processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general purpose processor may be a microprocessor or any typical processor, controller, microcontroller, or state machine. The processor 1117 may also be implemented as a combination of computing devices, such as a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. In at least one embodiment, particular processes and methods may be performed by circuitry designed for a given function.

[0218] In at least one embodiment, the memory 1118 may include a dosing parameter database 119. The dosing parameter database 1119 may include relationships between dosing quantities (including exposure time), light intensities, distances between the panels and the treatment surface, and size of the treatment surface, among other data associated with treatment via the illuminator system 1105. For example, a specific duration of exposure to light from the illuminator 1100 can be associated with a specific light intensity, a specific distance between the panels and the treatment surface, and a specific size of the target surface. The processor 1117 can use the data stored in the dosing parameter database 1119 to determine the appropriate dosing parameters for a treatment session for a patient.

[0219] In at least one embodiment, the controller 1115 may include an input / output (I / O) circuit 1120. The I / O circuit 1120 may be configured to receive signals or data from external devices and transmit signals or data to external devices.

[0220] In at least one embodiment, the controller 1115 may include a user interface 1121. The user interface 1121 may be a touch screen. The user interface 1121 may be configured to display the information received by the controller 1115 via the I / O circuit 1120 or retrieved from thememory 1118. The user interface 1121 may be configured to receive input from a user. For example, the user interface 1121 may have interactive sections with which a user can interact with and provide information. The interactive sections may be buttons, switches, or input fields, among others. The controller 1115 may receive the user input via the I / O circuit 1120 and may be configured to store the user input in the memory 1118 or use the user input to generate an output. For example, the user interface 1121 may be configured to provide a display that shows the orientation and position of the illuminator 1100 based on information received from the distance sensors 111 and the sensors 1110. For example, when the illuminator 1100 is in a use configuration, the user interface 1112 may show the illuminator 1100 in its current position. The display may include a current distance of each panel 110 from the treatment area detected by the distance sensors 111.

[0221] In at least one embodiment, the controller 1115 may be communicab ly coupled with one or more components of the illuminator system 1105. For example, the controller 1115 may be communi cably coupled with a distance sensor 111. The distance sensor 111 may be configured to transmit a signal to the controller 1115 indicative of the distance between the panel 110 and the treatment area. The controller 1115 may be communicab ly coupled with a sensor 1110. The sensor 1110 may be configured to transmit a signal to the controller 1115 indicative of the position or orientation of the illuminator 1100. The controller 1115 may be communi cably coupled with the mounting mechanism 140. The controller 1115 may be configured to transmit a command to the mounting mechanism 140 to orient the illuminator 1100 in a desired position. The controller 1115 may be communi cably coupled with the panels 110 of the illuminator 1100. The controller 1115 may be configured to transmit a command to the panels 110 to orient the panels 110 in a desired configuration (e.g., U-shaped). The controller 1115 may be communicably coupled with the components via a wired or wireless connection.

[0222] As seen among FIG. 25, FIG. 26, FIG. 27, FIG. 28, FIG. 29 and FIG. 30, at least one of the panels 110 of the illuminator system 1105 (e.g., panel 110c) may include a patient cooling fan system 166. The patient cooling fan system 166 may be configured to blow air across a surface of the panel 110 such that the air is tangential to a patient’s skin to provide a soothingeffect to the patient. The patient cooling fan system 166 includes a fan plenum 174. The fan plenum 174 may define a serpentine path for air to flow, shown as air path 175. For example, the fan plenum 174 may include a body 178 and a neck 179. The body 178 defines a cavity for receiving the air. The cavity can have a first thickness. The body 178 transitions to the neck 179 that has a second thickness. The first thickness is larger than the second thickness. The neck 179 can define a serpentine air path 175 for the airflow 176 until the air reaches the plenum outlet 177.

[0223] In at least one embodiment, the fan plenum 174 may be disposed within the panel 10. The patient cooling fan system 166 may include a fan 170. The fan 170 may be configured to draw air in from the environment and push the air into the fan plenum 174. The fan 170 can push the air through the air path 175 of the fan plenum 174 to a plenum outlet 177. The air path 175 and the plenum outlet 177 are configured to generate an airflow 176 that moves parallel, or substantially parallel, to the face of the panel 110.

[0224] In at least one embodiment, the panel 110 may include a plurality of fan plenums 174. For example, a first fan plenum 174 may be disposed at a first end of the panel 110 and a second fan plenum 174 may be disposed at a second end of the panel 110. The first and second fan plenums 174 may generate an airflow 176 that is parallel, or substantially parallel, to the face of the panel 110, but a first airflow 176 from the first fan plenum 174 may be directed in a first direction and a second airflow 176 from the second fan plenum 174 may be directed in a second direction. The second direction may be opposite the first direction. For example, the first airflow 176 may move down the face of the panel 110 and the second airflow 176 may move up the face of the panel 110.

[0225] In at least one embodiment, the heat source may be provided separately from the illuminator 1100 or integrated therein. In at least one embodiment, the heat source (a thermal delivery device) may be an infrared (IR) quartz heater. In at least one embodiment, the heat source may comprise frame mounted resistance tape heaters or a plurality of heaters, including at least one selected from the group including IR LEDs, resistance cartridge heaters, positivetemperature coefficient heaters, or IR quartz heaters, as mentioned above. The heat may be deliberately generated and directed towards the area to be treated, as opposed to ambient heat in the clinical setting or byproduct heat from one or more operating mechanisms of the illuminator. In at least one embodiment, the heat is intentionally generated and directed toward the patient and the patient is still further heated by ambient and / or byproduct heat. In at least one embodiment, the heat is administered in the form of a heat mask, such as a sodium acetate mask configured to heat upon crystallization. In at least one embodiment, the heat source is a heating pad.

[0226] Thus, components or operating mechanisms of the illuminator can be configured to generate heat that can be deliberately targeted toward the patient. For example, the illuminator may include one or more fans that draw air across such components or mechanisms to deliver heat to the patient. The heat may alleviate pain or discomfort experienced by the patient. And, as noted above, heating additionally accelerates the conversion of ALA to porphyrin.

[0227] The present techniques, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present disclosure.EXAMPLESExample 1

[0228] A human adult patient with non-melanoma skin cancer is administered sonidegib (daily, 200 mg) for about 6 to about 8 weeks or until one or more side effect symptoms are observed. Side effect symptoms include but are not limited to hair loss, change in taste, tiredness, nausea, diarrhea, weight loss, decreased appetite, vomiting, abdominal pain, itching, and headache. Administration of sonidegib is terminated prior to initiation of photodynamic therapy.

[0229] One photodynamic therapy session is as follows. A topical formulation of about 20% w / w of 5-aminolevulinic acid hydrochloride is applied to the treatment area(s) with thecancerous lesion(s). Treatment area(s) are occluded with a low-density polyethylene barrier and incubated for about 1 to about 3 hours. The treatment area(s) are cleaned, and an optical clarifying agent is applied to the treatment area(s) about 5 to about 10 minutes prior to illumination. The treatment area(s) are then illuminated with blue light at about 417 nm at an irradiance density of about 20 mW / cm2for about 1000 seconds, resulting in a dose of about 20 J / cm2. Photodynamic therapy sessions are repeated about every 4 to about every 6 weeks.

[0230] Alternatively, one photodynamic therapy session is as follows. A topical formulation of 10% w / w of 5-aminolevulinic acid hydrochloride in gel form is applied to the treatment area(s) with the cancerous lesion(s). Treatment area(s) are occluded with a foil barrier and incubated for about 1 to about 3 hours. The treatment area(s) are cleaned, and an optical clarifying agent is applied to the treatment area(s) about 5 to about 10 minutes prior to illumination. The treatment area(s) are then illuminated with red light at 635 nm at an irradiance density to result in a dose of about 37 J / cm2within ten minutes (or 37.5 J / cm2at 630 nm for ten minutes). Photodynamic therapy sessions are repeated about every 4 to about every 6 weeks.

[0231] Optionally, photodynamic therapy is halted to repeat administration of sonidegib for about 6 to about 8 weeks or until side effect symptoms are observed. Photodynamic therapy sessions are then resumed and repeated.Example 2

[0232] A human adult patient with non-melanoma skin cancer is administered sonidegib (daily, 200 mg) until one or more side effect symptoms are observed (e.g., after about 3 months to about 6 months of daily administration of sonidegib). Side effect symptoms include but are not limited to hair loss, change in taste, tiredness, nausea, diarrhea, weight loss, decreased appetite, vomiting, abdominal pain, itching, and headache. Administration of sonidegib is terminated prior to initiation of photodynamic therapy.

[0233] One photodynamic therapy (PDT) session is as follows. A topical formulation of 20% w / w of 5-aminolevulinic acid hydrochloride is applied to the treatment area(s) with thecancerous lesion(s). Treatment area(s) are occluded with a low-density polyethylene barrier and incubated for about 1 to 3 hours. The treatment area(s) are cleaned, and an optical clarifying agent is applied to the treatment area(s) 5 to 10 minutes prior to illumination. The treatment area(s) are then illuminated with blue light at 417 nm at an irradiance density of 20 mW / cm2for about 1000 seconds, resulting in a dose of about 20 J / cm2. Photodynamic therapy sessions are repeated every 4 to 6 weeks until the side effect symptoms due to administration of sonidegib have subsided. Once the side effect symptoms have subsided, treatment with sonidegib is resumed as described above and is again terminated upon observation of one or more side effect symptoms, after which the patient again undergoes PDT until the side effect symptoms subside. This cycle of sonidegib administration and PDT continues as needed for the patient.

[0234] Alternatively, one photodynamic therapy session is as follows. A topical formulation of 10% w / w of 5-aminolevulinic acid hydrochloride in gel form is applied to the treatment area(s) with the cancerous lesion(s). For example, 600 mg of 5-aminolevulinic acid hydrochloride in gel form may be applied. Treatment area(s) are occluded with a foil barrier and incubated for about 1 to 3 hours. The treatment area(s) are cleaned, and an optical clarifying agent is applied to the treatment area(s) 5 to 10 minutes prior to illumination. The treatment area(s) are then illuminated with red light at 635 nm at an irradiance density to result in a dose of about 37 J / cm2within ten minutes (or 37.5 J / cm2at 630 nm for ten minutes). Photodynamic therapy sessions are repeated every 4 to 6 weeks until side effect symptoms due to administration of sonidegib have subsided. Once the side effect symptoms have subsided, treatment with sonidegib is resumed as described above and is again terminated upon observation of one or more side effect symptoms, after which the patient again undergoes PDT until the side effect symptoms subside. This cycle of sonidegib administration and PDT continues as needed for the patient.

[0235] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0236] 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.

[0237] 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 be understood 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.

[0238] 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.

[0239] 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, thedisclosure also contemplates that in some embodiments, 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.

[0240] 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.

[0241] 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.

[0242] 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”).

[0243] 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 rangediscussed 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.

[0244] 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 in a patient in need thereof, the method comprising:(i) administering a hedgehog pathway inhibitor to the patient;(ii) applying to a region of skin on the patient, a topical composition comprising 5- aminolevulinic acid, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;(iii) incubating the topical composition on the region of skin; and(iv) illuminating the region of skin with a light source at an irradiance density of approximately 20 mW / cm2.

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

3. The method of claim 2, 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.

4. The method of any one of claims 1-3, 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.

5. The method of claim 4, 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.

6. The method of any one of claims 1-5, 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.

7. The method of claim 6, 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.

8. The method of claim 6, wherein the penetration enhancer is selected from a group consisting of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol.

9. The method of any one of claims 6-8, wherein the penetration enhancer is present in the topical composition in an amount of about 2% w / w to about 50% w / w.

10. The method of any one of claims 6-9, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 6-10, 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.

12. The method of any one of claims 6-11, wherein the at least one pharmaceutically acceptable excipient further comprises an anti-foaming agent.

13. The method of claim 12, wherein the anti-foaming agent is cyclomethicone.

14. The method of any one of claims 1-13, wherein the incubating step is performed for a period of about 15 minutes to about 10 hours.

15. The method of any one of claims 1-10, further comprising occluding the region of skin during the incubating step and prior to illuminating the region of skin with the light source.

16. The method of claim 15, wherein occluding the region comprises applying a lightblocking occlusive dressing to the region.

17. The method of claim 15, wherein occluding the region comprises applying a transparent film dressing to the region.

18. The method of claim 15, wherein occluding the region comprises applying a low density polyethylene barrier to the region.

19. The method of any of claims 16-18, further comprising applying a secondary barrier over the region that is occluded, wherein the secondary barrier comprises foil or elastic material.

20. The method of any one of claims 1-19, further comprising cleaning the region of skin after the incubating step and prior to the illuminating step.

21. The method of any one of claims 1-20, further comprising heating the region of skin either (1) after the incubating step and before the illuminating step or (2) during the illuminating step.

22. The method of any one of claims 1-21, further comprising heating the region of skin during the incubating step.

23. The method of any one of claims 1-22, wherein the light source delivers blue light.

24. The method of any one of claims 1-22, wherein the light source delivers red light.

25. The method of claim 23, wherein blue light is delivered at about 20 J / cm2.

26. The method of any one of claims 1-25, wherein the hedgehog pathway inhibitor is sonidegib or vismodegib.

27. The method of any one of claims 1-26, wherein the hedgehog pathway inhibitor is daily administered for about 6 weeks to 8 weeks prior to applying the topical composition.

28. The method of any one of claims 1-26, wherein the hedgehog pathway inhibitor is daily administered for about 3 months to about 6 months prior to applying the topical composition.

29. The method of any one of claims 1-26, wherein the hedgehog pathway inhibitor is daily administered until one or more side effects symptoms appear in the patient and prior to applying the topical composition.

30. The method of claim 29, wherein the one or more side effect symptoms comprise hair loss, change in taste, tiredness, nausea, diarrhea, weight loss, decreased appetite, vomiting, abdominal pain, itching, and headache.

31. The method of any one of claims 1-30, further comprising applying an optical clarifying agent to the region of skin prior to the illuminating step.

32. The method of claim 31, wherein the optical clarifying agent is a skin moisturizer.

33. The method of any one of claims 1-32, wherein steps (ii)-(iv) are repeated every 4 to 6 weeks.

34. The method of claim 33, wherein steps (ii)-(iv) are repeated every 4 to 6 weeks until side effect symptoms from step (i) subside from the patient.

35. The method of claim 34, wherein the method is repeated continuously.

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