PLR increase inhibitor and LMR decrease inhibitor

Abstract

This invention provides a novel means for suppressing the rise in PLR and / or the decline in LMR. [Solution] A PLR increase inhibitor and an LMR decrease inhibitor containing kefir as an active ingredient.

Description

Technical Field

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[0005]

[0001] The present invention relates to a PLR elevation inhibitor and an LMR decrease inhibitor.

Background Art

[0002] Early detection and treatment of cancer are important for cancer treatment. At the same time, accurately predicting the prognosis of patients after cancer treatment is equally important for improving the quality of life of patients in view of subsequent continuous examinations and the balance of patients' lives. Therefore, many researchers have conducted research on prediction methods for the prognosis of patients after cancer treatment.

[0003] White blood cells consist of five types: neutrophils, lymphocytes, basophils, eosinophils, and monocytes. And the following values showing specific ratios among them, namely LMR (Lymphocyte / Monocyte Ratio), NLR (Neutrophil / Lymphocyte Ratio), and PLR (Platelet / Lymphocyte Ratio), have come to be noted as immune markers for predicting the prognosis of patients: LMR = number of lymphocytes ÷ number of monocytes NLR = number of neutrophils ÷ number of lymphocytes PLR = number of platelets ÷ number of lymphocytes

[0004] Lymphocytes are said to play an important role in attacking virus-infected cells and cancer immunity. Lymphocytes include B lymphocytes, T lymphocytes, and natural killer cells. T lymphocytes, especially tumor infiltrating lymphocytes (hereinafter referred to as TIL), are said to play an important role in tumor immunity in the tumor microenvironment, and there are reports that high expression of tumor infiltrating lymphocytes contributes to the improvement of the prognosis of cancer patients. There are reports that a decrease in the number of lymphocytes in peripheral blood also reduces the number of tumor infiltrating lymphocytes that act antitumorally.

[0005] Monocytes differentiate into macrophages upon entering tissue and maturing. Macrophages infiltrate the stroma of cancer tissue and are called tumor-associated macrophages (TAMs). Chemokines released by TAMs are thought to suppress local tumor immunity by acting on Th2 cells and regulatory T cells. There are also reports that they promote cancer cell proliferation by releasing growth factors and cytokines involved in angiogenesis.

[0006] Neutrophils primarily play a role in killing bacteria during bacterial infections. Neutrophil production is induced by tumors producing angiogenic factors such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and is thought to produce and induce platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), matrix proteinase (MMP), and interleukin-6 (IL-6). There are reports that neutrophils create new blood vessels in cancer, promoting cancer growth and metastasis. Furthermore, there are reports that neutrophils suppress various immune cells, including lymphocytes.

[0007] Platelets are blood components produced in the bone marrow and play a central role in the complex reactions involved in hemostasis. Platelets work in conjunction with vascular endothelial cells and coagulation factors present in the plasma to stop bleeding, and they also supply substances necessary for maintaining the normal function of vascular endothelial cells. Furthermore, platelets are believed to be involved in various biological responses, including inflammatory responses, immune responses, infection defense, arteriosclerosis, and cancer metastasis.

[0008] As mentioned above, numerous studies have reported that these blood cell components interact within the immune system and play a wide variety of complex roles, making it difficult to summarize their functions simply. However, surprisingly, it has become clear that the ratio of LMR, NLR, and PLR can serve as an immune marker that predicts patient prognosis with high consistency.

[0009] Non-patent document 1 discloses that pre-treatment LMR is an independent prognostic factor in head and neck cancer patients treated with radiochemoradiotherapy, and that a significant relationship was found between high LMR and laryngeal cancer, T1-T2, and clinical stage I-II. Regarding survival, it discloses that low LMR was significantly correlated with a shortening of overall survival (OS) and disease-free survival (DFS). In short, non-patent document 1 discloses that the group with low LMR had a significantly lower survival rate and a poorer prognosis.

[0010] Non-patent document 2 discloses that low LMR was associated with event-free survival (EFS) as a prognostic indicator for head and neck squamous cell carcinoma (HNSCC), and points out its potential as a risk stratification tool for HNSCC patients in the era of personalized medicine and precision medicine. Event-free survival (EFS) refers to the period from the start date (the time when patients are randomly assigned to one of the groups) or the start of treatment until the occurrence of any event-related death, objective disease progression, or serious adverse event. In short, non-patent document 2 discloses that the group with low LMR had a significantly lower survival rate and a poorer prognosis.

[0011] Non-patent document 3 discloses that LMR and PLR are associated with 5-year overall survival (OS) in patients with resectable oral squamous cell carcinoma (OSCC). In short, non-patent document 3 discloses that the group with low LMR and the group with high PLR had significantly lower survival rates and a poorer prognosis.

[0012] Kefir is a fermented milk product originating from the Caucasus region of Russia. It is produced by fermenting animal milk, such as cow's milk, using kefir grains (kefir granules, kefir bacteria) originating from the Caucasus region as a starter culture. Kefir grains behave almost as if they were a single living organism, but scientifically they are a natural symbiotic organism of various microorganisms, including Lactobacillus kefiri, and one or more species of microorganisms from the genera Leuconostoc, Lactococcus, and Acetobacter, as well as lactose-fermenting yeast (e.g., Kluyveromyces marxianus) and non-lactose-fermenting yeast (e.g., Saccharomyces unisporus, Saccharomyces cerevisiae, Saccharomyces exiguus). In addition to its delicious taste as a fermented milk product, kefir is gaining popularity as a healthy food due to its various health-promoting functions.

[0013] To take advantage of the excellent properties of kefir, attempts have been made to create foods with even greater health-promoting functions by adding various food components to kefir. For example, Patent Document 1 (WO2002 / 076240) discloses a food product to which nattokinase has been added to kefir. Alternatively, for example, Patent Document 2 (JP 2006-75176) discloses the production of soy milk kefir using soy milk. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] International Public Gazette WO2002 / 076240 [Patent Document 2] Japanese Patent Publication No. 2006-75176 [Non-patent literature]

[0015] [Non-Patent Document 1] “Pretreatment lymphocyte-to-monocyte ratio as an independent prognostic factor for head and neck cancer”, Kano, S. et al., HEAD & NECK, February, 2017, Volume39, Issue2, Pages 247-253. https: / / doi.org / 10.1002 / hed.24576 [Non-Patent Document 2] “Systemic immune response in squamous cell carcinoma of the head and neck : a comparative concordance index analysis”, Tham, T. et al., European Archives of Oto-Rhino-Laryngology (2019) 276:2913-2922. https: / / doi.org / 10.1007 / s00405-019-05554-x [Non-Patent Document 3] “Are Comorbidities Associated with Overall Survival in Patients with Oral Squamous Cell Carcinoma?”, Jariod-Ferrer, UM et al., J Oral Maxillofac Surg 77:1906-1914, 2019. https: / / doi.org / 10.1016 / j.joms.2019.03.007 [Non-Patent Document 4] "A study on the usefulness of pre-treatment peripheral blood in predicting the prognosis of patients with oral squamous cell carcinoma," Hideaki Takahashi, Kensaku Matsui, Suguru Hirota, Yukio Yoshioka, Shigeaki Toratani, Tetsuji Okamoto, The 74th Annual Meeting of the Japanese Society of Oral Science (Niigata), April 16, 2020. [Overview of the project] [Problems that the invention aims to solve]

[0016] Under such circumstances, there has been a demand for a novel means of suppressing the increase in PLR and / or suppressing the decrease in LMR, for which a clinical effect regarding the prognosis of cancer patients has been confirmed.

[0017] Therefore, an object of the present invention is to provide a novel means of suppressing the increase in PLR and / or suppressing the decrease in LMR, for which a clinical effect regarding the prognosis of cancer patients has been confirmed.

Means for Solving the Problems

[0018] The present inventor has been engaged in the clinical practice of cancer treatment and has conducted intensive research for many years. As a result, the inventor has found that the increase in PLR and / or the decrease in LMR can be achieved by the means described below, and thus has reached the present invention.

[0019] Therefore, the present invention includes the following (1). (1) An agent for suppressing an increase in PLR, comprising kefir as an active ingredient. (2) An agent for suppressing a decrease in LMR, comprising kefir as an active ingredient. (3) An agent for suppressing an increase in PLR and suppressing a decrease in LMR, comprising kefir as an active ingredient.

[0020] (4) An agent for suppressing an increase in PLR, an agent for suppressing a decrease in LMR, or an agent for suppressing an increase in PLR and suppressing a decrease in LMR for administration to a cancer patient, which is any one of (1) to (3). (5) An agent for suppressing an increase in PLR, an agent for suppressing a decrease in LMR, or an agent for suppressing an increase in PLR and suppressing a decrease in LMR according to (4), wherein the cancer is oral cancer.

[0021] (6) An agent for suppressing an increase in PLR, an agent for suppressing a decrease in LMR, or an agent for suppressing an increase in PLR and suppressing a decrease in LMR according to (4), wherein the administration to the cancer patient is performed from 3 to 21 days before the start of treatment until at least the end of the primary treatment. (7) The cancer treatment performed from the initial consultation to the end of primary treatment is a therapy selected from surgery, chemotherapy, and radiotherapy, or a therapy combining two or more of these, as described in (6), a PLR elevation inhibitor, an LMR reduction inhibitor, or a PLR elevation inhibitor and an LMR reduction inhibitor.

[0022] (8) A pharmaceutical composition for suppressing the rise in PLR, comprising kefir as an active ingredient. (9) A pharmaceutical composition for inhibiting LMR decline, comprising kefir as an active ingredient. (10) A pharmaceutical composition containing kefir as an active ingredient for inhibiting the rise in PLR and the decrease in LMR.

[0023] (11) A food composition for suppressing the rise in PLR, comprising kefir as an active ingredient. (12) A food composition for inhibiting LMR decline, comprising kefir as an active ingredient. (13) A food composition containing kefir as an active ingredient for suppressing the rise in PLR and the decrease in LMR.

[0024] (14) Use of kefir for the manufacture of a pharmaceutical composition for inhibiting PLR increase, a pharmaceutical composition for inhibiting LMR decrease, a pharmaceutical composition for inhibiting PLR increase and LMR decrease, a food composition for inhibiting PLR increase, a food composition for inhibiting LMR decrease, or a food composition for inhibiting PLR increase and LMR decrease. [Effects of the Invention]

[0025] This invention provides a novel means for suppressing the rise in PLR and / or the decline in LMR. The clinical effects of suppressing PLR and / or LMR have already been confirmed regarding the prognosis of cancer patients, and means for achieving these effects have long been sought. This invention provides means for suppressing PLR and / or LMR, and through this suppression, it is expected to improve the prognosis of cancer patients.

[0026] Because the kefir according to the present invention has been consumed by humans for a long period of time, it itself has no side effects or safety concerns, and can be safely administered continuously over a long period of time. In cancer treatment, chemotherapy and radiation therapy are often administered over a long period of time, ranging from several weeks to several months, so the ability to safely administer the kefir continuously over a long period of time is a major advantage of the present invention.

[0027] Furthermore, because the kefir according to the present invention has been consumed by humans for a long period of time, it is highly palatable and easy to take orally. Nausea and other side effects often occur when chemotherapy and / or radiation therapy are administered in cancer treatment, so the excellent palatability and ease of administration are major advantages of the present invention. [Brief explanation of the drawing]

[0028] [Figure 1] Figure 1 shows a graph comparing the difference (LMR value at the end of primary treatment minus the LMR value at the initial consultation) between the kefir-free group and the kefir-consuming group, and a figure showing that there was a significant difference (p<0.0211) between the two groups. [Figure 2] Figure 2 shows a graph comparing the difference (PLR value at the end of primary treatment minus the PLR ​​value at the initial consultation) between the kefir-free group and the kefir-consuming group, and a figure showing that there was a significant difference (p<0.0381) between the two groups. [Modes for carrying out the invention]

[0029] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the specific embodiments listed below.

[0030] [PLR elevation inhibitor, LMR decrease inhibitor, PLR elevation inhibitor and LMR decrease inhibitor] In a preferred embodiment, the present invention provides a PLR elevation inhibitor containing kefir as an active ingredient.

[0031] In a preferred embodiment, the present invention provides an LMR reduction inhibitor containing kefir as an active ingredient.

[0032] In a preferred embodiment, the present invention provides a pre-pleuronidal rheumatoid arthritis (PLR) elevation inhibitor and low-level mesenteric rheumatoid arthritis (LMR) elevation inhibitor containing kefir as an active ingredient. That is, in a preferred embodiment, the present invention is capable of simultaneously achieving both PLR elevation inhibition and LMR reduction inhibition.

[0033] As described above in the background technology section, it has already been confirmed that suppressing the rise in PLR and / or the decline in LMR has clinical effects on the prognosis of cancer patients, and means to achieve these effects have long been sought. The present invention provides means to achieve the suppression of the rise in PLR and / or the decline in LMR, and therefore the above-mentioned effects can be expected through the suppression of the rise in PLR and / or the decline in LMR.

[0034] In a preferred embodiment, the kefir used in the present invention can be manufactured based on known manufacturing methods. Kefir can be manufactured by fermenting animal milk, i.e., milk from cows, horses, sheep, goats, etc., but preferably by adding kefir grains to milk and fermenting it. Furthermore, as the kefir used in the present invention, soy milk kefir and plant-based kefir can also be used, which are manufactured by adding kefir grains to soy milk or other plant-derived raw materials as starting materials and fermenting them. For information on the manufacturing methods of these, see, for example, Japanese Patent Application Publication No. 2006-75176. The kefir used in the present invention includes liquid and fluid kefir, as well as solids such as freeze-dried products thereof, which can be in the form of powders, granules, capsules containing them, etc., and may also be obtained by formulation by known methods.

[0035] Suitable kefir products for use include, commercially available products such as NKG Kefir-D (manufactured by Nippon Kefir Co., Ltd.), NKG Kefir-L (manufactured by Nippon Kefir Co., Ltd.), NKG Kefir-YT (manufactured by Nippon Kefir Co., Ltd.), NKG Kefir-R (manufactured by Nippon Kefir Co., Ltd.), NKG Kefir-SD (manufactured by Nippon Kefir Co., Ltd.), NKG Kefir-P (manufactured by Nippon Kefir Co., Ltd.), and NKG Soy Milk Kefir-SD (manufactured by Nippon Kefir Co., Ltd.).

[0036] The PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention contain kefir as an active ingredient. The PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention may be kefir itself in various forms, or may contain components other than kefir. The PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention can be a composition containing kefir as an active ingredient, for example, a pharmaceutical composition for inhibiting PLR elevation, a pharmaceutical composition for inhibiting LMR reduction, a pharmaceutical composition for inhibiting PLR elevation and LMR reduction, a food composition for inhibiting PLR elevation, a food composition for inhibiting LMR reduction, or a food composition for inhibiting PLR elevation and LMR reduction. In a preferred embodiment, the present invention also relates to a method for producing the above composition, which includes a step of incorporating kefir as an active ingredient. In a preferred embodiment, the present invention also relates to the use of kefir for producing the above composition.

[0037] In preferred embodiments, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention can be in various forms suitable for the method of administration. The PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention can be in the form of, for example, capsules, tablets, granules, powders, syrups, lozenges, licks, chewing gum, gummies, orally disintegrating tablets, drinks, sprays, emulsions, suppositories, injections, ointments, tapes, etc. When administered orally, they can be processed into tablets, capsules, lozenges, syrups, granules, powders, licks, chewing gum, gummies, orally disintegrating tablets, drinks, etc. and taken orally. Administration of the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention can be, for example, oral administration or parenteral administration, preferably oral administration or enteral administration, and particularly preferably oral administration. The PLR ​​elevation inhibitor, LMR decrease inhibitor, and PLR elevation inhibitor and LMR decrease inhibitor of the present invention can also be administered by incorporating them into food, beverages, or animal feed.

[0038] In a preferred embodiment, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention can be in the form of food or beverages. That is, the present invention also exists as a functional food for inhibiting PLR elevation and / or LMR reduction. A suitable form for a functional food is a tablet-shaped supplement. This allows for accurate determination of the amount of active ingredient ingested. Furthermore, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention can be in the form of food additives.

[0039] In a preferred embodiment, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention can be manufactured, for example, by formulating kefir with any additives such as pharmaceutically acceptable excipients. When formulating, the kefir content in the formulation can be, for example, 0.01 to 50% by mass, 0.1 to 25.0% by mass, or for example, 50 to 100% by mass, 75 to 100% by mass, or 90 to 100% by mass. When formulating, pharmaceutically acceptable known additives such as excipients, binders, disintegrants, lubricants, stabilizers, flavoring and deodorizing agents, diluents, and solvents for injection can be used. When formulating, known manufacturing methods can be used. Furthermore, the PLR ​​elevation inhibitor, LMR decrease inhibitor, and PLR elevation inhibitor and LMR decrease inhibitor of the present invention may be supplemented with auxiliary components commonly used in the fields of pharmaceuticals and food, such as lactose, sucrose, liquid sugar, honey, magnesium stearate, hydroxypropyl cellulose, various vitamins, citric acid, malic acid, amino acids, flavorings, inorganic salts, etc., as needed.

[0040] In a preferred embodiment, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation inhibitor and LMR reduction inhibitor of the present invention may be manufactured as a formulation with 100% kefir content by a known method without adding excipients or other additives to kefir.

[0041] [Dosage] In a preferred embodiment, the dosage and frequency of administration of kefir, the active ingredient according to the present invention, vary depending on the method of administration, treatment period, age, body weight, etc. The dosage can be appropriately selected from the range of 1 mg to 50 g per day for adults, for example, from 0.1 g to 50 g, 0.5 to 25 g, or 1 to 10 g per day for adults. The frequency of administration can be appropriately selected from once to several times a day, for example, from 1 to 6 times / day, 1 to 5 times / day, 1 to 4 times / day, 1 to 3 times / day, or 1 to 2 times / day. Since kefir has been consumed as a traditional food for a long period of time, there is no concern about side effects, and it is highly safe, so there is no problem even if the dosage is higher.

[0042] [Timing of administration] In a preferred embodiment, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention may be administered, for example, at least one day, preferably at least two days, preferably at least three days, preferably at least four days, preferably at least five days, preferably at least six days, and even more preferably at least one week before the start of cancer treatment. For example, it may be administered 1 to 21 days, 2 to 21 days, 3 to 21 days, 4 to 21 days, 5 to 21 days, 6 to 21 days before the start of cancer treatment, or 1 to 14 days, 2 to 14 days, 3 to 14 days, 4 to 14 days, 5 to 14 days, 6 to 14 days before the start of cancer treatment, or 1 to 10 days, 2 to 10 days, 3 to 10 days, 4 to 10 days, 5 to 10 days, or 6 to 10 days before the start of cancer treatment. Because kefir has been consumed as a traditional food for centuries, there is no problem with administering it anytime before cancer treatment begins.

[0043] In a preferred embodiment, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation and LMR reduction inhibitor of the present invention are administered, for example, from the aforementioned number of days before the start of cancer treatment until at least the day the primary cancer treatment is completed. "Until at least the day the primary cancer treatment is completed" means that the earliest the administration is completed is the day the primary cancer treatment is completed. In other words, "until at least the day the primary cancer treatment is completed" does not exclude the possibility of continuing to administer kefir after this day. Since kefir has been consumed as a traditional food for a long period of time, there is no problem with it being administered even after the completion of primary cancer treatment. Completion of primary cancer treatment means that curative treatment for the discovered cancer has been completed by surgery, chemotherapy, radiation therapy, or a combination selected from these.

[0044] [Target recipients] In a preferred embodiment, the PLR ​​elevation inhibitor, LMR reduction inhibitor, and PLR elevation inhibitor and LMR reduction inhibitor of the present invention can be administered to cancer patients. In a preferred embodiment, the cancer patients can be oral cancer patients.

[0045] In a preferred mode of implementation, a cancer patient may be a cancer patient receiving cancer treatment. Cancer treatments may include surgical therapy, chemotherapy, radiotherapy, or a combination of these selected from among. Chemotherapy refers to all cancer treatments involving the administration of anticancer drugs, and includes cancer treatments involving the administration of molecularly targeted drugs. Methods of administering anticancer drugs in chemotherapy include all types of administration methods. Examples of chemotherapy include systemic chemotherapy or superselective intra-arterial chemotherapy. Radiotherapy includes all types of radiotherapy.

[0046] [Suppression of PLR increase and suppression of LMR decrease] In this invention, suppression of PLR increase refers to the suppression of the increase in the platelet-to-lymphocyte ratio (PLR) of patients undergoing cancer treatment. Normally, the PLR ​​value at the end of primary treatment rises significantly from the PLR ​​value at the initial consultation.

[0047] In this invention, suppression of LMR decline refers to the suppression of the LMR decline in patients undergoing cancer treatment, where the LMR value at the end of primary treatment is normally significantly lower than the LMR value at the initial consultation.

[0048] As will be described later in the examples, for LMR and PLR, the initial values ​​are those obtained during a series of tests performed at the initial consultation, and the values ​​at the end of primary treatment are those obtained during tests performed before discharge following the completion of primary treatment. As will be described later in the examples, the values ​​that form the basis for these calculations can be counted by means known to those skilled in the art, as counts of white blood cells, platelets, neutrophils, monocytes, and lymphocytes in a normal blood test.

[0049] Although the mechanism by which kefir, the active ingredient in the present invention, suppresses the increase in PLR and the decrease in LMR is unknown, since kefir exhibits these effects through oral administration, i.e., systemic administration, it is thought that its effects are not limited to oral cancer but will show similar effects in suppressing the increase in PLR and the decrease in LMR for cancers in any part of the body.

[0050] [Methods for suppressing PLR increase and LMR decrease] In a preferred embodiment, the present invention also includes a method for suppressing PLR increase and a method for suppressing LMR decrease, comprising the step of administering kefir as an active ingredient to a target. Furthermore, in a preferred embodiment, the present invention also includes a method for suppressing both PLR increase and LMR decrease, comprising the step of administering kefir as an active ingredient to a target, that is, a method for simultaneously achieving PLR increase suppression and LMR decrease suppression. In a preferred embodiment, the above-mentioned target, timing of administration, and dosage can be adopted in these methods. [Examples]

[0051] The present invention will be described in detail below with reference to examples. The present invention is not limited to the examples illustrated below.

[0052] [Clinical research] A clinical study was conducted to investigate the relationship between changes in prognostic markers and prognosis based on whether or not kefir was consumed. Cancer patients were registered after obtaining their consent, based on a clinical research project approved by the Hiroshima University Clinical Research Ethics Committee (Approval Number C2016-0102).

[0053] [Background of cancer patients] Tables 1-1 to 1-3 summarize the characteristics of oral cancer patients who received kefir. Tables 2-1 to 2-2 summarize the characteristics of oral cancer patients who did not receive kefir.

[0054] [Table 1-1]

[0055] [Table 1-2]

[0056] [Table 1-3]

[0057] [Table 2-1]

[0058] [Table 2-2]

[0059] For 45 oral cancer patients diagnosed with squamous cell carcinoma who visited the Department of Oral and Maxillofacial Surgery at Hiroshima University Hospital between November 2016 and October 2018, the lymphocyte / monocyte ratio (LMR) and platelet / lymphocyte ratio (PLR) were calculated based on the white blood cell count, platelet count, neutrophil count, monocyte count, and lymphocyte count in the peripheral blood before treatment. The LMR and PLR values ​​were calculated at the time of initial consultation and at the completion of primary treatment. The initial consultation value refers to the value obtained during a series of tests performed at the initial consultation. The value at the completion of primary treatment refers to the value obtained during tests performed before discharge following completion of primary treatment.

[0060] [Administration of kefir] Kefir was administered orally in two sachets per day, one after breakfast and one after dinner, from one week before the start of treatment until the end of the first course of treatment. Each sachet contained 2.5g of dried kefir in granular form.

[0061] [Examination of changes in prognostic markers (LMR, PLR) depending on whether or not kefir is consumed] Regarding the changes in prognostic markers (LMR, PLR) with and without kefir intake, the difference between "(value at the end of primary treatment) - (value at the initial consultation)" was examined as follows. Note that the end of primary treatment refers to the point in time when treatment was completed by surgery, as shown in Tables 1-1 to 1-3 and Tables 2-1 to 2-2 above. In some cases, treatment was completed by adjuvant chemotherapy or adjuvant radiotherapy after or before surgery, and this point was also considered the end of primary treatment. In some cases, treatment was completed without surgery, after radiotherapy, chemotherapy, or a combination thereof, and this point was also considered the end of primary treatment. Thus, the end of primary treatment refers to the state in which curative treatment for the discovered cancer has been completed by surgery, chemotherapy, radiotherapy, or a combination selected from these.

[0062] The analysis was performed by calculating the difference between "(value at the end of primary treatment) - (value at the initial consultation)" using the statistical analysis software JMP ver13.01 (SAS Institute, Cary, NC, USA) and performing a Wilcoxon two-sample test. In the test, p < 0.05 was considered statistically significant.

[0063] [Results of an examination of changes in prognostic markers (LMR, PLR) depending on whether or not kefir is consumed] [LMR fluctuations] Figure 1 shows the results obtained by performing a Wilcoxon two-sample test on the variation in LMR.

[0064] In Figure 1, the horizontal axis shows the data from the group that did not consume kefir on the left and the data from the group that consumed kefir on the right. The vertical axis of Figure 1 shows the difference between "(LMR value at the end of primary treatment) - (LMR value at the initial consultation)". On the vertical axis of Figure 1, a value of 0 (zero) means that there was no difference between the LMR value at the initial consultation and the LMR value at the end of primary treatment, a value of + (plus) means that the LMR value at the end of primary treatment was greater than the LMR value at the initial consultation, and a value of - (minus) means that the LMR value at the end of primary treatment was less than the LMR value at the initial consultation.

[0065] As shown in Figure 1, the median value in the kefir-free group on the left was negative, indicating that LMR values ​​were generally lower after primary treatment compared to the initial consultation. On the other hand, in the kefir-consuming group on the right in Figure 1, the median value of "(LMR value at the end of primary treatment) - (LMR value at the initial consultation)" was positive, indicating that kefir consumption significantly suppressed the decline in LMR. In other words, it was found that kefir consumption suppressed the decline in LMR.

[0066] [PLR fluctuations] Figure 2 shows the results obtained by performing a Wilcoxon two-sample test on the variation in PLR.

[0067] In Figure 2, the horizontal axis shows the data from the group that did not consume kefir on the left and the data from the group that consumed kefir on the right. The vertical axis of Figure 2 shows the difference between "(PLR value at the end of primary treatment) - (PLR value at the initial consultation)". On the vertical axis of Figure 2, a value of 0 (zero) means that there was no difference between the PLR ​​value at the initial consultation and the PLR ​​value at the end of primary treatment, a value of + (plus) means that the PLR ​​value at the end of primary treatment was greater than the PLR ​​value at the initial consultation, and a value of - (minus) means that the PLR ​​value at the end of primary treatment was less than the PLR ​​value at the initial consultation.

[0068] As shown in Figure 2, the median PLR value in the kefir-free group on the left was positive, indicating that overall PLR values ​​had increased after primary treatment compared to the initial consultation. On the other hand, in the kefir-consuming group on the right in Figure 2, the median value of "(PLR value at the end of primary treatment) - (PLR value at the initial consultation)" was lower compared to the kefir-free group on the left, indicating that kefir consumption significantly suppressed the increase in PLR. In other words, it was found that kefir consumption suppressed the increase in PLR.

[0069] [Summary of findings on the changes in prognostic markers depending on whether or not kefir is consumed] A study examining the changes in prognostic markers from the initial consultation to the end of primary treatment due to kefir intake revealed that the PLR ​​difference was significantly lower in the kefir intake group compared to the non-kefir intake group, indicating that kefir intake suppressed the increase in PLR. Furthermore, the LMR difference was significantly higher in the kefir intake group compared to the non-kefir intake group, indicating that kefir intake suppressed the decrease in LMR. [Industrial applicability]

[0070] This invention provides a PLR increase inhibitor and an LMR decrease inhibitor. This invention is industrially useful.

Claims

1. A PLR elevation inhibitor containing kefir as an active ingredient.

2. An LMR reduction inhibitor containing kefir as an active ingredient.

3. An agent containing kefir as an active ingredient that inhibits the rise in PLR and the decrease in LMR.

4. A PLR elevation inhibitor, an LMR reduction inhibitor, or a PLR elevation inhibitor and LMR reduction inhibitor, according to any one of claims 1 to 3, for administration to cancer patients.

5. The PLR ​​elevation inhibitor, LMR decrease inhibitor, or PLR elevation inhibitor and LMR decrease inhibitor according to claim 4, wherein the cancer is oral cancer.

6. A PLR elevation inhibitor, an LMR reduction inhibitor, or a PLR elevation inhibitor and LMR reduction inhibitor, according to claim 4, wherein administration to cancer patients is carried out from 3 to 21 days before the start of treatment until at least the end of the first treatment.

7. The PLR ​​elevation inhibitor, LMR reduction inhibitor, or PLR elevation inhibitor and LMR reduction inhibitor according to claim 6, wherein the cancer treatment performed from the initial consultation to the end of primary treatment is a therapy selected from surgical therapy, chemotherapy, and radiotherapy, or a therapy combining two or more of these.

8. A pharmaceutical composition for suppressing the rise in PLR, comprising kefir as an active ingredient.

9. A pharmaceutical composition for inhibiting LMR decline, comprising kefir as an active ingredient.

10. A pharmaceutical composition containing kefir as an active ingredient for suppressing the rise in PLR and the decrease in LMR.

11. A food composition for suppressing PLR elevation, comprising kefir as an active ingredient.

12. A food composition for suppressing LMR decline, comprising kefir as an active ingredient.

13. A food composition containing kefir as an active ingredient for suppressing the rise in PLR and the decrease in LMR.

14. Use of kefir for the manufacture of a pharmaceutical composition for inhibiting PLR increase, a pharmaceutical composition for inhibiting LMR decrease, a pharmaceutical composition for inhibiting PLR increase and LMR decrease, a food composition for inhibiting PLR increase, a food composition for inhibiting LMR decrease, or a food composition for inhibiting PLR increase and LMR decrease.

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