Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery: a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03).

PURPOSE: Capecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery. METHODS: A total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale. RESULTS: There were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively). CONCLUSION: This trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS. TRIAL REGISTRATION: UMIN000024784.

Exploring the Potential Use of Natural Products Together with Alkalization in Cancer Therapy.

Cancer treatment is a significant focus in medicine, owing to the increasing global incidence of cancers. Patients with advanced cancers that do not respond to conventional therapies have limited options and an unfavorable prognosis. Consequently, researchers are investigating complementary approaches to conventional treatments. One such approach is alkalization therapy, which aims to neutralize the acidic tumor microenvironment (TME) by increasing its pH level. The acidic TME promotes inflammation, tumor progression, and drug resistance. Alkalization therapy has been demonstrated to be effective for various cancers. In addition, natural products, such as triterpenoids, parthenolides, fulvic acid, Taxus yunnanensis, and apple pectin have the potential to alleviate symptoms, maintain physical fitness, and improve treatment outcomes of cancer patients through their anti-inflammatory, antioxidant, and anticancer properties. In this review, we focus on the effects of alkalization therapy and natural products on cancer. Furthermore, we present a case series of advanced cancer patients who received alkalization therapy and natural products alongside standard treatments, resulting in long-term survival. We posit that alkalization therapy together with supplementation with natural products may confer benefits to cancer patients, by mitigating the side effects of chemotherapy and complementing standard treatments. However, further research is warranted to validate these clinical findings.

Effects of alkalization therapy on hepatocellular carcinoma: a retrospective study.

Background: In hepatocellular carcinoma (HCC) patients, is difficult to prevent recurrence even when remission is achieved. In addition, even with the advent of drugs that are effective for the treatment of HCC, a satisfactory extension of patient survival has not been achieved. To overcome this situation, we hypothesized that the combination of alkalization therapy with standard treatments will improve the prognosis of HCC. We here report the clinical results of HCC patients treated with alkalization therapy at our clinic. Patients and methods: Patients with HCC treated at Karasuma Wada Clinic (in Kyoto, Japan), from January 1, 2013, to December 31, 2020 were analyzed. Overall survival (OS) from both the time of diagnosis and the start of alkalization therapy for each patient was compared. The mean urine pH was also calculated as a surrogate marker of tumor microenvironment pH, and OS from the start of alkalization therapy was compared between patients with a mean urine pH of ≥ 7.0 and those with a mean urine pH of < 7.0. Results: Twenty-three men and six women were included in the analysis, with a mean age at diagnosis of 64.1 years (range: 37-87 years). Seven of the 29 patients had extrahepatic metastases. Patients were divided into two groups according to their mean urine pH after the initiation of alkalization therapy: 12 of the 29 patients had a mean urine pH of ≥ 7.0, and 17 had a mean urine pH of < 7.0. The median OS from diagnosis was 95.6 months (95% confidence interval [CI] = 24.7-not reached), and from the start of alkalization therapy was 42.3 months (95% CI = 8.93-not reached). The median OS from the start of alkalization therapy in patients with a urine pH of ≥ 7.0 was not reached (n = 12, 95% CI = 3.0-not reached), which was significantly longer than that in patients with a pH of < 7.0 (15.4 months, n = 17, 95% CI = 5.8-not reached, p < 0.05). Conclusions: The addition of alkalization therapy to standard therapies may be associated with more favorable outcomes in HCC patients with increased urine pH after alkalization therapy.

Corrigendum: Effects of alkalization therapy on hepatocellular carcinoma: a retrospective study.

[This corrects the article DOI: 10.3389/fonc.2023.1179049.].

Potential of Alkalization Therapy for the Management of Metastatic Pancreatic Cancer: A Retrospective Study.

Current treatments for patients with pancreatic cancer offer limited benefits. In this study, we applied alkalization therapy, which was efficacious for other solid tumors at our clinic, to stage 4 pancreatic cancer patients, and investigated its effect on disease prognosis. Patients with metastatic pancreatic cancer who were treated at Karasuma Wada Clinic in Kyoto, Japan, between January 2011 and April 2022, were included in the study. All patients received alkalization therapy (a combination of an alkaline diet, bicarbonate, and citric acid administration), alongside standard chemotherapy. Urine samples were collected to assess urine pH as a marker of whole-body alkalization. In the 98 patients analyzed, the median overall survival (OS) from the time of diagnosis was 13.2 months. Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH (p = 0.0639). Alkalization therapy may offer a viable approach to extending the survival of stage 4 pancreatic cancer patients, who typically have an unfavorable prognosis.

Retrospective observational study of a novel smartphone app on the management of patients with mild cognitive impairment or mild dementia.

Introduction: In this study, we aimed to evaluate the feasibility, utility, and potential effects of LQ-M/D App, a smartphone application developed by Life Quest Inc., Tokyo, Japan, for patients with mild cognitive impairment (MCI) and mild dementia. The app incorporates cognitive and physical exercise training, lifestyle habit acquisition features, and a continuity improvement feature added in the post-update version to enhance user engagement. The continuity improvement feature includes the optimization of training content, and disease education, and enables family monitoring via a family app. Methods: A retrospective analysis was conducted on app usage, cognitive and exercise training implementation and interruptions, questionnaire response rates, and cognitive assessments in a single institution. A total of 20 patients used the app, with 10 patients using the pre-update version without the continuity improvement feature, and the other 10 patients using the post-update version with the continuity improvement feature. Results and Conclusion: The results demonstrated that the LQ-M/D App could be effectively used by the study population, and the continuity improvement feature positively influenced app usage in several aspects. Although a potential association between app usage and cognitive ability was suggested, the scatter in the data points warrants cautious interpretation. Limitations of the study included a small sample size, a single institution setting, and the retrospective nature of the study. In the future, a randomized controlled trial design using a larger sample size and multiple institutions to further evaluate the effectiveness of LQ-M/D App in managing MCI and mild dementia should be performed.

Meaning and Significance of "Alkalization Therapy for Cancer".

Objectives of the Study: Our research aims to answer the following questions. Can cancer progression be stopped by changing the body condition of person with cancer? Can cancer be cured?If cancer progression can be stopped, what is the underlying mechanism? Theoretical Rationale for Alkalization Therapy: Almost 70 years ago, Goldblatt H. & Cameron G. reported on the idea of alkalization therapy. Before that, Otto Warburg had been studying the metabolism of cancer and had discovered the essential nature of cancer. He published a review in Science in 1956 under the title "On the origin of cancer cells". From his phenomena described above, we established the theoretical rationale for alkalization therapy, based on the question of "How does cancer form and what is its nature"? Limitations of Deductive Methods and Inductive Approaches: In this paper, we describe a method to reconstruct the limitations and weaknesses of modern cancer medicine as Science-based Medicine using an inductive method, and to present a new vision of cancer therapy. How should we treat cancer? (Case presentation): Using a specific clinical case, we present patients in whom were successfully treated with no or few anticancer drugs. Summary: The biggest weakness of current cancer treatments is that they only treat the cancer and not the actual patient. The "alkalization therapy" that we advocate does not compete with any of the current standard treatments, but improves the effectiveness of standard treatments, reduces side effects, and lowers medical costs.

Clinical review of alkalization therapy in cancer treatment.

One of the most unique characteristics of cancer metabolism is activated aerobic glycolysis, which is called the "Warburg effect", and is a hallmark of cancer. An acidic tumor microenvironment (TME) resulting from activated anaerobic glycolysis is associated with cancer progression, multi-drug resistance, and immune escape. Several in vitro and in vivo studies reported that neutralization of the acidic TME by alkalizing agents, such as bicarbonate, resulted in the suppression of cancer progression and a potential benefit for anti-cancer drug responses. In clinical settings, alkalizing effects were achieved not only by alkalizing agents, but also by a following a particular diet. An epidemiological study demonstrated that more fruits and vegetables and less meat and dairy products are associated with an increase in urine pH, which may reflect the alkalizing effect on the body. However, it remains unclear whether alkaline dietary intervention improves the effects of cancer treatment. Moreover, there are few clinical reports to date regarding cancer treatments being performed on patients together with alkalization therapy. In this review, we investigated whether alkalization therapy, which includes an alkaline diet and/or alkalizing agents, improves cancer treatment.

Understanding of cell death induced by the constituents of Taxus yunnanensis wood.

The ethanol extract from the wood of Taxus Yunnanensis (TY) induced apoptosis in all cancer cell lines tested, which was mainly due to activation of an extrinsic pathway in human colon cancer DLD-1 cells. The extrinsic pathway was activated by the upregulation of the expression levels of Fas and TRAIL/DR5, which led to the activation of caspase-8. Of note, the machinery of this increase in expression was promoted by the upregulation of MIR32a expression, which silenced MIR34a-targeting E2F3 transcription factor. Furthermore, ectopic expression of MIR32a or siR-E2F3 silencing E2F3 increased Fas and TRAIL/DR5 expression. Thus, the extract activated the extrinsic pathway through the MIR34a/E2F3 axis, resulting in the autocrine and paracrine release of TRAIL, and upregulated expression of death receptors Fas and DR5 in the treated DLD-1 cells, which were functionally validated by Fas immunocytochemistry, and using anti-Fas and anti-TRAIL antibodies, respectively. In vivo, TY showed significant anti-tumor effects on xenografted and syngeneic model mice. The extract may also aid in chemoprevention by selectively making marked tumor cells susceptible to the tumor immunosurveillance system.

Improved Chemotherapy Outcomes of Patients With Small-cell Lung Cancer Treated With Combined Alkalization Therapy and Intravenous Vitamin C.

Background/Aim: This study aimed to investigate the effects of the combination of alkalization therapy (an alkaline diet and bicarbonate therapy) and intravenous vitamin C treatment on chemotherapy outcomes in patients with small-cell lung cancer (SCLC) (study registration: UMIN000043056). Patients and Methods: Twelve patients with SCLC in the intervention group (receiving both alkalization therapy and vitamin C treatment together with chemotherapy) were retrospectively compared to 15 patients with SCLC in the control group (receiving chemotherapy only). Results: The mean urine pH of the intervention group was significantly higher than that of the control group (7.32±0.45 vs. 6.44±0.74, respectively; p<0.005). The median overall survival for the intervention group was 44.2 months (95% confidence interval=22.0-not reached), as compared with 17.7 months for the control group (95% confidence intervaI=13.5-not reached; p<0.05). Conclusion: The combination of alkalization therapy and intravenous vitamin C treatment may be associated with favorable outcomes in patients with SCLC receiving chemotherapy.

[Usefulness of serum procalcitonin measurement in the diagnosis of respiratory infectious diseases].

The serum concentration of procalcitonin (PCT) is specifically elevated in severe bacterial infections. In Japan, PCT has been used as a serum marker for bacterial sepsis since February, 2006. However, the evidence of it in respiratory infectious diseases is limited. In the present study, we analyzed 57 episodes of systemic inflammatory response syndrome in 53 inpatients to investigate the usefulness of serum PCT measurement in respiratory infectious diseases. Although the sensitivity and a negative predictive value in common bacterial infections were low, the specificity and positive predictive value were 95% and 93%, respectively. This suggests that the significance of serum PCT measurement relies on confirming the diagnosis of common bacterial infections. Analysis using a receiver operating characteristic (ROC) curve demonstrated that serum PCT was a more reliable measure of bacterial sepsis than leukocyte counts in the peripheral blood or serum C-reactive protein. In cases of community-acquired pneumonia, except atypical pneumonia, the hospital mortality rate was significantly higher in PCT-positive patients than in PCT-negative patients (38% vs. 0%), indicating that serum PCT could be a factor predicting in-hospital death.

Effects of Alkalization Therapy on Chemotherapy Outcomes in Metastatic or Recurrent Pancreatic Cancer.

BACKGROUND/AIM: The acidic tumor microenvironment is associated both with the progression and drug resistance of cancer. We aimed to investigate the effects of alkalization therapy performed concurrently with chemotherapy on the survival of advanced pancreatic cancer patients (study registration: UMIN 000035659). PATIENTS AND METHODS: Twenty-eight patients with metastatic or recurrent pancreatic cancer were assessed in this study. Alkalization therapy consisted of an alkaline diet with supplementary oral sodium bicarbonate (3.0-5.0 g/day). RESULTS: The mean urine pH was significantly higher after the alkalization therapy (6.85±0.74 vs. 6.39±0.92; p<0.05). The median overall survival from the start of alkalization therapy of the patients with high urine pH (>7.0) was significantly longer than those with low urine pH (≤ 7.0) (16.1 vs. 4.7 months; p<0.05). CONCLUSION: An alkalization therapy may be associated with better outcomes in advanced pancreatic cancer patients treated with chemotherapy.

Effects of Alkalization Therapy on Chemotherapy Outcomes in Advanced Pancreatic Cancer: A Retrospective Case-Control Study.

BACKGROUND/AIM: Neutralization of the acidic tumor microenvironment, which is associated with both progression and drug resistance of cancer cells, may be a new treatment option for progressing forms of cancer. We conducted a case-control study to investigate the effects of alkalization therapy, consisting of an alkaline diet with supplementary oral sodium bicarbonate, in patients with metastatic or recurrent pancreatic cancer (study registration no.: UMIN000036126). PATIENTS AND METHODS: Thirty-six patients in the alkalization group (Karasuma Wada Clinic; alkalization therapy plus chemotherapy) were retrospectively compared to 89 patients in the control group (Kyoto University Hospital; chemotherapy only). RESULTS: The median overall survival (OS) in the alkalization group was significantly longer than that in the control group (15.4 vs. 10.8 months; p<0.005). In the alkalization group, mean urine pH was significantly increased after alkalization therapy [6.38±0.85 (before) vs. 6.80±0.71 (after); p<0.05]. Furthermore, the median OS of patients with increased urine pH (pH>7.0 or ΔpH>1.0) in the alkalization group was significantly longer than that of the control group. CONCLUSION: Alkalization therapy may enhance the effects of chemotherapy in patients with advanced pancreatic cancer.

[A case of sarcoidosis with pleural involvement but with no mediastinal or hilar lymph node enlargement].

A 66-year-old woman was referred to our hospital because of right chest pain on inspiration. Chest X-ray film revealed diffuse opacities, predominantly in the lower lung field, and right pleural thickening. Serum ACE and lysozyme levels were elevated. Chest CT revealed diffuse ground-glass opacity, centrilobular granular nodules, bronchovascular bundle irregular thickening and right pleural irregular thickening over the right inferior lobe, but bilateral hilar lymph node enlargement was not present. Bronchoalveolar lavage (BAL) fluid demonstrated increased numbers of total cells and CD4 T-helper lymphocytes. The transbronchial lung biopsy specimen revealed non-caseating epithelioid cell granulomas. From these findings, we established a diagnosis of type III sarcoidosis with pleural involvement. The patient has been observed without treatment, and 10 months later the lung involvement and pleural thickening have disappeared.

[A case of hypersensitivity pneumonitis resulting from inhalation of Aspergillus niger in a greenhouse worker who raised roses].

A 57-year-old woman was referred because of exertional dyspnea, fever, and cough in June 2006. She had been employed to culture roses in greenhouses since 1991 and had developed a cough during the summer from 2003. Chest CT scan revealed diffuse centrilobular micronodules. Transbronchial lung biopsy specimens demonstrated alveolitis with lymphocytes and non-necrotizing epithelioid cell granulomas. After admission, both the patient's symptoms and laboratory data improved without medication. However, upon her return to work in the greenhouse, cough and exertional dyspnea reappeared. Aspergillus niger was detected in the greenhouse. Her serum was assayed for precipitating antibodies against various antigens, and precipitating antibodies against Aspergillus fumigatus, Aspergillus flavus, Aspergillus glaucus, and Aspergillus niger were demonstrated. In a double immunodiffusion test, cross-reactivity between Aspergillus niger and other Aspergillus species was indicated. Consequently, she was diagnosed as having hypersensitivity pneumonitis resulting from the inhalation of Aspergillus niger.

[A case of extranodal NK/T-cell lymphoma, nasal type, with skin ulceration and multiple nodules in the lung].

We report a rare case of extranodal NK/T-cell lymphoma, nasal type, with skin ulceration and multiple nodules in the lung, and will compare this case with others in the literature. A 54-year-old man was troubled with flare and swelling of his right arm for one month. He was referred to our hospital because of subcutaneous nodules with ulceration on the right arm, fever, and general fatigue. Chest radiograph revealed multiple nodular shadows in both lungs. The patient was admitted for further evaluation. Chest computed tomography revealed multiple nodules in both lungs with ground-glass opacities around some of them. Some nodules seemed to be clustered in the right lower lobe. Biopsy specimens of subcutaneous nodules and transbronchial biopsy specimens of pulmonary tissue demonstrated only extensive necrosis. A VATS lung biopsy from the right S9 was then taken. Pathological and immunohistological findings suggested a diagnosis of extranodal NK/T-cell lymphoma, nasal type (WHO classification), stage IVB. The patient was transferred to the department of hematology in another hospital for systemic chemotherapy, but died 2 months later.

Efficacy of oral administration of cystine and theanine in patients with colorectal cancer undergoing capecitabine-based adjuvant chemotherapy after surgery: study protocol for a multi-institutional, randomised, double-blinded, placebo-controlled, phase II trial.

INTRODUCTION: Although adjuvant capecitabine therapy for patients with colorectal cancer after surgery often causes adverse events (AEs), such as diarrhoea, stomatitis, anorexia and hand-foot syndrome (HFS), there are no standard prevention therapies. Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and are also expected to attenuate the AEs caused by capecitabine treatment. Therefore, our present study aimed to determine the safety and efficacy of cystine/theanine therapy in patients with colorectal cancer undergoing capecitabine-based adjuvant chemotherapy after surgery. METHODS AND ANALYSIS: A multi-institutional, prospective, randomised, double-blinded, placebo-controlled, phase II trial is being planned. Patients with colorectal cancer treated with capecitabine as an adjuvant chemotherapy will be randomised into either the cystine/theanine group (n=50) or placebo group (n=50). Data will be collected during four courses of capecitabine therapy. The primary endpoint will be incidence rate of diarrhoea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints are incidence rates of other AEs (CTCAE v.4.0-JCOG), scores of the Japanese version of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire module for all patients with cancer (QLQ-C30) and for patients with colorectal cancer (QLQ-CR29), incidence rate of HFS according to the HFS grading scale, protocol adherence, completion rate of four courses of capecitabine therapy and the proportion of completion without delay or dose reduction, time to completion of four courses of capecitabine and total dose of capecitabine. A sample size of 100 patients will be analysed between November 2016 and April 2018. ETHICS AND DISSEMINATION: Ethical approval was obtained at all participating institutions. The results of this study will be submitted for publication in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000024784; Pre-results.

[An autopsy case of invasive thymoma extending to the right atrium with superior vena cava syndrome as the initial manifestation].

We report a case of invasive thymoma presenting with superior vena caval obstruction and intracardiac extension. A 74-year-old man was admitted in July 2002 with swelling of the face and right upper extremity. Computed tomography of the chest revealed a small anterior mediastinal mass, which infiltrated the lumen of the superior vena cava extending into the right atrium. Invasive thymoma was strongly suspected, but he refused any medical treatment. His health declined steadily, with repeated right-sided heart failure. He died due to cardiac tamponade 50 months after his first visit. On autopsy, the tumor was diagnosed as a thymoma classified as type B3 according to the WHO histological classification. Formation of a tumor thrombus in the superior vena cava and the right atrium is a rare mode of extension of thymoma. In this respect, our case may be valuable for improving the understanding of the natural course of invasive thymoma.

Effects of an Alkaline Diet on EGFR-TKI Therapy in EGFR Mutation-positive NSCLC.

BACKGROUND: The acidic tumor microenvironment is associated with progression of cancers. The purpose of this study was to investigate the association between an alkaline diet and the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eleven advanced or recurrent NSCLC patients with EGFR mutations treated with EGFR-TKI after being instructed to follow an alkaline diet were retrospectively evaluated. RESULTS: The median progression-free survival (PFS) and overall survival (OS) were 19.5 (range=3.1-33.8) and 28.5 (range=15.4-46.6) months. The average dosage of EGFR-TKI was 56±22% of the standard dosage. Urine pH was significantly increased after the alkaline diet (6.00±0.38 vs. 6.95±0.55; p<0.05). CONCLUSION: An alkaline diet may enhance the effect of EGFR-TKI treatment in NSCLC patients with EGFR mutations.