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.

Protective effects of coffee consumption following liver transplantation for hepatocellular carcinoma in cirrhosis.

BACKGROUND: Increasing evidence suggests that coffee consumption might protect against hepatocellular carcinoma (HCC) and liver cirrhosis-associated death risk. Caffeine is a natural antagonist to extracellular adenosine and exhibits experimental tumoricidal activity. AIM: To evaluate if coffee consumption has beneficial effects on HCC recurrence after orthotopic liver transplantation (OLT). METHODS: Coffee consumption of patients before and after OLT for HCC was assessed and correlated with HCC recurrence. HepG2 cells were analysed for proliferation and metastasis potential after treatment with adenosine, in the presence or absence of adenosine receptor antagonists. Expression of adenosine receptors was determined, and known adenosine-mediated cancer pathways inclusive of MAPK and NF-kappa B were tested. RESULTS: Ninety patients underwent OLT for HCC. Sixteen (17.8%) patients experienced HCC recurrence after median time of 11.5 months (range 1-40.5). For overall survival postoperative coffee intake emerged as major factor of hazard reduction in a multivariate analysis (HR = 0.2936, 95% CI = 0.12-0.71, P = 0.006). Those with such postoperative coffee intake (≥3 cups per day) had a longer overall survival than those who consumed less or no coffee: M = 11.0 years, SD = 0.52 years vs. M = 7.48 years, SD = 0.76 years = 4.7, P = 0.029). CONCLUSIONS: Coffee consumption is associated with a decreased risk of HCC recurrence and provides for increased survival following OLT. We suggest that these results might be, at least in part, associated with the antagonist activity of caffeine on adenosine-A2AR mediated growth-promoting effects on HCC cells.

Vitamin D Supplementation and Survival of Patients with Non-small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non-small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D-binding protein (DBP) and survival were also examined.Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089-97. ©2018 AACR.

High Consumption of Green Tea Suppresses Urinary Tract Recurrence of Urothelial Cancer via Down-regulation of Human Antigen-R Expression in Never Smokers.

BACKGROUND/AIM: Smoking is a risk factor for carcinogenesis and progression of urothelial cancer (UC). Green tea polyphenol inhibits these malignant behaviors and suppresses human antigen R (HuR) expression, which is associated with malignant aggressiveness. This study aimed to clarify the anti-cancer effects of green tea based on the smoking status of UC patients. PATIENTS AND METHODS: Three hundred and sixty (260 with bladder cancer, BC and 100 with upper tract UC) patients were divided into three groups based on consumption of green tea: low (<1 cup/day, n=119), middle (1-4 cup/day, n=160), and high (>5 cup/day, n=81). HuR immunoreactivity was evaluated immunohistochemically in formalin-fixed specimens. RESULTS: In never smokers, multivariate analysis showed that the frequency of green tea consumption was a significant predictor (middle: hazard ratio, HR, 0.36, p=0.002; high: HR, 0.20, p=0.003) of urinary tract recurrence. A high consumption of green tea was associated with low rates of urinary tract recurrence and up-grading in UC patients. In BC, high consumption was associated with a lower risk of up-grading (p=0.011) and up-staging (p=0.041) in recurrent cancer. HuR expression in the high-consumption group was lower (p=0.019) than that in other groups. These significant findings were not detected in ever smokers. CONCLUSION: High consumption of green tea suppressed urinary tract recurrence and the risks of up-grading and up-staging by recurrence in never smokers. Our results suggested that HuR expression played important roles in such mechanisms.

The Role of Docosahexaenoic Acid (DHA) in the Control of Obesity and Metabolic Derangements in Breast Cancer.

Obesity represents a major under-recognized preventable risk factor for cancer development and recurrence, including breast cancer (BC). Healthy diet and correct lifestyle play crucial role for the treatment of obesity and for the prevention of BC. Obesity is significantly prevalent in western countries and it contributes to almost 50% of BC in older women. Mechanisms underlying obesity, such as inflammation and insulin resistance, are also involved in BC development. Fatty acids are among the most extensively studied dietary factors, whose changes appear to be closely related with BC risk. Alterations of specific ω-3 polyunsaturated fatty acids (PUFAs), particularly low basal docosahexaenoic acid (DHA) levels, appear to be important in increasing cancer risk and its relapse, influencing its progression and prognosis and affecting the response to treatments. On the other hand, DHA supplementation increases the response to anticancer therapies and reduces the undesired side effects of anticancer therapies. Experimental and clinical evidence shows that higher fish consumption or intake of DHA reduces BC cell growth and its relapse risk. Controversy exists on the potential anticancer effects of marine ω-3 PUFAs and especially DHA, and larger clinical trials appear mandatory to clarify these aspects. The present review article is aimed at exploring the capacity of DHA in controlling obesity-related inflammation and in reducing insulin resistance in BC development, progression, and response to therapies.

Effects of Pre-surgical Vitamin D Supplementation and Ketogenic Diet in a Patient with Recurrent Breast Cancer.

BACKGROUND: A woman, mother of one at the age of 19 years, was diagnosed with mammary adenocarcinoma in the right breast in 1985 at the age of 37 years. The patient underwent surgery (quadrantectomy), lymphadenectomy and radiotherapy. In 1999, an adenocarcinoma was diagnosed in the left breast, followed by adequate resection, radiotherapy and anti-oestrogen receptor treatment for 6 years. In March 2014, an infiltrating adenocarcinoma was diagnosed in the remaining part of the right breast that had been operated on and irradiated in 1985. CASE REPORT: The pre-surgical biopsy, showed weak positivity for progesterone receptor (PgR) (<1%), high positivity for oestrogen receptor (ER) (90%), high positivity for human epidermal growth factor receptor (HER2) (>10%, score 2+), and high positivity for the nuclear protein Ki67 (30%). In the three weeks between diagnosis and operation, when no other treatment had been planned, the patient decided to self-administer high doses of oral vitamin D3 (10,000 IU/day), and to follow a strict ketogenic diet. RESULTS: Following right mastectomy, analysis of the surgical specimen showed no positivity for HER2 expression (negative, score 0), and significant increase in positivity of PgR (20%). Positivity for ER and Ki67 were unaltered. CONCLUSION: This observation indicates that a combination of high-dose vitamin D3 and ketogenic diet leads to changes in some biological markers of breast cancer, i.e. negativization of HER2 expression and increased expression of PgR.

The COLON study: Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that may influence colorectal tumour recurrence, survival and quality of life.

BACKGROUND: There is clear evidence that nutrition and lifestyle can modify colorectal cancer risk. However, it is not clear if those factors can affect colorectal cancer treatment, recurrence, survival and quality of life. This paper describes the background and design of the "COlorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that may influence colorectal tumour recurrence, survival and quality of life" - COLON - study. The main aim of this study is to assess associations of diet and other lifestyle factors, with colorectal cancer recurrence, survival and quality of life. We extensively investigate diet and lifestyle of colorectal cancer patients at diagnosis and during the following years; this design paper focusses on the initial exposures of interest: diet and dietary supplement use, body composition, nutrient status (e.g. vitamin D), and composition of the gut microbiota. METHODS/DESIGN: The COLON study is a multi-centre prospective cohort study among at least 1,000 incident colorectal cancer patients recruited from 11 hospitals in the Netherlands. Patients with colorectal cancer are invited upon diagnosis. Upon recruitment, after 6 months, 2 years and 5 years, patients fill out food-frequency questionnaires; questionnaires about dietary supplement use, physical activity, weight, height, and quality of life; and donate blood samples. Diagnostic CT-scans are collected to assess cross-sectional areas of skeletal muscle, subcutaneous fat, visceral fat and intermuscular fat, and to assess muscle attenuation. Blood samples are biobanked to facilitate future analyse of biomarkers, nutrients, DNA etc. Analysis of serum 25-hydroxy vitamin D levels, and analysis of metabolomic profiles are scheduled. A subgroup of patients with colon cancer is asked to provide faecal samples before and at several time points after colon resection to study changes in gut microbiota during treatment. For all patients, information on vital status is retrieved by linkage with national registries. Information on clinical characteristics is gathered from linkage with the Netherlands Cancer Registry and with hospital databases. Hazards ratios will be calculated for dietary and lifestyle factors at diagnosis in relation to recurrence and survival. Repeated measures analyses will be performed to assess changes over time in dietary and other factors in relation to recurrence and survival.

Randomized, double-blind, placebo-controlled crossover study in men with prostate cancer and rising PSA: effectiveness of a dietary supplement.

OBJECTIVES: Epidemiological studies have shown significant relationships between the use of dietary components and prostate cancer incidence and mortality. Large studies of primary prevention, which confirm these findings, are desirable but costly and difficult to design. The present tertiary prevention study reports on the effect of a dietary supplement in comparison with placebo on the rate of increase of prostate-specific antigen (PSA). METHODS: 49 patients with a history of prostate cancer and rising PSA levels after radical prostatectomy (n = 34) or radiotherapy (n = 15) participated in a randomised, double-blind, placebo-controlled crossover study of a dietary supplement. Ethical approval of the protocol was obtained. Treatment periods of 10 weeks were separated by a 4-week washout period. The supplement consisted of soy, isoflavones, lycopene, silymarin and antioxidants as main ingredients. Changes in the rate of increase of PSA (PSA slope and doubling time) were the primary parameters of efficacy. Analyses according to intention to treat (ITT) and per protocol (PP) were carried out. RESULTS: Baseline parameters did not differ between randomised groups. Five participants were lost to follow-up, however 46 could be evaluated in an ITT analysis. PP analysis could be performed in 42 men with at least 5 PSA measurements. Per protocol analysis showed a significant decrease in PSA slope (p = 0.030) and (2)log PSA slope (p = 0.041). This translates into a 2.6 fold increase in the PSA doubling time from 445 to 1150 days for the supplement and placebo periods. No treatment-based changes in safety parameters were observed during the study. CONCLUSIONS: The soy-based dietary supplement utilised in this study was shown to delay PSA progression after potentially curative treatment in a significant fashion. More extensive studies of the supplement may be indicated.

Reliability and validity of a self-administered food frequency questionnaire in a chemoprevention trial of adenoma recurrence.

Various chemoprevention trials have assessed dietary intake by means of food frequency questionnaires. However, it is important to assess the degree to which such questionnaires can measure diet. We conducted reproducibility and validity analyses of our Arizona Food Frequency Questionnaire (AFFQ) in our recently completed, randomized, Phase III chemoprevention trial testing the effects of a wheat bran fiber supplement on colorectal adenoma recurrence. A total of 139 individuals provided a baseline and year 1 AFFQ and a set of 4-day dietary records collected over a period of 1 month. The reproducibility analyses of the AFFQ administered 1 year apart showed a mean intraclass correlation of 0.54 for unadjusted nutrients and 0.48 for energy-adjusted nutrients. The relative validity of the AFFQ, as compared with the average of the 4-day diet records, showed a mean deattenuated correlation of 0.49 (range, 0.22-0.65) for the baseline AFFQ and 0.49 (range, 0.25-0.67) for the year 1 AFFQ. When data from both AFFQs were combined and compared with the diet records, there was a slight improvement in the overall deattenuated correlations (mean, 0.56; range, 0.33-0.71). The correlations we observed for macro- and micronutrient intake were within the overall range of those reported in the literature. Reliability and validity studies of dietary instruments are feasible in the setting of a chemoprevention trial and should be conducted when the instrument's performance has not been previously assessed in the target population.

The role of dietary manipulation in biochemical recurrence of prostate cancer after radical prostatectomy.

In 1999, we continue to be faced with difficulties in treating prostate cancer, which remains the leading cause of cancer and the second leading cause of cancer-related deaths in men. In the prostate-specific antigen (PSA) era, we must also determine which therapies, if any, are appropriate for the treatment of a biochemical or PSA relapse. In view of the limited number of efficacious and durable treatments for prostate cancer recurrence, the medical community has had to investigate nontraditional therapies. In the recent past, an expanding body of evidence has implicated certain nutrients in carcinogenesis and cancer progression. This article discusses the role of diet in prostate carcinogenesis and the rationale for dietary manipulation as a treatment strategy for the prevention of primary and secondary (recurrent) prostate cancer.

Chemoprevention of metachronous adenomas of the large bowel: design and interim results of a randomized trial of calcium and fibre. ECP Colon Group.

A European multicentric intervention study, led by the colon group of the European Cancer Prevention Organization, is under way. The main aim of the study is to test the efficacy of oral calcium supplementation with 2 g calcium per day and oral dietary supplementation with mucilaginous substances (as 3.8 g of ispaghula husk) on adenoma recurrence. Secondary aims are the study of treatment efficacy on colonic cell proliferation and on stool bile acid and sterol concentration. Serum and plasma samples are also collected. To better interpret the effect of the intervention, a diet history questionnaire and an aspirin and anti-inflammatory drug questionnaire are administered. The aim will be achieved through a randomized placebo-controlled clinical trial using a parallel design in patients aged 35 to 75 at entry with a complete colonoscopy and a clean colon. Overall, 655 subjects have been included. All randomized patients are followed up every six months for 3 years. If one of the evaluated interventions proves efficient, the benefits of a simple, safe and inexpensive prophylaxy for a very common cancer will be clear.