Literature Review and Commentary

by Alan R. Gaby, MD

Inositol Hexaphosphate and Inositol Induce Remission in Stage IV Melanoma

A 59-year-old man was treated surgically in 2012 for stage IIIB melanoma on the left foot. Around a year later another melanoma lesion was excised from his left shin. In January 2015 he developed a new melanoma lesion on his left thigh, and was found to have mediastinal and hilar lymphadenopathy with multiple pulmonary nodules. At that time he was in stage IVB. He declined immunotherapy and targeted therapy and instead began taking 4,000 mg of inositol hexaphosphate (IP6) and 1,100 mg of inositol twice a day. Six months later, there was significant improvement, including a decrease in the size of the hilar and mediastinal lymph nodes and the lesion on the thigh. He went into complete clinical and radiological remission after being on IP6 and inositol for 2 years. He continued the treatment for another year and remained in remission at the time of this report.

Comment: IP6 (also known as phytate) occurs naturally in corn, soy, wheat bran, nuts, and other high-fiber foods. It is also found in mammalian cells and regulates a number of different biochemical processes. It inhibited many different tumor cell lines in vitro, including colon, breast, and melanoma. Inositol has also demonstrated anticancer properties. In animal studies, the combination of IP6 and inositol had anticancer effects that were greater than those seen with each individual compound. In the present case report, treatment with IP6 and inositol was associated with a complete remission in a patient with advanced melanoma. Controlled trials are needed to confirm these promising findings.

Khurana S, et al. Inositol hexaphosphate plus inositol induced complete remission in stage IV melanoma: a case report. Melanoma Res. 2019;29:322-324.

Fasting Followed by Plant-Foods Diet for Lymphoma

A 42-year-old woman presented with a palpable mass in the right inguinal region and was diagnosed by excisional biopsy with stage IIIa, grade 1 follicular lymphoma. She refused conventional therapy and underwent a medically supervised 21-day water fast, after which the enlarged lymph nodes were substantially smaller. The patient then consumed a diet consisting entirely of whole plant foods free of added sugar, oil and salt. At six- and nine-month follow-up visits, the patient’s lymph nodes were non-palpable, and she remained asymptomatic. CT and PET scans conducted after three years found no evidence of active disease.

Comment: In this case report, a 21-day water fast followed by a diet of whole plant foods appeared to induce remission in a patient with stage IIIa, grade 1 follicular lymphoma. Controlled trials are needed to confirm these promising findings. The mechanism of action of this treatment is not known.

Myers TR, et al. Follow-up of water-only fasting and an exclusively plant food diet in the management of stage IIIa, low-grade follicular lymphoma. BMJ Case Rep. 2018;2018:bcr-2018-225520.

Goldhamer AC, et al. Water-only fasting and an exclusively plant foods diet in the management of stage IIIa, low-grade follicular lymphoma. BMJ Case Rep. 2015;2015:bcr2015211582.

Does Eating Tomatoes Prevent Prostate Cancer?

The association between consumption of tomato products and risk of prostate cancer was examined in a prospective cohort study of 27,934 Adventist men (aged 30 years or older) living in the United States or Canada. The Adventist church recommends a healthy lifestyle, including avoidance of alcohol and smoking, and consumption of a plant-based diet. During 7.9 years of follow-up, 1,226 incident cases of prostate cancer were documented. Consumption of canned and cooked tomatoes more than four times a week, as compared with never consuming this food, was associated with a 28% lower risk of developing prostate cancer (p = 0.02).

Comment: This study is consistent with several other observational studies in which higher intake of tomato products was associated with a lower risk of prostate cancer. The possible anti-cancer effect of tomatoes is thought to be due at least in part to its high content of lycopene, a carotenoid that is known to enhance immune function. Tomatoes also contain a saponin called alpha-tomatine, which inhibited the growth of human prostate cancer cells in vitro.¹

Fraser GE, et al. Tomato consumption and intake of lycopene as predictors of the incidence of prostate cancer: the Adventist Health Study-2. Cancer Causes Control. 2020;31:341-351.

Association Between Meat Consumption, Cooking Methods, and Colorectal Cancer

The association between red and processed meat consumption and risk of colorectal cancer was examined in a prospective cohort study of 48,704 women (aged 35-74 years) in the United States and Puerto Rico who had a sister diagnosed with breast cancer. During a median follow-up period of 8.7 years, 216 colorectal cancer cases were documented. There was an increased risk of colorectal cancer when comparing the highest vs. the lowest quartile of processed meat consumption (hazard ratio [HR] = 1.52; p for trend = 0.02). A similar association was seen for specific meat products, including breakfast sausages and bacon. There was little evidence of an association between red meat consumption and colorectal cancer risk. However, there was a positive association with specific red meat products when cooking methods were considered; for example, grilled/barbequed steaks (HR = 2.23; 95% confidence interval [CI], 1.20-4.14) and hamburgers [HR = 1.98; 95% CI, 1.00-3.91).

Comment: In this study, consumption of processed meat or of red meat cooked at high temperatures was associated with an increased risk of developing colorectal cancer. Many processed meats are preserved by adding nitrites. Nitrites can be converted to carcinogenic nitrosamines in the stomach or during the cooking process. Nitrosamines appear to play a role in the pathogenesis of gastric cancer. In addition, an observational study found that higher intake of nitrosamines was associated with an increased risk of colorectal cancer.² The association between high-temperature cooking of meat and colorectal cancer might be explained in part by the fact that high-temperature cooking of meat results in the formation of carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons.

Mehta SS, et al. A prospective analysis of red and processed meat consumption and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2020;29:141-150.

Ketogenic Diet and Breast Cancer

Sixty Iranian women with locally advanced (n = 44) or metastatic (n = 16) breast cancer were randomly assigned to consume a medium-chain triglyceride-based ketogenic diet or a standard diet during the first three months of chemotherapy. In the patients with locally advanced cancer, Kaplan-Meier analysis conducted over a period of 25 months showed a significantly higher survival rate in those consuming the ketogenic diet than in the control group (p = 0.04).

Comment: Those of you who have followed my writings in the Townsend Letter know that I suspect that most of the nutrition research coming from Iran is fraudulent. There are two issues about the present study that lead me to question its credibility.

First, it does not seem possible to have conducted a 25-month survival analysis. Patients were enrolled between July 2017 and October 2018, and the paper was submitted to the journal on February 12, 2019. The patients who were enrolled near the end of the enrollment period could not have been followed up for more than 5 months. I emailed the man who was listed as having written the paper, and I asked him for clarification. He stated that the follow-up period lasted until June 2019, not February 12, 2019, because one of the reviewers asked him to add a survival analysis and to re-submit the paper. While that could be true, journals typically mention both the date the manuscript was originally received and the date the revisions were received. In this paper, there was no mention of a revised version being received. Even if one accepts the statement that the follow-up period was extended by 4 months, patients who were enrolled near the end of the enrollment period could not have been followed up for more than 9 months.

Second, in the Author Contribution section of the paper, the man with whom I corresponded was listed as having written the paper by himself, although 2 other contributors reviewed the manuscript. In reading this paper, I found it to be fairly well written in terms of grammar, sentence structure, and overall command of the English language. In contrast, the emails sent to me by this author demonstrated a poor grasp of English, containing sentences such as, “. . . we analysed data accord positive and negative. data accord row shown no accord column. . . . Because in metastatic patients diagnosis time differ to admit time to study.” Given the evidence that numerous companies in Iran are in the paper-selling business,³ one wonders who actually wrote this paper.

Khodabakhshi A, et al. Feasibility, safety, and beneficial effects of MCT-based ketogenic diet for breast cancer treatment: a randomized controlled trial study. Nutr Cancer. 2020;72:627-634.

Heating Extra-Virgin Olive Oil Decreases Its Polyphenol Content

Extra-virgin olive oil was processed at two different temperatures (120ºC and 170ºC), either for a short time (30 minutes for 120ºC, 15 minutes for 170ºC) or a long time (60 minutes for 120ºC, 30 minutes for 170ºC), to simulate common pan-frying conditions in a home kitchen. The mean polyphenol content decreased by 40% at 120ºC and by 75% at 170ºC, compared with raw olive oil. Increasing the cooking time decreased the content of hydroxytyrosol but had no significant effect on the content of total polyphenols.

Comment: Some of the beneficial effects of extra-virgin olive oil are thought to be due to hydroxytyrosol and other polyphenols. Hydroxytyrosol functions as an antioxidant and anti-inflammatory agent, as well as an inhibitor of platelet aggregation. Extra-virgin olive is preferable to refined olive oil because most of the polyphenols are lost in the refining process. Olive oil is often recommended for cooking because of its high concentration of monounsaturated fatty acids, which are resistant to heat-induced oxidation. In contrast, oils with high concentrations of polyunsaturated fatty acids (such as sunflower, safflower, and corn oil) are thought to be less safe for cooking because subjecting polyunsaturated fatty acids to high temperatures leads to the formation of potentially atherogenic lipid peroxides.

The present study demonstrates that heating extra-virgin olive oil results in the depletion of one or more of its beneficial constituents. While olive oil may still be preferable to other oils for cooking, the results of this study suggest that the greatest benefits are derived from consuming extra-virgin olive oil uncooked.

Lozano-Castellon J, et al. Domestic sauteing with EVOO: change in the phenolic profile. Antioxidants. 2020;9:E77.

Fish Oil and Cardiovascular Disease: Possible Influence of Polychlorinated Biphenyls

The association between consumption of omega-3 fatty acids from fish (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), dietary exposure to polychlorinated biphenyls (PCBs), and risk of cardiovascular disease was examined in a prospective cohort study of 32,952 women and 36,545 men in Sweden. During a mean follow-up period of 15.5 years, after adjustment for PCBs intake, there was a significant inverse association between EPA/DHA intake and risk of cardiovascular disease (hazard ratio [HR] comparing extreme quintiles, 0.79; p for trend = 0.04). After adjustment for EPA/DHA intake, there was a significant positive association between PCBs intake and risk of cardiovascular disease (HR comparing extreme quintiles, 1.31; p for trend = 0.005).

Comment: PCBs are organochlorine compounds that were used for various industrial and chemical applications. They were banned in the Western world in the 1970s, but they persist in the environment and are detectable in human tissues. PCBs are known to bioaccumulate in fish. In epidemiological studies, exposure to PCBs was associated with increased risk of cardiovascular disease, hypertension, obesity, and diabetes. In the present study, the beneficial effect of fish consumption on cardiovascular disease risk appeared to be compromised by co-exposure to PCBs. This interaction might explain in part the conflicting results in studies that examined the association between fish consumption and cardiovascular disease risk.

Regular use of a sauna may be effective for removing PCBs from the body. The concentration of PCBs in sweat after using a sauna is substantially higher than the concentration in urine. Regular sauna use has been associated with a decreased risk of cardiovascular disease, an effect that might be related in part to the removal of PCBs and other toxic compounds from the body.

Donat-Vargas C, et al. Cardiovascular and cancer mortality in relation to dietary polychlorinated biphenyls and marine polyunsaturated fatty acids: a nutritional-toxicological aspect of fish consumption. J Intern Med. 2020;287:197-209.

Possible Risk Associated with Tartrate-Containing Nutritional Supplements

The authors of this study analyzed the composition of previously unidentified urinary stones from the Mayo Metals laboratory database between 2010 and 2018. Thirty-five calcium tartrate stones were identified in 25 patients from the Mayo database, and two others were identified from the authors’ institution, for a total of 37 calcium tartrate stones in 27 patients. Thirty stones were pure calcium tartrate and the rest had elements of more common stones. The authors were able to locate and question three of the 27 patients. All three reported routine consumption of an energy drink (Spark), typically two-to-four servings per day for periods of one-to-three years. Spark contains (per serving) 500 mg of choline (as bitartrate and citrate) and 10 mg of L-carnitine (as tartrate).

Comment: Tartrate (the salt of tartaric acid) occurs naturally in some fruits and wine. It is also used as a preservative and flavoring agent (it gives foods a sharp, tart flavor). In addition, tartrate is added to some carbonated beverages and fruit jellies. The present study raises the possibility that excessive consumption of tartrate can lead to the formation of calcium tartrate kidney stones. For people supplementing with large amounts of choline or L-carnitine, it might be preferable to use forms other than tartrate or bitartrate salts.

Kleinguetl C, et al. Uncovering a novel stone in 27 patients: calcium tartrate tetrahydrate. Urology. 2019;126:49-53.