Summary: Magnesium, important for the human body for many reasons, can help with hot flashes due to menopause and treatment for breast and prostate cancer.

Hot flashes occur during the onset of menopause as abrupt changes in estrogen levels elicit vasomotor reactions through the hypothalamus, and they can also occur as estrogen levels are suppressed by chemotherapy in breast cancer treatment. A study recently published in the journal Supportive Care in Cancer presents evidence that magnesium helps to reduce menopausal hot flashes in breast cancer patients.

The authors derived a hot flash score from frequency and severity of hot flashes in breast cancer patients who had been experiencing at least 14 hot flashes a week, before and after taking 400 mg of magnesium oxide 400 mg for 4 weeks. The study subjects were allowed to increase the dose to 800 mg if needed. The results were impressive…

“The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 to 27.7, a 41.4% reduction… Hot flash score was reduced from 109.8, a 50.4% reduction. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial.”

These results are welcome because magnesium, the fourth most abundant mineral in the human body plays a vital role in hundreds of important pathways and is frequently subject to depletion. It is the ‘calming mineral’. The patients whose hot flashes were reduced likely obtained other benefits. The authors conclude:

“Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal.”

These findings are echoed in another report published in the Journal of Clinical Oncology. The author states:

“Hot flashes are common with natural menopause or induced estrogen deficiency from chemotherapy, tamoxifen, raloxifene, or the aromatase inhibitors. As many as 90% of perimenopausal women have hot flashes, and 40% of survivors of breast cancer rate their hot flashes rate the effect as “quite a bit” to “severe”.”

He notes that the common medications for hot flashes…

“…have potential adverse effects. Antidepressants can cause mental, emotional, and physical adverse effects. Megestrol acetate and medroxyprogesterone acetate, while effective, can potentially cause fluid retention, premenstrual symptoms, and deep vein thrombosis.”

He goes on to report clinical experience consonant with the previous study:

“Recently I saw two patients with breast cancer who volunteered that when they began magnesium supplements for reasons other than hot flashes, their hot flashes diminished within 24 hours and had not returned. In each case, the person was not expecting any relief from magnesium, so placebo effect is unlikely.”

It should be noted that men undergoing hormone blockade therapy for prostate cancer can also suffer from hot flashes. The potential benefits of magnesium apply to them too.

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Summary: women in the highest third of blood glucose levels were almost twice as likely to develop colorectal cancer over the course of the study.

More evidence that high blood sugar contributes to cancer is presented in a study just published in the British Journal of Cancer that examines the link between elevated fasting glucose and colorectal cancer in postmenopausal women. The authors state:

“It is unclear whether circulating insulin or glucose levels are associated with increased risk of colorectal cancer. Few prospective studies have examined this question, and only one study had repeated measurements.”

So they examined baseline fasting serum insulin and glucose values for 4902 non-diabetic women over 12 years, during which 81 cases of colorectal cancer turned up. The data showed a significant trend:

“Baseline glucose levels were positively associated with colorectal cancer and colon cancer risk: multivariable-adjusted hazard ratio (HR) comparing the highest (greater than or equal to 99.5 mg dl−1) with the lowest tertile (<89.5 mg dl−1): 1.74 and 2.25, respectively. Serum insulin and homeostasis model assessment were not associated with risk.”

In other words, glucose in the highest third almost doubles the risk. In this non-diabetic group an association with fasting insulin levels was not observed. However, I can say through extensive experience over 2-3 years having patients suffer through an extended glucose + insulin tolerance test that insulin can be often elevated later in the test but not in the fasting sample. The authors conclude:

“These data suggest that elevated serum glucose levels may be a risk factor for colorectal cancer in postmenopausal women.”

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Summary: the most extensive study to date reveals a modest but significant increase in breast cancer risk from alcohol consumption that should be balanced against the risk for cardiovascular disease.

An important study just published in JAMA (the Journal of the American Medical Association) goes further than all previous studies in examining the association between modest alcohol consumption over extended periods of time and breast cancer. The authors state:

“Multiple studies have linked alcohol consumption to breast cancer risk, but the risk of lower levels of consumption has not been well quantified. In addition, the role of drinking patterns (ie, frequency of drinking and “binge” drinking) and consumption at different times of adult life are not well understood.”

This new study is important because it followed women over a longer period of time and included for factors that can also alter breast cancer risk such as pregnancy, ionizing radiation, etc. in 105,986 nurses over 28 years as the authors set out to…

“…evaluate the association of breast cancer with alcohol consumption during adult life, including quantity, frequency, and age at consumption.”

Their data show that the amount of alcohol rather than frequency of drinking is associated with breast cancer risk, and that age doesn’t matter:

“During 2.4 million person-years of follow-up, 7690 cases of invasive breast cancer were diagnosed. Increasing alcohol consumption was associated with increased breast cancer risk that was statistically significant at levels as low as 5.0 to 9.9 g per day, equivalent to 3 to 6 drinks per week. Binge drinking, but not frequency of drinking, was associated with breast cancer risk after controlling for cumulative alcohol intake. Alcohol intake both earlier and later in adult life was independently associated with risk.”

Analysis of their data also revealed a trend for a 10% increase in breast cancer risk for each 10 gram increase in alcohol consumption. The mechanism is not certain, but because the greatest impact was on hormone receptor-positive breast cancer it is likely related to the tendency for alcohol to increase circulating levels of estrogen. The authors conclude:

“Low levels of alcohol consumption were associated with a small increase in breast cancer risk, with the most consistent measure being cumulative alcohol intake throughout adult life. Alcohol intake both earlier and later in adult life was independently associated with risk.”

As with everything else in medicine, the information needs to be considered in the context of each woman’s individual health and family history, including the balance of risks for cancer and heart disease.

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Summary:

• The use of PSA as a screening tool for aggressive prostate cancer (PCa) is not supported by scientific studies of its effectiveness.
• Many men are subject to disabling, sometimes even fatal, interventions based on PSA tests when they would never have developed aggressive prostate cancer.
• The U.S. Preventive Services Task Force has prepared a draft recommendation to stop screening in those who have not been diagnosed with prostate cancer.
• There are many who, having benefited from PSA screening for PCa, feel strongly that this recommendation by the USPSTF is irresponsible.
• A broader understanding of the underlying causes of elevated PSA and PCa offers a ‘middle path’ of judicious PSA screening, with a meaningful action plan that doesn’t corner patients and doctors into risky invasive procedures or the anxiety of doing nothing. Factors such as insulin resistance and estrogen-testosterone balance are of vital importance for prostate and general health.

Anyone reading this is surely aware of the controversy swirling around the  draft recommendation statement of the U.S. Preventive Services Task Force (USPSTF) that…

“…recommends against prostate-specific antigen (PSA)-based screening for prostate cancer…This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history.”

The Task Force did not evaluate the use of the PSA test for men with highly suspicious symptoms or those with a diagnosis prostate cancer. This recommendation is based on a number of studies finding that PSA (including PSA velocity, the rate at which PSA goes up) is a poor predictor of prostate cancer in general and aggressive prostate cancer in particular, and the assertion that widespread screening has resulted in many unnecessarily invasive and debilitating procedures that themselves can be disabling and even fatal. Feelings are riding high as a large body of public health statistics is pitted against those who feel that a PSA test may have saved their life or the life of a patient. But practitioners and patients face more than a quandary—the debate as it’s currently framed is flawed by a glaring omission.

The PSA discussion is presently structured to assume that the response to a rising PSA can only be ignored (in favor of ‘watchful waiting’) or acted on with invasive biopsies that can seriously damage quality of life and aggressive therapies for what may in fact be indolent, slow growing tumors. That’s it, the clinical decision-making path would appear to fork into only those two roads. Here’s the problem: there is a surprising blind spot for the extensive body of science done on the underlying causes of prostate cancer that offer important opportunities to benefit.  Bear in mind that inflammation or enlargement of prostate tissue caused by various disrupting factors can elevate PSA. These can often be treated with lifestyle or wholesome, non-invasive measures that also reduce the risk of other conditions like diabetes and cardiovascular disease. You may wish to read earlier posts on this topic by typing ‘prostate’ in the search box above. For now consider a couple of the most glaring omissions:

To ignore the role of insulin resistance and metabolic syndrome in prostate disease is gigantic clinical error. Consider just one paper published recently in Nature Reviews Urology in which the authors state:

“The metabolic syndrome is common in countries with Western lifestyles. It comprises a number of disorders—including insulin resistance, hypertension and obesity—that all act as risk factors for cardiovascular diseases. Urological diseases have also been linked to the metabolic syndrome. Most established aspects of the metabolic syndrome are linked to benign prostatic hyperplasia (BPH) and prostate cancer. Fasting plasma insulin, in particular, has been linked to BPH and incident, aggressive and lethal prostate cancer.”

Moreover…

“Overall, the results of studies on urological aspects of the metabolic syndrome seem to indicate that BPH and prostate cancer could be regarded as two new aspects of the metabolic syndrome, and that an increased insulin level is a common underlying aberration that promotes both BPH and clinical prostate cancer.”

This is so important yet has been so ignored. Here it is again:

“Key points

• The metabolic syndrome is a cluster of disorders, including type 2 diabetes, atherosclerotic disease manifestations, hypertension, obesity and dyslipidemia, and is prevalent in countries with Western lifestyles
• The most important common underlying endocrine aberration of these disorders is an increased insulin level, which is also linked to benign prostatic hyperplasia (BPH) and prostate cancer
• Most aspects of the metabolic syndrome are risk factors for BPH and prostate cancer, which seems to suggest that these tumors are themselves aspects of the metabolic syndrome”

Insulin at high levels due to receptor resistance damages sensitive tissues and can act as a tumor promoter. The authors conclude:

“Urologists need to be aware of the effect that the metabolic syndrome has on urological disorders and should transfer this knowledge to their patients.”

Another of the most egregious omissions in prostate cancer management and prevention is attendance to the role played by estrogens in PCa development and progression. Consider a paper published in 2007 in the Journal of Cellular Biochemistry in which the authors observe:

“Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer.”

Furthermore…

“Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression…In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells.”

After reviewing other aspects estrogen stimulation of prostate tissue including the opposing role of ERα and ERβ receptors, the authors conclude:

“In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest.”

The authors of a review published subsequently in European Urology recognized the dual role of estrogen receptors in prostate cancer when they set out to…

“…examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.”

They report evidence for the effects of estrogenic stimulation of prostate tissue:

“The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models…The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor…The progressive emergence of the ERα and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth.”

Moreover…

“The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling.”

The authors also conclude:

“Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression.”

A paper just published in the journal Endocrinology and Metabolism Clinics of North America echoes the theme:

“The mainstay targets for hormonal prostate cancer (PCa) therapies are based on negating androgen action. Recent epidemiologic and experimental data have pinpointed the key roles of estrogens in PCa development and progression. Racial and geographic differences, as well as age-associated changes, in estrogen synthesis and metabolism contribute significantly to the etiology.”

The authors go on to report on how estrogens and estrogen mimics contribute to development of PCa, and the roles of the different estrogen mediators in the process.

As is often the case, the principle of balance comes into play as examined in a fine paper published in The Journal of Steroid Biochemistry & Molecular Biology on the estrogen:androgen ratio in the prostate gland. The authors state:

“Although androgens and estrogens both play significant roles in the prostate, it is their combined action – and specifically their balance – that is critically important in maintaining prostate health and tissue homeostasis in adulthood. In men, serum testosterone levels drop by about 35% between the ages of 21 and 85 while estradiol levels remain constant or increase. This changing androgen:estrogen (T:E) ratio has been implicated in the development of benign and malignant prostate disease.”

They review the role of the aromatase enzyme in the production of estrogens from androgens, and the fact that its aberrant expression plays a critical role in the development of malignancy in a number of tissues. In the case of PCa, it leads to an altered T:E ratio that is associated with the development of disease. And since we do have for treatment purposes wholesome modulators of estrogen receptor function as well as aromatase enzyme inhibitors…

“The role of estrogen and the T:E balance in the prostate is further complicated by the differential actions of both estrogen receptors, α and β. Stimulation of ERα leads to aberrant proliferation, inflammation and pre-malignant pathology; whereas activation of ERβ appears to have beneficial effects regarding cellular proliferation and a putative protective role against carcinogenesis.”

Clinicians who manage, support patients with, or endeavor to prevent prostate cancer must bear their conclusion in mind:

“Overall, these data reveal that homeostasis in the normal prostate involves a finely tuned balance between androgens and estrogens. This has identified estrogen, in addition to androgens, as integral to maintaining normal prostate health, but also as an important mediator of prostate disease.”

A more comprehensive perspective on the use of PSA

There far more evidence for the application of these and other factors in prostate cancer development and expression that are equally important for conditions ranging from cardiovascular disease and diabetes to dementia than can be presented in this post. It is clear, however, that we must go beyond the fascination with the false promise of ‘silver bullet’ medications and lure of lucrative procedures to properly examine and treat the more complex web of underlying factors that support prostate cancer. In the judicious hands of a skilled clinician who has the knowledge and experience to evaluate the risk of prostate cancer in the context of the total health of their patient, observing an elevation of PSA offers more than a specter of indecision over the stark choices of invasive procedures or doing nothing. It is an opportunity to intervene in positive and wholesome ways that advance the overall, not just prostate, health of the patient in their care.

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A sound personalized strategy for eating, exercise and evidence-based supplementation to support healthy insulin regulation decreases the risk for a host of diseases. A paper just published in the journal Hepatology identifies metabolic syndrome as a major risk factor for liver cancer. The authors state:

“Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the United States. We therefore examined the association between metabolic syndrome and the development of these cancers.”

They examined the data for 3649 HCC cases and 743 ICC cases in comparison with 195,953 control subjects for the prevalence of metabolic syndrome (taking into consideration other risk factors for HCC (hepatitis, alcoholic liver disease, etc) and ICC (biliary cirrhosis, cholangitis, hepatitis, alcoholic liver disease, inflammatory bowel disease, etc). What did the data show?

“Metabolic syndrome was significantly more common among persons who developed HCC and ICC than the comparison group. In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio = 2.13) and ICC (odds ratio = 1.56).”

In other words, the adjusted odds ratio for hepatocellular carcinoma (HCC) was 213% (more than double) and 56% for intrahepatic cholangiocarcinoma (ICC). And very significantly, 43% of the patients with liver cancer had no other previously established risk factors for it. Considering that both HCC and ICC are on the increase, the authors’ conclusion is notable:

“Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population.”

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More can be done to prevent skin cancer than shield against excessive exposure to ultraviolet radiation. There is a growing body of evidence supporting the effectiveness of substances taken internally for skin protection and health. Consider a paper published in the journal Photochemical & Photobiological Sciences in which the authors observe:

“Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer…Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis…A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties.”

They examined selected chemopreventive including apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against cancer causing UV radiatoin in laboratory and living systems. Having attended to the mechanism of chemopreventive action of these dietary botanicals they concluded:

“We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation.”

A paper published last year in Archives of Dermatological Research updated the data on polyphenols and other phytochemicals as skin cancer chemopreventive agents with special reference to the effect of suboptimal immunefunction on vulnerability to skin cancer . The authors state:

“Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc.. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse, or retard the process of these harmful events in the UV-exposed skin.”

They examined data from a number of studies on the photoprotective effects of green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, particularly in reference to UV-induced skin inflammation, oxidative stress, and DNA damage. The authors conclude:

“The laboratory studies conducted in animal models, suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage.”

Of great interest is a paper published in the journal Cancer Letters that specifically considers the role of UV radiation-induced immune suppression. The authors note:

“Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression…Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis.”

Their summary of studies investigating the photoprotective efficacy of dietary agents included green tea polyphenols, grape seed proanthocyanidins and silymarin. Based on this body of data they…

“…present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) The induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) Stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis….The supplementation of the use of sunscreens with these dietary agents may provide an effective strategy for the prevention of melanoma and nonmelanoma skin cancers in humans. The dietary botanical agents discussed are considered to be non-toxic and pharmacologically safe for human consumption.”

More recently there have been investigations of the chemopreventive properties of specific agents, such as a paper published in Experimental Dermatology on an extract of Curcuma longa (turmeric).

“…[partial purification from C. longa (PPC)] was used to investigate the alpha-melanocyte-stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway…In cells stimulated α-MSH, PPC inhibited cellular melanin contents, tyrosinase activity and expression of melanogenesis-related proteins including microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein (TRP)…was activated by PPC in α-MSH-stimulated B16F10 cells…MEK/ERK or Akt activation by PPC may contribute to reduced melanin synthesis via MITF and its downstream signal pathway including tyrosinase and TRPs in α-MSH-induced melanogenesis.”

In other words, the turmeric extract was shown to regulate pathways intrinsic to the production of melanoma in a way that would inhibit its development. More evidence for the inhibitory effect on melanogenesis of curcumin, the principal medicinal extract of turmeric, was recently reported in the journal Phytotherapy Research. The authors observe:

“Plant derived compounds, as potentially safe and effective skin lightening agents (SLAs), have attracted great attention from many researchers. Curcumin is a plant-derived polyphenol, which has been reported to suppress melanogenesis in B16 melanoma cells.”

They specifically investigated whether curcumin affects the development of melanoma in cultured human melanocytes. Additionally, they sought to elucidate the molecular mechanisms by assessing the effects of curcumin on melanin synthesis, cellular tyrosinase activity, the expression of melanogenesis-related proteins, tyrosinase, tyrosinase-related protein 1 and 2, and the activation of a number of melanogenesis-regulating signals in human melanoma cells. The data they obtained is very promising:

“The results showed that the melanin content and tyrosinase activity, as well as the expression of melanogenesis-related proteins in human melanocytes, were significantly inhibited by curcumin in a dose dependent manner. In addition, PI3K/Akt/ GSK 3β, ERK and p38 MAPK were activated by curcumin, while inhibitors of these signals attenuated the inhibitory effects of curcumin on melanogenesis.”

Thus they concluded…

“These results suggest that curcumin inhibits melanogenesis in human melanocytes through activation of Akt/GSK 3β, ERK or p38 MAPK signaling pathways.”

And another study just published in the International Journal of Molecular Medicine demonstrates the same findings.

 ”The present study was designed to assess the potential inhibitory activity of curcumin on the α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway in B16F10 melanoma cells. The molecular mechanism of curcumin-induced inhibitory activity on the α-MSH-stimulated melanogenesis signal pathway, including expression of melanogenesis-related proteins and activation of melanogenesis-regulating proteins, was examined in B16F10 cells.”

The authors report essentially the same effects of curcumin as described in the earlier paper, including the influence of tyrosinase activity, the expression of melanogenesis-related proteins, and melanogenesis-regulating signals. They state in conclusion:

“Our results suggest that the suppressive activity of curcumin on α-MSH-stimulated melanogenesis may involve the down-regulation of MITF and its downstream signal pathway through the activation of MEK/ERK or PI3K/Akt.”

Evidence has been accumulating for some time that green tea polyphenols also protect against skin carcinogenesis. A paper published in Photodermatology, Photoimmunology & Photomedicine reported that green tea constituents protect against UV-induced DNA damage. The authors state:

“Antioxidant compounds in green tea may be able to protect against skin carcinogenesis and it is of interest to investigate the mechanisms involved. A study was therefore conducted to determine whether the isolated green tea polyphenol (−)-epigallocatechin gallate (EGCG) could prevent ultraviolet radiation (UVR)-induced DNA damage in cultured human cells.”

Of special interest is that…

“This work was then extended to investigate whether drinking green tea could afford any UVR protection to human peripheral blood cells collected after tea ingestion.”

They compared DNA damage induced by UVR in cultured human cells with and without EGCG, and then conducted the same assay on peripheral white blood cells isolated from 10 adult human volunteers before and after drinking 540 ml of green tea. What did the data show?

“The in vivo trials of green tea also demonstrated a photoprotective effect, with samples of peripheral blood cells taken after green tea consumption showing lower levels of DNA damage than those taken prior to ingestion when exposed to 12 min ultraviolet A (UVA) radiation.”

Thus they conclude:

“The studies showed that green tea and/or some constituents can offer some protection against UV-induced DNA damage in human cell cultures and also in human peripheral blood samples taken post-tea ingestion.”

A paper more recently published in the Journal of Photochemistry and Photobiology adds further evidence that green tea can protect against DNA damage from ultraviolet radiation. The authors state:

“Oral ingestion of green tea is a potent dietary source of antioxidant polyphenols. These compounds are of interest as they may be able to provide additional protection to the body to help prevent the deleterious effects of ultraviolet A and visible radiation (UVA/VIS) produced indirectly via reactive oxygen species (ROS) in sunlight exposed skin.”

They too exposed white blood cells drawn from healthy human volunteers to UV irradiation after ingestion of green tea and measured the levels of DNA damage. They conclude:

“The findings…indicate that drinking green tea did significantly reduce the genotoxic effects observed in peripheral blood cells 60 min following ingestion when artificially exposed to 12 min of UVA/VIS irradiation in the laboratory. It is postulated that this protection is afforded by the polyphenol compounds (known to be contained within green tea) via scavenging or quenching of the damaging ROS induced by this form of light exposure.”

Ellagic acid, another polyphenol found in pomegranate and berries, has also been studied for its ability to reduce skin damage due to UV-B irradiation. The authors of a paper published in Experimental Dermatology state:

“This study examined photoprotective effects of ellagic acid on collagen breakdown and inflammatory responses in UV (ultraviolet)-B irradiated human skin cells and hairless mice. Ellagic acid attenuated the UV-B-induced toxicity of HaCaT keratinocytes and human dermal fibroblasts. Non-toxic ellagic acid markedly prevented collagen degradation by blocking matrix metalloproteinase production in UV-B-exposed fibroblasts.”

Interestingly, in regard to wrinkle production ellagic acid…

“…attenuated UV-B-triggered skin wrinkle formation and epidermal thickening…In addition, this compound mitigated inflammatory intracellular cell adhesion molecule-1 expression in UV-B-irradiated keratinocytes and photoaged mouse epidermis.”

The skin inflammation due to UV exposure noted in the authors’ conclusion is a contributing cause for skin cancer:

“These results demonstrate that ellagic acid prevented collagen destruction and inflammatory responses caused by UV-B. Therefore, dietary and pharmacological interventions with berries [and pomegranate] rich in ellagic acid may be promising treatment strategies interrupting skin wrinkle and inflammation associated with chronic UV exposure leading to photoageing.”

Sulforaphane, a compound found in cruciferous vegetables, has also been shown to reduce carcinogenic inflammation as documented in a paper just published in Molecular Carcinogenesis. The authors state:

“Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin, enhance inflammation, and drive skin carcinogenesis. Previously, we have shown that sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via nuclear factor (erythroid-derived 2)-like 2 (Nrf2)…Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses, it is relevant to assess the role of Nrf2 for photoprotection against…UVB-induced skin inflammation.”

To do this they induced skin inflammation by UVB irradiation in two groups of mice, with and without the Nrf2 genes that respond to sulforaphane. What did they find?

“SFN treatment of Nrf2 WT ['wild type', with Nrf2 genes] but not Nrf2 KO ['knockout', without Nrf2 genes] mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation. Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1β and interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT. Taken together, our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation, sunburn reaction, and SFN-mediated photoprotective effects in the skin.”

In other words, sulforaphane (SFN) from cruciferous vegetables like broccoli, Brussels sprouts and cabbages activated the Nrf2 genes that conferred protection against UVB-induced inflammation.

While there is evidence that polyphenols, green tea EGCG, curcumin, sulforaphane and other single agents protect against skin cancer, a combination of multiple agents may work best. The authors of a paper published in the journal Dermatologic Surgery note:

“The endogenous antioxidant system of the skin scavenges reactive oxygen species and combats ultraviolet induced oxidative skin damage. Supporting this cutaneous defense system with topical or oral antioxidants may provide a successful strategy for the treatment and prevention of skin cancer.”

They undertook a review of the evidence available in 2002 for treatment and prevention of melanoma and nonmelanoma skin cancers using antioxidants and vitamins. Their findings were mixed:

“Review of the literature demonstrates that the administration of synthetic retinoids has not proved beneficial for otherwise healthy patients with nonmelanoma skin cancer. Selenium supplementation has reduced the incidence of several internal malignancies but not of nonmelanoma skin cancer. Synergistic use of β-carotene with vitamins C and E has demonstrated prophylaxis against reactive oxygen radicals involved in nonmelanoma skin cancer and reduced sunburn reactions significantly. 1,25-dihydroxyvitamin D3 analog CB1093 has demonstrated promise as a therapeutic agent in the regression of the early stages of melanoma in specific cell lines.”

They support the use of a combination approach:

“Delivery of exogenous antioxidants in combination appears to be a more successful strategy for enhancing the cutaneous antioxidant system than the administration of isolated antioxidants alone. Vitamin D analogs may have a role in the medical therapy of melanoma.”

The authors of a paper published recently in the journal Seminars in Cutaneous Medicine and Surgery also assert that combining multiple agents may be significantly more effective than single agents in prevention of UV-induced skin cancer:

“With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer.”

Along these lines a promising study just published in the journal Nutrition and Cancer offers evidence that the multiherbal formulation Zyflamend inhibits melanoma growth. By way of background…

“Though isolated dietary components such as lycopene, resveratrol, and isothiocyanate compounds have been shown to provide limited protection against cancer development, the use of whole herbs and herbal extracts for the treatment of cancer remains of great interest. As suggested by earlier studies, the antiinflammatory activity of many plants available as intact products or as extracts has long been considered for supplemental therapeutics for cancer.”

They further observe:

“Zyflamend, a unique multiherbal extract preparation, is a promising antiinflammatory agent that has also been suggested to regulate multiple pathways in cancer progression. As Zyflamend contains ingredients that can suppress tumor cell proliferation, invasion, angiogenesis, and metastasis through regulation of inflammatory pathway products, we hypothesized that this preparation might inhibit melanoma proliferation.”

The authors designed their study to test the effect of Zyflamend on melanoma proliferation. They found that…

“Zyflamend inhibits melanoma growth by regulating the autophagy–apoptosis switch. Based on the responsible molecular mechanisms of Zyflamend, our study highlights the importance of the use of herbal preparations for the prevention and treatment of cancer.”

Interestingly, two earlier studies published in the same journal report that Zyflamend induces apoptosis (programmed cell death) of prostate cancer cells and inhibits malignant bone destruction and invasion while potentiating cytotoxicity.

A sound strategy for skin cancer prevention requires a comprehensive examination of the various possible contributing causes that addresses the unique needs of the individual. That being said, there is ample evidence that beneficial agents are available to play a role in protection from UV-induced irradiation that are worthy of consideration.

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There are many ways to fall prey to simplistic linear thinking when desperately seeking solutions to complex problems. Chronic Fatigue Syndrome can be a devastating illness; as attractive as a viral culprit may be to some, there is abundant evidence that attributing this complex condition to a singular cause unrealistically ignores the complexity of CFS and related conditions. A study just published in the Journal of Virology is the most recent ‘nail in the coffin’ for the notion that CFS is caused by the XMRV virus. The authors state:

“Chronic fatigue syndrome (CFS) is a multi-system disorder characterized by prolonged and severe fatigue that is not relieved by rest…Recently CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations.”

They analyzed blood samples from 100 CFS patients and 200 self-reported healthy volunteers using molecular, serological and viral replication assays. Interestingly, they also analyzed samples from patients in the original study that attracted so much media attention when it reported XMRV in CFS. What were the results?

“We did not find XMRV or related MLVs, either as viral sequences or infectious virus, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies.”

Attention to their conclusion may prevent clinicians and CFS sufferers from a fruitless diversion:

“Our findings do not support an association between CFS and MLV-related viruses including XMRV and off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.”

This is a thorough and detailed study, but is there any other evidence to support the assertion that we shouldn’t depend on XMRV as a linear viral cause for CFS? A study recently published in the journal Retrovirology also finds no association in cases across the US:

“Here we tested blood specimens from 45 CFS cases and 42 persons without CFS from over 20 states in the United States for both XMRV and MuLV. The CFS patients all had a minimum of 6 months of post-exertional malaise and a high degree of disability, the same key symptoms described in the Lombardi et al. study. Using highly sensitive and generic DNA and RNA PCR tests, and a new Western blot assay employing purified whole XMRV as antigen, we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS. Our findings, together with previous negative reports, do not suggest an association of XMRV or MuLV in the majority of CFS cases.”

Additional research published shortly after in the same journal came up with the same negative results for both CFS and prostate cancer in Japan:

“To evaluate the risk of XMRV infection during blood transfusion in Japan, we screened three populations–healthy donors (n = 500), patients with PC (n = 67), and patients with CFS (n = 100)–for antibodies against XMRV proteins in freshly collected blood samples. We also examined blood samples of viral antibody-positive patients with PC and all (both antibody-positive and antibody-negative) patients with CFS for XMRV DNA.”

Their data led them to the following conclusion:

“Our data show no solid evidence of XMRV infection in any of the three populations tested, implying that there is no association between the onset of PC or CFS and XMRV infection in Japan.”

A study recently published in PLoS ONE (Public Library of Science) goes a step further in examining the issue. The authors state:

“The novel human gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), originally described in prostate cancer, has also been implicated in chronic fatigue syndrome (CFS). When later reports failed to confirm the link to CFS, they were often criticised for not using the conditions described in the original study. Here, we revisit our patient cohort to investigate the XMRV status in those patients by means of the original PCR protocol which linked the virus to CFS.”

In addition to the PCR protocol used in the original study, the authors also assayed the sera of CFS patients for the presence of both the xenotropic virus envelope protein and a serological response to it. What did their data show?

“The results further strengthen our contention that there is no evidence for an association of XMRV with CFS, at least in the UK.”

Subsequent research also conducted in the UK and published in PLoS examined a highly susceptible cohort of patients for XMRV virus:

“We extracted peripheral blood DNA from a cohort of 540 HIV-1-positive patients (approximately 20% of whom have never been on anti-retroviral treatment) and determined the presence of XMRV and related viruses using TaqMan PCR.”

Even for this very vulnerable group XMRV was not proven to be a concern:

“In view of these negative findings in this highly susceptible group, we conclude that it is unlikely that XMRV or related viruses are circulating at a significant level, if at all, in HIV-1-positive patients in London or in the general population.“

The authors of a study just published in the Annals of Neurology go a step further in investigating whether XMRV could be a causative agent in CFS. Having acknowledged the pre-existing research, they state:

“A useful next step would be to examine cerebrospinal fluid, because in some patients CFS is thought to be a brain disorder. Finding a microbe in the central nervous system would have greater significance than in blood because of the integrity of the blood–brain barrier.”

The brain is at the core of the experience of fatigue; if the virus were to show up anywhere it should be there. What did they find?

“We examined cerebrospinal fluid from 43 CFS patients using polymerase chain reaction techniques, but did not find XMRV or multiple other common viruses, suggesting that exploration of other causes or pathogenetic mechanisms is warranted.”

Just because a virus may be found in the body of a patient with CFS or any other condition does not mean that it is a significant causal factor for their complaint. The authors of a paper published in the British Medical Bulletin undertook a survey of…

“…All papers including the wording XMRV were abstracted from the NIH library of medicine database and included in the analysis.”

They make the point that…

“An increasing number of papers now refute the association of XMRV with human disease in humans although there is some evidence of serological reactivity to the virus. While it is unlikely that XMRV is a major cause of either prostate cancer or CFS, it can infect human cells and might yet have a role in human disease.”

But there is a big difference between being present in human cells and being a cause of disease. This is illustrated by a fascinating study published in the Journal of Virology showing that XMRV does not efficiently replicate and spread in human tissue. The authors state:

“To determine whether XMRV can replicate and spread in cultured PBMCs even though it can be inhibited by A3G/A3F, we infected phytohemagglutinin-activated human PBMCs and A3G/A3F-positive and -negative cell lines (CEM and CEM-SS, respectively) with different amounts of XMRV and monitored virus production by using quantitative real-time PCR.”

They summarize their findings by concluding:

“We found that XMRV efficiently replicated in CEM-SS cells and viral production increased by >4,000-fold, but there was only a modest increase in viral production from CEM cells (<14-fold) and a decrease in activated PBMCs, indicating little or no replication and spread of XMRV…Overall, these results suggest that hypermutation of XMRV in human PBMCs constitutes one of the blocks to replication and spread of XMRV.”

Wishing for a single linear cause that will lend itself to the discovery of a ‘magic bullet’ for conditions that are engendered by a multi-causal systemic web of factors is a flaw that has hindered progress in the treatment of chronic disease. In the case of CFS, dysregulation of the brain-immune axis is a core component. This demands that the clinician integrate a panoramic systems view with a nuanced investigation of individual functional elements. There is a world of science to delve into here; research just published in the journal NMR In Biomedicine offers a taste of the brain aspect. The authors in order to:

“…explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR [magnetic resonance] images has been extended to voxel-based regressions against clinical scores.”

The compared MR signal levels in 25 CFS subjects and 25 normal controls, including such clinical scores as fatigue duration, another score based on the 10 most common CFS symptoms, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24 hour blood pressure monitoring. What did their data show?

“In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1-weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction.”

In other words, there were strong correlations between CFS symptoms and pathological changes in the brain. The authors conclude:

“These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).“

How might such neurodegenerative changes come about? A paper published earlier in Autoimmunity Reviews discusses the autoimmune component of CFS:

“The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed.”

The main point: practitioners and patients should not be seduced by the wish for a ‘magic bullet’ treatment of a single linear cause for complex conditions that require a systems biology perspective. In the case of chronic fatigue syndrome, the brain-immune axis comes to the fore, with all its multifaceted considerations for functional assessment and treatment.

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An important study just published in Cancer Epidemiology, Biomarkers & Prevention adds to the  evidence that supplementation can be helpful rather than an impediment to oxidizing therapies. The authors set out to address a concern that has persisted in the face of mounting evidence to the contrary:

“Antioxidants may protect normal cells from the oxidative damage that occurs during radiotherapy and certain chemotherapy regimens; however, the same mechanism could protect tumor cells and potentially reduce effectiveness of cancer treatments. We evaluated the association of vitamin supplement use in the first 6 months after breast cancer diagnosis and during cancer treatment with total mortality and recurrence.”

They evaluated 4,877 women diagnosed with invasive breast cancer in Shanghai, China, between March 2002 and April 2006 for the correlation between supplement use and breast cancer total mortality and recurrence. Women were interviewed approximately 6 months after diagnosis and followed up by interviews and records. What did the data show?

“Vitamin use shortly after breast cancer diagnosis was associated with reduced mortality and recurrence risk, adjusted for multiple lifestyle factors, sociodemographics, and known clinical prognostic factors. Women who used antioxidants (vitamin E, vitamin C, multivitamins) had 18% reduced mortality risk and 22% reduced recurrence risk. “

Interestingly, in this study…

“The inverse association was found regardless of whether vitamin use was concurrent or nonconcurrent with chemotherapy, but was present only among patients who did not receive radiotherapy.”

The data were sufficient for the authors to conclude:

“Vitamin supplement use in the first 6 months after breast cancer diagnosis may be associated with reduced risk of mortality and recurrence…Our results do not support the current recommendation that breast cancer patients should avoid use of vitamin supplements.”

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COX-2 inhibitors, a form of non-steroidal antiinflammatory drug (NSAID) that targets the COX-2 enzyme,  have been recognized for their ability to prevent the growth of colon tumors. They have, however, also been proven to seriously increase the risk for heart attacks and strokes. The authors of paper published recently in the journal Current Colorectal Cancer Reports despite the early hopes for these medications:

“”Nonsteroidal anti-inflammatory drugs are one of the more studied groups of drugs in colorectal cancer chemoprevention because both epidemiological and experimental studies have shown that these drugs reduce the risk of developing colonic tumors. Cyclooxygenase-2 (COX-2), an isoform of cyclooxygenase, plays an important role in colorectal carcinogenesis…However, recent long-term studies have shown that these agents and probably some NSAIDs have an increased risk of cardiovascular events, which has changed the whole scenario.”

In another paper published in the subsequent issue of the same journal, the authors state:

“Recent studies of coxibs indicate that these agents are effective in reducing sporadic adenoma recurrence, but chronic use can result in serious cardiovascular toxicity. These data underscore the need for chemopreventive agents with acceptable risk-to-benefit ratios.”

Happily, a study published in the Annals of the New York Academy of Sciences offers evidence that curcumin, the benign natural phenol extracted from the spice turmeric, also offers a way to inhibit the COX-2 enzyme for colorectal cancer chemoprevention.

“…the AMPK cascade has emerged as an important pathway implicated in cancer control. In this study we investigated the effects of curcumin on apoptosis and the regulatory effect of the AMPK–cyclooxygenase-2 (COX-2) pathway in curcumin-induced apoptosis. Curcumin has shown promise as a chemopreventive agent because of its in vivo regression of various animal-model colon cancers. This study focused on exploiting curcumin to apply antitumorigenic effects through modulation of the AMPK–COX-2 cascade.”

Did curcumin show enough activity in this regard to be meaningful?

“Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 μmol/L and above. These apoptotic effects were correlated with the decrease in pAkt and COX-2, as well as the increase in p-AMPK.”

They further demonstrated that blocking the effect of curcumin resulted in an increase in COX-2 expression resulting in a replacement of apoptosis (cancer cell death)with proliferation. The authors add in conclusion:

“These results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt–AMPK–COX-2 cascade or AMPK–pAkt–COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells.”

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Many practitioners have used PSA velocity (the rate at which prostate-specific antigen values increase) as an important indicator to gauge the risk of aggressive prostate cancer and weigh the decision to proceed to biopsy. A study just published in the Journal of the National Cancer Institute reveals that PSA velocity is not a reliable indicator and can lead to many needless interventions. The authors state their intention to examine pre-existing assumptions about the significance of the rate of PSA change:

“The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE)…To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided.”

The current guideline based on an unproven assumption was clearly contradicted by their data:

“Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied.”

The implication of these findings is starkly articulated in their conclusion:

“We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.“

The authors of an accompanying editorial thoughtfully state:

“The results…suggest that using PSA velocity may not provide more information to either physician or patient as we try to come to a decision about interpreting the results of any screening…The studies by Zeliadt et al. and Vickers et al. help us refine and focus our clinical approach, but they also remind us that the use of PSA as a screening tool still leaves much to be desired. Indeed, after more than 20 years of PSA screening, it has been estimated that approximately 1 million men may have been unnecessarily treated for clinically insignificant prostate cancer.”

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