One-third of osteoporotic women taking oral bisphosphonates have elevated risk for bone fracture

Chemical structure of pyrophosphate (A, above) and bisphosphonates (B, below). P = phosphorus, O = oxygen, H = hydrogen, C = carbon, R = side chain. In bisphosphonates, the central oxygen atom is replaced with a carbon atom. All bisphosphonates share a common phosphorus-carbon-phosphorus motif with two side chains (R1 and R2 in the figure). The R2 side chain determines the chemical properties of the drug, and distinguishes individual types of bisphosphonates. This chemical structure affords a high affinity for calcium hydroxyapatite, allowing for rapid and specific skeletal targeting.

More than 53 million Americans age 50 and older, primarily women, have osteoporosis or are at high risk for the condition due to low bone density. A recent study of oral bisphosphonates, the most commonly prescribed osteoporosis treatment, found that approximately a third of women prescribed these drugs continue to be at elevated risk for bone fracture, an outcome that may have several origins.

Oral bisphosphonates are a pillar of preventive treatment for patients with osteoporosis and have been shown to be effective in reducing the risk of disabling bone fractures. It is known from clinical trials that no medication completely eliminates the risk of fracture. Additionally, medication effectiveness may be different in clinical practice compared to well-controlled research trials.

Research from the Regenstrief Institute-Merck (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.) collaboration suggests that many women still have indicators consistent with higher risk of fracture while taking these medications. The cross-sectional population health study was based on a retrospective database analysis of 7,435 women age 50 and older taking bisphosphonates for at least two years during the 2000-2012 time period. The analysis was published in the peer-reviewed journal Bone.

"While we found that a substantial proportion of patients who took oral bisphosphonates remain at risk for hip, spine, and other major fractures, this class of drug does improve bone density in the majority of patients and should remain a mainstay of osteoporosis management," said Erik Imel, M.D., the Indiana University School of Medicine endocrinologist and Regenstrief Institute-affiliated scientist who led the study.

"We limited our study to patients who were considered to be compliant with taking their medication, based on drug dispensing days covered, with the presumption being that those who filled prescriptions took the medication properly. We would expect even less benefit if patients fail to take their medication properly. To increase treatment effectiveness, patients and their doctors should be vigilant that the drug is taken reliably and properly. However, osteoporosis drugs are not enough. Physicians and their patients are well advised to discuss additional important modifications to decrease fall risk and fracture risk. These include exercise, smoking cessation, use of assistive devices such as canes or walkers, modifying the home to avoid obstacles that might lead to falls, and taking appropriate amounts of vitamin D and calcium."

Conducted under the auspices of a Regenstrief Institute-Merck collaboration, the retrospective cohort study utilized anonymized data from the Indiana Network for Patient Care, a health information exchange founded by the Regenstrief Institute. The study authors note that the data they used reflects real-life medical practice and patient behavior from a wide range of physicians and patient backgrounds. Adherence to bisphosphonate therapy was determined by prescription fulfillment records. Clinical data included information on bone density and fractures.

"We know that taking bisphosphonates decrease fracture risk compared to those not taking these drugs," Dr. Imel said. "But what about those women who weren't getting the anticipated benefit and are not improving bone density or even are losing bone density? What predicted that? The purpose of this study was to focus attention on those not doing well, in order to begin to decrease the odds of future fractures in this large group of vulnerable patients.

"Not everyone responds the same way to oral bisphosphonates or any drug. Various factors could convey continued risk of fracture in spite of bisphosphonate therapy, including other medical problems and risk factors for falling. Since we know that such a high percentage of women continue to have elevated fracture risk we -- doctors and patients -- need to focus on these factors," Dr. Imel said. "For example, we found that women who had other medical conditions in addition to low bone density--a frequent occurrence in this older population--had higher fracture risk. Taking some medications in combination with bisphosphonates seemed to increase fracture risk. However, having more medical conditions and taking more drugs are most likely markers of heightened risk rather than causative factors."

Neurologic problems, often linked to heightened risk of falls, as well as inflammatory and other chronic joint conditions including arthritis were found to be associated with higher odds of having a fracture among those taking bisphosphonates.

"I always tell my osteoporosis patients, 'Don't fall,'" said Dr. Imel. "They usually chuckle, and then we talk about things they can do to decrease the risk of falling, including proper footwear and assistive devices. Many patients are reluctant to use a cane or a walker. I try to get them to understand the importance of using any tool that decreases the chance of falling."

Maintenance lenalidomide treatment improves overall survival in multiple myeloma patients

In continuation of my update on lenalidomide 

 lenalidomide 

While several clinical trials have demonstrated that maintenance therapy with lenalidomide reduces the risk of disease progression in patients with multiple myeloma, there have been no definitive results regarding overall survival. While some previous studies found that maintenance lenalidomide after autologous hematopoietic stem cell transplant improved overall survival for newly diagnosed multiple myeloma patients, others showed no benefit to this approach. Philip McCarthy, MD, Director of Blood & Marrow Transplant at Roswell Park Cancer Institute (RPCI), will present the findings of an international team of researchers at the American Society of Clinical Oncology (ASCO) 52nd Annual Meeting in Chicago.

The new study is a meta-analysis of three randomized controlled trials conducted by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B) (CALGB) with support from the NCI, Intergroupe Francophone du Myélome (IFM), and the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA). It involved more than 1,200 participants. For this analysis, 605 patients with newly diagnosed multiple myeloma and treated with continuous lenalidomide (brand name Revlimid) following autologous stem cell transplant were compared to 604 patients who were treated with placebo or no maintenance. At seven years, 62% of those treated with maintenance lenalidomide had survived, compared to 50% of those in the control group. The benefit in overall survival was consistent across subgroups.

"Lenalidomide maintenance following autologous stem cell transplant can now be considered a standard of care for people with multiple myeloma," says Dr. McCarthy, senior author on the meta-analysis and Principal Investigator of the U.S. study, CALGB (Alliance) 100104. "The improvements over the last decade in terms of both survival and quality of life for patients with this disease are striking, and very encouraging."

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

The targeted therapy rucaparib, which has demonstrated robust clinical activity in ovarian cancer patients with a BRCA mutation, also showed promise in previously treated pancreatic cancer patients with the mutation, according to results from a phase II clinical study presented by Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, at the American Society of Clinical Oncology (ASCO) Annual Meeting. (Abstract # 4110).

rucaparib

Overall, a clinical benefit was observed in 32 percent of patients (6 of 19) treated with rucaparib. Of the 19 pancreatic patients, one had a complete response and two had partial responses, while four patients had stable disease. The objective response rate, the primary endpoint for the study, was 16 percent (3 of 19).

"These results are encouraging and further demonstrate the clinical significance of the BRCA cancer genes outside of breast and ovarian, and not just in women," Domchek said. "Importantly, it points us to a potential new treatment avenue for pancreatic cancer, an aggressive disease that's often caught in the later stages. Though smaller in number, some patients with advanced disease and carrying a BRCA mutation may benefit from the same targeted therapy being used today in the clinic to successfully treat some ovarian cancer patients."

Given the poor prognosis and limited treatment options in pancreatic cancer, new therapies to combat the disease are desperately needed: Earlier this year, the American Cancer Society reported that it is estimated that in 2016, nearly 42,000 people will die from the disease, surpassing the number of deaths from breast cancer by more than 1,000.

Recent studies have shown that rucaparib, a PARP inhibitor, effectively treats patients with platinum-sensitive, relapsed, high-grade ovarian cancer harboring a BRCA mutation. In a study presented at ASCO in 2015, researchers showed that treatment resulted in a 69 percent RECIST response rate in these patients. In April 2015, it received a U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation. The FDA's designation, created in 2012, is intended to expedite the development and review of new medicines - both drugs and biologic agents - that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The success in ovarian patients prompted a clinical study in pancreatic patients with the same mutation--about nine percent of pancreatic patients are BRCA1/BRCA2 positive.

The team enrolled participants with measurable, relapsed disease who received one to three prior rounds of chemotherapy for locally advanced or metastatic cancer. The trial included 11 male and eight female patients, with a median age of 57. Twenty-one percent of the patients tested positive for the BRCA1 mutation, while 79 percent tested positive for BRCA2.

The disease control rate (defined as partial response or stable disease for more than 12 weeks) for all patients was 32 percent (6 of the 19 patients) and 50 percent (three of six patients) in patients who received one prior line of chemotherapy. Four patients had stable disease, nine patients had progressive disease, and three were not evaluable for response. One patient was on the drug for 72 weeks and is continuing to receive the drug. The drug had an acceptable safety profile. Common treatment-emergent side effects included nausea (63 percent) and anemia (47 percent).

All patients who responded received only one prior line of chemotherapy therapy, suggesting that the drug may be an option earlier in the treatment course.

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

Metformin along with chemotherapy/radiation improves outcomes in head and neck cancer patients

In continuation of my update on metformin

Researchers at the University of Cincinnati (UC) College of Medicine have found that adding increasing doses of an approved Type 2 diabetes drug, metformin, to a chemotherapy and radiation treatment regimen in head and neck cancer patients is not well tolerated if escalated too quickly, but allowing slower escalation could be beneficial.

These findings are being presented via poster June 4 at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting: Collective Wisdom, being held June 3-7 in Chicago.

Trisha Wise-Draper, MD, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine, a member of both the Cincinnati Cancer Center and UC Cancer Institute and principal investigator on this study, says retrospective studies have shown improved outcomes in tumors treated with chemotherapy and radiation if they were also on metformin for diabetes.

"In head and neck squamous cell carcinoma, which develops in the mucous membranes of the mouth, nose and throat, diabetic patients taking a medication called metformin had better overall survival compared to those not on metformin when also treated with chemotherapy and radiation," she says. "Additionally, pancreatic cancer patients treated with chemotherapy and metformin required higher doses of metformin--1,000 milligrams twice a day--to experience positive results.

"In basic science studies, metformin has been shown to stop mTOR, a molecular pathway present and active in this type of head and neck cancer, and pretreatment with metformin resulted in a decrease in the occurrence of oral cavity tumors in animal models. In this study, we wanted to see if the combination of escalating doses of metformin with the chemotherapy agent cisplatin and radiation for head and neck cancer tumors in non-diabetic patients would be effective."

Wise-Draper says that metformin, which is an approved Type 2 diabetes medication, was provided by their investigational pharmacy. Metformin was administered orally in escalating doses for 7 to 14 days prior to starting the cisplatin and radiation and continued throughout standard treatment. Blood samples were collected before and after metformin treatment as well as during chemotherapy. Flow cytometry, a technique used to count cells, was used to detect the percent of circulating immune activated cells, and clinical laboratory tests including glucose, B12 and C-peptide (an amino acid that is important for controlling insulin) were performed.

"This is part of an ongoing clinical trial," says Wise-Draper. "We found that eight patients with advanced head and neck cancer have been enrolled so far; we plan to have 30 total. Due to the relatively quick escalation of metformin, the patients' tolerance was poor with higher doses of metformin when initiated 7 days prior to their chemotherapy and radiation therapy regimen.
"Therefore, the protocol was modified to allow slower escalation over 14 days. The most common toxicities observed included nausea (71 percent of patients) and vomiting (43 percent of patients), increase in creatinine (57 percent of patients), decreased white blood cell count (43 percent of patients) and pain when swallowing (43 percent of patients) with only nausea being directly attributed to metformin and the rest attributed to cisplatin and radiation."

She adds that there wasn't a substantial change in T cell or glucose levels with administration of metformin in the small sample of patients but that there were increased C-peptide levels in response to metformin administration.

"These results show that the combination of metformin and cisplatin and radiation was poorly tolerated when metformin was escalated quickly. However, there has been no significant increase in side effects thus far with the addition of metformin," Wise-Draper says. "The trial is continuing with escalation of metformin over a longer period of time to provide more data; we will also try to increase our sample size."

Cobimetinib combined with vemurafenib shows added benefit for melanoma with BRAF V600 mutation

In continuation of my update on Cobimetinib   and Vemurafenib

Cobimetinib (trade name: Cotellic) has been approved since November 2015 in combination with vemurafenib for the treatment of adults with advanced, i.e. metastatic or unresectable, melanoma with a BRAF V600 mutation. In a dossier assessment from March 2016, the German Institute for Quality and Efficiency in Health Care (IQWiG) found both advantages and disadvantages of cobimetinib in combination with vemurafenib in comparison with the appropriate comparator therapy vemurafenib alone. This resulted in an indication of a minor added benefit.

 Cobimetinib 

In the subsequent commenting procedure, the drug manufacturer presented further data analyses, which were now included in the assessment in a so-called addendum. This increased the extent of the added benefit: There is now an indication of a considerable added benefit of cobimetinib plus vemurafenib in comparison with vemurafenib .

  vemurafenib 

Third data cut-off of the approval study decisive

The manufacturer dossier was based on the study coBRIM, which was decisive for the approval. In this study, cobimetinib in combination with vemurafenib was directly compared with vemurafenib. Besides advantages, particularly in overall survival, several disadvantages also resulted from the data.

In the commenting procedure conducted by the Federal Joint Committee (G-BA) after IQWiG's dossier assessment, the manufacturer now in particular presented more informative analyses on symptoms and health-related quality of life from the third data cut-off, as well as further results for the fourth and fifth data cut-off. The third data cut-off was decisive for the benefit assessment because the recording of symptoms and health-related quality of life was discontinued shortly afterwards. It was investigated whether the data from the later cut-off dates raised doubts about the overall conclusion on the added benefit - which was not the case.

Additional positive effects in symptoms and quality of life

Study finds no added benefit of empagliflozin alone or in combination for type 2 diabetes

In continuation of my update on Empagliflozin

Empagliflozin (trade name: Jardiance) has been approved since May 2014 for adults with type 2 diabetes mellitus in whom diet and exercise alone do not provide adequate glycaemic control. In 2014, the German Institute for Quality and Efficiency in Health Care (IQWiG) concluded in its dossier assessment that an added benefit of the drug in comparison with the appropriate comparator therapies was not proven. Partly, the drug manufacturer had presented no relevant data; partly not only the drugs, but also the therapeutic strategies differed; in addition, the indirect comparisons were based on studies unsuitable for the assessment.

The manufacturer now requested a new benefit assessment due to "new scientific findings", and submitted two dossiers: one for empagliflozin alone, and one for empagliflozin in combination with metformin. IQWiG determined in both early benefit assessments that the dossiers still contained no data and analyses relevant or suitable for the research questions. Hence an added benefit of empagliflozin alone or in combination with metformin in comparison with the appropriate comparator therapies is still not proven. The analyses of the large study EMPA-REG-Outcome additionally submitted were unsuitable for an assessment of the added benefit in Germany.

Same studies, same problems

Both the single agent and the combination of empagliflozin with metformin are approved alone or in combination with other blood-glucose lowering drugs including insulin. According to the Federal Joint Committee (G-BA), this resulted in three and four research questions respectively. The manufacturer again presented no relevant data for five of these seven research questions so that an added benefit is not proven. One study of direct comparison as well as several studies for indirect comparisons, all of which had already been cited in the dossier or in the commenting procedure in 2014, were available for the other two research questions.

The assessment of the data from the indirect comparison was incomplete with regard to content, although it had been known to the manufacturer since the first dossier assessment which patient-relevant outcomes were important. In particular, there was no information on specific adverse events for which a disadvantage of empagliflozin versus the comparator therapy was shown. The information provided on one of the indirect comparisons had the same deficiency; furthermore, there were contradictions to the clinical study reports. The second indirect comparison was not evaluable because the studies compared were not sufficiently similar and because therapeutic strategies instead of drugs were compared with one another again.

Hence there was no hint of an added benefit of empagliflozin in comparison with the appropriate comparator therapies for the single agent or for the fixed combination.

Study EMPA-REG-Outcome unsuitable for the assessment of the added benefit

Both dossiers additionally contained a description of the EMPA-REG-Outcome study used by the manufacturer to answer a question posed by the manufacturer itself, i.e. whether empagliflozin (alone or with metformin) in addition to standard treatment offers an added benefit for patients at high cardiovascular risk in comparison with standard treatment alone plus placebo.

The antidiabetic therapy in this study cannot be considered standard treatment, however: The blood-glucose lowering treatment was not escalated appropriately and the upper threshold values mentioned in guidelines were not consistently respected. And even if treatment was escalated, this was mostly done as emergency treatment, but not as part of a planned treatment expansion.

Effects in favour of empagliflozin mainly in Latin America and Asia

Moreover, marked regional differences were notable: Effects in favour of empagliflozin mainly occurred in study centres in Latin America and Asia, whereas in Europe, partly advantages and partly disadvantages of empagliflozin were shown. Finally, the study addressed neither the G-BA's research questions nor the appropriate comparator therapies specified there.

Thomas Kaiser, Head of the IQWiG Drug Assessment Department, commented on this attempt by the manufacturer to prove an added benefit for at least certain patients: "This is a wasted opportunity. It should be welcomed that studies of this size and this duration, which are therefore potentially informative, are conducted. But it was conducted with obvious deficiencies. Experts had pinned high hopes on this study, particularly as, in contrast to other large outcome studies, it appeared to produce positive results at first glance. A thorough analysis of the study and the results in European participants did not confirm this impression, however."

Chemical compound eCF506 may be highly effective at blocking growth of breast cancer cells

A drug for breast cancer that is more effective than existing medicines may be a step closer thanks to new research. Scientists have identified a chemical compound that is highly effective at blocking the growth of breast cancer cells in the laboratory.

The compound - called eCF506 - targets a molecule called Src tyrosine kinase that is required for breast cancer cells to grow and spread.

 eCF506

Drugs that target the same molecule are already being tested in clinical trials. Researchers say eCF506 is different because it is more selective and doesn't affect other molecules in the cell.

This may mean it will be more effective and have fewer side effects than the other drugs in development but further studies are needed, researchers say.

The study identified the compound using a pioneering approach that uses imaging techniques to directly visualise the effects of candidate drugs on cells.

The team from the University of Edinburgh says the discovery proves that this approach offers a powerful and cost-effective method of discovering new medicines for cancer and other diseases.

The study, published in the Journal of Medicinal Chemistry, was funded by the Medical Research Council, Wellcome Trust and the commercialisation catalyst Sunergos Innovations.

Dr Asier Unciti-Broceta, who led the study at the University's Cancer Research UK Edinburgh Centre, said: "eCF506 is the first drug candidate of a second generation of Src inhibitors that will not only help to understand the complexity of some cancers but also the development of safer combination therapies."

Professor Neil Carragher, Head of the Edinburgh Cancer Discovery Unit at the University of Edinburgh, who co-led the study, said: "This candidate drug will need to undergo further preclinical testing before it can be taken forward into clinical trials but these early findings are very promising.

"The result provides further support for our new drug discovery approach, which aims to deliver more effective medicines at reduced costs for patients and healthcare providers."

Ref : http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b00065

Antimuscarinic drugs effective in improving OAB symptoms

In a recent study of patients with overactive bladder (OAB), a 30 mg extended release formulation of propiverine hydrochloride was at least as effective and safe as a 4 mg extended release formulation of tolterodine tartrate. Both medications are called antimuscarinic drugs that block certain cell receptors, but propiverine differs from other antimuscarinics because of a dual mode of action.

Propiverine hydrochloride was more effective than tolterodine tartrate in terms of decreasing patients' voiding frequency per 24 hours and their average number of incontinence episodes per 24 hours.

"More than two-thirds of patients reported an improvement of their OAB symptoms after 2 weeks of treatment increasing to 77.8 and 88.9% of patients after 8 weeks of treatment for tolterodine ER 4 mg and propiverine ER 30 mg, respectively," wrote the authors of the BJU International study.

Antimuscarinic drugs effective in improving OAB symptoms

Taking vitamin D with quetiapine can help avoid new-onset diabetes risk

In continuation of my update on quetiapine

Atypical antipsychotics, though effective for treating disorders like schizophrenia, bipolar disorder, and depression, gives patients a heightened risk of developing new-onset diabetes. A new data mining study, however, has found a way to relieve this side effect. The study, published in Scientific Reports, shows that taking vitamin D ameliorates the risk of developing new-onset diabetes from atypical antipsychotics like quetiapine.

 quetiapine.

The consequences of developing diabetes from taking antipsychotics are dire, as they occasionally cause life-threatening conditions and sometimes even death.

Members of Shuji Kaneko's lab at Kyoto University looked for potential antidotes on the US FDA's Adverse Event Reporting (FAERS) system, which is the largest database of self-reported adverse side effects. "We found that patients who had coincidentally been prescribed vitamin D with quetiapine were less likely to have hyperglycaemia," says Kaneko. "It's unusual for vitamin D to be prescribed with quetiapine because it is typically prescribed to treat osteoporosis; in fact, there were only 1232 cases in the world where vitamin D was prescribed with quetiapine. Data mining proved helpful in locating these cases."

The team confirmed this finding with further tests on mice; the group of mice that was fed vitamin D along with quetiapine had significantly lower levels of blood sugar than those that took only quetiapine.

"Interestingly, vitamin D on its own doesn't lower diabetes risk, but it certainly defends against the insulin-lowering effects of quetiapine," elaborates lead author Takuya Nagashima. "We clarified the molecular mechanisms of how quetiapine causes hyperglycaemia using datasets in a genomics data repository. Through this we found that quetiapine reduces the amount of a key enzyme called PI3K that gets produced. Vitamin D stops quetiapine from lowering PI3K production."

"Databases like FAERS aren't just for making drug regulations; they have so much potential for side-effect relief using pre-existing drugs," says Kaneko. "There's a lot we can hope for from reverse translational research like this. "

Ref : http://www.kyoto-u.ac.jp/en/research/research_results/2016/160523_2.html

Walnuts may improve your colon health: Eating walnuts changes the gut microbiome and reduces cancer growth, study shows

In continuation of my update on walnuts  

A team of researchers from UConn Health and The Jackson Laboratory for Genomic Medicine found that mice that ate 7-10.5 percent of their total calories as walnuts developed fewer colon cancers. The effect was most pronounced in male mice, which had 2.3 times fewer tumors when fed walnuts as part of a diet similar to the typical American's. That's equivalent to a human eating about an ounce of walnuts a day.

"Our results show for the first time that walnut consumption may reduce colon tumor development," said Principal Investigator Dr. Daniel W. Rosenberg of UConn Health. "There is accumulating evidence that eating walnuts may offer a variety of benefits related to health issues like cancer. This study shows that walnuts may also act as a probiotic to make the colon healthy, which in turn offers protection against colon tumors."

Walnuts are packed with compounds known to be important nutritionally. They have the most polyunsaturated fatty acids of all the commonly eaten tree nuts, as well as the highest ratio of omega-3 to omega-6 fatty acids, and high levels of a form of Vitamin E with anti-cancer properties.

But walnuts are not merely the sum of their chemical parts, and it may be as a whole food that they pack the most significant anti-cancer punch against colon cancer, the third most common cancer in the world. Other studies have shown walnuts have promise warding off diseases connected to diet and lifestyle, including heart disease, diabetes and neurological disorders.

Rosenberg, a cancer researcher and professor of medicine at UConn Health and Dr. Masako Nakanishi, a research associate in the Center for Molecular Medicine at UConn Health tested the cancer prevention qualities of walnuts on mice fed two different diets. One group of mice ate a standard lab mouse chow, while the other group ate a chow that captured the nutritional profile of the typical American diet. Subsets of both groups were supplemented with walnuts.

Interestingly, male mice fed the Western diet fortified with 10.5 percent walnuts showed the greatest decrease in colon tumors compared with mice fed no walnuts.

To figure out why walnuts were beneficial, the UConn Health team collaborated with Dr. George Weinstock and colleagues at The Jackson Laboratory. Weinstock's lab took fecal samples from the mice and analyzed the communities of bacteria living in their digestive tracts. They found that walnut consumption tended to push the gut microbiome toward an ecology that was potentially protective against cancer. It's not clear exactly how this works, but there are clues. For example, previous research has shown that some gut bacteria digest fiber into compounds with anti-inflammatory properties that may reduce tumor initiation. The microbiome analyses also reflected interesting differences between male and female. Males on walnut-free diets tended to have less-diverse gut flora than females. Adding walnuts to the diets of male mice brought their microbiomes closer to those of female mice on either of the diets. Whether this change contributes to the protection seen in male mice remains to be determined.

Because the studies were done only in mice, more testing needs to be done in humans before walnuts can be unequivocally recommended as a cancer-prevention agent. Rosenberg's group is working with a nutritionist and surveying human colonoscopy patients about their diets as part of a longer term study in humans.

However, Rosenberg isn't waiting for the final word. Even right now, he says, "I try to eat walnuts every day."

Topical skin creams effective to treat superficial basal cell carcinoma

In continuation of my update on imiquimod and fluorouracil

Basal cell carcinoma is one of the most common cancers and its incidence is increasing worldwide, putting a significant burden on health services. Topical treatments are available for superficial basal cell carcinoma (BCC) but there has a lack of long-term follow-up data to guide treatment decisions. A three-year randomized controlled clinical trial has found that two topical creams are effective in most primary, low-risk superficial BCC, comparing favorably with photodynamic therapy (PDT), as reported by investigators in the Journal of Investigative Dermatology.

More than 80% of all skin cancers are BCC, arising from the basal cells (i.e., small, round cells found in the lower layer of the epidermis). There are over two million cases a year in the U.S. and the lifetime risk of developing a BCC before the age of 85 years is one in five people. The prognosis is excellent, but it can cause significant disfigurement by invading surrounding tissues.

While most types of BCC require surgery, superficial BCC can be treated topically with noninvasive treatments such as PDT, imiquimod cream, fluorouracil cream, cryosurgery or electrodessication and curettage.

Investigators in the Netherlands report the results of a three-year follow-up of a randomized controlled trial that compared three noninvasive treatments that included imiquimod and fluorouracil cream. "The main advantages of noninvasive treatments are good cosmetic outcome, preservation of surrounding tissue, and potential for home application of either creams," explained lead investigator Marieke Roozeboom of the Department of Dermatology, Maastricht University Medical Center in the Netherlands. "Throughout the last two decades there has been a growing interest in these non-surgical therapies, which offer the possibility of avoiding surgery and reducing demands on busy medical practices."

However, prior to this study there has been a lack of randomized controlled trials with a long-term follow-up that compare the effectiveness of noninvasive treatments. Consequently, there is no consensus in international BCC guidelines on the first choice of noninvasive therapy for superficial BCC.

A total of 601 patients with a superficial BCC participated in this study: 202 patients were treated with methylaminolevulinate photodynamic therapy (MAL-PDT), 198 with imiquimod cream, and 201 with fluorouracil cream. The three study groups had a similar distribution of baseline characteristics, with the exception of tumor size.

Around 80% of patients with superficial BCC were tumor free after imiquimod treatment after three years. The clearance rate was 68% for patients treated with fluorouracil and 58% for individuals receiving PDT.

 imiquimod   fluorouracil

"Based on our findings, both imiquimod and fluorouracil are effective noninvasive treatments in most primary, low-risk superficial BCC, but the data provide no definite evidence for superiority of imiquimod to fluorouracil," commented Dr. Roozeboom. "Both creams have an equal cosmetic outcome and risk of local adverse events. Fluorouracil has the advantage of being less expensive than imiquimod. However, between one- and three-year follow-up, more recurrences were diagnosed in the fluorouracil group compared with the imiquimod group."

Fasnall drug appears to inhibit tumor growth by promoting cancer cell death

A promising new compound appears to impede a process that fuels breast cancer in mice, a discovery that could have implications in the treatment of a host of cancers.

On top of short-circuiting the proliferation of cancer cells, a new agent that the researchers called Fasnall also contributed to the death of existing cancer cells, according to scientists from The Ohio State University and Duke University.

The mice injected with Fasnall survived for an average of 63 days, more than double the lifespan of the mice in the control group. After three weeks, tumors in the mice that received Fasnall were about two-thirds the size of those in the control group, the researchers report in a study published in the journal Cell Chemical Biology.

When researchers tried Fasnall alongside the chemotherapy drug carboplatin, they saw tumors shrink and survival increase more than with either agent by itself.

The study focused on mice with HER2-positive breast cancer, which is responsible for about one in five breast cancer diagnoses in women. But because of the critical role of an enzyme called fatty acid synthase in a variety of cancers, this work could have much broader implications, said Ohio State's Jesse Kwiek, an associate professor of microbiology and microbial infection and immunity.

The discovery, five years in the making, was speedy by drug development standards, he said.

"We started with an idea and got it to work in a mouse in a relatively short amount of time," Kwiek said.

"It's a promising starting point."

He and Duke's Timothy Haystead, a cancer biologist who co-led the study, are seeking a patent.

Fasnall inhibits the normal activity of fatty acid synthase, which regulates cell growth and proliferation.

"Tumor cells are quite dependent on that enzyme as a fuel source for survival," Haystead said. "If you nail this target, you're selectively striking the tumor rather than normal cells. And not only do you starve the tumor cell of its energy source, but also trigger changes that convince the cell to essentially kill itself."

Scientists exploring opportunities to close the doors on cancer growth have known for some time that many solid tumors depend on fatty acid synthase. Most other cells in the body are either less reliant on the enzyme, or don't need it at all, reducing the chances that harmful side effects would overshadow benefits.

All of that makes for an obvious, but thus far tricky, target for cancer fighters in the lab.

"It's always this balance where you try to identify molecules that are more important to the malignancy than to the host," Kwiek said. "You're looking for these little tweaks - little advantages."

In this case, that means interrupting fatty acid synthesis, effectively robbing the cancer of a molecule it needs in order to grow.

"Fasnall inhibits the ability of this enzyme to make palmitic acid, a molecule important for many cellular processes," Kwiek said.

And when the enzyme isn't doing its normal job, it appears to be diverted elsewhere - to a place where it has the added benefit of provoking the programmed death of cancer cells.

Before the mouse study, the research team sifted through a pool of 3,400 molecules looking for one that was efficient at knocking out fatty acid synthase in pig mammary glands without causing much residual harm. They first narrowed the field to about 1,300, then to 13 strong contenders.

Then the researchers examined each of the 13 finalists' activity within a cell. Fasnall rose to the top. Not only did it inhibit the tumor-fueling activity, it didn't take much of the compound for that to happen, which lowered the chances it would be toxic to the mice.

The discovery stemmed from an effort to look for novel treatments for cancer and HIV. Fatty acid synthase, disrupted by Fasnall, plays a role in both. The research team has not yet published results on their HIV work.

"Cancer is uncontrolled cell division, and fatty acid synthase helps make the raw materials that make the cells divide," Kwiek said.

The mice in the study showed no signs of major side effects, such as weight gain or loss or significant changes in liver enzymes, he said.

It appears the dose could be increased from the amount used in this research and that could produce more dramatic results, Kwiek said.

Fasnall needs more testing in animals before it can be employed in human studies, the researchers said. Other fatty acid inhibitors are under review, but thus far none has made it to market and none operates in precisely the way Fasnall does, Kwiek said.

The mechanism by which it works is less likely to run up against drug resistance in the cancer cells than some other approaches, Haystead said.

Its potential as one element of a cancer treatment cocktail is attractive, because it's possible Fasnall would offset the need for high doses of potent treatments that come with serious side effects, Haystead said.

"There are a huge gamut of implications and some may be better than others. Our job now is to sort of move this molecule down the clinical path," he said.

The researchers caution that this is the first, albeit big, step in a process that would take years if all goes well.

"This is just a mouse model of a single cancer," Kwiek said.

Specific commercial red algae could help combat food allergies

 

Seaweed has long been a staple food in many Asian countries and has recently caught on as a snack food in America as a healthful alternative to chips. The edible algae that fall in the category of seaweed are low-calorie and packed with nutrients. In addition, now scientists have found that a type of commercial red algae could help counteract food allergies. They report their findings in mice in ACS' Journal of Agricultural and Food Chemistry.

Food allergies are a major global health issue that can be life threatening in some cases. One 2014 study by researchers at Mount Sinai Hospital estimates that the condition affects about 8 percent of children and 5 percent of adults worldwide. In people who are allergic, certain compounds in food trigger a cascade of immune system reactions that lead to symptoms such as hives, wheezing and dizziness -- and in the worst cases, anaphylactic shock. Previous research has suggested that certain seaweed varieties contain polysaccharides with anti-asthmatic and anti-allergy effects. But no one had investigated whether similar molecules in Gracilaria lemaneiformis, a commercial variety of red algae, might have similar properties. Guang-Ming Liu and colleagues wanted to find out.

The researchers isolated polysaccharides from G. lemaneiformis and fed them to a group of mice sensitive to tropomyosin, a protein that is a major shellfish allergen. Another group of mice, also sensitive to tropomyosin, did not get the polysaccharides. After both groups were given the allergen, allergy symptoms in the treated mice were reduced compared to the untreated animals. Further studying polysaccharides from G. lemaneiformis could help lead to a better understanding of food allergies and their prevention, the researchers say.

Ref : http://pubs.acs.org/doi/abs/10.1021/acs.jafc.6b01086