Study on common bacterium presents new pathway to combat gastric cancers

A common bacterium that more than half of people have in their gut can use hydrogen gas present in the gastrointestinal tract to inject a cancer-causing toxin into otherwise healthy cells, according to a recently published study led by University of Georgia researchers.

The bacterium's reliance on hydrogen presents a pathway to potential new treatment and preventive measures in fighting gastric cancers, which kill more than 700,000 people per year, said corresponding author Robert Maier, Georgia Research Alliance Ramsey Eminent Scholar of Microbial Physiology in the Franklin College of Arts and Sciences.

Previous studies solidified the relationship between stomach ulcers and cancer and certain strains of Helicobacter pylori, a stomach-dwelling bacterium that causes 90 percent of all gastric cancers. Earlier research also found a link between a toxin known as CagA, or cytotoxin-associated gene A, and cancer formation, but the new study exposes how the bacterium uses hydrogen as an energy source to inject CagA into cells, resulting in gastric cancer, Maier said.

"There are many known microbes in the human gut that produce hydrogen and others that use hydrogen. The implications of the study are that if we can alter a person's microflora, the bacterial makeup of their gut, we can put bacteria in there that don't produce hydrogen or put in an extra dose of harmless bacteria that use hydrogen," Maier said. "If we can do that, there will be less hydrogen for H. pylori to use, which will essentially starve this bacteria out and result in less cancer."

Changing the microbial makeup of a person's gut sounds complicated, but scientists are already exploring ways to do so through the use of probiotics, antibiotics, nutritional regimes and even fecal transplants.

Although many people carry the H. pylori bacterium, it can take decades for the infection to develop into cancer, providing an opening for aggressive preventive measures in people who have a high risk of developing tumors, said lead author Ge Wang, a senior research scientist in the Department of Microbiology. The presence of H. pylori strains with both CagA and high hydrogen-utilizing activity within patients can potentially serve as biomarkers for predicting future cancer development.

An earlier study led by Maier, "Molecular Hydrogen as an Energy Source for Helicobacter pylori," published by the American Association for the Advancement of Science in 2002, showed that the presence of hydrogen in the gastric chamber was important for bacterial growth, but it wasn't until the current study that researchers learned of the strong cancer connection: The bacterium harnesses the energy from hydrogen gas, via an enzyme known as hydrogenase, to severely disrupt host cell function, leading to cancer.

"If hydrogen is in the gastric mucosa, of course a bacterium will use it," Maier said. "It's an excellent energy source for many bacteria out in nature. But we didn't realize that pathogens like H. pylori could have access to it inside an animal in a way that enables the bacterium to inject this toxin into a host cell and damage it."

Not all strains of the bacteria cause cancer, but those with CagA are known carcinogens. Using human-derived gastric cells, Wang analyzed the hydrogenase activity in the cells that were infected with different strains — both cancer causing and non-carcinogenic — of H. pylori. He found more activity in the cancer-causing strains. After using genetic engineering to knock out the DNA fragment containing the hydrogenase-inducing genes, which prevented those strains from deriving energy from hydrogen, he found that the strain he created could no longer move the cancer-causing toxin into the gastric cells. Collaborators at Vanderbilt University took Wang's in vitro model and adapted it to test the theory in gerbils, which confirmed the UGA researchers' findings.

Cocoa flavanol consumption linked to improvements in cardiometabolic biomarkers

To the tantalizing delight of chocolate lovers everywhere, a number of recent studies employing various methods have suggested that compounds in cocoa called flavanols could benefit cardiovascular health. Now a systematic review and meta-analysis of 19 randomized controlled trials (RCTs) of cocoa consumption reveals some further pieces of supporting evidence.

The meta-analysis in the Journal of Nutrition, an assessment of the combined evidence from all 19 RCTs, focused on whether consumption of flavanol-rich cocoa products was associated with improvements in specific circulating biomarkers of cardiometabolic health as compared to consuming placebos with negligible cocoa flavanol content. In all, 1,139 volunteers were involved in these trials.

"Our meta-analysis of RCTs characterizes how cocoa flavanols affect cardiometabolic biomarkers, providing guidance in designing large, definitive prevention trials against diabetes and cardiovascular disease in future work," said corresponding author Dr. Simin Liu, professor and director of the Center for Global Cardiometabolic Health at Brown University who worked with epidemiology graduate student and lead author Xiaochen Lin. "We found that cocoa flavanol intake may reduce dyslipidemia (elevated triglycerides), insulin resistance and systemic inflammation, which are all major subclinical risk factors for cardiometabolic diseases."

Liu noted some limitations in the trials. All studies were small and of short duration, not all of the biomarkers tracked in these studies changed for the better, and none of the studies were designed to test directly whether cocoa flavanol consumption leads to reduced cases of heart attacks or type 2 diabetes.

But taking into account some of these heterogeneities across studies, the team's meta-analysis summarizing data from 19 trials found potential beneficial effects of flavanol-rich cocoa on cardiometabolic health. There were small-to-modest but statistically significant improvements among those who ate flavanol-rich cocoa product vs. those who did not.

The greatest effects were seen among trial volunteers who ate between 200 and 600 milligrams of flavanols a day (based on their cocoa consumption). They saw significant declines in blood glucose and insulin, as well as another indicator of insulin resistance called HOMA-IR. They also saw an increase in HDL, or "good," cholesterol. Those consuming higher doses saw some of the insulin resistance benefits and a drop in triglycerides, but not a significant increase in HDL. Those with lower doses of flavanols only saw a significant HDL benefit.

In general, Lin said, where there were benefits they were evident for both women and men and didn't depend on what physical form the flavanol-rich cocoa product was consumed in --dark chocolate vs. a beverage, for example.

"The treatment groups of the trials included in our meta-analysis are primarily dark chocolate -- a few were using cocoa powder-based beverages," Lin said. "Therefore, the findings from the current study apparently shouldn't be generalized to different sorts of chocolate candies or white chocolates, of which the content of sugar/food additives could be substantially higher than that of the dark chocolate."

The authors therefore concluded, "Our study highlights the urgent need for large, long-term RCTs that improve our understanding of how the short-term benefits of cocoa flavanol intake on cardiometabolic biomarkers may be translated into clinical outcomes."

Animal studies examine role of raspberry products in weight management and motor function

 

The latest issue of the Journal of Berry Research includes two new animal studies that investigate the effects of raspberry consumption in helping to support healthy weight and motor function (strength, balance and coordination). Future studies are needed to support the results found in these studies.

One-cup of frozen red raspberries has only 80 calories, is an excellent source of vitamin C, and provides nine grams of fiber (more fiber than any other berry). Like most berries, raspberries are a low-glycemic index food. Raspberries contain phytochemicals, such as ellagic acid, quercetin, gallic acid, cyanidins, pelargonidins, catechins, kaempferol and salicylic acid.

Animal and cellular studies examining how phytochemicals may work at the molecular level suggest that certain phytochemicals may help slow age-related declines. Age is the number one risk factor for many chronic diseases. Likewise, obesity is a major risk factor for chronic disease. These latest animal studies examine two important areas of health where raspberry products may play a role in weight management and also support motor function.

OBESITY

An animal study conducted by researchers at Oregon State University found that when added to a high-fat, high-sucrose diet, raspberry products and raspberry phytochemicals were found to significantly decrease weight gain associated with a high-fat, high calorie diet. Raspberry juice and raspberry puree concentrates were provided at 10% of total energy (the equivalent of 200 calories in a 2,000 calorie diet), and a combination of ellagic acid and raspberry ketone were provided at 0.2% weight/weight.

In the study, 76 male mice were divided into the following diets: a low-fat control group (10% calories from fat), a high-fat control group (45% calories from fat) and seven "high-fat treatment" groups that included a high-fat diet plus either raspberry juice concentrate, raspberry puree concentrate, raspberry fruit powder, raspberry seed extract, raspberry ketone and a combination of equal parts of ellagic acid and raspberry ketone.

"The addition of raspberry juice concentrate, raspberry puree concentrate and the combination of ellagic acid plus raspberry ketones to the high fat diet significantly reduced weight gain observed in the high-fat fed mice," said Dr. Neil Shay, Principal Investigator. "In the case of the high-fat and raspberry juice concentrate diet, weight gain was reduced to a level that was statistically equivalent to the weight gain of the low-fat fed mice, despite the fact that all high-fat fed groups consumed the same amount of calories and more energy than the low-fat control group throughout the study."

The researchers concluded that the intake of a reasonable level of some raspberry food products may influence some of the metabolic consequences of consuming a high-fat, high-calorie diet in the development of obesity in male mice.

"We hope that the findings from this study can help guide the design of future clinical trials," said Dr. Shay.

MOTOR FUNCTION

Researchers from the Human Nutrition Research Center on Aging at Tufts University evaluated the effectiveness of a red raspberry-supplemented diet on age-sensitive measures of learning, memory and motor performance in older rats.

In this 10-week study, red raspberry supplementation was found to significantly improve motor skills. Specifically, compared to rats fed a standard well-balanced diet, rats fed a diet supplemented with freeze-dried raspberry extract performed better on tests which measured psychomotor coordination and balance, as well as tests that measure muscle tone, strength, and stamina.

"These results may have important implications for healthy aging," said lead researcher Barbara Shukitt-Hale, PhD. "While further research in humans is necessary, animal model studies are helpful in identifying deficits associated with normal aging."

Combination treatment with CDK4/6 inhibitor improves progression-free survival in HR breast cancer patients

The addition of the CDK4/6 inhibitor ribociclib to letrozole therapy significantly improves progression-free survival in postmenopausal women with hormone receptor-positive advanced breast cancer, researchers reported today at the ESMO 2016 Congress in Copenhagen.

The first interim analysis of data from the randomized, double-blind MONALEESA study showed a 44% improvement in progression-free survival with ribociclib plus letrozole as a first-line treatment combination.

"This was THE definitive study to demonstrate the superiority of the combination of ribociclib and letrozole over letrozole alone," said principle investigator, Professor Gabriel Hortobagyi, from the University of Texas MD Anderson Cancer Center in Houston, Texas, US.

Researchers randomized 668 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, who had not undergone any prior systemic treatment, to ribociclib (600 mg/day, 3 weeks on/1 week off) and letrozole (2.5 mg/day, continuous), or letrozole plus placebo.

                                

ribociclib                                                                                  letrozole

In the ribociclib arm, there was a 44% improvement in the primary objective of progression-free survival compared to the placebo arm (HR: 0.556, p = 0.00000329). Median progression-free survival was 14.7 months in the placebo arm, but was not reached in the ribociclib arm at data cut-off.

"The results of this trial represent a compelling proof of principle, and suggest a paradigm shift in metastatic, HR+ breast cancer. They also suggest that testing combinations of ribociclib with other inhibitors of various signaling pathways might lead to additional progress in the management of several subtypes of breast cancer," Hortobagyi said.

Patients with measurable disease at baseline showed a significantly higher objective response rate to ribociclib plus letrozole compared to letrozole alone (53% vs. 37%; p=0.00028), and improved clinical benefit rate (80% vs. 72% p=0.02).

Serious adverse events occurred in fewer than 5% of patients in both arms but other adverse events were significantly more common in the ribociclib arm. Neutropenia occurred in 59% of patients in the ribociclib arm compared to 1% of the placebo arm; leukopenia occurred in 21% vs 1%; lymphopenia in 7% vs. 1%, and patients in the ribociclib arm had a higher incidence of elevated alanine aminotransferase and elevated aspartate aminotransferase.

The number of deaths in the study was too low to enable a reliable analysis of the impact of ribociclib therapy on overall survival.

Commenting on the findings, Professor Giuseppe Curigliano, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy, said, "I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib (already FDA approved) and abemaciclib (under development)."

"The addition of ribociclib to letrozole does increase the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib."

Curigliano also suggested that further studies of ribociclib should examine the use of cancer biomarkers to better identify patients who would respond to the combination.

Researchers report high response rate with single drug in phase I/II trial of paediatric brain cancer

In continuation of my update on Dabrafenib

A high response rate with a single drug in a phase I/II trial of paediatric brain tumour has set the stage for combination therapy with higher response and lower toxicity, researchers reported at the ESMO 2016 Congress in Copenhagen.

"The likelihood of curing a child with a low-grade glioma is very high," said lead author Dr Mark Kieran, Director, Paediatric Medical Neuro-Oncology, Dana-Farber Boston Children's, Boston, US. "In fact many children don't suffer lifelong from the tumour but rather from the cognitive damage and secondary malignancies caused by radiation therapy."

He continued: "The development of drugs that target the specific causative mutation of the tumour and avoid long-term toxicities may revolutionise the treatment of paediatric brain cancer."

Up to 10% of paediatric low-grade gliomas have the BRAF V600 mutation. Today researchers reported the phase I and phase II trial results of dabrafenib, a selective inhibitor of mutant protein. The study included 32 patients aged one to 16 years with BRAF V600-mutant low-grade glioma, of whom 15 participated in the phase I trial and 17 were in the phase II trial.

The phase I trial, which focused on determining the recommended phase II dose, did not find any significant dose-limiting toxicities. The recommended dose was therefore based on the pharmacokinetic activity of the drug and was set at 4.5 mg/kg/day for patients aged 12 years and older and 5.25 mg/kg/day for patients under the age of 12.

The phase II trial assessed toxicities with dabrafenib, and whether it could stop tumours from growing or cause them to shrink. "Paediatric low-grade gliomas are a little bit unique in that patients can survive their entire life with a tumour that stops growing, unlike other cancers which need to be completely removed," said Kieran.

The objective response rate was 72%, with 23 out of 32 patients responding to the drug. In two patients the tumour disappeared and in 11 patients the tumour shrunk by more than half - of these 13 patients eight are still on the therapy. Thirteen patients had stable disease of at least six months' duration, and 11 of them are still on the therapy.

Regarding adverse events, there were no cases of squamous cell carcinoma, which has been observed in previous trials of dabrafenib in adults with BRAF V600E positive tumours, most of whom have melanoma. One patient had an allergic reaction to the drug. Minor side effects were similar to those seen in adults, including transient fever, upset stomach, fatigue and skin rash.

Studies in adults with BRAF V600E mutations have shown that combining a BRAF inhibitor with a MEK inhibitor reduces toxicity and produces more activity for a longer period of time. The encouraging results with dabrafenib in children have provided the impetus for phase I and II trials with a MEK inhibitor to determine the dose and toxicities, and a trial combining the two drugs is now underway.

Kieran said: "We want to make the response rate with dabrafenib even higher by combining it with a MEK inhibitor since that works in adults. Adding two drugs together normally produces twice as much toxicity. But much of the toxicity from the BRAF drug is inhibited by the MEK drug, so the combination is less toxic than either drug alone, which is unusual."

Kieran concluded: "The finding that dabrafenib can shrink tumours or stop them growing is exciting and has led to trials with a MEK inhibitor and now the combination of drugs. This combined therapy may completely change the way we treat low-grade gliomas in children with this mutation. The caveat is that these targeted personalised drugs are relatively new so we need to make sure that they don't have any long-term developmental toxicities in children."

Commenting on the findings, Professor Michael Weller, chairman, Department of Neurology, University Hospital Zurich, Switzerland, said: "The encouraging thing about this study is that this targeted treatment seems to work. At the moment in neuro-oncology we know almost everything about the molecular make-up of gliomas in adults and in children but we have not really been able to translate all this knowledge into an effective therapeutic agent."

"These findings will have implications for clinical practice because many parents are willing to travel all around the world to get access to a promising treatment," he continued. "We have almost no randomised data for brain tumours in children, at least for gliomas, because the tumours are too rare and the trials are difficult for ethical reasons."

Weller concluded: "We need longer follow up to find out how long the responses last and whether we get long-term survival. And then of course in children we want to know if there is any long-term toxicity."

No added benefit proven for pulmonary arterial hypertension drug, IQWiG finds

  

In continuation of my update on Selexipag

Selexipag (trade name: Uptravi) is approved for long-term treatment of pulmonary arterial hypertension (PAH) in adults with moderate to severe symptoms. The drug can be used either as combination therapy with other blood-pressure lowering drugs or as monotherapy in patients who are not candidates for these therapies. Selexipag has been on the market in Germany since May 2016. In an early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined whether this drug has advantages or disadvantages in comparison with the appropriate comparator therapy.

The limitation of the comparator therapy to a specific drug and the subsequent division of the population in the dossier were inadequate. The only study cited by the drug manufacturer for one of its subpopulations compared selexipag with placebo. However, no added benefit can be inferred from such a comparison.

Hence the manufacturer presented no suitable data for the assessment of the added benefit of selexipag, and IQWiG concluded: An added benefit of selexipag in comparison with the appropriate comparator therapy is not proven.

Selective widening of vessels and inhibition of tissue growth

In PAH, the pulmonary artery is narrowed, and the heart has to work harder to pump oxygen-poor blood through the pulmonary artery into the lungs. The permanently increased workload of the right heart chamber decreases the body's oxygen supply. The high blood pressure (hypertension) is often caused by another heart or lung disease, e.g. by chronic obstructive pulmonary disease (COPD) or a congenital heart defect.

Selexipag aims to widen the pulmonary artery and slow down the overload of the heart. The drug is approved for long-term treatment of PAH patients who have no symptoms at rest but who have slight (WHO functional class II) or marked (WHO functional class III) limitation of physical activity. These restrictions cause symptoms such as dyspnoea, tiredness, chest pain, or dizziness. Selexipag is an option as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase-5 (PDE-5) inhibitor, or as monotherapy in patients who are not candidates for these therapies.

PARP inhibitor prolongs progression-free survival in patients with recurrent ovarian cancer

 

The PARP inhibitor niraparib significantly improves the outcome of platinum-sensitive recurrent ovarian cancer, according to full data from the ENGOT-OV16/NOVA trial presented for the first time at the ESMO 2016 Congress in Copenhagen and published in the New England Journal of Medicine (NEJM). The trial met its primary endpoint, with niraparib considerably prolonging progression-free survival compared to placebo.

"There are limited treatment options in recurrent ovarian cancer," said lead author Dr Mansoor Raza Mirza, chief oncologist, Rigshospitalet, Copenhagen University Hospital, Denmark and medical director of the Nordic Society of Gynaecological Oncology (NSGO). "Cumulative toxicity with platinum-based chemotherapy and lack of additional benefit limits its use. We then pause treatment until the next relapse and start combination chemotherapy."

"The current options for maintenance therapy in the EU are bevacizumab, which can only be given once and improves progression-free survival by just a few months, and the PARP inhibitor olaparib, which is only approved in patients with a germline BRCA mutation (about 10-15% of ovarian cancer patients). No maintenance therapy is approved outside the EU," he continued.

This phase III trial was performed in collaboration with European Network of Gynaecological Oncology Trial groups (ENGOT). The ENGOT-OV16/NOVA trial evaluated the efficacy and safety of the PARP inhibitor niraparib as maintenance therapy in patients with recurrent ovarian cancer who respond to platinum-based chemotherapy. Patients were assigned to cohorts by BRCA mutation status and randomised 2:1 to receive niraparib 300 mg or placebo once daily.

The trial included 553 patients, of whom 203 had the germline BRCA mutation and 350 did not. Niraparib significantly improved the primary endpoint of progression-free survival compared to placebo in both cohorts, as well as in all subgroups.

Median progression-free survival with niraparib compared to placebo was 21.0 vs 5.5 months in the germline BRCA mutation group (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.173 to 0.410, p<0.0001), 9.3 months vs 3.9 months in the non-germline BRCA mutation group (HR 0.45, 95% CI 0.338 to 0.607, p<0.0001), and 12.9 vs 3.8 months in a subgroup of the non-mutation cohort who had homologous recombination DNA repair deficiencies (HRD) (HR 0.38, 95% CI 0.243 to 0.586, p<0.0001).

More than 10% of patients had grade 3/4 adverse events following treatment with niraparib, of whom 28% had thrombocytopaenia, 25% had anaemia, and 11% had neutropaenia. These were resolved with dose adjustments and patients could continue their treatment. Patient-reported outcomes were similar with niraparib and placebo. Patients on niraparib maintained symptom control and had a quality of life comparable to those on placebo.

Significant improvements were also observed in all secondary endpoints. Compared to placebo, niraparib significantly prolonged the second progression-free survival, time to first subsequent treatment, and chemotherapy-free interval in the mutation and mutation-free groups, and in the HRD subgroup.

"This is a breakthrough for patients with ovarian cancer," said Mirza. "We have never seen such large benefits in progression-free survival in recurrent ovarian cancer. Niraparib significantly improved all endpoints across a broad patient population representing 70% of all ovarian cancer patients. These landmark results could change the way we treat this disease."

He concluded: "Once it is approved by the regulatory authorities, I'll consider niraparib for all my patients with recurrent ovarian cancer who respond to platinum regardless of BRCA status."

Commenting on the results, Dr Andrés Poveda, head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain, said: "This study more than doubles the population of patients who benefit from a PARP inhibitor."

"Personalised medicine has arrived in high grade serous ovarian cancer," he continued. "This was the first trial to use HRD to select patients for treatment and showed that it is a useful strategy. We also know that PARP inhibitors benefit patients with BRCA mutations."

Poveda concluded: "Future studies are needed to unravel which patients with HRD are not responders to PARP inhibitors and why, and which patients are long responders and why. We also need to know if there are other non-HRD factors, such as cyclin E positivity, that predict which patients will respond to treatment.

Combination treatment for myocardial infarction shows no added benefit compared to ASA monotherapy

The drug ticagrelor has been approved since February 2016 for adults who had a myocardial infarction a year or more ago and are at a high risk of a new myocardial infarction or stroke. Ticagrelor is used together with low-dose acetylsalicylic acid (ASA). In its dossier assessment published in early July 2016, the German Institute for Quality and Efficiency in Health Care (IQWiG) determined an indication of a minor added benefit of ticagrelor in comparison with the administration of ASA alone.

 acetylsalicylic acid(ASA)   Ticagrelor

On the inclusion of additional analyses that the drug manufacturer provided in the commenting procedure conducted by the Federal Joint Committee (G-BA), the Institute now came to a different conclusion, however: An added benefit is not proven because positive effects are called into question by negative effects.

Non-severe bleeding notably more common

The dossier had only contained data on severe bleeding. There were no data on non-severe bleeding that are clinically relevant. The results of the analyses subsequently submitted by the manufacturer were to the disadvantage of ticagrelor: Since these bleeding events were notably more common than under ASA monotherapy, IQWiG determined proof of greater harm with the extent "considerable".

No data on quality of life

In addition, there were no data on quality of life. Particularly in coronary heart disease (CHD), this is a very important outcome criterion however, which is even more important in view of side effects such as dyspnoea. "Disease-related quality of life" is the first treatment goal listed in the recently published revised version of the National Care Guideline for Coronary Heart Disease.

Since, on the one hand, greater harm was proven for an additional outcome, and, on the other, no data on quality of life were available, the positive effects, including the ones regarding mortality and late complications, were called into question by the negative effects. In the overall consideration, no added benefit of ticagrelor plus ASA in comparison with ASA monotherapy could be derived from the data.