Antifungal drug kills dormant colorectal cancer cells

Colorectal cancer is the fourth most commonly diagnosed type of cancer in the United States. Though various treatments are available for it, certain tumor cells are therapy-resistant. Now, research suggests that an antifungal drug may be effective against these persistent cells.

Can itraconazole, an antifungal drug, eliminate therapy-resistant cancer cells and halt tumor progression?

The drug itraconazole is typically used in the treatment of fungal infections.

These can include certain types of vaginal yeast (vulvovaginal candidiasis) and fungal infections on the hands and feet (Tinea pedis and Tinea manuum).

But researchers from the Cancer Research UK Cambridge Institute have suggested a brand new use for this substance — namely, as a treatment that is able to eliminate dormant tumor cells in colorectal cancer.

This is one of the most common cancer types in the U.S., and an estimated 140,250 people will learn that they have this disease in 2018, according to the National Cancer Institute (NCI).

“One of the biggest challenges in treating any cancer is the diversity of different cells within the same tumor,” explains co-lead author Dr. Simon Buczacki, who participated in the new study investigating the effect of itraconazole on dormant colorectal cancer cells.

In this study, he continues, the team “targeted a type of cell that lies asleep within bowel tumors, remaining unresponsive to treatment and putting the patient at risk of their cancer coming back.”

In experiments conducted on mice, Dr. Buczacki and team found that the antifungal drug may be able to trigger the death of a type of colorectal cancer cell typically immune to treatment.

These tumor cells are found in a state of inactivity, or “dormancy,” so they do not respond to the usual therapies, such as chemotherapy, that target and destroy active cancer cells.

So, even as a treatment is effective in destroying most malignant cells, these dormant units will remain unaffected, putting the person at risk of having a recurrence of the cancer later on.

Itraconazole halts tumor progression

In the study — the findings of which have been published in the Journal of Experimental Medicine— the researchers worked with cancer tumors grown in mice models of colorectal cancer.

First of all, they focused on identifying which signaling pathways were involved in controlling cell dormancy in the case of cancer tumors. They saw that, for colorectal cancer, there are two: Wntand “hedgehog” pathways.

Then, they tested the effectiveness of various drugs on these two pathways, and it was then that they noticed itraconazole’s therapeutic potential.

Dr. Buczacki and team discovered that itraconazole interfered with the Wnt pathway, which led to the elimination of the dormant cells and blocked the growth of the cancer tumor.

“What’s interesting is that this drug seems to kick both dormant and non-dormant cells into action,” notes Dr. Buczacki.

“It forces cells back into a short cycle of growth,” he explains, “before slamming on an irreversible ‘stop’ button, entering a permanent standstill that’s known as senescence.”

Following these promising results, the team would eventually like to test the effectiveness of this drug in clinical trials, on patients with colorectal cancer at an advanced stage.

Another step would be to ascertain whether itraconazole would be more effective on its own, or used in combination therapy, administered alongside other drugs.

Prof. Greg Hannon — the director of the Cancer Research UK Cambridge Institute — comments on the discovery, calling the research an “innovative study” that “has taken a step toward addressing one of the biggest challenges in cancer research.”

“The presence of drug-resistant, dormant tumor cells is a problem in many types of cancer,” he says.

“If we find ways to target these cells in bowel cancer, it might provide insights into tackling the problem of dormant tumor cells more broadly.”

Prof. Greg Hannon

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Knowledge gaps found for non-drug therapy in pediatrics ADHD

There are considerable gaps in knowledge relating to the effectiveness of non-pharmacologic treatments for attention-deficit/hyperactivity disorder (ADHD) in pediatric patients, according to a review published online May 30 in Pediatrics.

Adam P. Goode, D.P.T., Ph.D., from Duke University in Durham, N.C., and colleagues examined the comparative effectiveness of non-pharmacologic treatments for ADHD among individuals age 17 years and younger. Studies that compared any ADHD non-pharmacologic treatment strategy with placebo, pharmacologic, or another non-pharmacologic treatment were included. Random-effects meta-analysis was used to generate pooled estimates for comparisons with at least three similar studies.

Fifty-four studies of non-pharmacologic treatments were identified, including neurofeedback, cognitive training, cognitive behavioral therapy, child or parent training, dietary omega fatty acid supplementation, and herbal and/or dietary approaches. The researchers found that there was no new guidance relating to the comparative effectiveness of non-pharmacologic treatments. In pooled results for omega fatty acids, there were no significant effects for parent or teacher ratings of ADHD total symptoms.

“Despite wide use, there are significant gaps in knowledge regarding the effectiveness of ADHD non-pharmacologic treatments,” the authors write.

One author disclosed financial ties to the pharmaceutical industry.

 Explore further: Some dietary interventions improve ADHD symptoms

More information: Abstract/Full Text (subscription or payment may be required)

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Walk faster, live longer

Speeding up your walking pace could extend your life, research led by the University of Sydney suggests.

Walking at an average pace was found to be associated with a 20 percent risk reduction for all-cause mortality compared with walking at a slow pace, while walking at a brisk or fast pace was associated with a risk reduction of 24 percent. A similar result was found for risk of cardiovascular disease mortality, with a reduction of 24 percent walking at an average pace and 21 percent walking at a brisk or fast pace, compared to walking at a slow pace.

The protective effects of walking pace were also found to be more pronounced in older age groups. Average pace walkers aged 60 years or over experienced a 46 percent reduction in risk of death from cardiovascular causes, and fast pace walkers a 53 percent reduction.

Published today, the findings appear in a special issue of the British Journal of Sports Medicine (from the BMJ Journals group) dedicated to Walking and Health, edited by lead author Professor Emmanuel Stamatakis from the University of Sydney’s Charles Perkins Centre and School of Public Health.

“A fast pace is generally five to seven kilometres per hour, but it really depends on a walker’s fitness levels; an alternative indicator is to walk at a pace that makes you slightly out of breath or sweaty when sustained,” Professor Stamatakis explained.

A collaboration between the University of Sydney’s Charles Perkins Centre and Faculty of Medicine and Health, the University of Cambridge, University of Edinburgh, University of Limerick and University of Ulster, the researchers sought to determine the associations between walking pace with all-cause, cardiovascular disease and cancer mortality.

Linking mortality records with the results of 11 population-based surveys in England and Scotland between 1994 and 2008—in which participants self-reported their walking pace—the research team then adjusted for factors such as total amount and intensity of all physical activity taken, age, sex and body mass index.

“Walking pace is associated with all-cause mortality risk, but its specific role—independent from the total physical activity a person undertakes—has received little attention until now,” Professor Stamatakis said.

“While sex and body mass index did not appear to influence outcomes, walking at an average or fast pace was associated with a significantly reduced risk of all-cause mortality and cardiovascular disease. There was no evidence to suggest pace had a significant influence on cancer mortality however.”

In light of the findings, the research team is calling for walking pace to be emphasised in public health messages.

“Separating the effect of one specific aspect of physical activity and understanding its potentially causal association with risk of premature death is complex,” Professor Stamatakis said.

“Assuming our results reflect cause and effect, these analyses suggest that increasing walking pace may be a straightforward way for people to improve heart health and risk for premature mortality—providing a simple message for public healthcampaigns to promote.

“Especially in situations when walking more isn’t possible due to time pressures or a less walking-friendly environment, walking faster may be a good option to get the heart rate up—one that most people can easily incorporate into their lives.”

More information: Emmanuel Stamatakis et al, Self-rated walking pace and all-cause, cardiovascular disease and cancer mortality: individual participant pooled analysis of 50 225 walkers from 11 population British cohorts, British Journal of Sports Medicine (2018). DOI: 10.1136/bjsports-2017-098677

https://bit.ly/2J5JbmA

#ASCO18: Merck beats Roche in big squamous lung cancer survival numbers

Over the last few years, non-squamous non-small cell lung cancer data has grabbed most of the attention in immuno-oncology. Not this ASCO.

It’s the squamous form of lung cancer that’s in the spotlight this time, and on Sunday morning at the American Society of Clinical Oncology annual meeting, Merck & Co. was the star of the show, upstaging Roche with better data.

Both Roche and Merck rolled out positive numbers for their PD-1/PD-L1 checkpoint inhibitors in previously untreated squamous patients, setting them up for a marketplace battle. But Merck one-upped its rival by showing a larger benefit, as well as overall survival data that Roche doesn’t yet have.

Saturday, the Swiss pharma giant got the party started, unveiling results from its ImPower-131 study that showed its Tecentriq, when combined with chemotherapy, reduced the risk of worsening disease or death by 29% compared with chemo alone.

Sunday, though, Merck’s Keytruda, combined with chemo, showed it could cut that same risk by 44% and pare down the risk of death by 36%, according to data from the drugmaker’s Keynote-407 study. That’s a performance Roy Baynes, Merck SVP and head of global clinical development, called “truly remarkable.”

The numbers aren’t directly comparable, of course, because the studies were designed differently. “There were a lot of differences in the way these trials were run,” said Dan Chen, VP and global head of cancer immunotherapy development for Roche’s Genentech unit. And Baynes agreed that “there are all sorts of risks in doing cross-trial comparisons, not least of which” is that the patient populations weren’t exactly the same.

Still, pharma watchers will compare them, and some analysts expect Keytruda to leverage its data to prevail in the market showdown—especially given its positioning in first-line lung cancer on the whole. Right now, it’s the only member of its class to bear the FDA’s blessing for use in previously untreated patients,, and it has not one, but two approvals.

“Barring any surprises, we see Merck in a dominant position going forward,” Credit Suisse analyst Vamil Divan wrote to clients ahead of the data release.

Roche, for its part, eagerly awaits its chance to share overall survival data for the Tecentriq-chemo team in squamous lung cancer. While that data aren’t yet mature, “you can clearly see the start of that separation” in survival when the stats are charted, Chen said.

And in the meantime, he encouraged industry watchers to look at the body of evidence Tecentriq has so far produced across histologies and as part of different regimens.

“To date, all of these studies are positive,” he said. “I think that’s probably the better way to look at all of this.”

https://bit.ly/2sr4uVE

#ASCO18: Array to update on Phase 3 melanoma trial

Array BioPharma Inc. (Nasdaq: ARRY) announced that it will present data from the Phase 3 COLUMBUS trial of encorafenib and binimetinib in advanced BRAF-mutant melanoma in an oral presentation on June 4, 2018, at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

“Binimetinib and encorafenib is the first targeted therapy to demonstrate over 30 months median overall survival in a Phase 3 trial and we look forward to presenting the results from the COLUMBUS trial at ASCO,” said Ron Squarer, Chief Executive Officer. “With nearly 15 months median progression-free survival and an attractive tolerability profile, these data underscore the potential of this combination to become an important new treatment option for patients with BRAF-mutant advanced, unresectable or metastatic melanoma.”

As previously announced, the most common Grade 3/4 adverse events (AEs) seen in more than 5% of patients were increased gamma-glutamyltransferase (GGT) (9%), increased creatine phosphokinase (7%), and hypertension (6%) in the encorafenib plus binimetinib group.

https://bit.ly/2H0S1fO

U.S. Supreme Court case could limit physician referral power

A case before the U.S. Supreme Court on how antitrust laws are enforced has the potential to affect health care in a way that would harm patient care and interfere with a physician’s duty to a patient to provide the best medical care.

The case before the nation’s highest court, State of Ohio et al. v. American Express Company et al., involves how a credit card company operates, although this may seem far removed from the practice of medicine, the underlying issue the justices are considering is how federal antitrust laws are applied. Their ruling could upend how the courts determine whether anti-steering provisions are violated under the Sherman Act.

If the nation’s highest court upholds a ruling by the 2nd U.S. Circuit Court of Appeals, it would mean dominant health insurers or dominant hospital systems could create contracts that include anti-referral rules that prohibit physicians from referring patients to out-of-network specialists for innovative or medically-necessary tests that would provide the patient with the best care. So argues an amicus brief the Litigation Center for the American Medical Association and State Medical Societies and the Ohio State Medical Association filed with the U.S. Supreme Court.

“Material interference with physicians’ medical judgments threatens physician autonomy, damages the doctor-patient relationship, decreases medical innovation and lowers the overall quality of patient care,” the Litigation Center brief states. “The antitrust laws have historically played an instrumental role in preventing such outcomes. This court should ensure that antitrust law’s vital role in health care continues.”

Why the ruling would impact medicine

Under the 2nd Circuit’s decision, it would be extremely difficult for a patient or physician to prove to a court that antitrust laws were being violated.

A plaintiff—whether that is the government, physician or a patient—would have to net out the harm to one group of consumers with the potential benefits to another group. For example, if a physician were barred from referring a patient to a particular specialist or if a patient were unable to obtain a particular test, the court would balance that harm against the speculative benefits to other patients and insurance subscribers, the amicus brief tells the court.

If the Supreme Court allows the lower-court decision to stand, “it would provide greater leeway for dominant entities to impose contractual restraints on a physician’s ability to refer their patients for care which the physician deems best in their medical judgment,” the brief states.

“Physicians will have no choice but to accept those restrains because rejecting them means turning away a large number of patients whom physicians would otherwise be able to serve, which is untenable from both a business and ethical standpoint,” the brief says. “Physicians would then have to weigh, against what they deem best for their patients, the consequences of their breaching their contractual obligations. It would be difficult for them to find recourse under the antitrust laws in such situations.”

Physicians would be prevented from making referrals based on their best judgment and on best medical outcomes for their patients, the Litigation Center and OSMA conclude. “In this way, these restrictions could be wholly at odds with the physician’s ethical responsibilities. And because such restrictions could limit quality and choice, they raise competitive concerns that the antitrust laws traditionally have proscribed,” they told the Supreme Court in their brief.

Justices heard oral arguments in February and a ruling is expected by the end of June.

https://bit.ly/2srKimk

Becoming Their Own Doctors: Coping With Patient Requests in Information Age

Hello. I’m Dr Charles Vega, and I am a clinical professor of family medicine at the University of California at Irvine. Welcome to Medscape Morning Report, our 1-minute news story for primary care.

It probably comes as no surprise to primary care physicians to learn that the frequency with which patients come in asking for a specific intervention—a drug, a blood test, an imaging study—has increased over the past 30 years.

A large analysis of data from a Dutch primary care network, collected from 1985 to 2014, confirms this trend. Requests for lab tests or an imaging study more than doubled. A request for a specific drug was up more than 20%.

What may be surprising is the percentage of compliance with these requests, which also increased significantly. Physicians are complying 70%-100% of the time. The investigators attributed this increase to a greater sense of patient empowerment and easy access to medical information.

The question is: Is this trend positive or negative? It’s important to have empowered patients involved in active decision-making, but not every patient request is reasonable, or even safe. What do you think? Please use the comment button to voice your opinion on this new research.

https://wb.md/2kO2sdD