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‘Impressive’ Activity in Biliary Cancer with Combo Therapy

A precision-medicine treatment strategy showed “impressive” activity in patients with a rare but aggressive biliary tract cancer, according to a study reported here.

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) led to objective responses in about 40% of patients with BRAF-mutated biliary tract cancer. An additional 40-45% of 33 evaluable patients had stable disease.

“Nearly every patient had some tumor reduction,” said Zev Wainberg, MD, of the University of California Los Angeles, at the Gastrointestinal Cancers Symposium. “The duration of response at 6 months was 66%. Many of the patients who had stable disease also had durable clinical benefit.”

The cohort had a median progression-free survival (PFS) exceeding 9 months and a median overall survival (OS) of almost a year, he added. The safety profile of dabrafenib/trametinib was consistent with previously reported clinical experience.

The results are “incredibly impressive,” said Heinz-Josef Lenz, MD, of the University of Southern California Norris Cancer Center in Los Angeles.

“I think it is important to recognize that most of these patients were heavily pretreated,” he said. “I don’t think I need to convince you that this treatment is very effective.”

Given the multiple potentially actionable mutations in biliary tract cancer, the study could represent just the first step toward expanded and more effective treatment options for the aggressive disease, Lenz added. Better understanding of the tumor microenvironment — particularly signaling between normal tissue, stromal tissue, and tumor tissue — should provide insights to inform development of new therapeutic strategies.

Multiple mutations have been identified in association with biliary cancer, including BRAF in about 5% of tumors overall, perhaps more often in intrahepatic tumors, Wainberg continued. Previous studies of dabrafenib/trametinib, which simultaneously inhibits BRAF and MEK, demonstrated activity in several types of cancer associated with the BRAF V600E mutilation , including melanoma, non-small cell lung cancer, and anaplastic thyroid cancer.

Wainberg reported findings from the biliary cancer cohort of phase II ROAR trial, which evaluated the dabrafenib/trametinib combination in multiple types of advanced rare cancer associated with BRAF V600E. The biliary cancer subgroup included 35 patients, most of whom had received two or more prior lines of therapy.

The median duration of exposure to dabrafenib/trametinib was 6 months and ranged to 32 months. All but five patients continued study medication for more than 3 months. The trial had a primary endpoint of investigator-assessed response.

Among 33 evaluable patients, 14 (42%) had partial responses with the combination therapy. An independent review committee concluded that 12 (36%) patients achieved objective responses. An additional 15 patients had stable disease by investigator assessment, 13 by independent review. Both reviews found that four patients had progressive disease as best overall response. Two patients were not evaluable, according to the independent review committee.

About a third of patients received one or more additional treatments after dabrafenib/trametinib, including chemotherapy, surgery, small-molecule inhibitors, immunotherapy, biologic therapy, and radiation therapy.

The biliary cancer cohort had a median PFS of 9.2 months by investigator assessment. Median OS was 11.7 months.

N0 new or unexpected adverse events occurred during treatment with dabrafenib/trametinib. The most commonly reported treatment related adverse events were pyrexia (40%); rash (29%); nausea, diarrhea, and fatigue (23% each); and chills (20%). Adverse events leading to dose reduction occurred in 37% of patients and adverse events leading to dose interruption in 54%. One patient (3%) had an adverse event that led to permanent discontinuation.

Two patients died of sepsis, but neither death was considered treatment related, said Wainberg.

Genetic analysis of tissue samples from 16 patients yielded findings consistent with previously reported observations about the genetic landscape of biliary tract cancer. Tumor mutational burden was low (<6 mut/Mb) in all evaluable patients.

“These results represent the first prospectively analyzed cohort of patients with BRAF V600-mutant biliary tract cancer treated with the combination of BRAF and MEK inhibitors,” Wainberg concluded. “Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancer and should be considered a meaningful therapeutic option for these patients. BRAF V600 is an actionable driver mutation and should be considered for routine testing in patients with biliary tract cancer.”

The ROAR basket trial was supported by Novartis.

Wainberg disclosed relevant relationships with Aduro Biotech, Array BioPharma, Bristol-Myers Squibb, Five Prime Therapeutics, Genentech, Lilly, Merck, Merck KGaA, Novartis, Sirtex Medical, Pfizer, and Plexxikon.


Mixed Results with Immune Therapy in Advanced, Refractory Colon Cancer

Immune therapies continued to achieve limited success in the treatment of microsatellite stable (MSS) refractory or advanced colorectal cancer (CRC), according to studies presented here.

In a study of 180 patients with advanced, refractory CRC, the combination of PD-L1 inhibitor durvalumab (Imfinzi) plus a monoclonal antibody against CTLA-4, tremelimumab extended overall survival (OS) to a median of 6.6 months (hazard ratio 0.72, (90% CI 0.54-0.97, P=0.07) compared with a median of 4.1 months for best supportive care (BSC), reported Eric Chen, MD, PhD, University Health Network in Toronto, and colleagues.

But the combination had no effect on progression-free survival (PFS) at 1.8 months (90% CI 1.8-1.9 months) versus 1.9 months (90% CI 1.8-1.9 months) for BSC, Chen said in a presentation at Gastrointestinal Cancers Symposium (GICS).

In a separate study of 121 patients in stage IV CRC limited to liver metastases, tecemotide (L-BLP25), a vaccine that targets the MUC1 antigen, failed to have any effect on either recurrence-free survival (RFS) or OS, regardless of the level of MUC1 expression, reported Carl Schimanski, MD, PHD, on Klinikum Darmstadt in Germany, and colleagues.

“A number of large clinical trials looking at anti-PD-L1 inhibitor monotherapy, or anti-PD-L1 inhibitors given in various combinations, have all been negative in microsatellite stable CRC, and even if you select patients for PD-L1 positivity, none of the MMS patients have responded to anti-PD-1 therapy, so single agent treatment has not been successful in this population,” said GICS discussant Michael Overman, MD, of MD Anderson Cancer Center in Houston.

And while he did not totally dismiss the potential benefit of treating refractory CRC with the combination of durvalumab plus tremelimumab, “I think we need confirmation of these findings to have confidence in them before this data is incorporated into any clinical practice,” Overman stated.

As for the anti-cancer vaccine, tecemotide, here again, “all trials have been negative in regards to their primary OS endpoint,” he said.

Thus, oncologists continue to confront challenges in the use of immune therapy in the treatment of MMS CRC, Overman said.

The Canadian CO.26 trial randomized patients with advanced CRC who had failed all standard CRC regimens to either IV durvalumab (1500 mg) every 28 days along with IV tremelimumab (75 mg) given on day 1 for the first four cycles plus BCS (n=119) or BCS alone (n=61). Over 85% of patients received at least 90% of planned doses of the active therapy arm, Chen reported.

At a median follow-up of 15.2 months, no complete responses (CRs) were observed in either arm and there was only one partial response (PR) in the combination arm. On the other hand, the disease stabilized in 22.7% of patients on the combination strategy compared with only 6.6% of those treated with best supportive care (P=0.006). Rates of grades 3 and 4 abdominal pain, fatigue and lymphopenia were all significantly higher in the active therapy arm compared with BSC (P<0.01).

Nevertheless, Chen suggested that quality of life was not adversely affected by this particular regimen, and that “Results from this study suggest that the combination of durvalumab and tremelimumab prolongs overall survival of patients with refractory colorectal cancer compared to best supportive care.”

He added that “this is the first study demonstrating immune checkpoint blockade effectiveness in colorectal cancer patients unselected for mismatch repair deficiency.” Colorectal tumors are classified according to their global genomic status, either microsatellite instable (MSI) or MMS. MSI is the molecular fingerprint of a mismatch repair deficiency, where immune checkpoint blockade has demonstrable activity.

In the second trial, Schimanski noted that 79 patients with stage IV CRC limited to liver metastases received tecemotide after undergoing resection of both the primary tumor and liver metastases (R0/R1). The vaccine was given as eight weekly, subcutaneous injections followed by 6-week maintenance intervals, until recurrence or a maximum of 2 years. Three days prior to the first tecemotide dose, patients were treated with cyclophosphamide at a dose of 300 mg/m2 to reduce regulatory T-cells.

The remaining 42 patients served as placebo controls. At a median of 6.1 months in the tecemotide arm and 11.4 months in the placebo arm, RFS rates were not significantly different between the twp groups. Similarly, OS rates for patients treated with tecemotide were 62.8 months (45.1 months-not achieved or NA) compared with NA (53.6 months to NA) for placebo controls, a difference which was again not statistically significant between the two groups.

However at 3 years, 69.1% of patients in the vaccine arm and 79.1% of patients in the control arm were still alive. prompting Schimanski to suggest that “the unexpectedly high OS rate highlights the critical importance of both accurate staging and intensive surveillance.”

The CO.26 trial was funded by AstraZeneca.

Chen disclosed support from AstraZeneca, Merck, Bristol-Myers Squibb (BMS), Novartis, Boston Biomedical and Seattle Genetics, as well as relevant relationships with Taiho, Eisai, reiStone, and PMRI.

Schimanski disclosed support from Merck KGaA.

Overman disclosed support from BMS, MedImmune, Merck, and Roche, as well as relevant relationships with BMS, Gritstone Oncology, MedImmune, and Roche/Genentech.


Metastatic Gastric Ca Treatments Show Mixed Results

Mixed results emerged from studies evaluating the efficacy of two novel therapies for patients with metastatic gastric cancer, researchers reported.

In one study, trifluridine/tipiracil (FTD/TPI, Lonsurf) was shown to be an effective treatment option for patients with metastatic gastric cancer, regardless of prior gastrectomy.

In the other, the monoclonal antibody andecaliximab plus the chemotherapy regimen mFOLFOX6 (mFOLFOX + ADX) as a first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma failed to improve overall survival.

Both studies were presented here at the 2019 Gastrointestinal Cancers Symposium.

TAGS Trial

According to David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, who presented the study on FTD/TPI, the only potentially curative treatment for early stage gastric cancer is surgery, with 5-year survival rates after gastrectomy of 90% or more in Japan and Korea and 40% to 75% in non-Asian countries.

Furthermore, the disease recurs in up to half of patients, while 40% of patients with metastatic disease have had a previous gastrectomy.

The phase III TAGS study had demonstrated that FTD/TPI is effective and safe for patients with heavily pretreated metastatic gastric cancer. Here, Ilson and his colleagues evaluated the efficacy and safety of the FTD/TPI in patients with or without gastrectomy.

Patients were randomized two-to-one (337 in the FTD/TPI arm and 170 in the placebo arm) to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo.

Of the 507 patients in the study, 147 in the FTD/TPI arm had a prior gastrectomy compared to 74 in the placebo arm.

In the total study population, median overall survival was 5.7 months in the FTD/TPI arm compared to 3.6 months in the placebo arm (HR 0.69). Progression-free survival was 2.0 vs 1.8 in the FTD/TPI and placebo arms, respectively (HR 0.57).

The overall and progression-free survival data of patients with prior gastrectomy “mirrored the data seen in the overall treatment population,” Ilson reported, with overall survival improving by 2.6 months in the FTD/TPI arm (HR 0.57).

As for safety, hematologic adverse events such as neutropenia/leukopenia were more frequent among those patients treated with FTD/TPI, but these did not lead to more frequent treatment discontinuation.

“I think the data from this study reinforce the benefit of TPI as prolonging survival versus placebo, regardless of gastrectomy,” Ilson concluded.

Combination Treatment

In a prior phase I/IB study, the combination of mFOLFOX6 and ADX “revealed encouraging anti-tumor activity in patients with gastric or gastroesophageal junction adenocarcinoma,” noted Manish A. Shah, MD, of Weill Cornell Medicine in New York City.

He presented a phase III, randomized, double-blind, multicenter study comparing the efficacy and safety of mFOLFOX with or without ADX in patients with untreated HER2-negative gastric or gastroesophageal junction adenocarcinoma.

From September 2015 to May 2017, 432 patients were randomized to receive either mFOLFOX plus ADX (218) or mFOLFOX with placebo (114).

The primary endpoint was overall survival, with secondary endpoints of progression free survival, objective response rate, and safety.

As for statistical assumptions regarding overall survival, “we were aggressive,” said Shah. “We wanted to demonstrate a real improvement in benefit with andecaliximab, so we were hoping to improve overall survival from 11.5 months to 16.4 months.”

However, Shah reported, “disappointingly, we didn’t see an improvement in survival with ADX.”

Overall survival was a median of 12.5 months (95% CI 11.2-14.0), compared to 11.8 months (95% CI 10.3-13.5) in the ADX and placebo groups, respectively (HR 0.93).

Median progression-free survival was 7.5 months compared to 7.1 months in the ADX and placebo groups, respectively (HR 0.84), while the overall response rate was 50.5% vs 41.1% in the ADX and placebo groups, respectively.

Adverse events were comparable in the two groups, with the most frequent being nausea, diarrhea, neutropenia, and fatigue.

Shah did note that elderly patients — 65 and older — did better on ADX than other subgroups. Median overall survival in that group was 13.9 months compared to 10.6 months in the placebo group, while progression-free survival was 8.7 months compared to 6.5 months.

The apparent increased activity of the combination of mFOLFOX with ADX in patients ages 65 or older needs further study, Shah said.

Shah disclosed institutional research funding from Boston Biomedical, Gilead Sciences, Merck, and Oncolys BioPharma.

Ilson disclosed consulting or an advisory role with AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly/ImClone, Merck, Pieris Pharmaceuticals, and Roche/Genentech.

Stress fracture? Your foot hitting pavement wasn’t the main problem

It starts as a persistent and irritating pain in the foot or lower leg, then it gets more intense, maybe with swelling, and soon a runner knows she’s being sidelined by one of the most common running injuries: a stress fracture. These tiny cracks in the bone can halt training for months or even end a sports season.

A segment of the multibillion-dollar wearables industry aims to save potential victims from this fate, but a Vanderbilt University engineering professor found a major problem: the devices are measuring the wrong thing.

Working with a local running club, an orthopedic specialist who advises the NFL Players Association and a team of Vanderbilt engineers, Assistant Professor of Mechanical Engineering Karl Zelik discovered that sensors only measuring the impact of the foot hitting pavement — which is what virtually all of them do — tell users little about the forces on bones that lead to stress fractures.

His research confirmed that the vast majority of force on the bone is actually from muscles contracting, not from the foot’s impact on the ground, a finding widely overlooked by both the wearables industry and many scientific studies.

Zelik’s research, appearing today in the peer-reviewed journal PLOS One and titled “Ground reaction force metrics are not strongly correlated with tibial bone load when running across speeds and slopes: Implications for science, sport and wearable tech,” offers the most clear and simple demonstration of the problems underlying the existing tools and prevailing methods for assessing bone stress and injury risk.

“We looked through the recent scientific literature, and we found that more than 50 scientific publications each year report or interpret their results based on this incorrect assumption that ground reaction force is representative of internal structure loading — the stress on bones and muscles inside the body,” said Zelik, a former college track and field standout. “Measuring ground reaction force may be convenient, but it’s the wrong signal.”

Wearable accelerometer and pressure sensors already on the market may help monitor bone stress injury risks, but only if they combine information about the ground reaction force and the force from muscles pulling against the bone. In general, you cannot assume that increases in ground reaction force indicate increases in bone stress, said Emily Matijevich, a mechanical engineering Ph.D. student in Zelik’s lab and herself an avid runner.

Matijevich performed the lab work that the study outlines, testing 10 runners over a range of speeds and slopes.

“We used high-speed, motion-capture cameras to track runners’ movement and a special force-measuring treadmill to record the ground reaction force under their feet,” she said. “We then combined these signals using biomechanical algorithms to estimate the compressive force experienced by the tibia bone in the shank, a common place for stress fractures to occur. In nearly all cases, we found that the ground reaction forces were not strongly correlated with tibial bone loading.”

In several cases, lower ground reaction forces actually meant more stress on the tibia, a finding opposite of what most athletes believe and counter to how most existing wearables work.

This research began two years ago, when Vanderbilt University Assistant Professor of Orthopaedics Leon Scott, who serves on the NFL Players Association’s health and safety committees, asked Zelik a simple question: Could wearable sensors be used effectively to prevent the stress fractures Scott saw in his clinic every day?

Matijevich, Zelik and Scott are now exploring new ways to monitor bone stress non-invasively, and recently filed a patent application for a system that fuses data from multiple wearable sensors to estimate tibia loading from both muscle contractions and ground reaction forces. They’re seeking commercial partners to develop this new wearable tech and explore applications to recreational runners, military cadets and elite athletes.

Scott said the combination of wearable sensors and new algorithms the team is developing gives a far better picture of bone stress, with the potential to help runners lower their chance of injuries.

“There’s only so much you can do when the game is going, because those are high-speed injuries, but we can do something about stress fractures during training and conditioning,” Scott said. “Right now, we don’t have great tools to tell us what’s happening to the bones other than experience and anecdote and these are, unfortunately, failing quite a few people.”

Story Source:

Materials provided by Vanderbilt University. Original written by Heidi Hall. Note: Content may be edited for style and length.

Brain cells that make pain unpleasant

If you step on a tack, neurons in your brain will register two things: that there’s a piercing physical sensation in your foot, and that it’s not pleasant. Now, a team of scientists at Stanford University has identified a bundle of brain cells in mice responsible for the latter — that is, the negative emotions of pain.

Pain research has traditionally focused on the neurons and molecules at the front line of pain perception — the cells in nerves that process stings, cuts, burns and the like — and ultimately convey a physical threat message. What Grégory Scherrer, PhD, assistant professor of anesthesiology and of neurosurgery, and Mark Schnitzer, PhD, associate professor of biology and of applied physics, are studying goes one step further. “We’re looking at what the brain makes of that information,” Scherrer said. “While painful stimuli are detected by nerves, this information doesn’t mean anything emotionally until it reaches the brain, so we set out to find the cells in the brain that are behind the unpleasantness of pain.”

Backed by animal-brain imaging and molecular testing, the researchers have found an ensemble of cells in the amygdala, a region of the brain classically associated with emotion and fear, that seems to specifically function as an on-off switch for pain aversion. And although the finding was made in mice, there’s reason to think it could one day serve as a therapeutic target for human pain, since the mouse and human amygdala aren’t so different in function. Researching this group of cells could reveal a potential treatment for chronic pain, the scientists hope.

The idea is that patients suffer from the emotional unpleasantness of pain, rather than pain sensation itself. If there’s a way to dull the emotional hurt, rather than the physical sensation of pain, that could be big for chronic pain patients.

A paper describing the results of the study will be published Jan. 18 in Science. Scherrer and Schnitzer, who is also a Howard Hughes Medical Institute investigator, share senior authorship. Postdoctoral scholar Gregory Corder, PhD and former postdoctoral scholar Biafra Ahanonu, PhD, are the co-lead authors.

Peeping at pain neurons

The amygdala seemed to the researchers a logical place to start, since it’s a well-established hub for emotion in the brain. Within the amygdala, they narrowed their search by looking for neurons in mice that were active during brief pain stimulation — such as a drop of hot, but not scalding, water applied to a paw. Neurons that are active express more of a specific gene called c-Fos, and indeed, a sea of c-Fos-expressing neurons flared after this stimulus.

“But that really only tells you that those neurons were active at some point, and it’s not specific enough,” Scherrer said. “What we wanted was to look at the neurons of freely moving animals.”

To observe the deep-seated wiring of a mouse’s brain, Scherrer partnered with Schnitzer, who had developed a “miniscope” — a microscope about the length of a small paper clip, which could be affixed to a mouse’s head to record activity in its brain. They positioned the device strategically to visualize the amygdala. The mouse, alive and well, could stroll as it pleased, while the miniscope recorded calcium flux in the neurons, a proxy for cell activity.

The scientists monitored the mouse brains with the microscope, watched the mice detect something uncomfortable, observed the aversive reactions and then checked which neurons were active. “With this setup, we identified a set of neurons in the amygdala that selectively encodes signals related to the emotional aspects of a painful experience,” Schnitzer said.

When the mice touched a drop of uncomfortably hot or cold water (neither of which were severe enough to injure the mice) they withdrew, signaling to the scientists that the rodents were not pleased. Upon this withdrawal, the microscope’s recording showed a bundle of neurons firing in the amygdala — specifically in the basolateral region — suggesting that these neurons were specifically responsible for the emotion of pain.

It was, however, still possible that this basolateral ensemble was simply firing to relay general emotion, rather than specifically the unpleasantness of pain. So, the researchers fed the mice sugar water — a sweet treat known to bring joy to any mouse — and kept an eye on the collection of neurons suspected to relay displeasure. As expected, those neurons stayed silent.

“There’s also a difference between experiencing pain and experiencing something annoying, so we further wanted to test if the amygdala neurons active during pain were also associated with overall negative emotion, rather than pain particularly,” Scherrer said.

What miffs a mouse? The same things that might bother a sibling: tiny puffs of air to the face, an unappetizingly bitter taste or a very bad smell. While bothering the mice, the researchers again monitored the basolateral amygdala pain ensemble, and here, too, the neurons remained subdued.

Tracking the perception of pain

“After all of that, we concluded that this ensemble of neurons selectively responds during pain,” Scherrer said. “But it still didn’t fully demonstrate that they underpinned the emotional response.”

To investigate that question more deeply, the researchers set up a walking track with three invisible lanes: On the far left was a cold strip, on the right, a hot one; and in between the two was a temperate middle ground. (For context, walking in the two outer lanes was comparable to briefly walking barefoot on pavement in the midst of winter or summer, respectively — uncomfortable, but not permanently damaging.)

Normal mice that walked on the track gradually learned that the middle lane was tolerable, while the outer two were unpleasant. But in a select group of mice, the researchers temporarily disabled the bundle of amygdala pain neurons thought to relay feelings of physical discomfort. These mice — free of pain-incited unpleasantness — skittered around the outer regions, undeterred by the extreme temperatures.

What’s intriguing about this, Scherrer said, was that these mice weren’t bereft of physical feeling. “Pain was just no longer unpleasant for them,” he said. The rodents could still feel and respond to physical sensations, but the stimuli they once perceived as unpleasant (hot or cold drops of water) were no longer bothersome. When exposed to a drop of hot water, for example, the mice with a muted basolateral neural ensemble would move their paw away from the dropper, signaling that they felt the stimulus — but they would move their paw back to its original position, something that normal mice did not do. This is a crucial part of harnessing the ensemble as a tool in pain therapy, Scherrer said, as an animal, or human, without the ability to physically feel anything at all leaves them vulnerable to injury.

Long term, Scherrer aims to confirm that the function of the basolateral ensemble in mice is the same as it is in people, and then down the line, find a safe and effective way to silence the ensemble’s function without interfering with other neurons.

“There’s really no good treatment for chronic pain in humans, and that’s a major driver of the opioid epidemic,” Scherrer said. “But you’ll notice, patients who take opioids for pain report that they can still feel the sensation of pain but say it’s less bothersome — the emotions of pain are different. Our big future hope is that the cells in the basolateral ensemble could be a tactic to curb the ailment of pain without causing addiction and thus, ideally, act as a possible substitute for opioid treatment.”

Other Stanford authors of the study are former Stanford postdoctoral scholar Benjamin Grewe, PhD; and research scientist Dong Wang, PhD.

The study was funded by the National Institutes of Health (grants R00DA031777, R01NS106301, K99DA043609, F32DA041029 and T32DA35165), the New York Stem Cell Foundation, the Rita Allen Foundation, the American Pain Society, the National Science Foundation, the Howard Hughes Medical Institute, the Bill and Melinda Gates Foundation and the Swiss National Science Foundation.

Story Source:

Materials provided by Stanford Medicine. Original written by Hanae Armitage. Note: Content may be edited for style and length.

Journal Reference:

  1. Gregory Corder, Biafra Ahanonu, Benjamin F. Grewe, Dong Wang, Mark J. Schnitzer, Grégory Scherrer. An amygdalar neural ensemble that encodes the unpleasantness of painScience, 2019 DOI: 10.1126/science.aap8586

Home-based hypertension program produces ‘striking’ results

Hypertension, or high blood pressure, is a widespread clinical problem affecting nearly half of all adults. Despite the serious consequences that can result from hypertension, which puts patients at increased risk for heart attacks, strokes and other cardiovascular events, elevated blood pressures often remain untreated or undertreated for years, and the control rate for hypertension hovers at just 50 percent. Seeing opportunities for improvement, innovators and clinicians at Brigham and Women’s Hospital have developed a new home-based, care-delivery program aimed to improve hypertension control rates quickly and at significantly lower cost than traditional, office-based blood pressure programs. The new approach, piloted among 130 participants, helped 81 percent of patients bring their blood pressures under control in, on average, just seven weeks. The results of the pilot study are published this week in Clinical Cardiology.

“This is a striking result, especially given the very short time frame in which control was reached: an average of seven weeks,” said corresponding author Naomi Fisher, MD, director of the Hypertension Service and Hypertension Specialty Clinic at the Brigham. “There are a few notable health care systems that have matched or exceeded this control rate, but most clinical practices do not approach this rate of success.”

To overcome some of the challenges that clinical practices face, Fisher and colleagues combined several innovative strategies to create their program. Enrolled participants each received a Bluetooth-enabled blood pressure device that could automatically transmit the blood pressure measurements patients took at home into their electronic medical records. Patients had easy and frequent access to “patient navigators” — non-physicians who had been trained to use a clinical algorithm developed by hypertension specialists. The program enabled rapid assessment and medication dosage adjustments for the patients.

The pilot was conducted as a prospective cohort study. The team enrolled 130 patients whose blood pressure was uncontrolled (greater than 140/90 mmHg). Patients were recruited from two clinics to test efficacy in two settings: a Brigham primary care clinic (800 Huntington Ave.), and the Brigham’s Watkins Cardiovascular Clinic. All adults were eligible except pregnant women and those with advanced kidney disease. Enrolled patients were given a Bluetooth-enabled blood pressure device and taught how to use it. Patients were instructed to measure their blood pressure at home twice daily in duplicate. Medication adjustments were made every two weeks until home blood pressure was controlled at <135/85 mmHg.

The team’s next step will be to scale up the program to test its generalizability and sustainability. With this approach, the team anticipates significant cost effectiveness and cost savings, in addition to the prevention of cardiovascular events and death from treating hypertension more intensively in men and women.

“The time-honored model of treating hypertension via traditional visits to the doctor is neither effective nor sustainable,” said Fisher. “Development of innovative solutions to manage hypertension effectively and efficiently, and thus reduce the cardiovascular risk burden in larger populations, is critical. Organizations can and should develop and adopt innovative technologies to create sustainable solutions for the control of hypertension.”

Story Source:

Materials provided by Brigham and Women’s HospitalNote: Content may be edited for style and length.

Journal Reference:

  1. Naomi D.L. Fisher, Liliana E. Fera, Jacqueline R. Dunning, Sonali Desai, Lina Matta, Victoria Liquori, Jaclyn Pagliaro, Erika Pabo, Mary Merriam, Calum A. MacRae, Benjamin M. Scirica. Development of an entirely remote, non-physician led hypertension management programClinical Cardiology, 2019; DOI: 10.1002/clc.23141

How common virus reactivates after transplantation

A new study in Science challenges long-held theories of why a common virus — cytomegalovirus, or CMV — can reactivate and become a life-threatening infection in people with a compromised immune system, including blood cancer patients undergoing bone marrow transplantation.

The discovery, to be published in Science‘s Jan. 18 issue, used a newly developed mouse model and could pave the way for cheaper, safer therapies to protect patients from CMV.

“This is a big deal for the bone marrow transplantation field,” said Dr. Geoffrey Hill, the paper’s senior co-author and director of Hematopoietic Stem Cell Transplantation at Fred Hutchinson Cancer Research Center. “Our study shows for the first time that antibodies can play a dominant role in controlling CMV reactivation. This is turning dogma on its head.”

Previous research on CMV reactivation has focused on T cells, the celebrated disease fighters of the immune system. There had been occasional hints that antibodies produced by immune system B cells played some role against CMV, but it seemed to be a supporting role. Clinical trials using antibodies to fight the virus were disappointing, Hill said.

But Hill and his research team found that strain-specific antibodies made from B cells are responsible for keeping CMV suppressed in mice, without the need for any other immune cells.

A future therapy could work by collecting the CMV-thwarting antibodies from patients who have been exposed to the virus and who are undergoing bone marrow transplant. The antibodies would be purified and multiplied in the lab, then returned to the patient after transplant.

At Fred Hutch, Hill and colleagues are now pursuing clinical studies to test the approach.

“Most people don’t see any symptoms of the virus because their healthy immune systems keep CMV in check,” Hill said. “But it can roar back to life in anyone with a compromised immune system, and the results can be life-threatening.”


CMV, a type of herpes virus, infects at least half of adults by age 40. The virus can cause life-threatening complications such as pneumonia, hepatitis and gastroenteritis and has plagued allogenic transplant patients for decades. CMV infection is the most common complication of bone marrow transplantation. Just over 8,000 people in the United States received allogenic transplants in 2017 for blood cancers, including leukemias and lymphomas, and other blood disorders, according to the Center for International Blood & Marrow Transplant Research.

“Just having been exposed to the virus in the past predicts a worse outcome, despite new antiviral medications. It’s a major problem,” said Hill, who cares for patients at Seattle Cancer Care Alliance, the Hutch’s clinical care partner.

To find out the fuller story, Hill, who worked at the QIMR Berghofer Medical Research Institute until 2018, and Mariapia Degli-Esposti at the Lions Eye Institute in Perth, Australia, created the first animal model of CMV reactivation. They infected mice with CMV so that the animals experienced the primary infection followed by virus dormancy, as a person would. Three months later, the researchers gave the mice a bone marrow transplant, effectively wiping away their immune systems and replacing them with new donor marrow.

In a series of experiments looking at the roles of different types of immune cells, the team found that B cells played a critical role in controlling CMV. That is, transplanted mice that had no pre-existing B cells and thus lacked antibodies saw CMV spring back to life within 10 days of the transplant.

The group then looked into different strains of the virus, since CMV exists in many related but differing forms and can change over the course of infection. The researchers used eight different strains of CMV and found mice given the antibody from the same strain of the virus that they were exposed to previously were protected completely from CMV coming back.

Since earlier clinical trials had used antibodies from pooled sources, the strain-specific CMV protection had been hidden.

The National Health and Medical Council of Australia funded the study.

In addition to Hill and Degli-Esposti, co-authors of the paper are Jose Paulo Martins, Christopher E. Andoniou, Peter Fleming, Rachel D. Kuns, Iona S. Schuster, Valentina Voigt, Sheridan Daly, Antiopi Varelias and Siok-Keen Tey. The scientists involved in the discoveries could benefit financially from this work in the future.

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Materials provided by Fred Hutchinson Cancer Research CenterNote: Content may be edited for style and length.

Journal Reference:

  1. Jose Paulo Martins, Christopher E. Andoniou, Peter Fleming, Rachel D. Kuns, Iona S. Schuster, Valentina Voigt, Sheridan Daly, Antiopi Varelias, Siok-Keen Tey, Mariapia A. Degli-Esposti, Geoffrey R. Hill. Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantationScience, 2019; 363 (6424): 288 DOI: 10.1126/science.aat0066