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Treatment with the drug olaparib significantly reduced the risk of disease progression or death from metastatic pancreatic cancer, according to findings from the recently completed, international, phase-III POLO (Pancreas cancer OLaparib Ongoing) trial.

Olaparib (trade name LYNPARZA, jointly developed and commercialized by AstraZeneca and Merck) is a PARP inhibitor. It targets cancer cells that have a defect in DNA damage repair.

Progression-free survival, the primary endpoint in this study, was 7.4 months on the olaparib arm, and 3.8 months on the placebo arm. From 6 months onwards, more than twice the proportion of patients on the olaparib arm were progression-free.

"This is clearly a practice changing trial," said cancer specialist Hedy Kindler, MD, lead author of the study and a professor of medicine at the University of Chicago. "It will change how we think about patients with metastatic pancreatic cancer and who should consider germline testing."

This global study -- to be featured at the Plenary Session at ASCO, the annual meeting of the American Society for Clinical Oncology in Chicago, and published online June 2 in the New England Journal of Medicine -- is the first from a randomized trial to validate a targeted treatment in a biomarker-selected population of pancreatic cancer patients.

Pancreatic cancer tends to be "very resistant to treatment," said Kindler. "There are few drug regimens with significant activity, and most clinical trials of new agents are unfortunately negative."

"This is a devastating disease, with the briefest survival of any solid tumor," Kindler said. Pancreatic cancer will soon become the second leading cause of cancer death in the United States.

The randomized, double-blind, placebo-controlled phase III POLO trial focused on a selected group of patients with metastatic pancreatic cancer who had inherited mutations in the BRCA 1 and 2 genes.

The study screened 3,315 patients at 119 centers on 4 continents for germline BRCA mutations, which were detected in 7.5 percent of patients. After they received at least 16 weeks of platinum-based chemotherapy, 154 patients were randomized to receive either olaparib or placebo. Treatment continued until radiological exams detected progression of the disease.

Beyond the improvement in progression-free survival, there were no new safety concerns with olaparib. Health-related quality of life was maintained with treatment.

"About a quarter of these patients responded to olaparib for a median of two years, which is truly remarkable in a disease where most patients survive for less than a year," said Kindler, an internationally recognized authority on the treatment of pancreatic cancer and malignant mesothelioma.

"That's almost unheard of," she added. "When we saw the progression-free survival data, my first reaction was a little scream of joy. We finally made real progress in the treatment of a subset of patients with advanced pancreatic cancer."

One of Kindler's patients has been on the study for more than two years. "He's leading a normal life," she said, "feeling fine, living well and taking his pills twice a day."

"In a disease where almost nothing works," she added, "it is truly remarkable to finally have a drug that makes such a difference, even for a small subset of patients."

"A strategic approach of first-line platinum-based chemotherapy followed by maintenance olaparib treatment should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation," Kindler said.

Treatment with dabrafenib and trametinib, a drug combination designed to target cancers that harbor certain BRAF gene mutations, was effective in a trial of 35 patients representing 17 distinct tumor types. The single-arm phase two study (Arm H), met its primary endpoint. The results will be orally presented on Monday, June 3rd at the annual meeting of the American Society of Clinical Oncology (Meeting Abstract 3002). Arm H is one of multiple treatment arms in the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) trial. NCI-MATCH is being co-led by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute (NCI), part of the National Institutes of Health.

"NCI-MATCH's Arm H met its primary endpoint with an overall objective response rate of 33 percent," said lead researcher April K.S. Salama, MD, a medical oncologist at Duke University. "These results are especially relevant given that this was a heterogeneous cohort of heavily pre-treated patients who had meaningful clinical benefit."

The NCI-MATCH precision medicine trial assigns patients with solid tumors, lymphomas, or multiple myeloma with progression on prior treatment to a targeted therapy based on genetic alterations identified in pre-treatment biopsies. Rare cancers with no available treatment also qualify. Arm H (EAY131-H) evaluated the combination of the BRAF inhibitor dabrafenib (DAB) and the MEK inhibitor, trametinib (TRM), in patients with any of four particular BRAF gene variants: V600E, V600K, and two very rare variants, V600R and V600D.

Patients with melanoma or thyroid cancer were not eligible because the U.S. Food and Drug Administration (FDA) had approved DAB/TRM for these indications and there were late-phase trials in process at the time the study opened. Those with colorectal cancers were ineligible because of the established intrinsic resistance to BRAF/MEK-inhibiting therapies. Initially, patients with non-small cell lung cancer were allowed, but later excluded after the FDA approved DAB/TRM for this indication.

Patients received standard doses: DAB 150 mg orally twice a day and TRM 2 mg orally once a day on 28-day cycles until disease progression or intolerable toxicity. Restaging was performed every two cycles. The primary endpoint was objective response rate (ORR). The secondary endpoints were progression-free survival, 6-month progression-free survival, and overall survival.

Trial Results

Arm H enrolled 35 participants between January 2016 and February 2018. All 35 patients had the BRAF V600E variant. Of 33 evaluable patients, nearly 50 percent had three or more lines of prior therapy. The median age was 63 years. Race distribution was 88 percent white, three percent black, and three percent multi-race, with six percent not reported. The representation of females was 58 percent.

The arm met its primary endpoint a partial response in 11 patients, for an overall ORR of 33.3 percent (90% CI 19.9%, 49.1%), with a median duration of response (DoR) of 12 months. Varied histologies had a DoR of > 12 months: histiocytic sarcoma, cholangiocarcinoma and mixed adenoneuroendocrine carcinoma of unknown primary, among others.

Median progression-free survival was 11.4 months, and median overall survival was 28.8 months.

Most of the 17 distinct histologies were represented as single cases, with some exceptions:

Three of four patients with cholangiocarcinoma, a rare cancer that forms in the bile ducts, had confirmed partial responses. The fourth patient had a significant reduction in target lesions. However, new lesions appeared on subsequent re-imaging, so this was not considered a confirmed partial response.

Among seven lung primary cases, one patient had a partial response and five had stable disease. The seventh lung case had an 80 percent reduction in RECIST target measurements, but this patient was not evaluable because their scan was outside the pre-specified protocol window. Six of the seven cases were adenocarcinomas.

Five of six gynecologic cases had a partial response and the other had stable disease. Five cases were a rare subtype--low-grade papillary seous adenocarcinoma of the ovary.

Adverse events (AE) were comparable to previously reported profiles of DAB/TRM; no new AEs were identified. The most frequent grade 3 AEs were fatigue, neutropenia, hyponatremia, hypophosphatemia, and urinary tract infection; there was one grade four sepsis; no grade five AEs.

"These results support the conclusion that BRAF/MEK combination therapy has widespread activity across multiple cancer types whose tumors harbor BRAF mutations," said Keith T. Flaherty, M.D., a medical oncologist at Massachusetts General Hospital Cancer Center in Boston and ECOG-ACRIN study chair for the overall NCI-MATCH trial. "Continuing to explore this regimen in cancers for which this is not yet a standard regimen is warranted," he said.

Dabrafenib and trametinib were provided by Novartis Pharmaceuticals under a Cooperative Research and Development Agreement with the NCI.

"NCI-MATCH is an ongoing and dynamic trial," said Alice Chen, MD, a medical oncologist at the NCI, head of the NCI's Early Clinical Trials Development Program, and NCI study chair for the overall NCI-MATCH trial. "Its signal-finding approach will likely influence how cancer clinical trials are designed and conducted in the future, as treatments that show promise may advance to more definitive studies."

Correlative analyses are planned.

Results from the phase III NRG Oncology clinical trial GOG 0261 comparing paclitaxel plus carboplatin (PC) to paclitaxel plus ifosfamide (PI) in women with stage I-IV, recurrent carcinosarcoma of the uterus or ovary, indicate that the PC combination treatment should be considered a standard of care for this patient population. The study concludes that among uterine cancer patients treatment with PC was not inferior to PI based on the primary objective overall survival (OS), and PC was associated with longer progression-free survival (PFS) outcomes when compared with PI. These results were recently presented at the American Society for Clinical Oncology (ASCO) Annual Meeting and was awarded a "Best of ASCO" designation.

"While they are rare, gynecologic carinosarcomas are extremely aggressive and there has been a great deal of debate surrounding what the ideal or optimal treatment regimen would be for the women who have these malignancies," stated Matthew A. Powell, MD, of the Washington University School of Medicine and the lead author of the NRG-GOG 0261 abstract. "Previous Phase 2 research suggested that paclitaxel combined with carboplatin may improve outcomes for this patient population in terms of safety and convenience of treatment, so we tested this against a treatment regimen that included paclitaxel and ifosfamide."

Results from the NRG GOG 0261 clinical trial including 449 eligible patients in the primary uterine carcinosarcoma cohort estimate median overall survival at 37 months for those who received PC compared to 29 months for the PI treatment arm (HR = 0.87; 90% CI = 0.70 to 1.075; p 0.1 for superiority (S). Additionally, median PFS was 16 months for women who received PC and 12 months for women who received PI (HR = 0.73; p =

"The hope is to continue to improve survival and quality of life outcomes for women who experience this rare malignancy," added Dr. Powell.

DALLAS, June 3, 2019 -- Effective antiretroviral therapy has changed the human immunodeficiency virus (HIV) from a progressive, fatal disease to a chronic, manageable condition that is associated with higher rates of heart attacks, strokes, heart failure, sudden cardiac deaths, and other diseases compared to people without HIV, according to a new scientific statement from the American Heart Association published in the Association journal Circulation.

People living with HIV are at increased risk of heart and blood vessel diseases because of interactions between traditional risk factors, such as diet, lifestyle and tobacco use, and HIV-specific risk factors, such as a chronically activated immune system and inflammation characteristic of chronic HIV.

Tobacco use, a major risk factor for cardiovascular diseases, is common among people living with HIV. In a nationally representative U.S. sample, 42% of people living with HIV were current smokers. Heavy alcohol use, substance abuse, mood and anxiety disorders, low levels of physical activity and poor cardiorespiratory fitness are also common among people living with HIV and may contribute to elevated risk for diseases of the heart and blood vessels, according to the statement.

"Considerable gaps exist in our knowledge about HIV-associated diseases of the heart and blood vessels, in part because HIV's transition from a fatal disease to a chronic condition is relatively recent, so long-term data on heart disease risks are limited," said Matthew J. Feinstein, M.D., M.Sc., chair of the writing group for the statement and assistant professor of medicine and preventive medicine at the Feinberg School of Medicine, Northwestern University in Chicago, Illinois.

In addition, people living with HIV are often stigmatized and face significant barriers to optimal health care, such as education level, where they live, healthcare literacy, disenfranchisement from the healthcare system, cognitive impairment, injection drug use, internalized and anticipated stigma, gait and mobility impairment, frailty, depression and social isolation. There are also disparities in care based on age, race, ethnicity and gender.

Another area of concern is the aging population of people living with HIV - 75% of people living with HIV are over age 45. "Aging with HIV differs greatly from the aging issues facing the general population," said Jules Levin, M.S., in an accompanying patient perspective. Levin has been living with HIV for 35 years and is the founder and executive director of the National AIDS Treatment Advocacy Project.

"On average, people living with HIV who are over 60 years old have 3-7 medical conditions, including heart attacks, strokes, heart failure, kidney disease, frailty and bone diseases and many take 12-15 medications daily. As they age, people living with HIV are often alone and disabled, emotionally homebound due to depression, and are socially isolated. In addition, they often suffer from lack of mobility and an impaired ability to perform normal daily functions. We urgently need better awareness and more patient-focused research and care efforts for this vulnerable population," said Levin.

Providing scientifically based recommendations on how to reduce the risk of cardiovascular disease among people living with HIV is also challenging. "There is a dearth of large-scale clinical trial data on how to prevent and treat cardiovascular diseases in people living with HIV. This is an area of research that is needed for informed decision-making and effective CVD prevention and treatment in the aging population of people living with HIV," said writing group chair Feinstein.

To assess a person living with HIV's cardiovascular risk, the statement advises a nuanced approach. This approach includes quantifying traditional heart disease risk factor burden using tools such as American Heart Association/American College of Cardiology Atherosclerotic Disease Risk Calculator, which estimates a person's ten-year risk of having a heart attack, stroke or other cardiovascular condition, as a starting point. However, the authors caution that people living with HIV may have a higher risk than indicated by the calculator. Additional considerations that should be factored into the heart disease risk assessment include family history of heart disease and HIV-specific factors, such as whether or not a patient started antiretroviral therapy soon after diagnosis.

To keep people living with HIV healthy, Feinstein emphasizes the importance of a healthy lifestyle that includes smoking cessation, adequate physical activity, eliminating or reducing the amount of alcohol consumed and a healthy diet. In addition, medications such as statin drugs, which lower cholesterol, and other medications that make blood less likely to form clots may be helpful, although more clinical trial data are needed.

A consortium of scientists from the Medical Imaging Center (University Medical Center Groningen), Van 't Hoff Institute for Molecular Sciences (University of Amsterdam), Palacky University in Olomouc, the University of Nantes, Stratingh Institute for Chemistry (University of Groningen) and the European Laboratory for Non-Linear Spectroscopy in Florence have developed an entirely new class of molecular photoswitches that meet many of the 'holy grail' requirements so far thought to be impossible to achieve. The results have been published in Nature Communications on 3 June.

In our macroscopic world, we are used to being able to switch a device on or off depending on whether we need it or not. Such control is not only useful in the macroscopic world but also one of the holy grails at the molecular scale. Molecular photoswitches are in this respect of particular interest as they allow for a non-invasive and localized means to activate, for example, a drug where and when it is needed. Such switches exist but are far from ideal as they require harmful ultraviolet light for their operation rather than harmless visible light, which is a show-stopper from a medical settings point of view.

Furthermore, they cannot exclusively be switched from one state to the other, and normally do not function under physiological conditions of the human body. Absorption bands describe which wavelengths of light are needed for switching. When the absorption bands of the 'on' and 'off' state overlap, switching between the two states requires light of the same wavelength, which is very ineffective. If the absorption bands are, however, well separated switching between the 'on' and 'off' state can be done with high specificity and efficiency with light of different wavelengths. Molecular switches that would meet such requirements are thus highly sought after, but up till now, nobody has been able to come up with a suitable design.

Best of both worlds

Thioindigo and azobenzene are two chemical motifs that are extensively being used in molecular switches albeit that they suffer from the previously mentioned drawbacks. Dr Wiktor Szymanski at the University Medical Center Groningen realized that a fusion of these two should also be able to function as a photoswitch, and -similar to crossbreeding- would very likely have improved properties compared to its 'parents'. 'However, the initial results were very disappointing', says Mark Hoorens, the PhD student at the UMCG who synthesized the iminothioindoxyl (ITI) compound and tried to switch it. 'We didn't see any change in the absorption spectrum when we irradiated it, nothing seemed to happen. We therefore lost interest in this compound and went on with other research.'

Looking faster

At the 2017 International Symposium on Photopharmacology organized in Groningen, the group discussed their results with scientists of the Molecular Photonics group at the University of Amsterdam. Based on that discussion it was concluded that it might be worthwhile to repeat the irradiation experiments using the facilities at the University of Amsterdam which have a better time resolution. The new experiment produced a surprising result. 'At first, we did not believe our eyes' say Mark Hoorens and Michiel Hilbers (UvA). 'We saw a completely separated absorption band appear 100 nm to the red of the steady-state absorption band of ITI with a lifetime of about 10 to 20 milliseconds and in the first instance even suspected that we were looking at contamination in the sample'. One of its 'parents' absorbs in the UV region and has band separation, while the other parent absorbs in the visible light region but does not have good band separation.

The new switch has the best of both. Such properties have never before been observed in a photoswitch. Follow-up experiments confirmed that ITI is indeed the fully-visible-light switch the scientists were looking for. Experiments on a femto- and picosecond timescale performed in the laboratories of dr. Mariangela Di Donato at the European Laboratory of Non-Linear Spectroscopy allowed for further mechanistic studies. Mariangela says: 'From these studies, it became clear that ITI switches on an ultrafast timescale of a few hundreds of femtoseconds, similar to how fast the visual pigment in our eyes is switched when light falls on it'.

Quantum calculations

The final confirmation was provided by quantum chemical calculations performed by Dr Adèle Laurent (University of Nantes) and dr. Miroslav Medved' (Palacky University in Olomouc). These calculations predicted absorption maxima of the two photo-isomers that were very similar to those observed experimentally, but also a barrier for switching back to the original form that fitted excellently the observed lifetime. 'In the first instance, we were quite puzzled by this gigantic 100 nm band separation', say Laurent and Medved', 'but our calculations now provide a logical explanation for this. What is even better is that they allow us to predict how ITI can be modified to meet the specific requirements of its users'.

ITI at work

Mark Hoorens has by now synthesized several varieties that have been further characterized in Amsterdam, Florence, Nantes and Olomouc. From these studies, it has become clear that ITI is an incredibly versatile switch that can be operated under a wide variety of experimental conditions including, importantly, biological ones, and with properties that are relatively easy to tune. As the consortium puts it: 'the future is bright - and in the visible range'!

Research led by faculty at Children's National published online June 3, 2019, in Nature Communications shows that the sudden appearance of symptoms in limb-girdle muscular dystrophy type 2 (LGMD2B) is a result of impaired communication between different cell types that facilitate repair in healthy muscle. Of particular interest are the fibro/adipogenic precursors (FAPs), cells that typically play a helpful role in regenerating muscle after injury by removing debris and enhancing the fusion of muscle cells into new myofibers.

LGMD2B is caused by mutations in the DYSF gene that impair the function of dysferlin, a protein essential for repairing injured muscle fibers. Symptoms, like difficulty climbing or running, do not appear in patients until young adulthood. This late onset has long puzzled researchers, as the cellular consequences of dysferlin's absence are present from birth and continue through development, but do not impact patients until later in life.

The study found that in the absence of dysferlin, muscle gradually increases the expression of the protein Annexin A2 which, like dysferlin, facilitates repair of injured muscle fiber. However, increasing Annexin A2 accumulates outside the muscle fiber and drives an increase in FAPs within the muscle as well as encourages these FAPs to differentiate into adipocytes, forming fatty deposits. Shutting down Annexin A2 or blocking the adipocyte fate of FAPs using an off-the-shelf medicine arrests the fatty replacement of dysferlinopathic muscle.

"We propose a feed-forward loop in which repeated myofiber injury triggers chronic inflammation which, over time, creates an environment that promotes FAPs to accumulate and differentiate into fat. This, in turn, contributes to more myofiber damage," says Jyoti K. Jaiswal, MSc, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children's National and the study's senior author.

"Adipogenic accumulation becomes the nucleating event that results in an abrupt decline in muscle function in patients. This new view of LGMD2B disease opens previously unrealized avenues to intervene," adds Marshall Hogarth, Ph.D., the study's lead author.

A research team led by Jaiswal collaborated with Eduard Gallardo and Jordi Diaz Manera, of Hospital de la Santa Creu in Barcelona, Spain, to examine muscle biopsies from people with LGMD2B who had mild to severe symptoms. They found that adipogenic deposits originate in the extracellular matrix space between muscle fibers, with the degree of accumulation tied to disease severity. They found a similar progressive increase in lipid accumulation between myofibers predicted disease severity in dysferlin-deficient experimental models. What's more, this process can be accelerated by muscle injury, triggering increased adipogenic replacement in areas that otherwise would be occupied by muscle cells.

"Accumulation and adipogenic differentiation of FAPs is responsible for the decline in function for dysferlinopathic muscle. Reversing this could provide a therapy for LGMD2B, a devastating disease with no effective treatment," predicts Jaiswal as the team continues research in this field.

Promising off-the-shelf drugs include batimastat, an anti-cancer drug that inhibits the extracellular matrix enzyme matrix metalloproteinase. This drug reduces FAP adipogenesis in vitro and lessens injury-triggered lipid formation in vivo. In experimental models, batimastat also increases muscle function.

After 3 years, 80% of men with metastatic hormone-sensitive prostate cancer who received enzalutamide along with testosterone suppression were alive compared to 72% of men who received standard care.

Chicago - Enzalutamide, an oral androgen receptor inhibitor, can improve outcomes for men with metastatic hormone-sensitive prostate cancer (mHSPC), according to a large study presented by Christopher Sweeney, MBBS of Dana-Farber Cancer Institute's Lank Center for Genitourinary Oncology, during the American Society of Clinical Oncology (ASCO) Annual Meeting.

Interim analysis of the ANZUP-led international randomized, phase III ENZAMET trial demonstrated that among men with mHSPC who received testosterone suppression, those also given enzalutamide survived longer overall than those who were also given standard nonsteroidal androgen receptor inhibitors. Among trial participants, 80% of those treated with enzalutamide were alive after three years compared to 72% of the men who received the standard inhibitors.

"These findings are truly practice-informing, adding an effective drug option in treating mHSPC," said study co-chair Sweeney who presented results during the ASCO plenary session. The plenary session features four studies deemed to have the greatest potential impact on patient care, out of more than 6,000 featured abstracts at the 5-day conference. The details were published simultaneously in the New England Journal of Medicine.

"Adding enzalutamide to testosterone suppression in men with mHSPC can give much better cancer control and much longer survival," said Sweeney. "This is true both for patients with high burden of disease, with multiple bone metastases or liver metastases, as well as men with a lower burden of disease. The new treatment option is especially relevant for men who cannot tolerate chemotherapy and have a lower burden of disease."

"The benefits of enzalutamide had already been established for prostate cancers that are no longer responding to hormonal therapy," said Ian D. Davis, MBBS, PhD, ANZUP chair and study co-chair. "The actual result in patients starting hormonal therapy, noting patients had a 60% improvement in the time it takes to detect the cancer growing again along with a 33% increase chance of survival, was far higher than we expected."

One important question that the trial sought to understand was how well enzalutamide compared to, or combined with, docetaxel, a chemotherapy drug approved for the condition that was given to about 45% of trial participants. ENZAMET showed that in this population, "enzalutamide and docetaxel are both active and are reasonable alternatives but have different side effects, costs, risks and benefits," Sweeney said.

Early analysis suggests that among men with a lower burden of metastatic disease given testosterone suppression, enzalutamide may offer more benefit than docetaxel, Sweeney said. However, he cautioned that this finding needs further investigation. Combining testosterone suppression with both enzalutamide and docetaxel delayed time for the disease to progress, but the researchers must follow up on trial participants to see if this triplet combination also improves quality of life and overall survival.

Overall in ENZAMET, side effects known to be associated with enzalutamide were observed and resulted in a modest increase in adverse events compared to men receiving one of the standard non-steroidal anti-androgens.

The National Cancer Institute estimates that 175,000 men will be diagnosed with prostate cancer and 32,000 men will die from the disease this year in the United States. About 95% of men are diagnosed with localized disease via prostate specific antigen (PSA) screening. Most are cured by surgery or radiation, and some don't need treatment, Sweeney said.

The remaining 5% of patients initially present with very aggressive disease, and many other patients relapse after treatment for localized disease but tend to have slower disease progression. The U.S. Food and Drug Administration has approved enzalutamide for men where the disease continues to progress, both for men who have been treated with docetaxel and men who have not. Other hormone treatments also have been approved.

ENZAMET is a collaborative investigator-initiated study led by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group and sponsored by the University of Sydney, in collaboration with the Canadian Cancer Trials Group, Dana-Farber and Cancer Trials Ireland. Around the world, 83 research institutions participated. The trial enrolled 1,125 participants and followed them for a median of 34 months. Astellas Pharma provided drug and financial support for ENZAMET but was not involved in the conduct or analysis of the study. Other funding came from Cancer Australia and the Canadian Cancer Society.

Receiving a blood transfusion during curative surgery for the most common type of liver cancer (hepatocellular carcinoma) is associated with a much higher risk of cancer recurrence and dying prematurely, according to new research being presented at this year's Euroanaesthesia congress (the annual meeting of the European Society of Anaesthesiology) in Vienna, Austria (1-3 June).

The risk was markedly increased even when only a small amount of blood was transfused, researchers say. Findings showed that transfusion of 1 to 4 units of blood increased the risk of cancer recurrence by 23% and death by 55% compared to matched controls.

"Our findings from a large cohort highlighted a significant association between red blood cell transfusions and the risk of cancer recurrence as well as a dose-response relationship between the amount of transfusions and death after curative surgery for liver cancer", says Dr Ying-Hsuan Tai from Taipei Medical University Shuang Ho Hospital in Taiwan who led the research.

"The reason why blood transfusions substantially worsen cancer prognosis remains unclear, but it is likely to be related to the suppressive effects on the immune system."

Hepatocellular carcinoma (HCC) is the fifth most common form of cancer worldwide and the third most common cause of cancer-related deaths. It occurs frequently in people with cirrhosis (scarring of the liver) due to previous damage from hepatitis B or C virus, or long-term alcohol abuse.

Surgery to remove the cancer and a margin of healthy tissue that surrounds it (resection) is a curative treatment for people with early-stage liver cancers who have normal liver function. Whilst advances in liver surgery have reduced operative blood loss considerably, liver resection still carries the risk of excessive blood loss and need for blood transfusion.

The extent to which blood transfusion worsens cancer outcomes after surgery is poorly understood. For several decades, research has reported conflicting findings, and has been unable to conclude whether blood transfusion itself is causing problems, or if other factors such as the underlying medical conditions that make surgery necessary might be to blame.

In this study, Tai and colleagues investigated the effect of perioperative blood transfusion on cancer prognosis following HCC resection in 1,469 patients without lymph node involvement or metastasis undergoing surgery at Taipei Veterans General Hospital, Taipei, Taiwan between 2005 and 2016. Researchers assessed postoperative disease-free survival and overall survival up to September 2018. Using statistical modelling (a technique called inverse probability of treatment weighting) they were able to match patients who had equivalent age and health conditions when comparing their outcomes.

Almost 1 in 3 patients (30%; 447 patients) received 1 to 4 units of allogeneic (from another individual) blood during or within 7 days of surgery, whilst more than 1 in 10 (12%; 179 patients) were given more than 4 units.

During a median 45 month follow-up, analyses showed that cancer was 23% more likely to recur in patients who received a transfusion (1-4 units) compared to those not given a transfusion, whilst those who received more than 4 units faced a 18% greater risk of recurrence compared with those who received none.*

Compared to those not given a transfusion, patients given 1-4 units of blood were 55% more likely to die from any cause, whilst those receiving 4 or more units had almost double the risk of death.

The authors conclude: "These data highlight the need for randomised trials to evaluate the influence of transfusion on cancer outcome and identify the level of anaemia that patients undergoing liver cancer surgery can withstand (or the minimum amount of blood they need to have transfused) with minimal adverse effects in order to guide practice. Until these trials have been completed, surgeons should use practices that reduce the risk of bleeding and the need for transfusion."

A team of Japanese scientists has used facial recognition technology to develop an automated system that can predict when patients in the intensive care unit (ICU) are at high risk of unsafe behaviour such as accidentally removing their breathing tube, with moderate (75%) accuracy.

The new research, being presented at this year's Euroanaesthesia congress (the annual meeting of the European Society of Anaesthesiology) in Vienna, Austria (1-3 June), suggests that the automated risk detection tool has the potential as a continuous monitor of patient's safety and could remove some of the limitations associated with limited staff capacity that make it difficult to continuously observe critically-ill patients at the bedside.

"Using images we had taken of a patient's face and eyes we were able to train computer systems to recognise high-risk arm movement", says Dr Akane Sato from Yokohama City University Hospital, Japan who led the research.

"We were surprised about the high degree of accuracy that we achieved, which shows that this new technology has the potential to be a useful tool for improving patient safety, and is the first step for a smart ICU which is planned in our hospital."

Critically ill patients are routinely sedated in the ICU to prevent pain and anxiety, permit invasive procedures, and improve patient safety. Nevertheless, providing patients with an optimal level of sedation is challenging. Patients who are inadequately sedated are more likely to display high-risk behaviour such as accidentally removing invasive devices.

The study included 24 postoperative patients (average age 67 years) who were admitted to ICU in Yokohama City University Hospital between June and October 2018.

The proof-of-concept model was created using pictures taken by a camera mounted on the ceiling above patients' beds. Around 300 hours of data were analysed to find daytime images of patients facing the camera in a good body position that showed their face and eyes clearly.

In total, 99 images were subject to machine learning--an algorithm that can analyse specific images based on input data, in a process that resembles the way a human brain learns new information. Ultimately, the model was able to alert against high-risk behaviour, especially around the subject's face with high accuracy.

"Various situations can put patients at risk, so our next step is to include additional high-risk situations in our analysis, and to develop an alert function to warn healthcare professionals of risky behaviour. Our end goal is to combine various sensing data such as vital signs with our images to develop a fully automated risk prediction system", says Dr Sato.

The authors note several limitations including that more images of patients in different positions are needed to improve the generalisability of the tool in real life. They also note that monitoring of the patient's consciousness may improve the accuracy in distinguishing between high-risk behaviour and voluntary movement.

People admitted to NHS hospitals with a cardiac arrest over the weekend do not face a higher risk of dying compared to those admitted during the week, according to new research presented today at the British Cardiovascular Society (BCS) Conference in Manchester.

The research led by Dr Rahul Potluri, founder of the ACALM study unit at Aston University, investigated 4,803 people going to hospital with a cardiac arrest.

The team looked at five-year survival for people suffering a cardiac arrest and being treated in an NHS hospital. They found that there were no differences in survival for those admitted on the weekend.

The research was adjusted to account for external factors which could influence death rates, such as age, gender, ethnic group, and the most common causes of death in the UK.

A cardiac arrest is when an electrical fault in the heart occurs, causing it to suddenly stop pumping blood round the body. The chances of surviving an out-of-hospital cardiac arrest are around 1 in 10, but with swiftly-administered CPR and the use of a defibrillator, a huge difference can be made to the chances of survival.

This study follows on from work previously presented at the BCS conference suggesting that there is a 'weekend effect' in people going to hospital with heart failure or atrial fibrillation, the most common type of abnormal heart rhythm. However, the presence of cardiac arrest teams working 24 hours a day, all year round, could be responsible for the same standard of care and outcome of those suffering a cardiac arrest whether they are being treated in the week or at the weekend.

Dr Rahul Potluri, Clinical Lecturer in Cardiology at Aston Medical School, said:

"No matter which day of the week someone goes to hospital with a cardiac arrest, they have the same chance of survival, and that should be hugely reassuring to the public.

"By no means is the weekend effect a blanket phenomenon. We know that it does exist for people affected by other heart conditions. It's therefore important to tease out who is affected by the weekend effect through research in order to ensure that specialist healthcare services are delivered when and where they are needed most."

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation said:

"This is a success story, and shows the life saving importance of specialist teams working in the NHS. A cardiac arrest is a medical emergency and statistics show that for every minute that passes without CPR and defibrillation, a person's chance of survival decreases by around 10 per cent.

"If you see someone who has suddenly collapsed and is unresponsive, it is vital that you call 999 and start administering CPR immediately to increase their chances of survival. When the emergency services arrive, you can rest assured that you've done your bit and the specialists are ready and waiting to take over."

Dr Shajil Chalil, Consultant Cardiologist at Blackpool Teaching Hospitals NHS Foundation Trust and co-author, said

"You can't choose when you're struck down by a devastating cardiac arrest. But our research potentially highlights the major value of cardiac arrest teams in hospitals set-up to ensure optimal care for these heart patients every minute of every day."

New research presented at this year's Euroanaesthesia congress in Vienna, Austria (1-3 June) shows that mortality in patients who had undergone heart bypass surgery was over 4 times higher in individuals with a high body fat mass, while body mass index (BMI) by itself was not associated with an increase in mortality. The research was conducted by Dr Xavier Leroy of the Department of Anaesthesia and Resuscitation, CHU Lille, Lille, France and colleagues.

There is conflicting evidence about the existence of the so-called obesity paradox when it comes to cardiac surgery, which is the theory that obesity as defined by BMI may offer a protective effect to the patient and reduce their risk of post-operative mortality. The authors suggest that other factors which are known to impact clinical outcomes in a range of settings such as body composition, referring to fat mass (FM) and lean body weight (LBW), may complicate the situation and lead to the inconsistent results seen in previous research.

The team performed a retrospective study of 3373 patients who had undergone elective cardiac surgery with cardiopulmonary bypass from January 2013 until December 2016. Patient BMI (measured using the WHO definition) and body composition were calculated from clinical and administrative records and compared to patient mortality within 30 days of the operation. A further analysis was performed to investigate the association of BMI and body composition with a prolonged stay in the intensive care unit (ICU), with prolonged defined as being in the uppermost quartile (patients in the highest 25%) of length of stay (LOS).

Across the entire sample of patients, mortality within 30 days occurred in 2.1% of cases and significant differences were observed among BMI, FM, and LBW categories. Unlike BMI however, FM and LBW were found to be independently associated with mortality.

The 25% (quartile) of patients with the highest fat mass (FM) were 4.1 times more likely to die than 25% with the lowest fat mass; and the 25% of patients with the lowest lean body weight (muscle) were 2.8 times more likely to die than the 25% of patients with the highest lean body weight.

There was no observed association between BMI and 30-day mortality but the authors did find an independent association between BMI and length of stay in the ICU. The authors conclude: "BMI was independently associated with a prolonged ICU length of stay, as were being in the highest fat mass and lowest lean body weight categories," explains Dr Leroy. "The lower the LBW or the higher the FM and BMI were, the longer the length of stay in intensive care."

He concludes: "Overall, our findings showed that unlike BMI, lower lean body weight and higher fat mass in patients were independently associated with increased mortality after heart bypass surgery."

Patients who underwent total knee replacement and used a smartphone app (PainCoach) at home after surgery consistently reduced opiate painkiller use and improved pain control, according to new research being presented at this year's Euroanaesthesia Congress (the annual meeting of the European Society of Anaesthesiology) in Vienna, Austria (1-3 June).

The more the study participants used the app, the more likely they were to lower pain scores and decrease their use of opioids.

"These are important findings given the current demands on the healthcare system and the growing misuse of prescription painkillers worldwide", says author Dr Amar Sheombar from Kliniek ViaSana in the Netherlands. "Few clinically-tested mobile apps exist with clear measurable goals to guide patients in pain control and opiate use at home after surgery."

To investigate the effect of the PainCoach app on pain and opiate use, Dutch researchers randomly assigned 71 patients (aged 56-70 years) undergoing total knee replacement to the app and usual care (38 patients) or usual care alone (33) in the first 2 weeks at home after surgery [1].

The mobile app allows patients to input their pain level (no pain, bearable pain, unbearable pain, or untenable pain)--based on this information and the amount of days after surgery, the app offers advice on drug pain relief use and exercises or rest.

Questionnaires were used to establish opiate use (oxycodone) and pain levels at rest, during activity, and at night, as well as other pain drug use, experiences with exercises, pain acceptance, function, and quality of life. Participants completed questionnaires preoperatively, daily during the first two weeks, and after 1 month.

Amount of app use was also recorded, with 'active use' defined as at least 12 uses of the app over 2 weeks. During the study, average Visual Analogue Scale (VAS) pain score was 23 (the scale is 0 to 100 where 100 represents the highest pain) and average opiate use across the group was less than half (0.4) of one 5mg oxycodone tablet per day.

Compared to the control group, users of the PainCoach app used 23% less opiates and 15% more paracetamol in the first 2 weeks following surgery.

Regular (active) use of the app led to further reduction in opiate use and improved pain control during activity and at night. Regular app users (19 patients) reported four times faster reduction in pain during activity, six times faster reduction in pain at night, and 44% less opiate and 76% less gabapentin use (taken to relieve nerve pain) compared to controls. Opiate use was substituted by 21% more paracetamol use in regular app users.

"Knowing that 80% of interactive advice is remembered may explain why regular use of the PainCoach app contributes to lower pain scores and reduced opiate use", says Dr Sheombar. "Digital innovations like smartphone health-care apps must empower patients and deliver patient-centric care. Three-quarters of the study patients found our app valuable and wanted to use it for real-time feedback and support. In the current study population opiate use was already low--the app might have a much stronger effect in patient populations where pre-operative opiate use is much higher."

Longer term use of opioids can lead to physical dependence and difficulty stopping use. Misuse of prescription painkillers is a growing public health problem worldwide. In the USA, an estimated 18 million Americans misused prescription painkillers at least once in the past year, and overdose deaths involving prescription opioid pain relievers were five times higher in 2016 than in 1999 [2].

ABSTRACT LBA1008

Adding the targeted therapy ribociclib to hormone therapy significantly improved overall survival (OS) in premenopausal patients with advanced hormone receptor-positive (HR+) breast cancer, according to results of the MONALEESA-7 Phase III clinical trial led by researchers at The University of Texas MD Anderson Cancer Center.

The combination resulted in 70.2 percent OS at 42 month follow up compared to just 46 percent OS in patients receiving hormone therapy plus placebo. This corresponds to a 29 percent lower risk of death in patients receiving the combination therapy. The authors also reported no new side effects than those previously described. This is the first demonstration of a survival advantage from the addition of a biological therapy to hormonal therapy.

The trial results published this month in the New England Journal of Medicine and will be presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. The current results build upon the primary endpoint data previously reported at the 2017 San Antonio Breast Cancer Symposium and published in Lancet Oncology.

"The data from MONALEESA-7 provide clear evidence that ribociclib offers a significant survival advantage compared to hormone therapy alone in premenopausal patients," said senior author Debu Tripathy, M.D., chair of Breast Medical Oncology. "Breast cancer in younger women is known to be more aggressive and have distinct genetic changes compared to postmenopausal patients, so this provides a much-needed therapeutic option for these patients."

Ribociclib is one of a class of drugs that inhibit cyclin-dependent kinases 4/6 (CDK4/6), proteins necessary for progression of the cell cycle. In 2018, ribociclib became the first CDK 4/6 inhibitor approved by the Food and Drug Administration for treatment of premenopausal patients with advanced HR+ breast cancer in combination with hormone therapies.

The international, randomized Phase III clinical trial enrolled 672 metastatic breast cancer patients, all of whom were pre- or peri-menopausal (ceased having periods within the last year) at diagnosis with HR+, HER2-negative disease. Participants could not have had prior hormone therapy for advanced disease or more than one cycle of chemotherapy for advanced disease.

Patients were randomized to receive either ribociclib (335) or placebo (337) in combination with tamoxifen or a nonsteroidal aromatase inhibitor (NSAI), and goserelin, an ovarian suppression drug. In the ribociclib arm, 87 patients (26 percent) received tamoxifen, compared with 90 patients (26.7 percent) in the placebo arm.

The median duration of treatment with ribociclib was approximately two years, which is eight months longer than it was at the time of primary analysis of progression-free survival. No new toxic effect emerged with the longer follow-up. The most common adverse event was neutropenia, which occurred in 63.5 percent of patients in the ribociclib group compared to 4.5 percent of patients in the placebo arm. Hepatobiliary toxic effects occurred in 11 percent and 6.8 percent respectively.

"This study confirms the benefits of these drugs are similar in both pre- and post-menopausal patients with advanced hormone receptor-positive breast cancers, and it further validates the clinical value of adding ribociclib for these patients," said Tripathy.

Initial results of NRG-LU001 indicate that, although the diabetes agent metformin was well-tolerated by patients, the agent has not clearly improved progression-free survival (PFS) or overall survival (OS) for trial participants with locally advanced non-small cell lung cancer (NSCLC). These results are based on local center reported outcomes. Trial participants will continue to be followed for changes in their status. The initial report of these results were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting and the abstract was awarded a "Best of ASCO" designation.

"In previous pre-clinical studies, metformin enhanced the response of human non-small cell lung cancer (NSCLC) models to radiotherapy and chemotherapy," stated Dr. Theodoros Tsakiridis, MD, PhD, of McMaster University and lead author of the NRG-LU001 abstract. "The pre-clinical data suggested a potential benefit for patients with lung cancer. For that, we pursued the NRG-LU001 trial to examine whether metformin could indeed improve outcomes in patients with stage III NSCLC treated with standard of care chemotherapy and radiotherapy."

In NRG-LU001 patients were randomly assigned either to the control arm that received standard chemotherapy and radiotherapy alone or to the experimental arm that received chemotherapy, radiotherapy, and 2000mg of metformin per day during those treatments. This study was designed to detect a 15% improvement in 12-month PFS from 50% to 65% or, equivalently, a HR of 0.622. Following treatment, researchers tracked the participating patients for changes in survival outcomes, toxicities or side effects, time to local-regional progression (TTLRP), and time to distant metastasis (TTDM).

NRG-LU001 closed to accrual in December 2016 after completing accrual and randomization of the pre-planned number of 168 patients. There was no statistically significant difference in rates or grade of toxicity between the two arms, indicating that metformin was well-tolerated by patients. At the time of analysis, local centers reported 102 PFS events. The 1- and 2-year PFS rates were 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in the control arm, and 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the experimental treatment arm with metformin. OS at 2 years was 65.4% (95% CI: 53.5, 75.0) in the control arm and 64.9% (95% CI:53.1, 74.5) in the experimental arm (HR=1.03 (95% CI: 0.64, 1.68). Deaths were due to lung cancer in 90% of the control arm and 71% of the experimental arm. These initial results of NRG-LU001 yielded no differences between treatment arms for TTLRP and TTDM.

"While finding no difference in the primary endpoint, between treatment arms was disappointing, we are heartened to observe better than expected PFS and OS rates in both arms of this study" said Dr. Heath Skinner, MD, PhD of the UPMC Hillman Cancer Center who was Co-Principal Investigator of the trial, along with Dr. Tsakiridis. "We plan to complete secondary analyses with a central clinical and radiological review of all cases, as well as biomarker studies involving the biospecimens collected during this trial."

The results of NRG-LU001 demonstrate the value of continued investigation of NSCLC, one of the deadliest cancers worldwide, in multi-institutional settings such as NRG-Oncology.

This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC).

June 1, 2019--More than 1 in 10 people with a range of non-cancerous lung diseases may be sick as a result of inhaling vapors, gas, dust or fumes at work, according to a joint American Thoracic Society and the European Respiratory Society statement published in the ATS's American Journal of Respiratory and Critical Care Medicine.

In "The Occupational Burden of Nonmalignant Respiratory Diseases: An Official American Thoracic Society and European Respiratory Society Statement," 13 clinical and research experts from the two respiratory societies analyzed scores of studies of the connections between occupational hazards and lung disease. The studies were conducted around the world over more than two decades.

The authors included a range of respiratory conditions, ranging from asthma and COPD to scarring fibrosis and selected infections. They did not study cancer of the lung and pleura, the membrane surrounding the lungs, because the occupational burden for those conditions, which can be substantial, has already been reported. Similarly, they did not include in their burden estimate asbestosis, silicosis and coal workers' pneumoconiosis (black lung), because those conditions are entirely work-related.

"The role of occupational factors in most lung disease is under-recognized," said Paul D. Blanc, MD, MSPH, chief of the Division of Occupational and Environmental Medicine at the University of California San Francisco, who along with Carrie A. Redlich, MD, MPH, director of the Occupational and Environmental Medicine Program at Yale University, led the group effort. "Failure to appreciate the importance of work-related factors in such conditions impedes diagnosis, treatment and, most importantly of all, prevention of further disease."

Specifically, the authors estimated the occupational burden of these lung diseases:

Asthma, 16 percent

Chronic obstructive pulmonary disease (COPD) 14 percent

Chronic bronchitis, 13 percent

Idiopathic pulmonary fibrosis, 26 percent

Hypersensitivity pneumonitis, 19 percent

Sarcoidosis and other granulomatous disease, 30 percent

Pulmonary alveolar proteinosis, 29 percent

Community-acquired pneumonia (in working-age adults), 10 percent

Tuberculosis (in silica dust-exposed workers), 2 percent.

Dr. Blanc said that some of these findings, particularly those for asthma and COPD, reinforce earlier burden estimates. Other estimates, such as those for idiopathic pulmonary fibrosis and community-acquired pneumonia in working-age adults, highlight "a newly appreciated magnitude of risk."

Dr. Blanc added that the authors hope that the statement will cause clinicians to consider not just the respiratory condition but also the patient's occupation and "will move policy makers to take seriously the prevention of such diseases among working women and men around the globe."