Body

Head and neck cancer is the sixth most common cancer worldwide, and while effective treatments exist, sadly, the cancer often returns.

Researchers at the University of Cincinnati have tested a new combination therapy in animal models to see if they could find a way to make an already effective treatment even better.

Since they're using a Food and Drug Administration-approved drug to do it, this could help humans sooner than later.

These findings are published in the journal Cancer Letters.

Christina Wicker, PhD, a postdoctoral fellow in the lab of Vinita Takiar, MD, PhD, led this research which she says will hopefully extend the lives of patients one day.

"Head and neck cancer, like any cancer, is truly life-altering," she says. "Head and neck cancer could impact your throat, tongue or nose, and patients often can't swallow, talk or eat; it truly takes away some of the most social, enjoyable parts of life."

Researchers in this study combined radiation therapy with a drug (telaglenastat) that stops a key enzyme in a cell pathway that becomes altered in cancer cells, causing those cells to grow rapidly and resist treatment. Wicker says this drug has already been studied in multiple clinical trials to see if it could improve treatment of various cancers.

"Until now, no one has examined if this drug has the potential to improve radiation treatment in head and neck cancer. Most importantly, this drug compound has been well tolerated by patients and causes minimal side effects," she says.

Using animal models, researchers found that the drug alone reduced the growth of head and neck cancer cells up to 90%, and it also increased the efficacy of radiation in animals with head and neck tumors by 40%.

"With these results, and especially with previous clinical trials showing that the drug is well tolerated by patients, there is the potential to move more rapidly into head and neck cancer clinical trials," Wicker says. "In the future, we hope this drug will be used to make radiation treatments for head and neck cancer even more effective."

Currently, the most common treatment for that cancer is radiation therapy, but the cancer eventually returns in up to half of patients, Wicker says, and often it doesn't respond as positively to treatment the second time around.

"When [traditional] drugs are less effective, cancer growth becomes difficult to control, which can lead to the cancer quickly spreading to other organs," she says. "It is very important that scientists and clinicians develop new cancer treatments to improve treatment of this type of cancer, and hopefully our findings will provide one more option to help patients."

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2019.1267, Hai Zou and Shengqing Li from the Institute of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China consider ECMO/CRRT combined support in the treatment of critically ill SARS-CoV-2 pneumonia patients.

The authors of this article explored the experience with, and complications of, extracorporeal membrane oxygenation (ECMO) combined with continuous renal replacement therapy (CRRT) for treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia.

The survival rate of patients with cardiopulmonary failure treated with ECMO/CRRT in whom conventional treatment failed in this group was 100%, which indicates that combined treatment with ECMO and CRRT is an important treatment technique.

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2019.1266, Zhuzhi Wen, Jingying Hou, Zun Mai, Huifen Huang, Yangxin Chen, Dengfeng Geng and Jingfeng Wang from Sun Yat-sen University, Guangzhou, China and Guandong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China consider predictive value of blood pressure, heart rate, and blood pressure/heart rate ratio in a Chinese subpopulation with vasovagal syncope.

Blood pressure, heart rate and ratios of blood pressure to heart rate in the titled position during the simplistic tilt test had predictive value with regard to the presence, pattern, and stage of syncope during the head-up tilt test.

Ratios of blood pressure to heart rate derived from ambulatory blood pressure monitoring (ABPM) may be better predictors of the presence and pattern of vasovagal syncope (VVS), while ABPM-derived blood pressure should be used to predict the time when syncope will happen.

The authors found significant correlations in blood pressure to heart rate ratios between ABPM and the simplistic tilt test, and different VVS patterns had different correlative features. Parameters from both ABPM and the simplistic tilt test may be promising alternatives to the head-up tilt test in VVS evaluation.

CHICAGO (January 21, 2021): A multimodal pain regimen (MMPR) designed to minimize opioid exposure and relieve acute pain associated with traumatic injury kept patient self-reported pain scores low while also reducing the daily and total amount of opioid drugs given to trauma patients. Results from the first study of its kind to evaluate an MMPR in a rigorous, randomized controlled trial are published online as an "article in press" by the Journal of the American College of Surgeons in advance of print.

"Opioids should not be considered the pillar of treatment for acute pain after injury," said lead study author John A. Harvin, MD, FACS, an associate professor for the department of surgery, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth) and trauma surgeon at the Red Duke Trauma Institute at Memorial Hermann-Texas Medical Center.

Trauma patients are at particularly high risk for developing an opioid drug disorder.1 These patients often have injuries that affect several parts of the body and require multiple surgical procedures resulting in acute pain that cannot be managed by local or regional anesthesia.2 About 15 percent of trauma patients are at high risk for persistent opioid use as they are more likely than the general population to have a history of substance abuse.3,4

Multimodal pain regimens are increasingly being used to reduce opioid exposure, control acute pain, and enhance recovery after surgery.5-9 The trauma team at the Red Duke Trauma Institute and UTHealth developed an MMPR for trauma in 2013. The regimen decreased opioid exposure by 31 percent as well as patients' pain score ratings.10 However, it involved the use of high-cost drugs not widely available in the hospital, such as intravenous acetaminophen, and drugs at discharge that were not covered by insurers. The regimen also included the medication tramadol that was considered at the time to be a weak opioid but is now considered to be a narcotic-like drug.

In 2018, the trauma team evaluated the Multimodal Analgesic Strategies in Trauma (MAST) MMPR, which only provides opioids for breakthrough pain. MAST MMPR includes four classes of medications: acetaminophen, nonsteroidal anti-inflammatory agents--ketorolac and naproxen--local lidocaine anesthetic patches, and gabapentin.

This pragmatic study compared the effectiveness of the original MMPR with the MAST MMPR, both of which could be escalated or de-escalated by providers. The study included all trauma patients who were admitted over the course of a year to the Red Duke Trauma Institute, a teaching hospital for McGovern Medical School. Patients were randomized in the emergency department to be placed on either the original MMPR or the MAST MMPR.

A total of 1,561 patients across all levels of injury were included in the study. Nearly half of patients in both groups had rib fractures, 20 percent had a traumatic brain injury, and 32 percent had long bone fractures. Twelve percent of patients in both groups underwent laparotomy (surgical opening of the abdomen), 4 percent underwent thoracotomy (surgical opening of the chest), and 1-2 percent underwent amputation of a limb.

Patients who received the generic MAST MMPR had less overall exposure to an opioid than patients in the other group. Per day, patients in the MAST MMPR received 14 fewer oral morphine milligram equivalents (MME): MAST MMPR patients had 34 MME per day versus 48 MME per day for the MMPR group. This amount is roughly equivalent to 10 milligram of oxycodone per day during hospitalization. Fewer patients in the MAST MMPR were discharged with a prescription for an opioid--62 percent versus 67 percent.

Pain scores were the same in both groups of patients: The median Numeric Rating Scale for pain was 3.3 for MAST MMPR and MMPR patients.

Although this study was intended to answer a local question about MMPRs developed by at the Red Duke Trauma Institute and UTHealth, its findings have broad implications. "We used a generic pain regimen that is affordable at discharge. The discharge medications acetaminophen and naproxen can be bought over the counter. The only drug that requires a prescription is gabapentin and an as-needed opioid, if prescribed," Dr. Harvin explained.

This regimen may be adopted by any trauma center, although implementing it will take time. "The MAST MMPR is a regimen that can be duplicated in any trauma center. However, first the culture of an institution needs to change. Implementation requires education, auditing feedback about responsible opioid prescribing, physician and nursing champions to lead efforts to change clinical practice, and managing the expectations of how to treat pain with other, non-opioid adjuncts," he added.

The MAST MMPR is now standard practice at the Red Duke Trauma Institute and UTHealth physicians. The regimen is being adapted for the treatment of acute burn pain and additional interventions are being studied to better control acute pain and reduce opioid exposure in the first 72 hours of hospital admission.

"Post-traumatic pain, even in the most severely injured patient, can be effectively treated in an opioid-minimizing manner," Dr. Harvin concluded.

What The Study Did: This JAMA Insights review provides clinical details of anaphylactic reactions reported to and verified by the Centers for Disease Control and Prevention in the first week of use of the Pfizer-BioNTech COVID-19 vaccine in the United States.

Authors: Tom Shimabukuro, M.D., M.P.H., M.B.A., of the CDC in Atlanta, is the corresponding author.

To access the embargoed study:  Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2021.0600)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

BOSTON - Regular aspirin use has clear benefits in reducing colorectal cancer incidence among middle-aged adults, but also comes with some risk, such as gastrointestinal bleeding. And when should adults start taking regular aspirin and for how long?

There is substantial evidence that a daily aspirin can reduce risk of colorectal cancer in adults up to age 70. But until now there was little evidence about whether older adults should start taking aspirin.

A team of scientists set out to study this question. They were led by Andrew T. Chan MD, MPH, a gastroenterologist and chief of the Clinical and Translational Epidemiology Unit at Massachusetts General Hospital (MGH). Their report appears in JAMA Oncology.

The researchers carried out a pooled analysis of two large U.S. cohort studies: The Nurses' Health Study (January 1980 - June 2014) and the Health Professionals Follow-up Study (January 1986 - January 2014). These two studies contributed data on more than 94,500 participants' use of aspirin over about 35 years, offering a unique opportunity to understand the effect of aspirin use across the lifespan on cancer risk.

The researchers found that regular aspirin use was linked to lower colorectal cancer risk among people aged 70 or older. However, this advantage was only significant among people who started taking aspirin before the age of 70. People who started regular aspirin use at the age of 70 or older did not seem to reap any benefit.

"There is considerable evidence that aspirin can prevent colorectal cancer in adults between 50 and 70 years old," says Chan. "But it has not been clear whether the effect is similar in older adults."

Aspirin is considered the most well-established agent that protects against colorectal cancer (CRC). It is currently recommended by the U.S. Preventive Services Task Force for people aged 50-59 years with specific cardiovascular risk profiles because of its protective effect against heart disease.

However, the recent Aspirin in Reducing Events in the Elderly (ASPREE) trial reported that participants who took a daily low dose of aspirin (100 mg) after age 70 for about five years actually had an unexpected 30% higher risk of death from cancer. The vast majority of the ASPREE participants (89%) had never taken aspirin regularly before joining the study. Chan's team also recently reported that ASPREE participants on aspirin did not experience an increase or decrease in risk of developing a cancer despite having an increase in risk of death from cancer.

That led to the question: Does regular aspirin benefit or harm people older than 70 and does it matter when aspirin was started?

The current study confirms that initiating aspirin at an older age was not associated with a lower risk of colorectal cancer. However, importantly, there is a potential benefit of continuing aspirin if is started at an earlier age. These results, the researchers say, "strongly suggest that there is a potential biological difference in the effect of aspirin at older ages which requires further research."

Adds Chan: "As people get older, if they are not already taking aspirin, a discussion is warranted about whether to start aspirin after weighing the benefits against the risks."

The sight of healthcare workers wearing personal protective equipment (PPE) to protect against transmission of SARS-CoV-2 is something the world has become accustomed to. However, a new study analysing the impact of PPE staff shows that the number and variety of issues they experience increases as their time in PPE without a break increases, ranging from tiredness and headaches in the first hour to nausea, vomiting and dizziness as they head towards four hours continuously in PPE.

The study is by Dr Tom Hutley, Dr Lynsey Woodward and Mr Joshua Berrington based at the University Hospitals Dorset NHS Foundation Trust, Bournemouth, UK, and was presented at the Winter Scientific Meeting of the Association of Anaesthetists, held online this year.

PPE was introduced in hospitals in the UK for all hospital workers from March 2020 in order to protect them against the risk of exposure to SARS-CoV-2. "It quickly became apparent that there was an issue with staff wellbeing caused by wearing PPE," explains Dr Hutley. "In this study, we surveyed our staff to collect data on the impact that PPE was having on both their wellbeing and the functionality of the team."

Over a 2-week period in June 2020, an online survey was presented to anaesthetists,
surgeons and theatre staff working at the Royal Bournemouth and Poole hospitals. The
information was distributed via email, posters in staff rest areas and morning team
meetings. Participants were asked to answer a range of questions regarding the use of
PPE and their wellbeing as a result of wearing it. Questions also included the perceived
impact on the performance of the theatre team as a whole.

The questionnaire was completed by 106 members of staff. The most commonly
reported average time spent in PPE was 2-3 hours (42%) with 10% spending 4 hours in PPE without a break. Two thirds (67%) of respondents reported that the longest period of time wearing PPE without a break was more than 4 hours, and 82% experienced tiredness, 76% thirst and difficulty hearing, and 72% reported headaches. Only one person said they experienced no adverse symptoms from wearing PPE.

Surgeons reported the lowest average time and the least total time in PPE and also the lowest number of symptoms. Respondents were asked two separate questions regarding their comfort in PPE: 1) How comfortable do you feel while wearing PPE? 2) How comfortable do you feel at the end of the day while wearing full PPE? They answered using a 1 to 10 scale system (1: very uncomfortable to 10: very comfortable); 23% of staff rated their comfort level below 3 while wearing PPE. By the end of the day, this increased to 44% of respondents.

Almost all of those surveyed (92%) felt wearing enhanced PPE affected team performance. Two thirds (65%) of respondents strongly agreed with the statement, 'PPE has an effect on the performance of the team.' Various respondents also added extra comments to their survey response, concerning the quality of PPE and PPE hampering communication causing confusion and misunderstanding.

The authors conclude: "Our survey shows that PPE has a negative impact on staff wellbeing and team performance. We are now looking at the introduction of personal respirators and new communication resources, such as whiteboards and walkie-talkies. The authors feel floating staff members are vital to facilitate adequate breaks. The survey is currently being repeated to review staff's wellbeing in PPE with our changing pathways."

A brain pressure disorder that especially affects women, causing severe headaches and sometimes permanent sight loss, has risen six-fold in 15 years, and is linked to obesity and deprivation, a new study by Swansea University researchers has shown.

Rates of emergency hospital admissions in Wales for people with the disorder were also five times higher than for those without.

The condition is called idiopathic intracranial hypertension (IIH). It causes increased pressure in the fluid surrounding in the brain. This can lead to severely disabling headaches as well as vision loss, which can be permanent.

The research team, from Swansea University Medical School, used anonymised health records of Welsh patients held in the SAIL databank, a national healthcare database managed by the University. They analysed 35 million patient years of data from 2003 to 2017. They identified 1,765 people with IIH during that time, 85% of whom were women.

They recorded the body mass index of people in the sample and estimated their relative deprivation using a standard national scoring system. For each person with IIH, they compared three people with a comparable profile who did not have the condition.

They found:

A six-fold increase in the number of cases of the disorder over the course of the study - from 12 cases per 100,000 in 2003 to 76 cases in 2017.

Rates of emergency hospital admissions were 5 times higher in people with IIH, compared to others - 9% of people with IIH require brain surgery to try and preserve vision.

There were strong links for both men and women between body mass index and risk of the disorder.

Obesity rates in Wales over the same period rose from 29% of the population to 40%

For women only, deprivation was linked to risk, even after adjusting for body mass index. Women in the most deprived areas had 1.5 times greater risk of developing the disorder than women in the least deprived areas

Dr Owen Pickrell of Swansea University Medical School, who led the study, said:

"The considerable increase in idiopathic intracranial hypertension we found may be due to many factors but likely mostly due to rising obesity rates. What is more surprising from our research is that women who experience poverty or other socioeconomic disadvantages may also have an increased risk, independent of obesity."

More research is needed to determine which socioeconomic factors such as diet, pollution, smoking or stress may play a role in increasing a woman's risk of developing this disorder.

At present we don't know exactly what causes IIH, but the link with deprivation evident in our research could help provide clues.

Our findings offer yet more reasons why it is essential to address the obesity epidemic, deprivation and inequalities in Wales."

Schools are closing again in response to surging levels of COVID-19 infection, but staging randomised trials when students eventually return could help to clarify uncertainties around when we should send children back to the classroom, according to a new study.

Experts say that school reopening policies currently lack a rigorous evidence base - leading to wide variation in policies around the world, but staging cluster randomized trials (CRT) would create a body of evidence to help policy makers take the right decisions.

The pandemic's rapid onslaught meant many public health policies had to be put into practice quickly despite uncertainty about the risks from SARS-CoV-2 and the effectiveness of various prevention measures.

An international research team say that when governments renew steps toward re-opening schools, there will be an opportunity to answer questions about the impact of closures on transmission of the virus, as well as when and how these restrictions can be safely lifted.

Led by scientists at the University of Birmingham, the team - which includes experts from Harvard University, the University of Pennsylvania and Western University, Canada - today published their findings in Clinical Trials.

Report co-author Professor Karla Hemming, from the University of Birmingham's Institute of Applied Health Research, commented: "As COVID-19 cases and deaths ebb and flow around the world, the question of when and how to withdraw public health policies is pressing.

"Many regions face new waves of outbreaks and new lockdowns. Whether and when schools can re-open and stay open will continue to be a question of upmost importance, but policymakers are left to make such decisions in the absence of rigorous evidence.

"Given the impact of school closures on both education and the economy, schools cannot remain closed indefinitely. But when and how can they be reopened safely? A cluster randomized trial is a rigorous and ethical way to resolve these uncertainties."

Researchers noted wide variation between countries. Swedish schools remained open for under-16s throughout the pandemic, whilst Denmark, Germany, and Norway reopened schools after a period of closure. Italy and Spain chose to keep schools closed until autumn last year, whilst schools in Austria, the Czech Republic, and Russia have at times closed. Variability is also seen within the United States at state and county level.

Justifications for these decisions varied, with some officials relying on local test positivity rates and others focusing on numbers of new cases within schools.

Re-opening primary schools in Quebec, Canada, was associated with relatively few new cases, yet opening primary and secondary schools in Israel was associated with several outbreaks and the re-closure of some schools.

The researchers say CRTs are well suited to the rigorous evaluation of public health policies, with key aspects of trial design deserving special attention:

1. Running such a study should only be considered when community transmission is under control and the health system has capacity.

2. As the main interest is community transmission of SARS-CoV-2, the study would have to include many municipalities or regions.

3. Entire regions (including all schools within) would be randomized to either remain closed or to re-open.

4. For schools reopening, this would mean operating under precautions, including social distancing, mask wearing, and possibly evening testing. Teachers and children are clinically extremely vulnerable should be allowed to remain at home.

5. For schools remaining closed, the burdens of keeping schools closed require careful consideration, especially for those who are more vulnerable at home.

The colons of African-Americans and people of European descent age differently, new research reveals, helping explain racial disparities in colorectal cancer - the cancer that killed beloved "Black Panther" star Chadwick Boseman at only 43.

Scientists led by UVA Health's Li Li, MD, PhD; Graham Casey, PhD; and Matt Devall, PhD, of the Center for Public Health Genomics, found that one side of the colon ages biologically faster than the other in both African-Americans and people of European descent. In African-Americans, however, the right side ages significantly faster, explaining why African-Americans are more likely to develop cancerous lesions on the right side and why they are more likely to suffer colorectal cancer at a younger age, the researchers say.

"Our discovery provides novel insight of the mechanistic underpinning for the observed racial disparities in age-of-onset and anatomical distribution of colon neoplasia," said Li, the leader of the Cancer Control and Population Health program at UVA Cancer Center. "Side-specific biological aging of the colon might emerge as a novel biomarker to guide the development of personalized prevention and intervention strategies."

Colons Old Beyond Their Years

African-Americans are disproportionately affected by colorectal cancer. The American Cancer Society reports that African-Americans are 20% more likely to develop colorectal cancer and 40% more likely to die from it. Overall colorectal cancer rates have declined in America in recent years, but African-Americans have not seen the same decreases as people of European descent. And even as the overall rates have dropped, the rate among younger people has gone up.

While doctors have long appreciated these disparities, they haven't really understood the causes. The new study helps answer those questions. It's the first to show that the right and left side of the colon actually age differently.

The researchers made this determination by looking at the DNA in colon tissue, and the "epigenetic" changes that come with age. These epigenetic changes are not alterations to the genes but changes that affect how the genes work and how well they can do their jobs.

The scientists found that the right side of the colon in most African-Americans had suffered a unique pattern of "hypermethylation," affecting gene expression. It was, in essence, like the right side was old beyond its years. This, the researchers believe, could contribute to African-Americans' increased cancer risk and could explain why they are more likely to develop cancerous lesions on the right side.

The research could also explain why younger people of European descent are more likely to develop lesions on the left side - the side that tends to age faster in that group.

"These findings highlight the importance of colon sidedness to biology of colorectal cancer," Casey said. "The fact that the colon biology of people of African and European ancestry differ further highlights the critical importance of more research involving participation of people of African descent."

Li and his team say further investigation of what they have found could lead to better ways to treat and prevent colorectal cancers.

"We are working to validate our discovery in independent patient cohorts," Li said. "Our discovery is a step forward in our effort to prevent colorectal cancer and reduce racial disparities in this deadly disease."

Philadelphia, January 21, 2021 - Researchers have developed a new integrated genetic/epigenetic DNA-sequencing protocol known as MultiMMR that can identify the presence and cause of mismatch repair (MMR) deficiency in a single test from a small sample of DNA in colon, endometrial, and other cancers. This alternative to complex, multi-step testing workflows can also determine causes of MMR deficiency often missed by current clinical tests. Their results are presented in the Journal of Molecular Diagnostics, published by Elsevier.

MMR genes monitor and repair errors that can occur in normal cell replication and recombination. In some inherited and acquired cancers, one or more of the MMR genes are deactivated. "The impact of MultiMMR is broad. Tumors with MMR deficiency respond well to new cancer immunotherapies," explains lead investigator Trevor J. Pugh, PhD, Department of Medical Biophysics, University of Toronto; Princess Margaret Cancer Centre, University Health Network; and Ontario Institute for Cancer Research, Toronto, ON, Canada. "Determining whether an individual has an inherited form of MMR deficiency can also allow clinicians to enroll patients in active surveillance, engage in risk-reduction strategies, and provide genetic testing to relatives - potentially improving patient outcomes."

Standard clinical testing for MMR deficiency can be inconsistent, requiring multiple tests and types of expertise, resulting in suboptimal care for patients. Next-generation sequencing tests have gained popularity and are being used in clinical laboratories. However, they do not identify all genetic variations for MMR deficiency, and additional testing is often required.

The MultiMMR simultaneously tests for promoter methylation, mutations, copy number status, copy neutral loss of heterozygosity, and microsatellite instability from a small amount of DNA. In this study the researchers sequenced DNA from 142 specimens (82 normal and 60 tumor samples) from 82 patients with MMR-associated colorectal, endometrial, and brain cancers. As a positive control, the results for 45 patients were compared with previous clinical testing using conventional assays. They also used MultiMMR to profile a commercially available DNA control that includes 11 variants that are challenging to detect with next-generation sequencing.

To detect the presence of MMR deficiency, MultiMMR promoter methylation and microsatellite instability analyses found 95 percent and 97 percent concordance with clinical testing, respectively. In detecting variants responsible for the MMR deficiency, MultiMMR matched the clinical testing results in 23 out of 24 cases. The test identified all 11 mutations in the synthetic mix in multiple sequencing runs and identified the mismatch repair deficiency in 29 patients with incomplete or inconclusive testing. The panel was able to identify causes of MMR often missed by the current clinical cascade.

"We have shown that the presence and cause of MMR can be determined in a single test, from a single aliquot of DNA, thereby making best use of available tissue, streamlining workflows, and improving integrated reporting for Lynch and related hereditary cancers," comments lead author Leslie Oldfield, MSc, Department of Medical Biophysics, University of Toronto; and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

The researchers note that current cascade testing protocols may not be able to meet increased demand for universal tumor testing in patients with colorectal and endometrial cancers. Many next-generation sequencing tests do not screen for microsatellite instability and promoter methylation alongside somatic mutations, for example.

"Eligibility for immunotherapy is often contingent on MMR status, so timely and robust testing is important," adds Ms. Oldfield. "MultiMMR streamlines the process and distinguishes the type of MMR deficiency with improved turnaround time, can scale well with increasing demands, and can provide clinicians with important information to inform patient management and treatment decisions."

A pain management regimen comprised mostly of over-the-counter medication reduced opioid exposure in trauma patients while achieving equal levels of pain control, according to a new study by physician-researchers at The University of Texas Health Science Center at Houston (UTHealth.)

Results of the study, which was conducted at the Red Duke Trauma Institute at Memorial Hermann-Texas Medical Center, were published today in the Journal of American College of Surgeons.

"The research shows us that seriously injured people with acute pain can effectively be treated with an opioid-minimizing strategy," said John Harvin, MD, MS, associate professor in the Department of Surgery at McGovern Medical School at UTHealth and first and corresponding author of the study. "Narcotics are not the mainstay of therapy for acute pain." Harvin is also an attending trauma surgeon at the Red Duke Trauma Institute.

The randomized study assessed two different combinations of various non-opioid pain relievers in a total of 1,561 patients. Researchers sought to determine which combination could better reduce opioid exposure in the hospital and after discharge for patients with acute trauma, like pelvic and rib fractures.

One opioid-minimizing treatment strategy is known as the "original," because in 2013, Harvin's team began administering it as a first-line pain regimen and prescribing opioids only as needed. It contains more potent medications including intravenous and oral acetaminophen, celecoxib, pregabalin, naproxen, gabapentin, tramadol (a narcotic), and as needed, oxycodone. This strategy reduced opioid exposure by 31%, but the tramadol made it not opioid-minimizing and it involved more expensive drugs that are not widely available.

In the search for a more ideal strategy, the team created the MAST regimen, named after the study, which is called Multi-Modal Analgesic Strategies in Trauma. It included much more generic and affordable medications: oral acetaminophen, naproxen, gabapentin, lidocaine patches, and as needed, opioids. The only drug that requires a prescription is gabapentin.

Patients randomized to the MAST regimen received less opioid exposure per day - 34 morphine milligram equivalents (MME) compared to 48, and were more likely to be discharged without an opioid prescription, including tramadol (38% versus 33%). No clinically significant difference in pain scores were seen.

"Our first hypothesis was that the original regimen would provide better acute pain control because those medications theoretically should have performed better. We thought if we could control acute pain better upfront then we could use less narcotics overall, but the MAST regimen achieved equal levels of pain control and overall reduced opioid exposure, likely because it only included opioids as needed. Narcotics do not need to be the first line of therapy for acute pain control," Harvin said.

The National Institute on Drug Abuse reports 128 people die every day from opioid overdose, based on data from 2018. The research is timely as opioid overdoses are on the rise, especially during the pandemic.

Data collected by the UTHealth School of Biomedical Informatics Center for Health System Analytics shows that in 2020, first responders in Houston received an average of 90 calls per month for opioid overdoses, with June peaking at 116 calls. That's up from the 60 calls per month they averaged in 2018, and 80 in 2019.

"Last year we had a record number of opioid overdoses in America. It continues to be a serious problem that has been largely overshadowed by COVID-19. However, the COVID pandemic is acutely exacerbating the opioid epidemic," Harvin said.

Many in the medical community say the problem stems in part from standards issued by The Joint Commission in 2011, which require pain to be assessed as a fifth vital sign and encouraged more aggressive pain treatments, including opioids.

Since then, many health providers have relied on opioids to manage acute pain. While prescription drugs from surgery aren't the only cause of opioid addiction, they are a big contributor, Harvin said.

"The best way to decrease someone's risk for long-term use is to minimize their exposure during hospitalization and at discharge, and we now know there are excellent non-opioid medications available that effectively treat pain. We know that culture change will take time and effort, but we're excited to be learning how to best leverage opioid-minimizing drugs to improve care, and to offer a new model that can be adopted by any trauma center."

"Although there is still much work to be done to optimize and to individualize pain regimens for our diverse trauma population, this trial demonstrates the ability of Level 1 trauma centers to rapidly and efficiently learn from patients using rigorous research methodology while simultaneously improving patient care," said Lillian Kao, MD, MS, professor of surgery with McGovern Medical School and senior author of the study. "This type of continuous learning and improvement is facilitated by a close relationship between the academic center (UTHealth), the trauma center (Red Duke Trauma Institute), and our research infrastructure (Center for Translational Injury Research)." Kao is also the division director of acute care surgery at Memorial Hermann-TMC.

The MAST regimen is now standard practice by UTHealth physicians at the Red Duke Trauma Institute. Researchers are working to adapt it for the treatment of acute burn pain.

HOUSTON -- Researchers from The University of Texas MD Anderson Cancer Center have developed the first comprehensive framework to classify small-cell lung cancer (SCLC) into four unique subtypes, based on gene expression, and have identified potential therapeutic targets for each type in a study published today in Cancer Cell.

SCLC is known for rapid, aggressive growth and resistance to treatment, which leads to poor outcomes. While recent advances in immunotherapy and targeted therapy have improved survival for non-small cell lung cancer (NSCLC), progress for SCLC has been limited.

"For decades, small-cell lung cancer has been treated as a single disease because the tumors all look similar under the microscope, even though they behave very differently," said Lauren Averett Byers, M.D., associate professor of Thoracic/Head & Neck Medical Oncology and senior author of the study. "Our study provides a transformative new system to define four major groups of small-cell lung cancer and, for the first time, an avenue for personalized treatment of the second most common type of lung cancer."

Four major subtypes of SCLC

Although previous research identified three possible subtypes of SCLC based on transcription factors, which indicate whether particular genes are turned "on" or "off," a large number of SCLC tumors didn't fit into one of the three groups. Rather than trying to apply a hypothesis to the remaining tumors, Byers' team took an unbiased bioinformatics approach--letting the data from a large set of SCLC tumor samples speak for itself. This led to a 1,300 gene "signature" that confirmed the three previously observed groups (A, N and P), plus a previously unrecognized fourth group (I) with a unique immune landscape.

The first three groups are defined by activation of the ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P) genes. The fourth type, SCLC-I, is characterized by an inflamed gene signature with a high expression of multiple immune genes, including significantly greater levels of genes indicating the presence of CD8-positive cytotoxic T cells.

"Our paper shows that the inflamed group has a distinct biology and environment and tends to be more responsive to immunotherapy," Byers said. "Identifying the inflamed group is very important because so far there have not been any validated biomarkers for small-cell lung cancer that predict which patients get the most benefit from immunotherapy."

Based on recent clinical trials, immunotherapy has become part of the standard of care for SCLC. However, all clinical trials for SCLC, including those using immune checkpoint inhibitors, have had limited success. This study could help explain why, as the results suggest different classes of drugs may be more effective in specific subtypes. For example, in the samples from this study, SCLC-I was most sensitive to immune checkpoint blockade, SCLC-A to BCL2 inhibitors, SCLC-N to Aurora kinase inhibitors and SCLC-P to PARP inhibitors.

"Immunotherapy plus chemotherapy is currently the backbone of treatment for all advanced small-cell lung cancer patients, but not all patients experience the same benefit," said Carl Gay, M.D., Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology and lead author of the study. "Our results provide an opportunity to think about immunotherapy approaches that are specific to the inflamed group, which has a very different microenvironment, separately from combination approaches that might activate the immune response in the other three groups."

Study methods and analysis

The research team first identified the four groups by applying non-negative matrix factorization to previously published data from 81 SCLC patients with surgically resected tumors. Most patients in this data set had early-stage disease, which is not typical. Because SCLC is so aggressive, it's most often diagnosed at an advanced stage. To validate the four subtypes in late-stage disease, Byers' team also analyzed data from 276 SCLC patients enrolled in the Phase III IMpower133 clinical trial, which established the current standard of care for advanced SCLC and represents the largest available SCLC data set to date.

"Looking at the bigger data set of what a more typical patient looks like, the four major groups came out very clearly again, including the novel inflamed group we identified," Byers said. "We also showed that you don't have to use the full 1,300 gene panel. We have developed immunohistochemistry tests that we're working toward adapting for the clinic to more quickly and easily classify SCLC tumors."

One of the known challenges of SCLC is that it often develops resistance to treatment, even after an initial response. To determine if "subtype switching" causes resistance, the authors used single-cell RNA sequencing to evaluate tumor evolution in a series of patient-derived SCLC models. The study suggests that SCLC-A tends to switch to SCLC-I after being treated with chemotherapy, which could contribute to treatment resistance.

A path toward personalized treatment for SCLC

Using the SCLC subtype framework in future clinical trials will be necessary to verify the study findings, particularly regarding the therapeutic vulnerabilities for each group.

"Now we can develop more effective strategies for each group in clinical trials, taking into account that they each have different biology and optimal drug targets," Byers said. "As a field, small-cell lung cancer is about 15 years behind non-small cell lung cancer's renaissance of biomarkers and personalized therapies. This represents a huge step in understanding which drugs work best for which patients and gives us a path forward for personalized approaches for small-cell lung cancer."

Vaccinating people over 60 is the most effective way to mitigate mortality from COVID-19, a new age-based modeling study suggests. Although vaccination of younger adults is projected to avert the greatest incidence of disease, vaccinating older adults will most effectively reduce deaths, the analysis shows. Less than one year after SARS-CoV-2 was identified, deployment of multiple vaccines against the virus has been initiated in several countries. Although vaccine production is being rapidly scaled up, demand will exceed supply for the next several months. An urgent challenge is the optimization of vaccine allocation to maximize public health benefit. To quantify the impact of COVID-19 vaccine prioritization strategies on cumulative incidence of the disease, mortality, and years of life lost, Kate Bubar and colleagues used a mathematical model to compare five age-stratified prioritization strategies. The approach varied assumptions about the total available vaccine supply, country-specific age structure, and age-varying efficacy of a hypothetical vaccine. It used data from countries around the world. In one of the modeling strategies using a highly effective, transmission-blocking vaccine prioritized to adults ages 20-49 years, cumulative disease incidence was minimized. However, in most scenarios where the vaccine was prioritized to adults over 60, mortality and years of life lost were minimized. This suggests optimal benefit - in the terms Bubar et al. evaluated - comes from prioritization of older individuals. If a vaccine is less efficacious in older adults, however, priority could be given to younger age groups, the authors say. To increase the available doses, further priority should be given to seronegative individuals, say the authors, whose work also assessed target-based vaccinations focused on serological status; vaccinating seronegative individuals improved efficiency of the vaccine in reducing overall transmission. The framework the authors applied can be used to compare impacts of prioritization strategies in other contexts, they say. They note several limitations of their study, including that it considers variation in disease risk only by age. They note that "other considerations are crucial, from equity in allocation between countries to disparities in access to healthcare, including vaccination, that vary by neighborhood."

In a related Perspective, Meagan Fitzpatrick and Alison Galvani discuss how the study by Bubar and colleagues suggests the optimal approach for COVID-19 vaccination is different than the optimal strategy for influenza vaccination, which indicates giving vaccines to school-age children as the priority. "Although it may seem intuitive that the optimal strategies against influenza and COVID-19 would be identical," Fitzpatrick and Galvani write, "vaccine optimization is not one size fits all, even for apparently similar pathogens." Shifts necessitating vaccinating older people first for SARS-CoV-2 are related to various factors, they say, including that the average number of secondary infections arising from a single SARS-CoV-2 case, when everyone is assumed to be susceptible, is typically double that of influenza virus. What's more, influenza vaccines have variable age-specific efficacy, with reduced protection for older people; so far, data from ongoing phase III clinical trials of a SARS-CoV-2 vaccines has shown similar efficacy across age groups.

Vaccinating older adults for COVID-19 first will save substantially more U.S. lives than prioritizing other age groups, and the slower the vaccine rollout and more widespread the virus, the more critical it is to bring them to the front of the line.

That's one key takeaway from a new University of Colorado Boulder paper, published today in the journal Science, which uses mathematical modeling to make projections about how different distribution strategies would play out in countries around the globe.

The research has already informed policy recommendations by the Centers for Disease Control and the World Health Organization to prioritize older adults after medical workers.

Now, as policymakers decide how and whether to carry out that advice, the paper--which includes an interactive tool--presents the numbers behind the tough decision.

"Common sense would suggest you want to protect the older, most vulnerable people in the population first. But common sense also suggests you want to first protect front-line essential workers (like grocery store clerks and teachers) who are at higher risk of exposure," said senior author Daniel Larremore, a computational biologist in the Department of Computer Science and CU Boulder's BioFrontiers Institute. "When common sense leads you in two different directions, math can help you decide."

For the study, Larremore and lead author Kate Bubar, a graduate student in the Department of Applied Mathematics, teamed up with colleagues at the Harvard T.H. Chan School of Public Health and the University of Chicago.

They drew on demographic information from different countries, as well as up-to-date data on how many people have already tested positive for COVID-19, how quickly the virus is spreading, how fast vaccines are rolling out and their estimated efficacy.

Then they modeled what would happen in five different scenarios in which a different group got vaccinated first: Children and teenagers; adults ages 20 to 49; adults 20 or older; or adults 60 or older (considering that about 30% of those eligible might decline). In the fifth scenario, anyone who wanted a vaccine got one while supplies lasted.

Results from the United States, Belgium, Brazil, China, India, Poland, South Africa, Spain and Zimbabwe are included in the paper, with more countries included in the online tool.

Different strategies worked better or worse, depending on local circumstances, but a few key findings jumped out.

In most scenarios, across countries, prioritizing adults 60+ saved the most lives.

"Age is the strongest predictor of vulnerability," said Larremore, noting that while pre-existing conditions like asthma boost risk of severe illness or death, age boosts vulnerability more. "You have an exponentially higher likelihood of dying from COVID-19 as you get older."

The authors also note that, while the vaccines being distributed now are believed to have about a 90 to 95% chance of protecting against severe disease, researchers don't yet know how well they block infection and transmission. If they don't block it well and asymptomatic spreaders abound, it again makes the most sense to vaccinate older adults. If nothing else, they'll be personally protected against grave disease.

Only in scenarios where the virus is under control and the vaccine is known to block infection and transmission well does it make sense to move younger adults to the front of the line. That is not the situation in the United States right now.

"For essential workers who might be frustrated that they are not first, we hope this study offers some clarity," said Bubar. "We realize it is a big sacrifice for them to make but our study shows it will save lives."

So will a faster rollout, they found.

For instance, all other things being equal, if the rollout speed was to be doubled from current rates under current transmission conditions, COVID-19 mortality could be reduced by about 23%, or 65,000 lives, over the next three months.

The paper also suggests that in some situations where COVID has already infected large swaths of the population and vaccine is in short supply, it might make sense to ask younger adults who have already tested positive to step to the back of the line.

"Our research suggests that prioritizing people who have not yet had COVID could allow hard-hit communities to stretch those first doses further and possibly get to some of the herd immunity effects sooner," said Larremore.

The authors stress that vaccines alone are not the only tactic for helping win the race against COVID.

"To allow the vaccine to get to folks before the virus does, we need to not only roll out the vaccine quickly and get it to the most vulnerable people. We have to also keep our foot on the virus brake with masks, distancing and smart policies," said Larremore.