Body

ANN ARBOR, Michigan -- Physicians did not recognize side effects from radiation therapy in more than half of breast cancer patients who reported a significant symptom, a new study finds.

The study compared reports from 9,941 patients from practices across the state of Michigan who received radiation therapy following lumpectomy. Patients filled out standard symptom reporting tools for four common side effects during their radiation treatment: pain, itchy skin, swelling and fatigue. At the same time, physicians assessed patients' symptoms using a standardized tool called the Common Toxicity Criteria for Adverse Events.

Researchers compared these two sets of symptom reports and found incidences where physicians reported no issue even though patients reported substantial concerns. This under-recognition occurred in 31% of patients reporting pain, 37% of patients with itchy skin, 51% of patients with swelling and 19% of patients with fatigue.

"Physicians sometimes miss when their patients are having substantial symptoms. Recognizing side effects is critical for physicians to provide supportive care to help patients manage their symptoms," says study author Reshma Jagsi, M.D., D.Phil., Newman Family Professor and deputy chair of radiation oncology at Michigan Medicine.

Jagsi will present the findings at the 2020 San Antonio Breast Cancer Symposium. The study included 29 practices throughout Michigan as part of the Michigan Radiation Oncology Quality Consortium, a collaborative quality initiative funded by Blue Cross Blue Shield of Michigan and the Blue Care Network.

The study found that side effects were more likely to be missed in younger patients and Black patients, suggesting that better methods to detect symptoms in these patients could help reduce disparities in patient experiences and outcomes.

"If physicians are less likely to pick up on symptoms that Black patients are experiencing, this might help explain why their symptoms become so severe and also might guide us toward interventions to reduce race-based disparities in experiences of cancer treatment," says Jagsi, a member of the University of Michigan Rogel Cancer Center.

The team proposes additional research to understand why certain populations are more likely to have their symptoms missed and how to overcome any issues of misconceptions or mistrust between patients and providers.

"Patient-reported outcomes provide an important complement to physician evaluations. Improving symptom detection may be a targetable mechanism to reduce disparities in cancer treatment experiences and outcomes, at least in the setting of breast radiation therapy," Jagsi says.

Among patients in New York City with gynecologic cancer and COVID-19, Black patients younger than 65 years of age were five times more likely to require hospitalization than non-Blacks in the same age group. Even though Black patients with gynecologic cancer represented only one-third of patients in this study, they accounted for 41 percent of deaths due to COVID-19 when compared with non-Black patients. These findings are published in CANCER, a peer-reviewed journal of the American Cancer Society.

In the study of 193 patients treated at eight New York City hospitals, 71.6 percent of Black patients required hospitalization, compared with 46.0 percent of non-Black patients. Of the 34 patients (17.6 percent) who died from COVID-19, 14 (41.2 percent) of the patients were Black. Investigators found that the disparities in COVID-19 severity were driven by a higher prevalence of comorbidities among Black patients rather than aspects related to cancer or its treatment.

"The underlying causes of racial disparities are multifactorial and include limited access to healthcare, social determinants of health, racism, and discrimination. The COVID-19 pandemic has only heightened these and brought awareness," said senior author Bhavana Pothuri, MD, MS, of NYU Langone Health. "It is critical we learn from this and address these longstanding differences in health outcomes among Black patients not just in gynecologic cancer, but across all disciplines."

Humans are more prone to develop carcinomas compared with our closest evolutionary cousins, the great apes. These cancers begin in the epithelial cells of the skin or the tissue that covers the surface of internal organs and glands, and they include prostate, breast, lung, and colorectal cancers. A new study published in FASEB BioAdvances reveals a human-specific connection between advanced carcinomas and a gene called SIGLEC12.

Additional studies related to this gene, which has several uniquely human features, and the protein it encodes (called Siglec-XII) could potentially lead to broad-based advances in cancer prognostics, diagnostics, and therapeutics.

"Siglecs are typically expressed in immune cells, and it was surprising to find Siglec-XII on epithelial surfaces. While a mutant form of Siglec-XII is expressed only in about 30% of normal humans, it was found to be present in a high proportion of advanced carcinomas. This could help explain why humans are more prone to aggressive carcinomas, which are rare in chimpanzees," said co-author Nissi Varki, MD, Professor of Pathology at the University of California San Diego School of Medicine.

Although weight loss surgery is a highly effective treatment for obesity, it can be detrimental to bone health. A new study published in the Journal of Bone and Mineral Research suggests that exercise may help address this shortcoming.

The study randomized 84 patients undergoing weight loss surgery to an exercise group or a control group for 11 months. The exercise group performed high impact, balance, and resistance exercises three times per week.

Twelve months after surgery, participants in the exercise group had higher bone mineral density measurements at the lumbar spine and the forearm compared with those in the control group. Also, participants who attended at least half of the exercise sessions had higher bone mineral density at the femoral neck than those in the control group.

"These findings showed that a structured exercise program may be a valid treatment option to minimize weight loss surgery-induced bone loss, which may be particularly important since many patients undergo surgery in early adulthood or even at pediatric ages," said lead author Florêncio Diniz-Sousa, MSc, of the University of Porto, in Portugal. "As stated in recently released World Health Organization physical activity guidelines, regular exercise should be a priority for everyone, including patients who have undergone weight loss surgery."

SAN ANTONIO - Extended follow-up data from the phase III monarchE trial showed that adding the cyclin-dependent kinase (CDK) inhibitor abemaciclib (Verzenio) to standard adjuvant endocrine therapy continued to improve invasive disease-free survival (IDFS) among patients with high-risk, node-positive, early-stage, HR-positive, HER2-negative breast cancer, according to data presented at the 2020 San Antonio Breast Cancer Symposium, held Dec. 8-11.

“While many patients with HR-positive early breast cancer will not experience recurrence on endocrine therapy alone, approximately 20 percent may experience disease recurrence in the first 10 years, often in the form of incurable metastatic breast cancer," said Priya Rastogi, MD, associate professor at the University of Pittsburgh School of Medicine, medical oncologist at UPMC Hillman Cancer Center and medical director of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation.

"The risk of recurrence is higher among patients whose cancer has certain clinical and/or pathological risk factors such as a high number of positive lymph nodes, large tumor size, or a high cellular proliferation as measured by tumor grade or biomarkers," Rastogi continued. "There is a significant unmet need for this patient population, and research must be done to find new treatment options to help prevent early breast cancer from returning for these patients."

Earlier results from an interim analysis of the monarchE trial, which is comparing abemaciclib plus adjuvant endocrine therapy with endocrine therapy alone in 5,637 patients with high-risk, node-positive, early-stage, HR-positive, HER2-negative breast cancer, have been previously reported. After a median follow-up of 15.5 months and 323 invasive disease-free events, it was found that the addition of abemaciclib to endocrine therapy reduced the risk of invasive disease by 25 percent. The two-year IDFS rates in the combination arm and the endocrine therapy alone arm were 92.2 percent and 88.7 percent, respectively.

The current study describes an extended follow-up of this trial, capturing results from 395 invasive disease-free events with a median follow-up time of 19 months.

Following surgery, and radiotherapy and/or chemotherapy as indicated, patients were randomly assigned to receive standard of care adjuvant endocrine therapy with or without abemaciclib (150 mg twice per day for two years). Eligibility criteria included having at least four positive nodes, or having one to three positive nodes in combination with either grade 3 disease, a tumor of at least 5 cm, or centrally assessed high Ki-67 status (where "high" is defined as at least 20 percent positivity in tumor cells). Higher levels of Ki-67 protein are indicative of a fast-growing, aggressive tumor with increased probability of recurrence.

At the time of this analysis, 1,437 patients (25.5 percent) had completed the two-year treatment period and 3,281 patients (58.2 percent) were in the two-year treatment period. Compared with patients who received endocrine therapy alone, those who also received abemaciclib had a 28.7 percent reduced risk of invasive disease. The two-year IDFS rate in the combination arm and the endocrine therapy alone arm was 92.3 percent and 89.3 percent, respectively. Further, the researchers observed an improvement in the two-year distant relapse-free survival (DRFS) rate among patients who received the combinatorial treatment compared with those who received endocrine therapy alone (93.8 percent versus 90.8 percent, respectively).

The researchers also evaluated outcomes among 2,498 patients with centrally assessed high Ki-67 status. Among patients in this cohort, those who received the combination treatment had a 30.9 percent decreased risk of invasive disease compared with those who received endocrine therapy alone. The two-year IDFS rates in the combination arm and the endocrine therapy alone arm were 91.6 percent and 87.1 percent, respectively.

"Across the spectrum of data for abemaciclib, we have observed a consistent benefit, in all subgroups," said Rastogi. Safety data from this trial were consistent with the known safety profile of abemaciclib and no new safety signals were observed.

"These results may mark a notable treatment advance in the last two decades for people living with high-risk, node-positive, HR-positive, HER2-negative early breast cancer," Rastogi continued. "These clinically meaningful results have the potential to change how high-risk, HR-positive, HER2-negative early breast cancer is treated."

Rastogi noted that overall survival data are immature at this time, and additional follow-up is warranted.

SAN ANTONIO - Among patients with breast cancer treated with radiotherapy, under-recognition of symptoms was common in reports of pain, pruritus, edema, and fatigue, with younger patients and Black patients having significantly increased odds of symptom under-recognition, according to data presented at the 2020 San Antonio Breast Cancer Symposium, held Dec. 8-11.

"Recognizing side effects is necessary for physicians to provide supportive care to help patients manage their symptoms," said Reshma Jagsi, MD, DPhil, the Newman Family Professor and deputy chair of the Department of Radiation Oncology and director of the Center for Bioethics and Social Sciences in Medicine at the University of Michigan.

"Physicians sometimes miscalculate the severity of patients' symptoms, which can lead to reduced quality of life," Jagsi continued. "In our study, we found that physicians are more likely to miscalculate symptom severity when patients have certain characteristics, including patients who are younger and patients who are Black."

The researchers compared patient-reported outcome (PRO) evaluations with physician Common Terminology Criteria for Adverse Events (CTCAE) assessments among 9,868 patients with breast cancer who were treated with radiotherapy after lumpectomy at 29 practices across Michigan that are enrolled in the Michigan Radiation Oncology Quality Consortium (MROQC). Patient and physician ratings of four symptoms were collected independently and compared: breast pain, pruritus (itchy skin), edema (swelling), and fatigue.

CTCAE grades range from 0 to 5, with grade 0 referring to an absent symptom and grade 5 referring to death related to the symptom. Patients were deemed to have substantial symptoms if they reported moderate or severe pain, if they reported bother often or all of the time from itching or swelling, or if they had significant fatigue most of the time or always.

Physicians were deemed to under-recognize pain when patients reported moderate pain that the physicians recorded as grade 0, or when patients reported severe pain that the physicians recorded as less than or equal to grade 1. Similarly, physicians were deemed to under-recognize pruritus or edema when they recorded these symptoms as grade 0 and patients reported bother often or all of the time from itching (pruritus) or swelling (edema). Lastly, physicians were deemed to under-recognize fatigue when they recorded this symptom as grade 0 and patients reported having significant fatigue most of the time or always.

Under-recognition of pain, pruritis, edema, and fatigue was found in 30.9 percent, 36.7 percent, 51.4 percent, and 18.8 percent of reports in patients having substantial symptoms, respectively.

Among the 5,510 patients who reported at least one substantial symptom during radiotherapy, 53.2 percent had under-recognition of at least one of the four symptoms.

To evaluate predictors of symptom under-recognition, the researchers performed multivariable logistic regression analyses. They found that several factors were associated with symptom under-recognition, including age, race, and treatment regimen.

Compared with patients ages 60-69, patients younger than 50 and patients ages 50-59 had 35 percent and 21 percent increased odds of symptom under-recognition, respectively.

Compared with white patients, Black patients had 92 percent increased odds of symptom under-recognition, and patients of races other than Black or Asian had 82 percent increased odds of symptom under-recognition.

Other factors associated with symptom under-recognition included patients not treated with a supraclavicular field (radiation directed at an area of lymphatic drainage) and patients treated with conventional fractionation (compared with hypofractionation).

"It is possible that there is a misconception among medical professionals about the pain tolerance of patients based on age and race," Jagsi noted. "Our study identifies some concerning patterns that need to be evaluated in future research, along with opportunities for intervention to improve the quality and equity of cancer care delivery," she added.

"Improving symptom detection is a potential way to reduce disparities in cancer treatment experiences and outcomes, at least in the setting of breast radiation therapy," Jagsi said.

Limitations of the study include its observational nature.

This study and MROQC were sponsored by Blue Cross Blue Shield of Michigan (BCBSM) and the Blue Care Network as part of the BCBSM Value Partnership program. Jagsi receives support from the Susan G. Komen Foundation and the National Institutes of Health (NIH).

Jagsi has stock options as compensation for her advisory board role in Equity Quotient, a company that evaluates culture in health care companies. Jagsi has received personal fees from Amgen and Vizient and grants for unrelated work from the NIH, the Doris Duke Foundation, the Greenwall Foundation, the Komen Foundation, and BCBSM for the MROQC. Jagsi has a contract to conduct an investigator-initiated study with Genentech. Jagsi has served as an expert witness for Sherinian & Hasso and Dressman Benzinger LaVelle law firms, and she is an uncompensated founding member of TIME'S UP Healthcare and a member of the Board of Directors of the American Society of Clinical Oncology.

SAN ANTONIO - Women who receive mastectomy and reconstructive surgery as part of breast cancer treatment may face the risk of developing persistent use of opioids and sedative-hypnotic drugs, according to data presented at the 2020 San Antonio Breast Cancer Symposium, held Dec. 8-11.

"It has become clear that short-term exposure to opioids for any reason can lead to long-term dependence, given the highly addictive potential of these agents," explained the study's lead author, Jacob Cogan, MD, a fellow in hematology/oncology at NewYork-Presbyterian/Columbia University Irving Medical Center in New York. "Many patients receive this initial exposure around the time of surgery, and patients with cancer are at particularly high risk of becoming dependent on opioids post-operatively."

Cogan added that another class of addictive medications, sedative-hypnotics, are frequently prescribed to patients with cancer, but have received less attention relative to opioids. Patients with cancer may receive sedative-hypnotic prescriptions around the time of surgery to combat anxiety or insomnia. In this study, he and colleagues aimed to assess breast cancer patients' risk of becoming dependent on opioids and/or sedative-hypnotic drugs after mastectomy with reconstruction surgery.

Researchers used the MarketScan health care claims database to evaluate women who underwent mastectomy and reconstruction between 2008 and 2017. They identified prescriptions for opioids and sedative-hypnotics during three time periods: the pre-operative period (365 days to 31 days prior to surgery); the peri-operative period (31 days prior to 90 days after their surgery); and the post-operative period (90 days to 365 days after surgery).

The researchers identified 25,270 women who were not prior users of opioids and 27,651 who were not prior users of sedative-hypnotics. Patients who had no use in the first time period but filled at least one prescription in the perioperative period and at least two prescriptions in the post-operative period were considered new chronic users.

Results showed that 13.1 percent of opioid-naive patients become new persistent opioid users after mastectomy and reconstruction. Meanwhile, 6.6 percent of sedative-hypnotic-naive patients become new persistent sedative-hypnotic users. When removing "non-user" patients from these groups (i.e., those who did not receive or fill a perioperative controlled substance prescription), the rates rose to 17.5 percent and 17 percent, respectively.

The study also found that the chance of becoming a persistent user of both types of controlled substances was significantly increased among women under age 60, those with a breast cancer diagnosis (versus those who had prophylactic surgery), and those treated with chemotherapy. As the number of risk factors increased, the risk of becoming a persistent user also increased.

"I hope that our study can increase awareness that these are addictive medications, and a brief exposure for surgery-related pain or anxiety can lead to long-term use," Cogan said. "Both patients and providers should be aware of this issue, and of the risk factors that elevate an individual patient's risk."

Cogan said the study results do not suggest that opioids and sedative-hypnotic drugs should be avoided. "Rather, patients should be vigilant about taking these medications only when necessary, and they should work closely with the prescribing provider to attempt to minimize risk of dependence," he said.

Cogan noted that a limitation of the study is that it is based on claims that providers submitted to insurance companies. These may not be fully accurate and are not submitted in a uniform fashion from provider to provider.

SAN ANTONIO - Older patients with hormone receptor-positive breast cancer who did not receive radiation therapy after breast-conserving surgery had higher rates of local recurrence but similar 10-year survival rates when compared to patients who received postoperative radiation therapy, according to updated 10-year data from the PRIME II study, presented at the 2020 San Antonio Breast Cancer Symposium, held Dec. 8-11.

"Over half the patients diagnosed with breast cancer in developed countries are over the age of 65 years," said Ian Kunkler, FRCPE, professor of clinical oncology at the Western General Hospital, University of Edinburgh. Despite the less aggressive breast cancers typically diagnosed in this population, most patients who undergo breast-conserving surgery continue to be treated with whole breast radiation therapy after surgery, he explained. "We were interested in determining whether older patients with low-risk breast cancer could be spared radiation therapy."

The PRIME II study enrolled 1,326 patients with non-metastatic hormone receptor (HR)-positive breast cancer. All patients were at least 65 years of age, had undergone breast-conserving surgery, and were receiving adjuvant hormone therapy. Patients were randomly assigned to either receive or not receive radiation therapy after surgery. Kunkler and colleagues previously reported greater rates of local recurrence (defined as recurrence in the same breast as the primary tumor) in patients who did not receive radiation therapy, but no significant differences in overall survival, distant metastases, or new breast cancers between the two arms after five years.

The latest data presented at the symposium report results from a 10-year follow-up. Kunkler reported that the rate of local recurrence after 10 years was significantly greater in patients who did not receive radiation therapy compared with patients who did (9.8 percent vs. 0.9 percent).

While postoperative radiation therapy affected the risk of local recurrence, it did not significantly impact certain other clinical outcomes. After 10 years, patients who did not receive radiation therapy had similar rates of distant metastasis (1.4 percent vs. 3.6 percent), recurrence in the opposite breast (1.0 percent vs. 2.2 percent), and overall survival (80.4 percent vs. 81.0 percent) as patients who did receive radiation therapy. Most deaths were due to reasons other than breast cancer.

"We found that omitting postoperative radiation therapy did not compromise survival or increase the risk of distant metastasis," said Kunkler. "Based on these results, we believe that omission of radiation therapy after breast-conserving surgery should be an option for older patients with localized, HR-positive breast cancer who are receiving adjuvant hormone therapy and meet certain clinico-pathological criteria."

A limitation of the study is that only a few patients with grade 3 tumors were recruited, so the results of the study may not be applicable to patients with high-grade tumors or with tumors larger than 3 centimeters. An additional limitation is that data on comorbidities or adherence to adjuvant hormone therapy were not collected.

The first human challenge trial to test COVID-19 treatments and vaccines is set to begin in January in the United Kingdom. These trials, in which healthy volunteers are infected with the virus after being given different vaccines under development, have sparked ethical debates around the benefits of developing a vaccine quickly and the risks of directly exposing people to coronavirus.

"I looked for a compelling ethical objection to challenge trials for COVID-19 vaccines but found none -- assuming they have the huge benefits and low risks that have been claimed," said Daniel Hausman, a research professor at Rutgers Center for Population-Level Bioethics. He discussed the findings of his recently published paper in the Journal of Medicine & Philosophy examining ethical issues of challenge trials.

What are the benefits and risks of challenge trials?

Human challenge trials involve giving healthy volunteers a candidate vaccine or a placebo and deliberately exposing them to coronavirus in order to test the effectiveness of the therapy.

Since researchers don't have to wait for participants to be exposed to the virus naturally, some suggest challenge trials will save considerable time and thousands of lives in the midst of the pandemic. By selecting only a small number of young and healthy volunteers, the risk that any would be hospitalized would be very low, and the risk of permanent injury or death lower still.

One might think that the possibility that challenge trials would save thousands of lives could easily justify subjecting well-informed volunteers to these risks. However, some ethicists and some members of the public still have qualms. It is these that I try to understand and respond to.

What ethical questions arise in challenge trials?

One argument rests on the general principle that researchers ought not to expose healthy volunteers to more than minimal risks, unless the research has therapeutic value for the volunteers. Since the participants in the control arm of a human challenge trial are exposed to the virus without any vaccination, these studies violate the general principle and are ethically unacceptable.

In my paper, I respond that the principle is mistaken. Taken seriously, it would rule out most research. While there must be an expected benefit to justify imposing risks on participants, the benefit does not need to be for participants themselves.

Another argument rests on the principle that it is never morally permissible to intentionally harm innocent people. Human challenge trials would violate that principle, but so do other practices that are unobjectionable, such as kidney transplants from live donors, which intentionally impose harm on the donors. Once again, the supposed principle is mistaken.

Finally, there are doubts about how much risk experiments can impose on the whole group of participants, even if the risk to each individual is small. That's a judgment call, but given the potential benefits from human challenge trials, I would call it in their favor.

Are the ethical questions around challenge trials compelling?

If volunteers are harmed or killed, it risks potentially undermining the public's confidence in medical research and professionals, and some oppose challenge trials because of this. This is a serious concern, but the potential benefits seem to justify these risks.

After examining each of these arguments, the ethical questions around potential harms are not compelling when considering the massive benefits challenge trials are expected to provide in the COVID-19 pandemic.

Blood tests for 'biomarkers' such as cholesterol and inflammation could predict whether you will be disabled in five years - according to research from the University of East Anglia.

A new study shows how people's biological health can predict disability and healthcare demand in five years' time.

But the researchers also found that people on higher-incomes were more likely to seek GP appointments and outpatient treatments for their medical problems - with evidence of pro-rich inequity across all types of health service use.

Dr Apostolos Davillas from UEA's Norwich Medical School, said: "We know that the poorest people in England miss out on more than a decade of good health compared with the richest.

"We wanted to find out more about the links between people's social status and their future health - and see whether blood tests could predict future disability and use of health care services."

The researchers looked at elevated bloodstream 'biomarkers' - these are the tell-tale markers linked to different diseases, and they are an objective measure of health.

Biomarkers can tell researchers a lot about what is going on in people's bodies - even before symptoms of disease begin. Testing for 'bad' cholesterol in the bloodstream for example can show a risk of heart disease.

Dr Davillas' previous research has shown how biomarkers for stress are linked with socioeconomic position and revealed some of the hidden mechanisms connecting social inequality to health.

The researchers studied blood biomarkers from 5,286 participants involved in Understanding Society, the UK Household Longitudinal Study.

They looked at things like cholesterol, liver and kidney function and inflammation - the body's response to infections or chronic stress.

They also looked at measures of obesity, grip strength, resting heart rate, blood pressure, and lung function among the participants.

Dr Davillas said: "What we found is that underlying biomarker differences are linked with future disability - and that we could actually predict people's level of disability in five years' time, based on the biomarkers in their blood.

"We also found that people's biological health is linked with future demand on healthcare services such as GP and outpatient consultations, as well as time spent in hospital.

"We tried to investigate the mechanism for why this happens and found that people with impaired biological health may develop disability in five years' time - resulting in increased health care and social needs."

But as a by-product of the analysis, the team found that people with higher incomes were more likely to seek the health care they need for their medical problems. This means that there is pro-rich inequity in health care use.

"In a publicly funded health care system, pro-rich inequity in health care use may be because people on lower low-incomes are heavily time-constrained, due to harsher employment and living arrangements, and may be more constrained in seeking the health care they need," Said Dr Davillas.

The team say their work has important policy implications, particularly for screening programmes and prevention strategies.

Dr Davillas said: "We found that the markers which matter most for disability progression are associated with lung function, grip strength, obesity, anaemia, stress-related hormones and liver function.

"Indicators such as blood pressure and cholesterol, which are the current focus of public health screening programs, are less useful as predictors of disability.

"The NHS England Health Check program mainly offers blood pressure, cholesterol tests and BMI measurements every five years to those aged 40-74.

"But our research shows that a broader set of blood-based biomarkers should be considered for public health screening programmes.

"This is increasingly feasible using dried blood spot sampling - drops of whole blood collected on filter paper from a finger prick - which offers a minimally invasive basis for carrying out a wide range of blood tests at low cost.

"We also focused our study on people who were apparently healthy, so they wouldn't normally be prioritised by the health care system. We hope our findings could lead to better policies for prevention strategies - which could potentially help the NHS save money.

"Moreover, our results show pro-rich inequity across all types of health service use.

"We hope our findings will help lead to policies to secure more equal health care opportunities across the UK."

The brain can be affected by a number of different types of tumour and this leads to serious complications such as epileptic attacks, brain edema, haemorrhage, or thrombosis. Hitherto, there have been no uniform standards available for the diagnosis and treatment of these common symptoms. An international team of researchers comprising experts from the leading oncology societies ESMO (European Society for Medical Oncology) and EANO (European Association of Neuro-Oncology) has now compiled international guidelines and standards for the treatment of these complications, and these have been published in the top journal Annals of Oncology (Impact Factor: 18.2). As EANO President, Matthias Preusser, Head of the Division of Oncology (MedUni Vienna's Department of Medicine I) initiated these international guidelines and has played a leading role in coordinating them in his capacity as last author.

"Every year, around 18 million people worldwide are diagnosed with cancer and up to every second patient with an advanced tumour develops brain metastases, especially in cases of lung, breast or skin cancer. Due to the breadth of this field, the new guidelines are of huge significance," explains Preusser. "Two of the largest societies have therefore joined forces to produce uniform standards."

With the aid of algorithms and numerous diagrams, a reference work has been produced to ensure that patients throughout the world receive high-quality treatment for the complications associated with brain tumours. Questions such as "how does one manage brain edema?" or "what should I do in the event of an epileptic attack or neurocognitive impairment?" are addressed in detail by the interdisciplinary panel of authors.

"The new guidelines that we have compiled can be applied and implemented all over the world and should therefore lead to a significant increase in patient safety," stresses Preusser, who has simultaneously co-authored guidelines for the correct treatment of glioma (a specific type of central nervous system brain tumour), which have recently been published in the leading journal Nature Reviews Clinical Oncology (Impact Factor: 53.2, https://doi.org/10.1038/s41571-020-00447-z).

South African study data were used to evaluate the safety of the vaccine in the results just published, but not its efficacy [which refers to the percentage reduction of disease].

"As there were very few Covid-19 cases that occurred in South Africa at least 14 days after volunteers had received their second dose of vaccine, data from South Africa was not included in the pooled efficacy analysis," says Professor Shabir Madhi, Executive Director of the Vaccines and Infectious Diseases Analytics Research Unit (VIDA) at Wits University, who leads the trial in South Africa and who is a joint first author of the paper.

"The results being reported today herald a milestone in the development of Covid-19 vaccines, with the results now having gone through rigorous scientific peer review and being available for interrogation by the general scientific community and the public," he says.

In the paper, University of Oxford and AstraZeneca researchers present a pooled analysis of Phase 3 trials of a vaccine against SARS-CoV-2 across two different dose regimens, resulting in an average efficacy of 70.4%.

The efficacy data are based on 11,636 volunteers across the UK and Brazil, and combined across three groups of people vaccinated - two groups who received a standard dose prime vaccination followed by a standard dose booster vaccination, and one group (in the UK only) who received a low dose prime vaccination followed by a standard dose vaccination.

"The vaccine is also being evaluated in the study amongst 2100 South Africans, who are still being followed up for Covid-19 illness before an analysis can be done in South Africa on the efficacy of the vaccine," says Madhi.

The peer reviewed data further revealed that no hospitalisations or severe disease was observed in the vaccinated groups.

"This Covid-19 vaccine has the greatest prospect of being deployed in low- and middle-income countries in the immediate future compared to the mRNA Covid-19 vaccines," says Madhi. "In addition to its modest cold-storage requirements compared to mRNA vaccines, the Oxford vaccine is also likely to be more available, as it is easier to scale-up in manufacturing capacity, and will likely be the most affordable of the three Covid-19 vaccines for which the safety and efficacy has now been reported."

Professor Andrew Pollard, Director of the Oxford Vaccine Group and Chief Investigator of the Oxford Vaccine Trial, said: "Today, we have published the interim analysis of the phase 3 trial and show that this new vaccine has a good safety record and efficacy against the coronavirus. We are hugely grateful to our trial volunteers for working with us over the past eight months to bring us to this milestone."

The pooled analysis in the study shows that the overall vaccine efficacy at least 14 days after the second dose was 70.4%; the standard dose / standard dose sub-groups showing 62.1% efficacy, and with the low dose / standard dose sub-group demonstrating 90.0% efficacy. No hospitalisations or severe disease were observed in the vaccinated groups.

The authors further report on an extensive safety database from volunteers in the UK, Brazil and South Africa accompanying the efficacy findings; of 24,103 trial volunteers, and 73,480 'person-months' of safety follow up, only three from 170 reported serious adverse events were possibly related to the vaccine.

Of these, one was considered 'possibly related' to the ChAdOx1 nCoV-19 vaccine, one occurred in the control group, and a further case of severe fever in the vaccinated group was considered to be an expected vaccine-related event.

Two updates to the trial protocol are reported by the authors in this publication; the move from the originally planned single dose study to a two-dose study following early immunogenicity results, and the addition of a low dose / standard dose protocol following the observation of difference in the results of quantification methods between delivery of batches of the vaccine.

Of the 11,636 volunteers in the UK and Brazil included in this initial analysis of efficacy, the majority are in the 18-55 age range (UK 87% and Brazil 90%), with those aged 56 or older contributing 12%. As only five cases included in the primary analysis occurred in those who were more than 55 years old, the vaccine efficacy in older age groups could not be assessed but will be determined in future analyses after more cases have accrued in this age range.

The researchers also investigated the potential for the vaccine to prevent asymptomatic disease, through the use of weekly swabbing by UK trial volunteers. These data indicate that the low dose / standard dose vaccine may provide a protection against asymptomatic infection, but stress that these data are at an early phase, with too high a level of uncertainty to be certain that this vaccine will protect against asymptomatic infection.

Further analysis is ongoing into these data, and will be provided to the regulators to enable them to best decide on dose protocols, should this vaccine be granted emergency use authorisation.

Madhi says, "It is essential that the South Africa government is pro-active in pursuing all options to ensure early access - at an affordable price - for large quantities of Covid-19 vaccine to be made available in South Africa, with immunization ideally starting before a widespread resurgence of Covid-19, which I anticipate will be more prevalent in the first quarter of 2021."

Scientists of the Intelligent Logistics Centre at St Petersburg University have developed a new Case-Based Rate Reasoning (CBRR) model for predicting the dynamics of epidemics. Using this method, the researchers are preparing forecasts for the spread of COVID-19 in Russia. The predictions are based on data on the dynamics of the epidemic in countries where the disease was recorded earlier.

The scientists faced a challenge when they began to build their first forecasts in April-May 2020: all available models for mathematical forecasting the dynamics of epidemics did not work for COVID-19.

'In April-May 2020, there were no statistics on the dynamics of the new virus yet, while such statistics are available for viruses already known to mankind. The class of models available at that time was therefore not applicable for forecasting the dynamics of the epidemic. It was necessary to develop a new approach and a new CBRR model. Its feature is that, to predict the epidemic evolution in Russia, it uses data on the dynamics of the spread of the new coronavirus in countries where the epidemic began earlier than in our country,' said Professor Victor Zakharov, Head of the Intelligent Logistics Centre at St Petersburg University, Head of the Department of Mathematical Modelling of Energy Systems at St Petersburg University, Doctor of Physics and Mathematics.

Having established the new model for Russia as a whole, the scientists started to update their forecasts for St Petersburg and Moscow on a weekly basis (their forecasts are available on the website of the Intelligent Logistics Centre at St Petersburg University). According to the latest forecasts, in Russia the daily increase in new cases of COVID-19 over the past two weeks ranges from 24,000 to 27,000. On 3 December 2020, for the first time this figure exceeded 28,000. If this level of growth continues for 7 to 10 days, Russia will flatten the curve of the number of new cases. If it then begins to decrease, scientists believe that Russia may peak on 21-22 December 2020 in the number of active cases: that is according to the number of sick people on a particular day. On these days, the number of infected people in the country as a whole could range from 514,000 to 517,000. These values must be taken into account in order to understand the load level of the health care system and plan its work for the future.

The new CBRR model is built on an iterative approach: the data on which the predictions are based is updated in real time for a period of 2-3 weeks. Thus, the real course of the epidemic over the last analysed time period makes it possible to calculate more accurately the forecast of its dynamics in the near future. 'The forecast for Russia and the United States in the spring was built 2-3 weeks ahead of the current time. In the forecasts for St Petersburg and Moscow, we rely on the data of the previous days (2-3 weeks) and make predictions using the same model, but adjusted for these data,' said Victor Zakharov.

'The developed CBRR model includes an iterative procedure for the heuristic selection of interval lengths, a set of values of percentage growth, and other significant parameters. These include: peaks in terms of the increase in new cases and possible periods of peak height; and peaks in terms of the number of active cases. A significant component of the iterative procedure is the formation of the chain of countries with epidemic spread (Epidemic Spreading Chain, ESC), which includes several countries ranked by the time they reach the same levels of the selected parameters. The country for which the forecast is being built is called the Country Follower, the rest of the countries we refer to as Country Predecessors,' added Victor Zakharov.

Professor Zakharov noted that for the correct tuning of the model, it is necessary that the ESC countries use relatively identical measures against the epidemic spread: quarantine, self-isolation, social distancing, and the like. As he clarified, the epidemic in the Russian Federation, the country-follower, is characterised by a later date when the same percentage growth rates were reached in comparison with other countries. 'Based on this fact, when modelling and predicting the dynamics of the epidemic in Russia, we included Italy, Spain, Great Britain, and France as country-predecessors in the ESC chain. The sequentially generated evolution trajectory of the statistical data on the epidemic, for example, the total number of infected people, is compared with the actual statistical data,' said Victor Zakharov.

Phase 2 trials in 1,200 adults, young children, and infants suggest new poliovirus vaccine may have the potential to overcome outbreaks caused by a mutated polio strain linked to the oral vaccine that typically circulates in areas of low immunisation coverage, and poses one of biggest barriers to eradication.

Scientists have developed the first poliovirus vaccine against a mutated form of the disease that is causing disease outbreaks across Africa and Asia. Designed to be more genetically stable than the licensed Sabin oral vaccine [1], the new vaccine appears to be as safe and provides similar immune responses when tested in healthy adults, children, and infants, according to new research published in two papers in The Lancet.

The new vaccine, known as nOPV2, is directed against poliovirus type 2, and has improved genetic stability and is less likely to mutate and revert into a form of the virus that can cause infection and paralytic disease.

Based on the results from these phase 2 clinical trials, nOPV2 vaccine has received an Emergency Use Listing (EUL) recommendation from WHO making it the first vaccine ever to go through this pathway that is meant for global health emergencies. The aim is to now use the vaccine for outbreak response for vaccine-derived poliovirus that is increasing across Africa as well as Afghanistan, Pakistan, the Philippines, Malaysia, and other countries. Currently, outbreaks are being tackled using the original Sabin oral vaccine for type 2 polio, which risks seeding further outbreaks in areas of persistently low immunisation coverage.

Lead author of the study in adults, Professor Pierre Van Damme from the University of Antwerp in Belgium says: "Millions of people potentially have no immunity to the spread of vaccine-derived virus, which is caused when the weakened live virus in oral polio vaccines mutates and regains its ability to become infectious, cause disease, and spread in communities with low vaccination rates. The nOPV2 vaccine appears at least as safe and effective as the Sabin vaccine and genetically more stable, and could be a key breakthrough towards a polio-free world." [2]

Vaccine-derived poliovirus - a global public health emergency

Polio is a highly infectious viral disease, which mainly affects children under five, with around one in 200 infections resulting in paralysis. Of those paralysed, 5-10% die when their breathing muscles become immobilised. While there is no cure, polio can be prevented through vaccination against the three polio types, 1, 2 and 3 in trivalent vaccines.

Before being suspended due to the COVID-19 pandemic, vaccination campaigns had almost eradicated wild polio virus from the world--with cases falling by over 99% since 1988, from an estimated 350,000 cases to 33 reported cases in 2018 [3]. Wild-type 2 and 3 polioviruses have been declared eradicated by the WHO, with wild-type 1 only persisting in parts of Afghanistan and Pakistan.

In low- and middle-income countries, the oral vaccine is used because of its low cost and ease of use, needing only two drops per dose, and because it induces intestinal immunity which decreases transmission of the live virus in conditions of poor sanitation. In most high-income countries, a more expensive, injectable vaccine, which contains inactivated viruses incapable of causing disease is used, but it does not induce intestinal immunity, which means that vaccinated individuals can still shed orally-acquired virus.

In recent years, eradication efforts have been challenged by increasing outbreaks of circulating vaccine-derived poliovirus (cVDPV), with over 90% of cases caused by mutations in a strain of type 2 poliovirus. This risk is what led to the global withdrawal of the type 2 component of the oral trivalent vaccine in May 2016. However, this effort failed to curb all type 2 poliovirus transmission, with numbers of type 2 cVDPV cases increasing from 71 in 2018 to 739 cases in 2020 (as of Dec 3, 2020). In response, WHO maintained its categorisation of type 2 cVDPV as a Public Health Emergency of International Concern on October 22, 2020 [4].

Developing more genetically stable type 2 poliovirus vaccines

To address this global emergency, the Global Polio Eradication Initiative supported the development of more genetically stable type 2 polioviruses for vaccines. Like the licensed Sabin type 2 monovalent oral polio vaccine (mOPV2), the new oral vaccine candidates (nOPV2-c1 and nOPV2-c2) are derived from the live, infectious virus, but have been modified to reduce the likelihood of reverting to a type of the virus that can cause infection and disease in rare circumstances.

An earlier phase 1 trial in 30 healthy adult volunteers, published in The Lancet, found that the new vaccine candidates were safe and immunogenic and more genetically stable than the 60-year-old licensed mOPV2 [5].

In new research, published today, scientists evaluated the two nOPV2 candidates in parallel clinical studies in adults, young children, and infants in two different countries to assess their safety and immunogenicity compared with the licensed Sabin mOPV2 they are designed to replace.

Testing the candidate vaccines in healthy adults

Because the original Sabin mOPV2 was withdrawn in 2016, before the nOPV2 candidates were developed, it was not possible to compare the vaccines at the same time. For this reason, Belgian researchers did two randomised trials in healthy Belgian adults (aged 18-50 years): a prospective phase 4 study of Sabin mOPV2 from January to March 2016 (before global withdrawal) to provide historical control data, and a phase 2 study of both nOPV2 candidates from October 2018 to February 2019. Participants in both trials had previously been fully vaccinated against polio as part of routine immunisations.

In the historical control study, 100 participants were enrolled and received one or two doses of Sabin mOPV2. In the phase 2 study, 250 volunteers were randomly assigned to receive either one or two doses of a nOPV2 candidate or a placebo, 28 days apart. Immune responses were assessed on the day of vaccination, then 4 weeks after their first and second vaccinations. Participants recorded any adverse events throughout the study.

Results showed that both nOPV2 candidates were as safe and well-tolerated as mOPV2, and generated a similar immune response--achieving 100% seroprotection (an antibody response capable of preventing infection) after one dose for both nOPV2 candidates compared with 97% and 98% for one or two doses of mOPV2.

Adverse reactions to the vaccines were mild and similar across vaccine groups (the most common effects were fatigue, headache, abdominal pain, diarrhoea, and muscle pain). Four serious adverse events occurred, one of which was deemed possibly related to the nOPV2-c2 vaccine--an influenza-like illness that last for 6 days after the second dose. Initial analysis of viruses shed in stool samples suggested higher genetic stability of the nOPV2 candidates than Sabin mOPV2.

Vaccine trials in healthy children and infants

Following these promising safety results in fully vaccinated adults, researchers conducted two randomised trials in Panama in healthy young children (aged 1-4 years) and infants (aged 18-22 weeks) who had been previously immunised with existing vaccines: a historical control phase 4 study with Sabin mOPV2 from October 2015 to April 2016 (before global withdrawal), and a phase 2 study with low and high doses of the two nOPV2 candidates between September 2018 and September 2019.

Overall, 150 children (50 in control study and 100 in nOPV2 study) and 684 infants (110 controls and 574 in nOPV2 study) were enrolled and received at least one study vaccination. Immune responses were assessed 1 and 4 weeks after their first vaccination and 4 weeks after their second vaccination. Parents recorded any adverse events for 28 days after each vaccination.

The results indicate that in infants, one or two doses of both nOPV2 candidates were safe and well tolerated, with similar immunogenicity to mOPV2--despite mOPV2 recipients having higher baseline immunity at the start of the study.

Adverse reactions to the vaccines were mild and similar irrespective of vaccine or dose (the most common effects were loss of appetite, abnormal crying, irritability, and fever), and no serious adverse events were considered linked to vaccination. The death of one infant who was admitted to hospital after developing pneumonia was not deemed to be associated with nOPV2.

The nOPV2 candidates also had lower stool shedding rates 28 days after vaccination than seen with mOPV2 in the control study.

Lead author of the studies in children and infants, Dr Ricardo Rüttimann from the US non-profit Fighting Infectious Diseases in Emerging Countries, says, "Our findings show that both novel OPV2 candidates are safe, well-tolerated, and immunogenic in young children and infants. However, on-going monitoring in the field and additional studies will strengthen these observations to confirm the safety and effectiveness of the vaccine as it gets used under EUL for outbreak response. Ultimately, in order to eradicate all forms of polio, countries must improve routine and supplementary immunisation campaigns to ensure enough children are reached to boost population immunity high enough so that the virus can no longer survive." [1]

The authors note some limitations to their studies, including that they included just 1,200 individuals, so additional information will still be needed on longer-term safety and duration of protection. They also point out that although the studies were designed to be aligned as far as possible in terms of study centres, population, design, and analyses, a direct comparison was not possible because of the global withdrawal of mOPV2 in 2016.

Writing in a linked Comment, Kimberley Thompson from the non-profit Kids Risk, USA (who was not involved in the study) welcomes these promising findings and writes: "Both studies used the best possible methods to compare novel and monovalent OPV2 given global OPV2 containment constraints. Both are limited by the small numbers of trial participants (eg, observations of reversion and rare events like vaccine-associated paralytic polio would require use in millions of people, similar to OPV), different participant immunity profiles, and the potential for secondary monovalent OPV2 exposure for the historical controls but not the novel OPV2 trials."

She adds, "Future studies will reveal the true value of novel OPV2, as well as similar efforts to develop novel OPV strains for types 1 and 3. Ultimately, the development of novel OPVs could lead to an easier-to-deliver and more cost-effective poliovirus vaccine option than inactivated poliovirus vaccine for countries that rely on OPV."]

Leesburg, VA, December 9, 2020--According to an open-access Editor's Choice article in ARRS' American Journal of Roentgenology (AJR), post-neoadjuvant therapy (NAT) changes in metabolic metrics from PET/MRI and morphologic metrics from CT were associated with pathologic response and overall survival in patients with pancreatic ductal adenocarcinoma (PDA).

"Imaging metrics associated with pathologic response and overall survival in PDA could help guide clinical management and outcomes for patients with PDA receiving emergent therapeutic interventions," wrote first author Ananya Panda of the department of radiology at the Mayo Clinic in Rochester, Minnesota.

Panda and colleagues' retrospective study included 44 patients (22 men, 22 women; average age 62) with 18F-FDG avid borderline resectable or locally advanced PDA on pre-treatment PET/MRI, who also underwent post-NAT PET/MRI prior to surgery between August 2016 and September 2019. CA 19-9, metabolic metrics from PET/MRI, and morphologic metrics from CT (n = 34) were compared between pathologic responders (College of American Pathologists scores 0 and 1] and nonresponders (scores 2 and 3).

In borderline resectable or locally advanced pancreatic cancer undergoing neoadjuvant therapy, pre- vs. post-treatment changes in tumor metrics on PET/MRI (complete metabolic response, ΔSUVmax, ΔSUVgluc) and CT (RECIST, volume change) were associated with major pathologic response (AUC = 0.71-0.83; p

Reiterating that PET/MRI and CT metrics can help guide post-NAT pancreatic cancer treatment decisions, the authors of this AJR article concluded that by comparison, serum CA 19-9 was not associated with pathologic response or survival.