Body

Researchers at the Garvan Institute of Medical Research have discovered that three patients with a severe genetic immunodeficiency spontaneously repaired the harmful variants in their DNA and restored normal immune function over time.

As cells grow and divide to produce new cells, DNA is copied from the parent cell to provide instructions for the new daughter cells. Random changes that occur as the DNA is copied are usually harmless but in some cases are associated with the development of diseases like cancer.

However, the Garvan-led Clinical Immunogenomics Research Consortium Australasia (CIRCA) found three patients with DOCK8 deficiency had repaired the faulty genes through a rare DNA change known as somatic reversion.

"DOCK8 deficiency is a rare, inherited condition caused by errors in the DOCK8 gene and is characterised by recurring bacterial, viral and fungal infections as well as severe allergic reactions and some cancers. Unexpectedly, one patient in the CIRCA network with DOCK8 deficiency and two overseas also underwent somatic reversion. This surprising discovery has implications for future therapies and treatments for the often-fatal disease," says Professor Stuart Tangye, Immunity and Inflammation Research Theme Leader at the Garvan Institute and co-senior author of the findings published in today's issue of the Journal of Clinical Investigation.

Current treatment options

Patients with DOCK8 deficiency experience painful and debilitating symptoms that start from a very young age and can be difficult to diagnose due to the rarity of the condition.

"Symptoms of DOCK8 deficiency are typically managed with topical skin treatments and antibiotics. But for most patients to have the long-term hope of a normal life, they require a bone marrow transplant to replace their DOCK8-deficient immune cells with normal healthy cells from a compatible donor," says Assistant Professor Cindy Ma, co-senior author of the paper.

In their study, the researchers used sophisticated genetic, molecular, cellular and functional analyses to examine the immune cells of three patients diagnosed with DOCK8 deficiency - one in Sydney and two in France.

The patients, who were between 18 and 45 years old, had been suffering from infections and rashes since shortly after birth, had each begun experiencing significant improvements in their health in the absence of significant treatments.

The researchers analysed the genome of the patients' immune cells and observed that some cells had undergone somatic reversion - they had accumulated random mutations within the DOCK8 gene when it was copied that reverted the harmful variations in their DNA back to the normal DNA code.

"Each patient exhibited improvements in their severe allergic disease and a reduction in the number of severe infections as more immune cells began producing the normal DOCK8 protein," says Dr Bethany Pillay, co-first author of the paper.

"One of the patients, a 25-year-old woman living in Sydney, experienced a general improvement in health from mid-adolescence and has had no major infections in recent years. We tracked her progress for a number of years and saw effects on the immune system similar to those of DOCK8-deficient patients who have undergone a bone marrow transplant. She was repopulating her blood stream with normal, healthy cells over time"

Implications for future therapies

DOCK8 deficiency affects hundreds of patients globally, and without interventions such as bone marrow transplants or rare "rescue events" like somatic reversion, 50% of patients die before they turn 20 years old.

One emerging approach to treating inherited immunodeficiencies like DOCK8 deficiency is gene therapy, whereby a patient's own cells are removed and harmful gene variants are replaced with healthy versions. These cells are then injected back in the patient's body where the risks of rejection are much lower as the cells originated in the patient's own body.

Gene therapy has been used to successfully treat a small but growing number of genetic diseases, Professor Tangye says, however it is not currently available to patients with DOCK8-deficiency.

"What our study suggests is that introducing even a few healthy cells into those patients with rare genetic conditions may be an effective treatment, if these cells multiply over time, and are therefore a promising potential therapy in the future."

(Singapore--January 30, 2021 11:00 p.m. SPT/January 30, 2021 10:00 a.m. EST)-- Nivolumab monotherapy is an effective treatment option for relapsed malignant mesothelioma (MM), according to research presented today at the International Association for the Study of Lung Cancer World Conference on Lung Cancer.

Malignant mesothelioma is an intractable cancer, and no phase III trial has yet shown an improvement in overall survival following the standard first line chemotherapy doublet comprising pemetrexed and cisplatin or carboplatin since it was licensed in 2004.

Professor Dean Fennell, chair of Thoracic Medical Oncology at the University of Leicester in collaboration with Professor Gareth Griffiths and his team at the Southampton Clinical Trials Unit, University of Southampton, UK, presented results of the Checkpoint Blockade for Inhibition of Relapsed Mesothelioma (CONFIRM) study, funded by Cancer Research UK/Stand Up To Cancer. The investigator-led, placebo-controlled randomized phase III trial involved 24 centers in the United Kingdom.

Nivolumab is a programmed death-1 (PD-1) inhibitor that has shown activity in previously treated malignant mesothelioma in two single-arm phase II clinical trials.

In the CONFIRM trial, 332 adult patients with previously treated, unresectable, histologically confirmed MM (pleural or peritoneal) and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned to nivolumab (n = 221) or placebo (n = 111).

Participants were stratified by epithelioid vs nonepithelioid histology. The co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS); key secondary endpoints included best overall response and safety.

Overall survival was immature but showed significantly longer survival with nivolumab (events 232 [target 291]; median, 9.2 vs 6.6 months; HR, 0.72; 95% CI: 0.55-0.94; P=0.02). Investigator-assessed progression-free survival was longer for nivolumab vs placebo (3.0 vs 1.8 months; HR 0.61; 95% CI, 0.48-0.77; P 1% (in 34% of included patients) and survival. Grade 3-4 treatment-related adverse events were reported in 19% of patients who received nivolumab and in 6.3% who received placebo. Treatment discontinuation due to toxicity occurred in 13.1% (nivolumab) versus 2.7% (placebo).

"CONFIRM met its co-primary endpoints of improved overall survival and progression-free survival with nivolumab vs placebo in relapsed malignant mesothelioma. The safety profile of nivolumab was consistent with its known profile with no new safety signals. Nivolumab monotherapy is an effective treatment option for [patients with this disease," said Prof. Fennell.

"CONFIRM gives good evidence that this treatment approach should be considered for the new standard of care for these patients," said Prof. Griffiths

"Therapeutic alternatives are always welcome in the contest of a difficult-to-treat diseases such as malignant pleural mesothelioma," said Dr. Giorgio Scagliotti, interim IASLC CSO, "and this study contributes to increase our range of treatment opportunities in the setting of relapsed/recurrent disease."

(Singapore--January 30, 2021 11:00 p.m. SPT/January 30, 2021 10:00 a.m. EST)-- A study presented today by researchers with the Ministry of Health and Welfare in Taiwan confirmed the effectiveness of low-dose computed tomography (LDCT) screening in a pre-defined, never-smoker, high-risk population. The research was presented today at the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer.

In Taiwan, lung cancer is the leading cause of cancer mortality, and 53% of those have died of lung cancer were never-smokers. The National Lung Cancer Screening Trial (NLCST) and NELSON Trials demonstrated that the use of low-dose CT is effective for lung cancer screening; however, most of the lung cancer screenings focused on heavy smokers, which may not be suitable for an East Asian population as this population tend to have higher incidence of lung cancer in never-smokers.

The researchers, led by Dr. Pan Chyr Yang, of the National Taiwan University College of Medicine, Taipei/Taiwan, developed by the Taiwan Lung Cancer Screening for Never Smoker Trial (TALENT), a nationwide lung cancer LDCT screening study focused on never-smokers. TALENT's goal is also to develop an effective strategy for screening of lung cancer in never-smoker and establish a risk prediction model to identify high-risk population that may benefit from LDCT screening.

The TALENT study enrolled and followed 12,011 individuals between February 2015 and July 2019. To be enrolled in the trial, participants must have been between 55 and 75 years of age and never-smokers. In addition, participants must have had one of the following risk factors for lung cancer: family history of lung cancer within the third-degree of relations, passive smoking exposure, tuberculosis or chronic obstructive pulmonary disease, cooking index of 110 or greater, and absence of ventilation during cooking.

Of the 12,011 individuals, 6,009 (50 %) had family history of lung cancer, and 2,094 (17.4%) were considered positive on screening. Of these, 395 participants (3.3%) underwent lung biopsies or surgeries. Lung cancer (2.6%) was diagnosed in 313 patients, with 255 (2.1%) diagnosed with invasive lung cancer--all but one was adenocarcinoma and 96.5% were diagnosed with stage I disease. The remaining 81 patients had benign lung disease or a malignancy other than cancer.

The prevalence of lung cancer was 3.2% and 2.0% (p

"Most importantly, 96.5% patients were stage 0 or 1, [and] were potentially curable by surgery," said Dr. Yang. "Our study also revealed the high risk of family history, especially those [participants] with a first-degree family history of lung cancer."

"The study revealed that LDCT screening for lung cancer in never-smoker with high risk may be feasible, which is very important to all who are fighting against lung cancer, [considering] the increasing global threat for lung cancer in never-smoker. Most importantly, the study showed that family history of lung cancer may increase the risk of lung cancer," he added.

Dr. Yang said his team plans to develop a risk score predictor that includes the family history, and genetic and environmental factors for identification of high-risk population who can benefit from LDCT screening for lung cancer in never-smokers. A standard screening protocol will be established, and Dr. Yang and his team will advise the authority to formally implement the LDCT for lung cancer screening in Taiwan.

"We hope the screening program can benefit patients suffering from lung cancer especially in those countries with high incidence of lung cancer in never smoker," he said.

"This study paves the way to additional studies in this unique group of high-risk individuals," Dr. Scagliotti, IASLC interim CSO said, "in order to maximize the benefits of early detection of lung cancer."

CHICAGO (January 30, 2021) -- Women are significantly less likely than men to undergo coronary artery bypass grafting (CABG) using guideline-recommended approaches, which may result in worse outcomes after surgery, according to a scientific presentation at the 57th Annual Meeting of The Society of Thoracic Surgeons.

"This study highlights key differences between women and men in surgical techniques used for CABG and reveals opportunities to improve outcomes in women," said Oliver K. Jawitz, MD, from Duke University in Durham, North Carolina.

Using the STS Adult Cardiac Surgery Database--which contains records of nearly all CABG procedures performed in the US--Dr. Jawitz and colleagues from Duke and The Johns Hopkins University School of Medicine in Baltimore, Maryland, identified adult patients who underwent first-time isolated CABG from 2011 to 2019. Researchers analyzed detailed demographic, clinical, and procedural data from more than 1.2 million patients.

The correlation between female sex and three different CABG surgical techniques that are recommended in official US and European guidelines was examined closely. According to Dr. Jawitz, all of these surgical approaches--grafting of the left internal mammary artery (LIMA) to the left anterior descending (LAD) artery, complete revascularization, and multiarterial grafting--have been associated with improved short and/or long-term outcomes. However, the results showed that women were 14%-22% less likely than men to undergo CABG procedures with these revascularization strategies.

"With these findings, we did in fact see less aggressive treatment strategies with women," said Dr. Jawitz. "It is clear that sex disparities exist in all aspects of care for patients with coronary artery disease (CAD), including diagnosis, referral for treatment, and now, in surgical approaches to CABG. We must ensure that female patients undergoing CABG are receiving evidence-based, guideline-concordant techniques."

A cardiac surgeon who was not affiliated with the study said that the sheer volume of patient records analyzed is meaningful. "This was an important study, especially since it utilized the world's largest cardiac surgical database to document a difference in surgical strategies between men and women who underwent coronary bypass surgery, said Robbin G. Cohen, MD, MMM, from Keck School of Medicine of the University of Southern California in Los Angeles. "Now we need to understand the reasons for this disparity and the implications for both short- and long-term results."

While multifactorial, the undertreatment of CAD in women largely stems from a failure to recognize key differences in cardiovascular risk factors and symptoms in females compared with males, explained Dr. Jawitz.

Women are much more likely to experience atypical, subtler symptoms of heart disease such as fatigue, abdominal pain, nausea, vomiting, indigestion, and back pain. Sometimes, women do not even feel the obvious chest pain and pressure that are characteristic of CAD. As far as risk factors, women have their own unique set, including relatively high testosterone levels prior to menopause, increased hypertension during menopause, and higher levels of stress and depression.

Another challenge has been that women's health historically has been focused largely on mother and child issues, as well as early diagnosis and treatment of breast cancer. These conversations need to include a stronger emphasis on cardiovascular risk factors and interventions, which is vital to successfully tackling the leading cause of death for women in the US--heart disease, according to Dr. Jawitz.

In addition, women tend to have a longer time from symptom onset to diagnosis and from diagnosis to medical intervention. Each of these delays allows the disease to worsen over time, increasing the risk for poor surgical outcomes. And when women finally are referred for bypass surgery, they continue to be disadvantaged, since they often do not receive CABG with LIMA to LAD, complete revascularization, or multiarterial grafting--all of which are associated with improved outcomes.

"Delayed diagnosis of CAD in women leads to late initiation of key behavioral and pharmacologic interventions for minimizing heart disease risk, as well as delayed referral for invasive diagnostic and therapeutic procedures, including surgical revascularization with CABG," said Dr. Jawitz. "This often means that by the time female patients undergo these procedures, they have more severe disease than males, as well as a greater number of comorbidities, which leads to worse outcomes."

In some clinical trials, women remain grossly underrepresented. According to an unrelated analysis of research data, less than 40% of all people enrolled in cardiovascular clinical trials from 2010 to 2017 were women. Lack of knowledge often is cited as a reason for these persistent disparities.

"The evidence available for various therapies and interventions is disproportionally based on male cardiovascular biology," said Dr. Jawitz. "But as research in this area becomes more robust, data will continue to emerge showing that cardiovascular disease manifests differently by sex. Raising awareness will go a long way toward minimizing sex differences in CAD outcomes."

Moving forward, guidelines must be developed that reflect the important differences between men and women in CAD manifestation, which certainly will require increased representation of female patients in clinical trials of cardiovascular therapies, explained Dr. Jawitz.

"Now that we have identified specific differences in surgical approaches to CABG between females and males, we must further elucidate how these differences result in disparate outcomes such as increased mortality, readmissions, and complications," he said. "These findings will help inform the development of sex-specific guidelines for the diagnosis and management of cardiovascular disease."

(Singapore--4:45 p.m. SPT/3:45 a.m. EST January 30, 2021--Using a host immune classifier (HIC) test for patients with non-small cell lung cancer (NSCLC) may provide better predictors of treatment response and improve outcomes, according to research presented today at the International Association for the Study of Lung Cancer's 2020 World Conference on Lung Cancer Singapore.

Immune checkpoint inhibitors have revolutionized cancer care in patients with advanced stage aNSCLC, but better predictors of treatment response are still needed to guide treatment decisions for patients diagnosed with NSCLC, according to Dr. Wallace Akerley, of Huntsman Cancer Institute in Salt Lake City, Utah. HIC (Host Immune Classifier) is a serum proteomic measure of inflammation. Hot implies that the tumor is inflamed.

Researchers from 33 sites enrolled 3,500 patients with NSCLC in a prospective, observational study that assessed the ability of clinical factors and a clinically validated, blood-based, HIC to predict immune checkpoint inhibitor (ICI) therapy outcomes.

Results in a real-world clinical setting, overall survival (OS) of subjects with newly diagnosed aNSCLC did not differ significantly between ICI and ICI+ chemotherapy (median OS (mOS): 9.4 vs. 12.5 months; hazard ratio, 0.80 [95% CI: 0.54-1.19], p = 0.28).

Results demonstrated that subjects receiving ICI indicated that HIC (HIC defined in title, better performance status (PS) and younger age, but not high PD-L1 expression (either 50% or 90% cutoff) were significantly associated with longer OS. When adjusted for covariates in a multi-variate analysis, HIC and age remained significant predictors of OS (p = 0.0006 and p = 0.005), while PS did not (p = 0.40).

"The HIC test provides clinically meaningful information in addition to currently used clinical factors to potentially help guide immunotherapy treatment decisions for patients with newly diagnosed NSCLC," said Dr. Block.

Philadelphia, January 29, 2021--Researchers at Children's Hospital of Philadelphia (CHOP) have developed a gene therapy vector for blood disorders like sickle cell disease and beta-thalassemia that is potentially safer and more effective than those currently used in gene therapy trials for those conditions. The vector, an engineered vehicle for delivering functional copies of the hemoglobin gene to correct a genetic abnormality, leads to the production of more hemoglobin with a lower dose, minimizing the risk of toxic side effects.

The findings were published today in Molecular Therapy.

"These results have many potential benefits for the successful treatment of patients affected by beta-globinopathies like sickle cell disease and beta-thalassemia, including a better dose response, a minimized chance of clonal expansion and tumorigenesis, a reduced cost of therapy, and a potentially reduced need for chemotherapy or radiation before beginning gene therapy," said Laura Breda, PhD, research assistant professor at CHOP and first author of the paper. "All of us in the CuRED Frontier Program at CHOP are dedicated to finding new and improved curative therapies for blood disorders, and we look forward to taking steps to move this vector into clinical trials."

Sickle cell disease and beta-thalassemia are genetic blood disorders caused by errors in the genes for hemoglobin, a protein consisting of globin and iron-containing subunits that is found in red blood cells and carries oxygen from the lungs to tissues throughout the body. The disorders, sometimes referred to as beta-globinopathies due to mutations in the beta-globin gene, lead to serious health complications, ranging from delayed growth and jaundice to pain crises, pulmonary hypertension, and stroke.

Because children with beta-globinopathies have two abnormal copies of the hemoglobin gene - one from each parent - researchers have explored gene therapy as a potential breakthrough treatment. Using an engineered carrier called a vector to introduce a functional copy of the beta-globin gene, this therapy has the potential to restore normal hemoglobin production in patients with beta-globinopathies. However, there are challenges to this approach, including limited dose response, dose-related toxicities, and the need in many cases for myeloablation, a procedure in which the bone marrow is suppressed via chemotherapy or radiation before gene therapy can begin.

In order to reduce unwanted side effects and increase effectiveness of gene therapy for these conditions, the CHOP researchers developed a new vector using an engineered lentivirus, the same retrovirus used to create gene therapy vectors in ongoing gene therapy trials for beta-globinopathies. The lentiviral vectors currently in use all contain the human beta-globin gene along with its promoter; three so-called hypersensitive sites that are important for gene transcription; and a truncated version of intron 2, which does not code for proteins.

The CHOP researchers hypothesized that including the full intron, rather than a truncated one, in addition to other genomic elements that promote uniform expression of the beta-globin gene would enhance beta-globin - and thus functional hemoglobin - expression. Based on this hypothesis, the research team generated five novel lentiviral vectors by combining different additional genomic elements. As a benchmark, they also generated three vectors similar to those that have already been used in clinical trials, which they used to compare to their novel vectors.

Using a variety of in vitro and in vivo screening approaches, the researchers found that one of their vectors, ALS20, expressed significantly higher transgenic hemoglobin levels than other vectors currently used to treat beta-globinopathies. Compared with the three benchmark vectors, ALS20 produced 157%, 84%, and 40% more adult hemoglobin, which would have a greater clinical impact on patients, especially those who require higher hemoglobin production to become transfusion independent. ALS20 was also more powerful, with a lower dose providing higher hemoglobin production, which could reduce the need for myeloablation and possibly allow for in vivo delivery methods.

From a safety standpoint, ALS20 viral particles did not contain unwanted genomic RNA byproducts, and mice treated with ALS20 exhibited normal physiology without any proliferative disorders or cancerous formations compared with controls.

"Considering the body of evidence presented in this work, we believe that ALS20 is an outstanding candidate for the successful treatment of beta-globinopathies," said senior author Stefano Rivella, PhD, Kwame Ohene-Frempong Chair on Sickle Cell Anemia and Professor of Pediatrics at CHOP. "Our vector may not only provide safer therapy with a reduced probability of genome toxicity and milder conditioning requirements, but it may also improve the efficacy and offer a competitive product for the gene therapy market."

Washington, DC — Blood pressure that remains elevated over of time — known as chronic hypertension — has been linked to heart disease, which is the leading cause of death in the United States. Recent research has shown that persistent high blood pressure may also increase the risk for stroke and overall mortality. Yet, only about 1 in 4 adults with chronic hypertension have their condition under control, according to the Centers for Disease Control and Prevention.

In a new study to be presented today at the Society for Maternal-Fetal Medicine's (SMFM) annual meeting, The Pregnancy Meeting™, researchers from the University of Pittsburgh will unveil findings that suggest that women who develop high blood pressure during pregnancy and who continue to have elevated blood pressure postpartum are at an increased risk for developing chronic hypertension.

The study looked at 368 women who had normal blood pressure during pregnancy and followed them for six to 18 months after delivery. For six weeks following childbirth, women took their blood pressure at home using a remote monitoring system connected to their smart phones. A total of 5,958 blood pressure readings were collected.

Results found that at their first postpartum visit, nearly half of the women (49.5 percent or 182) had developed high blood pressure. These women had a slower decline in blood pressure in the first six weeks following delivery and higher blood pressure at their postpartum visit compared to the remaining women (50.5 percent or 186) who did not develop high blood pressure.

"By leveraging data from our widely scaled postpartum hypertension remote monitoring program, we were able to discover that a woman's blood pressure in the first six weeks after childbirth appears to be an important indicator of whether she is likely to develop chronic hypertension six to 18 months later," said one of the study's lead authors, Eesha Dave, MD, a resident physician in obstetrics and gynecology at UPMC Magee-Womens Hospital in Pittsburgh.

"This information helps us to better identify women who may be at risk of developing cardiovascular problems later in life and take preventative steps," said another one of the study's lead authors, Alisse Hauspurg, MD, a maternal-fetal medicine subspecialist and assistant professor at University of Pittsburgh.

PITTSBURGH, Jan. 29, 2021 - A study led by UPMC Children's Hospital of Pittsburgh and the University of Pittsburgh School of Medicine shows that Black children are 18% less likely to get imaging tests as part of their emergency department visit compared to White children. Hispanic children are 13% less likely to have imaging done than Whites.

The researchers suggest that this disparity results from overuse in White children, though underuse in minority children probably plays a part as well. The root cause likely stems from both patient preferences and implicit bias among providers.

"Something else is going on here that's beyond the clinical, that's beyond the diagnoses," said study lead author Jennifer Marin, M.D., M.Sc., associate professor of pediatrics, emergency medicine and radiology at Pitt, and medical director of point-of-care ultrasound at UPMC Children's Hospital. "Cultural factors that come with people's race, gender, religion, etc., should not be associated with testing when getting that test is clearly not beneficial to the patient and potentially harmful."

The study, published today in JAMA Network Open, used pediatric emergency department billing data from 52 hospitals across 27 states plus the District of Columbia from 2016 to 2019 to measure racial disparities across all types of diagnostic imaging. This is the largest, broadest study of its kind to date.

Even after controlling for confounding factors, such as health insurance, diagnosis and household income, the data showed that doctors were ordering significantly fewer imaging tests for Black and Hispanic children than for White children. The effect was even stronger among patients who weren't admitted to the hospital--suggesting they weren't severely injured or sick.

While the data cannot distinguish between a test that was warranted and a test that wasn't, prior research has shown examples of more frequent imaging in White children compared to other races, with no differences in clinical outcomes. The researchers suspect that the differences they see in testing are largely driven by unnecessary testing among Whites.

That's a concern because some forms of imaging, specifically CT scans and X-rays, expose children to radiation, which likely increases their cancer risk.

"An unnecessary CT at five years old is not the same as an unnecessary CT at 70 years old," Marin said. "If you think of it in terms of lifetime risk, a five-year-old has 80-ish years to go on and develop malignancy, versus a 70-year-old who only has 15 years."

False positives and waste in medical spending also are concerning when tests are being ordered unnecessarily.

"We may get an image and the radiologist may see something--and that something may not be of clinical significance--then the child has to be subjected to downstream testing and monitoring," Marin said. "That's an added burden and stress on the family and added cost on the health care system."

(Singapore--January 29, 2021 11:00 p.m. SPT/10:00 a.m. EST)--On February 27, 2020, the flagship journal of the International Association for the Study of Lung Cancer, the Journal of Thoracic Oncology, published a case study that described two patients from Wuhan, China who recently underwent lung lobectomies for adenocarcinoma and were retrospectively found to have had COVID-19 at the time of surgery.

Eleven months later, the lung cancer research community gathered virtually at the IASLC 2020 World Conference on Lung Cancer Singapore to share a number of research findings examining the intersection of COVID-19 and lung cancer. Researchers from a variety of countries participated in a press briefing to examine the connection between lung cancer and COVID-19.

The press briefing will be moderated by IASLC President-Elect Dr. Heather Wakelee, chief of the Division of Medical Oncology at Stanford University and deputy director of the Stanford Cancer Institute. Patient Advocate and lung cancer survivor Ivy Elkins, MBA, cofounder of the EGFR Resisters and a member of the IASLC Lung Cancer News (ILCN) Editorial Group, will contribute insights from the advocacy community's perspective.

Earlier this year, Ms. Elkins co-authored an article for ILCN that reported that Black patients, Indigenous People, patients of Pacific island descent, and Hispanic patients are 3.7 times, 3.5 times, 3.1 times, and 2.8 times, respectively, more like to succumb to COVID-19, than White patients.(1) These disparities cannot be explained by differences in income alone.(2) It is, therefore, very likely that the pandemic will only exacerbate lung cancer health care delivery gaps in these already disenfranchised communities.

Studies Underscore Significance of Mental Health Impact and Importance of Support Organizations

The fear of contracting COVID-19 among patients with lung cancer is palpable, and three new research studies presented today underscore how vulnerable patients with lung cancer feel as they cope with the pandemic.
Dr. Domenico Galetta, of the Medical Thoracic Oncology Unit of IRCCS Oncology Istitute of BARI Italy, examined 176 patients with lung and breast cancers, as well as lymphoma, for signs of psychological distress and found that about a quarter of them report severe symptoms of Post traumatic stress disorders (PTDS) with female presenting higher levels when compared with males.
(Featured Poster, FP06.04).

"Patients with lung cancer have higher distress compared to the other groups. This condition risks being overlooked by clinical concerns, so we underline the importance [in our abstract] to place even more attention on the psychological needs of patients," he reports.

Another study conducted by the Chicago-based LUNGevity Foundation echoed Dr. Galetta's findings. The group surveyed 302 patients with lung cancer about anxiety regarding access to lung cancer care, patient preparedness to navigate care, and information needs (Abstract 3800).

Overall, 96% of respondents were concerned that the pandemic will affect their cancer care, and 46% reported interruption in lung cancer care, including not being able to see their doctor. Another 18% said they experienced increased difficulty in receiving appropriate care, and 45% of respondents worry about accessing care post pandemic.

"Our study reveals that patients with lung cancer continue to feel vulnerable and ill-equipped to navigate cancer care post shelter-in-place. Indeed, patient-specific factors (treatment status) and local COVID-19 caseload are important predictors of patient worries. Access to healthcare should be taken into account both during patient--physician discussions and during lung cancer-care planning at a systems-level," according to Jessica Selig, LUNGevity Foundation, Research, Chicago.

At a time when patients are in more need of support services, including mental health support, organizations that provide these services report their resources have been negatively affected during the pandemic.

The Global Lung Cancer Coalition (GLCC) is a partnership of 40 patient organizations across 29 countries, dedicated to improving outcomes for patients with lung cancer. The GLCC conducted a survey of its members and found that 64% receive more requests from patients with lung cancer as compared with before the pandemic, but 67% had closed or discontinued services such as support groups and seminars. GLCC found that 18 percent of organizations surveyed added new programs such as new digital services, including calls to patients and online consultations and extending helpline hours and adding new online content.

"Patient advocacy and support organizations are providing more support to patients during the pandemic. However, many organizations have seen a decrease in funding, making it more challenging to [continue or increase support programs]. Patient organizations need urgent financial support to continue to meet increased patient needs and, for some, to survive," said Dr. Matthew Peters, of Concord Hospital, Concord, Australia (Abstract 3384).

Would the Pandemic Affect Access to Lung Cancer Care or Slow Diagnosis? One Study From Spain Suggests That Occurred in 2020

A study conducted by a group led by Dr. Roxana Reyes, of the Hospital Clínic de Barcelona, Thoracic Oncology Group, Barcelona, collected data of new cases of lung cancer diagnosed in two periods, during COVID and the same period in 2019, and found a decrease in the incidence by 38% during COVID.

Of those, researchers found that in the group of NSCLC there was more symptomatic and severe disease at diagnosis compared to 2019, with worse outcomes (Abstract 3700).

"During COVID, the number of new cases diagnosed decreased by 38% (43 NSCLC; 19 SCLC), compared to before-COVID period (67 NSCLC; 33 SCLC)," Dr. Reyes reported.

"Among those hospitalized, the mortality during hospitalization was 44% vs. 17% before COVID."

TERAVOLT Study Reveals Persistently High COVID-19 Mortality Rates Among Patients with Thoracic Malignancies but no Significant Difference According with Race or Ethnicity

Previously reported data on patients with thoracic malignancies who develop COVID-19 have suggested a higher mortality rate compared to the general population and to other cancer types, particularly in patients aged 65 or older or those patients suffering from active or progressive disease. This underscores importance of COVID-19 vaccination in this vulnerable patient population, when available.

The TERAVOLT study, a multicenter, international observational study composed of a cross-sectional component and a longitudinal cohort component that examined more than 1,000 patients with both lung cancer and COVID-19, found that overall mortality remains high, and males have significantly higher hospitalization and mortality rates compared to females. Importantly the researchers found no significant differences in COVID-19 related mortality among different racial or ethnic groups, according to Dr. Umit Tapan, of Boston Medical Center in Boston. (Poster P09.18).

Can Telemedicine Play a Role for Patients with Lung Cancer During the Pandemic?

Although much of the world has moved to remote working and virtual meetings, there was concern about medicine's ability to adapt to the constraints caused by COVID-19. The use of telemedicine has flourished, but what role might it play for patients with complex diseases such as lung cancer?

Previous research has shown that patients with lung cancer who pursue an exercise regimen before treatment, a process known as prehabilitation , may increase their chances of survival. However, since the COVID-19 pandemic, the capacity to deliver face-to-face hospital appointments has significantly been reduced. If these crucial in person visits are curtailed by COVID-19, patients may suffer.

However, a study by Stephanie Wynne, of Guy's Cancer Centre, Guy's and St. Thomas' NHS Foundation Trust, , London, demonstrated that virtual, home-based prehabilitation is feasible and may improve patients' pre-surgical physical activity levels and exercise capacity (Abstract 3614).

(Singapore Embargoed for 7:23pm EST on January 29, 2021 to coincide with publication in the Journal of Clinical Oncology) -- Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic non-small cell lung cancer (NSCLC) for patients with a PD-L1 tumor proportion score of greater than or equal to 50% and no targetable EGFR or ALK aberrations, according to research presented today at the International Association for the Study of Lung Cancer's World Conference on Lung Cancer.

The research was presented by Dr. Michael Boyer, clinical professor of medicine at the Chris O'Brien Lifehouse and the Central Clinical School of the University of Sydney, Sydney, Australia.

Previously, the KEYNOTE-024 study showed that pembrolizumab monotherapy significantly improved survival versus platinum-doublet chemotherapy for patients with metastatic NSCLC, a PD-L1 TPS greater than or equal to 50%, and no targetable EGFR or ALK aberrations.

Boyer and his research group, which consisted of centers in Europe, Asia, and North America, conducted the randomized, double-blind, phase III KEYNOTE-598 study (NCT03302234) to determine whether adding ipilimumab to pembrolizumab improved efficacy over pembrolizumab alone in this population.

The trial enrolled 568 participants -- 284 received a combination of pembrolizumab and ipilimumab and 284 were randomly assigned to receive pembrolizumab and placebo.

Patients were randomly assigned 1:1 to ipilimumab at 1 mg/kg every six weeks or to saline placebo for up to 18 cycles. Patients in both arms received 200 mg of pembrolizumab every three weeks for up to 35 cycles. Random assignment was stratified by European Cooperative Oncology Group score of (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). Treatment differences in the primary endpoints of overall survival and progress-free survival were assessed by the stratified log-rank test in the intent-to-treat population.

The protocol-specified first interim analysis (IA1) was planned to occur when approximately 255 deaths occurred and approximately 12 months had passed since the last participant was randomly assigned. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time between ipilimumab/pembrolizumab and placebo/pembrolizumab of less than or equal to 0.2 at the maximum observation time and less than or equal to 0.1 at 24 months of follow-up.

With 272 deaths, median overall survival was 21.4 months for patients who received ipilimumab/pembrolizumab compared to 21.9 months for placebo/pembrolizumab (HR, 1.08 ;95% CI: 0.85-1.37; p = 0.74). Restricted mean survival time differences were -0.56 at the maximum observation time and -0.52 at 24 months, which met the futility criteria, according to Dr. Boyer.

With 372 events, median progression-free survival was 8.2 months for the ipilimumab/pembrolizumab group compared with 8.4 months for placebo/pembrolizumab (HR, 1.06; 95% CI: 0.86-1.30; p = 0.72). The objective response rate was 45.4% in both arms; median duration of response was 16.1 months for the ipilimumab/pembrolizumab group vs 17.3 months for placebo/pembrolizumab. Treatment-related adverse events occurred in 76.2% of patients in the ipilimumab/pembrolizumab group versus 68.3% for the placebo group.

Dr. Boyer reported that based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue both ipilimumab and placebo.

"As a consequence of the results of this study, monotherapy with pembrolizumab remains a standard of care for this population of patients. Despite the benefits of this type of treatment, almost 50% of these patients die of their disease within two years, so future research will focus on other ways to improve outcomes," he reported.

What The Study Did: Maternally derived antibodies are a key element of neonatal immunity. This study examined the association between maternal and neonatal SARS-CoV-2-specific antibody concentrations because understanding the dynamics of maternal antibody responses to SARS-CoV-2 infection during pregnancy and subsequent transplacental antibody transfer can inform neonatal management as well as maternal vaccination strategies.

Authors: Scott E. Hensley, Ph.D., of the University of Pennsylvania in Philadelphia, and Karen M. Puopolo, M.D., Ph.D., of the Children's Hospital of Philadelphia, are the corresponding authors.

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

(doi:10.1001/jamapediatrics.2021.0038)

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

What The Study Did: Researchers investigated the association between county-level social risk factors and COVID-19 cases and deaths, as well as weekly changes in cumulative cases and mortality, using publicly available data sets as of July 29, 2020.

Authors: Renuka Tipirneni, M.D., M.Sc., of the University of Michigan in Ann Arbor, is th corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.36462)

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

CHICAGO (January 29, 2021) -- Structural racism thwarts a large proportion of black patients from receiving appropriate lung cancer care, resulting in worse outcomes and shorter lifespans than white patients with the disease, according to research presented at the 57th Annual Meeting of The Society of Thoracic Surgeons.

"Many studies have shown that there are disparities between the outcomes of black and white patients, but have done little to elucidate why these disparities are occurring," said Chandler Annesi, a medical student from Boston University School of Medicine in Massachusetts. "As we show in our research, segregation, the resulting devaluation of black communities, and other downstream factors have led to wide disparities in lung cancer outcomes."

For this study, Annesi, Michael Poulson, MD, and colleagues from Boston Medical Center in Massachusetts examined data from 193,369 white and 35,649 black patients who were diagnosed with non-small cell lung cancer (NSCLC) from 2004 to 2016 and living in one of the 100 most populous US counties. This information was obtained from a database of the Surveillance, Epidemiology, and End Results Program and National Cancer Institute.

An important demographic measure that researchers used was the index of dissimilarity (IoD), which establishes the "evenness" with which two groups are distributed across geographic areas. According to Annesi, the IoD helped determine the impact of segregation on stage at presentation, surgical resection, and survival.

"We show that disparities between black and white patients can be explained by the level of segregation of the county in which they live," said Dr. Poulson. "This is likely representative of factors like poverty, access to health care, and social mobility, which particularly affect black individuals in more segregated areas."

The researchers found that with increasing residential segregation, black patients were 30% more likely to be diagnosed with advanced stage NSCLC than white patients. Additionally, black patients had a 47% decreased likelihood of receiving surgery (one of the most common and effective treatments for early stage NSCLC), while white patients had an 18% decreased likelihood with increasing residential segregation.

"This study is a very novel contribution to the literature," said Thomas K. Varghese Jr., MD, MS, from the University of Utah in Salt Lake City, who was not directly involved in this research. "For too long, we've known that irrespective of the disease categories, minorities in general have worse outcomes. They also have more morbidity and more mortality. The outcomes just aren't the same. This particular study is an exploration into the why. Why is this occurring? And, uniquely the authors point out that where you live makes a huge difference in terms of cancer treatment outcomes, and we need to do something about it."

The results also demonstrated that median cancer-specific survival significantly differed between black patients in more segregated areas (10 months) and those in less segregated areas (12 months). The cancer-specific survival for black patients when compared to white patients was 10 months and 13 months, respectively.

"Black patients are more likely to die stage-for-stage when compared to their white counterparts. However, it is important to note that this increased mortality is based on discrimination, not on genetics, as we show in our study," said Dr. Poulson.

The study revealed that residential segregation and, ultimately, discriminatory practices reach into the health care system and impact the outcomes of black patients, but the underlying reasons for these complex and deep-seated lung cancer care disparities still are not fully understood.

According to Annesi, a long history of discriminatory practices have forced black Americans into blighted areas and the effects are still apparent today.

In general, people with lower socioeconomic status face more barriers and systemic-level issues, including poor access to high-quality health care, lack of insurance, limited availability of appropriate facilities, lower screening rates, delays in treatment after diagnosis, and lower treatment adherence.

"All of these factors are related to the discriminatory policies that lead black Americans to be more vulnerable to these conditions," said Annesi.

While many black patients live in urban areas with large hospital systems nearby, insurance coverage can greatly limit their ability to access that care. This is particularly apparent in states that do not have expanded Medicaid, leading to many individuals--who are disproportionately black--going without coverage, explained Annesi. The cost of transportation or lack of work flexibility also may preclude their ability to seek care. Similarly, copays (even small ones) may be burdensome for families that are barely able to afford groceries.

Another important factor is the financial distress that is associated with cancer management, which often prevents adequate care--starting prior to diagnosis, during imaging, and through treatment. The costs of care and the impact of some treatments on employment/disability are especially burdensome to those patients who are socioeconomically disadvantaged.

"Disparities are created and as such can be dismantled," said Annesi. "While it will take time and willingness to reverse discriminatory policies that have led to the disparities that we see today, health care teams can use this information to understand the unique barriers that black patients may face."

Addressing Barriers to Care and Raising Awareness

Importantly, physicians and all members of the health care team must become part of the solution and advocate for their patients at every level (individual, state, and federal). This involves identifying at-risk patients, particularly in "minoritized and marginalized" communities (especially those who are uninsured) and making sure they are prioritized within facilities offering discounted or free care. Also essential is working to make lung cancer screening available and convenient. "Simply catching disease at an earlier stage can vastly improve mortality," said Annesi.

Community cancer centers could help rectify some of the logistical challenges that patients face when they live in areas where access to care and lung screening is limited. However, Annesi explained that the centers would have to provide much of the care that the patients need (i.e., imaging, labs, treatment options) in order to be successful and limit the barriers that patients would face if required to travel elsewhere.

An integrated, multipronged approach is another "extremely important" strategy that may help reduce treatment and outcome gaps between black and white patients with lung cancer, according to Annesi. This type of intervention may include a "warning" system connected to electronic health records that sends alerts about missed appointments or milestones to the health care team. Also part of this strategy would be consistent communication among the various clinical teams, as well as relationships and open lines of communication between trained nurse navigators and patients.

"It is important to realize that race matters, and for patients and families, particularly black individuals, to know that lung cancer is not one's fault," said Annesi. "Years of discrimination have set up the background for these disparities, and it is imperative that hospitals and clinics address the difficulties that some patients too often encounter."

Structural racism is defined as the macrolevel systems, social forces, institutions, ideologies, and processes that interact with one another to generate and reinforce inequities among racial and ethnic groups.

In a study evaluating the BioNTech-Pfizer COVID-19 vaccine's ability to neutralize the B.1.1.7 ("UK") viral variant, researchers found no loss of immune protection compared to that against the original Wuhan reference strain. Their analysis was based on blood samples from 40 people who had received the BioNTech-Pfizer COVID-19 vaccine during clinical trials. The authors conclude their results show it is "unlikely that the UK variant virus will escape ... protection" as mediated by this vaccine. In September 2020, the SARS-CoV-2 lineage B.1.1.7 was discovered in the United Kingdom. It subsequently increased in prevalence, showed enhanced transmissibility, and spread to other continents. The B.1.1.7 variant has a series of mutations in its spike (S) protein, which it uses to gain entry to host cells. Whether a virus with the large number of mutations found in the spike protein of lineage B.1.1.7 could be neutralized by the blood sera from people who had received the BioNTech-Pfizer COVID-19 vaccine is an important question. To investigate, Alexander Muik, Ugur Sahin and colleagues generated SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein. They tested these viruses with blood sera of 40 people who had received the BioNTech-Pfizer COVID-19 vaccine following the recommended regimen of two doses administered 21 days apart. The sera had slightly reduced but largely preserved neutralizing titers against the B.1.1.7 lineage pseudovirus, they found. This suggests the UK variant won't "escape" vaccine-mediated protection, as provided by this vaccine. The authors note that the non-replicating pseudovirus system they used may be a potential limitation of the study. They also conclude: "Although sustained neutralization of the current B.1.1.7 variant is reassuring, preparation for potential COVID-19 vaccine strain change is prudent. Adaptation of the vaccine to a new virus strain would be facilitated by the flexibility of mRNA-based vaccine technology."

SORLA is a protein trafficking receptor that has been mainly studied in neurons, but it also plays a role in cancer cells. Professor Johanna Ivaska's research group at Turku Bioscience observed that SORLA functionally contributes to the most reported therapy-resistant mechanism by which the cell-surface receptor HER3 counteracts HER2 targeting therapy in HER2-positive cancers. Removing SORLA from cancer cells sensitized anti-HER2 resistant breast cancer brain metastasis to targeted therapy.

HER2 protein is a strong driver of tumor growth. HER2 amplification occurs in about 20 % of breast cancers and overexpression or amplification of HER2 is also commonly found in bladder and gastric cancers. HER2 targeting therapies, such as Herceptin, are widely used in clinical care and it plays an important role in the treatment of HER2-positive cancers.

However, some patients will eventually progress during the Herceptin treatment and therapy resistance is frequently linked to the upregulation of HER3 receptor. The newly discovered role of SORLA in supporting HER3 expression and drug resistance offers novel possibilities to target drug-resistant HER2 positive cancers in the future.

"HER2 tumors can become therapy resistant by upregulating HER3. Currently these tumors are un-druggable as there are no HER3 targeted therapies available. Our study showed that removing SORLA protein from drug-resistant HER2-positive cancer cell lines sensitized breast cancer brain metastasis to anti-HER2 therapy. To date, very little has been known about SORLA in cancer. Our discovery that HER3 receptor-induced drug resistance is dependent on SORLA was surprising, since this cancer type and its resistance mechanisms have already been widely studied," says lead author, Post-doctoral Researcher Hussein Al-Akhrass from Turku Bioscience at the University of Turku, Finland.

New understanding of these mechanisms enabled the possibility to control the growth of breast cancer cells in their most aggressive situation when they form tumors in the brain.

In vitro cell culture experiments showed that SORLA protein promotes the recycling of HER3 receptor back to plasma membrane, where the receptor is active and drives the proliferation of cancer cells. When SORLA was removed, HER3 receptor was destroyed in cells leading to sensitization of the cells to anti-HER2 therapy.

The next goal for the research group is to find a way to block the function of SORLA in tumor cells and therefore if there could be a way to develop SORLA targeting treatment.