The new analysis suggests that 78% to 92% of lung cancers in patients who have never smoked can be treated with precision drugs already approved by the Food and Drug Administration to target specific mutations in a patient’s tumor. The researchers found that most never-smokers’ lung tumors had so-called driver mutations, specific mistakes in the DNA that fuel tumor growth and that can be blocked with a variety of drugs. In contrast, only about half of tumors in people who smoke have driver mutations.

The study appears Sept. 30 in the Journal of Clinical Oncology.

“Most genomic studies of lung cancer have focused on patients with a history of tobacco smoking,” said senior author Ramaswamy Govindan, MD, a professor of medicine. “And even studies investigating the disease in patients who have never smoked have not looked for specific, actionable mutations in these tumors in a systematic way. We found that the vast majority of these patients have genetic alterations that physicians can treat today with drugs already approved for use. The patient must have a high-quality biopsy to make sure there is enough genetic material to identify key mutations. But testing these patients is critical. There is a high chance such patients will have an actionable mutation that we can go after with specific therapies.”

In the U.S, about 10% to 15% of lung cancers are diagnosed in people who have never smoked, and that proportion can be has high as 40% in parts of Asia.

The researchers analyzed lung tumors from 160 patients with lung adenocarcinoma but no history of tobacco smoking. They also compared data from these patients to data in smokers and never-smokers from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium, projects led by the National Institutes of Health (NIH) to characterize different types of cancer. The scientists verified never-smoker status by examining the mutation patterns in these patients and comparing them to mutation patterns in lung cancers of patients who had smoked. Past work led by Govindan and his colleagues found that smokers’ lung tumors have about 10 times the number of mutations as the lung tumors of never-smokers.

“Tobacco smoking leads to characteristic changes in the tumor cells, so we can look for telltale signs of smoking or signs of heavy exposure to secondhand smoke, for example,” said Govindan, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But very few of these patients’ tumors showed those signs, so we could verify that this was truly a sample of lung cancer tumors in patients who had never smoked or had major exposure to tobacco smoke.”

The researchers also found that only about 7% of these patients showed evidence of having mutations present at birth that raised the risk of cancer — either inherited or arising randomly — furthering the mystery of what causes lung cancer in never-smokers.

“There appears to be something unique about lung cancer in people who have never smoked,” Govindan said. “We didn’t find a major role for inherited mutations, and we don’t see evidence of large numbers of mutations, which would suggest exposure to secondhand smoke. About 60% of these tumors are found in females and 40% in males. Cancer in general is more common among men, but lung cancer in never-smokers, for some unexplained reasons, is more common among women. It is possible additional genes are involved with predispositions to cancers of this kind, and we just don’t know what those are yet.”

The study also shed light on the immune profiles of these tumors, which could help explain why most of them do not respond well to a type of immunotherapy called checkpoint inhibitors. Unlike the smokers’ lung tumors studied, very few of the never-smokers’ tumors included immune cells or immune checkpoint molecules that these drugs trigger to fight the cancer.

“The most important finding is that we identified actionable mutations in the vast majority of these patients — between 80% and 90%,” Govindan said. “Our study highlights the need to obtain high-quality tumor biopsies for clinical genomic testing in these patients, so we can identify the best targeted therapies for their individual tumors.”

This work was supported by the National Institutes of Health (NIH), grant numbers 2U54HG00307910 and U01CA214195; and the Mesothelioma Biomarker Discovery Laboratory.

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Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.

The study — which covers more than 1,500 cases in the Dallas area since May 2020 — offers a snapshot of what doctors believe is happening in communities across the country. The research shows the proportion of pregnant COVID-19 patients requiring hospitalization increased to 10 to 15% in late August and early September, more than double the percentage of last year before the emergence of the Delta variant.

“This is a concerning trend, and we’re primarily seeing these cases in unvaccinated women,” said Emily Adhikari, M.D., Assistant Professor of Obstetrics and Gynecology, and a lead author of the study published in the American Journal of Obstetrics and Gynecology.

Dr. Adhikari said the findings offer the first objective evidence that the case number and severity of illness in pregnant women rose with a spike in the Delta variant. The study included 1,515 pregnant women diagnosed with COVID-19 who received care from Parkland Health & Hospital System — Dallas County’s public hospital — from May 2020 through Sept. 4, 2021.

Overall, 82 patients had severe or critical illness, including 10 requiring ventilators, and two deaths. The proportion of severe or critical cases was around 5% until after the new year, and were then largely nonexistent in February and most of March.

However, the rise of the Delta variant coincided with a new wave of hospitalizations that peaked this August and early September, including more than a third of COVID-19 cases the week of Aug. 29. By this time, genetic sequencing conducted at UT Southwestern showed nearly all the local variants sequenced were the Delta B.1.617.2 strain.

Of the 82 patients hospitalized since May 2020, all but one were unvaccinated.

Dr. Adhikari acknowledged that some women fear the vaccine may not be safe to take during pregnancy, but said research has debunked those concerns. She co-authored a JAMA article earlier this year that elaborated on the issue of vaccines and pregnancy.

Dr. Adhikari said pregnant women are at greater risk for complications with any type of severe respiratory infection, so these findings further emphasize the need for pregnant and lactating women in all communities to get vaccinated for COVID-19.

“If they are exposed and infected, they run a higher risk of severe illness from this most recent Delta variant,” said Dr. Adhikari, Medical Director of Perinatal Infectious Diseases at Parkland. “Pregnant women should get immunized as soon as possible.”

The genomic sequencing that revealed nearly all the local SARS-CoV-2 variants were Delta was performed in the McDermott Center Next Generation Sequencing (NGS) Core with analysis performed by the McDermott Bioinformatics Lab, both under the supervision of Helen H. Hobbs, M.D., a Howard Hughes Medical Institute investigator and Professor of Internal Medicine and Molecular Genetics, who directs the Eugene McDermott Center for Human Growth and Development at UT Southwestern. Jeffrey SoRelle, M.D., Assistant Professor of Pathology and a co-author on the study, is collaborating with Dr. Hobbs by providing all positive COVID-19 samples tested at UT Southwestern and interpreting sequencing results with support from a rapid, focused PCR-based test. The collaboration with the McDermott Center Next Generation Sequencing (NGS) Core at UT Southwestern allows whole genome whole sequencing of SARS-CoV-2 virus in a state-of-the-art facility that performs NGS coupled with bioinformatic analysis.

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In a recent study published in Frontiers in Immunology, Prof. Chiharu Nishiyama, Kazuki Nagata, and Ayumi Okuzumi from the Tokyo University of Science and Prof. Hiroshi Nagase from the University of Tsukuba attempted to understand the effects of opioids on the immune system. They tested the effects of KNT-127 — an artificially synthesized opioid that activates delta opioid receptors — on immune responses in live animal and cell culture experiments.

When mice with inflammatory bowel disease (IBD) were treated with KNT-127, they showed a reduction in the severity of colitis — a form of colon inflammation — indicated by lower weight loss and colon atrophy and improved disease activity scores. Similar results were also obtained in a recovery model, confirming the beneficial effects of KNT-127 against colonic inflammation.

Although these results were promising, an important caveat still loomed. “Before proceeding with additional experiments, we had to rule out the role of CNS opioid receptors in the anti-inflammatory effects of KNT-127,” says Prof. Nishiyama, the lead researcher on the study. To address this, the researchers performed similar experiments with YNT-2715, a peripheral KNT-127 that cannot cross over from the blood to the brain. The results were similar to those observed with KNT-127, confirming that its anti-inflammatory effects were indeed CNS-independent.

Encouraged by this, the group examined other immune-related effects of KNT-127 treatment in the colitis model. They found that during disease progression, the opioid reduced the serum levels of IL-6, a pro-inflammatory factor, while also decreasing the number of macrophages in the mesenteric lymph nodes (MLNs). Interestingly, they also observed an increase in the number of regulatory T cells (Tregs) in MLNs. Together, their results showed that KNT-127 suppresses the inflammation caused by macrophages during disease progression and enhances the anti-inflammatory response due to Tregs during recovery.

Finally, to understand the direct effects of KNT-127 on immune cells, the researchers performed in vitro experiments in which they treated macrophages derived from bone marrow or T cells from spleen with the drug. The results were consistent with those from animal experiments, revealing increased secretion of the pro-inflammatory signals as well as enhanced development of Tregs in response to KNT-127 treatment.

Altogether, the findings demonstrated that KNT-127 can directly act on immune cells and reduce the severity of inflammation, making it a good candidate for the treatment of IBD. “Several people around the world suffer from diseases related to colon inflammation, and so far, optimal treatment strategies are lacking. Our findings show that KNT-127 and other activators of opioid receptors could be promising therapeutic options for such diseases,” comments Prof. Nagase, the chief drug developer behind the synthetic opioid, while also cautioning of the road ahead. “Of course, before these drugs are used clinically, additional experiments will be required to elucidate how they exert their immunomodulatory functions and what their effects on other immune diseases are,” he adds.

Nevertheless, Prof. Nishiyama and her team are confident that their study represents an important milestone, not only towards the treatment of IBD but also towards our understanding of the “brain-gut axis” — the interrelationship between brain and gut function — which has received increasing attention in recent years. “Today, we know that poor mental health has physical manifestations. For example, stress worsens inflammation in the gut, which in turn affects the health of the brain. Our results on the immune-related effects of opioids, which commonly act on the brain, is a step toward unraveling the biological mechanisms that govern the reciprocative relationship of gut health and the immune system with the CNS,” mentions Prof. Nishiyama, excited about what the future holds.

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Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.