Category: 8. Health

Introduction

Severe and persistent mental illnesses (SPMI) encompass psychiatric conditions including psychotic disorders (eg, schizophrenia), affective and mood disorders (eg, bipolar disorder, major depression), anxiety disorders including posttraumatic stress disorder (PTSD) and trauma-related conditions, and developmental disorders such as autism spectrum disorder (ASD).

Emerging research supports a multifactorial causation model in which polygenic genetic vulnerability interacts dynamically with diverse modifiable environmental factors, notably including postinfectious inflammation and substance use (petty drug abuse), as key pathways affecting illness onset and persistence^1,2,3

Genetic Vulnerability Across Disorders

• Psychotic disorders such as schizophrenia demonstrate heritability estimates up to 80%, mediated by genetic variants affecting neural networks and cognitive endophenotypes.⁴
• Mood and affective disorders show high polygenic risk (40% to 70%) overlapping with psychosis and anxiety disorders.⁵
• Anxiety, obsessive compulsive disorder (OCD), PTSD, and trauma-related disorders share moderate to high heritability (40% to 65%) along with genetic overlap with mood disorders.^6,7
• Autism spectrum disorder is highly heritable (70% to 90%) with broad genetic heterogeneity impacting related developmental and psychiatric vulnerabilities.⁸ The majority of spectrum-disorder patients suffer with neuropsychiatric comorbidities such as depression, epilepsy, anxiety, and psychosis such as schizophrenia.^9,10

Environmental Risk Factors

Key environmental contributors to SPMI include:

1. Parental Communication Deviance: Fragmented, ambiguous family communication patterns elevate risk for schizophrenia spectrum and impact social and emotional development relevant to mood, anxiety, and autistic spectrum conditions.^3,11,12
2. Inadequacy or Deprivation, Maltreatment: Whether intentional or not, caretakers can directly affect physical and psychiatric well-being.^13-17
3. Childhood Lead Exposure: Lead neurotoxicity disrupts brain development and neurotransmission, increasing multifactorial risk for psychiatric and neurodevelopmental disorders.^2,18
4. Head Injury/Traumatic Brain Injury (TBI): Neural damage and neuroinflammation after traumatic injury amplify genetic vulnerability to psychosis, mood, anxiety, and developmental impairments.^5,19
5. Postinfectious Inflammation: Systemic infections trigger cytokine storms and brain neuroinflammation disrupting neurotransmitter systems, neuroendocrine regulation, and sometimes induc autoimmune injury, contributing to diverse psychiatric syndromes.^1,20
6. Petty Drug Abuse: Use of caffeine, tobacco or nicotine, cannabis, alcohol, and energy drinks constitutes a modifiable environmental risk factor interacting with genetic vulnerability, elevating risk and persistence of psychiatric disorders.⁵

Post-Infectious Inflammation as a Distinct Environmental Factor

Infections provoke systemic immune activation with elevated cytokines (IL-6, TNF-α, IL-1β) that signal across the blood-brain barrier activating microglia, causing neuroinflammation, impaired synaptic plasticity, neurotransmitter balance disruption, and sometimes autoimmune neuronal injury.^1,20 These contribute to onset or worsening of depression, psychosis, PTSD, OCD, and neurodevelopmental disorders.

Concluding Thoughts

Severe and persistent mental illnesses arise from the intersection of inherited genetic liability, aberrant communication in the family, and multiple environmental risks including concussion/TBI, environmental toxin exposure, postinfectious inflammation, and petty drug abuse.¹⁷

Together, neuroinflammation, exposures to environmental toxins, brain trauma, family environment, and substance use or abuse synergistically disrupt brain function governing cognition, mood, and behavior. Prevention and treatment must integrate approaches addressing infectious, toxic, psychosocial, and substance-related risks to reduce illness burden and improve outcomes.

Dr Best is the director of The Neuroscience Center in Deerfield, Illinois.

References

1. Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021;78(6):682-683.

2. McFarland MJ, Reuben A, Hauer M. Contribution of childhood lead exposure to psychopathology in the us population over the past 75 years. J Child Psychol Psychiatry. 2024.

3. Roisko R, Wahlberg KE, Hakko H, et al. Communication deviance in parents of families with adoptees at a high or low risk of schizophrenia-spectrum disorders and its associations with attributes of the adoptee and the adoptive parents. Psych Res. 2011;185(1):66-71.

4. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187-1192.

5. Robinson N, Bergen SE. Environmental risk factors for schizophrenia and bipolar disorder and their relationship to genetic risk: current knowledge and future directions. Front Genet. 2021;12:686666.

6. Burton CL, Park LS, Corfield EC, et al. Heritability of obsessive–compulsive trait dimensions in youth from the general population. Transl Psychiatry. 2018;8:191.

7. Mataix-Cols D, Fernández de la Cruz L, Beucke JC, et al. Heritability of clinically diagnosed obsessive-compulsive disorder among twins. JAMA Psychiatry. 2024;81(6):631-632.

8. Sandin S, Lichtenstein P, Kuja-Halkola R, et al. The heritability of autism spectrum disorder. Am J Psychiatry. 2017;318(12):1182.

9. Hughes JR, Melyn M. EEG and seizures in autistic children and adolescents: further findings with therapeutic implications. Clin EEG Neurosci. 2005;36(1):15-20.

10. Underwood JFG, DelPozo-Banos M. Neurological and psychiatric disorders among autistic adults: a population healthcare record study.Psychological Medicine. 2022;53(12):5663-5673.

11. Levy DL, Coleman MJ, Sung H, et al. (2010). The genetic basis of thought disorder and language and communication disturbances in schizophrenia. J Neurolinguistics. 2010;23(3):176-192.

12. de Sousa P, Varese F, Sellwood W, et al. Parental communication and psychosis: a meta-analysis. Schizophr Bull. 2014;40(4):756-768.

13. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291-1305.

14. McGrath JJ, Eyles DW, Pedersen CB, et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry. 2010;67(9):889-894.

15. Schulz-Heik RJ, Rhee SH, Silvern LE. Testing genetic and environmental mediation. Behavior Genetics. 2009;40(3), 338-348.

16. South SC, Schafer MH, Ferraro KF. Genetic and environmental overlap between childhood maltreatment and adult physical health. twin research and human genetics. 2015;18(5):533-544.

17. Uher R. Gene–environment interactions in severe mental illness. Frontiers in Psychiatry. 2014;5:48.

18. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187-1192.

19. Orlovska S, Pedersen MS, Benros ME, et al.Head injury as risk factor for psychiatric disorders: a nationwide register-based follow-up study of 113,906 persons with head injury. Am J Psychiatry. 2014;171(4):463-469.

20. Okobi OE, Ayo-Farai O, Tran M, et al. The impact of infectious diseases on psychiatric disorders: a systematic review. Cureus. 2024.

Jocelyn Solis-Moreira is a freelance health and science journalist based in New York.

There’s nothing like shutting the bathroom door, maybe even locking it and hiding away from one’s family, even just for a few minutes.

The toilet has long been a sanctuary to catch up on some light reading and, for the harried parent, a spot for some rare “me time.” But the amount of toilet time has become a more pressing medical issue as people shift from reading physical books and magazines to endlessly scrolling on their smartphones.

There are consequences to sitting longer than we used to on the toilet: People are reporting a higher rate of hemorrhoids when they bring their smartphones to the bathroom, according to a new study in PLOS One.

Hemorrhoids are groups of veins in the rectum and outside the anus that can swell and enlarge due to increased pressure, which can create itchiness, discomfort, pain and bleeding.

This new research provides concrete evidence of what many have long suspected: People lose track of time in the bathroom when they have their phones, said Dr. Trisha Pasricha, the study’s senior author, a gastroenterologist at Massachusetts General Hospital and an instructor at Harvard Medical School.

All this scrolling is messing with people’s health.

“The entire business model of these social media apps is to distract us, make us lose track of time and addict us to the algorithm,” Pasricha said. “We’re just now understanding how much smartphones impact lots of other factors in our lives.”

The study invited 125 adults undergoing a screening colonoscopy to complete a survey on their toilet habits, including whether they scroll online in the bathroom. The survey also asked questions about straining, fiber intake and exercise routines — additional factors involved in hemorrhoid risk. Confirmation of hemorrhoids was detected by endoscopy.

Sixty-six percent of survey respondents reported regularly using their smartphones on the toilet. Those who did spent significantly more time on the loo than people who left their smartphones outside the bathroom. About 54% of respondents reported using their phones to read news, while about 44% spent their time on social media.

How much did mindless scrolling on the toilet affect hemorrhoid risk? Researchers found regular smartphone use on the toilet was associated with a 46% greater risk of having hemorrhoids. About 37% of smartphone users spend over five minutes on the toilet compared with 7% of non-smartphone users.

Hemorrhoids are often associated with prolonged sitting; however, the risk is higher when sitting for too long on a toilet. The open toilet seat compresses the rectal area, keeping your bottom in a lower position than if you were sitting on a chair. Over time, the increased pressure from the toilet seat can cause blood to pool in the rectum.

“When you’re sitting on an open toilet bowl, you have no pelvic floor support,” Pasricha said.

Along with spending more time sitting, using a smartphone on the toilet may increase the risk of hemorrhoids due to poor posture.

Dr. Hima Ghanta, a colorectal surgeon at Holy Name Medical Center in New Jersey who was not involved in the study, said people tend to hunch when looking down at their phones, which isn’t ideal for excretion because the rectum and anus curve from the colon. The squatted position is a better option for a smooth bowel movement.

“People way back who had to squat did not tend to have as many issues, but because we changed the angle we’re evacuating and sitting longer, these are exacerbating factors for hemorrhoids,” Ghanta said.

What about constipation? The study results suggest the issue is most likely the time spent sitting on the toilet rather than straining, Pasricha said.

People who used their smartphones weren’t more constipated than those who didn’t, she said. “They didn’t actually strain harder to have a bowel movement than the ones who didn’t. My hypothesis is that it’s passive smartphone use that causes these hemorrhoidal cushions to become engorged and bulge, and that’s what leads to hemorrhoids.”

While the study involved only adults 45 years and older, Pasricha said the results can also apply to younger people, as they are the most likely to always carry their phones with them.

“It was helpful to have this (45 and older) group because there were people who didn’t use their smartphones on the toilet. So we had a comparison group,” Pasricha explained. “Having a third of people not bringing their smartphones to the bathroom helped us understand what a baseline could look like, especially as I imagine the situation is more profound for younger individuals.”

Dr. Sandhya Shukla, a gastroenterologist at Atlantic Coast Gastroenterology Associates in New Jersey who was not involved in the study, said she is seeing younger patients diagnosed with hemorrhoid issues. Though other factors, such as low fiber intake and obesity, can explain why this is happening, she said that scrolling mindlessly on the toilet is one of the major contributors.

The simplest answer is to avoid bringing your phone to the bathroom. If you do bring it, however, all the doctors recommend limiting your sitting time. Gastroenterologists previously advised people to spend no more than 10 minutes sitting on the toilet. Three to five minutes would be ideal.

“A lot of expert consensus is three minutes per bowel movement, but everyone is different,” Shukla said.

Setting a timer can be helpful if you’re prone to mindless scrolling. Pasricha also recommended checking in with yourself after two TikTok videos to see whether you’re having a productive toilet session. If the magic isn’t happening, it’s better to get up and try again later than to sit and wait on the toilet bowl.

Ghanta explained it best: There are many things in life we’re rushing to get through, and we often say to slow down and take time to smell the roses. But not on the toilet.

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Triple-negative breast cancer is particularly aggressive and difficult to treat; but recent research may offer a new way to target the often-deadly disease. 

A team of researchers from the University of Mississippi found that coating nanoparticles containing cancer therapies in a sugar-like substance makes them more effective in targeting this cancer. They published their research in Advanced Healthcare Materials. 

It’s called triple-negative because it does not have any of the three things that we have developed treatments to target in cancer. It particularly affects young women, and it particularly affects Black and African American women. 

What that means is we really urgently need to think creatively about new ways to try and treat this cancer.” 

Eden Tanner, assistant professor of chemistry and biochemistry

More than 1 in 10 breast cancer diagnoses are for triple-negative breast cancer. This cancer is particularly difficult to treat because it does not create high levels of estrogen, progesterone or the protein HER2, all of which are usually used to target cancer for drug delivery. 

Mississippi’s rates of triple-negative breast cancer are higher than average. A 2024 report from the University of Mississippi Medical Center showed that 37% of breast cancer cases treated at the center between 2016 and 2023 were triple-negative – more than double the national average. 

The aggressive nature of this cancer, combined with its resistance to many usual therapies, means its mortality rate is higher than that of other cancers. 

While this cancer may not elevate levels of usual drug targets, the research team found a novel way to deliver cancer therapies directly to the cancer cells. 

“One thing that’s consistent across all of the patients (with triple-negative breast cancer) is that they overexpress glucose transporters to bring more sugars to the cells,” Tanner said. “Essentially, it has a sweet tooth. So, how can we get it to take its medicine? We wrap it in sugar.” 

By coating the nanoparticle cancer therapy in sugar, the researchers effectively “trick” the cancer into absorbing the medication, Tanner said. 

“The drug itself is encapsulated in the nanoparticle, which is then coated in the glucose,” said Mira Patel, a junior chemistry major from Vicksburg, Mississippi. 

When injected into the bloodstream, these sugar-coated cancer therapies can “hitch a ride” on red and white blood cells, Tanner said. Riding the blood cells like a bus, the medication travels across the body and ultimately becomes trapped by the cancer’s glucose transporters. 

“Because triple-negative breast cancer cells overexpress GLUT-transporters, there’s more of an affinity between the nanoparticles and those cells,” said Patel, a co-author of the study who first joined the Tanner Lab through the ARISE Summer Program as a high school junior. 

“This method could provide something that will change the way we treat this cancer in the future, and in a way that won’t affect our regular, healthy cells.” 

Triple-negative breast cancer is not the only disease that overexpresses glucose transporters, meaning the drug delivery method could be used to treat other illnesses. 

“We haven’t tested the technology on those other diseases yet, but there’s a good reason to believe that a similar strategy might work,” Tanner said. “That’s exciting news for diseases like colon cancer, brain cancer and fatty liver disease, which also have high levels of glucose transporters.” 

Before it can be put into practice, however, the researchers must test the delivery method in disease conditions. Given the prevalence of triple-negative breast cancer in the state, the results of their work could save lives in Mississippi. 

“One of our strongest motivations as a research group is to think about scientific innovations that can really help Mississippians,” Tanner said. “Given the profile of our state, we feel particularly motivated to address these problems.” 

This material is based on work supported by the National Institutes of Health grant no. P20GM130460. 

AUSTIN, Texas, Sept. 03, 2025 (GLOBE NEWSWIRE) — A new study found that babies born by C-section had 83% lower odds of developing eczema when their families participated in a 6-month gut health support program, compared to those who didn’t receive the intervention.

The research, published today in the medical journal Pediatric Allergy and Immunology, showed that just 6% of babies in the intervention group developed eczema, compared to 29% in the control group. The study highlights how targeted gut health interventions during a baby’s first months may help reduce risks of immune-related conditions.

Study Details

The randomized controlled trial followed 54 full-term babies born by C-section over six months. Families were randomly divided into two groups: 25 babies received personalized gut health support from Tiny Health, while 29 served as controls without the program.

Parents in both groups collected stool samples from their baby’s diaper at the beginning of the study and again after three months. The intervention program included a detailed microbiome analysis, personalized nutrition and probiotics guidance, and coaching from microbiome specialists. Researchers tracked changes in gut bacteria and surveyed parents about their babies’ health outcomes.

Why C-Section Babies Face Higher Risks

About one in three U.S. babies are born by C-section annually. Unlike vaginal birth, C-section birth means babies may miss out on beneficial bacteria normally transferred from mother to child during birth. Instead, their guts are often colonized by hospital-associated bacteria that can be antibiotic-resistant and related to gut inflammation later in life.

Research shows these early differences in the gut microbiome — the community of bacteria and other microbes living in the digestive system — can persist for years and are associated with higher microbiome risks of eczema, allergies, asthma, and even conditions like obesity and type 1 diabetes.

“Our data show that early microbiome support can shift gut bacterial patterns away from those associated with eczema and allergies,” said Dr. Kimberley Sukhum, Head of Science at Tiny Health. “The first 1,000 days are a critical window of opportunity, when the gut microbiome can be most effectively shaped for lifelong immune health.”

Key Findings Beyond Eczema

By the study’s end, babies who received the intervention showed several positive changes:

• Higher levels of beneficial bacteria: Bifidobacterium reached a median relative abundance of 82% (a 51% increase from the first sample) compared with 55% in the control group
• Better nutrient processing: More genes in their microbiome for digesting HMOs, which are beneficial complex sugars in breastmilk
• Gut bacteria more similar to vaginal birth: Lower “C-section index” scores, meaning their gut bacteria composition trended toward those of vaginally-born babies

What This Means for Parents

For the estimated 1.2 million C-section babies born in the U.S. each year, these findings suggest early gut health interventions may significantly reduce chronic disease risk.

More than 20 million children in the U.S. now live with a diagnosed allergic condition. Eczema alone affects up to 1 in 5 infants and is the first step in the atopic march — the progression of allergic diseases from eczema to food allergies, hay fever, and eventually asthma. By addressing gut imbalances early, parents can potentially disrupt or reverse this progression.

“As a mom of a C-section baby who struggled with eczema and food sensitivities, I wanted to turn what I’d read about course-correcting the infant gut into a reality for myself and other parents,” said Cheryl Sew Hoy, CEO and Founder of Tiny Health. “Research now shows that the first 1,000 days can profoundly shape a child’s lifelong health, and growing awareness among both parents and medical professionals means families can benefit from these insights much earlier.”

Broader Health Impact

According to the CDC, over 100 million Americans have eczema, food allergies, or hay fever, and 28 million have asthma. Annual costs related to asthma alone surpass $81 Billion. This study reinforces the microbiome’s role in immune health – and offers a proactive, evidence-based path to prevention to reduce national health and economic burdens.

Research Methodology, Limitations, and Next Steps

This randomized controlled trial ran from August 2023 to May 2024, and included healthy, full-term infants born by C-section and under 3 months old at enrollment. Parents sent in their baby’s stool samples at the beginning and after three months and completed health surveys at multiple time points to track outcomes. Researchers used advanced shotgun metagenomic sequencing to analyze gut bacteria composition and function.

The research was conducted as an open-label trial, meaning participants knew whether they were receiving the intervention. No adverse effects were reported in either group during the study period.

Despite limitations including a focused sample size and short-term follow-up, this preliminary study’s statistically significant results are highly encouraging, with Tiny Health already advancing larger-scale studies to build upon these promising outcomes.

About Tiny Health

Tiny Health is the first and only precision microbiome wellness platform designed for lifelong health — from the first 1,000 days to the last. Founded in 2020 and built by microbiome scientists and physicians, Tiny Health uses shotgun metagenomics to deliver strain-level and functional microbiome insights. Its clinical-grade gut and vaginal tests help families and practitioners address the root causes of many chronic conditions with evidence-based interventions. Trusted by over 80,000 people, Tiny Health is redefining the microbiome as a cornerstone of personalized wellness. Learn more at tinyhealth.com.

Media Contact:
Hannah Goering
press@tinyhealth.com

Study Citation: Nieto PA, Nakama C, Trachsel J, et al. Improving immune-related health outcomes post-cesarean birth with a gut microbiome-based program: A randomized controlled trial. Pediatr Allergy Immunol. 2025; 36:e70182. doi:10.1111/pai.70182

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/2d4fddd9-c762-4080-8c39-2652750450f6

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide¹ with surgery being the first choice of treatment in appropriate cases. Due to increasing exposure to cigarette smoke, chronic obstructive pulmonary disease (COPD) is reported in 40–70% of lung cancer patients.^2,3 COPD is not only a major risk factor for lung cancer development,^2,4,5 but also increases postoperative morbidity and mortality following lung cancer resection.⁶

Risk stratification in lung cancer is essential for optimizing preoperative patient selection and minimizing postoperative morbidity and mortality. COPD severity assessed by the Global Initiative for Chronic Obstructive Lung Disease staging system (GOLD, grades I–IV)⁷ is an important predictor of perioperative morbidity. Specifically, patients with severe COPD (GOLD III–IV) are at a higher risk of poor postoperative outcomes compared to those with mild-moderate disease (GOLD I–II).^8,9

Previous studies showed that reduced forced expiratory volume in one second (FEV₁) and reduced diffusing capacity of carbon monoxide (DLCO) are significantly associated with postoperative complications and decreased long-term survival in non-small cell lung cancer (NSCLC) patients.¹⁰

Based on these considerations, preoperative rehabilitation programs aiming the improvement of lung function in COPD patients¹¹ have gained increasing attention as a potential strategy to enhance postoperative outcomes in high-risk lung cancer patients.¹² This increases the likelihood that lung cancer surgery will achieve positive outcomes in carefully selected patients with severe COPD and can be seen as an increasingly viable treatment option.^13–16 In clinical practice, a careful preoperative evaluation for surgical eligibility routinely includes pulmonary function tests (FEV₁ and DLCO), imaging studies (tumor topography, TNM classification and COPD severity), and the assessment of cardiopulmonary reserve (eg maximum oxygen consumption during physical exertion, VO₂max).

However, high volume studies providing a comparative analysis of COPD severity grades (I–II vs III–IV) in operable lung cancer patients focusing specifically on postoperative short-term and long-term survival are still lacking.

These are extremely important, as the number of lung resections with curative intent is increasing due to optimized surgical techniques. In addition, the prevalence of COPD has also increased, leading to an overall increase in COPD patients undergoing surgery for diagnosed lung cancer. For this high-risk group, it is crucial that perioperative management is continuously optimized.

The present study was conducted in a large thoracic surgery department and aimed to comprehensively characterize operable lung cancer patients with varying degrees of COPD severity (I–IV) in order to gain valuable insights. Known predictors influencing postoperative complications and perioperative outcome were examined in a large cohort and new predictors were identified. In addition, postoperative morbidity, mortality and independent predictors of shortened long-term survival were examined in detail.

Materials and Methods

Study Design and Population

This single center retrospective study was conducted at the Lung Tumor Center Munich, Department of Thoracic Surgery of Asklepios Lung Clinic Gauting, Germany, between January 1^st 2011 and December 31^st 2020. Ethical approval was obtained from the Ethics Committee of the Ludwig-Maximilians-University Munich (reference number 21-0036). The study included all patients with operable primary NSCLC, undergoing curative anatomical resections (segmentectomy, lobectomy, bilobectomy or pneumonectomy). Patients undergoing anatomical resections for non-malignant lesions and lung cancer patients undergoing wedge resection were excluded. For patients having had more than one tumor resection, only the first operation was considered for analysis purposes. Conversely, patients who did not receive a diagnosis of COPD were excluded from the study (Figure 1).

Figure 1 Study flow chart illustrating patient enrollment at study entry. 1663 patients undergoing anatomical resections between January 1st 2011 and December 31st 2020, 1187 (71.4%) patients without COPD were excluded from the study. Thus, 476 patients (28.6%) with operable primary lung tumors and COPD were included. Based on the GOLD classification of COPD,7 patients were categorized into two groups: Group 1 with mild or moderate obstruction (COPD grade I–II, 409 patients, 85.9%) and Group 2 including patients with severe obstruction (COPD grade III–IV, 67 patients, 14.1%). Abbreviation: COPD: chronic obstructive pulmonary disease.

Data Assessments/Sources

Clinical parameters were extracted from patient files, as well as from the Munich Cancer Registry. Preoperatively, all patients were staged according to the National Comprehensive Cancer Network (NCCN) guidelines.¹⁷ Patients underwent pre- or intraoperative bronchoscopy, pathological lymph node evaluation and FDG-PET/CT scan. Meanwhile, the method of choice for lymph node evaluation was EBUS-TBNA. In the past, a mediastinoscopy was performed in cases of suspected lymph node involvement. Patients with clinical stage II or more also receive a cranial MRI. NSCLC were classified according to the 7^th edition of the Tumor Node Metastasis (TNM) staging system^18,19 and The Union for International Cancer Control (UICC),²⁰ while histopathological specimens were analyzed according to the World Health Organization Classification of lung tumors (2015).²¹ The decision regarding the administration of curative surgical therapy, taking into account the tumor stage, performance status and cardiopulmonary condition, was discussed in the interdisciplinary tumor board in accordance with the guidelines.¹⁷

Clinical parameters included demographics such as age at resection, sex, body mass index (BMI), smoking status, pack-years (PY), comorbidities, American Society of Anesthesiologists (ASA) Score and the Charlson Comorbidity Index (CCI),²² laboratory (blood counts, C-reactive protein (CRP), creatinine, lactate dehydrogenase (LDH), albumin, neuron specific enolase (NSE), cytokeratin fraction 21-1 (CYFRA 21-1), carcinoembryonic antigen (CEA), pro-gastrin-releasing peptide (proGRP), respiratory vital capacity (VC), forced expiratory volume in one second (FEV₁), diffusing capacity of the lung for carbon monoxide (DLCO) and maximum rate of oxygen consumption during physical exertion (VO₂max), performed according to the ESTS Guidelines only in patients with impaired lung function (FEV₁ or DLCO<60%). Tumor characteristics were assessed according to the pathological (pTNM) tumor stage, histopathological type, tumor location, as well as tumor grading. Data regarding surgical approach (eg minimally invasive vs open surgery, extent of anatomical resection, surgical and anesthesia time, intraoperative blood loss), as well as postoperative morbidity, intensive care unit (ICU) stay and mortality were collected.

COPD severity was classified according to the Global Initiative for Obstructive Lung Disease (GOLD) criteria based on preoperative spirometry⁷ with FEV₁/ FVC<0.7 and FEV₁≥80%/<80%/<50% and /< 30% as a percentage of the predicted value for grade I/II/III and IV, respectively. The diagnosis of COPD and its severity were taken from the patient files.

The follow-up of the patients was carried out in conjunction with regular tumor follow-ups, in accordance with the guidelines.¹⁷ These take place every three months for the first two years after surgery, then every six months until the fifth year and then every year. Patients who received adjuvant therapy postoperatively were followed up during this therapy. With regard to mortality, all patient data was updated with the help of the death register or by contacting patients’ relatives.

Endpoints and Outcomes

The primary endpoint of the study was the comparative analysis of clinical parameters stratified by COPD severity in patients with operable NSCLC, to comprehensively characterize the patient cohort with NSCLC and COPD.

The secondary endpoint of the study was the uni- and multivariable survival analysis of operable NSCLC patients in relation to COPD severity, to identify significant predictors for postoperative complications and mortality.

Based on the above-mentioned endpoints, the outcome of the study was defined as long-term overall survival in operable patients with lung cancer and COPD.

Statistical Analysis

Based on GOLD criteria for COPD severity,⁷ patients were divided into Group 1 (mild or moderate obstruction, COPD I–II) and Group 2 (severe obstruction, COPD III–IV). A descriptive analysis of clinical demographics, laboratory, lung function and histological parameters was performed. Continuous variables were presented as median and interquartile range (IQRs/ 1^st quartile-3^rd quartile) or mean (± standard deviations). Group comparisons (COPD I–II vs COPD III–IV) were performed using the Mann–Whitney U-test for continuous variables (eg age, BMI, PY, laboratory and lung function parameters) and chi-square or Fisher’s exact test for categorial variables (Tables 1–5).

Table 1 Demographic Characteristics of Study Population

Table 2 Preoperative Laboratory Parameters of Study Population

Table 3 Pathological Characteristics of Study Population

Table 4 Technical Aspects of the Surgical Approach

Table 5 Postoperative Morbidity and Mortality of Study Population

Univariate survival analysis evaluated overall survival (OS) and disease-free survival (DFS). OS was defined as time from surgical resection of the lung tumor to the last contact (censoring) or death (event). DFS was defined as the time interval between lung resection and the first documented relapse. Long-term survival probabilities were calculated using Kaplan–Meier survival analysis by using Log rank test (Mantel-Cox, Figures 2 and 3).

Figure 2 Kaplan–Meier survival analysis including patients at risk, reported events (death) and patients censored (October 2024) illustrating the overall survival of the whole cohort (A), according to COPD severity (B), serum C-reactive protein levels on admission preoperatively (C), VO2max preoperatively (D), tumor stage of the intraoperative specimens (E), as well as hilar or mediastinal lymph node involvement of the intraoperative specimens (F). Comparison of the survival estimates was analyzed by Log rank test. Values of p<0.05 were considered significant. Abbreviations: OS, overall survival; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; VO2max, maximum rate of oxygen consumption during physical exertion; pT, tumor stage of the intraoperative specimens according to the TNM7;19 pN1-2+, hilar or mediastinal lymph node involvement of the intraoperative specimens according to the TNM7.19

Figure 3 Kaplan–Meier survival analysis including patients at risk, reported events (death) and patients censored (October 2024) illustrating the disease-free survival of the whole cohort (A), according to COPD severity (B), serum C-reactive protein levels on admission preoperatively (C), VO2max preoperatively (D) tumor stage of the intraoperative specimens (E), as well as hilar or mediastinal lymph node involvement of the intraoperative specimens (F). Comparison of the survival estimates was analyzed by Log rank test. Values of p<0.05 were considered significant. Abbreviations: DFS, disease-free survival; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; VO2max, maximum rate of oxygen consumption during physical exertion; pT, tumor stage of the intraoperative specimens according to the TNM7;19 pN1-2+, hilar or mediastinal lymph node involvement of the intraoperative specimens according to the TNM7.19

A multivariable survival analysis was performed by Cox proportional hazard model to investigate the independent predictive role of COPD severity and other clinical parameters on survival (Figure 4, Table 6 and Supplementary Table S1). This analysis was reproduced using three selection methods (Enter, Forward Likelihood Ratio/Forward LR and Backward Likelihood Ratio/Backward LR) and validated using decision tree analysis with two independent algorithms (Classification and Regression Trees (CRT) and Quick, Unbiased, Efficient Statistical Tree (QUEST), Figure 4). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for independent predictors. Cut-off values were derived using receiver-operator characteristics (ROC) analysis and the Youden criterion. All analyses were performed after excluding missing data from the database using SPPS software (Version 26, IBM, Armonk, New York, USA). P-values <0.05 were considered as statistically significant.

Figure 4 Multivariable Cox proportional hazard model including patients at risk, reported events (death) and patients censored (October 2024) illustrating the survival plot (A) and hazard plot (B) of patients experiencing COPD III–IV, large tumors (pT3-4), hilar or mediastinal lymph node involvement (pN1-2+), serum CRP>0.6 mg/dL and VO2max<17 mL/min/kg as significant independent predictors of worse long-term OS. Decision tree analysis including the independent predictors of OS with absolute values (n) and percentages indicating death events for each condition/ node (C). Cox regression analysis was performed by Enter, Forward Likelihood Ratio and Backward Likelihood Ratio selection methods. Decision tree analysis was performed using two algorithms (Classification and Regression Trees/CRT; Quick, Unbiased, Efficient Statistical Tree/ QUEST). Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein levels; VO2max, maximum rate of oxygen consumption during physical exertion; pT, tumor stage of the intraoperative specimens according to the TNM7;19 pN1-2+, hilar or mediastinal lymph node involvement of the intraoperative specimens according to the TNM7.19

Table 6 Cox Proportional Hazard Regression Analysis

Results

Study Population

The patient selection process is depicted in Figure 1. Of 1663 patients admitted for anatomical resections of the primary lung tumor, 476 patients with COPD (193/40.5% female, 283/59.5% male, median age 67.28 [60.57; 73.27] years) were included. 149 patients (31.3%) had a history of COPD I, 260 patients (54.6%) COPD II, 66 patients (13.9%) COPD III and one patient (0.2%) COPD IV. Group 1 (COPD I–II) comprised 409 patients (85.9%) and Group 2 (COPD III–IV) 67 patients (14.1%).

Demographic Characteristics

Patient demographics are presented in Table 1. The entire cohort was characterized by a homogenous BMI 25.66 [22.44; 29.07] kg/m² and nicotine consumption (40.1% active smokers, 40.00 [30.00; 60.00] PY) without significant differences between groups. Isolated or combined comorbidities, as assessed by CCI,²² were not significantly associated with COPD severity in both groups. While lung function parameters were significantly lower in Group 2 (COPD III–IV, Table 1), preoperative laboratory parameters were not associated with COPD severity (Table 2).

Primary Tumor Characteristics and Surgical Approach

The primary tumor characteristics are summarized in Table 3. Tumors were homogenously distributed on both sides of the lungs, irrespective of COPD severity (right side 58.2% in Group 1 and 62.7% in Group 2). The most common tumor localization was the upper lobes (right upper lobe 34.0% in Group 1 and 34.3% in Group 2; left upper lobe 26.2% in Group 1 and 28.4% in Group 2). A homogenous distribution for all tumor stages (pT_1-4) was reported, with pT₂ being the most frequent stage (44.5% in Group 1 and 45.3% in Group 2), corresponding to UICC stage I (50.3% in Group 1 and 53.7% in Group 2). No significant differences in the distribution of histological subtypes and differentiation grades of the primary tumor were observed between groups.

The characteristics of the surgical approach were summarized in Table 4. In the majority of cases, an open surgical approach was performed (64.3% in Group 1 and 55.2% in Group 2). Conversion to open surgery was required in 11.0% of patients in Group 1 and 13.4% in Group 2. Regarding the extent of the surgical procedure, Group 2 patients underwent more frequently segmentectomies in comparison to Group 1 patients (3.9% vs 16.4%, p<0.001).

Independent of COPD severity, surgery time was comparable between groups, with a median surgery time of 182.00 [145.25; 220.00] minutes in Group 1 and 187.50 [142.25; 225.50] minutes in Group 2. Similarly, median blood loss was 400 [300.00; 500.00] mL in both groups, with no significant differences reported (p=0.423, Table 4).

Perioperative Morbidity and Mortality

The perioperative patient care was comparable between groups. The cumulative volume of the pleural fluid drained via chest tubes was not significantly different between groups (median volume 1930.00 [1250.00; 2800.00] mL). The chest tube was removed after 6 [5.00; 8.00] days. Mortality during follow-up was significantly higher in Group 2 (61.2% vs 45%, p=0.0014). A detailed description of postoperative morbidity and mortality is provided in Table 5.

Group 2 patients experienced a higher frequency of prolonged air leaks (>5 days, 8.7% in Group 1 and 17.9% in Group 2, p=0.020). The most common postoperative complications were pneumonia (16.1% in Group 1 and 26.9% in Group 2, p=0.032), prolonged invasive ventilation (>2 days, 3.7% in Group 1 and 10.4% in Group 2, p=0.016), arrhythmias (8.2% in Group 1 and 17.9% in Group 2, p=0.012) and secondary wound infections (1.2% in Group 1 and 4.5% in Group 2, p=0.057, Table 5). Consecutively, the in-hospital stay in Group 2 patients was significantly longer when compared to Group 1 patients (15.0 [12.0; 20.0] days in Group 1 vs 18.0 [15.0; 27.0] days in Group 2, p=0.0004, Table 5).

Univariate Analysis of Risk Factors

Overall Survival

Overall, 225 death events were reported during 1955 follow-up years. The median overall survival (OS) for the entire cohort was 75.5 [62.7–88.2] months (Figure 2A).

Patients aged 65 years or older had a significantly decreased OS compared to younger patients (5-year OS: 52.6% vs 62.8%, p=0.002). Male patients had a significantly worse prognosis compared to female patients (5-year OS: 52.4% vs 63.4%, p=0.023).

Patients with COPD III–IV had a significantly decreased OS in comparison to patients with COPD I–II (5-year OS: 44.0% vs 59.0%, p=0.001, Figure 2B). Correspondingly, mortality was significantly higher in patients with COPD III–IV in comparison to COPD I–II patients (61.2% vs 45.0%, p=0.014, Table 5).

Patients with the following comorbidities experienced significantly decreased OS compared to those without: lung fibrosis (5-year OS: 12.5% vs 57.8%, p<0.001), arterial hypertension (5-year OS: 51.6% vs 63.1%, p=0.020), ischemic heart disease (5-year OS: 44.5% vs 58.8%, p=0.046), peripheral arterial disease (5-year OS: 37.7% vs 59.0%, p=0.006), and moderate-severe kidney insufficiency (5-year OS: 51.0% vs 56.9%, p=0.044). Reflecting the multimorbidity of patients with lung cancer and COPD, an ASA score >2 and a CCI>2 were associated with decreased OS (5-year OS for ASA score >2: 55.1% vs 67.4%, p=0.010 and 5-year OS for CCI>2: 54.4% vs 65.9%, p=0.014, respectively).

Laboratory parameter associated with decreased OS included: serum CRP>0.6 mg/dL (5-year OS: 44.8% vs 69.2%, p<0.001, Figure 2C), albumin<3.75 mg/dL (5-year OS: 49.2% vs 64.8%, p=0.015) and creatinine>1.2 mg/dL (5-year OS: 45.4% vs 60.6%, p=0.005). A serum CYFRA 21–1 level >1.96 ng/mL was associated with decreased OS (5-year OS: 50.9% vs 64.2%, p=0.003). Patients with VO₂max>17 mL/min/kg had a better prognosis compared to those with lower VO₂max values (5-year OS: 61.2% vs 51.1%, p = 0.025, Figure 2D).

While topography of the primary tumor was not associated with OS, the following tumor characteristics were significantly linked to decreased OS: large tumors (5-year OS: pT_3-4 38.0% vs pT_1-2 61.6%, p<0.001, Figure 2E), lymph node involvement (5-year OS: pN_1-2 36.5% vs pN₀ 66.5%, p<0.001, Figure 2F), presence of metastasis (5-year OS: M₀ 58.3% vs M₁15.0%, p<0.001), non-adenocarcinoma histological subtypes (5-year OS: 60.4% vs 51.7%, p=0.046) and low differentiation grade (5-year OS: G₃ 48.8% vs G_1-2 63.4%, p = 0.010). Patients undergoing open surgery had significantly worse OS compared to those treated with minimally invasive techniques (5-year OS: open surgery 49.3% vs VATS 69.9%, p<0.001).

Patients experiencing major complications had significantly worse OS when compared to those patients without: acute thromboembolism (5-year OS: 0% vs 57.6%, p=0.001), hoarseness due to recurrent laryngeal nerve paralysis (5-year OS: 0.0% vs 57.7%, p<0.001), prolonged intubation (5-year OS: 30.7% vs 58.3%, p=0.003), re-intubation (5-year OS: 29.1% vs 58.7%, p<0.001) or tracheotomy (5-year OS: 0.0% vs 57.5%, p<0.001). Patients experiencing a postoperative local relapse (5-year OS: 31.6% vs 63.5%, p<0.001) or tumor progress (5-year OS: 27.6% vs 63.5%, p<0.001) demonstrated a significantly decreased OS.

Disease Free Survival (DFS)

We identified 77 tumor relapses (16.2%) in cumulatively 1812 years of follow-up. The mean DFS for the entire cohort was 134.94 [128.57–141.32] months (Figure 3A) and for patients experiencing tumor relapse 16.27 [12.77–19.78] months.

The 5-year DFS in patients with COPD III–IV was lower in comparison to the patients with COPD I–II (72.5% vs 81.2%, p=0.059, Figure 3B).

Preoperative laboratory (eg CRP>0.6 mg/dL, Figure 3C) and lung function parameters (eg VO₂max>17 mL/min/kg, Figure 3D) were not significantly associated with tumor relapse. Patients with serum CYFRA 21–1 levels >1.96 ng/mL had a significantly lower DFS when compared to those with lower CYFRA 21–1 levels (5-year DFS: 75.7% vs 82.5%, p=0.041).

Patients with large tumors (pT_3-4, 5-year DFS 60.8%), lymph node involvement (pN_1-2, 5-year DFS 64.8%), presence of metastasis (M_1, 5-year DFS 45.8%) and low differentiated tumors (G₃, 5-year DFS 75.7%) had a significantly decreased DFS when compared to the patients with smaller tumors (pT_1-2, 5-year DFS 85.4%, p<0.001, Figure 3E), without nodal (5-year DFS 86.3%, p<0.001, Figure 3F) or extranodal metastatic disease (5-year DFS 80.9%, p=0.007) or high differentiated tumors (G_1-2, 5-year DFS 83.2%, p=0.035).

Anatomical resections were significantly linked to DFS (5-year DFS: lobar resections 82.4% vs multilobar resections 67.5%, p=0.003). Among postoperative complications, hoarseness due to recurrent laryngeal nerve paralysis was the only complication significantly associated with decreased DFS (5-year DFS: 0.0% vs 80.5%, p=0.018).

Multivariable Analysis of Risk Factors

Multivariable Cox regression analysis identified the following parameters as independent negative predictors of long-term OS: COPD III–IV (Group 2), large tumors (pT_3-4), hilar or mediastinal lymph node involvement (pN_1-2), as well as elevated serum CRP levels (>0.6 mg/dL) and decreased VO₂max<17 mL/min/kg (Figure 4A, B and Table 6). These predictors increased the risk of death by 1.6-, 1.3-, 2.1-, 1.6-, and 1.4-fold, respectively (Figure 4A, B and Table 6). These results were reproduced using three selection methods (Enter, Forward LR and Backward LR) and further validated using decision tree analyses with two independent algorithms (CRT, QUEST, Figure 4C). Accordingly, COPD severity showed a significant role in patients with normal CRP levels (<0.6 mg/dL) and no lymph node involvement (pN_0, Figure 4C). The regression model is summarized in Table 6.

The robustness of the abovementioned predictors was further analyzed in relation to clinically relevant confounders, previously insufficiently characterized in combination with COPD severity, TNM staging, lung function, and laboratory parameters. When considering age >65 years, sex, BMI, nicotine consumption, histology, operative approach and surgical extent as potential confounders, the multivariable analysis showed qualitatively unchanged results (Supplementary Table S1). Importantly, these results were validated through two multivariable models, demonstrating robustness and consistency in our findings.

Disscusion

The aim of the study was to comprehensively characterize a cohort of patients with operable lung cancer and varying COPD grades to identify independent predictors of reduced long-term overall survival (OS) and optimize preoperative risk stratification and patient care. This study was conducted in a high-volume thoracic surgery clinic comprising 1663 operable lung cancer patients with co-occurring COPD (28.6%) in line with previous reports.^23–25 The distribution of COPD grades (I/II/III/IV-31.3%/ 54.6%/13.9%/0.2%) was in line with previous findings (I/II/III-50.6%/42.0%/7.4%²⁵). This concordance demonstrates the validity of our results and allows for further considerations.

The present study specifically analyzed well-established clinical parameters including preoperative laboratory and lung function tests, comorbidities, as well as radiological, histological tumor and surgical characteristics, in relation to short and long-term postoperative outcomes. Accordingly, the univariate analysis stratifying patients into two COPD severity groups, showed no significant differences in laboratory parameters, BMI, smoking history or associated comorbidities. These findings are consistent with previous studies, reporting that the coexistence of COPD in lung cancer patients was independent of factors such as age, sex and smoking history.^3,24

No significant differences were observed in our study regarding the topography, TNM classification, histological subtypes and differentiation grades of the primary tumors. These findings are consistent with previous studies, reporting no significant correlation between COPD severity and TNM stage. This suggests that lung function alterations do not directly influence tumor size, lymph node involvement, or metastasis.⁶ Regarding the relationship between histological subtypes and COPD severity, prior studies have reported contradictory results. While some studies observed an increased frequency of squamous cell carcinoma in COPD patients,^26–28 others found no specific histological correlation with COPD.²⁹

Although no association between surgical approaches (open vs minimally invasive) and COPD severity was observed, COPD III–IV patients underwent more frequently segmentectomies. These results align with previous studies addressing the outcomes of the surgical approach,^30,31 and the increased frequency of segmentectomies in patients with compromised lung function.³² Although segmentectomy has been proposed as a feasible treatment option for patients with impaired lung function, limited data are available addressing this approach in patients with varying COPD grades. Our study shows that the increased frequency of segmentectomies in COPD III–IV patients reflect their significantly reduced lung function (Table 1) and clinical condition, in line with existing evidence supporting sublobar resections in high-risk patients.^30,33–35 Accordingly, Yang et al found comparable survival probabilities for patients undergoing segmentectomies, when compared to those undergoing lobectomies.³²

Reflecting functional and radio-morphological alterations (eg air trapping, incomplete fissures), patients suffering from severe COPD experienced more frequently a prolonged air leak, as well as respiratory and cardiac complications, further validating adverse postoperative events reported in other surgical cohorts.^8,25

The abovementioned parameters were incorporated in a survival analysis considering COPD severity and relevant clinical confounders. This analysis identified serum levels of CRP>0.6 mg/dL, albumin>3.75 g/dL, creatinine>1.2 mg/dL and CYFRA 21–1>1.96 ng/mL as significant risk factors for a decreased OS. These associations were in line with previous studies, showing worse outcomes in lung cancer patients with elevated inflammatory parameters (>0.4 mg/dL³⁶), impaired kidney function (creatinine>1.2 mg/dL^37,38) or increased tumor markers (CYFRA 21–1>4.18 ng/mL³⁹). Similarly, our study identified a VO₂ max<17 mL/min/kg as significant factor for reduced OS in accordance with prior findings (VO₂max<12 mL/min/kg⁴⁰ or <15 mL/min/kg⁴¹).

Additional clinical parameters associated with worse OS included male sex, age >65 years and the presence of comorbidities such as respiratory diseases (eg lung fibrosis), cardiovascular conditions (eg arterial hypertension, ischemic heart disease), peripheral vascular disease and severe chronic kidney disease.^42–46 These widely documented associations suggest that lung cancer patients with COPD often experience a higher burden of comorbidities, negatively affecting survival. In line with this comorbidity profile, an ASA>2 and a CCI>2 were also identified as risk factors for reduced survival in our study. Although these associations are well-established in broader patient populations, there are no studies addressing all these risk factors together in lung cancer patients with varying COPD grades, making our findings particularly valuable.

In line with studies reporting the non-inferiority of minimally invasive procedures compared to open approaches in patients with operable lung cancer,^47–49 our study specifically demonstrated a survival benefit upon minimally invasive procedures in the subgroup of lung cancer patients with COPD. This particular aspect of our study underlines the importance of less invasive and painful surgical approaches in patients with relevant comorbidities and impaired lung function.

Consistent with previous studies, large tumors (pT_3-4), lymph node involvement (pN_1-2), presence of metastasis (M₁), non-adenocarcinoma histology, a low differentiation grade (G₃) and local tumor relapse were associated with worse survival outcomes.^50–53 Moreover, acute thromboembolism and prolonged mechanical ventilation were confirmed as negative predictors of OS, aligning with previous findings^54–56 in patients with associated respiratory⁴⁵ and cardiac comorbidities.⁵⁷

The abovementioned OS probabilities were in line with significantly reduced DFS estimates in patients experiencing elevated CYFRA 21–1 levels, large tumors (pT_3-4), lymph node involvement (pN_1-2), metastasis (M₁) or a low tumor differentiation grade (G₃). Patients undergoing lobar resections showed an improved DFS compared to those undergoing multilobar resections, highlighting the critical role of parenchymal sparing surgery in patients with compromised lung function.^14,15,58

The clinically meaningful parameters that were found to be significant in the univariate survival analysis were included in the multivariable Cox regression analysis to show their independent predictive value. This analysis revealed COPD III–IV, pT_3-4, pN_1-2 as well as CRP>0.6 mg/dL and VO₂max<17 mL/min/kg as significant independent predictors of worse long-term OS, increasing the risk of death by 1.6-, 1.3-, 2.1-, 1.6-, and 1.4-fold, respectively. These findings provide additional value in comparison to previous reports identifying only COPD severity and tumor growth as independent predictors of OS in lung cancer patients.^50,59–61

Notably, these predictors and confounders represent clinically established parameters that are routinely collected on hospital admission in most Thoracic Surgery, Pneumology and Oncology departments. Their routine availability underscores their potential usefulness as practical tools for preoperative risk assessment and patient selection for surgical treatment.¹⁴

From a clinical point of view, COPD is a progressive, irreversible and life-threatening disease that significantly worsens the prognosis of lung cancer patients. Beyond increasing the risk of lung cancer (4-to 6-fold higher, with an annual incidence of 0.8–1.7%^1,27,29–31), COPD contributes to tumor progression through mechanisms such as chronic inflammation, immunosuppression, oxidative stress, tissue remodeling, epithelial to mesenchymal transition, and smoking-related tissue damage.^2,4,62,63 As a result, the co-occurrence of COPD in lung cancer patients represent a challenge in the perioperative patient management resulting in higher morbidity and mortality. Our results are consistent with previous studies and confirm that COPD patients have an increased risk of developing postoperative complications such as pneumonia, prolonged medical ventilation,⁴⁵ and cardiovascular events.⁴³ These risks emphasize the need for a rigorous preoperative cardiopulmonary and radiological evaluation, to determine the optimal extent of the surgical procedure.

The strength of our study lies in its comprehensive comparative analysis of a large cohort of patients with operable NSCLC and varying COPD severity. This aspect is particularly relevant, given the increasing prevalence of environmental and cigarette smoke exposure as major contributors to both COPD and lung cancer. Unlike previous studies primarily addressing patients with mild/moderate obstruction, our cohort includes a representative subgroup of patients with severe COPD, and thus provides valuable insights into an underrepresented patient cohort previously insufficiently characterized. This is of particular interest in the preoperative risk stratification and assessment of surgical eligibility.

Notably, our study observed a higher frequency of segmentectomies in COPD III–IV patients, highlighting the importance of adopting individualized, less invasive surgical approaches for patients with relevant comorbidities and severely impaired lung function.

Moreover, identifying high-risk patients may help in selecting candidates for preoperative rehabilitation programs designed to improve preoperative lung function and patient condition.^11,14,64,65 These aspects are particularly relevant to assess the appropriate extent of surgery as well as improve postoperative outcomes.

The present study has several limitations. First, due to the retrospective nature of the manuscript, which included patients from 2011 to 2020, it was not always possible to collect complete data for all patients or prospectively assess variables for the specific purpose of this study. However, missing data were found to be <10% for the majority of the selected variables, thus reducing the likelihood for non-significant results. One exception was VO2max, since assessment of the cardiopulmonary condition was performed according to ESTS Guidelines only in patients with impaired lung function (FEV1 or DLCO<60%). When excluding VO2max from the analysis, the cox proportional hazard model turned out qualitatively unchanged results validated by three selection methods (Enter, Forward LR and Backward LR).

Second, the number of patients with severe COPD limited the multivariable regression analysis to a maximum of six variables, selected based on clinical relevance.

Conclusions

In summary, this study performed a comprehensive descriptive analysis of operable lung cancer patients with varying COPD grades, and identified a panel of clinically meaningful parameters significantly associated with COPD severity and long-term survival. These predictors may help in preoperative risk stratification and assessment of surgical extent, particularly given the increased postoperative morbidity and mortality observed in lung cancer patients with COPD. For future research, we recommend validating our results in multicenter randomized controlled trials to consolidate the findings.

Abbreviations

ARDS, acute respiratory distress syndrome; ASA, American Society of Anesthesiologists; BMI, body mass index; CEA, carcinoembryonic antigen; CCI, Charlson Comorbidity Index; CIs, confidence intervals; CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease; CRT, Classification and Regression Trees; CYFRA 21-1, cytokeratin fraction 21–1; DFS, disease-free survival; DLCO, diffusing capacity of the lung for carbon monoxide; FEV₁, forced expiratory volume in one second; GOLD, Global Initiative for Obstructive Lung Disease; HRs, Hazard ratio; ICU, Intensive care unit; IQRs, interquartile range; LDH, lactate dehydrogenase; LMU, Ludwig-Maximilians-University of Munich; LR, Likelihood Ratio; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; NSE, neuron specific enolase; OS, overall survival; pM, Metastasis of the intraoperative specimen; pN, Lymph node status of the intraoperative specimen; proGRP, pro-gastrin-releasing peptide; pT, Tumor stage of the intraoperative specimen; PY, pack-years; QUEST, Quick, Unbiased, 205 Efficient Statistical Tree; RNL, recurrent laryngeal nerve;; ROC, receiver-operator characteristics; TIA, transient ischemic attack; TNM, Tumor node metastasis staging system; VATS, video-assisted thoracoscopic surgery; VC, vital capacity; VO2max, maximum oxygen consumption during physical exertion; UICC, The Union for International Cancer 157 Control; WHO, World Health Organization; ROC, receiver operating characteristics.

Data Sharing Statement

The datasets of the current study are available from the corresponding author upon reasonable request.

Ethics Approval and Consent to Participate

Approval for this retrospective, non-interventional study was obtained from the Ethics Committee of the Ludwig-Maximilian’s University Munich (LMU), Germany (reference number 21-0036). This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local ethical and legal requirements. A database with the parameters collected was created for the study. The names of the patients and all other confidential information are subject to medical confidentiality and the provisions of the Federal Data Protection Act (BDSG). Personal data and findings about the patient were collected, stored, encrypted (pseudonymized) and stored in the shared database at the University of Ludwig Maximilian University. The administration of the data was carried out by the applicant or study director as the person responsible for the study. The need for written informed consent was waived by the above-mentioned ethics committee due to retrospective nature of the study.

Acknowledgments

We thank all colleagues from the Asklepios Lung Clinic Gauting, Germany, Departments of Thoracic Surgery, Radiology, Pneumology and Pathology for excellent clinical patient care, clinical expertise and support in the data collection.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

There is no funding to report.

Disclosure

Prof. Dr. Niels Reinmuth reports personal fees from Amgen, personal fees from Astra Zeneca, personal fees from Bristol-Myers Squibb, personal fees from Boehringer-Ingelheim, personal fees from Daiichi-Sankyo, personal fees from GlaxoSmithKline, personal fees from Hoffmann-La Roche, personal fees from Janssen, personal fees from Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Sanofi, personal fees from Takeda, outside the submitted work. The authors declare no conflict of interest.

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Daily use of an interferon-alpha (IFN-α) nasal spray lowers the risk of COVID-19 infection in adults with cancer, a new randomized controlled trial finds.

For the multicenter study, published last week in Clinical Infectious Diseases, researchers at the University of Melbourne in Australia randomly assigned participants to receive daily IFN-α nasal spray (217 participants) or a saline placebo (216) from December 2020 to April 2023. Participants had solid-tumor or blood cancer with no history of COVID-19 infection.

Participants who developed influenza-like symptoms in the 90 days after randomization collected nasal swabs for polymerase chain reaction (PCR) testing for COVID-19, influenza A/B, respiratory syncytial virus, parainfluenza, adenovirus, seasonal coronavirus, picornavirus, and/or human metapneumovirus, or they had COVID-19 rapid antigen testing. 

Study visits occurred at 30, 60, and 90 days, at which time participants provided blood samples and completed a questionnaire. 

“Preventative measures, such as vaccination and monoclonal antibodies, have dramatically improved outcomes but many cancer populations experience breakthrough infections and have suboptimal vaccine responses,” the authors wrote.

Lower rates in younger, female, vaccinated patients

The COVID-19 infection rate was lower in the IFN-α group than in placebo recipients (8.3% vs 14.4%), for a 40% reduced risk. The incidence of other viral respiratory infections was 5.1% in both groups, but the case numbers were too low to reach a conclusion about efficacy. 

There may be a role for short-term IFN-α nasal spray in addition to vaccination and monoclonal antibodies in preventing COVID-19.

In the 389-person per-protocol cohort, rates of COVID-19 infection in IFN-α and placebo recipients were 7.7% and 16.0%, indicating half the risk. Other respiratory virus incidence was 4.6% and 5.7% in the two groups, respectively. 

A subgroup analysis demonstrated lower COVID-19 incidence in IFN-α recipients younger than 65 years (relative risk [RR], 0.48), women (RR, .44), and vaccinated recipients (RR, 0.50) but no difference by cancer type, disease severity, hospitalization, or death. IFN-α was well tolerated.

The researchers noted that IFN-α has antiviral, antimicrobial, antiproliferative, and immunomodulatory effects. “There may be a role for short-term IFN-α nasal spray in addition to vaccination and monoclonal antibodies in preventing COVID-19,” they wrote.

Bottom line: This study discovered a circuit in the brain that connects stress with increased glucose and therefore may link stress to type 2 diabetes. In stressful situations, this circuit from the amygdala to the liver naturally provides a burst of energy. When introducing chronic stress and a fatty diet, researchers observed a disruption in the circuit’s output, specifically, an excess of glucose production in the liver. Long-term elevations in glucose can cause hyperglycemia and increase the risk of developing type 2 diabetes.

Why this study is unique: This is the first time researchers have described the connection between the medial amygdala in the brain-a specific area of the amygdala that responds to stress-and liver glucose production. The study, conducted in an animal model, represents a new way of targeting diabetes and shows how important stress is as a driver of diabetes and increased mortality.

To date, most studies have focused on how the hypothalamus and brain stem regulate blood glucose. These are regions in the brain that are homeostatic, controlling functions like hunger, thirst, and digestion. Showing that the amygdala, an area traditionally associated with emotion, also controls blood glucose is a major shift in thinking.

Why the study is important: These findings have significant consequences for how we think about preventative medicine and the causes of illness, including stress and social determinants of health. People admitted to the hospital with abnormal glucose responses (too high or too low) experience significantly higher rates of complications and death. Additionally, it has been demonstrated that chronic stress is linked to an increased risk of type 2 diabetes, which affects 500 million people worldwide.

How the research was conducted: To understand how stress changes brain activity in the amygdala, researchers monitored neural activity in the medial amygdala in mice. They found that many different types of stress, from social stress to visual stress, increased the medial amygdala activity and as expected, increased the mice’s blood glucose.

They then switched on the medial amygdala neural activity in unstressed mice, which reproduced the same rise in glucose associated with stress, without causing stress-induced changes in behavior. This suggests that the circuit from the medial amygdala governs the glucose responses to stress.

Researchers then traced the neuronal connections from the medial amygdala through the hypothalamus to the liver, which showed that stress switched on the neurons connecting the medial amygdala and the hypothalamus, resulting in an increase in glucose released from the liver.

Results: The study showed that exposure to a range of acute stressors rapidly increases circulating blood glucose by 70 percent. At the time of the stress exposure, medial amygdala neuron activity was increased about twofold. Because this change in activity occurred before the change in blood glucose, we hypothesized that the medial amygdala could be driving this increase in glucose. To test this, researchers switched on medial amygdala neurons in unstressed mice, resulting in a 50 percent increase in blood glucose.

To determine the mechanism through which neural activity in the medial amygdala increased blood glucose, we used viruses to identify and map the neural circuits involved and found that medial amygdala neurons have major connections through the hypothalamus to the liver. When we switched on the amygdala connections to the hypothalamus, the amount of glucose released from the liver almost doubled.

Furthermore, researchers found that a combination of repeated stress and fatty diet altered the circuit between the medial amygdala and liver, resulting in long-term increased glucose, even when the mice were no longer exposed to stress. The research shows that, when exposed to repeated stressors, this circuit became desensitized, resulting in a decreased neural and glucose response to subsequent stress, pushing the mice toward diabetes.

These findings suggest that repeated stress disrupts the medial amygdala-to-hypothalamus-to-liver circuit, increasing liver glucose release.

What this study means for doctors and patients: This study gives clinicians a better understanding of the mechanisms linking stress and glucose control, opening new avenues to develop treatments to help reduce the risk of diabetes and improve glucose control for individuals with diabetes, particularly in individuals with elevated stress levels. By understanding the neural circuits through which stress controls glucose, we can identify therapies that help to regulate blood glucose and mitigate the risk of type two diabetes.

What the next steps are for this work: These findings suggest further research is required to study the medial amygdala-to-hypothalamus-to liver circuit in more detail, examine the types of neural cells involved, and observe how short-term and long-term stress changes the circuit structure and gene expression.

Additional research can also help understand if taking steps to reduce stress will reverse the disruption in the circuit, lowering the risk of diabetes and returning the circuit to healthy function.

Quotes: “The results of this study not only change how we think about the role of stress in diabetes, but also how we think about the role of the amygdala. Previously, we thought the amygdala only controls our behavioral response to stress-now, we know it controls bodily responses, too. The impact of stress on diabetes is enormous. But it’s not just diabetes: stress has broader impacts on many other conditions. This means that addressing the social determinants that contribute to stress may improve health, including diabetes” says Dr. Stanley.

Funding: This work was supported by the American Diabetes Association “Pathway to Stop Diabetes” Grant, and in part by grants from the National Institutes of Health and Department of Defense.

Compared with crushed ticagrelor, intravenous cangrelor provided immediate, effective platelet inhibition, with no increase in major bleeding and lower mortality rates in patients with acute myocardial infarction and cardiogenic shock, according to late-breaking research presented in a Hot Line session today at ESC Congress 2025.

Cardiogenic shock is a life-threatening condition in which the heart cannot pump enough blood to meet the body’s needs. It is present in around 4.6% of patients admitted to hospital for acute myocardial infarction (MI) and is associated with in-hospital mortality rates of 44%. Reperfusion using primary percutaneous coronary intervention (PCI) remains the only universal therapeutic approach that improves prognosis.

Achieving early and effective platelet inhibition is vital for reperfusion at the microcirculatory level in patients with MI complicated with cardiogenic shock. However, major randomized trials on the efficacy and safety of antiplatelet drugs have not included patients with cardiogenic shock. Currently, oral crushed ticagrelor tablets are given; however, the parenteral, direct-acting, reversible P2Y12 inhibitor, cangrelor, may address issues that occur during cardiogenic shock, including poor absorption and impaired liver metabolism. The DAPT-SHOCK-AMI trial – comparing IV cangrelor with crushed ticagrelor – is the first-ever randomized study evaluating the efficacy and safety of antiplatelet agents in this setting.”

Principal Co-Investigator, Professor Zuzana Motovska from the Charles University and University Hospital Kralovske Vinohrady, Prague, Czechia

This double-blind, placebo-controlled randomized trial was conducted at 29 sites in Czechia, France, Germany, Poland and Slovakia. Key inclusion criteria were acute MI with an indication for emergency primary PCI and cardiogenic shock that fulfilled at least two of: a) systolic blood pressure <90 mmHg in the absence of hypovolaemia, b) need for vasopressor and/or inotropic therapy and c) signs of organ hypoperfusion. Patients were randomized 1:1 to receive IV cangrelor (IV bolus of 30 μg/kg followed by a continuous infusion at 4 μg/kg) or oral ticagrelor (crushed tablets at a 180-mg loading dose and then a maintenance dose of 90 mg twice daily). In the cangrelor group, 30 minutes before the end of the cangrelor infusion, 180 mg of ticagrelor (crushed tablets) was administered, followed by a maintenance dose of 90 mg twice daily. Cangrelor-placebo and ticagrelor-placebo were administered in the same form as their active counterparts. The study medication was administered to all enrolled patients on top of concomitant aspirin. In total, 605 patients were randomized. The mean age was 65 years and 22.6% were women.

The primary laboratory endpoint (defined as platelet reactivity index <50% at the end of primary PCI) was achieved in 100% of patients with cangrelor and in 22.1% with ticagrelor (p for superiority<0.0001).

At 30 days, the primary clinical endpoint was not met: 37.6% of patients in the cangrelor group and 41.0% of patients in the ticagrelor group experienced all-cause death, MI or stroke (difference −3.5%, 95% confidence interval [CI] −11.2% to 4.3%; p for noninferiority=0.13).

The incidence of all-cause mortality at 12 months was 43.6% in the cangrelor group and 49.2% in the ticagrelor group (difference: −5.6%; 95% CI −13.5% to 2.4%), while the incidence of cardiovascular mortality was 26.8% and 33.2%, respectively ( −6.4%; 95% CI −13.7% to 0.9%).

The incidence of major bleeding at 30 days was 6.4% in the cangrelor group and 5.2% in the ticagrelor group (p=0.53).

Improvements were noted in primary PCI outcomes, periprocedural complications, early reinfarction and stent thrombosis rates with cangrelor compared with ticagrelor.

Principal Co-Investigator, Professor Deepak Bhatt from the Icahn School of Medicine at Mount Sinai, New York, USA, concluded: “Compared with crushed ticagrelor, IV cangrelor provided immediate, effective platelet inhibition and improved several secondary and exploratory clinical outcomes without increasing major bleeding. If verified in larger trials, IV cangrelor could represent a major advancement in the treatment of cardiogenic shock.”

Home-based hypertension care led to reductions in systolic blood pressure and improvements in hypertension control in South Africa, according to late-breaking research presented in a Hot Line session today at ESC Congress 2025 and simultaneously published in the New England Journal of Medicine.

Hypertension is the primary risk factor for stroke and heart disease, which are leading causes of death in South Africa. Despite the wide availability of low-cost, effective therapies, hypertension control remains extremely poor in resource-limited settings. Obstacles include a lack of patient confidence to manage their own hypertension care, overcrowded clinics with long wait times and the cost of transport to clinics. Our trial aimed to assess the effectiveness and implementation of reliable, home-based, technology-supported interventions to improve blood pressure control in low-resourced rural South Africa.”

Doctor Thomas Gaziano, IMPACT-BP trial’s Co-Principal Investigator, Mass General Brigham (MGB) and Harvard Medical School, Boston, USA

IMPACT-BP was an open-label, randomized controlled trial conducted at the Africa Health Research Institute (AHRI) in KwaZulu-Natal, South Africa, in which patients were recruited from two public-sector primary healthcare clinics. The implementation study was designed with Co-Principal Investigator, Doctor Mark Siedner of AHRI and MGH, Professor Nombulelo Magula of the University of KwaZulu-Natal, and the KwaZulu-Natal Provincial Department of Health.

Adult patients were eligible if they had evidence of uncontrolled hypertension as defined by South African Department of Health Guidelines: two measurements of systolic blood pressure (SBP) >140 mmHg and/or diastolic BP (DBP) >90 mmHg, taken a minimum of 6 months apart.

Patients were randomized to one of three strategies: 1) standard-of-care, clinic-based blood pressure (BP) management; 2) home-based BP self-monitoring supported by the provision of BP machines, community health workers (CHWs) who conducted home visits for data collection and medication delivery, and remote nurse-led care assisted by a mobile application with decision support; or 3) an enhanced CHW group in which BP machines included cellular technology to transmit BP readings automatically to the mobile application. The primary outcome was change in SBP from enrolment to 6 months.

In total, 774 patients were randomized. The mean age was 62 years, 76% were women, 14% had diabetes and 47% were living with HIV.

Compared with standard-of-care, mean SBP at 6 months was lower in the CHW group (−7.9 mmHg; 95% confidence interval [CI] −10.5 to −5.3; p<0.001) and the enhanced CHW group (−9.1 mmHg; 95% CI −11.7 to −6.4; p<0.001). In the standard-of-care group, hypertension control at 6 months was 57.6% compared with 76.9% in the CHW group and 82.8% in the enhanced CHW group. Improved BP with home-based care appeared to persist at 12 months.

Severe adverse events (2.7%) and deaths (1.0%) were uncommon overall and similar across groups. Retention in care remained more than 95% in both intervention groups, with patients reported to have enjoyed managing their own hypertension.

Summarising, Doctor Siedner said, “This study is an important example of how making models of chronic disease care more convenient – taking it from the clinic to patients’ homes and letting them play a major role in their own care – can substantially improve hypertension outcomes.”

Of particular value was that the programme was successful in a community that has historically had low access to care. Professor Magula concluded: “Achieving hypertension control in over 80% of people in a predominantly Black African community in rural South Africa is a clear example that equitable health care access can be achieved in disadvantaged communities. Similar models of care that address structural barriers could be considered to improve hypertension control in other remote and resource-limited settings. Expansion of the model to include the care of people with multiple comorbidities may also be valuable.”

For individuals diagnosed with early breast cancer, the long-term risk of developing a second primary cancer is low—around 2% to 3% greater than the general population)—according to findings published by McGale et al in The BMJ.

The researchers say this information can help reassure many breast cancer survivors who believe their risk of a second primary cancer is much higher than these results suggest.

Study Background and Methodology

Breast cancer survivors are at increased risk of developing second primary cancers, but risk estimates from previous studies are inconsistent. The risk and type of a second cancer can also be affected by the initial treatment received, as well as social, lifestyle, and genetic factors.

To address this uncertainty, British researchers used data from the National Cancer Registration and Analysis Service for England to estimate the long-term risks of second primary cancers compared with the general population, and the various factors associated with these risks.

Their findings are based on 476,373 women diagnosed in England from 1993 to 2016 with early invasive breast cancer at ages 20 to 75 years who underwent surgery.

Key Findings

Over a follow-up period of up to 20 years, 64,747 women developed a second primary cancer, but the absolute excess risks compared with risks in the general population were small. 

By 20 years, 13.6% of women had developed a nonbreast cancer (mainly uterine, lung, or colorectal cancer)—2.1% more than expected in the general population. Additionally, 5.6% had developed a contralateral breast cancer—3.1% more than expected.

When patients were grouped by age at first breast cancer diagnosis, the excess risk of a second nonbreast cancer varied little across age groups. However, the excess risk of a contralateral breast cancer was greater in younger than in older women. For example, for a woman whose first breast cancer was diagnosed at age 60, her estimated risks of developing a new cancer by the age of 80 were 17% for nonbreast cancer and 5% for contralateral breast cancer, compared to risks of 15% and 3%, respectively, for women of the same age in the general population. For a woman diagnosed at age 40, her estimated risks of developing a second cancer by the age of 60 were 6% for both nonbreast and contralateral breast cancer, compared to 4% and 2%, respectively, for women in the general population.

When patients were grouped according to other adjuvant treatments they received after surgery, radiotherapy was associated with higher rates of contralateral breast and lung cancers, endocrine therapy with uterine cancer (along with reduced contralateral breast cancer), and chemotherapy with acute leukemia.

Based on these results, the researchers estimate that around 7% of excess second cancers may be due to the use of adjuvant therapies but noted that their benefits outweigh this small risk in almost all circumstances where these treatments are recommended.

The authors acknowledged that their findings may be affected by incomplete cancer registry data for some variables. They also did not have information on family history, genetic predisposition, and lifestyle choices such as smoking.

Patient Opinions

Still, these results are reassuring and should be shared widely, said two patient authors in a linked opinion article, who noted that finding detailed information on the risks of second cancers after breast cancer was particularly difficult. In general, the benefits of treatments in protecting patients from recurrence of breast cancer far outweigh the potential downsides, the patients wrote, and such information should be available and offered by clinicians at the time that adjuvant therapies are discussed. They acknowledged that not everyone will want all the details at diagnosis, but say it should be there for those who do want it and for those who seek it later. “Information on risks should be readily available. It helps us to plan our lives and think ahead to the future,” they concluded.

Disclosure: For full disclosures of the study authors, visit bmj.com.