Welcome to the  9^TH Edition of The Clinical Chronicle!

August brings Lung Cancer and NTM Awareness, a reminder of how far medicine has come. What were once diagnoses with few or no options are now met with targeted therapies, immunotherapy, and precision diagnostics that are transforming survival and quality of life.

In this edition, we spotlight the FDA’s approval of zongertinib for HER2-mutant lung cancer, new evidence linking interstitial lung disease with cancer risk, and late-window thrombolysis in stroke from the HOPE trial. We also explore how CPAP’s cardiovascular impact may depend on patient phenotype, the kidney-protective promise of combination therapy in diabetic CKD, and the latest data on Kisunla in Alzheimer’s disease. Each story offers a clear view of how today’s breakthroughs are shaping the care of tomorrow.

Stay sharp. Stay ahead.

Featured Story

A Game-Changer for HER2-Mutant Lung Cancer: FDA Greenlights Zongertinib

Oral targeted therapy delivers a 75% response rate in advanced non-squamous NSCLC

The FDA has granted accelerated approval to zongertinib (Hernexeos) for unresectable or metastatic non-squamous NSCLC with HER2 tyrosine kinase domain (TKD) activating mutations, based on the Beamion LUNG-1 trial.

In patients pretreated with platinum chemotherapy but no prior HER2-targeted therapy, the objective response rate was 75%, with over half lasting six months or more. Those who had received a HER2 antibody-drug conjugate still achieved a 44% response rate.

Common side effects were diarrhea, hepatotoxicity, rash, fatigue, and nausea. Key warnings include hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The Oncomine Dx Target Test was also approved to identify eligible patients. For now, zongertinib offers a long-awaited targeted option for a population with few effective therapies.

Source: FDA

In Focus

Study Finds Striking Lung Cancer Risk in ILD Patients

Long-term Swedish data show small cell carcinoma risk more than triples in ILD

A prospective analysis of more than 5.4 million individuals in Sweden found that interstitial lung disease (ILD) carries a more than twofold increased risk of lung cancer, even after adjusting for age, sex, smoking-related conditions, education, and calendar period.

Over three decades of follow-up, lung cancer incidence reached 355.4 per 100,000 person-years in people with ILD compared with 26.2 per 100,000 without. Sibling-controlled analyses confirmed the elevated risk, pointing toward non-genetic factors such as environmental exposures, chronic inflammation, and shared disease pathways.

The danger spanned all histological subtypes, with the greatest risk for small cell carcinoma (adjusted HR 3.29) followed by squamous cell carcinoma and adenocarcinoma. Patients with both ILD and smoking-related diseases faced the highest risk, highlighting the critical importance of smoking cessation at diagnosis.

Lead author Weimin Ye, MD, PhD urged adoption of more comprehensive lung cancer screening for ILD patients, combining imaging with blood-based biomarkers to improve early detection and outcomes.

Source: JAMA

Inflammatory Bowel Disease Linked to Elevated Risk of Interstitial Lung Disease

Large Swedish cohort shows risk remains high even after accounting for familial factors

A nationwide Swedish cohort study of 85,705 individuals with inflammatory bowel disease (IBD) and 412,677 matched controls found a 48 percent higher risk of developing interstitial lung disease (ILD) in IBD patients. In sibling-controlled analyses, the risk climbed to 81 percent, confirming that the association persists beyond shared genetics or early environmental exposures.

Over a median 14 years of follow-up, ILD occurred at 34 per 100,000 person-years in IBD compared with 20 per 100,000 in controls. The elevated risk was consistent across major subtypes, with ulcerative colitis and Crohn’s diseaseboth significantly associated with ILD.

Researchers emphasized that IBD should be recognized as an underlying risk factor for ILD. They recommend that gastroenterologists actively ask about respiratory symptoms and refer to pulmonology when concerns persist, as earlier diagnosis may help reduce ILD-related morbidity and mortality.

Source: AJG

Head-to-Head Trial Finds No Single Best Sedative for ICU Patients

Large UK trial finds dexmedetomidine, clonidine, and propofol perform similarly for extubation time

In the A2B trial, involving 1,404 critically ill adults across 41 UK ICUs, neither dexmedetomidine nor clonidineshortened the time to successful extubation compared with propofol. Median times were 136 hours for dexmedetomidine, 146 hours for clonidine, and 162 hours for propofol — differences that were not statistically significant.

Sedation quality, delirium rates over 180 days, and mortality were similar across groups. However, both alpha2-adrenergic agonists were linked to 54–55 percent greater risk of agitation and significantly higher rates of bradycardia (RR 1.62 with dexmedetomidine, RR 1.58 with clonidine) than propofol.

Editorialists suggested tailoring sedation strategy to the patient’s phase of illness: propofol may suit deeper sedation needs, while alpha2 agonists can be considered for lighter sedation or when enteral administration is preferred. The findings reinforce that no single sedative is best for all ICU patients and that a dynamic, individualized approach remains essential.

Source: JAMA

Next in Practice

HOPE Trial Gives Hope for Expanding Alteplase Window for Selected Stroke Patients

Perfusion-based selection shows benefit up to 24 hours after onset

The HOPE trial, conducted at 26 stroke centers in China, found that alteplase administered 4.5 to 24 hours after stroke onset improved functional outcomes in patients with large or medium vessel occlusions who were not planned for endovascular therapy and had salvageable brain tissue on CT perfusion.

Among 372 randomized patients, 40.3 percent in the alteplase group achieved excellent functional outcomes (mRS 0–1 at 90 days) versus 26.3 percent in the control group (adjusted RR 1.52, 95% CI 1.14–2.02). The alteplase arm also showed better overall mRS distribution, with no difference in 90-day mortality between groups.

The benefit came at the cost of higher symptomatic intracerebral hemorrhage (3.8% vs 0.5%, adjusted RR 7.34) and a non-significant trend toward more parenchymal hematomas.

HOPE builds on prior late-window thrombolysis data, using less restrictive imaging criteria and including medium-distal vessel occlusions, making its findings more reflective of real-world practice. Investigators stressed that results do not apply to patients eligible for thrombectomy, but support considering late-window IV thrombolysis in carefully selected, imaging-confirmed cases.

Source: JAMA

CPAP and the Heart: When It Helps and When It May Harm

Pooled trial data show cardiovascular benefit in high-risk OSA, potential harm in low-risk cases

A pooled analysis of the RICCADSA, ISAACC, and SAVE trials involving 3,549 patients with moderate to severe obstructive sleep apnea (OSA) and cardiovascular disease found no overall cardiovascular benefit of CPAP compared with usual care (MACCE 16.6% vs 16.3% adjusted HR 1.00).

When patients were stratified by OSA phenotype, results shifted. In the high risk subgroup defined by elevated hypoxic burden or heightened heart rate response to apneas, CPAP showed a trend toward benefit (MACCE 15.2% vs 17.5% adjusted HR 0.83) reaching statistical significance in those without excessive sleepiness and without elevated blood pressure.

In low risk OSA, CPAP trended toward harm (MACCE 18.2% vs 14.9% adjusted HR 1.22). Potential explanations include cardiovascular strain from positive airway pressure or device related sleep disruption.

Investigators suggested targeting CPAP for cardiovascular prevention to patients with high risk features. Editorialists noted limitations from low adherence and selective enrollment and called for trials in obese moderate to severe OSA patients comparing compliant CPAP use with GLP 1 receptor agonist therapy.

Source: EUROPEAN HEART JOURNAL

Evidence at a glance

Meta-analysis Supports Structured Exercise for Atrial Fibrillation Management

Evidence shows symptom reduction and improved exercise capacity without added risk

A meta-analysis of 20 randomized trials involving 2,039 patients with atrial fibrillation (AF) found that exercise-based cardiac rehabilitation significantly improved AF symptom severity, burden, frequency, duration, and recurrence over an average follow-up of 11 months.

Participants in exercise programs achieved a mean VO₂ peak increase of 3.18 mL/kg/min compared with controls, a change considered both statistically and clinically meaningful. Benefits were also seen in the mental component of quality of life, though not in the physical component. Importantly, there was no increase in serious adverse events with exercise (2.9% vs 4.1%).

Effects were consistent across AF subtypes, exercise doses, and program formats, whether delivered in person or remotely. The authors urged that AF management guidelines be updated to recommend structured exercise alongside pharmacologic and ablation therapies, noting its safety, accessibility, and cost-effectiveness.

Experts emphasized that exercise remains one of the most effective and widely available interventions for cardiovascular health and called for it to become a core element of AF care.

Source: BMJ

CONFIDENCE Trial: Combination Therapy Beats Monotherapy for Albuminuria in Diabetic CKD

Finerenone plus Empagliflozin delivers rapid and sustained UACR reduction

In the CONFIDENCE trial, a randomized study of 818 patients with type 2 diabetes, chronic kidney disease (CKD), and albuminuria, the combination of finerenone and empagliflozin reduced the urinary albumin-to-creatinine ratio (UACR) by 52 percent from baseline at 180 days. This effect was 29 percent greater than with finerenone alone and 32 percent greater than with empagliflozin alone (P<0.001 for both comparisons).

The reduction occurred quickly, with a more than 30 percent drop in UACR by day 14 and over 40 percent by day 90. More patients on combination therapy achieved UACR reductions of 30, 40, and 50 percent compared with either monotherapy.

After a 30-day washout, UACR levels partially rebounded but remained below baseline in the combination and finerenone groups. Safety findings included mild, reversible increases in serum potassium, early but reversible declines in eGFR and systolic blood pressure, and low discontinuation rates from adverse events.

Investigators emphasized that initial combination therapy may overcome treatment delays and achieve faster, larger albuminuria reductions than stepwise therapy. Long-term effects on cardiovascular and kidney outcomes remain to be determined.

Source: NEJM

Poor Sleep Patterns Linked to 172 Diseases

Large UK Biobank study ties sleep irregularity to broad range of chronic conditions

An analysis of data from over 88,000 adults in the UK Biobank has linked poor sleep patterns to 172 different diseases, including dementia, Parkinson’s disease, type 2 diabetes, primary hypertension, and acute kidney failure. For 92 of these diseases, more than 20 percent of the risk was attributable to poor sleep behavior.

Researchers found that sleep regularity, not just duration, was a critical factor. Irregular bedtimes and disruption of the circadian rhythm were associated with higher risks for multiple conditions. For 42 diseases, including gangrene, fibrosis, cirrhosis, and age-related debility, the risk was at least doubled.

Experts noted that the findings highlight sleep as a modifiable health behavior with broad impact across neurological, cardiovascular, endocrine, and immune systems. While the study establishes associations rather than causation, it reinforces the need for targeted interventions and integration of sleep health into preventive care.

Clinicians recommend maintaining a consistent bedtime, optimizing the sleep environment, and addressing issues such as snoring, gasping, or persistent fatigue with a healthcare provider, as these may indicate treatable sleep disorders.

Source: SCIENCE.ORG

Kisunla (Donanemab) Sustains Alzheimer’s Benefits for 3 Years

TRAILBLAZER ALZ 2 extension shows slower decline with early treatment and expert guidance for safe use

Donanemab (Kisunla) delivered sustained clinical benefit at 3 years in early symptomatic Alzheimer disease in the TRAILBLAZER ALZ 2 extension. Compared with matched untreated ADNI controls, treated participants had 1.2 fewer CDR SB points of decline at 36 months.

Starting earlier mattered. Early starters had a 27% lower risk of progression to the next clinical stage over 3 years.

Amyloid clearance was consistent. More than 75% reached amyloid PET negativity within 76 weeks. In those who finished treatment by 52 weeks, mean amyloid stayed below 24.1 centiloids at 3 years, with reaccumulation estimated at 2.4 centiloids per year.

Safety remained aligned with prior reports. No new signals emerged. ARIA remains the key risk, higher in APOE4 homozygotes, and the new dosing schedule approved in July aims to reduce ARIA E.

Appropriate use recommendations from an independent panel highlight the importance of selecting suitable patients, ensuring regular MRI follow-up, and providing clear counseling on risks and expectations.

Source: ELI LILLY

Upcoming Events & Deadlines

1. CHEST 2025: 19-22 October, 2025 - Chicago

2. IDWeek 2025 : October 8 - 12, 2025 - Philadelphia

3. ACP Arizona 2025: Oral Vignettes Competition - Deadline September 14

4. ATS Abstracts and Case Reports: Deadline Nov 5, 2025