Dysphagia secondary to esophageal obstruction is a rare but clinically relevant presentation in the setting of non-small cell lung cancer (NSCLC). While pembrolizumab demonstrates efficacy in metastatic NSCLC with high programmed death-ligand 1 (PD-L1), diagnostic challenges in distinguishing pseudoprogression from true progression and paradoxical disease progression pose a clinical challenge, highlighting complexities inherent in immune checkpoint inhibitor resistance mechanisms. We present the case of an 82-year-old Caucasian woman with a diagnosis of stage IV NSCLC with extremely high PD-L1 expression who developed accelerated disease progression on pembrolizumab monotherapy. Following 11 cycles of immunotherapy, the patient developed life-threatening esophageal obstruction due to a massively enlarged subcarinal lymph node, causing significant extrinsic compression. This resulted in food impaction necessitating urgent endoscopic management, followed by aspiration pneumonia requiring medical intensive care unit admission. Endoscopic evaluation revealed a critically narrowed esophageal lumen with ulcerated and necrotic mucosa. To facilitate nutritional support and airway protection, a gastrostomy tube was inserted. This case highlights several key clinical points: mediastinal lymphadenopathy can result in life-threatening esophageal compression requiring immediate intervention; high PD-L1 expression level is no guarantee of immunotherapy efficacy and may paradoxically be associated with aggressive disease progression; tissue sampling is imperative to differentiate between true progression versus pseudoprogression; and gastrostomy tube insertion is a vital palliative intervention for malignant esophageal obstruction secondary to extrinsic compression.

Invasive pulmonary aspergillosis (IPA) is a serious complication, particularly in patients with existing structural lung disease like interstitial lung disease (ILD). Angioinvasive IPA can lead to pulmonary artery pseudoaneurysm (PAP), which is a rare but life-threatening source of massive hemoptysis. We present the case of a 78-year-old white American male with ILD (potentially from Agent Orange exposure) and chronic hypoxic respiratory failure, dependent on home oxygen, who presented with recurrent, massive hemoptysis. Computed Tomography Angiography (CTA) showed a 1.5 cm PAP in the right upper lobe cavity. Despite no classical causative immunosuppression, a diagnosis of pulmonary aspergillosis was supported by bronchoalveolar lavage (BAL) culture and galactomannan testing. Although invasive disease was suspected, the possibility of an aspergilloma with a semi-invasive component could not be excluded due to lack of prior imaging. Urgent coil embolization was performed to control the hemorrhage, followed by antifungal treatment with voriconazole. This case underscores the need for early suspicion of pulmonary aspergillosis in ILD patients, utilizing BAL and CTA for diagnosis, and combining endovascular embolization with antifungals. Given the absence of prior imaging and underlying fibrotic lung disease, distinguishing invasive disease from semi-invasive or chronic forms can be challenging.

Background: Alpha-1 antitrypsin deficiency (A1ATD) is a hereditary disorder affecting approximately 1 in 2,000 to 5,000 individuals of European ancestry. While severe deficiency (PiZZ genotype) is well-characterized, the clinical significance of relatively intermediate deficiency states (serum A1AT 40-80 mg/dL), predominantly comprising PiSZ, PiMZ, and PiSS genotypes, remains poorly defined. This study aimed to compare hepatic and pulmonary outcomes in patients with moderate versus mild intermediate A1ATD. Methods: Using the TriNetX US Collaborative Network (43 healthcare organizations), we identified 1,410 adult patients with A1ATD (ICD-10 code E88.01) and serum A1AT levels between 40-80 mg/dL. Patients were stratified into two cohorts- 40-60 mg/dL (n=324) and 60-80 mg/dL (n=324) after 1:1 propensity score matching for age, sex, race, BMI, diabetes, and baseline laboratory values. Exclusion criteria included A1AT level of less than 40 mg/dL, pre-existing cirrhosis, and other chronic liver diseases. Primary outcomes included emphysema, COPD exacerbation, cirrhosis, hepatic decompensation, and mortality. Results: Following propensity matching, baseline characteristics were well-balanced except for albumin (4.0±0.8 vs 4.2±0.6 g/dL, p=0.001) and INR (1.4±0.6 vs 1.2±0.4, p=0.001). Patients with A1AT 40-60 mg/dL demonstrated trends toward increased emphysema risk (10.8% vs 7.4%; OR 1.51, 95% CI 0.88-2.61, p=0.133; HR 1.63, 95% CI 0.97-2.74, log-rank p=0.063) and cirrhosis (10.5% vs 7.4%; OR 1.47, 95% CI 0.85-2.53, p=0.169; HR 1.58, 95% CI 0.94-2.66, log-rank p=0.085). No significant differences were observed for COPD exacerbation (14.2% vs 13.0%, p=0.646), hepatic decompensation (4.6% vs 3.7%, p=0.555), or mortality (OR 1.07, p=0.854). Conclusions: The observed trends toward worse outcomes with lower A1AT levels (40-60 mg/dL range, likely enriched for PiSZ genotype) warrant further investigation in larger cohorts with genotype confirmation. Limitations include a lack of genotyping data, reliance on ICD-10 coding, and potential type II error due to limited sample size. These preliminary findings highlight an important knowledge gap in understanding disease burden among the more prevalent intermediate A1ATD.

Background/Objectives: Prior U.S. surveillance studies reported modest pulmonary hypertension mortality declines through 2020, but contemporary trends incorporating expanded combination therapy and novel therapeutics remain uncharacterized. This study analyzed primary pulmonary hypertension (PPH) mortality trends and demographic disparities from 2018 to 2024. Methods: A retrospective, population-based cross-sectional study was conducted using the CDC WONDER Underlying Cause of Death database (2018–2024, Single Race series). Deaths with ICD-10 code I27.0 as the underlying cause were identified. Age-adjusted mortality rates (AAMRs) per 100,000 population were standardized to the 2000 U.S. standard population. Deaths were stratified by sex, race, calendar year, and U.S. Census Region. Mortality rate ratios with 95% confidence intervals were calculated using exact Poisson methods. Results: From 2018 to 2024, 1,831 deaths were attributed to PPH. Annual deaths declined from 344 to 199, a 42.2% reduction, with the AAMR decreasing from 0.10 to 0.06 per 100,000 (estimated compound annual rate of change, 9.3%). Women accounted for 69.5% of deaths (female-to-male AAMR ratio, 2:1). Black individuals had the highest AAMR (0.10 vs. 0.06 per 100,000 for White individuals; Black-to-White ratio, 1.67:1). The South bore the highest burden (43.1% of deaths; crude rate, 0.09 per 100,000) while the Northeast had the lowest (12.3%; crude rate, 0.06 per 100,000). Conclusions: PPH mortality declined substantially from 2018 to 2024, coinciding with increased adoption of combination therapy and the introduction of sotatercept. Persistent disparities by sex, race, and geography suggest therapeutic advances may not be reaching all populations equitably, underscoring the need for targeted interventions to improve access to PAH-specific therapies.

Background/Objectives: Prior U.S. surveillance studies described changes in pulmonary hypertension mortality through 2020, but contemporary national data focused specifically on deaths coded as primary pulmonary hypertension (PPH; ICD-10 I27.0) are limited. We examined temporal, sex, racial, and geographic patterns in I27.0-coded mortality in the United States from 2018 to 2024. Methods: CDC WONDER Underlying Cause of Death data were analyzed. Annual deaths and mortality rates were examined by year, sex, Single Race 6 category, and U.S. Census region. Results: A total of 1831 deaths were coded as I27.0. Annual deaths declined from 344 in 2018 to 199 in 2024, while the exact crude rate declined from 0.105 to 0.059 per 100,000. Women accounted for 69.5% of deaths. Black individuals had a higher age-adjusted mortality rate than White individuals (0.10 vs. 0.06 per 100,000). The South accounted for the largest share of deaths (43.1%), although the West had a marginally higher exact crude rate. Conclusions: Deaths assigned to I27.0 declined substantially during 2018–2024. This trend occurred during a period of major evolution in PAH care, but the ecological design cannot determine whether therapeutic advances caused the decline. Changes in coding, classification, and assignment of underlying cause may also have contributed. Persistent demographic disparities warrant further investigation.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The sequential approval of CFTR modulators ivacaftor (2012), lumacaftor/ivacaftor (2015), tezacaftor/ivacaftor (2018), and elexacaftor/tezacaftor/ivacaftor (2019) has transformed CF care, but population-level mortality trends across therapeutic periods have not been comprehensively assessed. We conducted a retrospective analysis of CF mortality in the United States from 1999 to 2024 using CDC WONDER Underlying Cause of Death data (ICD-10 codes E84.0–E84.9). Age-adjusted mortality rates (AAMR) per 100,000 were calculated using the 2000 U.S. standard population. The study period was divided into three periods: pre-modulator (1999–2011), early modulator (2012–2018), and elexacaftor/tezacaftor/ivacaftor (2019–2024). Annual mortality trends were evaluated using segmented log-linear Poisson regression, with annual death counts as the outcome and the corresponding U.S. population as an offset. Candidate models with multiple change points were compared to identify distinct temporal segments. Annual percent changes (APCs) and 95% confidence intervals (CIs) were estimated for each segment. Prespecified therapeutic periods, including pre-modulator (1999–2011), early modulator (2012–2018), and ETI period (2019–2024), were retained for descriptive analyses. Trends were stratified by sex and U.S. Census Region. A total of 10,959 CF deaths were recorded over 26 years. In the pre-modulator period, mortality was stable at a mean of 478 deaths/year (AAMR 0.14–0.17). The early modulator period showed a modest 5.4% reduction in mean annual deaths (452/year). The period following ETI availability was associated with a decline to 263/year, a 47% reduction from the pre-modulator period (AAPC −8.6%/year). The AAMR declined from 0.17 (1999) to 0.07 (2024). The female-to-male death count ratio shifted from 1.05 to 0.97 across periods, though age-adjusted rates were identical between sexes within each period, and this finding should be interpreted cautiously. Regionally, the South’s share of CF deaths grew from 37.2% to 41.6% despite absolute declines in all regions, suggesting potential geographic disparities that warrant further investigation with individual-level data. Segmented regression identified change points in 2005 and 2015. Mortality declined significantly from 1999 through 2005 (APC, −2.70%; 95% CI, −4.01% to −1.37%), remained stable from 2006 through 2015 (APC, +0.21%; 95% CI, −0.47% to +0.90%), and declined sharply from 2016 through 2024 (APC, −9.76%; 95% CI, −10.66% to −8.84%). CF mortality in the United States has declined by more than half since the introduction of CFTR modulators. The shift in the sex-based death count ratio and the concentration of remaining deaths in the South are hypothesis-generating observations that require confirmation with individual-level data. These ecological findings cannot establish causation, as concurrent changes in supportive care, lung transplantation practices, and COVID-19 pandemic effects may have contributed to the observed trends.