Citations

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Introduction Pulsed Electric Field (PEF) Ablation has been used as an adjunct therapy for cancer. Robotic-Assisted Bronchoscopy (RAB) enables precise access to pulmonary lesions for biopsy and ablative therapy. However, anatomic obstructions within the airway may prohibit access to peripheral targets. We report a case in which robotic bronchoscopy navigation for the delivery of PEF was not initially possible due to a new anatomic airway obstruction secondary to radiation fibrosis. We were able to utilize therapeutic bronchoscopy to re-cannulate the airway and deliver the PEF via the robotic bronchoscope. Case Report A 68-year-old man with a history of left lung adenocarcinoma was treated with surgery, chemoradiation and durvalumab consolidation therapy. Surveillance imaging 4 years later revealed consolidation in the right upper mediastinum. A bronchoscopy brush biopsy confirmed adenocarcinoma and received systemic chemotherapy. Later a PET-CT showed a non FDG avid enlarged right paratracheal lesion. Follow-up CT revealed complete obstruction of the right middle lobar bronchus with associated middle lobe collapse likely secondary to radiation. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of the right paratracheal lesion confirmed malignancy on onsite cytopathology. Subsequently, we performed two PEF ablations targeting the involved lesion. Repeat PET-CT demonstrated two hypermetabolic foci in the right hilum and right supraclavicular region. However, the previously PEF treated paratracheal lesion was not PET avid. We used a RAB to navigate into the right upper lobe and identified the anterior segment to be obstructed in addition to the previously noted right middle lobe. Due to this, the robotic bronchoscope couldn’t be advanced to the right hilar PET avid lesion. Utilizing guidewires, balloon dilatation and fluoroscopy we re-cannulated the obstructed right upper lobe segment and subsequently advance the robotic bronchoscope to the target in the right upper lobe. Under cone-beam guidance, multiple biopsies were obtained and confirmed as malignant. Following this, the INUMI PEF needle was deployed. We delivered two PEF activations to the right hilar PET-avid lesion. Subsequent systemic staging using linear EBUS identified station 4R lymph node involvement, positive for malignancy on rapid onsite cytopathologic evaluation. The 4R lymph node was superior to the previously treated paratracheal lesion. We then deployed the INUMI PEF needle, and PEF ablation was performed successfully. Discussion To our knowledge, this is the first reported instance of combining robotic and therapeutic bronchoscopy to overcome airway obstruction to facilitate the distal treatment of peripheral target with PEF. This abstract is funded by: None

Abstract Rationale Treatment of hematologic malignancies has been revolutionized by Chimeric antigen receptor T -cell (CAR-T) therapy. Pulmonary complications are increasingly being reported, however, there are no standardized timelines for pulmonary function test (PFTs) assessment before or after the infusion. We aimed to evaluate changes in lung function (TLC, RV, FEV1, and FEV1/FVC) pre- and post-CAR-T therapy and examine whether these parameters correlate with the development of specific pulmonary complications. Methods We conducted a retrospective chart review of patients above the age of 18 with any malignancy who received CAR-T therapy between June 12, 2018, and December 26, 2023. Pre-CAR-T PFTs were obtained closest to the infusion date, and post-CAR-T PFTs were recorded at the earliest available time following infusion. Pre- and post-CART pulmonary function tests were compared using non-parametric paired tests. In addition, we examined the relationship between baseline PFTs and the subsequent occurrence of pulmonary complications after CAR-T infusion. The Wilcoxon signed-rank test was applied to assess both the magnitude and direction of change while Sign test was used to evaluate only the direction to confirm the consistency of results. These tests were chosen due to small sample size and non-normal distribution of data. Results Among the 68 patients in our cohort, paired pre- and post- CAR-T measurements of pulmonary function were available for 18 patients. FEV1 declined significantly post-infusion (2.70 ± 0.81 L vs 2.28 ± 0.74 L; Z= -2.55, p = 0.011), the FEV1/FVC ratio remained stable (77.8 ± 8.0 vs 80.9 ± 12.2, p = 0.53). Mean TLC and RV remained stable (TLC 5.70 ± 1.18 L vs 4.66 ± 1.02 L, p = 0.17 and 2.13 ± 0.62 L vs 2.00 ± 0.70 L, p = 0.58). There was no significant correlation between the baseline lung function and the development of pulmonary complications. Conclusion Only the pattern of FEV1 decline following CAR-T therapy infusion demonstrates a significant decline, whereas other PFTs, although reduced, did not show significance. While these findings may suggest a restrictive ventilatory pattern, additional data on lung volumes are required to accurately characterize the underlying type of pulmonary function impairment. Although limited by small sample size and non-uniform timing of PFT assessments, this highlights the need for a routine pre-CAR-T pulmonary function evaluation to inform patient selection and baseline risk stratification. This abstract is funded by: None

Abstract Background With recent advances in oncology, tyrosine kinase inhibitors like imatinib play a significant role in gastrointestinal stromal tumor (GIST) treatment but can cause rare pulmonary complications. When new respiratory symptoms arise after starting these agents, differentiating drug toxicity from other lung diseases is important for timely management. Case Presentation A 72-year-old man with GIST, recently started on imatinib, presented with acute dyspnea and hypoxia. His medical history included chronic obstructive pulmonary disease and a 40-pack-year smoking history. Chest CT revealed new bilateral interstitial infiltrates absent on imaging two months ago, prior to imatinib initiation. The differential diagnosis included imatinib-induced pneumonitis versus atypical infection. Bronchoscopy showed yellowish nodular mucosa throughout the trachea and bronchi, mucus plugging, and airway narrowing in the left lower lobe. Endobronchial biopsies demonstrated amyloid deposits consistent with tracheobronchial amyloidosis. The bronchoalveolar lavage was negative for infection and, therefore, corticosteroid therapy was initiated, resulting in clinical and radiographic improvement. The findings supported a diagnosis of imatinib-induced pneumonitis coexisting with tracheobronchial amyloidosis. Discussion This case highlights the diagnostic challenges when drug-induced pneumonitis occurs along with structural airway abnormalities. Tracheobronchial amyloidosis, although rare, can cause airway obstruction and coexist with inflammatory lung conditions. The temporal association with imatinib, exclusion of infection, and steroid responsiveness indicate imatinib-induced pneumonitis as the primary cause of the acute symptoms, with concurrent amyloid deposition contributing to airway pathology. Conclusion In patients developing new pulmonary symptoms after starting tyrosine kinase inhibitors, drug-induced pneumonitis should be strongly suspected. The coexistence of airway diseases such as tracheobronchial amyloidosis can complicate diagnosis and management, highlighting the need for thorough evaluation including bronchoscopy and tissue biopsy to guide treatment. This abstract is funded by: None

Abstract RATIONALE There are limited studies evaluating the association between chimeric antigen receptor T-cell (CAR-T) therapy and interstitial lung abnormalities (ILA). Our study aims to investigate this potential relationship to better understand pulmonary complications following CAR-T therapy. Methods We conducted a retrospective chart review of patients aged 18 or older with any malignancy who received CAR-T therapy between June 12, 2018, and December 26, 2023. Chest imaging, including PET or CT scans, was reviewed for each patient; the closest scan before CAR-T therapy and the most recent scan afterward. We identified ILA based on findings that included ground-glass opacities, reticular abnormalities, traction bronchiectasis, honeycombing, or non-emphysematous cysts involving more than 5% of lung zones. We excluded dependent atelectasis, paraspinal fibrosis, aspiration-related changes, mild focal or unilateral abnormalities, and smoking-related centrilobular nodularity without other findings. Results A total of 66 patients had adequate imaging data both before and after CAR-T infusion. Before therapy, 17 patients (25.8%) demonstrated ILA, while 49 (74.2%) did not. Following CAR-T therapy, the overall prevalence of ILA increased to 31 patients (47.0%). Among those who did not have ILA before CAR-T, 16 of 49 (32.7%) developed new ILA following therapy. Conversely, among those with pre-existing ILA, 14 of 17 (82.4%) showed persistent or progressive ILA post-CAR-T. This distribution demonstrated a statistically significant association between pre- and post-CAR-T ILA status (χ² = 10.8, p = 0.001), indicating that pre-CAR-T ILA status strongly predicted post-CAR-T ILA persistence or worsening. When evaluating post-CAR-T ILA in relation to clinical outcomes, among those with pre-CAR-T ILA, 52.9% (n = 9) were deceased at follow-up, compared to 55.1% (n = 27) among patients without ILA. The difference in mortality between the groups was not statistically significant (χ² = 2.34, p = 0.31). 19 of 31 patients (61.3%) with post-CAR-T ILA were deceased at last follow-up, compared with 17 of 37 (45.9%) in those without ILA. Although mortality was numerically higher among patients with post-CAR-T ILA, this difference did not reach statistical significance (χ² = 1.04, p = 0.308). Conclusion Our study demonstrates a statistically significant association between pre- and post-CAR-T interstitial lung abnormalities, suggesting that CAR-T therapy may contribute to the progression or development of ILAs. These findings highlight the need for closer pulmonary monitoring during CAR-T treatment. This abstract is funded by: None

Glioblastoma is a highly aggressive disease with poor patient outcomes despite current treatment options, which consist of surgery, radiation, and chemotherapy. However, these strategies present challenges such as resistance development, damage to healthy tissue, and complications due to the blood–brain barrier. There is therefore a critical need for new treatment modalities that can selectively target tumor cells, minimize resistance development, and improve patient survival. Temozolomide is the current standard chemotherapeutic agent for glioblastoma, yet its use is hindered by drug resistance and severe side effects. Combination therapy using multiple drugs acting synergistically to kill cancer cells and with multiple targets can provide increased efficacy at lower drug concentrations and reduce side effects. In our previous work, we designed a therapeutic peptide (Bac-ELP1-H1) targeting the c-myc oncogene and demonstrated its ability to reduce tumor size, delay neurological deficits, and improve survival in a rat glioblastoma model. In this study, we expanded our research to the U87 glioblastoma cell line and investigated the efficacy of Bac-ELP1-H1/hyperthermia treatment, as well as the combination treatment of temozolomide and Bac-ELP1-H1, in suppressing tumor growth and extending survival in athymic mice. Our experiments revealed that the combination treatment of Bac-ELP1-H1 and temozolomide acted synergistically to enhance survival in mice and was more effective in reducing tumor progression than the single components. Additionally, our study demonstrated the effectiveness of hyperthermia in facilitating the accumulation of the Bac-ELP1-H1 protein at the tumor site. Our findings suggest that the combination of targeted c-myc inhibitory biopolymer with systemic temozolomide therapy may represent a promising alternative treatment option for glioblastoma patients.

Common variable immunodeficiency (CVID) is associated with an increased risk of gastric cancer. The aim of the study was to determine the morphological features of CVID-associated gastric adenocarcinoma (CAGA) and of the background gastritis. The population of gastric cancer patients with CVID of Mayo Clinic in the period 2000-2010 was studied; 6 cases of CVID (2 males, 4 females, average age 47 years, age range 26-71 years) were found in 5793 patients with gastric cancer in the study period. Each patient underwent gastric resection for which histology slides were reviewed. Chronic gastritis variables, CVID-related findings, and features of the adenocarcinoma were recorded. CAGA was of intestinal type, with high number of intratumoral lymphocytes (ITLs). Cancer was diagnosed in younger patients than in the overall population of gastric cancer. Severe atrophic metaplastic pangastritis with extensive dysplasia was present in the background in 4 cases, with features of lymphocytic gastritis in 2 cases. Features of CVID (plasma cells paucity in 4 of 6 cases, lymphoid nodules prominent in four cases) could be detected. In summary, gastric adenocarcinoma at young age with ITLs, accompanied by atrophic metaplastic pangastritis, should alert the pathologist of the possibility of CAGA. It follows that, in presence of those characteristics, the search of CVID-associated abnormalities should be undertaken in the nonneoplastic tissues.

In keeping with the stated goal of providing the surgical pathologist with tools to recognize abnormalities of the gastrointestinal (GI) tract due to drugs (AGIDS), in part II of this review we embark in a more organ-based description of AGIDS. Adequate space is given to the numerous adverse gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Pill esophagitis, esophagitis dissecans, proton pump inhibitors’ effects, diaphragm disease, and the recently described effects of drugs such as olmesartan, mycophenolate, and of compounds such as yttrium-90 are highlighted among several others. The inclusion of drug effects in the differential diagnosis of “conventional” diseases (such as gastric antral vascular ectasia, graft-versus-host disease, ischemic colitis, acute colitis, collagenous enteritis, inflammatory bowel disease) is underscored to avoid sometimes significant diagnostic pitfalls. We reiterate the message of the necessary collaboration between pathologist and clinician in the recognition of these entities to provide the best patient care.

Abnormalities of the gastrointestinal (GI) tract due to drugs (AGIDs) are numerous and have significant impact. The aim of this narrative review is to help the practicing surgical pathologist recognize selected AGIDs. The adverse drug effects presented were chosen with an emphasis on recent and significant pathological and clinical contributions. The selection was based on a thorough review of the PUBMED-based literature and on the authors’ opinions and experience. In the first part of the review, diagnostic abnormalities due to crystals (eg, iron, biphosphonates, nonsystemic drugs), mitosis arresting drugs (colchicine, taxanes), and biological agents, especially ipilimumab, are discussed. Some AGIDs’ histopathologic features can be easily recognized. It is however the clinical correlation that in many cases of AGIDs will provide the necessary support for a drug effect diagnosis. The identification of AGIDs requires heightened awareness of the medical team in which close collaboration of pathologists and clinicians cannot be overemphasized.

Inflammatory cap polyposis (ICP) is a rare nonneoplastic polyposis of the colon of unknown etiology that can be confused with prolapse-induced polyps and hyperplastic polyposis. We contribute a case of ICP from a 59-year-old woman who was affected by severe constipation and hematochezia. Numerous sessile and semipedunculated polyps were found in the colon, all with cap of whitish fibrin. Histology revealed erosion of the surface, superficial dilated crypts filled with mucoid inflammatory exudate, and minimal crypt serration, all findings typical of ICP. Only the largest polyps had smooth muscle in the mucosa. Ki-67 showed modest expansion and irregular distribution of the crypts proliferative areas. Low-degree positivity for p16, similar to that of hyperplastic polyps, was found. CK20 was expressed as in normal mucosa. Distinguishing between ICP and other polyposis is important because of difference in management.