Citations

Abstract Introduction/Objective Cervical cancer remains a global health concern, with significantly higher incidence in countries like Peru compared to the U.S. Cytopathology plays a vital role in early detection and prevention, making it an important area of focus for aspiring pathologists. Methods/Case Report A medical student with an interest in pathology participated in a global health rotation in Cusco, Peru, at CerviCusco, a nonprofit clinic dedicated to cervical cancer care. Under the guidance of a trained cytotechnologist, the student engaged in hands-on cytopathology work, including processing and screening SurePath (Franklin Lakes, NJ) slides, and reviewing abnormal cases. The student had access to a microscope and dedicated time developing microscopy skills and learning cervical cytomorphology, with emphasis on identifying significant abnormalities. Results NA Conclusion This experience demonstrates the educational value of incorporating global health electives into medical training, especially in resource-limited settings with high disease burden. Exposure to such environments enhances foundational diagnostic skills and fosters an early appreciation for global health disparities. Expanding similar opportunities can enrich pathology education and inspire future contributions to international health efforts.

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) has a specific pathophysiology, with myocardial stiffening and systolic dysfunction only in advanced stages. We aimed to investigate the response to cardiac resynchronization therapy (CRT) in ATTR‐CM compared with heart failure. Methods In this multicenter, observational study, patients with ATTR‐CM receiving CRT (n=101) were matched to patients without amyloid cardiomyopathy by sex, age, and implantation type (CRT with versus without defibrillator versus conduction system pacing, upgrade versus first implant). We evaluated changes in QRS duration and echocardiographic parameters following CRT implantation and at the most recent available assessments. The study end points were all‐cause death alone or combined with heart failure hospitalization. Results Patients with ATTR‐CM (median age, 76 [interquartile range, 72–83] years, 98% men, left ventricular (LV) ejection fraction 30% [26–33]) showed greater QRS shortening after CRT implantation ( P =0.012), but not after a median of around 1 year ( P =0.152). There were no significant differences in the absolute LV ejection fraction changes immediately after implantation (+7 [+2/+10] versus +3 [0/+9] units; P =0.124), or to the last echo ( P =0.796), which was performed after 1.3 years in patients with ATTR‐CM and 2.9 years in patients without amyloid cardiomyopathy. Patients with ATTR‐CM had a shorter survival than controls ( P <0.001 for both end points). Patients with ATTR‐CM experiencing an early improvement in LV ejection fraction had a longer survival (log‐rank, 4.3; P =0.038). Conclusions Following CRT implantation, patients with ATTR‐CM show QRS narrowing and improvement in LV ejection fraction, not different from patients without amyloid cardiomyopathy. Early favorable LV remodeling seems to be associated with a lower risk of all‐cause death.

The author presents the case of a middle-aged woman who had a left parietal lobe infarct. Due to severe aortic regurgitation limiting her activity and aortic root aneurysm, the patient underwent aortic valve and aortic graft replacement, in addition to PFO closure. During this hospitalization, aortic root pathology was noted, leading to an ultimate diagnosis of giant cell aortitis.

Objectives: Diabetes mellitus and chronic pancreatitis are established risk factors for pancreatic ductal adenocarcinoma (PDAC). The co-occurrence of exocrine and endocrine pancreatic dysfunction may increase the risk of progression to PDAC and could play a role in early detection. We sought to explore this hypothesis by comparing PDAC risk among patients with diabetes mellitus (DM) and low fecal elastase (FE) in a real-world cohort of patients. Materials and Methods: A retrospective cohort study was conducted using the TriNetX research network including adults with continuous follow-up from 2016 to 2023. The cohort was stratified into 4 groups based on the presence or absence of DM, and normal FE (>200 µg/g) or low FE (<200 µg/g). The 4 groups included: (1) low FE and DM, (2) low FE without DM, (3) normal FE and DM, (4) normal FE without DM. Propensity score matching was performed to balance covariates including age, sex, race, comorbidities to allow for a 6-way comparison of PDAC risk between groups. Time-to-event analyses were conducted with Kaplan-Meier curves and Cox proportional hazards models to estimate hazard ratios (HR) and 95% CIs for the primary outcome of PDAC incidence. Results: Of the study cohort, 29,207 had fecal elastase levels. Low FE (<200 µg/g) was observed in 33% (n = 9585) of these patients. After 6-way comparisons, we observed a higher PDAC risk among individuals with both DM and low FE compared with other groups. The highest PDAC risk was observed in patients with both a low FE (<200 µg/g) and DM compared with those with a normal FE and without a history of DM (HR: 3.68; 95% CI, 2.07–6.53; P < 0.001). Sensitivity analysis using a stricter fecal elastase cutoff of <100 µg/g showed a similar finding, with the highest hazard ratio for PDAC among patients with both DM and very low FE levels (HR: 3.07, 95% CI, 1.37–6.91; P = 0.004). Conclusions: The coexistence of low fecal elastase and DM amplifies the risk of pancreatic ductal adenocarcinoma in our cohort of patients. These results suggest that fecal elastase values may be used to enrich the diabetic population for future PDAC risk stratification, though more studies are needed to validate these findings.

Background: Documentation burden is a major contributor to surgeon burnout, particularly in high-volume outpatient specialties such as hand surgery. These encounters often involve multiple concurrent diagnoses, procedural planning, and longitudinal care. Ambient artificial intelligence (AI) tools, which passively transcribe and summarize clinical encounters in real time, have the potential to streamline note generation and reduce cognitive load. Methods: Following institutional rollout of a commercially available ambient AI tool in early 2025, the system was adopted across all outpatient visits in a hand surgery clinic. Observations were collected regarding workflow adaptation, documentation quality, and perceived cognitive impact. To assess note characteristics, 14 carpal tunnel syndrome visit notes (7 AI-generated and 7 surgeon-written) were compared by word count, Flesch-Kincaid readability score, and inclusion of social and medical history. Results: AI-generated histories were longer and exhibited greater linguistic complexity compared with surgeon-written notes. Surgeon-written assessments were longer, more readable, and more consistent in structure and tone. Social history was documented more frequently in AI-generated notes. All AI-generated assessment and plan sections followed a structured, problem-based format. Conclusions: Ambient AI documentation can support the creation of more structured and contextually rich clinical notes in hand surgery settings. However, successful integration requires active clinician engagement and workflow alignment to balance efficiency with clinical accuracy. These findings highlight both the promise and the practical considerations of incorporating ambient AI into surgical documentation workflows.

Immunotherapy has transformed oncology, yet kidney complications increasingly affect outcomes. This review summarizes nephrotoxicity from immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell (CAR-T) therapies, and bispecific T-cell engagers (BiTEs). ICIs remain most used, with acute interstitial nephritis (AIN) as the hallmark lesion, while glomerular diseases and electrolyte abnormalities are less common. CAR-T therapy, though highly effective in hematologic cancers, carries risks of cytokine release syndrome, tumor lysis syndrome, and acute kidney injury (AKI). BiTEs, particularly teclistamab, show higher AKI rates than CAR-T, though mechanisms remain unclear. Early recognition, tailored management, and multidisciplinary collaboration are essential to ensure safe therapy and preserve kidney function.

Abstract Recurrent or refractory IDH-mutant (mt) gliomas represent a population with significant unmet clinical need. The Notch ligand delta-like 3 (DLL3) is a tumor-associated antigen that is highly and homogeneously expressed in IDH-mt gliomas but absent in normal brain tissue, making it an attractive therapeutic target. Tarlatamab is a half-life extended bispecific T-cell engager that targets DLL3 and CD3 to redirect cytotoxic T cells toward DLL3-expressing tumor cells. Given the specific expression of DLL3 in IDH-mt gliomas and promising activity of tarlatamab in other DLL3-positive tumors, this study investigates the safety, efficacy, and intracranial activity of tarlatamab in this patient population. TARGID is an open-label, phase II trial enrolling adult patients with histologically confirmed IDH1 or IDH2-mt astrocytoma or oligodendroglioma following up to two prior lines of systemic therapies. The study comprises two cohorts. Cohort 1 (n=10) includes patients with resectable disease who will receive up to three cycles of tarlatamab prior to surgery; postoperative continuation is permitted. The primary endpoint for this cohort is the change in CD8+ T-cell infiltration in tumor tissue and blood. Cohort 2 (n=34) includes patients with unresectable disease and uses a Simon’s optimal two-stage design (H0: P ≤ 0.1 versus H1: P ≥ 0.25). In the 1st stage, 13 patients will be accrued. If 2 or more responses are observed, 21 additional patients will be enrolled. Tarlatamab is administered intravenously at 10 mg every two weeks, following a 1 mg priming dose on Cycle 1 Day 1. The primary endpoint is objective response rate by RANO 2.0. Exploratory endpoints include DLL3 expression, circulating biomarkers, and immune correlatives. The trial is currently in activation, with first patient enrollment anticipated in Q3 2025. The study is supported by the provision of study drug from Amgen as an investigator-initiated trial.

Abstract BACKGROUND While most meningiomas are classified as low-grade tumors with indolent behavior, a subset is characterized by a more aggressive clinical course and patients undergo repeated resections and courses of radiation. Once these therapies fail, prognosis is poor and progression-free survival (PFS) rates at 6 months (PFS-6) are estimated to only be 43.6% for WHO grade 1 and 38% for WHO grade 2/3 meningiomas. Effective medical therapies are limited. Somatostatin receptor 2 (SSTR2) is expressed in a majority of meningiomas and represents a suitable treatment target. [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) is an SSTR2-targeted radioligand therapy, established as standard of care in the treatment of certain neuroendocrine tumors. Two ongoing non-randomized studies of 177Lu-Dotatate in meningiomas have reported encouraging efficacy compared to historical benchmarks. METHODS/STUDY DESIGN The MOMENTUM-1 study (RTOG 3523, NCT#06955169) is a multicenter, randomized, open-label study of 177Lu-Dotatate in adult patients with progressive intracranial WHO grade 1-3 meningiomas. Up to 130 eligible subjects are randomized in a 2:1 fashion to 177Lu-Dotatate at 7.4 GBq (200 mCi) every 4 weeks for 4 (+2 optional) doses or standard of care (SOC) medical therapy as defined by the protocol and deemed appropriate by the local investigator. Treatment responses are assessed by gadolinium-enhanced MRI brain and [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET imaging. At time of progression, cross-over from the SOC to the interventional treatment arm is allowed. The primary endpoint is PFS. Secondary endpoints include PFS-6, OS-12, OS, response assessments (ORR, DCR), safety/tolerability, and patient-reported outcomes. RESULTS/CONCLUSION MOMENTUM-1 is a multicenter, randomized, open-label, phase II study of 177Lu-Dotatate in adult patients with progressive WHO grade 1-3 meningioma. This clinical trial is expected to start enrolling patients in the United States in the third quarter of 2025. Details on study design, eligibility criteria for subject enrollment and study site eligibility criteria will be presented.

Abstract BACKGROUND Diffuse midline gliomas (DMGs) and posterior fossa group A (PFA) ependymomas are aggressive pediatric brain tumors. Most DMGs harbor histone H3.3K27M or G34R mutations, or exhibit EZHIP overexpression. With a median survival of just 9–15 months, DMGs are among the most lethal human cancers. PFAs, nearly universally overexpress EZHIP and have a 5-year survival rate of ~50%. Unlike K27M or EZHIP-overexpressing DMGs, G34R-mutant tumors retain H3K27me3. METHODS Using the RCAS/Nestin-TVA system, we introduced H3.3 K27M–, G34R–, or S31A–P2A–PDGFβ or H3.3WT–P2A–PDGFβ into neonatal mice. Controls included, histone mutants EZHIP alone and ΔEZHIP (PRC2-binding-deficient). Tumor bearing mice were assessed for incidence, grade, survival, and H3K27me3 and H3.3S31P status. RESULTS H3.3K27M, G34R, and S31A–P2A–PDGFβ induced high-grade gliomas with significantly reduced survival (p &lt; 0.001). Mechanistically, G34R—like K27M—reduced mitotic Ser31 phosphorylation (S31P), causing chromosomal instability and impaired p53 checkpoint function. S31A directly modeled loss of S31P and similarly drove high-grade tumor formation. H3.3WT–P2A–PDGFβ induced only low-grade lesions. EZHIP–P2A–PDGFβ enhanced tumor grade but not survival; only EZHIP fully abolished H3K27me3. ΔEZHIP and all unlinked constructs were non-tumorigenic. CONCLUSION These models establish a robust platform to dissect glioma drivers and chromatin vulnerabilities. We previously showed that H3.3K27M reduces S31P, promoting chromosomal instability and impaired p53 function. We now demonstrate that H3.3G34R also reduces S31P and drives tumor formation in vivo. Direct loss of S31P via H3.3S31A is likewise sufficient for gliomagenesis. Although EZHIP does not alter S31P, it promotes genome instability through distinct mechanisms—disrupting PALB2–BRCA2-mediated DNA repair and mislocalizing TopoIIα, a process dependent on H3K27me3. H3.3K27M, G34R, and EZHIP thus converge on genome instability through distinct pathways. This platform supports mechanistic and therapeutic studies and is now being expanded using tetracycline-regulated expression to investigate tumor maintenance.

Abstract Glioblastoma (GBM) diagnosis integrates morphology and tumor molecular alterations. Patients with classic morphology are designated as histologic GBM (hGBM). Patients without classic morphology harboring TERT promoter mutation (TERTp), or epidermal growth factor receptor amplification (EGFRamp), or combined gain of chromosome 7 and loss of 10 (+7/-10) designate molecular GBM (mGBM). We compared radiographic features, genomic alterations, and clinical outcome between hGBM and mGBM. 109 mGBM Mayo Clinic cases diagnosed between 1993-2021 were matched to 101 cGBM by age, sex, year of diagnosis, and TERT promoter (TERTp) status. Clinical and radiographic data abstraction was blinded. Progression-free and overall survival were compared across groups in the subset of patients who received standard of care. Contrast enhancement was present on index MRI (MRI at diagnosis) for 98% (96/98) hGBM and 50% (54/107) mGBM (p&lt;0.0001) patients. mGBM tumors harbored fewer total copy number alterations (median of 16.5 vs 20, p=0.029) and were less likely to have CDKN2A/B homozygous deletion (56% vs 77%, p=0.005). Among the 87 mGBM and 82 hGBM receiving standard of care, median overall survival was longer for mGBM versus hGBM (2.24 vs 1.62 years, p=0.016). mGBM patients with +7/-10 (HR=2.60, p=0.035) or CDKN2A/B (HR=3.61, p=0.002) had poorer overall survival compared to mGBM patients without the corresponding alteration. On index MRI mGBM patients without contrast enhancement had better overall survival compared to hGBM (HR=0.50; p=0.003) whereas there was no survival difference between mGBM with enhancement and hGBM. mGBM with enhancement on index MRI likely represent undersampled, or early / evolving hGBM. mGBM patients with non-enhancing MRI, younger than 60, with long symptom profile including seizures, and some combination of non-anaplastic morphology, TERTp only, no homozygous deletion of CDKN2A/B, and low copy number complexity may represent other IDHwt glioma entities. Caution is advised in counseling, management, discussing prognosis, and inclusion in clinical trials.