Citations

ABSTRACT Background We recently published the first real‐world multicenter and multi‐institutional study of cisplatin, gemcitabine, and durvalumab in patients with advanced biliary tract cancer (BTC). Here we present an expanded patient cohort with an increased sample size and longer median follow‐up. Methods The study population included patients with advanced BTC, who received cisplatin/gemcitabine plus durvalumab at 55 centers across 12 countries in Europe, the United States, and Asia. The primary endpoints of the study were progression‐free survival (PFS) and overall survival (OS). Secondary endpoints were overall response rate (ORR) and safety. Results Overall, 1358 patients were enrolled. Median PFS was 7.6 months (95% CI: 7.2–8.1), and median OS was 15.6 months (95% CI: 14.8–16.5). ORR was 35.6%, and DCR was 82.7%. Any grade AEs occurred in 1213 patients (89.3%). Grade 3–4 AEs occurred in 597 patients (43.2%). The rate of immune‐related AEs (irAE) was 20.3%. Grade 3–4 irAE occurred in 3.0% of patients. At the multivariate analysis for OS, normal albumin level (HR 0.68, 95% CI 0.57–0.81, p < 0.0001), CEA levels within normal ranges (HR 0.68, 95% CI 0.57–0.82, p < 0.0001), NLR < 3 (HR 0.62, 95% CI 0.52–0.74, p < 0.0001), ECOG PS 0 (HR 0.51, 95% CI 0.42–0.61, p < 0.0001), and prior surgery (HR 0.80, 95% CI 0.65–0.99, p = 0.036) were positive prognostic factors. Conclusion The updated findings, derived from an expanded cohort, further support the adoption of durvalumab in combination with gemcitabine and cisplatin in routine clinical practice, reinforcing the efficacy and safety outcomes demonstrated in the phase III TOPAZ‐1 trial.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. METHODS: Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in APOB , LDLR , or PCSK9 . A chart review was performed to collect demographics, personal, and family cardiovascular history. RESULTS: At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 APOB , 298 LDLR , and 5 PCSK9 . Sixty-six percent were female, the mean body mass index was 27.3, with 12.3% reporting a history of diabetes. Hypertriglyceridemia (≥150 mg/dL) was present in 39.5% and reduced HDL (<50 mg/dL) was present in 56.7% of patients. 27.5% of patients were not on cholesterol-lowering medications, and only 10% of FH carriers were at goal low-density lipoprotein cholesterol levels. A history of coronary artery disease was reported in 22.4% of the cohort. Nearly 90% of these participants were newly diagnosed carriers of FH. Only 30.8% of confirmed genetic diagnoses of FH satisfied clinical (Dutch lipid clinic network) criteria for a diagnosis. CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05212428.

Objective: Telemedicine addresses limitations in patient access, health care costs, and time spent by patients for health care visits. However, gender-based differences in patient satisfaction with this method are unclear. Our study aimed to evaluate gender-based differences in patient satisfaction for telemedicine (both video and telephone) and in-person health care visits. Methods: Patients were randomly selected to complete a patient satisfaction survey regarding their health care experiences after outpatient medical appointments at a large academic institution. Results: Of 476,777 total respondents, most patients were women (47.5%) and men (37.3%), with fewer patients in the categories transgender, other, or unknown/choose not to disclose (15.2%). Women and men were both satisfied with telemedicine by video or telephone (83.3% women versus 84.5% men rated their visit 5/5) and in-person visits (84.1% women versus 85.7% men rated their visit 5/5). Conclusions: Men and women were nearly equally satisfied with telemedicine and in-person visits, although both genders were slightly less satisfied with telemedicine video visits than in-person visits. The findings indicate that the ongoing integration of telemedicine into clinical practice could serve as a satisfactory alternative to in-person consultations for all patients.

Abstract Introduction/Objective Plasmablastic lymphoma (PBL) is a rare type of B-cell lymphoma with poor prognosis. They can arise de novo in immune deficiency/dysregulation, associated with transplant or transformation of low grade lymphoma. PBL has been reported with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Methods/Case Report 69-year-old male with CLL/SLL, treated with multiple chemotherapy regimens and was in remission. He developed generalized weaknesses. Radiology showed lymphadenopathy. Pathology was positive for DLBCL without MYC and BCL2 rearrangement. Flow cytometry revealed 1% CD5 and CD23 positive. TP53 is negative and mutated IGHV. The PD-1 was negative, favored de novo DLBCL. PET-CT and biopsy confirmed residual disease. For refractory DLBCL, CAR-T cell therapy was initiated. Patient developed PBL diffusely positive for CD138, MUM1, c-MYC and kappa; negative for CD19, CD20, PAX5, CD10, BCL6 and CD79a. MIB-1 was 90%. EBV and HHV8 were negative. BCMA was &gt;95 %, Teclistamab was initiated. The renal function deteriorated and proceeded with palliative care. Results NA Conclusion The nature of Richter transformation or de novo DLBCL into PBL in the setting of immunomodulation with CAR-T is rare occurrence. Molecular and clonality studies are needed to evaluate the pathways of losing B-cell markers to evade lineage specific therapy.

Abstract Background Cognitive impairment (CI) has diverse neurological etiologies, including Alzheimer’s Disease (AD), non-degenerative (ND) conditions, and cerebrospinal fluid (CSF) dynamic disorders, such as normal pressure hydrocephalus (NPH). The etiology of CI may be different to diagnose due to the overlap of non-specific symptoms. Various CSF biomarkers, such as amyloid beta (Aβ) 42, Aβ40, total Tau (t-Tau), and phosphorylated Tau 181 (p-Tau181), have been evaluated for their diagnostic utility in identifying the underlying cause for CI. Previous studies have suggested an isolated abnormal Aβ42 levels may be indicative of NPH in the appropriate clinical context. This study aims to further explore the clinical utility of AD-related CSF biomarkers to distinguish NPH from AD and ND causes of CI. Methods 240 patients were chart reviewed and categorized as either AD (n = 124), ND (n = 68), or NPH (n = 47) based on the etiologies of CI. Concentrations of Aβ40, Aβ42, t-Tau, p-Tau181 were measured in CSF (Cobas e601, Roche). Receiver operating characteristic (ROC) curves were plotted and optimal Youden cutoffs and areas under curve (AUCs) were calculated for each biomarker, and for selected ratios of biomarker combinations, for their ability to differentiate NPH from either AD or ND. Additionally, qualitative (abnormal/normal) result patterns for Aβ42, t-Tau, p-Tau181, and p-Tau181/Aβ42 ratio were reviewed for each patient, using established cut-offs for identifying AD (Aβ42≤1026 pg/mL, t-Tau&gt;238 pg/mL, p-Tau181&gt;21.7 pg/mL, p-Tau181/Aβ42&gt;0.023). Results p-Tau181/Aβ42 ratio demonstrated one of the highest AUCs (0.931) to separate NPH from AD (sensitivity=84.8%, specificity= 91.9%), and Aβ42 showed the highest AUC (0.856) to separate NPH from ND (sensitivity=71.6%, specificity=89.7%). When using previously established AD cut-offs, the combination of an abnormally low Aβ42 along with a normal p-Tau181/Aβ42 ratio yielded a sensitivity of 40.4% and a specificity of 96.4% in distinguishing NPH from other CI etiologies in this cohort. In contrast, abnormal results for both Aβ42 and p-Tau181/Aβ42 ratio had a sensitivity of 89.5% and a specificity of 87.0% in identifying AD, while normal results for both biomarkers had a sensitivity of 91.2% and a specificity of 90.1% in identifying ND. Incorporating the qualitative results for t-Tau and p-Tau181 into the evaluation did not enhance the diagnostic performance for distinguishing NPH, AD or ND in this cohort. Conclusion ROC analysis indicated that p-Tau181/Aβ42 and Aβ42 may help differentiate NPH from AD and ND, respectively. However, the combination of an abnormally low Aβ42 and a normal p-Tau181/Aβ42 ratio, using current AD cut-offs, demonstrated a lower sensitivity but high specificity in distinguishing NPH from the other CI etiologies in this cohort, suggesting this result pattern may be used for NPH rule-in in patients with CI.

Abstract Introduction/Objective Ovarian endometrioid carcinomas can display varied morphologic and immunophenotypic features, complicating diagnosis and grading. We analyzed adnexal tumors with absent or limited PAX8 expression to distinguish endometrioid carcinoma from histologic mimics such as sex cord-stromal and carcinoid tumors. Methods/Case Report We retrospectively reviewed ovarian tumors with epithelioid morphology and absent or limited PAX8 expression. Detailed histologic evaluation and immunophenotyping were performed. Features including sex cord-like morphology, background endometriosis, associated borderline components, and squamous morular or mucinous differentiation were assessed. PAX8, CK7 and β-catenin, sex cord and neuroendocrine markers were evaluated. Results Sixteen cases were identified (age 33–76, median 69). Sex cord-like morphology was present in all. Endometriosis or adenofibroma (n = 5), squamous/mucinous differentiation (n = 5), and hyalinized/corded patterns (n = 5) were observed. Most cases (13/16) lacked PAX8 expression; 14 showed aberrant nuclear β-catenin. Sex cord markers were negative. CK7 was negative or focal in 7 cases; 3 showed neuroendocrine marker expression. Conclusion Some ovarian endometrioid carcinomas lack PAX8 and mimic sex cord or neuroendocrine tumors, imposing diagnostic challenges. Aberrant β-catenin and characteristic morphology aid diagnosis. Ancillary testing, including immunohistochemistry and CTNNB1 mutation analysis, is essential to avoid misclassification and guide appropriate management.

Abstract Introduction/Objective Mutations in KIT and PDGFRA drive the majority of gastrointestinal stromal tumors (GIST) and inform targeted therapy selection. While single-driver mutations are typical, a subset of cases harbors multiple KIT mutations, complicating clinical interpretation. This study investigated the frequency, distribution, and inferred hierarchy of primary and secondary KIT mutations using DNA-based sequencing in a large GIST cohort. Methods/Case Report We retrospectively reviewed 579 GIST cases that underwent DNA-based next-generation sequencing using a custom panel targeting all coding exons of KIT and PDGFRA. Tumor-rich formalin-fixed paraffin-embedded (FFPE) tissue was required. In double-mutant cases, the mutation with higher variant allele frequency (VAF) was presumed to be primary. Results Mutations in KIT or PDGFRA were detected in 482/579 cases (83.2%). Among KIT-mutant cases, 28 had two mutations and one had three. Secondary mutations frequently occurred in exons 13, 14, and 17 and were significantly more common in non-gastric tumors (p &lt; 0.0001). Primary mutations most often involved exon 11. Conclusion VAF analysis enabled classification of mutation hierarchy in cases with multiple KIT mutations. The distinct anatomical and exon-specific distribution of primary vs. secondary mutations highlights their potential therapeutic implications and warrants further study.

Abstract Peanut allergy is a leading cause of food-induced allergy (prevalence of ∼1%). The diagnosis relies on evaluating clinical symptoms consistent with peanut exposure, supported by the detection of total peanut specific IgE (sIgE) and peanut component IgE antibodies (Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, Ara h9 and Bet v2) through serum or skin testing. However, sensitization patterns across different ages and regions in the United States remain largely unknown. In this study, we investigated regional and demographic patterns of peanut component sensitization in a large U.S. population tested for suspected peanut allergy. Retrospective data were collected from 13,702 individuals tested at Mayo Clinic Laboratories. sIgEs were measured using the ImmunoCAP system (Thermo Fisher Scientific). Samples with detectable total peanut sIgE (≥0.1 kU/L) were reflexed to testing for seven peanut component IgEs. Statistical analyses including linear regression and correlation matrix analysis were conducted using R Studio. Regional differences were assessed using care provider zip code information. Among the study population, 92.0% (12,604 of 13,702) had detectable total peanut sIgE, with the Western U.S. region exhibiting the highest detectable rate (95.6%), and the Southeast the lowest (85.6%) (p &lt; 0.001). On average, 3.38 different component IgEs were detectable per person with a detectable total peanut sIgE; 7.1% (892) had no detectable component IgEs, possibly due to antibodies against other peanut components. Correlation analysis revealed strong associations between Ara h2 and Ara h6 (r = 0.94), with moderate correlations observed between Ara h2, Ara h3, and Ara h6 to Ara h1 (r ranging from 0.72 to 0.77). Age-stratified analysis indicated higher total peanut sIgE detectable rates in children and adolescents (95.2%, ≤18 years) compared to adults (76.5%, &gt;18 years). Interestingly, adults were more likely than children to have negative results for all component IgEs. Sensitization rates to different peanut components varied, with Ara h2 (77.5%) and Ara h6 (73.2%) being the most frequently detected, followed by Ara h1 (56%), and Ara h3 (47.3%). Lower detectable rates were observed for Ara h8, Ara h9, and Bet v2 (34.8%, 26.1% and 22.7%, respectively). Regional analysis showed consistently high detectable rates for Ara h2 and Ara h6 (&gt;70%) across most areas (p &lt; 0.001) with slightly lower rates in the Southwest (&lt;63%). Bet v2, despite its overall low prevalence (&lt;24%), had a relatively higher detectable rate in the Southwest (29%). This study provides valuable insights into potential demographic and geographic factors influencing peanut allergy sensitization. Our study demonstrates that peanut sensitization patterns vary by age and geographic location. Children and adolescents exhibit higher detectable rates for total peanut sIgE and component IgEs compared to adults, with Ara h2 and Ara h6 as the most frequently detected and highly correlated components.

Abstract Introduction/Objective Microglandular adenosis (MGA) of the breast is an uncommon lesion characterized by a benign course. However atypical MGA (AMGA) and MGA-associated carcinoma have been described, suggesting that MGA may represent a non-obligate precursor of carcinoma. We report five cases of MGA-associated breast carcinoma and describe the key pathological features of this entity. Methods/Case Report Five cases of MGA-associated breast carcinoma were identified. Clinical data, histologic and immunohistochemical characteristics were reviewed and analyzed. Results All cases involved women with ages ranging 48 to 75 with a median of 70. Four of five cases demonstrated invasive carcinoma, while one case showed ductal carcinoma in-situ (DCIS). Invasive carcinomas encompassed various histologic types: metaplastic carcinoma with chondromyxoid matrix production (2 cases), invasive carcinoma with secretory features (1 case), and invasive carcinoma of no special type (ductal) (1 case). A morphologic transition from MGA to AMGA to carcinoma was observed in all cases. S100 was consistently positive in all cases. Myoepithelial markers demonstrated the absence of myoepithelial cells in the invasive carcinoma as well as MGA / AMGA component. Conclusion This series highlights the histologic spectrum and key diagnostic features of MGA-associated carcinoma. Awareness of this entity is crucial for appropriate diagnosis and clinical management.

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.