School of Medicine

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with limited population-based data. METHODS: Incidence trends and survival outcomes were analyzed using the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 955 cases were identified. The age-adjusted incidence rate increased from 0.158 in 2000 to 1.18 in 2022 (average annual percent change, 10.38%; p < 0.001), accelerating after 2012. Increases were more pronounced among females, older patients, regional-stage disease, and tumors > 2 cm. The 5-year disease-specific survival (DSS) and overall survival were 60.6% and 51.2%, respectively. Advanced age, non-parotid site, larger tumor size, lymph node metastasis, advanced stage, and non-surgical management were independent predictors of worse DSS. Patients diagnosed in 2013-2022 showed better DSS compared with those in 2004-2012 (64.7% vs. 52.0%, p = 0.048). CONCLUSION: SDC incidence has increased rapidly, possibly reflecting improved diagnostic recognition and reclassification, with only modest survival improvement over the past decade.

Esophageal squamous cell carcinoma (SCC) is a significant global health issue, and spindle cell squamous cell carcinoma (SpCC) is a rare variant accounting for up to 2% of cases. SpCC is characterized by a biphasic histological pattern comprising both carcinomatous and sarcomatous components. Patients typically present with dysphagia, painful swallowing, and weight loss. Diagnosis is challenging due to sampling limitations in biopsy specimens, often leading to misclassification as conventional SCC or sarcoma. In this case, a white American 65-year-old male presented with worsening dysphagia and weight loss. Endoscopic evaluation revealed a large fungating mass in the middle third of the esophagus. Initial biopsy showed a high-grade malignant neoplasm, but immunohistochemistry (IHC) was inconclusive. Further imaging confirmed a primary esophageal tumor with regional lymph node involvement. The patient underwent neoadjuvant therapy followed by surgical resection. Post-treatment pathology confirmed SpCC with nodal metastasis. SpCC pathogenesis remains unclear, but high Programmed death-ligand 1 (PD-L1) expression at the tumor invasive front, along with epithelial-mesenchymal transition (EMT) markers ZEB1 and TWIST, suggests a role in tumor progression. Molecular studies indicate frequent TP53 mutations, receptor tyrosine kinase alterations, and PI3K pathway mutations. While surgical resection remains the primary treatment, emerging evidence supports the role of PD-L1 inhibitors and targeted therapies. Despite its aggressive histology, SpCC has a relatively favorable prognosis when diagnosed early, with a five-year survival rate of approximately 60%. Further research is needed to optimize treatment strategies for this rare malignancy.

BACKGROUND: Cytomegalovirus (CMV) infection is common amongst both immunocompetent and immunocompromised patients. Patients with inflammatory bowel disease (IBD) are more prone to suffer from CMV complications. In this study, we investigated the utility of immunohistochemistry to diagnose CMV infection in patients with severe IBD. METHODS: We searched our pathology data system to identify patients with IBD from January 1, 2017 to December 31, 2021. We identified 5782 IBD cases, out of which 784 cases had severe activity with ulceration. CMV immunohistochemical stain (IHC) was performed on all 784 cases. Hematoxylin and eosin (H&E) staining slides were reviewed to evaluate the presence of characteristic nuclear or cytoplasmic CMV inclusions. H&E and IHC results were categorized as "single" if 1 cell stained positive or had characteristic inclusions, "rare" if 2-5 cells stained positive or had characteristic inclusions and "many" if more than 5 cells stained or had characteristic inclusions. Clinical outcomes, treatment and serum CMV viral loads were examined. RESULTS: A total of 29 cases out of 784 cases (3.7%) were positive for CMV by IHC. Seven cases (0.9%) showed many positive cells, 14 (1.8%) had rare positive cells and 8 cases (1%) showed single positive cells on IHC. The most frequently involved specimen type was the left colon. Twelve out of 29 cases (41%) didn't show characteristic cytoplasmic or nuclear inclusions on H&E stains prior to IHC. Out of these 12 cases, CMV IHC showed rare cells in 7 cases (58%) and single cells in 5 cases (42%). None of these cases show many positive cells on IHC. CMV viral load PCR was tested in 10 out of 29 cases (34%) and was positive in 80% of tested patients (8 out of 10). The majority of positive cases by PCR had many CMV inclusions on IHC (5 out of 8, 63%). Only 3 out of 12 patients with no H&E inclusions were tested with CMV PCR with 2 cases being positive (2 out of 12, 17%). These 2 cases were treated with antiviral treatment. Overall, CMV IHC helped to detect CMV positivity in only 12 out of 784 cases (1.5%) that were otherwise not apparent on H&E. CONCLUSIONS: These results suggest that CMV infection is rare in IBD patients with severe activity and ulceration and H&E should be used as a first line to detect viral inclusions in such patients. CMV IHC could only help to identify the CMV infection in a minority of cases with no characteristic inclusions on H&E stain.

Synapse loss is an early feature of prion disease, yet the underlying drivers are poorly understood. We recently found evidence of neuronal hyperactivity and synaptic loss in prion-infected mice. Herein, we identified increased Arc/Arg3.1 in patients with prion disease, suggesting heightened neuronal activity also occurs in the human prion-affected brain. To determine the signaling events initiated by prion aggregates (PrP^Sc), we developed a disease model in which human iPSC-derived excitatory neurons are stimulated with a PrP^Sc-mimetic antibody, POM1, that binds cellular prion protein (PrP^C). Within 2 h of POM1 exposure, we detected an Arc/Arg3.1 response together with transcriptomic changes previously reported in prion-infected mice. We identified altered phosphorylation of PLC-γ1, ERK1/2, and EGFR as additional PrP^C-triggered cell signaling events. These results suggest that PrP^C ligands, including PrP^Sc, trigger rapid signaling events linked to neuronal hyperactivity in human neurons, and indicate PLC-γ1 as a potential therapeutic target.

The rapid advances in HLA genotyping technology and the massive amounts of associated data have created a demand for better and more efficient laboratory data management practices. However, while some standards have been developed, there is a need for comprehensive guidelines that include all laboratory data-related processes such as messaging, storage and retention, documentation, reporting, validation and quality control. An important consideration in developing these recommendations is the feasibility of application in a laboratory setting without posing a substantial staff and cost burden for implementation and long-term maintenance and the availability of publicly available tools. This article presents evidence-based recommendations for multiple laboratory general data practices, focusing on HLA genotyping data and associated meta-data. These recommendations are compiled by experts in the fields of histocompatibility and immunogenetics (H&I) and representation from multiple H&I worldwide professional society leadership with the long-term goal of adopting these recommendations in future laboratory accreditation requirements.

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by therapy resistance. Focal adhesion kinase (FAK) is highly expressed in HGSOC, yet its impact on tumor-immune communication remains incompletely defined. Using three syngeneic ovarian cancer models, we show that FAK inhibition (FAKi) increased macrophage CXCL13 expression and promoted peritoneal B cell infiltration. Combining FAKi with low-dose pegylated doxorubicin and anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint blockade suppressed orthotopic ovarian tumor growth, extended survival, and induced tertiary lymphoid structures. Macrophage lineage factor GATA6 inactivation reduced CXCL13 expression, enhanced FAK-knockout tumor growth, and limited ascites B cell accumulation. Mechanistically, FAKi-treated or FAK-deficient tumor cells release exosomes enriched in omega-3 fatty acids that stimulated macrophage CXCL13 production. Exposure of macrophages to tumor-derived omega-3 lipids or eicosapentaenoic acid induced anti-tumor reprogramming and CXCL13 expression. Together, these findings reveal a tumor lipid-macrophage signaling axis activated by FAKi that supports B cell recruitment and anti-TIGIT immunotherapy.

Immunoassay-based urine drug screens are widely employed in clinical toxicology due to their speed, low cost, and ease of automation. However, these assays are inherently limited by antibody cross-reactivity, which can result in false-positive findings and incorrect interpretations with major implications for patient care, employment, and legal outcomes. This review updates prior literature by analyzing reported false-positive interferences published between 2013 and 2024 across commonly screened drug classes, including opioids, amphetamines, benzodiazepines, cannabinoids, barbiturates, phencyclidine (PCP), cocaine, ethanol, and ethyl glucuronide. A total of 61 studies met inclusion criteria from 569 unique publications retrieved via PubMed. Each report was categorized by level of evidence, ranging from single case reports to controlled spiking experiments. Despite advances in antibody specificity, immunoassay drug screens remain presumptive and require confirmation by orthogonal techniques such as gas or liquid chromatography coupled with mass spectrometry (GC-MS or LC-MS/MS). This review provides updated reference data on known interferents, emphasizes the need for laboratorian-clinician communication, and supports continued education on assay limitations. Reliable interpretation of presumptive immunoassay drug screen results remains essential to prevent inappropriate clinical care decisions.

Mycoplasma genitalium as a cause of genitourinary sexually transmitted disease symptoms often goes underdiagnosed in many patient populations. We investigated a patient population in Southern California at high risk for Chlamydia trachomatis (CT) and Neisseria gonorrhea (NG) infections to determine whether they also may be at high risk for Mycoplasma genitalium (MG) sexually transmitted infections that may be going untreated. We found that there was a relatively high prevalence of CT (13.9 %) and NG (9.0 %) in our population, but there was also a relatively high prevalence of undiagnosed MG infections (8.7 %). In this same patient population, there were few (0.5 %) subjects diagnosed with Trichomonas vaginalis (TV) infections; however, there were high numbers of coinfections identified for MG with CT and NG. We found high numbers of positive results in both symptomatic and asymptomatic individuals. We also identified that there were high numbers of subjects with genetic markers associated with resistance to macrolide antibiotics in the MG positive specimens. These data altogether strongly suggest that MG testing should be a routine part of screening for patient populations whether they are high- or normal-risk for sexually acquired infections.

BACKGROUND: The spirometric response to standard-of-care (SOC) immunosuppressive therapy for the management of bronchiolitis obliterans syndrome (BOS) has been sparsely reported in the literature. Data from a Medicare-approved Registry were analyzed to characterize the effectiveness/durability of a wide range of SOC interventions to manage the decline of lung function and to validate the study spirometric criteria for initiation of rescue therapy. METHODS: Lung transplant recipients with refractory BOS at 21 US collaborating centers were enrolled in the Registry. Data included both nonspirometric (eg, demographic, Immunosuppressive Regimens for management of BOS) and spirometric parameters (ie, forced expiratory volume in 1 s [FEV 1 ] measurements and derived indices). The utility of study FEV 1 criteria for treatment (ie, statistically significant rate of FEV 1 decline >30 mL/mo) was evaluated by comparing the spirometric course between participants who met or did not meet this criterion. RESULTS: Only 21% of participants treated with SOC therapy had >50% decrease (76 ± 25% decrease) in the rate of FEV 1 decline. Although 51% of participants had a partial response (rate of FEV 1 decline decreased on average 71%), 49% of participants had a substantial increase (mean increase 224%). The FEV 1 criterion for treatment was able to identify 19% of participants (48/258) who achieved durable stabilization (ie, nonsignificant rate of FEV 1 <30 mL/mo) with SOC therapy. CONCLUSIONS: Patients with BOS have a widely variable response to SOC therapy. Our findings support the use of FEV 1 rate of decline to assess response to SOC therapy and to ensure appropriate assignment of participants with refractory BOS to rescue therapy treatment cohorts.