Faculty Bibliography

Background: Growing evidence suggests the prognostic significance of SATS in patients with early-stage lung adenocarcinoma, in particular, those with sublobar resection. However, published studies used various definitions for STAS; the diagnosis of STAS may be subject to interobserver variability that, in turn, may result in the difference in prevalence and prognostic significance of STAS across institutions.
Design(s): The study cohort consisted of stage 1 lung adenocarcinomas resected at two institutions (cohort A: n=283; cohort B: n=198) during similar time periods with similarly decent follow-up. Both institutions had applied similar grossing/processing protocols. The prevalence of STAS and its association with clinicopathologic variables, recurrence free survival (RFS), and overall survival (OS) were compared between the cohorts. The variables included type of operation, AJCC 8th stage, histologic grade, as well as the presence of lepidic, micropapillary (mPAP), or solid (SOL) patterns (5% cut-off for presence).
Result(s): The prevalence of STAS was 7% in cohort A and 39% in cohort B (p<0.0001). The tumor histologic grade (high grade: 21% in A vs. 37% in B, p=0.0001) and AJCC stage (Stage 1B: 19% in A vs. 13% in B, p=0.048) also differed between the cohorts, while no difference was seen in the other variables. STAS was associated with high grade histology, the absence of lepidic and the presence of mPAP and SOL patterns (p<0.01 for all) in both cohorts, while it was also associated with stage 1B in cohort A (p=0.016). In multivariate analysis, STAS was associated with high grade histology (p<0.0001) and marginally with the presence of mPAP (p=0.065) in cohort A, and lobectomy (p=0.016), the presence of mPAP (p<0.0001) and SOL (p=0.027) in cohort B. Regarding survival, STAS was associated with shorter RFS (p=0.030) and OS (p=0.048) in cohort B and with shorter OS (p=0.040) and marginally with shorter RFS (p=0.060) in the sublobar resection subset of cohort B by univariate analysis, while STAS had no bearing on survival in the lobectomy subset or cohort A. Of note, no difference in RFS and OS was seen as a whole between the cohorts.
Conclusion(s): The prevalence and prognostic significance of STAS differ between the two institutional cohorts. While this may be explained in part by the difference in patient populations, subjectivity to the diagnosis of STAS may potentially contribute. Additional multi-institutional studies to better define and improve reproducibility of STAS are warranted

Patients with severe coronavirus disease 2019 from infection with severe acute respiratory syndrome coronavirus 2 mount a profound inflammatory response and are predisposed to thrombotic complications. Pulmonary vein thrombosis is a rare disease process resulting in pulmonary congestion, infarction, and potential mortality. This report describes a patient with coronavirus disease 2019 requiring venovenous extracorporeal membrane oxygenation for hypoxic respiratory failure who developed hemorrhagic infarction of the right lower lobe. During emergency exploration the patient was found to have a right inferior vein thrombosis and marked lobar hemorrhage mandating lobectomy.

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in group IIIB-IV TNM stage lung cancer and is associated with poor prognosis, as shown by decreased survival among subjects with early stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with IIIB-IV stage disease. In addition, this lower airway microbiota signature was associated with upregulation of IL-17, PI3K, MAPK and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL-17 inflammatory phenotype and activation of checkpoint inhibitor markers.

Many state-wide, city-wide, and hospital-wide changes have been implemented due to the ongoing COVID-19 crisis. We describe lessons learned in an anatomic pathology division at a tertiary care center during the peak of the COVID-19 pandemic in the hopes that knowledge of our experiences can benefit other pathology departments as they encounter this pandemic. Five categories that are critical in strategic planning for the COVID-19 pandemic are discussed: workload, departmental policy revisions, impact on faculty, workforce staffing, and impact on educational programs, including residency and fellowship training. Although the volume of COVID-19 testing had grown placing increased demands on the clinical pathology laboratory, the volume of anatomic pathology cases had declined during the COVID-19 peak. Lessons learned were widespread including changes in the anatomic pathology workflow due to declining surgical and cytologic case volumes and increases in autopsy requests. Modifications were required in gross room policies, levels of personal protective equipment, and workforce. Travel and meeting policies were impacted. Adaptations to residency and fellowship programs were vast and included innovations in didactic and interactive education. We must learn from our experiences thus far in order to move forward, and we hope that our experiences in an anatomic pathology department in the epicenter of the COVID-19 pandemic can help other pathology departments across the country.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

Immunohistochemical (IHC) stain for PD-L1 as a biomarker for immunotherapy is recommended in non-small cell lung cancer (NSCLC). Under the FDA, the selection of patients for pembrolizumab requires companion diagnostic testing using the Dako Agilent PD-L1 IHC 22C3 pharmDx kit performed on the Dako Autostainer Link 48 platform. However, because it is not widely available, there is need for cross-platform validation. Existing studies provide incomplete protocol detail. In our study, 73 lung tumors were stained using the FDA-approved test ('gold standard'). The same blocks were stained using two different models of the Ventana DISCOVERY platform (ULTRA, n = 73 and XT, n = 70) using different parameters, and interpreted by three pathologists. The ULTRA group met College of American Pathologists (CAP) validation criteria (concordance 91.8%) while the XT group did not (concordance 67.1%). Using tumor proportion score (TPS) ≥1% and TPS ≥50% as cut-offs, the ULTRA protocol had higher sensitivity (97.8% and 91.7%) than XT (73.3% and 60.9%) and similar specificity (ULTRA 88.9% and 100%, XT 88% and 100%). Discordance between ULTRA and XT was 27%, and in all these cases ULTRA was concordant with gold standard. Interobserver reliability was substantial for ULTRA and almost perfect for XT, providing evidence that staining rather than observer variability accounts for XT's inferior performance. Cross-validation of the clinically used 22C3 anti PD-L1 antibody test with substantial interobserver agreement is possible on the commonly used the Ventana DISCOVERY ULTRA automated instrument, while the validation failed on the XT. Cautious attention to detail must be paid when choosing cross-validation parameters.