Expression of PD-L1 in Patients With Malignant Peritoneal Mesothelioma: A Pilot Study.

INTRODUCTION: Frequency of PD-L1 expression and the role of immunotherapy in malignant peritoneal mesothelioma (MPM) have not been well characterized. The purpose of this study was to determine PD-L1 expression in patients with MPM and perform an exploratory analysis for associations between PD-L1 and its biological behavior in MPM. METHODS: Tumor samples were collected from patients undergoing surgical interventions between January 2018 and June 2020. Specimens were stained with anti-PD-L1 antibodies (Dako 22c3) and positivity was determined by tumor proportion score (TPS) or combined positive score (CPS) being ≥1%. RESULTS: Twenty one samples were obtained from 21 patients. Sixteen of 21 (76%) samples were CPS positive and 9 of 21 (43%) were TPS positive. Three samples had more aggressive biphasic/sarcomatoid histology and a high CPS and TPS (CPS: 3, 75, 95%; TPS: 2, 60, 90%). On an exploratory analysis, as the CPS or TPS threshold increased, there was a trend towards worse survival. CONCLUSIONS: MPM has a high frequency of PD-L1 expression, which may be associated with more aggressive tumor biology. These data provide the foundation for continued evaluation of checkpoint inhibition in patients with MPM.

Somatic Mutation of BAP1 Can Lead to Expression Loss in Non-Small Cell Lung Carcinoma: Next Generation Sequencing and IHC Analysis in A Large Single Institute Cohort.

Introduction. As a tumor suppressor, germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is a common finding in mesothelioma, melanocytic tumors, clear cell renal cell carcinoma and several other epithelial, mesenchymal and neural tumors. Incidence of BAP1 genetic alterations and subsequent expression loss has not been well established in non-small cell lung carcinoma (NSCLC) by large-scale studies. Design. After IRB approval, a total of 356 NSCLC cases of our institution between July 2016 and June 2020 were reviewed. The study cohort consisted of 214 (60%) adenocarcinomas, 89 (25%) squamous cell carcinomas, and 53 (15%) diagnosed as "non-small cell lung carcinoma" without specified subtype. All tumors underwent comprehensive target cancer gene next generation sequencing (Oncomine Assay). The protein expression status of BAP1 was subsequently evaluated by immunohistochemistry. Results. BAP1 somatic mutations were detected in 8 NSCLC tumors (incidence: 2.2%). Tumors harboring BAP1 mutations were all diagnosed at advanced stage and carried at least one additional genetic alteration. Immunohistochemically, four tumors showed complete loss of BAP1 protein expression, including two adenocarcinomas which harbored different missense BAP1 mutations and another two with bioinformatically predicated deleterious frameshifting mutations. Conclusion. Compared with known BAP1 loss associated other malignancies, such as mesothelioma, inactivation of BAP1 by somatic mutation is a rare occurrence in NSCLC. BAP1 mutations and loss of expression in NSCLC are accompanied by other complex genetic alternations, suggesting BAP1 mutation maybe a late event NSCLC carcinogenesis.

Follicular Bronchiolitis: Two Cases with Varying Clinical and Radiological Presentation.

Follicular bronchiolitis (FB) is a rare bronchiolar disorder associated with hyperplasia of the bronchial-associated lymphoid tissue (BALT). It is characterized by the development of lymphoid follicles with germinal centers in the walls of small airways. It falls under the category of lymphoproliferative pulmonary diseases (LPDs) and commonly occurs in relation to connective tissue disease, immunodeficiency, infections, interstitial lung disease (ILD), and inflammatory airway diseases. Computerized tomography (CT) findings include centrilobular nodules with patchy ground glass infiltrate, tree-in-bud findings, and air trapping. It can very rarely present as diffuse cystic lung disease. We present two cases of FB. The first case is associated with Human Immunodeficiency Virus (HIV) infection and asthma with diffuse cystic changes on the CT. The second case is associated with reactive airway disease and gastroesophageal reflux disease (GERD) with the classic centrilobular nodules and ground glass opacities on the CT.

Analysis and Comparison of Tissue-Marking Dye Detection via Light Microscopy, Telemicroscopy, and Virtual Microscopy.

Objectives: To examine the fidelity of ink color identification using light microscopy (LM), telemicroscopy (TM), and virtual microscopy (VM). Methods: Twenty H&E-stained frozen section slides, prepared after tissue inking with five stain combinations, were assessed by three pathologists using LM, TM, and VM. TM was performed using Mikroscan D2 slide scanner/LiveQ software with various objectives. VM was performed using Mikroscan D2 scanner/Qumulus software, specimens digitized at20×. Results: Sensitivity/specificity by LM was 100%/100% for all colors. TM showed high overall specificity but poor sensitivity, particularly red (54%). VM showed high specificity for all colors except black (69%) and, consequently, poor sensitivity for all colors except black (96%). Conclusions: TMD identification via telepathology showed loss of sensitivity/specificity vs LM and highlighted the need for caution when interpreting TMDs with digital technologies and the need for validation protocols.

A Giant Gastroschisis Associated with Pulmonary Hypoplasia and Spinal Anomaly: A Case Report and a Literature Review.

Gastroschisis most often occurs as an isolated anomaly and extragastrointestinal associations are rare. Most commonly, the anomalies associated with gastroschisis are cardiac and central nervous system abnormalities. Respiratory insufficiency has sometimes been reported in association with giant abdominal wall defects. Poor outcomes and prolonged ventilator support have been reported in giant gastroschisis and omphalocele, especially if associated with herniation of the majority of the liver. We report a case of a large gastroschisis that was associated with a kyphoscoliosis and pulmonary hypoplasia.

Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer.

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

Impact of weekly feedback on test ordering patterns.

OBJECTIVES: We examined the impact of weekly feedback reports on the test-ordering behavior of internal medicine residents. STUDY DESIGN: Retrospective analysis of a performance improvement effort. METHODS: In a large, urban, academic medical center, we extracted raw data on every inpatient laboratory test ordered by all internal medicine residents during two 26-week time periods. The pre-intervention phase established baseline ordering volume as each resident rotated through the various clinical services. The intervention consisted of a 1-hour educational seminar detailing the potential harm and costs of laboratory overutilization followed by the post intervention phase, which consisted of weekly feedback reports graphically illustrating individual versus group ordering patterns, where the identity of individual residents was protected. The total numbers of tests ordered during the 2 phases were compared using an independent t test. RESULTS: During the post intervention phase, we observed a net reduction of 21% in tests ordered-an average of 941 tests per week-with the greatest reduction in the chemistry section of the laboratory, followed by hematology, coagulation, and all others combined. This reduction in test volume corresponded to a $1.3 million reduction in charges. CONCLUSIONS: Providing physicians-in-training with a weekly feedback report detailing their test ordering volume in comparison with those of their peers is an effective method for reducing laboratory overutilization. Benefits to our approach include maintaining physician autonomy without alteration of existing infrastructure or disclosure of test fees.

Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma.

Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1, and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regulator of E-cadherin, a key protein that is lost during epithelial-mesenchymal transition (EMT). Moreover, we show that Notch1 signaling directly regulates Sox9 expression through a SOX9 promoter binding site, independently of the TGF-ß pathway, and that Sox9 participates in Notch-1 induced cell motility, cell invasion, and loss of E-cadherin expression. Together, the results identify a new functional role for a Notch1-Sox9 signaling axis in lung ADC that may explain the correlation of Sox9 with tumor progression, higher tumor grade, and poor lung cancer survival. In addition to Notch and TGF-ß, Sox9 also acts downstream of NF-κB, BMP, EGFR, and Wnt/ß-catenin signaling. Thus, Sox9 could potentially act as a hub to mediate cross-talk among key oncogenic pathways in lung ADC. Targeting Sox9 expression or transcriptional activity could potentially reduce resistance to targeted therapy for lung ADC caused by pathway redundancy.