Correlation of PD-L1 expression, clinicopathologic and molecular characteristics in an array of solid tumors: A large-scale real world study

Background: Programmed death ligand-1 (PD-L1) is a predictive marker of anti-programmed death protein 1 (PD- 1)/PD-L1 therapies for solid tumors. Limited literature exists correlating PD-L1 expression, clinicopathological & molecular profiles. We aimed to 1) correlate PD-L1 immunohistochemistry (IHC) results with these profile across multiple solid tumors & 2) assess clinical outcomes (overall survival (OS) & disease-free survival (DFS)) of PD-L1 status with / without anti-PD-L1 immunotherapy (IT). Design: All cases tested for PD-L1 IHC over 2 years (Aug 2019-Sep 2020) were retrieved for this study. Clinicopathological variables recorded included age, race, tumor type, type of PD-L1 clone, PD-L1 status (Tumor Proportion Score (TPS): negative:50%), Combined Positive Score (CPS): negative10), clinical stage, anti-PD-L1 IT. Microsatellite instability (MSI) status using IHC & Ploymerase chain reaction (PCR) assays was recorded. High PD-L1 was defined as PD-L1 expression of TPS \u3e50%/CPS\u3e10. Outcome studies included OS and DFS after generating Kaplan-Meier curves & compared using log rank test. Univariate analysis using Cox regression models were also used. Results: There were 205 cases tested for PD-L1 by IHC. Cohort included non-small cell lung cancers (127), head & neck carcinomas (37), gastric or gastroesophageal carcinoma (20), kidney or urothelial carcinoma (16), cervical carcinomas (5). Median age was 70 years (range 28-90). Most were high stage cancers [stage 1: 5/205, stage 2: 5/205, stage 3: 30/205, stage 4 165/205]. PD-L1 IHC clones included: 22C3 (152/205), 28-8 (21/205) & both (32/205). High PD-L1 expression was observed in 52/205 (25.3%), out of which [37/127 (29.1%) were adenocarcinoma, 13/54 (24%) were squamous cell carcinoma, 2/24 (4.1%) others]. Anti PD-L1 IT was given in 65/205 (31.7%) patients. Anti PD-L1 IT was significantly associated with longer median survival OS (p=0.015) & DFS (p=0.004) (Figure 1). PD-L1 status was significantly associated with OS (p=0. 034) but not DFS (p=0. 076) (Figure 1). High PD-L1 had shorter median survival and higher hazards of death in OS (HR=5.4, CI-1.3-23.1) irrespective of IT. Association between three groups of PD-L1 status when compared with IT was statistically significant (p=0.048, Figure 2). PD-L1 & MSI testing was available in 29 patients & did not show any statistical correlation in this small cohort. No significant difference in survival for those received IT (4/29) vs no IT (25/29) & tested for both PD-L1 & MSI (OS: p= 0.277, DFS: p= 0.107). Conclusions: This study supports the rational approach for PD-L1 therapy. High PD-L1 expression is more commonly seen in adenocarcinoma. Expression of high PD-L1 is associated with worse OS but not DFS. PD-L1 IT is significantly associated with longer median survival, OS & DFS. Larger, prospective studies are needed to support our findings

Bioenergetic Adaptations in Chemoresistant Ovarian Cancer Cells.

Earlier investigations have revealed that tumor cells undergo metabolic reprogramming and mainly derive their cellular energy from aerobic glycolysis rather than oxidative phosphorylation even in the presence of oxygen. However, recent studies have shown that certain cancer cells display increased oxidative phosphorylation or high metabolically active phenotype. Cellular bioenergetic profiling of 13 established and 12 patient derived ovarian cancer cell lines revealed significant bioenergetics diversity. The bioenergetics phenotype of ovarian cancer cell lines correlated with functional phenotypes of doubling time and oxidative stress. Interestingly, chemosensitive cancer cell lines (A2780 and PEO1) displayed a glycolytic phenotype while their chemoresistant counterparts (C200 and PEO4) exhibited a high metabolically active phenotype with the ability to switch between oxidative phosphorylation or glycolysis. The chemosensitive cancer cells could not survive glucose deprivation, while the chemoresistant cells displayed adaptability. In the patient derived ovarian cancer cells, a similar correlation was observed between a high metabolically active phenotype and chemoresistance. Thus, ovarian cancer cells seem to display heterogeneity in using glycolysis or oxidative phosphorylation as an energy source. The flexibility in using different energy pathways may indicate a survival adaptation to achieve a higher \u27cellular fitness\u27 that may be also associated with chemoresistance

A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3‐SCAPER gene fusion

Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as “animal‐type melanomas” and “epithelioid blue nevi.” Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in‐depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3‐SCAPER gene fusion.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/1/cup13566.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/2/cup13566_am.pd

A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3‐SCAPER gene fusion

Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as “animal‐type melanomas” and “epithelioid blue nevi.” Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in‐depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3‐SCAPER gene fusion.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/1/cup13566.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/2/cup13566_am.pd

Tribbles 2 pseudokinase confers enzalutamide resistance in prostate cancer by promoting lineage plasticity

Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching

Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract are genetically different from nodular fasciitis and lack USP6, ROS1 and ETV6 gene rearrangements

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145266/1/his13526_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145266/2/his13526.pd

The interplay of growth differentiation factor 15 (GDF15) expression and M2 macrophages during prostate carcinogenesis

M2 (tumor-supportive) macrophages may upregulate growth differentiation factor 15 (GDF15), which is highly expressed in prostate tumors, but the combined utility of these markers as prognostic biomarkers are unclear. We retrospectively studied 90 prostate cancer cases that underwent radical prostatectomy as their primary treatment and were followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least 1 year or more before their prostate cancer surgery. Using computer algorithms to analyze digitalized immunohistochemically stained slides, GDF15 expression and the presence of M2 macrophages based on the relative density of CD204- and CD68-positive macrophages were measured in prostate: (i) benign biopsy, (ii) cancer and (iii) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (P = 0.0004) and GDF15 (P \u3c 0.0001) showed significant inter-region expression differences. Based on a Cox proportional hazards model, GDF15 expression was not associated with BCR but, in men where GDF15 expression differences between cancer and TAB were highest, the risk of BCR was significantly reduced (hazard ratio = 0.26; 95% confidence interval = 0.09-0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a 5-fold increased risk of BCR (P = 0.01). Expression of GDF15 in prostate TAB was associated with M2 macrophage levels in both prostate cancer and TAB and appeared to moderate M2-macrophage-associated BCR risk. In summary, the relationship of GDF15 expression and CD204-positive M2 macrophage levels is different in a prostate tumor environment compared with an earlier benign biopsy and, collectively, these markers may predict aggressive disease

Racial differences in the systemic inflammatory response to prostate cancer

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk

Anti-androgenic activity of absorption-enhanced 3, 3\u27-diindolylmethane in prostatectomy patients

Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3\u27-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL; levels were undetectable at baseline and in follow-up samples. AR localization in the prostate was assessed with immunohistochemistry. After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion. Declines in PSA were observed in a majority of patients (71%). Compliance was excellent and toxicity was minimal. In summary, BR-DIM treatment resulted in reliable prostatic DIM levels and anti-androgenic biologic effects at well tolerated doses. These results support further investigation of BR-DIM as a chemopreventive and therapeutic agent in prostate cancer