LYMPHOCYTE-SPECIFIC TYROSINE KINASE EXPRESSION IN OVARIAN CANCER: A VALUABLE PROGNOSTIC INDICATOR

Cellular immune response, specifically tumor infiltrating lymphocytes (TILs), has been correlated to survival in epithelial ovarian cancer; however, specific gene expression patterns for this response remain poorly understood. The objective of this research was to investigate the prognostic and biologic significance of immune-related gene expression in high grade serous ovarian cancer (HGSOC). To do so, a panel of immune related gene expression was evaluated in HGSOC utilizing The Cancer Genome Atlas (TCGA) and validated in an independent cohort of ovarian tumors. Based on the strong association with survival, the cohort was grouped into LCK (lymphocyte specific tyrosine kinase) high and non-LCK high tumors and profiles of gene expression and clinical information were obtained. We demonstrate that mRNA upregulation of LCK was correlated with the strongest improvement in survival of the genes investigated. When compared to previously validated metrics such as cytolytic activity score (CYT), LCK proved to be a more discerning prognosticator across tumor types available in the TCGA. In ovarian cancer, correlated gene enrichments were notable for chemokine and immunoglobin complex related genes, ie B cell related transcripts. Therefore, this research shows that LCK is a biomarker of prognostic and biological importance, potentially due to its ability to capture the genomic signature of cooperative T and B cell interaction. This provides essential support for further investigation into the role of tumor infiltrating B cells (TIL-B) and tertiary lymphoid structures (TLS), from which insights into this cooperation can be drawn. As ovarian cancer is the leading cause of death from gynecologic malignancy, such insights have the potential to not only offer important prognostic information but also may provide novel therapeutic approaches to the treatment of this deadly disease

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasoundâ Guided Synovial Biopsies in Rheumatoid Arthritis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144312/1/art40453_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144312/2/art40453.pd

GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+thymocytes to polarize their MTOC in response to TCR stimulation

This is not in as prestigious a journal as the first paper described, but it is in a fine one (International Immunology) - and describes work that comes from our undergraduate lab alone. The work began years ago (Emily Hinchcliff, the co-first author, is almost finished with her medical school education at Harvard) but needed to be refined. We are perhaps even happier about this publication which represents the work of several students over several years. It may not take the world by storm, but it does add some very clear and crisp novel information about the molecular basis for differences in mature and immature T cell function. These differences underlie both our ability to generate an immune response and to avoid abnormal (autoimmune) responses - and are still rather mysterious. Specifically, we show that a kinase (GSK3) is regulated differently in the two cell types and is responsible for a failure of the young cells to develop a mature response to signals (polarization of a cytoskeletal structure). This \u27failure\u27 is probably a good thing and keeps the young cells from reacting before they have learned to modulate themselves. --author-supplied descriptio

Exceptional Response to Pembrolizumab for Treatment of Metastatic Chemorefractory Endometrial Carcinoma in a Patient with Lynch Syndrome: A Case Report

Advanced endometrial cancer is associated with poor outcomes and few treatment options exist. Recently, the US Federal Drug Administration approved pembrolizumab for the treatment of endometrial cancers that are deficient in mismatch repair and have high microsatellite instability (MSI). Lynch syndrome is an autosomal dominant disease that causes MSI-high endometrial cancer. We report a case of a 46-year-old woman with Lynch syndrome and advanced endometrial cancer who experienced progressive disease after treatment with chemotherapy with carboplatin and paclitaxel. She was then treated with single-agent pembrolizumab and had an exceptional response. She was noted to have a significant decrease in the size of a large uterine mass extending into the vagina and vulva, as well as decrease in the size of lymphadenopathy. Data are limited at this time for patients with Lynch syndrome treated with single-agent pembrolizumab. Our case report seeks to add to the body of literature that suggests that this patient population may particularly benefit from this novel therapy

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.)