The emphasis in contemporary medical oncology has been “precision” or “personalized” medicine, terms that imply a strategy to improve efficacy through targeted therapies. Similar attempts at precision are occurring in surgical oncology. Sentinel lymph node (SLN) mapping has recently been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity associated with comprehensive lymphadenectomy, yet obtain prognostic information from lymph node status. The Society of Gynecologic Oncology’s (SGO) Clinical Practice Committee and SLN Working Group reviewed the current literature for preparation of this document. Literature-based recommendations for the inclusion of SLN assessment in the treatment of patients with endometrial cancer are presented. This article examines: History and various techniques of SLN mapping in endometrial cancerPathology and clinical outcomes from SLN assessmentControversies and future directions for research in SLN assessment in endometrial cancer

Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.

Non-neural granular cell tumor (NNGCT; also known as primitive polypoid granular cell tumor) is a rare neoplasm composed of large ovoid cells with abundant granular cytoplasm, variable nuclear pleomorphism, and the potential for regional lymph node spread. In contrast to conventional granular cell tumor (GCT), NNGCT lacks S100 expression and can exhibit greater nuclear atypia and mitotic activity. Therefore, we investigated clinicopathologic features of 12 NNGCT, and also used next-generation sequencing to identify potential driver events in a subset of NNGCT and 6 GCT. NNGCT demonstrated mild-to-moderate nuclear pleomorphism, variable mitotic activity (0 to 10/10 high-power fields), and were S100. Genetic analysis of 5 cutaneous NNGCT revealed gene fusions involving the anaplastic lymphoma kinase gene (ALK) in 3 cases (60%). Specifically, an interstitial deletion of chromosome 2 resulting in an in-frame fusion of dyanactin 1 (DCTN1) to ALK was identified in 2 cases, and a translocation resulting in a fusion between sequestosome 1 (SQSTM1) on chromosome 5 and ALK was identified in one case. Two of 6 GCT (33%) showed gains of chromosome 7. No other molecular or chromosomal alterations were detected in NNGCT and GCT. ALK immunohistochemistry revealed weak-to-moderate positivity in 4/9 cutaneous NNCGT (44%) including all 3 tumors with ALK fusions. Three oral NNGCT lacked ALK expression. NNGCT with ALK immunostaining did not have morphologic features distinguishing them from those without ALK staining. Our results demonstrate that a subset of NNGCT harbor ALK fusions, suggest that NNGCT are molecularly diverse, and further substantiate NNGCT as distinct from GCT.

SummaryMelanoma is a cancer with a poorly understood molecular pathobiology. We find the transcription factors

Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is typically effective, but most patients will develop chemo-resistant disease.Mechanisms driving clinical chemo-response and -resistance in ovarian cancer are not well understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant platinum/taxane-based chemotherapy (NACT). NACT offers a window to profile pre-versus post-therapy tumor specimens, which we used to identify chemotherapy-induced changes to the tumor microenvironment. We hypothesized changes in the immune microenvironment correlate with tumor chemo-response and disease progression.We obtained matched pre-and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient n=6). We measured mRNA levels of 770 genes (NanoString), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in additional pre-NACT ascites samples (n=39) by multiplex ELISA. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multi-spectral immunohistochemistry. In NanoString analyses, transcriptional profiles segregated based on pre-and post-NACT status. The most upregulated gene post-NACT was IL6 (17.1-fold, adjusted p = 0.045). RPPA data were highly concordant with mRNA, consistent with elevated immune infiltration. Elevated IL-6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString, RPPA, and cytokine studies identified an activated inflammatory signaling network and induced IL6 and IER3 (Immediate Early Response 3) post-NACT, associated with poor chemo-response and decreased time to recurrence. Taken together, multi-omic profiling of ovarian tumor samples before and after NACT provides unique insight into chemo-induced changes to the tumor and microenvironment.We integrated transcriptional, proteomic, and cytokine data and identified a novel IL-6/IER3 signaling axis through increased inflammatory signaling which may drive ovarian cancer chemoresistance.