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The role of RANKL-RANK pathway in progesterone-driven mammary carcinogenesis and triple negative breast cancer tumorigenesis has been well characterized. However, and despite evidences of the existence of RANK-positive hormone receptor (HR)positive breast tumors, the implication of RANK expression in HR-positive breast cancers has not been addressed before. Here, we report that RANK pathway affects the expression of cell cycle regulators and decreases sensitivity to fulvestrant of estrogen receptor (ER)-positive (ER+)/HER2-breast cancer cells, MCF-7 and T47D. Moreover, RANK overexpressing cells had a staminal and mesenchymal phenotype, with decreased proliferation rate and decreased susceptibility to chemotherapy, but were more invasive in vivo. In silico analysis of the transcriptome of human breast tumors, confirmed the association between RANK expression and stem cell and mesenchymal markers in ER+HER2-tumors. Importantly, exposure of ER+HER2cells to continuous RANK pathway activation by exogenous RANKL, in vitro and in vivo, induced a negative feedback effect, independent of RANK levels, leading to the downregulation of HR and increased resistance to hormone therapy. These results suggest that ER+HER2-RANK-positive cells may constitute an important reservoir of slow cycling, therapy-resistance cancer cells; and that RANK pathway activation is deleterious in all ER+HER2-breast cancer cells, independently of RANK levels.

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of diseases characterized by autosomal dominant monogenic non-ketogenic diabetes mellitus, usually with early-onset, with a prevalence of 1-5% of all diabetes cases. A 72-year-old female was admitted with intestinal occlusion, anorexia, vomiting, and weight loss for four months. Medical history of type 2 diabetes mellitus, chronic pancreatitis with abnormal pancreatic development, and acute obstructive jaundice due to a mass in the head of the pancreas with duodenum extension four months before. Assuming surgically unresectable pancreatic neoplasm, digestive bypass surgery was performed. The pathologic examination of surgical specimens was negative for neoplasm. Abdominal imaging showed the pancreatic mass, proximal bowel distension and ascites, which was negative for neoplastic cells. A percutaneous biopsy of the mass revealed adenocarcinoma. Palliative chemotherapy was started. Next-generation sequencing revealed the variant c.-8G>T in the 5’ untranslated region (UTR) region of the adenosine triphosphate (ATP) binding cassette subfamily C member 8 (ABCC8) gene in heterozygosity, associated with the MODY 12 subtype. We report a possible case of MODY 12 diabetes with a phenotype not previously described: a non-neoplastic pancreatic mass that appears in a previously abnormally developed pancreas, with evolution to neoplasm along with the late development of diabetes mellitus. Although this ABCC8 gene mutation could be incidental, there could be a relationship between this mutation, pancreatic malformation, chronic pancreatitis and pancreatic neoplasm. Investigation of new phenotypes is critical, including the potential role of the ABCC8 gene in oncogenesis.

gene expression and oncogenic pathways. The developments in microarray and nextgeneration sequencing platforms enabled the genome-scale identification of molecular dysregulations at the level of mRNA and the possible genomics-guided stratification of tumors for eventual targeted therapeutics. Numerous whole-genome profiles decoding the landscape of molecular determinants of gastric tumors have been established from Japan, South Korea, and China. However, such larger profiles of gastric tumors are largely lacking from India. This is the first comprehensive genomewide expression landscape covering mRNA, miRNA, lncRNA, and splice variants from India.Methods: Gastric tumor samples were collected from our hospital in both liquid nitrogen and RNA later. Quality analysis was performed in Agilent Bioanalyzer 2100 using RNA 6000 Nano chips. Genome-wide expression profiling covering mRNA, miRNA, alternate splicing and lncRNA was performed using Affymetrix HTA 2.0 arrays. The dysregulated genes were compared with the profiles established from other countries. Integrative genomic analysis revealed the transcription factors OCT, NFkB, NFAT, STAT, LEF, AP, PAX, SP1, ELK1, NFYA to be up-regulated and HNF, GATA to be down-regulated in tumors. The tumour samples were then subtyped into eight different groups based on the differential activation of 21 oncogenic signaling pathways. The clinical features, intraoperative details and histopathological characteristics of the samples of the patients were collected. Patients were then followed up for a period of 2 years for recurrence and DFS was calculated. Correlation between genomic subtypes of the tumour samples and clinical outcomes/recurrence patterns were analysed.Results: 108 patients who underwent distal gastrectomy were included in the study and genome-wide expression profiling were performed with their tumour samples. Based on the differential activation of 21 oncogenic signaling pathways, gastric cancer in this South Indian cohort could be subdivided into eight different subtypes. Among the eight subtypes, the subtype GC-1 that showed activation of differentiation-related pathways (Notch, NFAT, SP1-D, RXRA, ECM, HIF1A) was the most prevalent (n¼36). The subgroup GC-7 that demonstrated no significant activation of any pathway had propensity for extranodal extension from lymph nodes when compared to the other types (p-value 0.17). Subgroup 5 and subgroup 7 had greater propensity for spread to regional lymph nodes (p-value 0.45 and 0.42, respectively). The patients belonging to subgroup 7 developed metastasis at an earlier date (p-value 0.08).

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e14007 Background: Brain metastases (BrMs) occur frequently in patients with breast cancer (BC) and represent one of the most difficult-to-treat events. Novel clinical tools are needed to identify BC patients at high risk of developing BrMs. Blood-based liquid biopsies represent a minimally invasive procedure that may detect surrogate markers of pathological changes occuring in the brain as a result of BrMs. Here we evaluated serum levels of a panel of brain-specific protein fragments in metastatic BC patients with BrMs, with no-BrMs and controls. Methods: Our cohort includes stage IV BC patients with BrMs (n= 27; median age 51 y.o.) and no-BrMs (n=50; median age 53.5 y.o.), and healthy controls (H) (n=23, median age 50 y.o.). Serum levels of 5 brain-specific protein fragments were measured by immunoassays and compared between groups. No-BrMs samples were collected at the time of metastatic disease diagnosis; BrMs samples were collected at BrMs diagnosis and before local treatment. Association with overall survival (OS) was evaluated by univariate Cox regression analysis. Results: All markers were significantly higher in patients with no-BrMs compared to H. Only Neurocan, Tenascin-R and GFAP were significantly higher in patients with BrMs compared to H. When comparing metastatic BC patients, significantly higher levels of Tau-A, Tau-C, Neurocan and GFAP were found in no-BrMs patients versus BrMs (Table). Association with OS was not found in BrMs patients, although a trend for high Tau-A levels to predict poor OS was detected in the no-BrMs group (HR 4.4, 95%CI 0.9-21.3, p=0.068). Conclusions: Protein fragments expected to be derived from brain remodeling consequent to BrMs were elevated in BC patients both with BrMs and no-BrMs at the time of sampling, with an overall trend for the highest levels to be found in patients with no-BrMs. This may suggest that brain remodeling processes are associated with BC and could partly explain the relatively high incidence of BrMs relapse in BC. Further studies requiring samples collected pre- and post-treatment are needed to further validate the diagnostic and prognostic value of these non-invasive biomarkers in BC BrMs setting. [Table: see text]

to neutropenic sepsis. Fatigue was also a relevant side-effect present in all the patients, grade 1 in most of them, but grade 3 or higher in 23 patients. The dose of chemotherapy was reduced in 35 patients. In 7 of these patients, dose reduction was due to a peripheral neuropathy. 28 patients had a response, 12 had stable disease, and 9 showed progression. 20/49 patients underwent radical surgery, 12 underwent chemoradiotherapy and 8 stopped the treatment and started a follow-up. Conclusion:FOLFIRINOX as neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma is a good option, providing that good supportive measures are in place to reduce side effects.Legal entity responsible for the study: The authors.