Undifferentiated carcinoma of the pancreas is an aggressive but rare tumor for which several other terms have been used to describe its histological appearance. In addition, as osteoclast-like giant cells may accompany undifferentiated carcinoma of the pancreas, the WHO Classification distinguishes undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) from plain undifferentiated carcinoma since there are a few histopathological and clinical differences. UC-OGC was initially thought to be associated with worse prognosis compared to invasive ductal pancreatic adenocarcinoma, since it is often unresectable at diagnosis and tends to recur rapidly even if completely resected. When true UC-OGGs are carefully dissected out from other anaplastic carcinomas, it becomes, however, clear that UC-OGCs do have more indolent behavior, especially the pure UC-OGCs. This mini-review summarizes the current knowledge on UC-OGC.

Aims: Glioblastoma (GBM) is the most common and lethal malignant brain tumor in adults. Glioma stem cells (GSCs) are implicated in this poor prognosis and in radio(chemo‐)resistance. We have previously demonstrated that among potentially highly specific GSC markers oligodendrocyte lineage transcription factor 2 (OLIG2) appears to be the most specific and cyclin D2 (CCND2) the only one related to cell cycle regulation. The purpose of this work was to investigate the clinical significance and the evolution of OLIG2 and CCND2 protein expression in GBM.Methods and results: Immunohistochemical expression analysis of Olig2 and Ccnd2 was carried out on a cohort of human paired GBM samples comparing initial resections with local recurrent tumors after radiation therapy (RT) alone or radio‐chemotherapy with temozolomide (RT‐TMZ). Uni‐ and multivariate logistic regression analysis revealed that significant risk factors predicting early mortality (<12 months) are: subtotal surgery for recurrence, time to recurrence <6 months, Ccnd2 nuclear expression at initial surgery ≥30%, and Olig2 nuclear expression <30% at second surgery after RT alone and RT‐TMZ.Conclusions: We demonstrated that patients for whom nuclear expression of Olig2 becomes low (<30%) after adjuvant treatments have a significantly shorter time to recurrence and survival reflecting most probably a proneural to mesenchymal transition of the GSCs population. We also highlighted the fact that at initial surgery, high nuclear expression (≥30%) of CCND2, a G1/S regulator specific of GSCs, has a prognostic value and is associated with early mortality (<12 months).

Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST) Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST

GISTs are sarcomas of the gastrointestinal tract often associated with gain-of-function mutations in KIT or PDGFRA receptor genes. While most GISTs initially respond to tyrosine kinase inhibitors, relapses due to acquired resistance frequently occur. The induction of ferroptosis, an iron-dependent form of non-apoptotic cell death, emerged as a novel therapeutic approach in cancers and remains poorly characterized in GISTs. We studied hallmarks of ferroptosis, i.e., lipid peroxidation, iron and glutathione content, and GPX4 protein expression in imatinib-sensitive (GIST882) and -resistant (GIST48) GIST cell lines. GIST cells were highly sensitive to the induction of ferroptosis by RSL3, which was reversed by liproxstatin and deferoxamine. Lipid peroxidation and ferroptosis were mediated by VP and CA3 in GIST cells through a significant decrease in antioxidant defenses. Moreover, VP, but surprisingly not CA3, inhibited a series of target genes downstream of YAP in GIST cells. The ferroptosis marker TFRC was also investigated by immunohistochemistry in GIST tissue arrays. TFRC expression was observed in all samples. High TFRC expression was positively correlated with high-risk GISTs, elevated mitotic count, and YAP nuclear localization, reflecting YAP activation. This study highlights ferroptosis as a novel cell death mechanism in GISTs, and a potential therapeutic target to overcome resistance to tyrosine kinase inhibitors.

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports are conflicting, with an important heterogeneity in methods to assess hENT1 expression. A multicenter cohort of 471 patients with a resected PDAC was used to assess simultaneously the predictive value of the 2 best described hENT1 antibodies (10D7G2 and SP120). Three additional antibodies and the predictive value of hENT1 mRNA were also tested on 251 and 302 patients, respectively. hENT1 expression was assessed in 54 patients with matched primary tumors and metastases samples. The 10D7G2 clone was the only hENT1 antibody whose high expression was associated with a prolonged progression free survival and overall survival in patients who received adjuvant gemcitabine. hENT1 mRNA level was also predictive of gemcitabine benefit. hENT1 status was concordant in 83% of the cases with the best concordance in synchronous metastases. The 10D7G2 clone has the best predictive value of gemcitabine benefit in PDAC patients. Since it is not commercially available, hENT1 mRNA level could represent an alternative to assess hENT1 status.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with a dismal prognosis. The five-year survival rate has not changed significantly in over 40 years. Current first-line treatments only offer a modest increase in overall survival in unselected populations, and there is an urgent need to personalize treatment in this aggressive disease and develop new therapeutic strategies. Evolving evidence suggests that the human microbiome impacts cancerogenesis and cancer resistance to therapy. The mechanism of action and interaction of microbiome and PDAC is still under investigation. Direct and indirect effects have been proposed, and the use of several microbiome signatures as predictive and prognostic biomarkers for pancreatic cancer are opening new therapeutic horizons. In this review, we provide an overview for the clinicians of studies describing the influence and associations of oral, gastrointestinal and intratumoral microbiota on PDAC development, progression and resistance to therapy and the potential use of microbiota as a diagnostic, prognostic and predictive biomarker for PDAC.