Neoadjuvant immunotherapy in microsatellite instability-high (MSI-H) duodenal adenocarcinoma leads to pathological complete response and paves the way for new strategies.

Duodenal adenocarcinoma is a rare digestive cancer, often diagnosed at a late stage and harbours a poor prognosis. The arrival of immunotherapy has changed the prognosis of many neoplasia, including digestive adenocarcinomas with MSI-H status. Hereby, we describe three cases of MSI-H locally advanced duodenal adenocarcinoma who received neoadjuvant treatment with a PD1 inhibitor, pembrolizumab. A partial metabolic and endoscopic response was observed in all patients after 2 cycles. Duodenopancreatectomy was performed at the end of treatment (4-6 cycles), and anatomopathological analysis demonstrated pathological complete response in all patients. Our case series paves the way for prospectively exploring neoadjuvant immunotherapy in duodenal MSI-H adenocarcinoma and raises the question of organ sparing surgery in case of complete clinical response as observed in gastric and colo-rectal adenocarcinomas.

[Colorectal cancer: ten years of illusion of progress but advances are on the horizon]. / Le cancer colorectal : dix années d'illusion de progrès mais des avancées sont à l'horizon.

Recent years have basically been marked by a modest progress in digestive oncology. Biologic drugs such as anti-EGFR and antiangiogenic antibodies have improved the overall survival of patients with advanced colorectal cancer for a few months, but did not alter adjuvant treatment paradigms after curative resection of a locally advanced colon cancer or of liver metastases. With the exception of the RAS gene mutations, predictive of lack of effectiveness to anti-EGFR antibodies, our knowledge of colon cancer tumor biology has hardly evolved. Long-awaited novelties come rather from fundamental discoveries about the different genomic subtypes of colorectal cancer and new immunotherapy approaches which both announce hopefully real giant leaps in the near future.

Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms.

Ras activation is a frequent event in human hepatocarcinoma that may contribute to resistance towards apoptosis. Salirasib is a ras and mTOR inhibitor that induces a pro-apoptotic phenotype in human hepatocarcinoma cell lines. In this work, we evaluate whether salirasib sensitizes those cells to TRAIL-induced apoptosis. Cell viability, cell death and apoptosis were evaluated in vitro in HepG2, Hep3B and Huh7 cells treated with DMSO, salirasib and YM155 (a survivin inhibitor), alone or in combination with recombinant TRAIL. Our results show that pretreatment with salirasib sensitized human hepatocarcinoma cell lines, but not normal human hepatocytes, to TRAIL-induced apoptosis. Indeed, FACS analysis showed that 25 (Huh7) to 50 (HepG2 and Hep3B) percent of the cells treated with both drugs were apoptotic. This occurred through activation of the extrinsic and the intrinsic pathways, as evidenced by a marked increase in caspase 3/7 (five to ninefold), caspase 8 (four to sevenfold) and caspase 9 (eight to 12-fold) activities in cells treated with salirasib and TRAIL compared with control. Survivin inhibition had an important role in this process and was sufficient to sensitize hepatocarcinoma cells to apoptosis. Furthermore, TRAIL-induced apoptosis in HCC cells pretreated with salirasib was dependent on activation of death receptor (DR) 5. In conclusion, salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis by a mechanism involving the DR5 receptor and survivin inhibition. These results in human hepatocarcinoma cell lines and primary hepatocytes provide a rationale for testing the combination of salirasib and TRAIL agonists in human hepatocarcinoma.

Why should the gastroenterologist bother about obesity? An oncologic point of view.

The incidence of obesity worldwide has increased dramatically during recent decades. As a consequence, obesity and associated co-morbidities constitute a serious threat in public health. Substantial epidemiologic evidence indicates that obesity is associated with increased risk of death, and increased incidence and progression of several cancers. Particular attention will be brought here to digestive and liver cancers. Plausible mechanisms by which obesity might participate to increased promotion and progression of cancer will be developed including hyperinsulinemia, insulin resistance and the pro-oxidative pro-inflammatory milieu characterizing the metabolic syndrome. We will focus on the specific case of hepatocellular carcinoma since the highest increase in mortality in obese individuals has been observed for this malignancy. Epidemiological evidence will be reviewed. We will next attempt to offer explanation for the higher risk of HCC in obese individuals although, at this point in time, we have insufficient knowledge to point towards the preeminence of factors directly related to obesity or more tightly linked to NASH itself, the underlying liver disease.

The Ras inhibitor farnesylthiosalicyclic acid (FTS) prevents nodule formation and development of preneoplastic foci of altered hepatocytes in rats.

BACKGROUND: Aberrant activation of oncogenes, such as Ras, likely contributes to the development of hepatocarcinoma (HCC). AIMS/METHODS: We evaluated in vivo the effect of intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) on Ras activation and the development of preneoplastic liver lesions in rats receiving weekly diethylnitrosamine (DEN) injections for 16weeks. Western blotting, quantitative PCR, immunohistochemistry, Tunel and caspase activity assays were used. RESULTS: FTS prevents liver nodule formation and reduces foci expressing the tumour marker GSTp. FTS abrogates DEN-induced Ras membrane activity, increases Tunel positive cells in transformed, GSTp-expressing hepatocytes, up-regulates caspase 3 and 8 activity, induces Fas, Fas ligand and JNK phosphorylation that occurs independently of TNFalpha and Trail. Cytochrome C release, Bax, Bcl2, Bcl-xl, Ki67 and nuclear cyclin D expression is not affected by FTS. CONCLUSIONS: FTS inhibits Ras activation and prevents preneoplastic liver nodule development by inducing apoptosis in transformed hepatocytes through activation of the Fas/Fas ligand system. FTS might be new molecule for HCC treatment.