A phase I study of continuous hepatic arterial infusion of Irinotecan in patients with locally advanced hepatocellular carcinoma

Purpose: Aim of this phase I study was to identify the maximum tolerated dose and dose limiting toxicity of continuous infusion of Irinotecan through a port-a-cath placed in the hepatic artery in patients with hepatocellular carcinoma and cirrhosis to explore new strategies in advanced hepatocellular carcinoma. Response rate and time-to-progression were analysed. Methods: Irinotecan was delivered as a five-day continuous infusion every 21 days, with increases of 2.5mg/m 2/day every three patients, starting from 7.5mg/m 2/day. Dose limiting toxicity corresponded to one patient in each triplet developing G4 haematological or G3 non-haematological toxicity, confirmed in two triplets. Twenty-eight patients (17 Child-Pugh A, 11 B) received treatment and tumour response was assessed after three courses completed by 22 patients. Results: Dose limiting toxicity was G3 diarrhoea in two patients, reached at 27.5mg/m 2/day and the recommended dose was set at 25mg/m 2/day. Nineteen of 30 patients experienced adverse events related to porth-a-cath placement and one died from liver ischemia and sepsis. Median time-to-progression was 11.3 months. Conclusion: Intrarterial infusion of Irinotecan is feasible in patients with hepatocellular carcinoma on cirrhosis at a recommended dose of 25mg/m 2/day, with no major adverse drug-related events, but with some concerns about the insertion and management of the intra-arterial device

Surgical second-look in high risk gastrointestinal stromal tumor of small intestine: A case report.

The peritoneum is one of the most common sites of distant gastrointestinal stromal tumor (GIST) metastases. In particular, GIST arising from the small intestine with resected minimal synchronous macroscopic peritoneal carcinomatosis or with primary tumor rupture has a higher risk of developing peritoneal recurrence. Current clinical practice does not envisage second-look surgery in GIST patients at high risk of developing peritoneal recurrence, and no literature data are available. PRESENTATION OF CASE: We describe a 45-year-old woman who underwent emergency surgical resection of jejunal GIST presenting with spontaneous tumor rupture, synchronous ovarian and minimal macroscopic peritoneal involvement, and subsequent second-look surgery after 13 months of imatinib treatment. DISCUSSION: Second-look surgery confirmed a 2.6cm lesion close to the mesenteric border of the fourth jejunal loop, and 11 peritoneal lesions with a macroscopic necrotic aspect related to treatment response. After conversion to an open procedure, a segmental jejunal resection was performed with removal of all peritoneal lesions and macroscopic radical cytoreduction. CONCLUSION: Second-look surgery in selected GIST patients may be performed after at least 12 months of medical treatment with tyrosine-kinase inhibitors to identify those patients with limited peritoneal disease not disclosed by instrumental imaging who could undergo radical cytoreduction of peritoneal lesions

Genome-wide analysis identifies MEN1 and MAX mutations and a neuroendocrine-like molecular heterogeneity in Quadruple WT GIST

Quadruple wild-type (WT) gastrointestinal stromal tumor (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathway mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST of which nine cases showed sufficient DNA quality for whole exome sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from whole transcriptome sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared with SDH and KIT/PDGFRA-mutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4, and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRNAs were differentially expressed specifically in quadruple WT GIST. Overexpression of specific molecular markers (COL22A1 and CALCRL) and genes involved in neural and neuroendocrine lineage (ASCL1, Family B GPCRs) were detected and further supported by predicted miRNA target analysis. Quadruple WT GIST show a specific genetic signature that deviates significantly from that of KIT/PDGFRA-mutant and SDH-mutant GIST. Mutations in MEN1 and MAX genes, a neural-committed phenotype and upregulation of the master neuroendocrine regulator ASCL1, support a genetic similarity with neuroendocrine tumors, with whom they also share the great variability in oncogenic driver genes