Preoperative Capecitabine, Oxaliplatin, and Irinotecan in Resectable Gastric or Gastroesophageal Junction Cancer: Pathological Response as Primary Endpoint and FDG-PET Predictions.

OBJECTIVES: This phase II trial was aimed at assessing the safety and activity of capecitabine, oxaliplatin, and irinotecan (COI regimen) as a preoperative treatment for resectable gastric cancer (GC) or gastroesophageal junction (GEJ) cancer. METHODS: Patients affected by T3-T4/N0-N+/M0 GC/GEJ cancer were treated with the COI regimen for 4 cycles followed by restaging and gastroresection with D2 lymphadenectomy. Four postoperative cycles were scheduled. The primary endpoint was pathological response rate according to Becker et al. [Cancer 2003;98:1521-1530]. The potential role of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as a predictive biomarker of pathological tumor response was assessed in a subgroup of 19 evaluable patients. RESULTS: Between January 2011 and October 2015, a total of 40 patients were enrolled. After the preoperative phase, 36 out of 40 patients (90%) were considered eligible for surgery: 12 patients (30%) achieved a pathological response. The most frequent grade 3/4 adverse events were diarrhea (27%), nausea (25%), and fatigue (17%). Grade 3 neutropenia occurred in 7.5% of patients. A lower standard uptake value at baseline FDG-PET/CT was associated with pathological response. CONCLUSION: COI combination is active with a manageable toxicity profile in patients with resectable GC or GEJ cancer. FDG-PET/CT imaging as a surrogate biomarker of pathological response in this setting appears fascinating but should be further investigated.

Fetal mesenchymal stromal cells from cryopreserved human chorionic villi: cytogenetic and molecular analysis of genome stability in long-term cultures.

BACKGROUND AIMS: First-trimester chorionic villi (CV) are an attractive source of human mesenchymal stromal cells (hMSC) for possible applications in cellular therapy and regenerative medicine. Human MSC from CV were monitored for genetic stability in long-term cultures. METHODS: We set up a good manufacturing practice cryopreservation procedure for small amounts of native CV samples. After isolation, hMSC were in vitro cultured and analyzed for biological end points. Genome stability at different passages of expansion was explored by karyotype, genome-wide array-comparative genomic hybridization and microsatellite genotyping. RESULTS: Growth curve analysis revealed a high proliferative potential of CV-derived cells. Immunophenotyping showed expression of typical MSC markers and absence of hematopoietic markers. Analysis of multilineage potential demonstrated efficient differentiation into adipocytes, osteocytes, chondrocytes and induction of neuro-glial commitment. In angiogenic experiments, differentiation in endothelial cells was detected by in vitro Matrigel assay after vascular endothelial growth factor stimulation. Data obtained from karyotyping, array-comparative genomic hybridization and microsatellite genotyping comparing early with late DNA passages did not show any genomic variation at least up to passage 10. Aneuploid clones appeared in four of 14 cases at latest passages, immediately before culture growth arrest. CONCLUSIONS: Our findings indicate that hCV-MSC are genetically stable in long-term cultures at least up to passage 10 and that it is possible to achieve clinically relevant amounts of hCV-MSC even after few stages of expansion. Genome abnormalities at higher passages can occasionally occur and are always associated with spontaneous growth arrest. Under these circumstances, hCV-MSC could be suitable for therapeutic purposes.

Perioperative Bevacizumab-based Triplet Chemotherapy in Patients With Potentially Resectable Colorectal Cancer Liver Metastases.

BACKGROUND: In colorectal cancer liver metastases (CRCLM), bevacizumab-based neoadjuvant strategies provide increased pathologic response. We aimed at assessing the activity of perioperative capecitabine, oxaliplatin, irinotecan, and bevacizumab (COI-B regimen) in patients with potentially resectable CRCLM, and investigating biomarkers for early prediction of pathologic response. PATIENTS AND METHODS: This was a single-center phase II study enrolling patients with liver-limited, borderline resectable disease and/or high-risk features. Patients received 5 preoperative and 4 postoperative cycles of biweekly COI-B (irinotecan 180 mg/m2 and bevacizumab 5 mg/Kg on day 1, oxaliplatin 85 mg/m2 on day 2, and capecitabine 1000 mg/m2 twice a day on days 2 to 6). The primary endpoint was pathologic response rate in the intention-to-treat population. A Simon 2-stage design was adopted to detect an increase from 30% to 50% with a power of 90%. Dynamic imaging biomarkers (early tumor shrinkage [ETS], deepness of response, maximum standardized uptake volume [SUVmax]/regression index) and next generation sequencing data were explored as surrogates. RESULTS: From June 2013 to March 2017, 46 patients were enrolled. Pathologic response was achieved in 63% patients (endpoint met), and responders achieved significantly better survival outcomes with respect to non-responders. The most frequent grade 3/4 adverse events were diarrhea and neutropenia (8.7%) in the preoperative phase and thromboembolic events (5.9%) in the postoperative phase. ETS and lower SUV-2 were significantly associated with pathologic response. CONCLUSION: The COI-B regimen is a feasible and highly active perioperative strategy in patients with molecularly unselected, potentially resectable CRCLM. ETS and SUV-2 have a promising role as imaging-based biomarkers for pathologic response.