Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility : a Single-Institution Experience

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value. OBJECTIVE: We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s). PATIENTS AND METHODS: From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36-86) and the median number of previous treatment lines was five (range 2-8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%). RESULTS: One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63-3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0-15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80-5.03] vs. 2.13 months [95% CI 1.77-2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17-9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33-10.80] vs. 7.18 months [95% CI 5.63-9.33], respectively, p = 0.06). CONCLUSIONS: This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment

Veno-venous bypass without heparin in orthotopic liver allotransplantation in the pig

It is now widely accepted that a veno-venous bypass is required to minimize the problems of the anhepatic phase in orthotopic liver transplantation. A technique that does not require systemic anticoagulation is needed to prevent damage by heparinization in hepatic patients. The use of heparin-bonded cannulas offers low risks of thromboembolic complication. Fourteen orthotopic liver transplantation were performed in pigs, including 7 with a roller pump and 7 with a centrifugal pump, without systemic anticoagulation and with heparin-bonded circuits except for the portal cannula, connectors, centrifugal pump head and the tract of the circuit on which the roller moves. All the circuits were previously utilized in clinical liver transplantation and repeatedly washed in saline solution and sterilized for each experiment. The haemodynamic control of the anhepatic state was excellent without hypotension and venous engorgement. In only one case a thromboembolic complication was noted. Arterial pressure, heart rate, urine flow, creatinine, arterial pH and thromboelastographic data did not change significantly while on bypass. No difference was found in the use of either a roller or a centrifugal pump even when the blood flow fell to less than 1000 ml/min to 500 ml/min

Orthotopic transplantation of partially hepatectomized liver in the pig

One of the major technical obstacles to liver transplantation in children is to find a liver of appropriate size because of the rarity of child donors. To overcome this difficulty an experimental study was carried out using only a portion of the donor liver (right liver) transplanted orthotopically in pigs. A group of 15 allotransplants were performed. A left hepatectomy of the liver graft was performed ex situ and the right liver amounted to 55% of the whole liver. A total of 13 animals survived for more than 5 days (5 to 30 days, with an average of 16). Upon killing, the liver weight was considerably more than that of the part transplanted. The absence of technical complications suggests that this procedure is safe and feasible

Activity-Based Anorexia Dynamically Dysregulates the Glutamatergic Synapse in the Nucleus Accumbens of Female Adolescent Rats

Intense physical activity and dieting are core symptoms of anorexia nervosa (AN). Their combination evolves into compulsivity, leading the patient into an out-of-control spiral. AN patients exhibit an altered activation of nucleus accumbens (NAc), revealing a dysfunctional mesocorticolimbic reward circuitry in AN. Since evidence exists that a dysregulation of the glutamate system in the NAc influences reward and taking advantage of the activity-based anorexia (ABA) rat model, which closely mimics the hallmarks of AN, we investigated the involvement of the glutamatergic signaling in the NAc in this experimental model. We here demonstrate that food restriction causes hyperactive and compulsive behavior in rodents, inducing an escalation of physical activity, which results in dramatic weight loss. Analysis of the glutamate system revealed that, in the acute phase of the pathology, ABA rats increased the membrane expression of GluA1 AMPA (\u3b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits together with its scaffolding protein SAP97. Recovery of body weight reduced GluN2A/2B balance together with the expression of their specific scaffolding proteins, thus suggesting persistent maladaptive neurotransmission. Taken together, AMPA and NMDA (N-methyl-D-aspartate) receptor subunit reorganization may play a role in the motivational mechanisms underlying AN