Rapamycin-enhanced mitomycin C-induced apoptotic death is mediated through the S6K1-Bad-Bak pathway in peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) is the most common secondary cancerous disease, and more effective novel regimens are needed. In this study, we identified a novel combination treatment for PC, chemotherapeutic agent mitomycin C in combination with mTOR (mammalian target of rapamycin) inhibitor rapamycin. We observed that the combination of mitomycin C and rapamycin induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The combination of mitomycin C and rapamycin inactivated p70 S6 ribosomal kinase (S6K1) and dephosphorylated Bad, leading to dissociation of Bcl-xL from Bak, which resulted in Bak oligomerization, mitochondria dysfunction and cytochrome c release. PF-4708671, a S6K1-specific inhibitor, enhanced the combination treatment-induced apoptosis, whereas S6K1 E389 DeltaCT-HA (S6K1 active form) dramatically decreased the induction of apoptosis. In addition, the combination treatment significantly inhibited LS174T intraperitoneal tumor growth in vivo. This study provides a preclinical rationale for apoptosis induction linked with the mTOR pathway through a combination of chemotherapeutic agents and mTOR inhibitor, and will support this combinatorial strategy to PC patients.

A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases from colorectal cancer.

BACKGROUND: Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP. METHODS: Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined. RESULTS: All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 µgPt h/mL, 49.3 ± 30.7 µg h/mL 5-FU (DL1), and 70.5 ± 35.5 µg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %). CONCLUSIONS: The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

Clinical scoring system: a valuable tool for decision making in cases of acute appendicitis.

OBJECTIVE: Decision making in cases of acute appendicitis poses a clinical challenge specially in developing countries where advanced radiological investigations do not appear cost effective and so clinical parameters remain the mainstay of diagnosis. The aim of our study was to devise a scoring system from our local database and test its accuracy in the preoperative diagnosis of acute appendicitis. METHODS: Clinical data from 401 patients having undergone appendectomy were collected to identify predictive factors that distinguished those with appendicitis from those who had a negative appendectomy. Ten such factors were identified and using Bayesian probability a weight was assigned to each and the results summated to get an overall score. A cut-off point was identified to separate patients for surgery and those for observation. The scoring system was then retrospectively applied to a second population of 99 patients in order to compare suggested actions (derived from the scoring system) to those actually taken by surgeons. The sensitivity, specificity and accuracy for the level of decision was then calculated. RESULTS: Of the 99 patients, the method suggested immediate surgery for 65 patients, 63 of whom had acute appendicitis (3.1% diagnostic error rate). Of the 33 patients in whom the score suggested active observation, 18 had appendicitis. The accuracy of our scoring system was 82%. The method had a sensitivity of 78%, specificity 89% and a positive predictive value of 97%. The negative appendectomy rate determined by our study was 7% and the perforation rate 13%. CONCLUSION: Scoring system developed from a local database can work effectively in routine practice as an adjunct to surgical decision making in questionable cases of appendicitis.