Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia.

OBJECTIVE: The glutathione system plays an essential role in antioxidant defense after surgery. We assessed the effects of intensive insulin treatment (IIT) on glutathione synthesis rate and redox balance in cancer patients, who had developed stress hyperglycemia after major surgery. METHODS: We evaluated 10 non-diabetic cancer patients the day after radical abdominal surgery combined with intra-operative radiation therapy. In each patient, a 24-hr period of IIT, aimed at tight euglycemic control, was preceded, or followed, by a 24-hr period of conventional insulin treatment (CIT) (control regimen). Insulin was administered for 24 hours, during total parenteral nutrition, at a dosage to maintain a moderate hyperglycemia in CIT, and normoglycemic blood glucose levels in IIT (9.3±0.5 vs 6.5±0.3 mmol/L respectively, P<0.001; coefficient of variation, 9.7±1.4 and 10.5±1.1%, P = 0.43). No hypoglycemia (i.e., blood glucose < 3.9 mmol/L) was observed in any of the patients. Insulin treatments were performed on the first and second day after surgery, in randomized order, according to a crossover experimental design. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and erythrocyte glutathione synthesis rates (EGSR), measured by primed-constant infusion of L-[2H2]cysteine, were assessed at the end of each 24-hr period of either IIT or CIT. RESULTS: Compared to CIT, IIT was associated with higher EGSR (2.70±0.51 versus 1.18±0.29 mmol/L/day, p = 0.01) and lower (p = 0.04) plasma TBARS concentrations (2.2±0.2 versus 2.9±0.4 nmol/L). CONCLUSIONS: In patients developing stress hyperglycemia after major surgery, IIT, in absence of hypoglycemia, stimulates erythrocyte glutathione synthesis, while decreasing oxidative stress.

Oxaliplatin-based chemotherapy in the treatment of elderly patients with metastatic colorectal cancer (CRC).

Elderly patients constitute a subpopulation with special clinical features that differ from those of the general population and are under-represented in clinical trials. We retrospectively analyzed the toxicity and efficacy of oxaliplatin-based chemotherapy in the treatment of elderly patients affected by metastatic (m) CRC. Seventy-five consecutive patients aged 65-75 years (median age 71 years), 51 males and 24 females, with mCRC and measurable disease, were analyzed. The primary site of metastases was the liver (38.6% of patients). The majority of patients had a performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) PS before treatment of 0-1 (96%). The overall response rate was 57.3%, median progression-free survival was 7 months and median overall survival was 27 months. The main hematological and extra-hematological toxicities (grade 3 or 4) were neutropenia (20.0%), and neurological toxicity or diarrhea (6.7%), respectively. No toxic death occurred. Oxaliplatin-based chemotherapy maintains its efficacy, and safety in elderly patients with mCRC and good PS. This regimen should be considered in the treatment of this particular setting of patients.

Cancer vaccines in phase II/III clinical trials: state of the art and future perspectives.

The topic of this review covers a very important branch of cancer research, cancer vaccination. The growing knowledge in tumor immunology has evolved rapidly, starting from nonspecific generic stimulation of the immune system to more specific approaches based on the availability of tumor antigens. The review covers molecular and cell biology, and pharmaceutical technology of cancer vaccines. Particularly, it is aimed at highlighting the results of cancer vaccines from phase II and III clinical trials, an issue that is of relevance to better understand how cancer vaccines can successfully complement antitumor therapy, including conventional chemotherapy and the recently developed target-based drugs.

Interferon-alpha for maintenance of follicular lymphoma.

BACKGROUND: Indolent non-Hodgkin's lymphoma, in particular follicular lymphoma (FL), is characterized by multiple remissions and relapses. Several studies have used interferon-alpha (IFN) to control this disease, both as induction and as maintenance therapy. It is not yet clear whether IFN can be associated with a survival benefit although it may prolong progression-free survival. OBJECTIVES: To determine the effects of IFN in the maintenance therapy of FL. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2008), MEDLINE (1966 to 2008), DARE (1990 to 2008), SCOPUS (searched December 2008) and Current Contents (1975 to 2008). . SELECTION CRITERIA: Randomised controlled trials of IFN versus no intervention or placebo, or IFN plus chemotherapy versus chemotherapy alone, in a maintenance setting in patients with non-Hodgkin's FL. Primary outcomes were overall survival and progression-free survival. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse events information from the trials. MAIN RESULTS: We included eight trials (1563 patients). The drug was IFN alfa-2b in six trials and alfa-2a in two. Trials were heterogeneous in terms of diagnosis of FL, using several classification systems. IFN had been compared with placebo/no intervention in five trials and other chemotherapy in three. The effect of IFN was similar to that of placebo on overall survival (hazard ratio (HR) 0.90, 95% CI 0.61 to 1.34) whereas IFN was more effective when added to chemotherapy (HR 0.68, 95% confidence interval (CI) 0.52 to 0.90). Considering IFN versus all comparators, IFN was effective in prolonging progression-free survival (HR 0.66, 95% CI 0.57 to 0.77) and overall survival (fixed effects HR 0.79, 95% CI 0.67 to 0.94, I(2) = 52%). After adjustment for heterogeneity this statistically significance disappeared (random effects HR 0.82, 95% CI 0.63 to 1.08). Toxicity and patients lost to follow up were significantly higher in the IFN groups. AUTHORS' CONCLUSIONS: There is evidence that addition of IFN as maintenance therapy for FL improves progression-free survival. A net benefit for overall survival is less evident. In the included studies, IFN was associated with significant toxicities that may have a major impact on a patient's quality of life.

mTOR pathway and mTOR inhibitors as agents for cancer therapy.

Research into mTOR, mammalian Target Of Rapamycin as an important drug target continues to be extremely interesting, both in terms of the increased molecular knowledge being acquired at the basis of various human diseases, and also for possible applications in drug cancer therapy. The mTOR signaling system plays a key role in several transduction pathways that are necessary for cell cycle progression and cellular proliferation. Drugs known as mTOR inhibitors have been included in ongoing and in recently completed cancer trials. New insights into the mTOR signaling system are helping to clarify the functionality of key mTOR components, and especially their possible role in apoptosis, angiogenesis and tumor progression. Three other molecules, already approved for therapeutic use and being commercialized (Everolimius, Temsirolimus and Zotarolimus) are added to Rapamycin (also known as Sirolimus), the parent drug of the mTOR inhibitors. Of these, only Temsirolimus is currently approved in the treatment of renal cell carcinoma, while the others are approved for organ transplant rejection and coronary artery restenosis. There are at least 10 other molecules currently under development for clinical and preclinical studies. This review offers an updated synopsis of the mTOR signaling system, in particular as regards relevant aspects of cancer research, looks at the known mTOR inhibitors and gives a systematic vision of current trials for each individual molecule subject to clinical investigation.

A centralized Pharmacy Unit for cytotoxic drugs in accordance with Italian legislation.

RATIONALE: In May 2002, a centralized Unit for cytotoxic drug preparations [Unità Farmaci Antiblastici (UFA)] was established at the Centro di Riferimento Oncologico, Aviano, Italy. The Unit was created following provisions under Law 626/94 (Legislative Decree - Ministry of Health), governing the safe handling of cytotoxic drugs. New guidelines governing drug preparation ('NBP' standards of preparation) published in Italian Pharmacopoeia (2002, XI Edition) have been mandatory since 2004 and set out rules for proper pharmacy practice applicable also to antineoplastic drug preparations. Aims and objectives To review legislation on cytotoxic drug preparation and compliance within our Unit, to assess current quality levels and identify those areas requiring improvement. METHODS: The study reviewed: (1) the organization and equipment of the Unit UFA and its working methodology; (2) written documentation concerning work procedures; (3) the stability and sterility of injectable drug formulations; (4) staff training, occupational exposure and risk management; (5) accidents and mistakes occurring in the UFA service. RESULTS: The study showed up the strengths of our Unit and identified those areas which need improvement to guarantee product quality excellence. CONCLUSIONS: A critical evaluation of the whole cytotoxic preparation process is a useful method for quality improvements to be initiated. Knowledge regarding risks, techniques, and procedures for handling antineoplastic drugs is growing. Ongoing analysis will ensure greater patient and health care worker safety.