PTEN deficiency and mutant p53 confer glucose-addiction to thyroid cancer cells: impact of glucose depletion on cell proliferation, cell survival, autophagy and cell migration.

Proliferating cancer cells oxidize glucose through the glycolytic pathway. Since this metabolism is less profitable in terms of ATP production, cancer cells consume large quantity of glucose, and those that experience insufficient blood supply become glucose-addicted. We have analyzed the response to glucose depletion in WRO and FTC133 follicular thyroid cancer cells, which differ in the expression of two key regulators of the glucose metabolism. WRO cells, which express wild type p53 and PTEN, showed a higher rate of cell proliferation and were much less sensitive to glucose-depletion than FTC133 cells, which are PTEN null and express mutant p53. Glucose depletion slowed-down the autophagy flux in FTC133 cells, not in WRO cells. In a wound-healing assay, WRO cells were shown to migrate faster than FTC133 cells. Glucose depletion slowed down the cell migration rate, and these effects were more evident in FTC133 cells. Genetic silencing of either wild-type PTEN or p53 in WRO cells resulted in increased uptake of glucose, whereas the ectopic expression of PTEN in FTC133 cells resulted in diminished glucose uptake. In conclusion, compared to WRO, FTC133 cells were higher glucose up-taker and consumer. These data do not support the general contention that cancer cells lacking PTEN or expressing the mutant p53R273H are more aggressive and prone to better face glucose depletion. We propose that concurrent PTEN deficiency and mutant p53 leads to a glucose-addiction state that renders the cancer cell more sensitive to glucose restriction. The present observation substantiates the view that glucose-restriction may be an adjuvant strategy to combat these tumours

On the universality of anomalous one-dimensional heat conductivity

In one and two dimensions, transport coefficients may diverge in the thermodynamic limit due to long--time correlation of the corresponding currents. The effective asymptotic behaviour is addressed with reference to the problem of heat transport in 1d crystals, modeled by chains of classical nonlinear oscillators. Extensive accurate equilibrium and nonequilibrium numerical simulations confirm that the finite-size thermal conductivity diverges with the system size $L$ as $\kappa \propto L^\alpha$. However, the exponent $\alpha$ deviates systematically from the theoretical prediction $\alpha=1/3$ proposed in a recent paper [O. Narayan, S. Ramaswamy, Phys. Rev. Lett. {\bf 89}, 200601 (2002)].Comment: 4 pages, submitted to Phys.Rev.

Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study.

BACKGROUND: Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001-everolimus-in patients with BTC progressing after prior chemotherapy. PATIENTS AND METHODS: This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP). RESULTS: Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8-4.0) months, and the median OS was 7.7 (5.5-13.2) months. The median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events. CONCLUSION: Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94

Efficacy of nivolumab in pre-treated non-small-cell lung cancer patients harbouring KRAS mutations

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations. Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3–4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively. Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations

Impact of use of oral anticancer drugs on activity of Italian oncology practices: results of a survey conducted by the Italian Society of Medical Oncology (AIOM)

AIMS AND BACKGROUND: In recent years, the number of oral anticancer drugs used in clinical practice has rapidly increased. The Italian Society of Medical Oncology (AIOM) conducted a survey to describe the impact of the use of oral anticancer drugs on the daily activity of Italian oncology practices. METHODS AND STUDY DESIGN: A survey questionnaire was distributed to the coordinators of the regional sections of AIOM. A 6-month period was considered, from January 1, 2010 to June 30, 2010. The survey addressed (1) quantitative aspects of the use of oral anticancer drugs; (2) practical aspects in the management of patients treated with these drugs; (3) issues related to treatment costs and reimbursement procedures. RESULTS: Thirty-six questionnaires were received from institutions distributed throughout the Italian territory. Oral anticancer drugs (both chemotherapy and molecularly targeted agents) accounted for a significant proportion (17%) of prescribed treatments. Among the responding institutions, there were different dispensation procedures of oral drugs to patients: drugs were dispensed by the pharmacist (57%) or directly by the medical oncologist (23%) or nurse (20%). The medical oncologist played a major role in the communication with patients (73% alone and a further 24% in cooperation with other professional figures) and was the point of reference in the event of side effects in 97% of cases. In most cases, the reimbursement of drug costs was separated ("File F" procedure) from the flat fare received by the hospital for outpatient visits or day-hospital access. CONCLUSIONS: Optimal organization of oral anticancer treatment warrants the cooperation and integration of multiple professional figures. At least three figures are involved in patient management in the hospital: the medical oncologist, the nurse, and the hospital pharmacist. Oral anticancer treatments are associated with specific reimbursement issues: in the majority of cases, the cost of the drug is reimbursed separately from the cost of patient access

Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC)

This study was performed to determine the activity of adding continuous infusion (CI) of 5-fluorouracil (5-FU) to gemcitabine (GEM) vs GEM alone in advanced pancreatic cancer (APC). In all, 94 chemo-naïve patients with APC were randomised to receive GEM alone (arm A: 1000 mg m−2 per week for 7 weeks followed by a 2 week rest period, then weekly for 3 consecutive weeks out of every 4 weeks) or in combination with CI 5-FU (arm B: CI 5-FU 200 mg m−2 day−1 for 6 weeks followed by a 2 week rest period, then for 3 weeks every 4 weeks). Overall response rate (RR) was the primary end point and criteria for decision were planned according to the Simon's optimal two-stage design. The overall RR was 8% (arm A) and 11% (arm B) (95% confidence interval: 0.5–16% and 2–22%), respectively, and stable disease was 29 and 28%. The median duration of RR was 34 weeks (range 25–101 weeks) for GEM and 26 weeks (range 16–46 weeks) for the combination. The median progression-free survival (PFS) was 14 weeks (range 2–65 weeks) and 18 weeks (range 4–51 weeks), respectively. The median overall survival (OS) was 31 weeks (range 1–101 weeks) and 30 weeks (1–101 weeks). Toxicity was mild in both arms. This study does not show promising activity in terms of RR, PFS and OS for the double combination arm in APC