Ciência e terapia do câncer

Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed type of injuries are often encountered. Serious drug-induced hepatotoxicity is an infrequent but life-threatening complication often identified through post marketing drug safety surveillance. The main toxicities of Tyrosine Kinase Inhibitors (TKI) therapy are fatigue, rash, diarrhea, hypertension, stomatitis, hand-foot syndrome, hypothyroidism and cardiac toxicity. Whilst most multitargeted TKI exhibit most of the side-effects noted above, each TKI has its particular profile. Sunitinib is an oral multikinase inhibitor that blocks the activity of VEGFR-2 and PDGFR, as well as Src, Abl, insulin-like growth factor receptor-1 and fibroblast growth factor receptor-1 tyrosine kinases, approved by the United States Food and Drug Administration (FDA) in January 2006 for treatment of renal cell carcinoma and gastrointestinal stromal tumor after disease progression or intolerance of Imatinib mesylate. In preapproval clinical trials, two patients reportedly experienced hepatotoxicity during treatment with sunitinib. Although both patients had evidence of liver metastasis before receiving sunitinib, the FDA deemed the suggestion of hepatotoxicity equivocal. We report the case of a patient treated for metastatic renal carcinoma who presented a hepatic cytolysis after introduction the sunitinib: 50mg/day, this is a second report case in the English literature in our knowledge. Clinicians should be aware of this possible adverse effect of sunitinib, and continued pharmacovigilance is imperative to accurately quantify the possible risk of sunitinib-related hepatotoxicity.

Purpose: To assess the impact of external radiotherapy on the survival of patients with early stage endometrial cancer in a population-based setting. Patients and methods: Using information from the Geneva Cancer Registry, we identified all patients who underwent operations for endometrial cancer between 1980 and 1996. We excluded patients with tumours that had spread beyond the uterus, patients without myometrial invasion and patients with poorly differentiated, deeply invasive tumours. Adjusting for other prognostic variables, a Cox proportional hazards analysis was used to calculate the diseasespecific risks and the overall mortality risks in patients treated with brachytherapy or external radiotherapy compared with non-irradiated patients. Stratified analyses were performed for patients with 'low-risk' (superficial myometrial invasion, grades 1-2) and 'high-risk' (superficial invasion grade 3 or deep invasion grades 1-2) tumours. Results: For the 162 patients with low-risk tumours, external radiotherapy was significantly associated with an increased overall mortality (hazard ratio [HR]: 6.4, 95% CI: 1.3-30.2) and endometrial cancer mortality (HR: 9.4, 95% CI: 1.0-86.7). In the group of patients with high-risk tumours (n=108), neither brachytherapy nor external radiotherapy modified the endometrial cancer mortality risk. Conclusion: External radiotherapy does not reduce mortality from early stage endometrial cancer and is associated with a significantly increased overall and endometrial cancer mortality risk among patients with superficially invasive grade 1-2 tumours.

The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. An increased activity is recognized in the majority of clinical relevant hypoxic/ischemic episodes and human cancers .HIF-1 is considered a central regulator of the adaptation response of cancer cells to hypoxia that makes it a therapeutic target in solid tumors. In this article, the biochemical pathways that are regulated by HIF-1 and the factors that regulate HIF-1 expression are briefly discussed .as targeting HIF-1, may selectively kill tumor cells that adapt to low O2 concentrations.

Objective: Second primary tumours (SPT) have been implicated in the dismal overall survival (OS) of head and neck Squamous cell carcinomas (HNSCC). The incidence of SPT, the SPT diagnostic time-lag and the impact on OS were assessed. Subjects and methods: 363 consecutive patients treated for primary Oral SCCs (1967-2004) were analyzed retrospectively in this study. 95.1% and 90.5% of patients reached a minimum follow-up period of 3 and 5 years respectively. Results: Of 363 patients; 68 (18.7%) were diagnosed with metachronous SPT, 49 (13.5%) developed upper aerodigestive tract (UAD)-SPT, 28 (7.7%) were diagnosed with HNSCC-SPT, and 21 (5.8%) developed lung or esophageal carcinoma. Patients with subsequent HNSCC-SPT had a better median survival during follow-up than those not diagnosed with SPTs (p=0.0018). The rate of mortality in these patients showed a substantial increase compared to patients with no subsequent SPT Diagnosis after 144 months. After 200 months the survival experience was no better than those without SPT. Conclusion: These results suggest a better OS for patients afflicted with HNSCC-SPT. This also reflects that at least some of the noted improved OS of HNSCC-SPT patients is due to temporally cumulated risk associated with developing SPT.

Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation, which is seen in as many as 80% of patients with advanced malignancy. It accounts for an estimated 20-30% of all cancer-related deaths. The mechanism by which cancer induces skeletal muscle atrophy in cachexia involves tumor-derived cytokines, including TNF?, IL-1, and IL-6. Upon interaction with their unique receptors on skeletal muscle, these cytokines activate NF-kappaB, a transcription factor crucial for atrophy related sarcomere proteolysis to occur. The significance of NF-?B is highlighted in studies demonstrating that genetic inhibition of NF-?B ameliorates cancer-induced muscle loss in vivo. In the present study, we evaluate a selective NF-kappaB inhibitor (NBD peptide) which targets the IkappaB complex to prevent cancer-induced skeletal muscle atrophy in an established mouse model (C26 adenocarcinoma). We identified for the first time that NBD peptide can directly inhibit tumor-induced NFkappaB activation in skeletal muscle, resulting in a decrease loss of lean muscle. We also identified that NBD peptide reduces the expression of the tumor induced ubiquitin ligases MuRF-1 and MAFbx/Atrogin-1 necessary for atrophy. These findings highlight that NBD peptide may be a potential selective therapeutic agent for the treatment of cancer cachexia.