An original administration of ifosfamide given once every other week: a clinical and pharmacological study

Ifosfamide (IFOS) is a bifunctional alkylator with a wide spectrum of activity in solid tumors and has an autoinductive liver metabolism through P450 cytochromes. Autoinduction might permit a better therapeutic index for combination therapy. A phase I trial was investigated with interpatient dose escalation of a single dose of IFOS given every 2 weeks in advanced solid tumor patients. IFOS, its dechloroethylated and active 4-hydroxy metabolites, were measured at cycles 1 and 2 at the end of infusion, 2 and 5 h later, using gas chromatography. IFOS elimination was considered as following monocompartimental model kinetics. The results of 20 patients from January 2004 to June 2006 were included. The median of previous chemotherapies was 2 (0-5). The primary tumor was most often ovarian (5), peritoneal (3), sarcoma (2), melanoma (2) or miscellaneous (8). Ten patients received 2.5 g/m2 and the other 10 patients received 3 g/m2. A total of 79 cycles were evaluable for toxicity. The median number of cycles was 4 (1-8). No grade 3-4 toxicity, no alopecia at first dose level and no toxicity-related fatal events were noted. One objective response was noted in a pancreatic cancer patient and one sustained CA125 decline in a heavily pretreated ovarian cancer patient. A slight (7-10%) but reproducible decrease of areas under the curve was detectable at cycle 2, at both dose levels, related to autoinductive metabolism. Intraindividual variations (large SD) were noticed for each pharmacokinetic parameter. A patient-dependent autoinduction of IFOS metabolism was detected rather than a slight nondose-dependent autoinduction. The toxicity profile allows the development of bi-weekly IFOS-based combination therapies.     

Prognostic impact of tumour burden assessed by metabolic tumour volume on FDG PET/CT in anal canal cancer

Purpose

The aim of this study was to confirm the prognostic value of metabolic tumour volume (MTV) at the primary site on initial work-up FDG PET/CT in patients with squamous cell carcinoma (SCC) of the anal canal.

Methods

Patients with a recent diagnosis of SCC of the anal canal without metastases undergoing PET/CT for initial work-up and treated with (chemo)radiotherapy were retrospectively reviewed. Computer-aided MTV and SUVmax were determined. Survival rates were estimated using the Kaplan-Meier method. Cox regression analysis was used to evaluate prognostic variables of progression-free survival and overall survival (OS).

Results

The study group comprised 75 patients who had an initial work-up PET/CT. Five patients (6.7 %) had stage I disease, 22 (29.3 %) stage II disease, 20 (26.7 %) stage IIIA disease, and 28 (37.3 %) stage IIIB disease. Median follow-up was 51 months (range 10 – 117 months). Global 4-year OS was 82.7 %, ranging from 100 % in patients with stage I disease to 75 % in patients with stage IIIB disease. MTV at the primary site was significantly and independently correlated with OS (p?<?0.05), as patients with MTV less than 7 cm³ had a better prognosis. SUVmax was not correlated with survival parameters. Metabolic involvement of the inguinal lymph nodes was also correlated with a poor outcome in the univariate analysis (p?<?0.05).

Conclusion

MTV at the primary site is a prognostic biomarker in anal canal cancer. Hypermetabolic inguinal lymph nodes also appear to be correlated with survival.

     

Mort subite : y a-t-il une spécificité féminine ?

Sudden cardiac death is a major public health problem with around 40,000 cases per year in France. Epidemiological, clinical and prognostic differences according to gender have been described in most cardiovascular diseases, including sudden cardiac death. In this article, we will review gender differences in sudden cardiac death incidence, circumstance of occurrence, management, and prognosis.     

Dysfonction myocardique post-arrêt cardiaque

Post-resuscitation myocardial dysfunction (PRMD) is a frequent complication, which worsens hemodynamic status and may be lethal by itself. Early identification and treatment of this cardiac complication is one of the key-targets of support during hospitalization of these patients. Easy to identify using echocardiography, PRMD usually begins early after the resuscitation, and is completely reversible within 48 to 72 hours. Its presentation associates myocardial systolic and diastolic dysfunctions, even in the absence of coronary cause. However, detection and treatment of myocardial ischemia should be systematically performed when a coronary cause of cardiac arrest is suspected. To date, the most recommended treatment for systolic dysfunction remains dobutamine since no other pharmacological agents demonstrated its superiority in this setting. In the most severe cases, a mechanical circulatory assistance should be considered providing that neurological prognosis is not compromised.     

Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib

Epidermal growth factor receptor (EGFR)- and type 1 insulin-like growth factor receptor (IGF-1R)-dependent pathways are up-regulated in hepatocellular carcinoma (HCC), and cross-talks between both pathways have been described in other systems. Gefitinib, a specific EGFR inhibitor, has shown to reduce significantly, although not completely, HCC formation in rat cirrhotic liver. Here, we investigated whether IGF-1R-dependent pathways may interfere with EGFR signalling in hepatoma cells and, if so, whether such cross-talks may affect the antitumoral effect of gefitinib in these cells. We show that the proliferative action of IGF2 in HepG2 and Hep3B cells requires EGFR activation through the autocrine/paracrine release of amphiregulin. Thus, IGF2-induced extracellular signal-regulated kinase activity and DNA synthesis were inhibited by neutralizing antibodies against either EGFR or amphiregulin and by TAPI-1, a pharmalogical inhibitor of tumor necrosis factor-alpha converting enzyme, a sheddase of amphiregulin. Accordingly, IGF2 and EGF stimulating effects on cell proliferation were both strongly repressed by gefitinib. However, while gefitinib blocked Akt activation by EGF, it had no effect on Akt activation by IGF2 and did not cause apoptosis by its own. AG1024, a selective IGF-1R inhibitor, induced apoptosis and this effect was potentiated by gefitinib. In conclusion, we show that in HCC cells IGF2/IGF-1R activation triggers proliferative and survival signals through EGFR-dependent and -independent mechanisms, respectively. The IGF2/IGF-1R survival pathway may contribute to gefitinib resistance in these cells. Therefore, the inhibition of IGF2/IGF-1R signalling could potentiate the anti-tumoral effect of gefinitib in HCC.     

Mort subite,en quête d’une explication

Sudden cardiac death, mostly related to ventricular arrhythmia, is a major public health issue, with still very poor survival at hospital discharge. Although coronary artery disease remains the leading cause, other etiologies should be systematically investigated. Exhaustive and standardized exploration is required to eventually offer specific therapeutics and management to the patient as well as his/her family members in case of inherited cardiac disease. Identification and establishing direct causality of the detected cardiac anomaly may remain challenging, underlying the need for a multidisciplinary and experimented team.