Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial).

BACKGROUND: The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m(2) on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter. RESULTS: The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months. CONCLUSION: The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.     

Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study

Background: Oxaliplatin is a new cytotoxic agent from the diaminocyclohexane family with proven antitumor activity against colon cancer cell lines. Activity in patients with colorectal carcinoma previously treated with 5-fluorouracil has been studied in three single-agent phase II trials, showing a reproducible response rate of 10%. Here we report a phase II trial with oxaliplatin as a first-line chemotherapy for metastatic colorectal cancer.Patients and methods: Twenty-five patients were entered in the study. All of them had metastatic disease without previous chemotherapy, and at least one lesion had to be measurable by computed tomography (CT). Therapy consisted of a two-hour infusion of oxaliplatin at a dose of 130 mg/m² every 21 days.Results: The overall response rate determined by investigators was 20% (95% CI, 6.8%–40.7%). Eight patients (32%) had stable disease. The median time to disease progression in responders was six months (range four to nine). The median progression-free survival was four months and median overall survival 14.5 months (95% CI, 10–20 months). The main toxic effects were peripheral neuropathy (92%) and laryngopharyngeal dysesthesia (75%). No severe grade 3–4 neurotoxicities (NCI-CTC) were found. Gastrointestinal and hematological toxicities were mild.Conclusions: Oxaliplatin is an active agent in first-line chemotherapy for advanced colorectal cancer. It was well tolerated, caused no toxic deaths, had low hematotoxicity, well controlled gastrointestinal toxicity, and frequent but mild peripheral neurological symptoms. Therefore, it is of interest to associate oxaliplatin with other active compounds.     

Oral health–related food selectivity among French independently living elders

Impaired oral conditions are described as influencing food intake behaviour and contributing to poor nutritional status in elderly persons. In order to evaluate the influence of age and oral factors on food choice among independently living elderly, we investigated food selectivity and oral health status in elders (aged over 65 years) and in younger people (aged between 35 and 64 years). Food selective behaviour was appraised by using a food selectivity questionnaire based on traditional French dishes. A stepwise binary logistic regression analysis was done to sequentially identify age and oral conditions associated with oral discomfort–related food avoidance. Occlusal status and oral health–related quality of life contributed to food choice. Risk of oral discomfort–related food avoidance was significantly increased in people with fewer than seven occlusal functional units (OFUs) and with Geriatric Oral Health Assessment Index summary scores (GOHAI-ADD) indicating poor and average oral health–related quality of life (P < .05). Age was never a significant factor of food selective behaviour. The present data support the impact of occlusal status and oral health–related quality of life on food behaviour. Specific attention should be given in maintaining or restoring good oral conditions throughout the lifespan, especially occluding teeth.     

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Human cytomegalovirus (HCMV) exploits a range of strategies to evade and modulate the immune response. Its capacity to down-regulate MHC I expression was anticipated to render infected cells vulnerable to natural killer (NK) attack. Kinetic analysis revealed that during productive infection, HCMV strain AD169 first enhanced and then inhibited lysis of primary skin fibroblasts by a CD94/NKG2A(+)NKG2D(+)ILT2(+) NK line. The inhibition of cytotoxicity against strain AD169-infected fibroblasts was abolished by prior treatment of targets or effectors with anti-MHC I and anti-CD94 monoclonal antibodies, respectively, implying a CD94/HLA-E-dependent mechanism. An HCMV strain AD169, UL40 deletion mutant could not inhibit CD94/NKG2A(+) NK killing against skin fibroblasts. The contribution of UL40 to evasion of primary NK cells then was tested in a system where targets and effectors were MHC-matched. Primary NK cells activated with IFNalpha as well as cultured primary NK cell lines showed increased killing against DeltaUL40-infected fibroblasts compared with AD169-infected targets. This effect was abrogated by depletion of CD94(+) cells. These findings demonstrate that HCMV encodes a mechanism of evasion specifically targeted against a proportion of CD94(+) NK cells and show that this system functions during a productive infection.     

Perimount® Bovine Pericardial Valve to Restore Pulmonary Valve Competence Late after Right Ventricular Outflow Tract Repair

Objective. No ideal option exists for restoring pulmonary valve competence late after repair of the congenitally abnormal right ventricular outflow tract (RVOT). This has driven a continued search for new alternatives. Texas Children’s Hospital has recently used the Carpentier‐Edwards Perimount RSR Pericardial Aortic Prosthesis (Edwards Lifesciences, Irvine, Calif, USA) for this indication and reports the initial experience. Design. Retrospective chart review. Setting. Academically affiliated tertiary‐care pediatric hospital. Patients. Twenty‐six patients who underwent pulmonary valve replacement with the Perimount^® valve late after RVOT reconstruction between June 2002 and November 2005. Interventions. No prospective interventions. Outcomes Measures. Hospital morbidity and mortality. Valve function assessed by follow‐up visits and echocardiograms. Results. Mean age and weight of the patients were 20.3 ± 9.8 years (range 7.0–45.1 years) and 56.2 ± 18.1 kg (range 35.8–109 kg). Twenty‐two patients (85%) had severe pulmonary insufficiency (PI), 23 (89%) had symptomatic right heart failure, and 14 (54%) had moderate to severe right ventricular dysfunction. Average prosthetic valve size was 23 mm (range 19–27 mm). Twenty‐one (88%) patients were extubated within 24 hours. There was no hospital mortality. Median length of stay for all patients from day of surgery was 6 days (range 3–56 days). Median length of last echocardiography follow‐up was 12.4 months (range 0.1–37.6 months). At that time, 16 of the 26 (62%) patients had improved right ventricular function, no patient demonstrated significant RVOT obstruction, and 24 patients (92%) have no PI or mild PI. Freedom from death, reintervention, or reoperation on the pulmonary valve is 100% at 2.5 years. Conclusion. Initial results with the Perimount^® bovine pericardial tissue prosthesis for pulmonary valve replacement are encouraging. Further follow‐up is required to define long‐term function and durability.     

Activation of factor XI in plasma is dependent on factor XII [see comments]

The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.     

A miRNA signature for defining aggressive phenotype and prognosis in gliomas

Gliomas represent a disparate group of tumours for which there are to date no cure. Thus, there is a recognized need for new diagnostic and therapeutic approaches based on increased understanding of their molecular nature. We performed the comparison of the microRNA （miRNA） profile of 8 WHO grade II gliomas and 24 higher grade tumours （2 WHO grade III and 22 glioblastomas） by using the Affymetrix GeneChip miRNA Array v. 1.0. A relative quantification method （RT-qPCR） with standard curve was used to confirm the 22 miRNA signature resulted by array analysis. The prognostic performances of the confirmed miRNAs were estimated on the Tumor Cancer Genome Atlas （TCGA） datasets. We identified 22 miRNAs distinguishing grade II gliomas from higher grade tumours. RT-qPCR confirmed the differential expression in the two patients＇groups for 13 out of the 22 miRNAs. The analysis of the Glioblastoma Multiforme （GBM） and Lower Grade Glioma （LGG） datasets from TCGA demonstrated the association with prognosis for 6 of those miRNAs. Moreover, in the GBM dataset miR-21 and miR-210 were predictors of worse prognosis in both univariable and multivariable Cox regression analyses （ HR 1.19, P = O. 04, and HR 1.18, P = 0. 029 respectively）. Our results support a direct contribution of miRNAs to glioma cancerogenesis and suggest that miR-21 and miR-210 may play a role in the aggressive clinical behaviour of glioblastomas.