Epidemiology and natural history of central venous access device use and infusion pump function in the NO16966 trial

Background: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer.<p></p> Methods: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial.<p></p> Results: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6–4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction.<p></p> Conclusions: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings

MKLN1 splicing defect in dogs with lethal acrodermatitis

Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of similar to 1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN/:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo.Peer reviewe

Influence of dosing times on cisplatin-induced peripheral neuropathy in rats

Background: Although cis-diamminedichloro-platinum (CDDP) exhibits strong therapeutic effects in cancer chemotherapy, its adverse effects such as peripheral neuropathy, nephropathy, and vomiting are dose-limiting factors. Previous studies reported that chronotherapy decreased CDDP-induced nephropathy and vomiting. In the present study, we investigated the influence of dosing times on CDDP-induced peripheral neuropathy in rats. Methods: CDDP (4 mg/kg) was administered intravenously at 5:00 or 17:00 every 7 days for 4 weeks to male Sprague-Dawley rats, and saline was given to the control group. To assess the dosing time dependency of peripheral neuropathy, von-Frey test and hot-plate test were performed. Results: In order to estimate hypoalgesia, the hot-plate test was performed in rats administered CDDP weekly for 4 weeks. On day 28, the withdrawal latency to thermal stimulation was significantly prolonged in the 17:00-treated group than in the control and 5:00-treated groups. When the von-Frey test was performed to assess mechanical allodynia, the withdrawal threshold was significantly lower in the 5:00 and 17:00-treated groups than in the control group on day 6 after the first CDDP dose. The 5:00-treated group maintained allodynia throughout the experiment with the repeated administration of CDDP, whereas the 17:00-treated group deteriorated from allodynia to hypoalgesia. Conclusions: It was revealed that the severe of CDDP-induced peripheral neuropathy was inhibited in the 5:00-treated group, whereas CDDP-treated groups exhibited mechanical allodynia. These results suggested that the selection of an optimal dosing time ameliorated CDDP-induced peripheral neuropathy

Phase II study of cetuximab in combination with FOLFIRI as first-line treatment in patients with unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (FOLCETUX study): preliminary results

The aim of the study was to evaluate the efficacy and safety of cetuximab combined FOLFIRI as a first-line treatment for advanced gastric or GEJ cancer. Methods: Eligibility criteria were: histological diagnosis of stomach or GEJ adenocarcinoma, unresectable/metastatic disease, EGFR+, measurable disease, no CHT for advanced cancer. Pts received cetuximab weekly at 400 mg/m2 iv loading dose, then at 250 mg/m2 iv maintenance dose, CPT11 180 mg/m2 iv d1, LFA 100 mg/m2 iv followed by 5FU 400 mg/m2 iv bolus and 600 mg/m2 iv CI 22h d1-2 every 2 wks, for maximum of 24 wks; therapy with cetuximab alone was continued after 24 wks in CR/PR/SD. The activity was assessed by CT and PET at baseline and after 6 wks, and further by CT alone every 6 wks. Results: From november 2004 to september 2005 32/36 (88.8%) screened pts were EGFR+, and 25 were enrolled. Pt characteristics were: 17(68.0%) M, 8(32%) F; median age 65 years (39-78); median KPS 90 (70-100); 22(88%) stomach, 3(12%) GEJ; 14(56%) prior gastrectomy (total/subtotal); 10(40%) adjuvant CHT; 3(12%) locally advanced disease, 22(88%) metastatic disease. Median number of tretment wks was: 11(1-41). Median dose intensity was: 5FU 100% (25-100), CPT11 100%(25-100) and cetuximab 100% (90-100). At the presnt time, 19 pts are assessable for response (6 too early), and 22 for toxicity. The responses (RECIST) were: 3(16%) CR, 8(42%) PR, 58% CR+PR (95% CI:36-80%), 6(31.5%) SD, 2(10.5%) not evaluable. PFS at 3 months is 81.8% (95% CI:59-104%). Median TTP has not been reached. Gr 3-4 toxicity (CTC v3.0) was: 11(50%) neutropenia, 1(4.5%) thrombocytopenia, 2 (9%) hypertransaminasemia, 1(4.5%) hyperbilirubinemia. Cutaneous toxicity was: 5(22.7%) gr1, 10(45%) gr2, 1(4.5%) gr3. Two deaths occurred within 30 days (1 cardiac failure not treatment-realted; 1 febrile neutropenia). Conclusions: From the preliminary data, the combination of the cetuximab and FOLFIRI appears to be active in gastric and GEJ adenocarcinoma, with a high response and disease control rate. This treatment has been well-tolerated and the major toxicity appars to be limited neutropenia