Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.

BACKGROUND: Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. METHODS: This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20-400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5-10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. FINDINGS: Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy (<400 mg, n=16; 400 mg, n=15). During dose escalation, grade 2 dose-limiting toxic effects occurred in two patients; no grade 3-4 dose-limiting toxic effects were noted. Therefore, the maximum tolerated dose was not reached; the recommended phase 2 dose was selected as 400 mg twice daily. The most common treatment-emergent adverse events in all 32 patients were nausea (17 [53%]), diarrhoea (16 [50%]), and fatigue (16 [50%]). Grade 3 diarrhoea was noted in three (9%) of 32 patients; no grade 4 events were reported. Veliparib pharmacokinetics were dose proportional, with no effect on capecitabine pharmacokinetics. Tumour downstaging after surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. INTERPRETATION: Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. FUNDING: AbbVie Inc.

[Acute pielonephritis and renal abscesses in Piedmont and Aosta Valley]. / Indagine sulla pielonefrite acuta e sugli ascessi renali in Piemonte e Valle d'Aosta.

The Piedmont Group of Clinical Nephrology compared the activity of 18 nephrology centers in Piedmont and Aosta Valley as regards acute pielonephritis (APN). Data from more than 500 cases per year of APN were examined. The microbial spectrum of APN consists mainly of Escherichia coli and Klebsiella pneumoniae. Diagnosis was based on both clinical and radiological criteria in most of the centers (computed tomography-CT o Magnetic Resonance Imaging-MRI). In four centers diagnosis was made with the radiological criteria and in one center only with the clinical features. CT and MRI were performed in about 47% and 44% of cases respectively. Urine culture was positive in 22 up to 100% of cases. The most commonly used antibiotics were fluoroquinolones (ciprofloxacin or levofloxacin) and ceftriaxone (50% of centers) or amoxicillin/clavulanic acid (25% of centers). In 75% of the centers, patients received a combination of two antibiotics (aminoglycoside in 22% of them ). In 72% of the centers, almost 50% of the patients were re-examined, while 38.8% of centers re-examined all the patients. Renal ultrasound was inappropriate to identify abscesses. The mean of patients in whom renal abscesses were detected by CT or MRI was 18.2%. The analysis shows a high variability in the way of diagnosing and treating APN in Piedmont and Aosta Valley regions. This suggests that even if APN is a frequent pathological condition, practical recommendations are required.

Increased Expression of Monocyte CD11b (Mac-1) in Overweight Recent-Onset Type 1 Diabetic Children.

AIM: Compelling evidence implicates inflammation in the pathogenesis of type 1 diabetes mellitus (T1DM) and associated vascular complications. Obesity is also characterized by low-grade systemic inflammation. In this study, we characterized the inflammatory response in diabetes by analyzing the expression of a panel of activation markers on the surface of peripheral blood monocytes in recently-diagnosed T1DM patients. The potential effects of glycemic control and body mass index (BMI) on monocyte phenotype were also investigated. METHODS: Using flow cytometry, we analyzed the expression of CD11b, CD49d, CD54, CD62L and CD64 antigens on monocytes in a cohort of 51 T1DM patients (/= 85th percentile) had higher levels of monocyte activation than those who were not (BMI