ObjectiveThe aim of this study was to explore the effects of cholecalciferol supplementation on vitamin D levels, bone mineral density (BMD), body fat distribution and insulin sensitivity in vitamin D-deficient HIV-1-infected patients. MethodsTwenty vitamin D-deficient HIV-1-infected patients were prospectively treated with 2000 IU cholecalciferol/day for 14 weeks, whereafter treatment was continued with half this dosage until 48 weeks. BMD, body fat distribution, 1,25-dihydroxy vitamin D 3 (1,25(OH) 2 D 3 ), fasting glucose, insulin, adiponectin, leptin, interleukin (IL)-6 and tumour necrosis factor (TNF)-a were measured at baseline, and at 24 and 48 weeks. Parathyroid hormone (PTH), 25-hydroxy vitamin D 3 [25(OH)D 3 ], cholesterol and triglycerides were measured at baseline, and at 12, 24 and 48 weeks. ResultsAfter 24 weeks, cholecalciferol supplementation significantly increased 25(OH)D 3 and 1,25(OH) 2 D 3 levels and decreased PTH and insulin sensitivity. After 48 weeks, however, only 25(OH)D 3 levels remained significantly different from baseline, while the other parameter levels returned to baseline, suggesting a dose-response effect. Cholecalciferol had no effect on BMD, adipokines and triglycerides. ConclusionsThe effect of cholecalciferol treatment in this cohort appears to be dose dependent. Cholecalciferol dosages of !2000 IU are necessary to achieve 1,25(OH) 2 D 3 levels that significantly decrease PTH, but also negatively affect insulin sensitivity. The results of this hypothesis-driven explorative study need to be confirmed in larger clinical trials.Keywords: bone mineral density, cholecalciferol supplementation, HIV/AIDS, insulin sensitivity, vitamin D deficiency Vitamin D is mainly known for its function in regulation of calcium homeostasis and maintenance of bone mineralization. Serum 25(OH)D 3 levels are the best indicator of vitamin D status [3]. The optimal 25(OH)D 3 level needed for maintenance of adequate bone mineral density (BMD) is unknown. A significant positive association between 25(OH)D 3 levels and BMD has been observed in both Another emerging problem associated with the widespread use of HAART is the lipodystrophy syndrome, which is characterized by altered fat distribution (central fat accumulation and peripheral fat loss) and metabolic alterations (dyslipidaemia, insulin resistance and diabetes mellitus). The vitamin D receptor (VDR) has also been found on adipocytes, suggesting a role for vitamin D in fat metabolism [7]. Indeed, it was demonstrated in vitro that 1,25-dihydroxy vitamin D 3 [1,25(OH) 2 D 3 ] inhibits adipocyte differentiation through, among other effects, inhibition of peroxisome proliferator-activated receptor-g (PPAR-g) [7][8][9]. However, 1,25(OH) 2 D 3 can elicit a nongenomic action on adipocytes in vitro, resulting in increased intracellular calcium levels and corresponding stimulation of adipogenesis and inhibition of lipolysis [10].A number of genetic polymorphisms in the VDR gene and low 25(OH)D 3 levels have been associated with insulin resistance and wi...

Background: First-line treatment of HER2−negative LR/MBC with paclitaxel (T) and bevacizumab (A) has demonstrated improved progression-free survival (PFS) and overall response rate (ORR) when compared with T alone (E2100). We determined whether addition of capecitabine (X) to AT is safe and would be better effective than AT in women with HER2−negative LR/MBC. Methods: Eligibility criteria were age ≥18 & ≤75 years, measurable or non-measurable HER2−negative LR/MBC, ECOG PS 0–1 and no prior chemotherapy for LR/MBC. Patients were randomized in 1:1 ratio to receive AT (4-week cycle of T 90 mg/m2 on days 1, 8, 15 and A 10 mg/kg on days 1, 15 for 6 cycles, followed by A 15 mg/kg on day 1 given 3-weekly for subsequent cycles) or ATX (3-week cycle of T 90 mg/m2 on days 1, 8, A 15 mg/kg on day 1 and X 825 mg/m2 bid on days 1–14 for 8 cycles, followed by A 15 mg/kg on day 1 and X 825 mg/m2 bid on days 1–14 given 3-weekly for subsequent cycles). Treatment was discontinued at disease progression, unmanageable toxicity or withdrawal of consent. The primary endpoint was PFS. Secondary endpoints were overall survival, ORR, duration of response and toxicity. Efficacy was evaluated according to RECIST 1.0 and toxicity was assessed according to NCI CTCAE 3.0. Results: From June 2007 till December 2010, 312 patients were recruited at 36 sites. The median age was 56 years (range 32–76). Among all patients, 52% had ECOG 0, 85% were hormone-receptor positive, 86% had measurable disease and 8% had bone-only metastases. These factors were well balanced between both arms. A total of 48% and 33% of patients, respectively, received prior hormonal therapy or radiotherapy for LR/MBC. At the data cut-off of 1st June 2011, the median follow-up duration was 23 months. 311 patients received at least one cycle of treatment and were evaluable for safety. The median number of treatment cycles in AT was 9 and in ATX was 11 (both 33 weeks). An ORR of ≥40% was reached in patients with measurable disease in both groups. The incidence of serious adverse events (SAEs) was 47% and 40% for AT and ATX, respectively, while that of treatment-related SAEs was 12% and 19%, respectively. Treatment-related deaths were 2% for AT and 2% for ATX. The overall rate of AEs grade 3 or 4 was similar in both arms as shown in Table 1, except for hand-foot syndrome grade 3 and neutropenia grade 3 in ATX. In addition, 6 patients with pulmonary embolism were reported in ATX. Conclusions: ATX was well tolerable, although more patients experienced hand-foot syndrome grade 3 and thromboembolic events than patients treated with AT. The efficacy data will be presented at the meeting. Support: This study was supported by Roche. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-07.

Background: Anthracycline-based adjuvant chemotherapy has substantially improved breast cancer survival. Both the addition of taxanes as well as using a dose dense treatment schedule can further ameliorate outcome, but inter-individual differences exist. Here we present the efficacy and toxicity of dose dense scheduled doxorubicin/cyclophosphamide (ddAC) versus docetaxel/doxorubicin/cyclophosphamide (TAC), which is, to our knowledge, the first direct comparison of these treatment regimens. Methods: In this Dutch, multicenter phase III trial (ISRCTN61893718), patients with pT1-3, pN0-3, M0 breast cancer were randomized between six cycles of either A60C600 every 2 weeks or T75A50C500 every 3 weeks. All patients received pegfilgrastim. Patients were evaluated for recurrence-free survival (RFS) and overall survival (OS). Survival was compared in a Cox regression analysis and adjusted for known prognostic factors. These factors include age, type of surgery, tumor size, histological grade, ER/PR status, HER2 status, and lymph node status. Adverse events were reported according to the common toxicity criteria (CTCAE version 3.0). Results: Between 2004 and 2012, 664 patients were enrolled of whom 531 (80%) had node positive disease. At a median follow up of 5 years, OS was 92% in the ddAC treated subgroup and 93% in the TAC treated subgroup (adjusted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.42-1.34, intention to treat population). Forty-two breast-cancer specific deaths were equally divided over both treatment arms. Similarly, no significant difference in RFS was observed between both treatment groups (adjusted HR 0.85, 95% CI 0.55-1.32). Molecular subtypes were defined by St. Gallen criteria: 548 patients (83%) had estrogen receptor positive disease and 102 patients (15%) triple negative disease. No heterogeneity regarding treatment efficacy was observed in these subtypes. In particular, there was no survival benefit for ddAC or TAC in the triple negative subtype. Both treatment regimens were well tolerated. Whereas anemia was more frequent in ddAC treated patients (19% vs 4.7%; p<0.001), peripheral neuropathy occurred more frequently in TAC treated patients (4.6% vs 14.4%; p<0.001). The frequency of febrile neutropenia was not significantly different between the treatment arms (11% vs 12.5%; n.s.). Six patients developed congestive heart failure: 2 ddAC treated patients, 4 TAC treated patients. One ddAC treated patient and one TAC treated patient were diagnosed with acute myeloid leukemia after study treatment; another patient in the ddAC treatment group developed myelodysplastic syndrome. Conclusions: At a median follow up of 5 years no significant survival differences were observed between adjuvant ddAC and TAC, in all patients and in molecular subgroups, including triple negative. Our findings are in line with the Oxford overview, which reported no significant differences between taxane-based chemotherapy and more, non-taxane based chemotherapy given in a dose dense schedule. ddAC could be a reasonable alternative for patients with a contra-indication for TAC. Citation Format: van Rossum AGH, Oosterkamp HM, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok E, van Tinteren H, Kok M, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Rodenhuis S, Linn SC. Adjuvant dose dense doxorubicin-cyclophosphamide (ddAC) or docetaxel-AC (TAC) for high-risk breast cancer: First results of the randomized MATADOR trial (BOOG-2004-04) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-14-03.