Objective: To compare, in a phase 3, prospective, randomized, multi-center clinical trial functional outcome of reconstruction procedures following total mesorectal excision (TME). Summary Background Data: Intestinal continuity reconstruction following TME is accompanied by postoperative defecation dysfunctions known as ''anterior resection syndrome.'' Commonly used reconstruction techniques are straight colorectal anastomosis (SCA), colon J-pouch (CJP), and side-toend anastomosis (SEA). Comparison of their functional outcomes in prospective, randomized, multi-center studies, including long-term assessments, is lacking. Methods: Patients requiring TME for histologically proven rectal tumor, with or without neoadjuvant treatment, age ! 18 years, normal sphincter function without history of incontinence, any pretreatment staging or adenoma, expected R0-resection, were randomized for standardized SCA, CJP, or SEA procedures. Primary endpoint was comparison of composite evacuation scores 12 months after TME. Comparison of composite evacuation and incontinence scores at 6, 18 and 24 months after surgery, morbidity, and overall survival represented secondary endpoints. Analysis was based on ''per protocol'' (PP) population, fully complying with trial requirements, and intention-to treat (ITT) population. Results: Three hundred thirty-six patients from 15 hospitals were randomized. PP population included 257 patients (JCP ¼ 63; SEA ¼ 95; SCA ¼ 99). Composite evacuation scores of PP and ITT populations did not show statistically significant differences among the 3 groups at any time point. Similarly, composite incontinence scores for PP and ITT populations showed no statistically significant difference among the 3 trial arms at any time point. Conclusions: Within boundaries of investigated procedures, surgeons in charge may continue to perform reconstruction of intestinal continuity following TME at their technical preference.

BackgroundAdding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab.MethodsThis multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3–5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010.ResultsBetween September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15–35 %) and arm B (24 % [16/68]; 95 % CI 13–34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46–0.69) and 50 % (37/74; 95 % CI 0.39–0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7–11.3) in arm A and 8.5 months (95 % CI 6.5–11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent.ConclusionThis trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3–5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2823-y) contains supplementary material, which is available to authorized users.

The β-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2 -V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a β-3 sympathomimetic agonist, in a phase II trial including 39 JAK2 -V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2 -V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2 -V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone marrow biopsies were evaluated in 20 patients. We found an increase in the nestin + cells from a median of 1.09 (interquartile range 0.38-3.27)/mm 2 to 3.95 (interquartile range 1.98-8.79)/mm 2 ( P <0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0–3) to 0.5 (interquartile range 0–2) ( P =0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing JAK2 -V617F allele burden was not reached, the observed effects on nestin + mesenchymal stem cells and reticulin fibrosis is encouraging, and shows that mirabegron can modify the microenvironment where the JAK2 -mutant stem cells are maintained. (Registered at clinicaltrials.gov identifier: 02311569 .)

This systematic review and meta-analysis evaluated the influence of biological implant surface coatings on periimplant bone formation in comparison to an uncoated titanium reference surface in experimental large animal models. The analysis was structured according to the PRISMA criteriae. Of the1077 studies, 30 studies met the inclusion criteriae. Nineteen studies examined the bone implant contact (BIC) and were included in the meta-analysis. Overall, the mean increase in BIC for the test surfaces compared to the reference surfaces was 3.7 percentage points (pp) (95% CI -3.9-11.2, p = 0.339). Analyzing the increase in BIC for specific coated surfaces in comparison to uncoated reference surfaces, inorganic surface coatings showed a significant mean increase in BIC of 14.7 pp (95% CI 10.6-18.9, p < 0.01), extracellular matrix (ECM) surface coatings showed an increase of 10.0 pp (95% CI 4.4-15.6, p < 0.001), and peptide coatings showed a statistical trend with 7.1 pp BIC increase (95% CI -0.8-15.0, p = 0.08). In this review, no statistically significant difference could be found for growth factor surface coatings (observed difference -3.3 pp, 95% CI -16.5-9.9, p = 0.6). All analyses are exploratory in nature. The results show a statistically significant effect of inorganic and ECM coatings on periimplant bone formation. Abstract: This systematic review and meta-analysis evaluated the influence of biological implant surface coatings on periimplant bone formation in comparison to an uncoated titanium reference surface in experimental large animal models. The analysis was structured according to the PRISMA criteriae. Of the1077 studies, 30 studies met the inclusion criteriae. Nineteen studies examined the bone implant contact (BIC) and were included in the meta-analysis. Overall, the mean increase in BIC for the test surfaces compared to the reference surfaces was 3.7 percentage points (pp) (95% CI 23.9-11.2, p 5 0.339). Analyzing the increase in BIC for specific coated surfaces in comparison to uncoated reference surfaces, inorganic surface coatings showed a significant mean increase in BIC of 14.7 pp (95% CI 10.6-18.9, p < 0.01), extracellular matrix (ECM) surface coatings showed an increase of 10.0 pp (95% CI 4.4-15.6, p < 0.001), and peptide coatings showed a statistical trend with 7.1 pp BIC increase (95% CI 20.8-15.0, p 5 0.08). In this review, no statistically significant difference could be found for growth factor surface coatings (observed difference 23.3 pp, 95% CI 216.5-9.9, p 5 0.6). All analyses are exploratory in nature. The results show a statistically significant effect of inorganic and ECM coatings on periimplant bone formation.

Background. Functional outcomes of different reconstruction techniques have an impact on patients' quality of life (QoL), but information on long-term QoL is lacking. We compared QoL among three reconstruction techniques after total mesorectal excision (TME). Methods. Quality of life was assessed within a randomized, multicenter trial comparing rectal surgery using sideto-end anastomosis (SEA), colon J-pouch (CJP), and straight colorectal anastomosis (SCA) by the Functional Assessment of Cancer Therapy-Colorectal scale (FACT-C) before randomization and every 6 months up to 2 years post-TME. The primary QoL endpoint was the change in the Trial Outcome Index (TOI), including the FACT-C subscales of physical and functional well-being and colorectal cancer symptoms (CSS), from baseline to month 12. Pair-wise comparisons of changes from baseline (presurgery) to each timepoint between the three arms were analyzed by Mann-Whitney tests. Results. For the QoL analysis, 257 of 336 randomized patients were in the per protocol evaluation (SEA = 95; CJP = 63; SCA = 99). Significant differences between the reconstruction techniques were found for selected QoL scales up to 12 months, all in favor of CJP. Patients with SEA or SCA reported a clinically relevant deterioration for TOI and CSS at 6 months, those with SCA for CSS also at 12 months after TME. Patients with CJP remained stable. Conclusions. Although the three reconstruction techniques differ in their effects on QoL at months 6 and 12, these differences did not persist over the whole observation period of 24 months. Patients with a colon J-pouch may benefit with respect to QoL in the short-term.Total mesorectal resection (TME) has improved survival and reduced local recurrence in patients with rectal cancer. 1 Reconstruction techniques after TME include straight colorectal anastomosis (SCA), colon J-pouch (CJP), sideto-end anastomosis (SEA), and transverse coloplasty. 2 SCA leads to the loss of the rectal reservoir, which can cause high defecation frequency, fecal urgency, and