Kliniken Essen-Mitte

BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

BACKGROUND: Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS: In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS: Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS: Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

BACKGROUND: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). CONCLUSIONS: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

BACKGROUND: The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. METHODS: Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. RESULTS: Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. CONCLUSIONS: Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

PURPOSE: Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. The value of adding surgery to chemotherapy and radiotherapy is unknown. PATIENTS AND METHODS: Patients with locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B). Primary outcome was overall survival time. RESULTS: The median observation time was 6 years. The analysis of 172 eligible, randomized patients (86 patients per arm) showed overall survival to be equivalent between the two treatment groups (log-rank test for equivalence, P < .05). Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%; 95% CI, 52.1% to 76.5%) than in the chemoradiotherapy group (2-year progression-free survival, 40.7%; 95% CI, 28.9% to 52.5%; hazard ratio [HR] for arm B v arm A, 2.1; 95% CI, 1.3 to 3.5; P = .003). Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%, respectively; P = .03). Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival (HR, 0.30; 95% CI, 0.19 to 0.47; P < .0001). CONCLUSION: Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.

PURPOSE: Preoperative chemotherapy is an accepted standard in the treatment of localized esophagogastric adenocarcinoma. Adding radiation therapy to preoperative chemotherapy appears promising, but its definitive value remains unknown. PATIENTS AND METHODS: Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. A total of 354 patients were needed to detect a 10% increase in 3-year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual. RESULTS: The median observation time was 46 months. A total of 126 patients were randomly assigned and 119 eligible patients were evaluated. The number of patients undergoing complete tumor resection was not different between treatment groups (69.5% v 71.5%). Patients in arm B had a significant higher probability of showing pathologic complete response (15.6% v 2.0%) or tumor-free lymph nodes (64.4% v 37.7%) at resection. Preoperative radiation therapy improved 3-year survival rate from 27.7% to 47.4% (log-rank P = .07, hazard ratio adjusted for randomization strata variables 0.67, 95% CI, 0.41 to 1.07). Postoperative mortality was nonsignificantly increased in the chemoradiotherapy group (10.2% v 3.8%; P = .26). CONCLUSION: Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction.

BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Abstract Introduction Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies. Methods The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system. Results Based on the existing evidence, the substages were defined as follows: Stage I (IA1): non‐aggressive histological type of endometrial carcinoma limited to a polyp or confined to the endometrium; (IA2) non‐aggressive histological types of endometrium involving less than 50% of the myometrium with no or focal lymphovascular space invasion (LVSI) as defined by WHO criteria; (IA3) low‐grade endometrioid carcinomas limited to the uterus with simultaneous low‐grade endometrioid ovarian involvement; (IB) non‐aggressive histological types involving 50% or more of the myometrium with no LVSI or focal LVSI; (IC) aggressive histological types, i.e. serous, high‐grade endometrioid, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types without any myometrial invasion. Stage II (IIA): non‐aggressive histological types that infiltrate the cervical stroma; (IIB) non‐aggressive histological types that have substantial LVSI; or (IIC) aggressive histological types with any myometrial invasion. Stage III (IIIA): differentiating between adnexal versus uterine serosa infiltration; (IIIB) infiltration of vagina/parametria and pelvic peritoneal metastasis; and (IIIC) refinements for lymph node metastasis to pelvic and para‐aortic lymph nodes, including micrometastasis and macrometastasis. Stage IV (IVA): locally advanced disease infiltrating the bladder or rectal mucosa; (IVB) extrapelvic peritoneal metastasis; and (IVC) distant metastasis. The performance of complete molecular classification ( POLEmut , MMRd, NSMP, p53abn) is encouraged in all endometrial cancers. If the molecular subtype is known, this is recorded in the FIGO stage by the addition of “m” for molecular classification, and a subscript indicating the specific molecular subtype. When molecular classification reveals p53abn or POLEmut status in Stages I and II, this results in upstaging or downstaging of the disease (IICm p53abn or IAm POLEmut ). Summary The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence‐based context for treatment recommendations and for the more refined future collection of outcome and survival data.

•The phase III IMpassion131 trial evaluated atezolizumab combined with paclitaxel as first-line therapy for aTNBC.•The primary endpoint was investigator-assessed PFS, tested hierarchically in the PD-L1+ and then ITT populations.•Neither PFS nor OS was improved with the combination of atezolizumab plus paclitaxel in either population.•These findings may result from imbalances in prognostic features or chance findings in a relatively small trial.•IMpassion131 results highlight the need for further research into immunotherapy for TNBC. BackgroundIn the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC.Patients and methodsEligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint.ResultsOf 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel]. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug.ConclusionCombining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone.ClinicalTrials.govNCT03125902. In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC. Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel]. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone.

BACKGROUND: Mind-body medical interventions are commonly used to cope with depression and yoga is one of the most commonly used mind-body interventions. The aim of this review was to systematically assess and meta-analyze the effectiveness of yoga for depression. METHODS: Medline/PubMed, Scopus, the Cochrane Library, PsycINFO, and IndMED were searched through January 2013. Randomized controlled trials (RCTs) of yoga for patients with depressive disorders and individuals with elevated levels of depression were included. Main outcomes were severity of depression and remission rates, secondary outcomes were anxiety, quality of life, and safety. RESULTS: Twelve RCTs with 619 participants were included. Three RCTs had low risk of bias. Regarding severity of depression, there was moderate evidence for short-term effects of yoga compared to usual care (standardized mean difference (SMD) = -0.69; 95% confidence interval (CI) -0.99, -0.39; P < .001), and limited evidence compared to relaxation (SMD = -0.62; 95%CI -1.03, -0.22; P = .003), and aerobic exercise (SMD = -0.59; 95% CI -0.99, -0.18; P = .004). Limited evidence was found for short-term effects of yoga on anxiety compared to relaxation (SMD = -0.79; 95% CI -1.3, -0.26; P = .004). Subgroup analyses revealed evidence for effects in patients with depressive disorders and in individuals with elevated levels of depression. Due to the paucity and heterogeneity of the RCTs, no meta-analyses on long-term effects were possible. No RCT reported safety data. CONCLUSIONS: Despite methodological drawbacks of the included studies, yoga could be considered an ancillary treatment option for patients with depressive disorders and individuals with elevated levels of depression.

Biological, physical and clinical aspects of cancer treatment with ionising radiation

BACKGROUND: Systematic pelvic and paraaortic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited. METHODS: We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before participation in the trial. The primary end point was overall survival. RESULTS: A total of 647 patients underwent randomization from December 2008 through January 2012, were assigned to undergo lymphadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included in the analysis. Among patients who underwent lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenectomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P = 0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postoperative complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P = 0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P = 0.049]). CONCLUSIONS: Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications. (Funded by Deutsche Forschungsgemeinschaft and the Austrian Science Fund; LION ClinicalTrials.gov number, NCT00712218.).

OBJECTIVES: The aim of this study was to compare the performance of fecal lactoferrin (Lf), calprotectin (Cal), polymorphonuclear neutrophil elastase (PMN-e), as well as serum C-reactive protein (CRP) in patients with inflammatory bowel diseases (IBD) to address (a) whether these markers can differentiate IBD patients with endoscopically assessed inflammation from IBD patients without inflammation and from irritable bowel syndrome (IBS); (b) whether they correlate with endoscopic severity of inflammation; and (c) whether a combination of fecal markers with the respective disease-specific activity indices may increase the diagnostic accuracy with reference to the endoscopic severity of inflammation. METHODS: Fecal levels of Lf, Cal, and PMN-e and serum CRP were assessed in 139 patients undergoing diagnostic ileocolonoscopy (54 IBS patients, 42 ulcerative colitis [UC], 43 Crohn's disease [CD]). Disease activity was determined for CU with the colitis activity index (CAI) and for CD with the Crohn's disease activity index (CDAI). The performance of each marker with reference to endoscopic inflammatory activity was assessed by computing correlations, and sensitivity and specificity using published as well as adjusted cutoffs. A comprehensive activity index was computed by combining results from fecal markers, serum CRP, and a clinical activity index. RESULTS: UC or CD patients with active inflammation demonstrated significantly higher levels of Lf, Cal, and PMN-e in feces as well as serum-CRP when compared to patients with inactive inflammation as well as patients with IBS (all P < 0.05). Using adjusted cutoffs enabled a marked improvement of all markers with an overall diagnostic accuracy in IBD of 80.0% for Lf, 80.0% for Cal, 74.1% for PMN-e, 64.0% for CRP, and 79.0% for the respective clinical disease scores. Cal showed the highest diagnostic accuracy in CD (81.4%), whereas Lf was superior to the other markers in UC (83.3%). The comprehensive activity index yielded a further improvement of sensitivity and specificity, with a diagnostic accuracy of 95.3% for UC patients. CONCLUSION: The fecal markers Lf, Cal, and PMN-e are able to differentiate active IBD from inactive IBD as well as from IBS. None of these three stool markers is consistently superior in its ability to reflect endoscopic inflammation, but all three are superior to CRP in their diagnostic accuracy. A combination of the stool markers with the CRP and a disease-specific activity index in a categorical comprehensive activity index can increase the diagnostic accuracy with reference to the endoscopic inflammation in UC.

INTRODUCTION: The efficacy and the optimal type and volume of aerobic exercise (AE) in fibromyalgia syndrome (FMS) are not established. We therefore assessed the efficacy of different types and volumes of AE in FMS. METHODS: The Cochrane Library, EMBASE, MEDLINE, PsychInfo and SPORTDISCUS (through April 2009) and the reference sections of original studies and systematic reviews on AE in FMS were systematically reviewed. Randomised controlled trials (RCTs) of AE compared with controls (treatment as usual, attention placebo, active therapy) and head-to-head comparisons of different types of AE were included. Two authors independently extracted articles using predefined data fields, including study quality indicators. RESULTS: Twenty-eight RCTs comparing AE with controls and seven RCTs comparing different types of AE with a total of 2,494 patients were reviewed. Effects were summarised using standardised mean differences (95% confidence intervals) by random effect models. AE reduced pain (-0.31 (-0.46, -0.17); P<0.001), fatigue (-0.22 (-0.38, -0.05); P=0.009), depressed mood (-0.32 (-0.53, -0.12); P=0.002) and limitations of health-related quality of life (HRQOL) (-0.40 (-0.60, -0.20); P<0.001), and improved physical fitness (0.65 (0.38, 0.95); P<0.001), post treatment. Pain was significantly reduced post treatment by land-based and water-based AE, exercises with slight to moderate intensity and frequency of two or three times per week. Positive effects on depressed mood, HRQOL and physical fitness could be maintained at follow-up. Continuing exercise was associated with positive outcomes at follow-up. Risks of bias analyses did not change the robustness of the results. Few studies reported a detailed exercise protocol, thus limiting subgroup analyses of different types of exercise. CONCLUSIONS: An aerobic exercise programme for FMS patients should consist of land-based or water-based exercises with slight to moderate intensity two or three times per week for at least 4 weeks. The patient should be motivated to continue exercise after participating in an exercise programme.

BACKGROUND: Breast cancer is the cancer most frequently diagnosed in women worldwide. Even though survival rates are continually increasing, breast cancer is often associated with long-term psychological distress, chronic pain, fatigue and impaired quality of life. Yoga comprises advice for an ethical lifestyle, spiritual practice, physical activity, breathing exercises and meditation. It is a complementary therapy that is commonly recommended for breast cancer-related impairments and has been shown to improve physical and mental health in people with different cancer types. OBJECTIVES: To assess effects of yoga on health-related quality of life, mental health and cancer-related symptoms among women with a diagnosis of breast cancer who are receiving active treatment or have completed treatment. SEARCH METHODS: We searched the Cochrane Breast Cancer Specialised Register, MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), Indexing of Indian Medical Journals (IndMED), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal and Clinicaltrials.gov on 29 January 2016. We also searched reference lists of identified relevant trials or reviews, as well as conference proceedings of the International Congress on Complementary Medicine Research (ICCMR), the European Congress for Integrative Medicine (ECIM) and the American Society of Clinical Oncology (ASCO). We applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials were eligible when they (1) compared yoga interventions versus no therapy or versus any other active therapy in women with a diagnosis of non-metastatic or metastatic breast cancer, and (2) assessed at least one of the primary outcomes on patient-reported instruments, including health-related quality of life, depression, anxiety, fatigue or sleep disturbances. DATA COLLECTION AND ANALYSIS: statistic. We conducted subgroup analyses for current treatment status, time since diagnosis, stage of cancer and type of yoga intervention. MAIN RESULTS: We included 24 studies with a total of 2166 participants, 23 of which provided data for meta-analysis. Thirteen studies had low risk of selection bias, five studies reported adequate blinding of outcome assessment and 15 studies had low risk of attrition bias.Seventeen studies that compared yoga versus no therapy provided moderate-quality evidence showing that yoga improved health-related quality of life (pooled SMD 0.22, 95% CI 0.04 to 0.40; 10 studies, 675 participants), reduced fatigue (pooled SMD -0.48, 95% CI -0.75 to -0.20; 11 studies, 883 participants) and reduced sleep disturbances in the short term (pooled SMD -0.25, 95% CI -0.40 to -0.09; six studies, 657 participants). The funnel plot for health-related quality of life was asymmetrical, favouring no therapy, and the funnel plot for fatigue was roughly symmetrical. This hints at overall low risk of publication bias. Yoga did not appear to reduce depression (pooled SMD -0.13, 95% CI -0.31 to 0.05; seven studies, 496 participants; low-quality evidence) or anxiety (pooled SMD -0.53, 95% CI -1.10 to 0.04; six studies, 346 participants; very low-quality evidence) in the short term and had no medium-term effects on health-related quality of life (pooled SMD 0.10, 95% CI -0.23 to 0.42; two studies, 146 participants; low-quality evidence) or fatigue (pooled SMD -0.04, 95% CI -0.36 to 0.29; two studies, 146 participants; low-quality evidence). Investigators reported no serious adverse events.Four studies that compared yoga versus psychosocial/educational interventions provided moderate-quality evidence indicating that yoga can reduce depression (pooled SMD -2.29, 95% CI -3.97 to -0.61; four studies, 226 participants), anxiety (pooled SMD -2.21, 95% CI -3.90 to -0.52; three studies, 195 participants) and fatigue (pooled SMD -0.90, 95% CI -1.31 to -0.50; two studies, 106 participants) in the short term. Very low-quality evidence showed no short-term effects on health-related quality of life (pooled SMD 0.81, 95% CI -0.50 to 2.12; two studies, 153 participants) or sleep disturbances (pooled SMD -0.21, 95% CI -0.76 to 0.34; two studies, 119 participants). No trial adequately reported safety-related data.Three studies that compared yoga versus exercise presented very low-quality evidence showing no short-term effects on health-related quality of life (pooled SMD -0.04, 95% CI -0.30 to 0.23; three studies, 233 participants) or fatigue (pooled SMD -0.21, 95% CI -0.66 to 0.25; three studies, 233 participants); no trial provided safety-related data. AUTHORS' CONCLUSIONS: Moderate-quality evidence supports the recommendation of yoga as a supportive intervention for improving health-related quality of life and reducing fatigue and sleep disturbances when compared with no therapy, as well as for reducing depression, anxiety and fatigue, when compared with psychosocial/educational interventions. Very low-quality evidence suggests that yoga might be as effective as other exercise interventions and might be used as an alternative to other exercise programmes.

INTRODUCTION: Blood transfusion is associated with increased morbidity and mortality. We developed and implemented an algorithm for coagulation management in cardiovascular surgery based on first-line administration of coagulation factor concentrates combined with point-of-care thromboelastometry/impedance aggregometry. METHODS: In a retrospective cohort study including 3,865 patients, we analyzed the incidence of intraoperative allogeneic blood transfusions (primary endpoints) before and after algorithm implementation. RESULTS: Following algorithm implementation, the incidence of any allogeneic blood transfusion (52.5 vs. 42.2%; P < 0.0001), packed red blood cells (49.7 vs. 40.4%; P < 0.0001), and fresh frozen plasma (19.4 vs. 1.1%; P < 0.0001) decreased, whereas platelet transfusion increased (10.1 vs. 13.0%; P = 0.0041). Yearly transfusion of packed red blood cells (3,276 vs. 2,959 units; P < 0.0001) and fresh frozen plasma (1986 vs. 102 units; P < 0.0001) decreased, as did the median number of packed red blood cells and fresh frozen plasma per patient. The incidence of fibrinogen concentrate (3.73 vs. 10.01%; P < 0.0001) and prothrombin complex concentrate administration (4.42 vs. 8.9%; P < 0.0001) increased, as did their amount administered per year (179 vs. 702 g; P = 0.0008 and 162 × 10³ U vs. 388 × 10³ U; P = 0.0184, respectively). Despite a switch from aprotinin to tranexamic acid, an increase in use of dual antiplatelet therapy (2.7 vs. 13.7%; P < 0.0001), patients' age, proportion of females, emergency cases, and more complex surgery, the incidence of massive transfusion [(≥10 units packed red blood cells), (2.5 vs. 1.26%; P = 0.0057)] and unplanned reexploration (4.19 vs. 2.24%; P = 0.0007) decreased. Composite thrombotic/thromboembolic events (3.19 vs. 1.77%; P = 0.0115) decreased, but in-hospital mortality did not change (5.24 vs. 5.22%; P = 0.98). CONCLUSIONS: First-line administration of coagulation factor concentrates combined with point-of-care testing was associated with decreased incidence of blood transfusion and thrombotic/thromboembolic events.

IMPORTANCE: The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. OBJECTIVE: To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. MAIN OUTCOMES AND MEASURES: Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. RESULTS: Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). CONCLUSIONS AND RELEVANCE: Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01426880.

OBJECTIVES: To systematically review and meta-analyze the effectiveness of yoga for low back pain. METHODS: MEDLINE, the Cochrane Library, EMBASE, CAMBASE, and PsycINFO, were screened through January 2012. Randomized controlled trials comparing yoga to control conditions in patients with low back pain were included. Two authors independently assessed risk of bias using the risk of bias tool recommended by the Cochrane Back Review Group. Main outcome measures were pain, back-specific disability, generic disability, health-related quality of life, and global improvement. For each outcome, standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated. RESULTS: Ten randomized controlled trials with a total of 967 chronic low back pain patients were included. Eight studies had low risk of bias. There was strong evidence for short-term effects on pain (SMD=-0.48; 95% CI, -0.65 to -0.31; P<0.01), back-specific disability (SMD=-0.59; 95% CI, -0.87 to -0.30; P<0.01), and global improvement (risk ratio=3.27; 95% CI, 1.89-5.66; P<0.01). There was strong evidence for a long-term effect on pain (SMD=-0.33; 95% CI, -0.59 to -0.07; P=0.01) and moderate evidence for a long-term effect on back-specific disability (SMD=-0.35; 95% CI, -0.55 to -0.15; P<0.01). There was no evidence for either short-term or long-term effects on health-related quality of life. Yoga was not associated with serious adverse events. DISCUSSION: This systematic review found strong evidence for short-term effectiveness and moderate evidence for long-term effectiveness of yoga for chronic low back pain in the most important patient-centered outcomes. Yoga can be recommended as an additional therapy to chronic low back pain patients.