julilili42/papers huggingface dataset:
Nivolumab (NIVO) safety in patients with advanced melanoma (MEL) who have progressed on or after ipilimumab (IPI): A single-arm, open-label, multicenter, phase II study (CheckMate 172).
2016-05-20

9526 Background: NIVO, a programmed death-1 immune checkpoint inhibitor, improved response rates and progression-free survival (PFS) compared with chemotherapy in MEL patients (pts) who progressed after IPI in the phase III CheckMate 037 trial (Lancet Oncol 2015;16:375). We assessed NIVO monotherapy in pts with MEL who had progressed on or after IPI, including pts with poor prognostic factors who have been largely excluded from clinical trials (eg, ECOG performance status [PS] 2, brain metastases). Methods: In this ongoing phase II, single-arm, open-label, multicenter study, European pts with MEL who progressed on or after IPI are treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity (NCT02156804). The primary endpoint is safety; secondary endpoints include objective response rate (ORR). We report safety in the first 307 treated pts (database lock, November 2015; minimum follow-up of 6 months). Results: At baseline, 8% of pts had ECOG PS 2, 65% had M1c disease, 15% had a history of brain metastases, and 29% had received ≥ 3 prior therapies. Overall, 256 (84%) patients received at least 4 doses of NIVO, while 241 (79%) received > 4 doses. The incidence of treatment-related any grade and grade 3/4 adverse events (AEs) were 58% and 11%, respectively. Discontinuations due to treatment-related AEs occurred in 3% of pts. No treatment-related deaths were reported. The most common treatment-related select AEs (ie, potentially immune-related) were dermatologic (19%), endocrine (9%), gastrointestinal (7%), and hepatic (5%). ORR data are planned to be available for the presentation. Conclusions: CheckMate 172 represents the largest study of NIVO safety and efficacy in pts with MEL who progressed on or after IPI. In this initial report, NIVO demonstrated a safety profile consistent with previously reported clinical trial data. Clinical trial information: NCT02156804.
Incidence of germline mutations in risk genes including BRCA1/2 in consecutive ovarian cancer (OC) patients (AGO TR-1).
2016-05-20

5538 Background: Identification of families at risk for OC including recommendation for prophylactic surgery is the only effective method to reduce OC mortality. In addition, BRCA1/2 mutations are known as prognostic factor and target for treatment. Methods: Prospective counseling and testing of consecutive patients with first diagnosis or platinum sensitive relapse of invasive epithelial OC in Germany. Testing included 25 risk genes related to ovarian cancer (incl. BRCA1, BRCA2, ATM, PALB2, RAD51C, RAD51D, TP53, MLH1, MSH2, MSH6, PMS2). A positive mutation was defined as class 4/5 mutation and a positive family history (FH) was defined as at least one relative with breast cancer (BC) or OC or BC in personal history. Results: In total, 529 pts entered the study, of which 507 were analyzed so far: 270 (53%) patients with first diagnosis of OC and 237 (47%) patients with platinum sensitive relapse. Median age at registration was 61 years (range 18-93). In total, 21% were BRCA1/2 positive (BRCA positive) and 27% for a mutation in at least one risk gene. The incidence of mutations in BRCA1 was 15%, BRCA2: 6%, RAD51C: 1.8%, PALB2: 1.2%. Mutations in all others were found less frequently ( < 1%). Mutations in Lynch syndrome associated genes were found in 0.6%. The incidences did not differ significantly between patients at first diagnosis (BRCA1/2 positive: 19% / risk gene positive: 25%) and relapse (BRCA1/2 positive: 22% / risk gene positive: 30%). Histological subtype and grading were available for 439 patients (87%). The incidence of BRCA / risk gene in high grade serous OC (364/439; 83%) was 23% / 30% and 9% / 19% in all other histological subtypes (75/439; 17%) (p = ns). In elderly patients ( > 70 years at diagnosis), 13% carried a mutation in a risk gene compared to 31% of patients ≤ 70 years (p < 0.001). For 434 pts (86%) FH was evaluable. Of these, 42% had a positive FH. FH identified 69% of the BRCA1/2 positive patients, but missed 31%. Conclusions: 27% of all OC pts harbor a positive mutation in the genes analyzed. Age and FH are insufficient for identifying these patients. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer; limiting testing to BRCA1/2 analysis seems insufficient. Clinical trial information: NCT02222883.
4-Methyl-N-(4-methylpyridin-2-yl)-N-(3,4,5,6-tetrahydro-2H-pyran-4-yl)pyridin-2-amine
2016-05-20

In the title compound, C 17 H 21 N 3 O, the pyridine rings make a dihedral angle of 84.44 (5)°. In the crystal, a C—H...N interaction forms a chain of molecules propagating along the twofold screw axis.
Evaluation of photosensitivity in dabrafenib treated metastatic melanoma patients: Results from a phase IIa study.
2016-05-20

e21077 Background: Dabrafenib (DAB) and vemurafenib (VEM) are highly efficacious in melanomas harbouring BRAF V600 mutations. Serious photo toxicity (PT) has been reported in ~30% of patients (pts.) treated with VEM but only in ~2% of pts. treated with DAB. PT depends on patient’s habits of exposure and sun protection. However, the exact frequency of photosensitivity has to be determined by systematic photo testing. Methods: Primary objective was to characterize the potential of DAB to sensitize skin to UV exposure. We assumed the incidence of PT with DAB is > 0% but lower than those with VEM. An exact binomial test (p = 0.05, 2-sided) had 84% power to detect a difference between the Null hypothesis p0 of 0.8 and the alternative proportion pA of 0.3. Sample size was 10. Photo testing with UVA1/UVB-irradiation was done per standardized protocols: UVA1 (20-100J/cm2) and UVB (according to patient’s minimum erythema dose, up to 200mJ/cm2) without DAB (d1) and 2h after taking DAB (d2). PT was evaluated using the maximal occurring grade (G0: no erythema [ery], G1: light ery., G2: markedly ery., G3: ery. and induration) over 5 days follow-up. Adult patients (ECOG 0-2) with advanced melanoma and BRAF V600 mutation were eligible. All pts. received DAB 150 mg BID po according to the approved preparation. Results: Ten pts. were included (05/2014 - 07/2015). In all pts. UVA1 and UVB grades were documented before DAB intake (UVA1 - 4 pts. with G1, 5 pts. with G2 and 1 pt. with G3; UVB - 4 pts. with G0, 2 pts. with G1, 3 pts. with G2 and 1 pt. with G3). After DAB intake UVA1 and UVB grades were documented repeatedly (max. extent: UVA1 - 3 pts. with G1, 5 pts. with G2 and 2 pts. with G3; UVB - 3 pts. with G0, 1 pt. with G1, 4 pts. with G2 and 2 pts. with G3). In 2/10 cases an increase in PT grades from G1 to G2 and from G2 to G3 occurred in the UVA1 irradiated areas. For UVB an increase in 4 cases was seen (G1 to G2, G2 to G3, G0 to G1 and G1 to G2). None of the patients felt major discomfort due to irradiation. Conclusions: In contrast to published data of PT under VEM the observed PT of DAB was negligible low for UVA1. In the UVB irradiated area 4/10 pts. got an increase in PT by one grade after DAB intake. However, this increase in PT did not induce any clinical discomfort in the majority of pts. Clinical trial information: NCT02052193.
Risk assessment after neoadjuvant chemotherapy in luminal breast cancer: A prospectively planned validation of gene expression based and clinical prognostic scores in 428 residual tumor samples from two neoadjuvant clinical trials.
2016-05-20

522 Background: Gene expression assays are well-established prognostic tools for planning of adjuvant therapy in luminal breast cancer (BC). In the neoadjuvant setting, pCR is not an optimal prognostic factor in luminal BC, and additional parameters are needed. In this study, we evaluated the gene expression test EndoPredict (EP) performed on residual tumor specimen after NACT for predicting prognosis in patients (pts) with ER+/HER2- BC who did not achieve a pCR and compared its prognostic power with the CPS-EG score. Methods: 428 post-NACT FFPE samples of HR+/HER2- BC from the GeparTrio and -Quattro trials were evaluated for mRNA expression of BIRC5, RBBP8, UBE2C, IL6ST, AZGP1, DHCR7, MGP and STC2 by qRT-PCR. The molecular EP and the clinico-molecular EPclin scores were calculated using predefined algorithms and cutoffs. CPS-EG was determined as previously published (Marmé et al. Eur J Cancer). Uni- and multivariate Cox proportional hazard models were used. Results: 175 (41%) of the 428 pts were EPclin low-risk. The continuous EPclin score was significantly associated with poor DFS (HR 2.16 per score unit; 95% CI 1.86-2.51, p < 0.0001). Using predefined diagnostic cutpoints, EPclin high-risk pts had a significantly reduced DFS (HR 4.22; 2.57-6.92; p < 0.0001) and OS (HR 3.66; 2.00-6.69; p < 0.0001). Increased CPS-EG was also significantly linked to poor DFS (HR 2.95; 2.02-4.33; p < 0.0001) and OS (HR 3.70; 2.29-5.99; p < 0.0001). In a bivariate analysis, in contrast to CPS-EG the EPclin score remained significantly prognostic for reduced DFS (HR 2.09, 1.73-2.53, p < 0.0001) and OS (HR 2.16, 1.72-2.72, p < 0.0001). Conclusions: In this prospectively planned biomarker study we show that the information in the hybrid clinico-molecular EPclin score is also prognostic for DFS and OS after NACT and is superior to the clinical CPS-EG score. This approach can be used to assess prognosis after NACT in the luminal non-pCR patient population, and select patients for post-NACT therapies, e.g. treatment with CDK4/6 inhibitors. An additional prospective validation is planned in the ongoing Penelope trial.
Clinical outcome after multicenter, open-label phase II trial on post-surgery chemoradiation in combination with cetuximab in squamous cell carcinoma of the head and neck with high risk of locoregional recurrence.
2016-05-20

6028 Background: We performed an open label phase 2 trial and investigated the efficacy and toxicity of additional cetuximab during and after adjuvant radiochemotherapy (RCT) in head and neck cancer. Methods: 83 Patients with SCCHN were eligible for the study. 61.6 Gy (1.8/2.0/2.2Gy, d1-36) were administered using an integrated boost IMRT-technique. Cis-DDP (20 mg/m2, d1-5 and d29-33) and 5-FU (continuous infusion: 600 mg/m2, d1-d5 + d29-33) were given concurrently. Cetuximab started 7 days prior to RCT at 400 mg/m2 followed by weekly doses of 250 mg/m2. Maintenance cetuximab began after RCT at 500 mg/m2 every 2 weeks for six months. The study was conducted at 10 investigational sites recruiting in Germany from May 2008- December 2010. Results: The number of patients enrolled was 83. Five patients did not meet inclusion criteria leaving 78 for analysis. Median follow up was 1.5 years. 18 patients had events (death or progression) of which 10 were locoregional relapses. 2 year overall survival, disease free survival, and locoregional tumor control were 86% (95%CL 79-95%), 77% (95% CL 66-86%), and 82% (95%CL 93-78%). A total number of 1542 AEs including 196 SAEs were documented. No formerly unknown toxicities were observed. One patient died during RCT. The death was considered to be treatment related, but not related to cetuximab. Acute grade 3+4 toxicities not taking into account skin toxicity outside the radiation portals were observed in 58% of patients, which was below the predefined rate of 67% that was considered as maximally tolerable in these patients. With the expected exception of skin toxicity outside the radiation portals, most grade 3+4 toxcities regress within 6 weeks after RCT. Grade 3+4 late toxicities ( > day 90) were observed in 34% of patients. 20% of patients refuse further treatment with cetuximab after completion of RCT. Conclusions: Adjuvant RCT with concomitant and maintenance cetuximab is feasible and results in a favorable clinical outcome in high risk SCCHNC. Clinical trial information: EudraCT No. 2007-002659-17.
Correlation of AR-V7 expression in whole blood with efficacy of abiraterone acetate (ABI) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
2016-05-20

e23075 Background: Detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has been linked to primary resistance to ABI and enzalutamide (ENZ) (Antonarakis et al. N Engl J Med 2014). We have recently developed a RT-PCR assay for detecting prostate cancer (PCa)-associated transcripts in whole blood. Using this assay, which is not time sensitive and does not require CTC capture and enrichment, we correlated whole blood AR-V7 expression with outcomes on ABI. Methods: 2.5 ml whole blood was collected into PAXgene RNA tubes. RT-PCR was performed for the following genes: AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG. For each gene, the highest CT value among 20 normal controls was set as the threshold for a positive (+) test. Gene expression was correlated with the following clinical endpoints: PSA50 response rate (RR) (PSA decline ≥ 50% confirmed ≥ 3 weeks later), PSA30 RR, time to PSA (PCWG2 criteria) or clinical progression (change in anti-cancer therapy or decline in ECOG performance status (PS) ≥ 2 levels due to PCa), and overall survival (OS). Results: 37 mCRPC patients commencing ABI were recruited from 2 Canadian academic centres. Median age was 70. 59% received prior docetaxel. All pts were ABI and ENZ naïve. PSA50 RR was 37% and PSA30 RR was 48%. Median progression-free survival (PFS) was 3.8 months (mos) and median OS was 21.0 mos. 11% (4/37) of pts were AR-V7+. AR-V7+ pts had higher ALP (P= 0.04; Χ2), higher LDH (P= 0.07) and were more likely to be ECOG PS ≥ 2 (P= 0.052). AR-V7+ disease was associated with lower PSA50 RR (0% vs. 42%, P= 0.10; Χ2) and PSA30 RR (0% vs. 52%, P= 0.051) plus shorter median PFS (0.7 mos vs. 4.0 mos, P< 0.001; log-rank) and median OS (5.5 mos vs. 22.1 mos, P< 0.001). Other factors associated with worse OS were high ALP (P= 0.02), liver metastases (P= 0.03), ≤ 36 mos on primary hormone therapy (P= 0.04), HOXB13+ (P= 0.03) and KLK2+ (P< 0.001). Conclusions: AR-V7 expression in whole blood was associated with very poor outcomes on ABI. Our data serve to reinforce the potential utility of AR-V7 as a prognostic and predictive biomarker for mCRPC. Validation of these findings in larger datasets is ongoing.
Cryobiopsy to increase the detection rate of EGRF-mutations in non-small cell lung cancer.
2016-05-20

e20613 Background: Activating mutations in the epidermal growth factor receptor (EGFR) gene are pharmacological targets for EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small-cell lung cancer (NSCLC) and targeted TKI therapy improves survival in comparison to conventional chemotherapy. This retrospective single center study evaluates the detection rate of mutated EGFR obtained by bronchoscopic cryobiopsy, in comparison to standard sampling techniques. Methods: A total of 420 specimens (03/2008-07/2014) with pathologically confirmed NSCLC and EGFR mutation status tested by Sanger sequencing (Exon 18-21) were studied. Samples obtained by bronchoscopic cryobiopsy were compared with those obtained by other biopsy techniques such as bronchoscopic forceps biopsies, fine needle aspiration, imaging guided transthoracic core needle biopsies and surgical procedures. Results: The cryobiopsy group and the non-cryobiopsy group did not differ regarding smoking history, age and gender. Bronchoscopic cryobiopsy detected activating EGFR mutations in 28 of 126 patients (22.2%) while non cryobiopsy techniques detected mutations in 45 of 294 patients (14.3%) respectively (p = 0.046). 108 cryobiopsies were performed in the central airways, 18 were done in the peripheral airways. There was a non significant higher EGFR mutation rate in bronchoscopic biopsies harvested in the lung periphery compared to the central airways (27% vs. 16,8%). Conclusions: Bronchoscopic cryobiopsy increased the detection rate of activating EGFR mutations in NSCLC compared to other tissue sampling techniques by far. This difference cannot only be explained by an imbalance of biopsy localization. Samples obtained by cryobiopsy might provide better material to detect mutations of EGRF. The higher rate of EGFR mutations in the cryobiopsy group suggests, that there might be false negative results with current sampling techniques and therefore may explain response to TKI of EGFR wild type declared NSCLC patients. As the detection of EGFR mutations is crucial for treatment strategy, cryobiopsy may improve the outcome of a substantial number of patients. A prospective trial comparing cryobiopsy versus forceps biopsy will be initiated
Using ultrasound and palpation for predicting axillary lymph node status following neoadjuvant chemotherapy: Results from the prospective multi-center SENTINA trial.
2016-05-20

1054 Background: Prediction of downstaging of axillary lymph nodes following neoadjuvant chemotherapy (NACT) in previously cN1 patients is important for therapy management. This study aims to investigate the predictive value of palpation in axillary ultrasound in formerly cN1 patients following NACT in the prospective multi-center SENTINA study. Methods: The SENTINA trial is a 4-arm prospective multicenter cohort study designed to examine the Detection-Rate (DR) and False-Negativ-Rate (FNR) of a standardized Sentinel-Node-Biopsy (SLNB)-procedure in the neoadjuvant setting. In SENTINA, patients were categorized into four treatment arms according to axillary staging results before and after NACT using palpation, ultrasound (+/-FineNeedleBiopsy/CoreNeedleBiopsy). In this subset analysis we only included patients and their clinical evaluated axillary lymph node status from arm C (cN1 converted to cN0 after NACT) and D (cN1 remained cN1 after NACT) following NACT. Results: 1240 patients from 104 institutions entered the trial. 715 (arm C n = 592; arm D n = 123) patients, who presented initially with suspicious nodes were included into arm C/D and received evaluation following NACT using palpation und ultrasound. Palpation alone revealed a true negative result in 307 patients, true positive in 32 patients, false negative in 352 patients, demonstrating a FNR of 91.7% and a negative predictive value (NPV) of 46.6%. Ultrasound alone was associated with 299 true negative, 93 true positive and 296 false negative results following NACT with a FNR of 76.1%, and a NPV of 50.3%. Even the combined evaluation of palpation and ultrasound resulted in only 298 true negative (95 true positive, 294 false negative) results, providing a FNR of 75.6%, and a NPV of 50.3%. These results were similar to the result of ultrasound alone, indicating that investigators mainly decided on the basis of the ultrasound finding. Also investigators overall evaluation involving both methods demonstrated more than 2 involved nodes in 24.2% of patients with a cN0 axilla following NACT. Conclusions: Evaluation of the axilla by palpation and ultrasound is negatively impacted by NACT.
Intraoperative assistive technologies and insular gliomas surgery: Results from a volumetry-based retrospective cohort.
2016-05-20

e13525 Background: In the field of Glioma surgery, there has been an increasing interest in the use of assistive technologies to overcome the difficulty of preserving brain function while improving surgical radicality. In most reports, tumor localization has seldom been considered a variable and the role of intraoperative adjuncts is yet to be determined for gliomas of the insula. The present study aims to evaluate the efficacy of fluorescence-guided resection, neurophysiological monitoring, neuronavigation, and tractography in the Extent of Resection (EOR), functionality scores, overall survival and progression-free survival in a retrospective cohort of insular gliomas. Methods: We reviewed all cases of insular tumors operated on at the Department of Neurosurgery, University Hospital of Tübingen – Germany, between May 2008 and November 2013. Extent of resection was determined by comparative volumetric analysis. Mann Whitney, Chi-square and Kaplan-Meier functions were used for assessment of each technology’s effect on primary and secondary outcomes. Results: 28 cases (18 men (64%) and 10 women (36%); median age at diagnosis: 52,5 years, range 12 - 59) were considered eligible for the retrospective cohort. High grade gliomas accounted for 20 cases (71%) and the remaining 8 cases (29%) were low grade gliomas. The most used technologies were Intraoperative Neurophysiological Monitoring (64%) and Neuronavigation (68%). Fluorescence-guided resection with 5-ALA was the only technique associated with resections > 90% (p = 0,04). Secondarily, tractography determined higher rates of improvement in the postoperative Karnofsky performance status (50% vs 5%, p = 0,02); Conclusions: We demonstrate for the first time that for insular gliomas Intraoperative fluorescence with 5-ALA and DTI-based tractography may play a significant role in achieving higher EOR while preserving patients functionality.
Adverse event (AE) management in patients (pts) with relapsed and refractory multiple myeloma (RRMM) taking pomalidomide (POM) plus low dose-dexamethasone (LoDEX): A pooled analysis from 3 clinical trials.
2016-05-20

8031 Background: Pts with RRMM who are heavily pretreated often have advanced disease and comorbidities, increasing their susceptibility to AEs. The management of AEs is important to ensure that pts remain on the therapy for as long as needed to receive a clinical benefit. In this analysis, safety data from 3 POM + LoDEX clinical trials (Richardson Blood 2014; San Miguel Lancet Oncol 2013; Dimopoulos ASH 2015) were pooled to better characterize the safety profile of POM + LoDEX and management of AEs. Methods: The 3 trials enrolled pts with ≥ 2 prior therapies, including lenalidomide and bortezomib, who had progressed on or within 60 days of their last therapy. Pts received POM 4 mg/day on days 1-21 of each 28-day cycle and LoDEX 40 mg (20 mg for those > 75 years of age) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. Grouped AE terms were used for analysis. Results: A total of 1088 pts from the 3 trials were included in the safety population. The most common grade 3/4 AEs were neutropenia (56%), infections (34%), anemia (32%), and thrombocytopenia (26%). AEs were managed by dose modifications and/or supportive care (Table). The rate of grade 3/4 venous thromboembolic events was low (2%). Peripheral neuropathy (PN) of any grade occurred in 17% of pts; 1% experienced grade 3/4 PN. AEs leading to POM dose reductions or interruptions occurred in 24% and 66% of pts, respectively. AEs leading to discontinuation of POM were infrequent (7%). Conclusions: In this large pooled safety analysis, POM + LoDEX showed an acceptable safety profile in pts with RRMM. AEs were manageable, and discontinuations due to AEs were uncommon. Clinical trial information: NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010). POM + LoDEX (N = 1088) Dose management Median average POM dose (range), mg 4.0 (1.6-4.2) ≥ 1 dose reduction, % 24 For neutropeniaa 8 For thrombocytopeniaa 5 For infectionsa 4 Median time to AE onset (range), daysa Neutropenia (n = 693) 20.0 (1.0-591.0) Thrombocytopenia (n = 393) 15.0 (1.0-498.0) Infections (n = 748) 41.5 (1.0-493.0) Supportive care, % Anti-infective 88 Red blood cell transfusion 45 Granulocyte colony-stimulating factor 17 Platelet transfusion 14 a Grouped AE terms.
Local Church in the Global World
2016-05-21

This article gives a brief chronological overview of developments in Orthodox ecclesiology and then focuses on the last phase of this development, so-called ‘national ecclesiology’, which is the current Orthodox ecclesiological model. In the article, national ecclesiology is identified as one of the main sources of the problems which this church faces today. National ecclesiology is blamed for disabling the Orthodox churches from satisfactorily responding to the demands of the modern age, and for inhibiting her adaptation to the globalized pluralistic world. The author also attempts to give an answer to the question of what needs to be done in order to modernize Orthodox ecclesiology.