julilili42/papers huggingface dataset:
Limited versus extended pelvic lymphadenectomy in patients with bladder cancer undergoing radical cystectomy: Survival results from a prospective, randomized trial (LEA AUO AB 25/02).
2016-05-20

4503 Background: The extent of pelvic lymph node dissection (PLND) in bladder cancer patients (pts.) undergoing radical cystectomy may affect survival according to retrospective studies. The German Urologic Oncology Group (AUO) reports mature data of the first prospective, randomized clinical trial to evaluate the impact of a limited versus an extended PLND. Methods: Pts. with high-grade T1 or invasive urothelial bladder cancer (cT2-T4a) from 16 German centers were randomized 1:1 to receive a limited versus an extended PLND at the time of radical cystectomy. Limited PLND included 6 fields (bilateral obturator, internal and external iliac nodes) and extended PLND defined 14 fields (in addition bilateral deep obturator fossa, presacral, paracaval, interaortocaval and paraaortal nodes up to the inferior mesenteric artery). Pts. with neoadjuvant chemo- or radiotherapy were excluded, adjuvant chemotherapy was allowed. The primary endpoint was recurrence-free survival (RFS). Cancer-specific survival (CSS) was a secondary endpoint. The planned total sample size was 400 to detect an improvement in 5-year RFS from 50% to 65% (90% power, 2-sided test, p < 0.05) in the extended arm. Results: In total, 375 of 437 pts. were randomized from 02/2006 to 08/2010 and eligible for intention-to-treat analysis (191 limited and 184 extended PLND). The tumor was locally confined (≤ pT2 pN0) in 49.6% of patients and 24.0% were node positive (pN+). The median number of dissected nodes was 19 in the limited and 32 in the extended arm. The 5-year RFS rate was 62.0% in the limited compared to 69.3% in the extended arm which was statistically not significant (Hazard ratio (HR) = 0.80, 95% Confidence Interval (CI) (0.54-1.19); log-rank p = 0.28). The 5-year CSS rate was improved from 66.2% in the limited to 77.5% in the extended arm which was statistically not significant (HR = 0.70, 95%CI 0.45-1.10; log-rank p = 0.13). Conclusions: We observed a trend but no significant difference toward improved RFS and CSS with an extended PLND. The rate of recurrence was lower than expected in the limited arm, which might be due to the high number of resected nodes in this arm. Clinical trial information: NCT01215071.
A mutation-specific peptide vaccine targeting IDH1R132H in patients with newly diagnosed malignant astrocytomas: A first-in-man multicenter phase I clinical trial of the German Neurooncology Working Group (NOA-16).
2016-05-20

TPS2082 Background: Mutations in the gene for isocitrate dehydrogenase type 1 frequently occur in diffuse gliomas resulting in a point mutation (IDH1R132H) in most of the cases. Preclinical studies have shown that mutation-specific T helper (Th) cell responses spontaneously occur in patients with IDH1-mutated gliomas and that a peptide vaccine encoding IDH1R132H is therapeutic in a humanized mouse tumor model. Methods: NOA-16 (ClinicalTrials.gov Identifier: NCT02454634) is a multicenter, first-in-man, phase I clinical trial, which is planned to enroll 39 patients with newly diagnosed malignant astrocytomas with IDH1R132H mutations at eight German sites. The target population is molecularly enriched for an unfavorable prognosis within the IDH1-mutated subgroup by mandating (i) absence of co-deletion of 1p/19q and (ii) loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression. Patients aged ≥ 18 years with a Karnofsky performance score of ≥ 70 will receive radiotherapy only (cohort 1), combined radiochemotherapy with temozolomide (TMZ, cohort 2) or TMZ only (cohort 3) as the primary treatment based on the decision of the local investigator. Over a period of 32 weeks a total of eight vaccinations with an IDH1R132H peptide emulsified in incomplete Freund's adjuvant produced at a central good manufacturing practice (GMP) site will be administered subcutaneously with topical imiquimod starting three months after the initiation of primary treatment. The primary end points are safety and immunogenicity as measured by IDH1R132H-specific antibody and T cell responses. Secondary outcome measures include progression-free survival (PFS) and overall response rate (ORR). Enrollment started in June 2015. The DMC reviewed the trial in December 2015 and suggested that the trial continues as planned after the first three patients had completed the first vaccinations without a regime-limiting toxicity (RLT). Eight patients have been enrolled at three sites (as of January 2016). Clinical trial information: NCT02454634.
Upper-crustal cooling of the Wrangellia composite terrane in the northern St. Elias Mountains, western Canada
2016-05-20

This study presents the long-term exhumation history of the Wrangellia composite terrane of the remote and ice-covered northern St. Elias Mountains in southwest Yukon, northwest British Columbia, and adjacent Alaska. Detrital zircon and apatite fission-track age distributions are presented from 21 glacial catchments. The detrital sampling approach allows for a large spatial coverage (∼30,000 km2) and access to material eroded beneath the ice. An additional five bedrock samples were dated by zircon fission-track analysis for a comparison with detrital results. Our new thermochronology data record the Late Jurassic–mid-Cretaceous accretion of the Wrangellia composite terrane to the former North American margin and magmatism, which reset the older thermal record. The good preservation of the Jurassic–Cretaceous record suggests that Cenozoic erosion must have been limited overall. Nonetheless, Eocene spreading-ridge subduction and Oligocene–Neogene cooling in response to the ongoing Yakutat flat-slab subduction are evident in the study area despite its inboard position from the active plate boundary. The results further indicate an area of rapid exhumation at the northern end of the Fairweather fault ca. 10–5 Ma; this area is bounded by discrete, unmapped structures. The area of rapid exhumation shifted southwest toward the plate boundary and the center of the St. Elias syntaxis after 5 Ma. Integrating the new data with published detrital thermochronology from the southern St. Elias Mountains reveals an evolving concentration of deformation and exhumation, possibly within a large-scale, transpressional structure providing important constraints for geodynamic models of syntaxes.
MOR202 alone and in combination with pomalidomide or lenalidomide in relapsed or refractory multiple myeloma: Data from clinically relevant cohorts from a phase I/IIa study.
2016-05-20

8012 Background: MOR202, a HuCAL-derived, human IgG1 CD38 monoclonal antibody induces ADCC and ADCP as effector functions; preclinical models show high activity of single-agent MOR202 and synergy in combination with immunomodulatory drugs (IMiDs), lenalidomide (LEN) or pomalidomide (POM). Unlike other CD38 antibodies, MOR202 does not induce complement-dependent cytotoxicity thought to be a major contributor to infusion-related reactions (IRRs). Methods: This is aninterim analysis of a multicenter, dose-escalation phase I/IIa study of MOR202 in relapsed or refractory multiple myeloma (MM). Preliminarysafety and efficacy data from 3 cohorts of patients (pts) treated with MOR202 alone or with an IMiD are presented: MOR202 4, 8 and 16 mg/kg weekly; MOR202 8 or 16 mg/kg weekly with either LEN or POM. Primary objectives were to evaluate the safety, maximum tolerated dose (MTD)/recommended phase II dose of MOR202. Results: As of November 23, 17 pts were treated. Pts receiving MOR202 alone or with POM were relapsed/refractory to prior bortezomib and LEN with a median of 4 and 3 prior regimens respectively. Pts given MOR202 + LEN had a median of 2 prior regimens, mainly bortezomib, cyclophosphamide and autologous stem cell transplant. The MTD has not been reached. MOR202 alone or with an IMiD was well tolerated with mainly hematological toxicity. No MOR202-related study discontinuations or deaths were recorded. A 2-hour MOR202 infusion was feasible in all pts. IRRs (grade 1) were seen in only 1/17 pts. Responses were reported in 6/15 evaluable pts: 2 very good partial responses (VGPR) and 4 partial responses (PR) with 5/6 still ongoing. The longest duration of response was > 10 months in a pt given MOR202 alone; all 9 pts receiving MOR202 alone derived clinical benefit (1 VGPR, 2 PR and 6 stable disease). Preservation of high CD38 levels on MM cells under MOR202 therapy was shown. Conclusions: In this analysis, MOR202 given as a 2-hour infusion showed excellent infusion tolerability and overall safety profile. Promising preliminary efficacy and long-lasting tumor control was seen for MOR202 +/- IMiDs. Clinical trial information: NCT01421186.
ELOQUENT-2 update: Phase III study of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM)—Identifying responders by subset analysis.
2016-05-20

8037 Background: Extended follow-up of ELOQUENT-2 (NCT01239797) showed 27% reduction in risk of disease progression/death for ELd vs Ld and OS trend in favor of ELd (Dimopoulos M et al. ASH 2015; oral 28). We present subset analyses of extended 3-y follow-up. Methods: RRMM pts were randomized to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity (Lonial S et al. NEJM. 2015;373:621-31.). Coprimary endpoint: PFS. Key secondary endpoint: OS. Results: 646 pts randomized: 321 ELd, 325 Ld. Baseline demographics: median age 66 y; 32% of pts had del(17p), 9% t(4;14); median of 2 prior therapies; 35% refractory to last therapy. PFS and OS subset analyses shown in Table (data cut-off 13 Aug 2015). Median duration of response: ELd 20.3 vs Ld 16.6 mo. Conclusions: Subset analyses for ELd vs Ld were consistent with previous findings. PFS and OS benefit of ELd was seen across key subgroups, PFS benefit was durable over time. Clinical trial information: NCT01239797.PFS HR (95% CI) Median, mo (95% CI) ELd Ld Prior bortezomib Yes 0.68 (0.55–0.85) 18.5 (15.9–21.2) 12.9 (10.2–16.6) No 0.83 (0.58–1.21) 22.2 (16.6–30.3) 18.4 (13.9–22.9) Prior lenalidomide Yes 0.55 (0.24–1.25) 24.9 (12.0–NA) 7.4 (3.9–17.4) No 0.74 (0.61–0.91) 18.5 (16.5–22.2) 14.9 (12.3–17.5) del(17p)+ 0.70 (0.49–0.99); p = 0.042 21.2 (16.6–27.5) 14.9 (10.6–18.5) del(17p)- 0.73 (0.58–0.92); p = 0.007 18.5 (15.8–22.8) 14.8 (11.7–18.4) t(4;14)+ 0.52 (0.29–0.93); p = 0.027 15.8 (8.4–18.5) 5.6 (3.1–10.3) t(4;14)- 0.74 (0.60–0.91); p = 0.004 20.3 (17.3–23.3) 15.7 (13.0–18.5) Age < 65 y 0.74 (0.55–0.99); p = 0.043 19.4 (15.9–22.8) 16.6 (12.1–19.4) Age ≥ 65 y 0.72 (0.56–0.92); p = 0.009 18.5 (15.8–23.9) 13.9 (11.1–17.2) OS Risk High* 0.60 (0.37–0.97) 29.8 (22.2–NA) 24.8 (11.7–31.24) Low† 0.84 (0.28–2.52) NA (33.1–NA) 40.8 (35.2–NA) Standard 0.95 (0.72–1.26) 43.7 (40.1–NA) 47.6 (36.9–NA) del(17p)+‡ 0.66 (0.43–1.00) NA (35.8–NA) 36.4 (30.2–NA) del(17p)- 0.86 (0.66–1.14) 42.3 (36.7–NA) 40.8 (33.2–NA) Age < 65 y 0.77 (0.52–1.13) NA (42.9–NA) 40.9 (39.6–NA) Age ≥ 65 y 0.78 (0.58–1.03) 40.1 (30.5–NA) 32.2 (27.8–40.9) *ISS stage 2 or 3; t(4;14)+ or del(17p)+;†ISS stage 1 or 2; t(4;14)-, del(17p)- or 1q21-; age < 55 y; ‡≥ 1 cell del(17p)+
The DETECT study concept: Individualized therapy of metastatic breast cancer.
2016-05-20

TPS634 Background: Circulating tumor cells (CTCs) are found in blood samples of patients with early as well as metastatic breast cancer (MBC). The prognostic and predictive value of CTCs, whose phenotype may differ from the primary tumor, has been described already. However, treatment decisions often still result from the primary tumor's phenotype without considering CTC-characteristics. The importance of CTC phenotypes for guiding therapeutic decisions will be investigated within the DETECT studies. Methods: The DETECT study concept provides a prospective, multicenter, open-label clinical trial program comprising two phase III studies (DETECT III and V) and one phase II study (DETECT IV). Women with HER2-negative MBC are tested for CTCs and their HER2-phenotype. CTC detection is performed by the FDA-approved CellSearch System (Janssen Diagnostics, Raritan, USA). Patients with HER2-positive CTCs are recruited into DETECT III and randomized to a physician's choice chemo- or endocrine therapy +/- additional HER2-targeted treatment with lapatinib. Patients with only HER2-negative CTCs are included in DETECT IV. Postmenopausal women with hormone-receptor (HR)-positive MBC are treated with everolimus and a physician's choice endocrine therapy (DETECT IVa); women with triple-negative MBC or HR-positive tumors with indication for chemotherapy receive eribulin (DETECT IVb). In DETECT V/CHEVENDO, which started in autumn 2015, women with HER2- and HR-positive MBC are randomized to a dual HER2-directed therapy with pertuzumab and trastuzumab plus either chemotherapy or endocrine therapy. CTC-presence is not obligatory in DETECT V, but translational research projects focus on CTC-enumeration and the assessment of marker expression on CTCs in order to calculate an endocrine-responsiveness-score, which will be evaluated regarding to its suitability to predict treatment success. Perspective: Changes in the dynamic of CTCs during therapy and their HER2-phenotype may influence following therapy decisions. The DETECT study program evaluates the prognostic and predictive role of CTCs as well as a CTC based therapy and enables the establishment of a more personalized therapy for patients with MBC. Clinical trial information: NCT01619111, NCT 02035813, NCT02344472.
PRINCE: A phase III study comparing intermittent docetaxel therapy versus continuous docetaxel therapy in patients with castration-resistant prostate cancer.
2016-05-20

5005 Background: A randomized phase III study investigating the non-inferiority of an intermittent docetaxel compared to a continuous docetaxel treatment for patients with castration-resistant prostate cancer (CRPC). Methods: 187 patients were randomized to either an intermittent docetaxel treatment or to a continuous docetaxel treatment until discontinuation (docetaxel application in both arms was weekly 35mg/m2 or three-weekly 75mg/m2). The intermittent arm received docetaxel for one study sequence of 12 weeks and then paused until clinical disease progression, defined by one of the following criteria: increased serum PSA > 4ng/ml with an 50% increase over baseline level, radiological or symptomatic progression. The primary endpoint was one-year survival, which was tested for non-inferiority (efficacy margin 12.5 %). Secondary endpoints were overall survival (OS), progression free survival (PFS), median time to treatment failure (TTF) and toxicity. Final recruitment was not reached. Results: Of 156 eligible patients, 78 were allocated to each arm. One-year survival was 72.6% in the continuous arm vs. 75.8% in the intermittent arm and median OS 18.3 months (95% CI: 15-21.5) vs. 19.3 months (95% CI: 4.7-6.1) (P= .535). The intermittent treatment met the non-inferiority criteria in one year survival (difference to lower 95% CI: -0.1201), but not for OS, according to the result of a post-hoc analysis. The differences between the study arms in PFS and TTF were not significant. The median treatment holiday in the intermittent arm was 15 weeks (range 1-69), or 38% of the overall treatment duration. Safety profiles of both study arms were comparable. Conclusions: The intermittent docetaxel chemotherapy was non-inferior to a continuous therapy in one-year survival. It was well tolerated and may present a treatment option for patients with CRPC.
Prevalence of somatic mutations in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1 study).
2016-05-20

5544 Background: The mutation status of BRCA1/2 and other ovarian cancer (OC) predisposition genes is a valuable prognostic and predictive factor and widely used for clinical decision making. However, data on the prevalence of clearly somatic BRCA1/2alterations is sparse. Methods: We performed a consecutive cohort study of primary and recurrent OC patients by paired next generation sequencing (NGS) analysis of OC related genes using DNA derived from blood (Harter et al., co-submitted abstract) and FFPE tumor samples by a customized Agilent SureSelect XT gene panel. Analyses were complemented by detecting large genomic rearrangements (LGRs) in BRCA1/2 (MLPA). At the time of the data cut, 353 patients were analyzed (199 cases with first diagnosis and 154 with platinum sensitive relapse). Data analysis was restricted to likely deleterious variants (IARC class 4/5). Only variants present in the tumor sample but not in the corresponding blood sample were considered somatic. The minimum allele read frequency was set to 10%. Results: In this cohort (n = 353), 21.8% patients showed pathogenic germline mutations in BRCA1 (n = 59), BRCA2 (n = 17), or both (n = 1). Another 6.8% of the patients (n = 24) carried deleterious germline mutations in non-BRCA1/2 predisposition genes (Harter et al.). All class 4/5 germline mutations identified by NGS were confirmed in the corresponding tumors, with generally increased allele read frequencies. Germline LGRs were solely present in BRCA1 (n = 7) and confirmed in the tumor samples by MLPA. Deleterious somatic BRCA1/2 mutations were detected in 4.0% of the cases (9 BRCA1; 5 BRCA2). Another 1.1% (n = 4) carried somatic mutations in other DNA repair genes (ATM, PALB2, RAD51D, FANCM). Somatic TP53 mutations were found in 78.8% (n = 278) of the tumors, another 6.2% carried somatic mutations in PIK3CA (n = 16) and PTEN (n = 6). Conclusions: The prevalence of deleterious somatic BRCA1/2 mutations (4.0%) was lower than described (Pennington et al., 2014). Deleterious somatic mutations in other predisposition genes involved in DNA repair were rare (1.1%). In total, 84.9% of the class 4/5 mutations in BRCA1/2 or other predisposition genes identified in the tumor samples were of germline origin. Clinical trial information: NCT02222883.
Pazopanib vs pazopanib + gemcitabine in refractory soft tissue sarcoma: A randomized phase II trial of the AIO.
2016-05-20

11004 Background: There is a need for active chemotherapy combinations in anthracycline-refractory soft tissue sarcoma. Pazopanib, a TK-inhibitor of VEGF, PDGF and c-kit, significantly improves PFS (PALETTE-Trial, v. d. Graaf, Proc. ASCO 2011). Gemcitabine has shown single agent activity in anthracycline refractory patients (pts), and pazopanib/gemcitabine has shown to be (Plummer R., Cancer Chemother and Pharmacol 2013). This combination (arm A) was investigated against single agent pazopanib (arm B) in anthracycline refractory patients. Methods: From 9/11 - 7/14 90 patients with relapsed or refractory soft tissue sarcoma after at least 1 anthracycline based chemotherapy have been randomize, with life expectancy > 3 months, ECOG-PS 0-2, adequate organ function and at least 1 measurable lesion (RECIST). Primary endpoint (PE): rate of progression @ 3 months (PFS-R), with an anticipated PFS-R of 40 % (arm B) (PALETTE-trial) vs. =/> 60% (arm A), with 90 pts to demonstrate a significant difference (p < 0.05, 1-sided). Randomization was stratified by liposarcoma (lipo-sa)-histology and center. Results: 86 pts (A: 42 / B: 44; 2 pts in each arm not eligible) are evaluable (ITT), with a median follow up of 39 (21-54) months. The primary endpoint was met with 73.2% vs. 45.5% without progression after 3 months , HR 1.62 (CI: 1,16-2,27), p=0,005. For all histology excluding lipo-sa the difference was not significant: HR 1,24 (CI 0,89-1,74), p=0,28, but in lipo-sa with 9/9 (arm A) vs. 1/8 (arm B): HR 8 (CI 1.72-37.27), p<0,001. Response-rates: all pts 12% (A) vs. 5% (B), w/o lipo-sa 15% vs. 6%, lipo-sa. 0 vs. 0. PFS for all pts, adjusted for lipo-sa, was significantly improved with 5,6 (A) vs. 1,9 (B) months (median), HR 0,54 (CI 0,34-0,87), p=0,01. For the lipo-sa subgroup the PFS-difference was striking with 8,6 (A) vs. 1,5 months (B), but not significant. OS was not different for all pts, very likely due to cross over to gemcitabine after progression in arm B; however lipo-sa showed a numerical, non-significant difference: 25,4 vs. 11,1 months, HR 0,42 (CI 0,14-1,28). Toxicity was different, as expected, but tolerable, with mainly °3/4 hematological, and cardiovascular, GI, renal; SAE N=37 (A) vs 9 (B) with 2 fatal events in arm A (ARDS 1; unclear). Conclusion: Gemcitabine in addition to pazopanib significantly improves the PFS-rate at 3 months and overall PFS, with strongest effect in lipo-sa. Although OS was not increased, very likely due to post study crossover (data not shown), and despite higher toxicity, these data support the 2 drug combination for post-anthracycline treatment and evaluation in 1.line of lipo-sa. Clinical trial information: 2009-017261-32.
Preoperative chemoradiotherapy and the long-term run in curative treatment of locally advanced oesophagogastric junction adenocarcinoma: Update of the POET phase III study.
2016-05-20

4031 Background: In 2009 we published the results of a German phase III trial comparing preoperative chemotherapy (CT) with preoperative chemoradiotherapy (CRT) in locally advanced esophago-gastric junction adenocarcinoma (EGJ AC) (JCO 27:851). Three-year survival was increased from 28% to 48% by adding radiotherapy, but results did not reach statistical significance (p = 0.07). Methods: Fifty-nine pts vs 60 pts were randomized into preoperative CT vs CRT, respectively. Median observation time reached 10.5 years. Results: The rate of R0-resection was comparable between treatment arms (68% vs 72%). With regard to OS there was a strong trend in favour of CRT: survival rate at 5 years reached 24.4% (group A) and 39.5% (group B) (HR 0.65, 95%CI 0.42-1.01; two-sided log-rank p = 0.055). Moreover, we observed a significant improvement in local PFS after complete resection (R0/R1) by CRT compared to CT (HR 0.42, 0.19-0.93; p = 0.03). Disease free survival after complete resection was also improved by adding radiotherapy to CT (HR 0.61, 0.36-1.01, p = 0.053). Overall, there was no difference in survival between pts with Siewert type I and those with type II cancer, but pts with type II cancer appear to benefit even more from radiotherapy (type I HR 0.71; type II HR 0.60). Conclusions: Our results suggest that long-term survival of pts with locally advanced EGJ AC is best achieved with preoperative CRT. POET remains the single phase III trial comparing chemo- with chemoradiotherapy followed by surgery in this patient population. We urgently need a confirmatory trial to define preoperative CRT as standard treatment.