julilili42/papers huggingface dataset:
Quality-of-life (QOL) assessment in patients (pts) with metastatic melanoma receiving vemurafenib (V) and cobimetinib (C).
2015-05-20

9021 Background: The phase 3 coBRIM study showed significant improvement in progression-free survival in pts with metastatic melanoma on V + C compared with those on V and placebo (P) (HR, 0.51; 95% CI, 0.39-0.68, P< 0.001 (Larkin et al. N Engl J Med 2014;371:1867-1876). We report the evaluation of health-related QOL in coBRIM for V + C versus V + P, as measured by the European Organization for Research and Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). Methods: The EORTC QLQ-C30 was evaluated in pts with baseline (BL) and ≥ 1 post-BL assessment. Assessments were conducted on Days (D) 1 and 15 in cycles (C) 1 and 2 (each C = 28 days), and every other cycle thereafter until pt withdrawal or end of study. The analysis includes assessments up to C8D1. Each domain score, assessing global health status and QOL, and symptom scales were examined at BL and for each time point (change from BL) by treatment arm descriptively; formal statistical comparisons were not conducted. Clinically meaningful (CM) change was defined as a ≥ 10-point increase or decrease from BL. Results: The completion rate at BL for both treatment arms was 96.7% and was consistently high ( ≥ 88%). Across all functioning domains (cognitive, emotional, social, role, and physical) and symptoms (appetite loss, constipation, nausea and vomiting, dyspnea, pain, and fatigue), pts in the V + C arm reported better scores at 1 or more post-BL time points evaluated versus those in the V + P arm, but mean score change did not reach CM criteria. However, pts in the V + C arm experienced a CM or marginal improvement in insomnia (C2D15, C4D1, C6D1, C8D11), while no V + P pts showed CM change from BL in insomnia. The V + C arm experienced CM worsening of diarrhea from BL only at C1D15 and C2D15; no CM change from BL for diarrhea was observed in the V + P arm. Responder analysis showed that a higher percentage of pts in the V + C arm had CM score improvements from BL for all EORTC domains; the greatest differences were observed in insomnia (16%), social functioning (11%), fatigue (9%), and pain (7%). Conclusions: In pts with metastatic melanoma, V + C provided superior efficacy compared with V +P and symptom improvement for insomnia, social functioning, fatigue, and pain with similar QOL. Clinical trial information: NCT01689519.
Epitypification of Tilletia ehrhartae, a smut fungus with potential for nature conservation, biosecurity and biocontrol
2015-05-20

Tilletia ehrhartae, a smut fungus infecting perennial veldtgrass Ehrharta calycina, is epitypified and characterized using the Consolidated Species Concept, including morphology, ecology (host plant) and rDNA sequences (ITS and LSU). Tilletia ehrhartae is native and endemic to the Cape Floral Kingdom (located entirely in South Africa), but it has also been introduced to the alien artificial range of Ehrharta calycina in Australia and California. This smut has already caused some biosecurity problems in Australia as its spores were found to contaminate harvested wheat seeds, leading to confusion with Karnal bunt of wheat caused by Tilletia indica (which is absent in Australia), and therefore constituting a potential risk for Australian wheat export. The current global distribution of Tilletia ehrhartae, possible colonization history, and potential for nature conservation, biosecurity and biocontrol are discussed. The sequences generated in this work could serve as DNA barcodes to facilitate rapid identification of this important species.
Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin in advanced non-small cell lung cancer (NSCLC) patient.
2015-05-20

8051 Background: Variability of chemotherapy exposure may cause severe toxicity or lack of efficacy. Paclitaxel (PTX) exposure (time above a plasma concentration of 0.05mM, Tc > 0.05) has been shown to predict toxicity. Whereas carboplatin dose is adapted to kidney function, PTX dosing only accounts for body-surface area. We developed a PTX dosing algorithm for avoidance of supra- or subtherapeutic PTX exposure based on Tc > 0.05 determined from a single blood sample drawn 18-30 hours after starting PTX infusion. This study was initiated to validate PK-guided PTX dosing in advanced NSCLC patients. Methods: 304 patients with advanced NSCLC were randomly assigned to receive up to 6 cycles of first-line 3-weekly carboplatin AUC 6 combined with PTX either at a standard dose of 200mg/m2 (Arm A) or at a PK-guided dose (Arm B). Initial PTX dose in Arm B was between 150 to 200 mg/m2 based on age and sex, and subsequent PTX doses were adjusted according to the previous cycle PTX Tc > 0.05 to target a Tc > 0.05 between 26 and 31 hours. Dose reductions were permitted in both arms for chemotherapy-associated toxicity. The study had a power of 90% to detect a 11% reduction of grade 4 neutropenia with PK-guided PTX dosing. Results: Major patient characteristics were male gender in 67%, current smokers in 38%, ≥ 65 years of age in 50%, performance status of 2 in 8%, squamous-cell histology in 21%.Compared to standard dosing, PK-guided dosing of PTX reduced the incidence of grade 4 neutropenia (measured on day 15 of each cycle) (15% v 21%, P = 0.029), grade ≥ 2 neuropathy (14% v 27%, P < 0.001), and grade ≥ 3 neuropathy (1% v 8%, P < 0.001). Median PTX dose at cycle 6 was significantly lower with PK-guided dosing (132 v 197 mg/m2, P < 0.001), and the proportion of patients with supratherapeutic PTX exposure was reduced from 41% in cycle 1 to 2% in cycle 6. Objective response rate was 32% and 29% in Arms A and B (P = 0.70). Progression-free survival was 5.2 and 4.7 months in Arms A and B (hazard ratio 1.1, 95% CI 0.8-1.4, P = 0.54). Conclusions: PK-guideddosing of PTX improves the risk-benefit profile in patients with advanced NSCLC, primarily by a substantial reduction of PTX-associated neuropathy. Clinical trial information: 2010-023688-16.
A subgroup with improved overall survival from the phase 2 IMPACT study: Maintenance therapy of metastatic colorectal cancer patients with the TLR-9 agonist MGN1703.
2015-05-20

3049 Background: The double-blind placebo-controlled phase 2 IMPACT trial aimed to assess the clinical efficacy, safety, and immunological effects of the potent TLR9 agonist MGN1703, given at the dose of 60 mg subcutaneously twice weekly as switch maintenance after disease control due to first-line induction chemotherapy +/- bevacizumab in patients with metastatic colorectal cancer (mCRC). Methods: After randomization of 59 patients the trial was prematurely closed and final analysis showed a superior effect of MGN1703 compared to placebo with hazard ratios (HR) for the primary endpoint PFS on maintenance of 0.55 (p = 0.041) and 0.56 (p = 0.070) by local investigator assessment or independent radiological review, respectively. Exploratory PFS analyses of pretreatment characteristics identified patients with normalized CEA, objective response, and the presence of activated NKT cells at the end of induction chemotherapy to benefit the most from maintenance with MGN1703. The impact of these factors on the secondary endpoint overall survival (OS) is presented here. Results: OS data were not mature at time of final study analysis, since only 35% of MGN1703 patients and 50% of placebo patients had an event. The HR for OS of the whole study population was 0.63 (median 22.6 vs. 15.1 months). The subgroup of patients randomized into the study with confirmed RECIST response had a HR of 0.40 (median 24.5 vs. 15.1 months), suggesting this may be the population with greater benefit. HR for patients with normalized CEA or with activated NKT cells were 0.69 and 0.43, respectively. Based on this evidence, patients with mCRC and objective response after standard induction therapy are randomized in the phase 3 IMPALA study to standard treatment or switch maintenance with MGN1703. CEA and activated NKT cells are stratification factors for the study and will be prospectively assessed. Conclusions: The pretreatment characteristics predictive of a PFS benefit in the IMPACT study seem to retain their value also in exploratory analyses for OS. This information has been used to design the phase 3 IMPALA study, currently recruiting patients. Clinical trial information: NCT01208194.
Does extent of resection matter in recurrent glioblastoma? Lessons from the DIRECTOR trial.
2015-05-20

2041 Background: The role of surgery for recurrent glioblastoma is under debate. Tumor volume at recurrence was prognostic in single-institution retrospective studies, but no data from prospective multicenter trials for recurrent glioblastoma have been published to date. Here, we report the association with outcome of surgery for recurrent glioblastoma in a well characterized patient cohort treated in the DIRECTOR trial, which evaluated the effect of two different dose-intensified temozolomide regimens at first recurrence of glioblastoma. Methods: We analyzed prospectively collected clinical, molecular and imaging data from the DIRECTOR cohort (N = 105). Imaging data was available from 87 patients. Volumetric analysis was performed based on gadolinium (Gd) enhancement on MRI and correlated with progression-free survival (PFS) and overall survival (OS). Proportional hazard models were applied to obtain prognostic factors. Results: 71 of 105 patients received surgery at recurrence. Prognostic factors were balanced between patients who had undergone surgery and those who had not, including age (P = 0.358), O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation (P = 0.965), isocitrate dehydrogenase (IDH)-1 mutation (P = 0.724), Karnofsky performance score (P = 0.880), or steroid intake before randomization (P = 0.950). Mean tumor volumes in patients who had received surgery were smaller at study entry than in patients who had not undergone surgery (3.0 cm3 [range 0-37] versus 6.8 cm3[range 1-23], P < 0.001). The outcomes in patients who did or did not receive surgery at recurrence were similar for PFS (2.0 months [95% CI 3.5-7.1] vs. 1.9 months [95% CI 1.9-6.4], P = 0.1974) and OS (9.2 months [95% CI 8.7-12.6] vs 9.4 months [95% CI 8.3-13.5], P = 0.9538). Among patients who underwent surgery for recurrence, post-surgery imaging was available in 59 cases. In these patients, complete resection of Gd-enhancing tumor (N = 39) versus residual detection of Gd enhancement (N = 20) was associated with improved OS (11.5 months [95% CI 9.3-15.1] vs. 6.7 months [95% CI 5.2-9.5], P = 0.006). Conclusions: Surgery at first recurrence of glioblastoma may improve outcome if complete resection of Gd-enhancing tumor is feasible.
Association of PD-L1 expression in melanoma with response and prognosis to ipilimumab.
2015-05-20

9044 Background: Immunotherapy with ipilimumab demonstrated a statistically significant survival benefit. In two large phase III trials responses were observed in 10-15% of patients. However, 64% of patients exhibited significant and 20% of the patients severe grade 3 and 4 side effects. Identifying predictive biomarker profiles could enable better treatment allocation. Methods: In this multicenter study 176 tumor samples from 125 patients with metastatic melanoma were analyzed for PD-L1 gene expression, thereof 78 patients had received ipilimumab (30 responders and 48 non-responders). mRNA was extracted from formalin-fixed paraffin embedded (FFPE) tumor tissue by a fully automated method and measured by quantitative RT-PCR. Differences of survival and PD-L1 expression between patient groups were assessed using the Mann-Whitney U test, the logrank test and the Kaplan-Meier technique. Results: Patients with low PD-L1 expression showed a significantly better survival than those with high expression of PD-L1 (p = 0.002) not considering the subsequent therapy. No statistical difference in PD-L1 expression between responders (n = 30) and non-responders (n = 48; p = 0.458) to ipilimumab was observed. Conclusions: Our results suggest that PD-L1 expression is not predictive for response to therapy with ipilimumab but is a positive prognostic marker for survival of melanoma patients.
Impact of salvage surgery and radiotherapy on overall survival in patients with recurrent primary urethral cancer.
2015-05-20

4568 Background: To evaluate the impact of salvage therapy (ST) on overall survival (OS) in recurrent primary urethral cancer (PUC). Methods: A series of 154 patients (109 men, 45 women; median age: 66, IQR: 58-76) were diagnosed with PUC at ten referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank was used to estimate the impact of ST on OS. The median follow-up was 21 months (mean: 32 months; IQR: 4-48). Results: The modality of primary treatment was cystectomy+urethrectomy in 43 (27.9%), total/partial urethrectomy in 39/6 (25.3/3.9%), transurethral resection in 39 (25.3%), chemoradiotherapy (CRT), radiotherapy (RT), chemotherapy (CT) and other in 9 (5.8%), 4 (2.6%), 3 (1.9%) and 9 (5.8%) patients, respectively. Neoadjuvant CT/CRT and adjuvant CT were administered to 16/9 (10.4/5.8%) and 23 (14.9%) patients, respectively. The locations of recurrences were: urethral in 28 (18.2%), lymph nodes (LN) in 18 (11.7%), LN+distant in 12 (7.8%), LN+distant+urethral in 9 (5.8%), LN+urethral in 6 (3.9%), distant in 5 (3.3%), distant+urethral in 4 (2.6%) and no recurrence in 72 (46.8%). In the 82 patients with recurrences, the modality of ST was surgery in 32 (39.0%), RT in 8 (9.8%), surgery+RT in 5 (6.1%) and none in 37 (45.1%). The 3-year OS for patients free of any recurrence (I), with solitary and/or concomitant urethral recurrence (II) and non-urethral recurrence (III) were 86.7%, 74.5/% and 41.7% respectively (p < 0.001 for I vs. III, p = 0.001 for II vs. III, p = 0.53 for I vs. II). In patients with recurrences, those who underwent ST had similar 3-year OS (surgery: 84.9%, RT: 80%, surgery+RT: 80%) compared to patients with no recurrence (86.7%, p = 0.79), and exhibited superior 3-year OS compared to patients who did not undergo ST (27.6%; p < 0.001 compared to surgery; p = 0.016 to RT-based ST; p = 0.53 for surgery vs. RT-based ST). Receipt of perioperative CT/CRT (N = 16) did not impact on 3-year OS after ST (79.3%) compared to no CT/CRT (N = 29, 85.5%, p = 0.95). Conclusions: In this study, patients who underwent surgery or RT-based ST for recurrent PUC demonstrated improved OS compared to those who did not receive ST and exhibited similar survival to those who never developed recurrence after primary treatment.
EPAZ: A randomized phase II trial comparing pazopanib with doxorubicin as first line treatment in elderly patients with metastatic or advanced soft tissue sarcoma of the Working Group Medical Oncology (AIO) and German Interdisciplinary Sarcoma Group (GISG).
2015-05-20

TPS10576 Background: 1/3 of STS patients are 60 years and older. Single agent doxorubicin is the mainstay of therapy in metastatic disease, which is frequently associated with hematological toxicity (grade 4 neutropenia in 34%; febrile neutropenia in 9%). We assume that comorbidities in the elderly population may limit tolerability of doxorubicin and novel agents may improve health-related quality of life (HR-QoL), while maintaining efficacy. Methods: This is a randomized, open-label, multicenter phase II study that compares pazopanib 800 mg OD to doxorubicin 75 mg/m2as first line treatment in elderly patients with metastatic or advanced STS (NCT01861951). A total of 120 patients will be recruited and randomized 2:1 to receive either pazopanib or doxorubicin, stratified by performance status (0-1 vs. 2) and histological subtype. HR-QoL (QLQ-C30) and comprehensive geriatric assessment (elderly minimal dataset of EORTC ETF) is determined throughout the course of the study, in order to assess the impact of treatment on the patient’s quality of life and daily living. Key inclusion criteria: age ≥ 60 years; progressive intermediate or high grade STS; ECOG PS 0-2; measurable disease (RECIST 1.1); availability of archived STS tissue; adequate organ function; no prior therapy for metastatic disease. Primary endpoint: Progression free survival (PFS) based on local tumor assessment according to RECIST 1.1. Key secondary endpoints include the incidence of grade 4 neutropenia and febrile neutropenia. For the latter endpoints, sensitivity analyses will be conducted to adjust for primary prophylaxis of granulocytopenia or febrile neutropenia. Other secondary endpoints include: HR-QoL, geriatric assessment, safety and tolerability, overall survival, objective response rate, PFS rate at 12 and 26 weeks, time to onset of response, and predictive biomarkers. The first patient was randomized on October 12, 2012. Currently, a total of 85 patients have been randomized. Clinical trial information: NCT01861951.
The DETECT Study Program: Personalized treatment in advanced breast cancer based on circulating tumor cells (CTCs).
2015-05-20

TPS11109 Background: The prognostic value of circulating tumor cells (CTC) in metastatic breast cancer (MBC) has been repeatedly shown, but potential implications of CTC presence and CTC phenotypes for treatment decisions are still not well understood. The main aims of the DETECT study program are to evaluate efficacy of individualized breast cancer treatments based on presence and phenotype of CTCs, and to investigate the role of CTCs in predicting specific treatment responses. Methods: In the phase III study DETECT III women with HER2-negative MBC but HER2-positive CTCs are randomized to physician ́s choice therapy (single-agent endocrine or single-agent chemotherapy) with or without HER2-targeted therapy with lapatinib. The phase II study DETECT IV offers two treatment options for women with HER2-negative MBC and only HER2-negative CTCs. Patients with hormone-receptor positive MBC receive endocrine therapy plus everolimus, and patients with triple-negative MBC or hormone-receptor positive MBC plus indication for chemotherapy receive cytostatic treatment with eribulin. In the phase IIIa study DETECT V, women with HER2-positive and hormone-receptor positive MBC are treated with either endocrine therapy or chemotherapy added to a dual HER2-targeted backbone treatment with trastuzumab and pertuzumab. Clinical efficacy will be estimated by CTC clearance and progression-free survival in DETECT III and DETECT IV. As the focus of DETECT V is on the comparison of safety and quality of life between the two treatment arms, primary and main secondary endpoints are rate of adverse events and quality-adjusted survival (Q-TWiST method). Translational research projects try to identify additional predictive markers of therapy response by molecular characterization of CTCs. Therefore, prevalence of CTCs using the FDA-cleared CellSearch System (Janssen Diagnostics, LLC) and their HER2 status is determined. As of January 2015, more than 1100 patients have been screened for CTCs, making the DETECT study program the worldwide largest trial for MBC. The results will provide crucial information regarding suitability of CTCs as liquid biopsy to guide more individualized therapy decisions. Clinical trial information: NCT01619111/NCT02035813/NCT02344472.
Analyzing the relationship of response and survival in patients with refractory or relapsed and refractory multiple myeloma (RRMM) treated with pomalidomide plus low-dose dexamethasone (POM + LoDEX) in the MM-003 trial.
2015-05-20

8593 Background: RRMM patients (pts) previously exposed to bortezomib (BORT) and lenalidomide (LEN) have short overall survival (OS). The phase 3 MM-003 trial (NCT01311687) demonstrated significantly longer OS in RRMM pts treated with POM + LoDEX vs HiDEX (HR, 0.74 [95% CI, 0.56-0.97], P = .0285). This post hoc analysis investigated OS based on the response status of pts at different cycles. Methods: Landmark analyses at the start of cycles (C) 3, 5, and 7 were performed using Kaplan-Meier methods and unadjusted Cox regression models. Time-dependent survival analyses captured response status over time. For both approaches, survival of ptswith stable disease (SD) was compared to that of pts with progressive disease (PD) or overall response (OR; ≥ partial response). Results: At C3, 38.4% of pts (116/302) randomized to POM + LoDEX attained SD, 14.6% PD, and 19.2% OR; 28% had no response data, most due to early discontinuation. The median OS from randomization by response status at C3 was 15.3 mos for SD, 6.3 for PD, and 17.5 for OR. The difference in OS at C3 between pts with PD or SD was significant (P < .001); that between pts with OR or SD was not (P = .32). A similar pattern was observed at C5 and C7. The time-dependent survival model showed a lower risk of death for pts with SD or OR vs PD (HR, 0.27 [95% CI, 0.17-0.44] and HR, 0.06 [95% CI, 0.02-0.16], respectively). For the HiDEX arm, small pt numbers per group (due to the lower response rate, 2:1 randomization, and shorter OS vs POM + LoDEX) made interpretation challenging. Conclusions: In the POM + LoDEX group, pts with SD at C3, C5, and C7 had OS comparable to pts who achieved a response by those times. Pts with either SD or OR had a longer OS than those with PD at the same time points. Clinical trial information: NCT01311687. Beginning of C POM + LoDEX (N = 302) SD PD OR C3 n 116 44 58 Median OS, mo 15.3 6.3 17.5 HR vs SD (95% CI) - 3.83 (2.39-6.14) 0.75 (0.43-1.31) P value vs SD - < .0001 .320 C5 N 57 31 56 Median OS, mo 16.6 11.0 18.0 HR vs SD (95% CI) - 2.81 (1.38-5.71) 0.74 (0.33-1.66) P value vs SD - .004 .462 C7 n 40 18 47 Median OS, mo Not reached 16.4 18.0 HR vs SD (95% CI) - 2.66 (0.89-7.94) 0.90 (0.3-2.67) P value vs SD - .080 .843
Combining Human Visual System Models for Geographic Gaze Contingent Displays
2015-05-20

We present a gaze-contingent display (GCD) in which we combine multiple models of the human visual system (HVS) to manage the visual level of detail (LOD). GCDs respond to the viewer's gaze in real time, rendering a space-variant visualization. We aim to measure the computational and perceptual benefits of the proposed HVS models in terms of data reduction and user experience. Specifically, we combine models of contrast sensitivity, color perception and depth of field; and customize our implementation for geographic imagery. We believe this research is relevant in all domains that use image interpretation.