tbuckley/cabot-search huggingface dataset:
Pattern and dynamics of recurrence after induction chemoradiotherapy (CCRT) followed by surgery (Trimodality Treatment) in stage iiia(N2) NSCLC: The impact of response to preoperative CCRT on recurrence.
Authors: Junghee Lee, Hong Kwan Kim, Yeong Jeong Jeon, Jong Ho Cho, Jae Ill Zo, Yong Soo Choi, Young Mog Shim, Hongryull Pyo, Yong Chan Ahn, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Jhingook Kim
Journal: Journal of Clinical Oncology (2016)

e20030 Background: The optimal treatment strategy for IIIa(N2) NSCLC remains uncertain with poor survival outcomes. Moreover, there have been few investigations about the pattern of failure, which allows further understanding of each treatment strategy. We have investigated the timing and pattern of recurrence after treatment of IIIa(N2) NSCLC with trimodality treatment. Methods: An institutional database of consecutive patients between 1997 and 2013 (N = 574) was reviewed retrospectively. Eligible patients had pathologically proven N2 disease of NSCLC and completion of a planned trimodality treatment. Results: The 5-year overall survival rate (5YSR) was 47% and the 5-year recurrence free survival rate (5Y-RFS) was 29%. Of the 299 patients (52.1% of total) who experienced recurrence, 26 (8.7%) had loco-regional failure, 248 (82.9%) had distant failure, and 25 (8.4%) had both, showing effective local control. The organs for distant recurrences were lung (N = 102, 41%), brain(N = 63, 25%), and bone (N = 63, 25%). The majority of recurrences were occurred within first 18 months, and the recurrence rate declined rapidly from 2 years after surgery. After induction CCRT, ypN0 patients (N = 229, 39.9%) showed 5YSR of 58.7% and 5Y-RFS of 42.9%. However, ypN2 patients (N = 270, 47%) showed 5YSR of 34.8% and 5Y-RFS of 17.0 %. Both of ypN0 and ypN2 showed similar loco-regional failure rate (p = 0.547), but more distant failure has occurred in ypN2 (p = 0.001). Conclusions: After trimodality therapy, effective local control had shown irrespective to the nodal eradication. And when nodal eradication was achieved, the survival outcome was quite good. However, in persistent N2 patients, the survival outcome was unsatisfactory considering the risk of surgery. Therefore, studies on mediastinal re-staging and tailored treatment according to the response to the induction CCRT should be needed. N Follow up time (months) < 6 6-12 12- 18 18-24 24-60 Local failure ypN0 2 (7.7) 1 (3.8) 4 (15.4) 1 (3.8) 1 (3.8) ypN2 4 (15.4) 6 (23) 2 (7.7) 0 0 Distant failure ypN0 24 (9.7) 27 (10.9) 8 (3.2) 11 (4.4) 8 (3.2) ypN2 31 (12.5) 54 (21.8) 19 (7.7) 34 (13.7) 8 (3.2)
Abstract 20456: Practice Level Variation in the Prescription of Direct Oral Anticoagulants: Insights From the NCDR PINNACLE Registry
Authors: Lucas N Marzec, Jingyan Wang, Kensey Gosch, Paul S Chan, Henry H Ting, Nilay D Shah, Thomas M Maddox
Journal: Circulation (2016)

Introduction: Previous work has demonstrated significant practice level variation in the rates of warfarin prescription for patients with non-valvular atrial fibrillation (AF). However, it is unkno...
Phase 3 zanubrutinib (BGB-3111) vs bendamustine + rituximab (BR) in patients (pts) with treatment-naïve (TN) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Authors: Peter Hillmen, Jennifer R. Brown, Brad S. Kahl, Paolo Ghia, Tadeusz Robak, Carol Marimpietri, Aileen Cohen, Jane Huang, Constantine Si Lun Tam
Journal: Journal of Clinical Oncology (2018)

TPS7581 Background: Inhibition of Bruton’s tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib has been shown to be a novel 2nd-generation, potent, and specific BTK inhibitor in clinical studies to date. Early clinical data suggest that zanubrutinib treatment in pts with TN (n = 16) or relapsed/refractory (R/R; n = 50) CLL/SLL induced deep and sustained responses, with a 94% overall response rate (ORR) including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). We hypothesize that zanubrutinib monotherapy may have superior efficacy and potentially improved safety vs standard BR chemoimmunotherapy in pts with TN CLL/SLL. Methods: This ongoing Phase 3, randomized, open-label, global study (NCT03336333, BGB-3111-304) compares the efficacy and safety of zanubrutinib vs BR in adult pts with TN CLL/SLL considered unsuitable for treatment with FCR (fludarabine, cyclophosphamide, rituximab). In Cohort 1, pts lacking del(17p) (n ≈ 420) are randomized 1:1 to oral zanubrutinib 160 mg twice-daily or BR x 6 cycles. Randomization is stratified by age ( < 65 vs ≥ 65 y), Binet stage (C vs A/B), geographic region (North America vs Europe vs Asia-Pacific) and IGHV mutational status (mutated vs unmutated). In Cohort 2, pts with del(17p) (n ≈ 47) are enrolled and all receive zanubrutinib as in Cohort 1. Key inclusion criteria include histologically confirmed CD20+ CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is progression-free survival (PFS) of zanubrutinib as compared to BR in Cohort 1 by independent review committee (IRC) according to iwCLL guidelines with modification for treatment-related lymphocytosis. The analysis of PFS between the 2 arms in Cohort 1 will be based on a log-rank test stratified by the randomization stratification factors. Key secondary end points include ORR, duration of response, overall survival, and safety in Cohorts 1 & 2. In Cohort 1, next-line treatment with zanubrutinib after IRC-confirmed progression on BR is included in the study design. Recruitment is ongoing. Clinical trial information: NCT03336333.
Stereotactic radiotherapy (SRT) for oligometastatic (OM) relapse and metastatic oligoprogression (OP) in renal cell carcinoma (RCC) patients (pts): A study of the GETUG group.
Authors: Emmanuel Meyer, Dinu Stefan, David Pasquier, Guillemette Bernadou, Gilles Calais, Christian Carrie, Christine Theodore, Laurence Albiges, Alberto Bossi, Pierre Maroun, Renaud de Crevoisier, Christophe Hennequin, Jean-Léon Lagrange, François Lesaunier, Jean-Michel Grellard, Benedicte Clarisse, Audrey Emmanuelle Dugue, Jean-Louis Habrand, Florence Joly
Journal: Journal of Clinical Oncology (2016)

e16105 Background: RCC is considered as radioresistant and radiation therapy of metastases is usually reserved only to palliate symptoms. However, by delivering ablative doses, SRT may increase local disease control. This study aimed to assess the place of SRT in the management of OM and OP RCC pts. Methods: Data of RCC pts receiving SRT with curative intent were retrospectively collected in 6 French referral centers. Local progression free survival (LPFS) for each lesion, progression free survival (PFS), survival without change of systemic treatment (TTS), and overall survival (OS) from the end of SRT were assessed in all included patients. Results: A total of 194 pts (Men = 76%, median age, 64 yrs) receiving SRT for 259 metastases (brain [n = 122]; bones [n = 89]; liver, lung, lymph nodes, kidney, pancreas, adrenal gland and soft tissues, [n = 48]) were included: 104 pts received SRT for OP during systemic therapy, 83 received initial SRT for OM relapse and 7 pts after a partial response to systemic treatment. Delivered doses by target ranged from 8 to 60 Gy in 1 to 11 fractions (median biologically effective dose BED7 = 54.4 Gy, from 13.3 to 180). Acute and late severe toxicity was observed in 6 (3%) pts. After a median pts follow-up of 13 (range 0-59) months (mo), complete, partial and stable local responses were observed in 17%, 38% and 36% of the treated lesions with a median LPFS of 17 (95% CI 15-25) mo. Among 131 relapsing pts, 36 had local relapse. Median LPFS for brain, bone and other lesions was 14, 15, 42 mo, respectively. Higher planned target volume and higher BED7 independently improved LPFS (HR 0.98, P= 0.001; HR 0.98, P= 0.0003). PFS, TTS, and OS were, 8 (6-10), 13 (10-17), and 29 mo (23–42), respectively. The median PFS, TTS, and OS were 9, 11 and 23 mo in pts treated for OP and 8, 14 and 34 mo in pts treated for OM. In 76% of OM pts, SRT was delivered without systemic therapy. Three of 7 pts treated with SRT after partial response to systemic treatment did not relapse after 22-mo median follow-up. Conclusions: SRT is effective and safe for OM and OP RCC pts and may delay introduction or change of systemic therapy. Prospective studies are needed to confirm these results.
Phase 1 study of pegargiminase combined with cisplatin and pemetrexed in patients with ASS1-deficient uveal melanoma.
Authors: Pui Ying Chan, Melissa Mary Phillips, Ramsay Khadeir, Stephen Ellis, Jim Thomson, Amanda Johnston, Xiaoxing Feng, Bor-Wen Wu, John S. Bomalaski, Michael Sheaff, Peter Wojciech Szlosarek
Journal: Journal of Clinical Oncology (2018)

2589 Background: Argininosuccinate synthetase (ASS1) loss is a biomarker to select for tumors sensitive to arginine deprivation therapy. In a phase 1 dose-escalation study of ASS1-deficient thoracic cancers, we demonstrated tolerability and a high disease control rate using weekly pegargiminase (ADI-PEG 20) combined with first-line pemetrexed (PEM) and cisplatin (CIS) chemotherapy (Beddowes et al., JCO 2017; ADIPEMCIS). Here, we report the safety and early activity of ADIPEMCIS in an expansion cohort of patients (pts) with metastatic uveal melanoma (UM). Methods: Chemotherapy naïve pts aged 18 years or older with ASS1-deficient, histologically proven metastatic UM were eligible. ADI-PEG 20 (36 mg/m2 i.m.) was administered weekly together with PEM (500mg/m2) and CIS (75 mg/m2) every 3 weeks for a maximum of 18 weeks. Pts with stable disease or better were eligible to continue on ADI-PEG 20 until disease progression. Adverse events (AEs) were graded using CTCAE v4.03. Radiological response was assessed by CT or MRI every 6-8 weeks according to RECIST 1.1, alongside pharmacodynamic and immunogenicity analyses, median progression-free and overall survival (PFS and OS) estimates. Results: 10 of 14 screened pts with ASS1-ve metastatic UM received ADIPEMCIS with a median of 1 line of prior therapy (i.e. ipilimumab monotherapy; range 0 to 5). Treatment was well tolerated; neutropenic sepsis was the only grade 3 AE (n = 1 pt). The best response was stable disease with a median PFS of 3.0 months (range, 1.3 to 8.1 months) and a median OS of 11.5 months (range, 3.2 to 24.0+ months). Despite the emergence of anti-ADI-PEG 20 antibodies, plasma arginine concentrations remained low by 18 weeks with a reciprocal increase in plasma citrulline. Tumor rebiopsies at progression revealed ASS1 re-expression (n = 2/2 pts). Conclusions: ADIPEMCIS is well tolerated and has activity in metastatic UM, for which there is no established therapy. Based on recent preclinical data showing synthetic lethality of combining ADI-PEG 20 with PD-1/PD-L1 inhibition, a phase 1 study of ADI-PEG 20 with immune checkpoint blockade is planned in advanced UM. ClinicalTrials.gov identifier: NCT02029690. Clinical trial information: NCT02029690.
Immunotherapy-treated melanoma brain metastases within the French national cohort, MelBase.
Authors: Clara Allayous, Stéphane Dalle, Jean-Philippe Lacour, Laurent Mortier, Caroline Dutriaux, Philippe Saiag, Sophie Dalac, Francois Aubin, Eve Maubec, Marie- Beylot-Barry, Thierry Lesimple, Jean-Philippe Arnault, Julie De Quatrebarbes, Pierre-Emmanuel Stoebner, Brigitte Dreno, Ichrak Chami, Raphael Porcher, Anita Kowal, Marie Thérèse Leccia, Celeste Lebbe
Journal: Journal of Clinical Oncology (2016)

9556 Background: Melanoma brain metastases (BM) are associated with poor prognosis. Although novel therapies such as ipilimumab (IPI) and anti-PD1 (aPD1: nivolumab and pembrolizumab) have shown their efficacy in BM, little information is available in their use in BM. We report the efficacy of immunotherapy treatment on melanoma BM in “real-life” condition within MelBase. Methods: MelBase is a French multicentric clinical and biological cohort dedicated to the prospective follow-up (FU) of adults with unresectable stage III or stage IV melanoma. Since March 2013, 754 patients were included (25 centers). Available data were collected (11/21/15) and analyzed (demography, overall survival (OS), progression-free survival (PFS), response rate). Results: 2 subgroups are presented: BM treated with IPI (sgI) and BM treated with aPD1 (sgaPD1).The characteristics at the initiation of the treatment are: SgI (n = 39): mean age was 61 years, 82% were PS 0-1, 32% had elevated LDH, 67% non-mutated BRAF. Median FU was 11.2 months. OS was 6.6 months (IC95 :4.7−12.5), PFS 2.4 months (IC95 :1.8−3.4). 29 patients were evaluated: 7% complete response (CR), 3% partial response (PR), 17% stable disease (SD) and 72% progressive disease (PD). The best overall response (BORR) was 8% and disease control rate (DCR) was 21%. In sgaPD1 (n = 39): mean age was 56 years, 79% were PS 0-1, 45% had elevated LDH, 49% non-mutated BRAF. Median FU was 5.6 months, OS 5.5 months (IC95 :3.7-not reached), PFS 2.8 months (IC95:2.4-not reached). 30 patients were evaluated: 3% CR, 13% PR, 18% SD and 44% PD. BORR was 15% and DCR 33%. Conclusions: IPI results are consistent with data published by Margolin (2014) and Queirelo (2015) with DCR ranging from 24 to 27% and median survival from 4.3 to 7.0 months. Concerning anti-PD1, our results are also consistent with DCR observed in Harriet (2015) study on 18 patients. We show the first survival data obtained in patients with BMs treated by anti-PD1. Although direct comparison is difficult outside a controlled study and aPD1 data need to mature, IPI and aPD1 show comparable efficacy in melanoma BM lower than efficacy with BRAF inhibitors.
Gut microbiome composition to predict resistance in renal cell carcinoma (RCC) patients on nivolumab.
Authors: Lisa Derosa, Valerio Iebba, Laurence Albiges, Marine Fidelle, Melodie Bonvalet, Emeline Colomba, Laurence Zitvogel, Bernard Escudier, Bertrand Routy
Journal: Journal of Clinical Oncology (2018)

4519 Background: Efforts are ongoing to identify mechanisms driving response/resistance to immune checkpoint inhibitors (ICI) in order to personalize therapy. Recently, we speculated that antibiotics (ATB)-related dysbiosis decreases activity of ICI in cancer pts. We and others reported that outcome with ICI in melanoma and epithelial cancers were influenced by the microbiome composition. Here we evaluated the impact of microbiome in RCC. Methods: Within a large cohort of RCC pts (n = 85) treated in the NIVOREN study with nivolumab at Gustave Roussy, we prospectively collected fecal samples (n = 69). Of note, the minority of them received ATB before starting ICI (n = 11). Pts were classified as either primary resistant (PD) or non-PD based on RECIST (outcome, 6 months PFS). Metagenomic (MG) data from whole genome sequencing (WGS) were analyzed by multivariate and pair-wise/fold ratio (FR). Then, ICI-resistant RENCA mice were compensated with fecal microbiota transplantation (FMT) from non-PD pts or with commensals identified by WGS-MG to restore responsiveness to ICI to establish cause-effect relationship between dysbiosis and resistance. Results: After a median follow-up of 14 months, 27 (39%) pts were PD and 42 (61%) pts were non-PD, based on best response. Considering pts who received ATB, 8 (73%) were PD and 3 (27%) were non-PD (p = 0.01). The microbiome alfa (intra-sample) and beta (inter-sample) diversity were not significantly different among PD and non-PD RCC pts. However, specific gut MG-fingerprints were related to best responses and/or PFS6. Excluding ATB treated patients, Akkermansia muciniphila and Bacteroides salyersiae were more abundant in non-PD pts with a FR of 2.65 (p = 0.01) and 27.09 (p = 0.05), respectively. Finally, we showed that Bacteroides (B. salyersiae but not B. xylanisolvens) or A. muciniphila could restore the efficacy of ICI in
Taking call for a hematology-oncology practice: Experience of two academic centers.
Authors: Saurabh Dahiya, Sakiko Suzuki, Ankit J. Kansagra, Jennifer Friderici, Leena Rahmat, Venu Gopal Bathini, James A. Stewart
Journal: Journal of Clinical Oncology (2016)

e18148 Background: Optimal management of Hematology/Oncology (HO) patients requires easy access to physician expertise. At many academic centers fellows take first call at night. There are few published data on “on call” experience. We conducted a quality improvement project to learn about this process at two academic centers. Methods: HO programs at Baystate Medical Center and the University of Massachusetts participated in a 4-week data collection period. The on-call fellows logged type, duration, and timing of calls. Effect size was used to measure magnitude of difference between institutions. Results: 223 calls were recorded. The mean patient age was 58.7y and 50.9% patients were female. Patients with solid tumors (52.5%) vs hematology problems(47.5%)were about equal. The majority of calls were less than 10mins (36% <5mins,42% 5-10mins). Long calls were most likely to occur Sundays and least likely on Tuesdays. Significant differences existed between the two institutions. At BMC, patient generated calls and healthcare calls were evenly spilt at 50%, whereas at U Mass >75% calls were healthcare professional generated. Conclusions: These data will help us educate patients regarding use of the physician call system and build a teaching curriculum for incoming fellows. Optimal use of nursing expertise during daytime hours might lessen night time calls. Nature of Calls Overall BMC UMass 223 106 117 n(%) n(%) n(%) Effect Size* Origin of Call(s) Patient generated 81(36.3%) 53(50.0%) 28(23.9%) Healthcare Professional 142(63.7%) 53(50.0%) 89(76.1%) 0.6,M** Patient Calls n=81 n=53 n=28 General issues 29(35.8%) 17(32.1%) 12(42.9%) Chemo side effects 11(13.6%) 11(20.8%) 0(0.0%) Cancer complications 15(18.5%) 7(13.2%) 8(28.6%) Fever 9(11.1%) 5(9.4%) 4(14.3%) Pain 6(7.4%) 6(11.3%) 0(0.0%) Imaging concerns 2(2.5%) 1(1.9%) 1(3.6%) Med refills 7(8.6%) 4(7.6%) 3(10.7%) Other 2(2.5%) 2(3.8%) 0(0.0%) 0.8,L Provider Calls n=142 n=53 n=89 ER 59(41.6%) 13(24.5%) 46(51.7%) Hospital patient 42(29.6%) 15(28.3%) 27(30.3%) Lab 23(16.2%) 15(28.3%) 8(9.0%) Outside hospital 1(0.7%) 0(0.0%) 1(1.1%) Hospice RN 1(0.7%) 1(1.9%) 0(0.0%) Med Refills 16(11.3%) 9(17.0%) 7(7.9%) 0.7,L** * Effect Size: <0.2= Small;0.5=Medium;0.8+=Large ** P<0.05
Abstract 17292: Role of Rotor Activation for the Maintenance of Atrial Fibrillation: Relation to the Complex Fractionated Electrogram Region
Authors: Yusuke Kanemaru, Hiroshige Yamabe, Hisanori Kanazawa, Miwa Ito, Shozo Kaneko, Takuya Kiyama, Hisao Ogawa
Journal: Circulation (2016)

Background: Complex fractionated electrogram (CFE) region has been suggested as the substrate of random wave propagation which maintains atrial fibrillation (AF).While the rotor has also been suggested as the driving sources for AF. But the relation between CFE and rotor remains unclear. Objectives: To define the maintenance mechanism of AF, we elucidated the significance of CFE and rotor for the maintenance of AF. Methods: Endocardial non-contact mapping was performed in 28 patients with AF (14 paroxysmal and 14 persistent AF patients). To define the maintenance mechanism of AF, the number of rotor and pivoting activation were analyzed during 1000 msec intervals. Then the number of pivot involved in the rotor activation was compared with that not involved in the rotor activation. Further, the relation between the CFE and the location of rotor and pivot were analyzed. We also analyzed the activation time involved in the rotor activation. Presence of rotor activation was defined when the circular activatio...
Phase 1B study of enzalutamide (ENZA) with or without sorafenib (SORA) in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: James J. Harding, Robin Kate Kelley, Benjamin R. Tan, Emily Iobst, Chayma Boussayoud, Kerri E. Muenkel, Richard K. G. Do, Joanne F. Chou, Marinela Capanu, Carmen Ruiz, Mariam Rodriguez Lee, John Wilton, Renuka V. Iyer, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2018)

4083 Background: Preclinical models indicate that androgen receptor (AR) interference with ENZA is deleterious to HCC; however, ENZA also activates feedback circuitry that may be overcome with the addition of SORA. Methods: This is a multicenter, National Comprehensive Cancer Network funded, phase 1B study of ENZA ± SORA unresectable/metastatic HCC pts (NCT02642913). In PART 1 of the study, a 3 + 3 dose de-escalation design with expansion cohort was used to establish the safety and ENZA recommended phase 2 dose (RP2D). In PART 2, a 3 + 3 dose escalation was used to establish the safety and RP2D of ENZA + SORA. Secondary objectives included response rate (RR) by RECIST 1.1, pharmacokinetics (PK), progression-free (PFS) and overall survival (OS). Correlative analyses included AR determination by immunohistochemistry and enumeration of pretreatment and on-treatment high definition circulating tumor cells (HD-CTCs). Results: 16 pts received ENZA 160mg QD on PART 1—median age 70/75% male/19% hepatitis B virus (HBV)/13% hepatitis C virus (HCV)/100% Child Pugh A/100% failed prior SORA. No dose limiting toxicity (DLTs) occurred and drug-related Grade 3 AEs were rare—hypertension (1), hyperglycemia (1), transaminitis (1), and electrolyte abnormalities (1). No objective responses were observed. 8/16 (53.3%) pts had stable disease (SD). Median PFS and OS were 1.8 and 9.4 months. 12 pts received ENZA 160mg QD with SORA 400mg QD or BID in PART 2—median age 72/83% male/8.3% HBV/33% HCV/100% Child Pugh A/100% treatment naïve. No DLTs were observed and drug-related Grade 3 AEs included hypertension (2), headache (1) and hypophosphatemia (1). No objective responses were observed. 7/12 (64%) pts had SD. AR was detected in 16/21 (76%) tumor samples and did not associate with RR (p = 0.61). ENZA enhanced the metabolism of SORA leading to a 60% reduction of SORA area under the curve (AUC)0-8hr at steady state. HD-CTCs were detected in 11/32 (34.3%) samples, and in 13 paired samples, treatment did not affect CTC concentrations (p = 0.9). Conclusions: Despite an adequate safety profile, ENZA has no single agent activity in AR (+) or (-) HCCs. ENZA + SORA development is limited by drug-drug interactions. Clinical trial information: NCT02642913.