tbuckley/cabot-search huggingface dataset:
Immunotherapy (I) for advanced, pre-treated, non-squamous NSCLC (APNS-NSCLC): Preliminary data of a pooled analysis.
Authors: Ilaria Morriconi, Chiara Cherubini, Emiliano Tamburini, Maximiliam Papi, Manuela Fantini, Emanuela Bianchi, Lorenzo Gianni, Ornella Carminati, Giuseppe Pasini, Valentina Arcangeli, Mario Nicolini, Caterina Gianni, Luigi Lazzari, Davide Tassinari
Journal: Journal of Clinical Oncology (2018)

e21032 Background: To assess the role of I for second line treatment of APNS-NSCLC. Methods: A pooled analysis of the final data of the CA209057, the KEYNOTE-010 and the OAK trial was performed. Overall Survival (OS) was the primary end point of the trial. The outcomes of patients with PD-L1 expression of 1%-49% (PD-L1 1%-49%), PD-L1 expression < 1% (PD-L1 < 1%) or mutated-EGFR (EGFR+) were analyzed comparing any checkpoint inhibitor with standard chemotherapy. An indirect comparison with network meta-analysis was performed between the different checkpoint inhibitors whenever a significant difference was observed in the pooled analysis. Direct and indirect comparisons were performed using a random effect model. Results: The outcome of 1720 patients was analyzed. 313 patients had been treated with Atezolizumab (A), 292 with Nivolumab (N), 270 with Pembrolizumab (P), and 845 with Docetaxel (D). The preliminary results were detailed in the table. Conclusions: Our data seem to confirm the role of I for APNS-NSCLC with PD-L1 1%-49%. On the contrary, not-significant benefits in terms of OS seem to emerge for patients with PD-L1 < 1% or EGFR+ expression. Likewise, no significant differences seem to emerge from the indirect comparisons between A, N and P for patients with a PD-L1 1%-49% expression. Although all these data need to be analyzed with caution, as expression of indirect comparisons, waiting further conformations from clinical trials they can support clinicians for daily clinical practice. OS Hazard Ratio CI95% A vs D (PD-L1 1%-49%) 0.571 0.423-0.771 P < 0.001 N vs D (PD-L1 1%-49%) 0.62 0.467-0.882 P = 0.001 P vs D (PD-L1 1%-49%) 0.76 0.604-0.956 P = 0.019 I vs D (PD-L1 1%-49%)* 0.66 0.555-0.786 P < 0.001 A vs N (PD-L1 1%-49%)** 0.921 0.609-1.392 P = 0.696 A vs P (PD-L1 1%-49%)** 0.751 0.541-1.043 P = 0.087 N vs P (PD-L1 1%-49%)** 0.816 0.597-1.116 P = 0.491 N vs D (PD-L1 < 1%) 0.9 0.66-1.214 P = 0.491 A vs D (PD-L1 < 1%) 1.04 0.619-1.747 P = 0.882 I vs D (PD-L1 < 1%)* 0.933 0.72-1.21 P = 0.601 P vs D (EGFR+) 0.88 0.453-1.71 P = 0.706 N vs D (EGFR+) 1.18 0.693-2.004 P = 0.542 I vs S (EGFR+)* 1.052 0.695-1.594 P = 0.81 Legend. CI95%: 95% Confidence Interval; *: Pooled Analysis; **: Network Meta-Analysis.
Positive effect on survival of epidural analgesia in patients undergoing cytoreductive surgery for peritoneal metastasis.
Authors: Clarisse Eveno, Etienne Gayat, Marie-Josee Caballero, Roberto Schiavone, Thierry Andre, Marc Pocard
Journal: Journal of Clinical Oncology (2017)

e15064 Background: Potential benefits of regional analgesia in reduction of cancer recurrence have been reported for colon and ovarian cancer. The aim of this study was to evaluate the influence of regional analgesia with patient controlled epidural analgesia (PCEA) on disease-free survival (DFS) and overall survival (OS) in patients with peritoneal metastasis (PM) of various origins operated to achieve cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods: From 2006 to 2015, 734 patients were operate on curative purpose to undergone CRS and HIPEC for PM. Three hundred patients for which details on PCEA were available were included in the present study. Aiming to obtain two well-balanced cohorts for available variables influencing early outcome and survival, the PCEA group was matched 1:1 with the non PCEA group by using a propensity score-based method. Results: Matching criteria included demographic characteristics, ASA score, origin of PM, presence of liver metastasis, Peritoneal Carcinomatosis Index (PCI) and complete resection. The median duration of follow-up was 18 months. In the matched cohort (PCEA: 68, non-PCEA: 68), early outcomes were comparable between the two group in terms of blood lost (200 vs 200 ml), transfusion (15 vs 18%), length of surgery (440 vs 450 min) and of hospitalization (12 vs 13 days) and major morbidity (25 vs 22%). After PS-matching, the PCEA group had better OS comparing non-PCEA (Hazard ratio and 95% confidence interval at 0.41 [0.21 – 0.86]). Improvement of DFS rate in PCEA group was observed only in the original sample but not after PS-matching (HR 95%CI: 0.70 [0.45 – 1.07]). Conclusions: In our study, regional analgesia is associated with improved overall survival and transient effect on disease-free survival in patients with peritoneal metastasis of various origins.
Identification of URST1 as a prognostic biomarker and therapeutic target for lung cancer.
Authors: Atsushi Takano, Yohei Miyagi, Yataro Daigo
Journal: Journal of Clinical Oncology (2018)

e24250 Background: Oncoproteins play a pivotal role in human carcinogenesis, therefore characterization of their function could lead to the development of novel prognostic biomarkers and/or therapeutic targets. Methods: Our strategies are as follows: i) Identification of up-regulated genes in lung cancers by means of cDNA microarray, ii) Validation of clinicopathological significance of their protein expression by tissue microarray, iii) Examination of their growth effect on cancer cells by siRNA and/or small molecule inhibitors. Results: We selected up-regulated in solid tumor 1 (URST1) by this screening. Immunohistochemical staining of URST1 showed that URST1 expression was observedin 231 (64.5%) of 358 NSCLCs (non-small cell lung cancer) that had undergone curative surgery, while it was observed in 11 (84.6%) of 13 small cell lung cancers (SCLC). High level of URST1 expression was associated with tumor size (P = 0.00941) and lymph node metastasis (P = 0.0322). In addition, high level of URST1 expression was associated with poor prognosis for NSCLC patients (P = 0.0003, by log-rank test). Multivariate analysis confirmed strong positive staining of URST1 was an independent prognostic factor. Suppression of URST1 expression by siRNA or treatment with small molecule inhibitor for URST1 activity inhibited mitosis and growth of lung cancer cell lines probably through G2/M arrest. Apoptosis assay revealed that inhibition of URST1 function appeared to partly induce apoptosis of cancer cells. Further functional analyses are warranted to develop new therapy targeting this molecule. Conclusions: URST1 is a possible prognostic biomarker and therapeutic target for lung cancer.
Subsequent treatment after abiraterone acetate + prednisone (AA + P) in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC): Detailed analyses from the phase 3 LATITUDE trial.
Authors: Kim N. Chi, Namphuong Tran, Susan Feyerabend, Nobuaki Matsubara, Mustafa Ozguroglu, Luis Enrique Fein, Alfredo Rodríguez Antolín, Boris Yakovlevich Alekseev, Giri Sulur, Andrew Protheroe, Peter De Porre, Susan Li, Youn C. Park, Suneel Mundle, Karim Fizazi
Journal: Journal of Clinical Oncology (2018)

5028 Background: Pts with NDx-HR mCNPC quickly progress to castration-resistant disease when using androgen deprivation therapy (ADT) alone. The LATITUDE study found significant improvement in OS and rPFS when AA + P was added to ADT. Pts receiving placebo (PBO) could cross over after unblinding at the first interim analysis. We present details on subsequent therapies pts received after unblinding at this second preplanned analysis. Methods: NDx-HR mCNPC pts were randomized 1:1 to AA (1 g QD) + P (5 mg QD) + ADT or PBOs + ADT. Secondary end points, median time to subsequent prostate cancer (PC) therapy and chemotherapy (chemo), and a post hoc exploratory end point, time to life-prolonging therapy, were analyzed by stratified proportional hazards model. Results: 1199 pts were enrolled (ITT). At median follow-up of 41.4 mo, median treatment exposure was 25.8 vs 14.4 mo (AA + P vs PBOs, respectively), and treatment was ongoing for 34% and 12% of pts receiving AA + P and PBOs, respectively. 60 PBOs pts crossed over to AA + P, with a median AA + P exposure of 2 mo (57/60 still on AA + P). The most common reason for discontinuation was progressive disease (AA + P, 40%; PBOs, 64%). Pts receiving subsequent and life-prolonging therapies (Table) were 37% and 26% on AA + P, and 58% and 45% on PBOs, respectively. Compared with PBOs, AA + P delayed time to subsequent PC therapy (HR [95% CI] 0.428 [0.361-0.507]), life-extending PC therapy (HR [95% CI] 0.398 [0.326-0.486]), and chemo (HR [95% CI] 0.471 [0.378-0.586]). Median duration of first life-prolonging therapy was 3.7 mo for AA + P (n = 155) and 5.7 mo for PBOs (n = 268). Conclusions: Adding AA + P to ADT delays the need for subsequent PC therapy vs ADT for pts with NDx-HR mCNPC. Time to subsequent therapy, life-prolonging therapy, and chemo strongly favored AA + P, even though most pts receiving PBOs remaining on treatment had crossed over to AA + P or other life-prolonging subsequent therapy. Clinical trial information: NCT01715285.Life-prolonging therapy AA + P (n = 597) PBOs (n = 602) Any, n (%) 155 (26) 268 (45) Docetaxel 127 (21) 207 (34) Enzalutamide 47 (8) 89 (15) Radium-223 23 (4) 39 (6) Cabazitaxel 17 (3) 42 (7) AA + P 12 (2) 76 (13)
TCT-314 Factors Influencing Bioresorbable vs. Metallic Stent Recoil and Underexpansion In Vivo Independent of Atherosclerosis: Angiographic Study in Normal Porcine Coronary Arteries
Authors: Nicolas Isaza, Gilberto Melnick, Marco Ferrone, Yanping Cheng, Gerard Conditt, Juan Granada, Grzegorz Kaluza
Journal: Journal of the American College of Cardiology (2018)
Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma
Authors: Jia Ruan, Peter Martin, Paul Christos, Leandro Cerchietti, Wayne Tam, Bijal Shah, Stephen J. Schuster, Amelyn Rodriguez, David Hyman, Maria Nieves Calvo-Vidal, Sonali M. Smith, Jakub Svoboda, Richard R. Furman, Morton Coleman, John P. Leonard
Journal: Blood (2018)
B-cell enrichment for next generation sequencing (NGS): An approach to detect actionable low frequency variants in B-cell lymphomas.
Authors: Maya P Panjikaran, Claire Orosco, Brian Kwok, Yu Xia, Lauryn Keeler, Paris Petersen, Gregory Sims, Jeffrey Falk, Christopher Scott, Armin Graber
Journal: Journal of Clinical Oncology (2018)

e24165 Background: To increase the sensitivity of NGS variant detection in B-cell lymphomas, an enrichment method was incorporated prior to nucleic acid isolation utilizing Tetrameric Antibody Complexes (TAC) with CD19 and/or CD20 antibodies on dextran-coated magnetic particles developed by Stemcell™ Technologies. CD19 antigen is present on mature B-cells and B-cell progenitors, but is lost upon maturation to plasma cells. CD20 is expressed on all stages of B-cell development except pro-B cells and plasma cells. Methods: Twenty specimens with various subtypes of B-cell lymphoma (diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, etc) were used. These specimens had varying levels of B-cells (0.1%-10%) prior to enrichment; up to 90% B-cells were detected by flow cytometry following enrichment. Each specimen was divided into two aliquots, one undergoing enrichment using CD19/CD20 antibodies and the other reserved for non-enriched testing. The library preparations from the pre-and post-enriched samples were sequenced and analyzed using a multi-gene capture-based NGS assay (NexCourse Complete). Results: Genomic alterations were evaluated across 236 genes and the variants were compared for the pre- and post-enrichment samples. Enrichment with B-cell antibodies improved detection of variants that were below the limit of detection (LOD) of the assay. For example, testing of a DLBCL sample (BCE008) detected a pathogenic variant in the EZH2 gene at 10.8% in the enriched aliquot that was present at only 1.5% in the non-enriched aliquot, which is below the 5% LOD of the assay. Several other variants in key genes like CARD11, BRAF, and CDKN1b were also identified, with the enriched samples displaying a 3 to 5 fold increase in variant allele frequencies compared to the matched non-enriched samples. Conclusions: Bone marrow and peripheral blood specimens consist of a mixture of hematopoietic cell types and potentially multiple disease processes; cases with low level involvement by B-cell lymphoma may potentially benefit from B-cell enrichment prior to NGS testing. Similar enrichment strategies can be also applied to T-cell lymphoma, acute leukemia and multiple myeloma.
Pharmacogenetic 3C interaction associated with the PDGFRA gene as a chromatin conformation marker for treatment with tyrosine kinase inhibitors.
Authors: Alexandre Akoulitchev, Aroul Ramadass, Jayne Green, Ulku Uzun, Jane Mellor, Ewan Hunter, Francis Grand
Journal: Journal of Clinical Oncology (2017)

e23054 Background: IDH1 mutations detected in glioma cells impair the insulator function between FIPL1L1 and PDGFRA at 4q12 ( Flavahan et al. 2016). We have used a high-resolution chromosome-conformation capture 3C analysis platform, EpiSwitch, and quantitative PCR, to map, evaluate, and quantify the TKI-sensitive conformational juxtaposition between FIP1L1 and PDGFRA. Loss of the insulator function in glioma prompted us to investigate the same interaction in the context of insulator loss with interstitial deletions at 4q12 in eosinophilic leukemias and AML. Methods: We tested a total of 72 primers in temperature gradient PCRs, with concentration matched negative controls, using the AML cell lines EOL-1 and HL-60. Products were sequenced in forward and reverse order. Dual label 5’FAM-BHQ1-3’hydrolysis probe assays, entirely specific for the PCR products, targeted the junction region of the 3C fragments. A reference 3C interaction was used as an internal copy number control for 3C library production. Results: EpiSwitch predicted and identified six 3C FIP1L1-PDGFRA interactions in different sequence orientations, within the 3D organization of the PDGFRA locus. The interaction D7 identified by the EpiSwitch qPCR assay was detected reproducibly in EOL-1 cells and glioblastoma tissue using both single step PCR and qPCR. An imatinib-sensitive AML cell line EOL-1 was used as a positive control for qPCR assays. Both AML and glioma cell lines tested positive using the assay as did glioma patient biopsies. The glioblastoma cell line DBTRG-05MG also tested positive for the D7 interaction at a maximum of 8.92 copies per 20 ng of the template. Conclusions: We confirmed and characterized, at high resolution, the conformational deregulation of FIP1L1 and PDGFRA in glioma. Additionally, our group detected the interaction in TKI-sensitive leukemia cell lines. The analysis of 3C microstructural alterations is consistent with latest insights into epigenetic regulation of PDGFRA. It provides a promising approach to the stratification of patients for tyrosine kinase inhibitor treatment, which could not be provided diagnostically with conventional sequencing approaches.
Abstract 19034: Activation of GPER1 at the Reperfusion Protects the Ischemic Myocardium Against Injury by Decreasing Mitophagy and Delaying the mPTP Opening
Authors: Yansheng Feng, Mihaela Lie, Ngonidzashe Benson Madungwe, Mohammad E. Kabir, Jean C. Bopassa
Journal: Circulation (2016)

Introduction: We recently showed that pre-ischemic estrogen (17 β-estradiol) treatment induces cardioprotective effects against ischemia/reperfusion (I/R) injury via G-protein coupled estrogen receptor1 (GPER1) activation by preserving mitochondrial integrity and function via MEK/ERK/GSK-3β pathway. Hypothesis: We investigated whether post-ischemic estrogen (PI-E2) treatment can also induce cardioprotective effects via GPER1 activation and determine whether PI-E2 action involves the reduction of mitophagy and the mitochondrial permeability transition pore (mPTP) opening. Methods: Male and ovariectomized female Sprague-Dawley rats were used. Hearts were subjected to 35 min of the left anterior descending artery occlusion followed by 180 min reperfusion. An estrogen bolus (50 mg/kg body weight) or PBS (same volume) was applied via the femoral vein 5 min before reperfusion, and GPER1 antagonist, G15, given 10 min before estrogen. Area at risk (AAR) was identified using Evans Blue dye and myocardial infarct s...
The value of cancer treatments: Patient and clinician perspectives.
Authors: Andrew Briggs, Camilla Baba, Anna Kaltenboeck, Allison Nicole Lipitz Snyderman, Emma McIntosh, Peter Bach
Journal: Journal of Clinical Oncology (2017)

e18320 Background: A number of frameworks for assessing the value of cancer treatments such as the National Comprehensive Cancer Network’s evidence blocks, Memorial Sloan Kettering Cancer Center’s Drug Abacus and ASCO’s value framework have been developed to help address the rising cost of cancer treatments. Yet the methodological basis for the inclusion of differing attributes, how to incorporate other contextual considerations and understand stakeholder trade-offs is unclear. This qualitative study aimed to identify contextual factors prioritized by stakeholders for inclusion in oncology value frameworks. Methods: A scoping review identified attributes currently included in value frameworks. Nominal group technique methods were then used in 3 focus groups representing cancer patients, oncology nurses, and physicians across a range of cancer specialties. Each group was tasked with ‘identifying important treatment features’ based on their own experience. Following discussions, participants ranked attributes in order of importance and group consensus identified the ‘top 6’ factors. Results: Twenty-one attributes were identified by the patient (n = 9), nurse (n = 10) and physician (n = 6) focus groups. All identified efficacy and safety/toxicity. Long-term adverse effects, alternative treatment options, quality of evidence and reputation of the treating oncologist/center were prioritized by patients. Nurse preferences centered on mode of administration, quality of life, communication and treatment innovation. Physicians focused on the burden and inconvenience of treatments to patients, functional outcomes, financial toxicity to patients, and societal costs. Conclusions: Although efficacy and safety/toxicity were prioritized in all groups, the prioritization of contextual factors across stakeholders highlights the need to further understand the relative value of possible ‘other’ attributes currently not reflected in frameworks thus, possibly failing to reflect the preferences of stakeholders.
Longitudinal analysis of quality of life outcomes in children during treatment for acute lymphoblastic leukemia: A report from the Children’s Oncology Group (COG) AALL0932.
Authors: Daniel Zheng, Xiaomin Lu, Wilhelmenia L. Ross, Anne L. Angiolillo, Reuven Schore, Lyn M. Balsamo, Meenakshi Devidas, Moira K. Whitley, Nina S. Kadan-Lottick
Journal: Journal of Clinical Oncology (2017)

10522 Background: 5-year event-free survival for average-risk acute lymphoblastic leukemia (AR-ALL) in children is ~95%. However, therapy involves multi-agent chemotherapy, frequent hospital visits (duration of therapy is 26 months for girls and 38 months for boys) and painful procedures that can adversely affect quality of life (QOL). Methods: AR-ALL patients enrolled on COG AALL0932 were offered participation if ≥4 years old at diagnosis with an English-speaking parent. At ~2, 8, 17, 26, and 38 (boys only) months after diagnosis, parents completed the PedsQL4.0 and the Family Assessment Device instruments for QOL (assessing physical and emotional functioning) and family functioning, respectively. The proportions of individuals scoring in the impaired range (i.e. 2 SD below population mean) were calculated at each timepoint. Patterns of impairment over time and potential predictors were examined. Results: 594 participants with AR-ALL (48% female, 68% white) were diagnosed at a median age of 5.6 (IQR: 4.6–7.1) years. At 2 months, a significant percentage of participants had impaired scores compared to population norms for physical (36.5 vs. 2.3; 95% CI 32.3-40.8) and emotional functioning (26.2 vs. 2.3; 95% CI 22.5-30.2). Although scores improved over time, elevations persisted at 26 months for physical (11.9 vs. 2.3; 95% CI 8.4-16.1) and emotional (9.8 vs. 2.3; 95% CI 2.0-6.7) functioning. In repeated measures analysis with multivariate modeling, emotional impairment at 2 months (OR 3.7; 95% CI 1.5-7.7) and abnormal family functioning (OR 1.5; 95% CI 1.1-2.1) significantly predicted emotional impairment. QOL outcomes were similar for girls at 26 months and boys at 38 months. Conclusions: Many children with AR-ALL experience severe impairment in both physical and emotional functioning that begins early in treatment and persists. Family functioning is a modifiable risk factor that may be targeted for early screening and intervention.
Impact of obesity on response in 751 myeloma patients receiving lenalidomide, bortezomib, and dexamethasone (RVd) induction.
Authors: R Donald Harvey, Jonathan L. Kaufman, Leonard T. Heffner, Craig C. Hofmeister, Mahdav V. Dhodapkar, Sagar Lonial, Ajay K. Nooka
Journal: Journal of Clinical Oncology (2018)

8046 Background: Obesity is a putative risk factor for the development of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Induction regimens for MM have evolved; and lenalidomide, bortezomib, and dexamethasone (RVd) produces an overall response rate of 82%. Response, tolerability and therapy duration are related to agent dose, dose intensity, and comorbidities, which may be higher in the obese. We analyzed the effect of anthropometric measures on response and therapy duration in patients (pts) receiving RVd induction. Methods: Height (cm), weight (kg), body surface area (BSA), and body mass index (BMI) were obtained from a database of 751 pts receiving RVd. Demographics including sex, self-reported race, ISS stage at diagnosis, and cytogenetic risk category were analyzed with anthropometric data in a multivariate model with response per IMWG criteria, progression-free survival (PFS) and overall survival (OS). Results: Anthropometric measures were available in 746/751 (99%) pts. Of 746 pts analyzed, 54% were male, 57% white, and 30% black. Median BMI (kg/m2) was 28 (range 17-53); BMI per category was underweight (≤ 18.5) 0.9%, normal (18.5- < 25) 25.7%, overweight (25- < 30) 35.7%, obese (30-40) 32.3%, and morbidly obese ( > 40) 5.3%. Median BSA (m2) was 1.94 (range 1.29-2.70). Median BMI and BSA were significantly higher in men (p < 0.05). Morbid obesity was more common in black versus white pts (8.4 vs 3.8%, p = 0.017) and women versus men (7.9 vs 3%, p = 0.03). Pts with BMI ≥ 40 had an estimated OS of 81 vs 98 months compared to pts with BMI < 40 (p = 0.071); unadjusted hazard ratio (HR) 1.47 (95% CI: 0.56-3.49). Response of VGPR or better did not show a significant association with higher BSA ( > 2.25) (80.3 vs 70.3%, p = NS). On multivariate analysis, PFS and OS showed no association with BMI or BSA. ISS stage 3 disease (HR 2.1; 95% CI 1.4-3.4) and high risk cytogenetics (HR 2.2; 95% CI 1.5-3.7) were significantly associated with shorter OS (p < 0.001). Conclusions: Obesity does not significantly impact depth or duration of response with RVd induction. We advocate use of full dose RVd regardless of BSA or BMI in pts with acceptable performance status and managed comorbid conditions.