tbuckley/cabot-search huggingface dataset:
Mitigation of tumor lysis syndrome (TLS) complications with venetoclax (VEN) in CLL.
Authors: Matthew Steven Davids, John Francis Seymour, Andrew Warwick Roberts, Barbara Eichhorst, Thomas J. Kipps, Anthony R. Mato, Stephan Stilgenbauer, Mehrdad Mobasher, Monali Bhardwaj Desai, Jalaja Potluri, German E. Pena, Maria E. Verdugo, Jacqueline Nielsen, Aimee Cyr, Leanne Lash Fleming, Michael J. Hallek
Journal: Journal of Clinical Oncology (2018)

7526 Background: VEN can cause rapid tumor debulking in patients (pts) with relapsed/refractory CLL. Current VEN dosing schedule with TLS prophylaxis/monitoring averts overt TLS, but further data on emergent biochemical changes during VEN initiation are needed to guide practice. Methods: Pts were included from phase 2 trials of VEN for CLL with del(17p) (n = 51) or prior BCRi therapy (n = 117). VEN started at 20 mg QD with ramp up to 400 mg over 5 wk. Pts were categorized as low (L) TLS risk (nodes < 5 cm and ALC < 25), medium (M; node ≥5 – < 10 cm or ALC ≥25), or high (H; node ≥10 cm or ≥5 cm and ALC ≥25). Laboratory values, AEs, and relevant concomitant medications during ramp up were analyzed. Results: TLS risk was categorized as 36% L, 36% M, and 27% H (see Table). 96% of pts completed ramp up; most in 5 wk. TLS AEs were reported in 4 pts (2 M; 2 H), with no clinical TLS and 1 laboratory TLS meeting Howard criteria (HC*). During VEN ramp up, 114 pts had potassium (K) > upper limit of normal (ULN) (1 K > HC); 21 were treated for rising or sustained K > ULN. 16 of these 21 had pre-VEN initiation K > ULN. 5/21 pts interrupted VEN for 1 day and all restarted VEN. 119 pts had phosphate (P) > ULN. 20 pts received P binder for P > HC during VEN ramp up and all others resolved without additional medication. Most instances were isolated; 4 pts had concurrent calcium (Ca2+) or uric acid (UA) changes, and P was not treated in these cases. 70% of pts received allopurinol and 20% allopurinol and rasburicase at VEN start. 6 pts received rasburicase in addition to ongoing prophylaxis. Though 144 pts had Ca2+ < lower limit of normal (LLN), only 6 were treated. Conclusions: Despite the frequency of K > ULN, treatment was applied in 13% of pts for rising or sustained elevation, and most had pre-VEN K > ULN. Most cases of P > ULN were isolated, asymptomatic, and resolved without intervention. VEN causes rapid tumor cytoreduction consistent with analyte changes, though clinical sequelae are rare and mitigated by approved dose ramp up, TLS prophylaxis/monitoring, and timely intervention. Clinical trial information: NCT01889186, NCT02141282. TLS risk n of pts L n = 61 M n = 61 H n = 46 All N = 168 K > ULN 41 40 33 114 > 6 mmol/L* 0 1 0 1 Treated 4 10 7 21 P > ULN 34 44 41 119 > 1.5 mmol/L* 18 27 34 79 Treated 1 8 11 20 Ca2+ < LLN 45 58 41 144 < 0.3 µmol/L* 0 4 4 8 Treated 0 3 3 6 UA > ULN 3 4 6 13 > 476 µmol/L* 2 2 4 8 Treated 2 1 3 6
Long term follow-up of frontline dasatinib in patients (pts) with early chronic phase chronic myeloid leukemia (CML-CP).
Authors: Abhishek Maiti, Hagop M. Kantarjian, Keyur Patel, Gautam Borthakur, Farhad Ravandi, Srdan Verstovsek, Alessandra Ferrajoli, Zeev Estrov, Tapan M. Kadia, Jeffrey A Skinner, Rebecca A Poku, Sara Dellasala, Rajyalakshmi Luthra, Elias Jabbour, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2016)

e18542 Background: Dasatinib produces higher and faster responses compared to imatinib. We report the long-term follow-up of the first phase II trial of dasatinib frontline therapy for pts with CML-CP. Methods: Starting 11/2005, we enrolled 150 newly-diagnosed CML-CP pts, initially randomized to dasatinib 100 mg once daily or 50 mg twice daily. From 6/2009 onwards all patients received 100 mg once daily. Response was assessed by European LeukemiaNet criteria. Transformation free survival (TFS), event free survival (EFS), failure free survival (FFS) and overall survival (OS) were calculated using Kaplan-Meier estimates. Cytogenetic and molecular response rates were calculated using an intent to treat analysis. Results: The median age at diagnosis was 48.2 years. Median follow-up was 55.9 mos. Response rates are summarized in Table 1. Seven pts discontinued dasatinib before 3 mos (4 non-compliance/financial, 3 toxicity) but remained in denominator on intention-to-treat analysis. Cumulative rate of complete cytogenetic response (CCyR) was 93%, major cytogenetic response (MCyR) 94%, major molecular response (MMR) 87%, and MR4.5 70%. Sustained (i.e., ≥2 yrs) MR4.5 was achieved in 74 (49%) pts; 5 of them eventually lost it. Median time to MMR and MR4.5 was 3.8 mos and 12 mos respectively. The 7-year OS, TFS, EFS and FFS rates were 94%, 94%, 91% and 68% respectively. Five pts died, and 113 (75%) continue receiving study drug. Reasons for discontinuation were toxicity in 17 pts (11%), resistant disease 9 (6%), personal, financial or compliance-related reasons 8 (5%), and death 3 (2%). Conclusions: Most pts treated with dasatinib achieve MR4.5 resulting in excellent long-term OS, EFS and FFS. These results underscore the high efficacy and adequate safety profile of dasatinib as frontline therapy for CML-CP. Clinical trial information: NCT00254423.Outcome of CML-CP pts treated with frontline dasatinib. Follow-up duration Evaluable pts CCyR MMR MR4.5 CMR* n (%) 3 mos 150 112 (75) 45 (30) 6 (4) 0 (0) 6 mos 141 125 (89) 95 (67) 29 (21) 8 (6) 1 y 135 126 (93) 101 (75) 50 (37) 16 (12) 3 y 100 91 (91) 86 (86) 64 (64) 33 (33) 5 y 65 57 (88) 55 (85) 43 (66) 29 (45) 7 y 37 31 (84) 31 (84) 27 (73) 22 (59) *CMR = undetectable transcripts with at least 100,000 abl copies detected.
Phase I trial of BMS-986253, an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors.
Authors: Julie Marie Collins, Christopher Ryan Heery, Renee Nicole Donahue, Claudia Palena, Ravi Amrit Madan, Julius Strauss, Margaret Elena Gatti-Mays, Jeffrey Schlom, James L. Gulley, Marijo Bilusic
Journal: Journal of Clinical Oncology (2018)

3091 Background: BMS-986253 is a novel fully human monoclonal antibody that binds to and inhibits IL-8, a chemokine that promotes immune escape and tumor progression. High serum IL-8 levels correlate with poor prognosis in various tumors (Sanmamed et al. Clin Cancer Res. 2014). IL-8 stimulates recruitment of myeloid-derived suppressor cells (MDSCs) and promotes epithelial-mesenchymal transition (EMT) in tumors conferring resistance to immune-mediated killing (David et al. Vaccines 2016). We have previously shown the ability of BMS-986253 to reduce mesenchymal features in cancer cells leading to enhanced susceptibility to NK and T cell-mediated lysis, and to decrease the frequency of granulocytic MDSCs in xenograft models. Decreases in serum IL-8 were also associated with response to anti–PD1 therapy in a small cohort of patients with melanoma and NSCLC (Sanmamed et al. Ann Oncol. 2017). Methods: Patients with metastatic or unresectable locally advanced malignant solid tumors were treated with BMS-986253 monotherapy at 4, 8, 16, or 32 mg/kg IV Q2W in a phase I, open-label, 3+3 dose-escalation study. The primary objective was to determine the safety and tolerability and establish the maximum tolerated dose (MTD). Pharmacokinetics and changes in serum cytokine levels including IL-8 were also evaluated. Results: Amongst 15 patients, no serious treatment-related adverse events (TRAEs) were observed and MTD was not identified through 32mg/kg. TRAEs occurred in 5 pts (33%), and all were Grade 1 except for Grade 2 fatigue, hypophosphatemia and hypersomnia in two patients receiving 32mg/kg. Eleven pts (73%) achieved stable disease (per RECIST v1.1) and 4 patients had progressive disease (27%). The progression free survival rate at 24 weeks for all patients was 73% with two-sided 95% CI [44%, 89%]. Reductions in serum IL-8 levels were observed at all dose levels. Conclusions: BMS-986253 monotherapy is well tolerated and associated with decreases in serum IL-8 across all doses tested. These data have informed combining this drug with Nivolumab and potentially other agents to evaluate the potential for synergetic activity in selected patient populations. Clinical trial information: NCT02536469.
Does margin status affect oncologic outcomes and survival in patients with papillary thyroid cancer?
Authors: Gauri Bhuchar, Soamsiri Niwattisaiwong, Rushad Patell, Jinesh Patel, Eren Berber, Michael Tabet, Tobenna Igweonu Nwizu, James Bena, Christian Nasr
Journal: Journal of Clinical Oncology (2016)

6097 Background: It is widely known that gross extrathyroidal extension (GEE) portends poor prognosis in patients with papillary thyroid cancer (PTC). There is controversy regarding the prognostic value of microscopic extrathyroidal tumor extension (MEE). American Joint Committee on Cancer 7th edition upstages patients with MEE. However, recent studies have shown no difference in cause-specific mortality and tumor recurrence in patients with MEE and those with clear margins. This is a retrospective, single center study that further elucidates the role of MEE in cause-specific mortality and tumor recurrence in patients with PTC. Methods: We conducted a cohort study of consecutive patients with PTC and without distant metastasis that underwent thyroidectomy at the Cleveland Clinic between 2003 and 2008. Pathology slides were reviewed to determine margin status. Recurrence between groups was compared using Pearson chi-square test. Kaplan-Meier estimates of survival were calculated and compared using Cox proportional hazards models. Results: 287 patients met the aforementioned study criteria and were included in the survival analysis. Of these, 21 patients were excluded from the recurrence analysis as they continued to have persistent disease after surgical resection. Median age was 49 years; 22% were males. 202 (70%) patients had clear margins, 69 (24%) had MEE and 16 (6%) had GEE. 5.2% of the patients with clear margins (N = 194) had recurrence compared to 16.4% of the patients with MEE (N = 61) (OR = 3.6, p = 0.004) and 25% of the patients with GEE (N = 8) (OR = 6.1, p = 0.020). 10 year survival of patients with clear margins was 99.5%, with MEE was 95.6% (HR = 4.6, CI = 0.77-27.60, p = 0.095) and with GEE was 75% (HR = 30.2, CI = 5.50-165.99, p < 0.001). Survival in patients with GEE was worse than those with MEE (HR = 6.3, p = 0.016). Conclusions: Contrary to recent literature that challenges the current staging guidelines, our study shows that rate of disease recurrence is significantly higher in patients with microscopic extrathyroidal extension when compared to those with clear margins. However, we agree that there is no significant difference in survival between the two groups.
Abstract 16293: Predictors of Late Presentation After an ST Elevation Myocardial Infarction
Authors: Oluwaseyi Bolorunduro, Blake Smith, Mason Chumpia, Poojitha Valasareddy, Mark Heckle, Mary Crouse, Benjamin Zambetti, Robert Ellis, Inyong Hwang, Neffertiti Efeovbokhan, Rami Khouzam, Guy Reed, Uzoma Ibebuogu
Journal: Circulation (2015)

Introduction: Time to reperfusion has been shown to be a major predictor of mortality after an ST elevation myocardial infarction (STEMI). Reducing delays to ER presentation should significantly improve time to reperfusion. This study sought to explore the factors that predict late presentation to ER after STEMI. Methods: A retrospective analysis was conducted using data from our tertiary institution 2008-2013. All patients admitted for STEMI during this period were identified. The “Symptom onset to door time (SODT)” was computed and a binary outcome variable (late presentation) was defined as a SODT &gt;180 minutes. The role of patient demographics, insurance status, socioeconomic factors, mode of transportation, and comorbidities were controlled for in the multivariable regression analysis to identify the predictors of late presentation. A subset analysis was conducted excluding patients transferred from outlying facilities. Results: During this period, 1144 patients were admitted for acute STEMI, with 348 of these patients having been transferred from outlying facilities. Mean age was 59 (+12.8) years, males accounted for 67% of this population, 28% had private insurance, 50% had public insurance and 22% were uninsured; 56% of this population was Black. 47.5% of patients presented after 180 minutes. On bivariate analysis, blacks, older age, insurance status, female gender and a family history of coronary artery disease were predictors of late presentation after STEMI. On controlling for confounders in our model, the only significant predictors for late presentation were race and insurance status. A subset analysis excluding transferred patients showed qualitatively similar results. Conclusion: Minority patients, publically insured and uninsured patients are more likely to present late after a STEMI, this difference in time to presentation may be a surrogate for health literacy in these populations and may be ameliorated by better health education.
TCT-743 The "multivalvular score" online app for the assessment of patients with concomitant mitral and aortic valve disease candidates to transcatheter aortic valve implantation: Prospective validation
Authors: Ignacio Amat-Santos, Carlos Cortes, Pablo Catala, Alvaro Aparisi, Hipolito Gutierrez, Roman Arnold, Ana Revilla-Orodea, Ignacio Amat-Santos
Journal: Journal of the American College of Cardiology (2018)
Patient-reported symptom burden in relapsed or refractory multiple myeloma.
Authors: Loretta A. Williams, Xin Shelley Wang, Qiuling Shi, Huei-Kai Lin, Araceli Garcia-Gonzalez, Catherine C. Davis, Charles S. Cleeland, Robert Z. Orlowski, Teresa Maria Zyczynski
Journal: Journal of Clinical Oncology (2016)

e18127 Background: Although clinician-rated toxicity reports from clinical trials in patients with relapsed or refractory multiple myeloma (MM) are available, information about symptom severity and functional impairment from the patients’ own perspective is limited. Methods: Of 171 patients with MM, more than 5 years from diagnosis, recruited into a cross-sectional study from a single academic site, 151 had relapsed/refractory (RR) disease and 20 had no active or stable disease and were not receiving treatment. Patients rated symptoms on a 0–10 scale via the myeloma module of the MD Anderson Symptom Inventory (MDASI-MM), a patient-reported outcome (PRO) measure. Patient characteristics (age, sex, race), performance status, time since diagnosis, MM treatment, and disease markers (β2 -microglobulin, hemoglobin, albumin) were collected. Results: Fatigue, numbness, pain, bone aches, and drowsiness were the most severe symptoms. However, RR patients reported significantly more severe fatigue (effect size [ES] = 0.85), muscle weakness (ES = 0.60), numbness and drowsiness (both ES = 0.56), and disturbed sleep (ES = 0.63) (all P< .05) than no/stable disease patients. RR patients also reported more severe symptom interference (work, activity, walking, ES = 0.72–0.84, all P< .01; enjoyment of life, mood, ES = 0.62–0. 67, P< .05). Anemia, female sex, and poorer performance status were predictors of fatigue severity (all P< .05) in RR patients. For patients receiving immune-modulating drugs, those receiving lenalidomide reported more severe pain than those receiving pomalidomide. For patients on proteasome inhibitors, those receiving bortezomib reported poorer appetite and more severe dry mouth than those receiving carfilzomib (all P< .05). Conclusions: The MDASI-MM was sensitive for identifying PRO symptom profiles, which can be useful for interpreting new drug trial results, managing patients in routine clinical practice, and identifying treatment clinical benefit and toxicity profiles. Future analyses should take into account line of treatment, duration of disease, and patient prognostic factors.
Development and validation of a prognostic nomogram for metastatic pancreatic cancer.
Authors: Junjie Hang, Lixia Wu, Jiadi Du, Kequn Xu, Hua Jiang
Journal: Journal of Clinical Oncology (2018)

e16220 Background: It is necessary to develop prognostic tools of metastatic pancreatic cancer (MPC) for optimizing therapeutic strategies. Thus, we try to develop a prognostic nomogram and use it in clinical practice. Methods: Data from clinical trials (NCT00844649, NCT01124786 and NCT00574275) and MPC patients in Changzhou No.2 People’s Hospital was used for analysis. The former two trials were taken as training cohort, the third was used as validation cohort and 80 MPC patients were seen as test cohort. Cox regression were used to search for prognostic factors in training cohort. We established a nomogram with these factors and verified it by C-index and calibration plots. The nomogram was externally verified in validation cohort. In test cohort, patients were divided into two-risk groups based on the cutoff value of nomogram total points (NTP) derived from training and validation cohort. Kaplan-meier analysis showed the stratification of overall survival (OS) for patients receving combination chemotherapy or monotherapy in two-risk groups. Results: In training cohort (n = 445), ECOG PS, liver metastasis, CA19-9, neutrophil and albumin were independent prognostic factors. Nomogram was established to predict OS and survival probability. The nomogram showed acceptable discrimination ability (C-index 0.683) and good calibration. NTP had the potential to stratify patients into two-risk groups with median OS of 11.7 and 5.6 months (P < 0.001). The nomogram was externally verified in validation cohort (n = 273) (C-index 0.699) , median OS of 9.3 and 6.0 months for two-risk groups with the same cutoff value (P < 0.001). Test cohort were divided into low-risk group (NTP < 144) and high-risk group (NTP≥144). In low-risk group, there was no difference in median OS between the patients receving monotherapy (7.3 months) or combination chemotherapy (9.8 months) (P = 0.765). However, in high-risk group, median OS was 6.5 months for patients receving monotherapy but 11.8 months for those receving combination chemotherapy (P = 0.049). Conclusions: Prognostic nomogram with NTP can predict OS for MPC precisely. In clinical practice, patients with high NTP can benefit more in OS from combination chemotherapy than monotherapy.
Clinical utility of plasma miR-371a-3p in testicular germ cell tumors.
Authors: Michal Mego, Ton Van Agthoven, Paulina Gronesova, Michal Chovanec, Vera Miskovska, Jozef Mardiak, Leendert Looijenga
Journal: Journal of Clinical Oncology (2018)

e16540 Background: Testicular germ cell tumors (TGCTs) are the most chemosensitive solid malignancy. However, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. miR-371a-3p is a new specific liquid biopsy biomarker for GCTs, however, data related to its clinical utility is limited. The aim of this study was to evaluate clinical utility of plasma miR-371a-3p level in TGCT patients starting systemic chemotherapy. Methods: This translational study included 199 TGCT patients with available plasma before 1st cycle (N = 180) and 2nd cycle (N = 127) of systemic first line chemotherapy, treated between July 2010 and May 2017. Plasma miR-371a-3p level were measured using the ampTSmiR test and were evaluated using the 2-ΔΔCT method, compared to disease characteristics and patients' outcome. Results: Pretreatment plasma miR-371a-3p levels were significantly associated with number of metastatic sites, presence of lung, retroperitoneal and mediastinal lymph node metastases, S – stage, IGCCCG risk group and favorable response to therapy. Patients with negative pretreatment plasma levels for miR-371a-3p had significantly better progression-free survival (PFS) and overall survival (OS) compared to patients being positive for miR-371a-3p (hazard ratio [HR] = 0.26, 95% CI 0.1 – 0.68, P = 0.02 for PFS and HR = 0.24, 95% CI 0.08 – 0.73, P = 0.04 for OS, respectively). Patients with a negative miR-371a-3p level in plasma baseline and before 2nd cycle of chemotherapy had superior PFS (HR = 0.09, 95%CI 0.01 – 14.09, P = 0.03) and OS (HR = 0.05, 95%CI 0.01 – 40.65, P = 0.001) compared to patients that became miR-371a-3p positive after 1st cycle of chemotherapy. Conclusions: This study demonstrates clinical value of plasma miR-371a-3p level in chemotherapy naïve GCT patients starting first line of chemotherapy to predict prognosis. Moreover, plasma miR-371a-3p was associated with several clinically relevant disease characteristics.
Lowering the <i>P</i> Value Threshold
Authors: Yongyue Wei, Feng Chen
Journal: JAMA (2018)

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Neoadjuvant FOLFIRINOX in patients with (borderline) resectable pancreatic cancer: A systematic review and patient-level meta-analysis.
Authors: Quisette Janssen, Stefan Buettner, Mustafa Suker, Georgios A Margonis, Alessandro Paniccia, Bassel F. El-Rayes, Nathan Bahary, Ian Chau, Peter Joel Hosein, Andrew H. Ko, Jill Lacy, Nigel Jamieson, Christoph Tinchon, Kyu-Pyo Kim, Marc G. Besselink, Johanna Wilmink, Marjolein Y.V. Homs, Casper H.J. van Eijck, Matthew H. G. Katz, Bas Groot Koerkamp
Journal: Journal of Clinical Oncology (2018)

e16207 Background: FOLFIRINOX is the standard treatment of patients with metastatic pancreatic cancer. Its effectiveness in the neoadjuvant setting in patients with (borderline) resectable pancreatic cancer ((B)RPC) remains debated. We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with (B)RPC. Methods: Studies with (B)RPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. Primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS), resection percentage, R0 resection percentage, and grade 3-4 adverse events. OS and PFS were calculated from treatment initiation. Authors of included papers were contacted to provide patient-level data. Results: We included 23 studies (9 prospective, 14 retrospective), comprising 779 patients with pancreatic cancer who were treated with FOLFIRINOX, whereof 304 (39.0%) patients had (B)RPC. The median number of chemotherapy cycles was 4.5 (range 2-13). The median OS varied between studies from 11.0 to 25.9 months, the median PFS varied from 5.7 to 16.8 months. Neutropenia (29.1%) and nausea/vomiting (19.8%) were the most common reported grade 3-4 adverse events. No reported deaths were attributed to FOLFIRINOX. The resection percentage after neoadjuvant FOLFIRINOX was 78.4%, with a R0 resection percentage of 87.5%. In a patient-level analysis of 258 patients (19 studies), the median OS was 24.1 months (95% confidence interval: 19.8 – 28.4) after a median follow-up of 21.8 months. Data on progression was available for 241 patients, of whom 153 patients (63.5%) showed progression, with a median PFS of 18.1 months (95% confidence interval: 15.1 – 21.0). Conclusions: Neoadjuvant FOLFIRINOX can be safely given to patients with (borderline) resectable pancreatic cancer, and results in a median overall survival of 24.1 months. These promising results need to be validated in a randomized study.