tbuckley/cabot-search huggingface dataset:
A multi-institution comparison of mitoxantrone, etoposide, and cytarabine (MEC) vs. high-dose cytarabine and mitoxantrone (Ara-C Couplets) therapy for patients with relapsed or refractory (R/R) acute myeloid leukemia.
Authors: Sonia Christian, Pritesh Rajni Patel, Shawn Griffin, Vaibhav Agrawal, Irum Khan, Karen Sweiss, Ardaman Shergill, Heiko Konig, John G Quigley
Journal: Journal of Clinical Oncology (2018)

e19005 Background: R/R AML has a poor prognosis, thus salvage chemotherapy is used as a bridge to HSCT, however the optimal regimen remains unknown. MEC is commonly used as salvage; ~ 66% of patients achieve CR, with median survival 36 weeks (Arcese et al., JCO, 1991). As the Ara-Couplets regimen has a similar CR/CRi (55%; Larson et al., Leukemia & Lymphoma. 2012), we compared efficacy and toxicity of these regimens in a multi-institution retrospective analysis. Methods: We analyzed records of 43 patients (15 from UIC, 28 from IU) treated with MEC (mitoxantrone 8 mg/m2, etoposide 80 mg/m2 and cytarabine 1 g/m2 x 5 days) and 36 patients treated with Ara-C Couplets (mitoxantrone 30 mg/m2 daily and cytarabine 2 g/m2 twice daily, days 1 and 5) between 1998 and 2017 (n = 79). Results: Baseline characteristics including gender, race, Charlson Comorbidity Index and age were well balanced. Unfavorable cytogenetics were seen in 14 of MEC and 9 of the Couplets patients (p = ns). CR/CRi was achieved in 21 MEC and 20 Couplets patients (p = 0.65), OS was 196 days vs. 240 days respectively (p = 0.46), and PFS 156 days and 117.5 days respectively (p = 0.86). Seventeen MEC (17/43; 39.5%) and Couplets patients (17/36; 47%) went onto HSCT (p = 0.49). Median ANC recovery was 32 (MEC) and 40 days (Couplets; p = 0.37), while median platelet recovery was significantly different, at 36 and 55 days respectively (p = 0.04). Notably, Grade 3/4 GI toxicity occurred in 8 MEC (18.6%) and only one Couplets patient (2.4%; p = 0.03). In the Couplets group, 2/36 patients experienced cardiac toxicity (5.6%; CHF grades 3/4). The most common adverse event was febrile neutropenia (FN; 95% (MEC) and 86% respectively; p = 0.09). Conclusions: This is the first study directly comparing these salvage regimens in R/R AML; and using a racially diverse population of patients. While both are equally effective as a bridge to HSCT, MEC results in significantly more GI toxicities, and a higher incidence of FN, despite faster platelet recovery. Comparative studies in this population are rare, suggesting the need for larger studies to establish the optimal salvage chemotherapy regimen.
P01.071 Genomic profiling identifies tubulin mutations that may predict response to depatuxizumab mafodotin in patients with glioblastoma
Authors: A B Lassman, L Roberts-Rapp, L He, X Lu, Z Zha, A Bhathena, P J Ansell, H K Gan, A M Scott, M van den Bent
Journal: Neuro-Oncology (2018)

BackgroundDepatuxizumab mafodotin (depatux-m) is an antibody-drug conjugate (ADC) composed of an EGFR-targeted antibody conjugated to a microtubule inhibitor warhead, monomethyl auristatin F. In a Phase 1 study in glioblastoma (GBM), selection for EGFR amplification (amp) enriched for patients (pts) likely to respond. We sought to identify other determinants of sensitivity.
Radiotherapy to demonstrate persistent overall survival benefit in locally advanced or metastatic anaplastic thyroid cancer.
Authors: Jennifer Ma, Andrew C. Bell, Benjamin H. Lok, Jonathan Eric Leeman, Erik Steven Anderson, Nadeem Riaz, Sean Matthew McBride, Ian Ganly, Ashok R. Shaha, Eric Jeffrey Sherman, Nancy Y. Lee, C. Jillian Tsai
Journal: Journal of Clinical Oncology (2018)

e18115 Background: Anaplastic thyroid cancer (ATC) is associated with poor prognosis and rapid tumor enlargement which affects nearby critical structures. Mortality is often secondary to complications of tumor volume rather than metastatic disease. Therefore, the role of radiotherapy (RT) in local tumor control is critical. Given the rarity of ATC, there is limited guidance on RT modality, fractionation (fx), and dose. Methods: We identified 104 patients (pts) with histologically confirmed ATC between 1984-2017. Overall survival (OS), locoregional control (LRC), and distant metastasis (DM) were analyzed with the Kaplan-Meier method. Prognostic factors were analyzed by Cox proportional hazards modeling. Adverse events (AE) were graded by CTCAE v.5.0. Results: Median age at diagnosis was 63 years (28-87) with a median follow-up of 5.5 months. Twenty-seven (26%) pts had metastatic disease prior to RT and 14 (13%) were alive at last follow-up. Concurrent chemotherapy with RT was administered in 99 (98%) pts and trimodality therapy in 52 (50%) pts. Of the 52 surgical pts, 37 (67%) had close surgical margins and 33 (59%) had positive lymph nodes. Chemotherapy included doxorubicin (70%), paclitaxel and pazopanib (25%), and other (5%). Eighty-five pts (82%) received IMRT; 77 (74%) were treated daily with a standard fx and 27 (26%) twice daily with a quad shot regimen. For standard fx, median dose was 59.4Gy (0.6-70) and median fx was 33 (3-36). One-year OS and LRC were 31% and 81% respectively. Pts receiving > 50Gy had longer 1-year OS than those receiving < 50Gy (38% vs 11%, p < 0.001). Persistent OS benefit was observed for RT > 50Gy (HR 0.3, 95%CI 0.2-0.7) and surgical resection (HR 0.5, 95%CI 0.3-0.9). Acute Grade 3 AE’s include dermatitis (20%), mucositis (13%), dysphagia (8%), and fatigue (7%). Subacute and late Grade 3 AE’s include fatigue and dermatitis. There were no Grade 4 subacute or late AE’s. Conclusions: Radiotherapy demonstrates a dose-dependent persistent OS benefit in locally advanced ATC with an acceptable toxicity profile. Aggressive RT plays an important role in the treatment of ATC and further prospective investigation is warranted to better characterize standard doses and regimens.
High number of PD-1 positive tumoral lymphocytes as a potent biomarker for adopting cytokine-induced killer cells in hepatocellular carcinoma.
Authors: Boyang Chang, Peihong Wu
Journal: Journal of Clinical Oncology (2017)

e15680 Background: Adjuvant cytokine-induced killer cell (CIK) treatment has shown potential in reducing recurrence rate and prolong survival of patients with hepatocellular carcinoma (HCC). We aim to evaluate the PD-1/PD-L1 expression in tumor cells and tumor infiltrative lymphocytes in HCC patients and their correlation with survival benefit from cytokine-induced killer cell therapy. Methods: Between 2004 and 2011, 290 HCC patients received curative section were retrospectively enrolled by one-to-one propensity score matching, including 145 cases received adjuvant CIK cell transfusion after surgery (Surgery-CIK group), and 145 cases underwent surgery only (Surgery only group). Immunohistochemistry (IHC) was used to measure the PD-1 and PD-L1 expression in formalin fixed paraffin embedded tissue of all subjects; IHC of CD4, CD8 and Foxp3 were also conducted in the surgery-CIK group to explore their correlation with PD1/PD-L1 expression and survival of HCC patients. Results: The surgery-CIK group had significantly improved overall survival (OS; HR 0.55, 95% CI 0.33-0.92) and disease-free survival (DFS; HR 0.59, 95% CI 0.42-0.83) as compared to the surgery-only group. In the surgery-CIK group, univariate analysis showed both high PD-L1 expression and a high number of PD-1 + TILs were significantly associated with improved OS, while only the high number of PD-1 + TILs was associated with improved DFS. Multivariate analyses showed a high number of PD-1 + TILs was the only independent factor predicting favorable OS (HR 0.19, 95% CI 0.08-0.45) and DFS (HR 0.40, 95% CI 0.24-0.66) in the surgery-CIK group. By contrast, in the surgery-only group, no significant associations between PD-1/PD-L1 expression and survival of patients were identified. Conclusions: A high number of PD-1 + TILs can serve as a potent biomarker to adopt CIK cell therapy in HCC patients after curative resection.
TCT-132 Balloon-Expandable ePTFE-Covered Stent for Obstructive Lesions in the Iliac Artery: 24-Month Results from the BOLSTER Trial
Authors: Georgios Bouras, John Laird, Thomas Zeller, Andrew Holden, Shanshan Zhou, Carlos Mena-Hurtado, Ecaterina Cristea, Alexandra Lansky, Alexandra Lansky
Journal: Journal of the American College of Cardiology (2018)
Plasma cell proliferation by SynKii multiplex immunohistochemistry (mIHC) for clinical use in multiple myeloma (MM).
Authors: Scott Ely, Peter Forsberg, Ruben Niesvizky, Tomer Martin Mark
Journal: Journal of Clinical Oncology (2016)

8056 Background: PC proliferation correlates with outcomes in MM. Increased proliferation identifies asymptomatic patients with an 80% probability of progression to symptomatic disease within 2 years, fulfilling International Myeloma Working Group (IMWG) criteria for a myeloma defining biomarker. However, the IMWG does not include proliferation in its criteria because it is rarely offered in the clinical setting due to lack of feasible methods. We devised and validated an mIHC method to determine PC proliferation, feasible in any diagnostic lab, using standard equipment and reagents. Methods: On a single trephine biopsy or clot section slide, Syndecan 1 (CD138) IHC with a red chromogen is performed in multiplex with Ki67 and a brown chromogen. 200 CD138+ PCs are counted as either proliferating (coexpressing Ki67) or not, and reported as a percent index,
Immune-related adverse events (irAEs) with ipilimumab treatment of advanced melanoma: A single institution review.
Authors: Caitlyn Nicole Myrdal, Ali McBride, Chiu-Hsieh Hsu, Srinath Sundararajan
Journal: Journal of Clinical Oncology (2018)

e21533 Background: Immune checkpoint inhibitors (CPI) are the mainstay for melanoma treatment. CPI pose a unique set of side effects and a complete understanding of irAEs is critical in reducing morbidity and mortality from immunotherapy. The purpose of this study is to evaluate the irAE profile of ipilimumab (IPI), in patients treated at the University of Arizona Cancer Center (UACC). Methods: After IRB approval, UACC EMR database was queried for patients with stage III-IV melanoma treated with IPI between 2011 and 2017. Demographics, treatment, irAEs and hospitalization details were collected. Adverse events were graded using the CTCAE v.4.0. Results: 62 patients were identified; 11 with stage III and 51 with stage IV melanoma. The median age was 64 of which 40 (65%) were male. Median dose was 3 mg/kg and the median number of cycles for stage III patients was 5 and stage IV was 4. In total, 124 irAEs were reported and 55/62 (89%) patients had an irAE. 14 patients (22.5%) had a grade 3 irAE and 2 (3%) had a grade 4 irAE. 13 patients (21%) were hospitalized and 17 patients (27%) stopped treatment secondary to an irAE. Colitis/diarrhea was the most common grade 3–4 irAE and contributed to 7 of the hospitalizations and 8 of the treatment cessations. Endocrinopathies such as adrenal insufficiency and hypophysitis were the second most reported grade 3–4 irAE and contributed to 4 hospitalizations. 15 patients (24%) had a pre-existing autoimmune (AI) disorder. Of these, 3 (20%) worsened significantly with IPI. A few rare serious irAEs were noted, including AI pericarditis and AI macular detachment. Of the 62 patients, 24 (39%) were treated with steroids for an irAE (12/24 with IV). 85/124 (68%) irAEs resolved by last follow up. No treatment related mortality was seen. 28 patients (45%) were alive at last follow up. Conclusions: Real world experience with IPI at our institution suggests a higher incidence of irAEs compared to landmark trials, highlighting the importance of irAE profile sampling in a more representative patient population. Rare serious irAEs can be seen with IPI. Most irAEs resolved with appropriate therapy. Early identification and management is critical in preventing serious treatment related adverse effects.
Hospital based costs associated with novel treatments and traditional B-Cell regimens in peripheral t-cell lymphoma (PTCL) patients.
Authors: James W. Gilmore, Kathy Belk, Christopher W Craver, Michael McGuire
Journal: Journal of Clinical Oncology (2016)

e18279 Background: PTCL is a difficult to treat, heterogeneous form of non-Hodgkins Lymphoma. Traditional B-cell lymphoma regimens (tBCLr) have been adapted for use in PTCL but have shown low response rates and short duration of response. Novel therapies (NT) for PTCL are available, but it is unclear how much additional costs are associated with these agents. Study objectives were to compare the treatment patterns and costs associated with NT and tBCLr in PTCL patients. Methods: A retrospective analysis examined PTCL patients who received both a NT (pralatrexate, romidepsin, brentuximab) and tBCLr (CHOP, ICE, EPOCH, etc.) using MedAsset data, a hospital administrative claims dataset covering inpatient/outpatient services. Costs were collected when patients were considered to be on therapy and standardized into cost/day. Between group differences were tested using analysis of variance and multivariable general linear regression with gamma distribution. Results: We identified 169 patients treated with NT (n = 189) and tBCLr (n = 176) across lines of therapy. Most NT regimens (79% vs 50%) were given to relapse patients and for longer median duration of therapy (DOT) (63 vs 23.5 days p < 0.05). tBCLr patients had higher mean total costs per day of therapy compared to NT [$1,834 (SD: 4,427) vs $1,055 (SD: 1,011) p < 0.05]. While on tBCLr, patients had higher mean numbers of inpatient admissions (1.02 vs 0.49 p < 0.05) and longer inpatient length of stay (8.8 vs 4.1 days p < 0.05). In a regression analysis, tBCLr regimens had an estimated 30% higher daily costs of $368 (IRR = 1.30 p < 0.05) and a 53% decreased DOT (IRR = 0.53 p < 0.05) after controlling for differences in patient groups. Conclusions: Results show that patients have longer DOT and lower per day costs when treated with NT compared to tBCLr, likely driven by fewer admissions and shorter length of stay. This analysis is limited in scope since patients treated by community oncologists not affiliated with hospitals are not considered. However, the results indicate that while NT have higher upfront drugs costs, they have the benefit of a longer time on treatment while the total daily cost of therapy appears comparable and possibly in favor of NT.
Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A
Authors: Sung Min Son, So Jung Park, Huikyong Lee, Farah Siddiqi, Jong Eun Lee, Fiona M. Menzies, David C. Rubinsztein
Journal: Cell Metabolism (2018)

Highlights•Leucine metabolizing enzymes impact mTORC1 activity•AcCoA, the final leucine metabolite, regulates mTORC1 activity by Raptor acetylation•AcCoA regulates mTORC1 in a cell-type-specific manner•Fasted tissues in mice have decreased AcCoA, acetylated Raptor, and mTORC1 activitySummaryThe mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell growth and metabolism. Leucine (Leu) activates mTORC1 and many have tried to identify the mechanisms whereby cells sense Leu in this context. Here we describe that the Leu metabolite acetyl-coenzyme A (AcCoA) positively regulates mTORC1 activity by EP300-mediated acetylation of the mTORC1 regulator, Raptor, at K1097. Leu metabolism and consequent mTORC1 activity are regulated by intermediary enzymes. As AcCoA is a Leu metabolite, this process directly correlates with Leu abundance, and does not require Leu sensing via intermediary proteins, as has been described previously. Importantly, we describe that this pathway regulates mTORC1 in a cell-type-specific manner. Finally, we observed decreased acetylated Raptor, and inhibited mTORC1 and EP300 activity in fasted mice tissues. These results provide a direct mechanism for mTORC1 regulation by Leu metabolism.Graphical abstract
Association of unplanned hospitalizations after chemotherapy with disease specific survival in a racially ethnically diverse population of women with epithelial ovarian cancer.
Authors: Shayan M Dioun, Eirwen Murray Miller, Jennifer Jorgensen, Joan Tymon-Rosario, Xianhong Xie, Xiaonan Xue, Dennis Yi-Shin Kuo, Nicole Suzanne Nevadunsky
Journal: Journal of Clinical Oncology (2018)

e17517 Background: Unplanned hospital admission following chemotherapy is a measure of quality cancer care. Large retrospective datasets have shown admission rates of 10-35% for women with ovarian cancer receiving chemotherapy. We sought to evaluate the prevalence and associated risk factors for hospital admission following chemotherapy in our racially diverse urban population. Methods: After IRB approval, clinicopathologic and treatment data were abstracted from all patients with epithelial ovarian cancer who received chemotherapy at our institution from 2005-2016. Two-sided statistical analyses and Cox regression analysis were performed using Results: Of 217 evaluable patients, 87 (40%) had unplanned admissions following chemotherapy: adjuvant 64 (74%) and neoadjuvant 23(26%). Thirty (14%) had more than one admission. In total, there were 1314 days of hospitalization. The median readmission duration was 3 days Body mass index and hypertension were predictive of readmission (p < 0.05). When comparing those readmitted more than once to those admitted once, both race and aspirin use were predictive of readmission (p < 0.05). Of those admitted more than once the self-identified race and ethnicity was 12 (40%) Hispanic, 8 (27%) White, 8 (27%)Black and 2 (7%) other. There was a significant difference in disease free (p = 0.01) and overall survival (p = 0.004) for patients with unplanned admission after chemotherapy as compared to those without admission. Conclusions: Readmission rates in our racially diverse patient population were higher than previously reported in the literature. Differences in overall and disease free survival warrant further research.
Abstract 19189: Long-term Outcomes of Catheter Ablation of Atrial Fibrillation in Elderly Patients
Authors: Ralph Matar, Martin Smith, Mohamed Bassiouny, Pulkit Chaudhury, Mina Chung, Thomas Dressing, Thomas Callahan, Patrick Tchou, Walid Saliba, Bruce Lindsay, Ousamma Wazni, Mohamed Kanj
Journal: Circulation (2015)

Introduction: Atrial fibrillation (AF) is highly prevalent in the elderly. Our aim is to evaluate the safety and efficacy of catheter ablation (PVI) in this population. Hypothesis: Catheter ablation(PVI) for AF is less effective in the elderly population. Methods: Data of 6824 consecutive patients who had PVI between January 2006 and July 2013 were reviewed. Patients ≥ 75 years were included in the study. Ablation strategy included isolation of all pulmonary veins as well as left atrial(LA) substrate modification as needed. Procedural complications and success (defined as freedom from any atrial arrhythmia lasting more than 30 seconds) were analyzed. Results: This study included 402 consecutive patients who underwent 452 ablation procedures. Of those patients, 76 were ≥ 80 years old. The mean age was 77.6 ± 2.5. 166 (41%) were female, and 148 (37%) had persistent AF. The median lifetime AF duration was 5 years (IQR: 2.5, 10). The mean CHADS2-VASC was 3.47 ± 2 and mean LV EF was 55.3% ± 9.1. 90% of patients were anticoagulated with warfarin, 8% with dabigatran, 2% with rivaroxaban, and 1 with enoxaparin. 28% of patients were also on aspirin and 2% on clopidogrel. Median follow up period was 394 days (IQR: 182, 777). Major complications included 1 ischemic stroke, 5 cases of tamponade during ablation, 8 cases of groin hematoma that required intervention, and 1 case of hemothorax. Minor complications included 8 small hematomas, and 1 hemodynamically stable pericardial effusion. After a single ablation, 154 (38.3%) patients remained arythmia free. 118 (29.3%) had infrequent paroxysmal AF, 39 (9.7%) had persistent AF, 42 (10.4%) had paroxysmal AF and AFL/AT, and 14 (3.5%) had persistent AF and AFL/AT. 9 (2.2%) had AT/AFL only. 21 (5.2%) patients had incomplete follow up. Five (1.2%) procedures were aborted; 4 due to complications with trans-septal puncture, and 1 due to electric silence of the LA. 50 patients underwent repeat ablation, increasing the freedom of AF to 42.0% Conclusions: AF ablation in the elderly is associated with a minimal increase in complications, most commonly in the form of access site hematoma. However, success rates are lower than that previously reported in younger patients.
Inherited defects in checkpoint kinase 2 (CHEK2) to confer increased susceptibility to testicular germ cell tumors.
Authors: Saud H. Aldubayan, Louisa T Pyle, Jennifer T. Loud, Mark H. Greene, Christopher Sweeney, Katherine Nathanson, Eliezer Mendel Van Allen, Douglas R Stewart, Davor Lessel
Journal: Journal of Clinical Oncology (2018)

1515 Background: Although up to 50% of testicular germ cell tumor (TGCT) risk is predicted to be inherited, no Mendelian TGCT predisposition genes have been so far identified. Recently, we showed that TGCTs are uniquely enriched for somatic DNA double-strand breaks. We hypothesized that inherited DNA repair gene (DRG) defects may drive TGCT susceptibility. Methods: A case-control germline mutation enrichment analysis was first used to screen 56 Mendelian DRGs in 205 unselected TGCT patients and 27,173 ancestry-matched cancer-free adults. Significant findings were then validated in independent cohorts of 448 unselected and 221 familial TGCT patients and matched controls. Results: Of 205 unselected TGCT patients in the discovery cohort, 24 pathogenic germline DRG mutations were identified in 22 patients (10.7%; 95% CI = 6.85-15.8). Unexpectedly, one-third of detected DRG mutations involved CHEK2, which ranked first as the most commonly mutated gene in TGCT patients. Unselected TGCT patients from the discovery cohort were almost four times more likely to carry a germline loss-of-function (LOF) mutation in CHEK2 compared with ancestry-matched controls (OR = 3.87; P = 0.0055). A similar degree of enrichment was also seen in an independent cohort of 448 unselected Croatian TGCT patients vs. 442 matched controls (OR > 1.4; P = 0.03) and a cohort of 221 familial TGCTs probands vs. 3,090 matched controls (OR = 6.12; P = 0.0014). In addition, the low-penetrance CHEK2 mutation (p.Ile200Thr) was found to be a Croatian founder TGCT risk mutation (OR = 4.03; P = 0.001). Finally, CHEK2 mutation carriers developed TGCTs at an earlier age compared with mutation-negative patients (8.43 years; P = 0.017). Conclusions: Our multi-center case-control analysis of 874 TGCT patients and matched controls provides validated evidence for CHEK2 as a novel moderately-penetrant TGCT susceptibility gene, making it the first clinically informative molecular biomarker that can be offered to TGCT patients and their at-risk relatives. In addition to providing an important insight into potential mechanisms driving TGCT susceptibility, our analysis also provides new avenues to explore TGCT preventive strategies in high risk patients.