tbuckley/cabot-search huggingface dataset:
Prediction of therapeutic outcomes in DLBCL from circulating tumor DNA dynamics.
Authors: David Matthew Kurtz, Florian Scherer, Aaron M. Newman, Alexander F.M. Craig, Michael Siavash Khodadoust, Alexander F. Lovejoy, Daniel M. Klass, Jacob J. Chabon, Cynthia Glover, Li Zhou, Chih Long Liu, Neel K. Gupta, Lauren Shizue Maeda, Ranjana H. Advani, Ronald Levy, Maximilian Diehn, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2016)

7511 Background: Responses to initial therapy in diffuse large B-cell lymphoma (DLBCL) are heterogeneous, where patients who fail to respond have poor outcomes. Early identification of failures remains a challenge. We report an empiric method to response prediction utilizing circulating tumor DNA (ctDNA) from as few as one cycle of therapy. Methods: We utilized CAPP-Seq, a next-generation sequencing platform for ctDNA detection (Newman AM et al, Nat Med 2014), to profile 33 patients with DLBCL from Stanford University during induction therapy. Tumor and germline DNA was sequenced to define tumor-specific somatic alterations, which were then followed in plasma DNA. Changes in ctDNA were compared with response rate (PET/CT, Deauville score < 4 defined as CR) and outcomes using a training/validation design. Results: To understand early dynamics of ctDNA, we serially profiled plasma from a training cohort of DLBCL patients throughout their first two cycles of immunochemotherapy (n = 12 patients, 114 samples; median 9/patient). In patients achieving a radiographic response, ctDNA levels declined within days of therapy. At onset of cycle 2 (day 22), patients achieving a CR had a greater reduction in ctDNA than those who did not (3.35-log vs 0.98-log reduction, p = 0.0014). Furthermore, all patients with a > 2-log reduction in ctDNA by cycle 2 achieved a CR (5/5), while those failing to reach this threshold did not (7/7; p = 0.0013). We therefore established a 2-log drop in ctDNA as a threshold to predict response. We tested the ability of this threshold to predict outcomes in an expanded cohort of 33 patients. This threshold significantly predicted CR rate (75% vs 22%, p = 0.01), PFS (p = 0.002) and OS (p = 0.001). Change in ctDNA remained significantly associated with improved PFS in multivariate analysis (p = 0.003) when controlling for IPI, cell of origin, and prior treatment. Finally, in a cohort of patients experiencing relapse, ctDNA heralded radiographic progression by a median of 148 days (n = 8). Conclusions: Circulating tumor DNA in DLBCL changes rapidly during treatment, with > 2-log decline in the first two cycles associated with response and survival. Studies utilizing the dynamics of ctDNA to risk stratify patients and guide therapy are warranted.
Strategies to minimize wastage of expensive drugs in expensive times: Cabazitaxel, a single center experience.
Authors: Nazanin Fallah-Rad, Roy Lee, Pamela Ng, Alan D. Smith, Aaron Richard Hansen, Anthony M. Joshua, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2017)

e18297 Background: Although approved for metastatic castrate-resistant prostate cancer (mCRPC), the use of cabazitaxel has been limited due to concerns over drug wastage. In Canada, Cabazitaxel costs $96.7/mg and comes prepackaged in 60 mg single-dose vials, a quantity higher than the average prescribed and provincially reimbursed dose based on body size. Despite a discount offered by Sanofi to help cover the costs of drug wastage, many centers still cannot afford to administer it. We investigated whether aggressively batching patients (pts) on the same day, and allowing for excess drug to be used for subsequent pts can result in cost-savings. Methods: Between 09/2015 and 09/2016, all mCRPC pts receiving cabazitaxel at Princess Margaret Cancer Center were only treated on Mondays. Left over drug in opened vials was used for subsequent pts treated on the same day. Pts were dosed according to clinical parameters and BSA, at a dose of 20mg/m2 every 3 weeks. We calculated the total number of vials used daily and the amount of drug (mg) wasted. We then compared costs of the new batching system to the standard practice of opening one vial per treatment session. Results: During the trial period, 28 patients, mean age 72.3 (range 45-91) received cabazitaxel as 2nd line (23 pts) or 3rd line (5pts) therapy until disease progression or toxicity. In total, they required 117 individual treatment sessions, administered on 53 treatment days. With the batching system, 91 cabazitaxel vials were used, in comparison to 117 vials required with standard practice. As a result, 26 vials were unopened, $149,760 CAD were saved, equating to a 22.2% cost reduction over a year. In terms of wastage, $121,154 CAD of Cabazitaxel was wasted compared to $251,808 CAD wasted without batching, a difference of $130,656 CAD. Conclusions: Batching of mCRPC pts receiving cabazitaxel on the same day was feasible at a single center and significantly reduced drug wastage. This approach could be applied to centers with adequate patient volumes to save costs and reduce a key barrier to the use of cabazitaxel. A similar strategy can also be applied to other drugs across the field of oncology and has similar implications for cost-savings.
Prognostic factors in critically ill patients with solid cancer admitted to medical intensive care unit.
Authors: Camille Baylot, Amandine Quivy, Adrienne Francopoulo, Olivier Guisset, Gilles Hilbert, Eric Frison, Alain Ravaud, Amaury Daste
Journal: Journal of Clinical Oncology (2018)

e18745 Background: Decision to transfer patients (pts) with solid cancer to intensive care unit (ICU) is still controversial and based of several considerations. Few studies evaluated the outcome of these patients. The aim of this study was to identify prognostic factors 30-day mortality for pts with solid cancer admitted to ICU. Methods: We conducted a retrospective cohort study of all consecutive pts with solid cancer admitted to ICUs of Bordeaux University Hospital, between January 2010 and December 2015. The study end point was 30-day mortality. Logistic regression analysis was performed to identify independent risk factors. Secondary end points were the description of the characteristics and outcomes of pts, ethical practices, and the study of risk factors of non-resumption of anti-tumoral treatment. Results: We included 235 patients with solid tumors: lung (33%), head-and-neck(23%), colorectal cancer (17%), renal cell carcinoma (17%). Most of them were in metastastic setting (60%).The most common causes of ICU admission were sepsis (56%) and/or respiratory failure (52%). During ICU, 92 pts (39%) required vasopressors, 51 pts (22%) non-mechanical ventilation, 33 pts (14%) OptiFlow, and 61 pts (26%) mechanical ventilation. ICU, 30-day, 90-day mortality rates were 24%, 36% and 50% respectively. After ICU stay, 44% of pts had restarting an anti-tumoral treatment. In univariate analysis, common prognostic factors of 30-day mortality and absence of resumption of anti-tumoral treatment were the number of organ failure (p = 0,005) and SAPS 2 score (p < 0,001). In multivariate analysis and after excluding SAPS 2 score, two or more organ failures (p = .005) and being under non-curative care (p = 0.028) were independent prognostic factors of 30-day mortality. Limitation of life-sustaining therapy was decided for 23% and 43% of pts before the admission and during the ICU stay, respectively. Conclusions: Our results indicate that the discussion of the admission in ICU should be based on the severity of the acute illness, while considering the stage palliative or curative of treatment. The number of organ failures is a variable quickly evaluable that can help oncologists and intensive care specialists in their decision.
Health care utilization trends in ductal carcinoma in situ admissions.
Authors: Nishi Shah, Rahul Ravilla, Issam Makhoul
Journal: Journal of Clinical Oncology (2016)

e18053 Background: Ductal carcinoma in situ (DCIS) is a neoplasm confined to breast ducts. The incidence of DCIS has increased since 1970s with acceptance of screening mammography. The treatment of DCIS has evolved over years (yrs) and mastectomy was replaced by lumpectomyy followed by radiation. Recently, there is a growing debate about whether a conservative approach of watchful waiting could be considered. The purpose of this study was to examine trends of national admissions among DCIS patients (pts) that undergo lumpectomy vs mastectomy (Unilateral vs Bilateral) and breast reconstruction surgery (BRS). Methods: Our study population was National inpatient sample data (2005-2011). Icd-9 codes were used to identify study population. Variables included pts undergoing lumpectomy, unilateral mastectomy (ULM), bilateral mastectomy (BLM), prophylactic mastectomy (PM) and BRS. We included pt characteristics such as age , insurance, race, family history (FH) of breast cancer (BC) and total in-hospital charge for procedures. Results: There were an estimated 62782 inpt admissions of DCIS pts (with no history of BC and no active breast malignancies) who underwent lumpectomy or mastectomy. Most pts fell in the age group of 45-64 years.73% of our population were Caucasian and 58% had private insurance. Of these, 10% underwent lumpectomy, 64% underwent ULM and 26% underwent BLM. 10% of pts underwent PM. Fig.1 shows trends of different procedures over yrs. 20% of pts who underwent BLM had a FH of BC. 13% of pts underwent BRS (16% in BLM vs 13% in ULM). Median charges for hospital stay for DCIS pts who underwent BLM, ULM and lumpectomy were $ 36679, $ 20514 and $ 18964 respectively. Conclusions: Our data likely captures a portion of DCIS pts who were admitted to the hospital after procedure and more pts are treated as an outpatient with lumpectomy. This possibly explains why 10% of pts underwent lumpectomy. Caucasians and pts with private insurance had more admissions likely due to higher screening of these pts. Large proportion of pts underwent BLM and 10% underwent PM. Number of pts undergoing mastectomy, PM has been unchanged over the yrs. Our data does not include pathology, excision or outpt treatment. Further studies to evaluate cost-effectiveness are required.
Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma.
Authors: Frederick Lundry Locke, Armin Ghobadi, Caron A. Jacobson, Eric D. Jacobsen, David Bernard Miklos, Lazaros J. Lekakis, Ira Braunschweig, Olalekan O. Oluwole, Yi Lin, Tanya Siddiqi, Abhinav Deol, Patrick Michael Reagan, Umar Farooq, Adrian Bot, Yizhou Jiang, John M. Rossi, Allen Xue, William Y. Go, Sattva Swarup Neelapu
Journal: Journal of Clinical Oncology (2018)

3003 Background: Axi-cel, an anti-CD19 CAR T cell therapy, demonstrated significant clinical benefit and a manageable safety profile for pts with refractory large B cell lymphoma in ZUMA-1 (Neelapu & Locke et al. NEJM. 2017). These results led to its approval by the US FDA for the treatment of adult pts with relapsed or refractory large B cell lymphoma after ≥ 2 prior lines of therapy. Here, we examined responses over time in phase 2 of ZUMA-1. Methods: Pts with refractory large B cell lymphoma received 2 × 106 CAR T cells/kg after low-dose conditioning (Neelapu & Locke et al. NEJM. 2017). Best objective response rates (BOR) were analyzed locally by investigators (local) and centrally by independent review committee (IRC; Cheson et al. J Clin Oncol. 2007); concordance was measured as the percentage of pts whose IRC matched local. Results: As of 8/11/17, median follow-up (f/u) was 15.1 mo for the 101 pts treated with axi-cel. While the BOR of 82% at primary analysis (PA; median f/u 8.7 mo) by local remained consistent (83%) at long-term f/u (LTFU; median of 15.1 mo), complete response (CR) rates increased from 54% to 58% (Table). Out of 34 pts with partial response (PR) at 1 mo, 11 (32%) converted to CR by the LTFU. High concordance (77% - 79%) was observed for objective response rates (ORR [CR + PR]) between local and IRC at all times assessed. Landmark analysis of progression-free survival (PFS) by response status (per local) revealed that most of the 60 pts with disease control (stable disease or better) at 3 mo had prolonged disease control with a 73% 12-mo PFS rate. Of the 42 pts with CR and 9 with PR at 3 mo, the 12-mo PFS rates were 79% and 78%, respectively. Conclusions: Treatment with axi-cel induces high response rates in pts with refractory large B cell lymphoma. CR rates increased through the LTFU, suggesting that responses deepen over time and that pts with PR can achieve CR as late as a year post-infusion. ORR at 3 mo may be prognostic for prolonged PFS. Drs Locke and Neelapu contributed equally. Clinical trial information: NCT02348216.Data-cut; median f/u, mos N = 101 BOR, n (%) ORR Concordance, % Local IRC ORR CR ORR CR PA; 8.7 83 (82) 55 (54) 72 (71) 52 (51) 77 YESCARTA USPI; 11.6 84 (83) 55 (54) 73 (72) 52 (51) 79 LTFU; 15.1 84 (83) 59 (58) 73 (72) 52 (51) 79
Development of a pan-cancer 15 gene expression signature to detect a subgroup driven by EMT/MAPK signalling.
Authors: Nuala McCabe, Laura A Knight, Bethanie Price, Andrena McCavigan, Aya El-Helali, Denis P Harkin, Charlie Gourley, Richard D. Kennedy
Journal: Journal of Clinical Oncology (2017)

11616 Background: Epithelial–mesenchymal transition (EMT) is the conversion of epithelial cells to mesenchymal cells and involves loss of cell–cell adhesion and cell polarity and increased motility, invasiveness and metastases. The EMT process has therefore been under investigation as a new target for anticancer drug discovery. The aim of this work was to develop an EMT biomarker suitable for formalin-fixed paraffin embedded (FFPE) tissue that could be used for patient treatment selection. Methods: Unsupervised hierarchical clustering of ovarian cancer gene expression data (TCGA. 2011) previously identified an EMT subgroup. We confirmed this EMT subgroup in FFPE tissue using 265 high grade serous ovarian cancer (HGSOC) FFPE samples. The analysis was extended to show existence of an EMT subgroup across a range of solid tumours including colon, lung, melanoma and prostate cancer. Further to this, a common gene list was generated to include only transcripts with high variability and expression across diseases, and used as a starting list for development of a 15 transcript assay which can be used to prospectively identify the EMT subgroup from archived tissue. Results: The 15 gene expression assay was a poor prognostic marker in Colorectal, (Relapse free survival: HR = 1.46 [95% CI:1.07-1.98]); Lung, (Relapse free survival: HR = 2.18 [95% CI:1.33-3.56]); Prostate cancer, (Biochemical recurrence: HR 2.49 CI: 1.43-4.34) and was associated with activated MAPK (phospho-MAPK) in preclinical models and clinical samples (p &lt; 0.05). The assay score was reduced by MEK inhibition (p &lt; 0.05) and elevated by KRAS, NRAS and MEK1 overexpression (p &lt; 0.05). The assay predicted response to the MEK inhibitors Trametinib and Selumetinib in cell line models (p &lt; 0.001). Conclusions: A 15 gene expression assay has been developed from FFPE samples across multiple diseases to detect an EMT molecular subgroup associated with MAPK signalling. The assay predicted sensitivity to MEK inhibitors in pre-clinical model systems. Further work aims to validate the assay as a predictive biomarker in clinical samples from patients treated with EMT or MEK targeted therapies.
Outcomes following progression on BRAF/MEK inhibition in metastatic melanoma.
Authors: Robert Mason, Sharon Heng, Victoria Atkinson
Journal: Journal of Clinical Oncology (2017)

9537 Background: Restrictions in Australia dictate the prescription of BRAF/MEK inhibitors prior to immunotherapy in BRAF mutant metastatic melanoma (BRMM). We analysed patients (pts) with advanced BRMM after treatment with a BRAF/MEK inhibitor and use of second line immunotherapy (PD-1 inhibitor or CTLA4 inhibitor). Methods: Patients (pts) with BRMM from Princess Alexandra Hospital treated between June 2013 to June 2016 were identified retrospectively. Demographics, treatment pattern and survival were analysed. Results: 92 pts were identified. 50% had an elevated LDH at diagnosis. 30 pts had brain metastasis at diagnosis, of these pts 11 had cerebral progression on BRAF/MEK. 41 pts had radiotherapy, 50% had stereotactic/gamma knife and 50% WBRT. 68 pts progressed giving a median progression free survival (PFS) of 9 months (95% CI 6.4 – 11.6 m). The median PFS for pts with normal LDH was 14 months, opposed to 9 months if elevated. On progression 31 pts (36.5%) were not offered second line immunotherapy due to rapid deterioration or declining performance status. 26 (30.6%) were treated with PD-1 inhibitor; 7 (8.2%) had Ipilimumab, of these, 4 then had PD-1; 1 had combination therapy; 23.5% of pts continued on BRAF/MEK at analysis. Of the patients exposed to immunotherapy, 27 pts experienced disease progression, giving a median PFS survival of 2.5 months (95% CI 1.2 –3.6m). Conclusions: After BRAF/MEK inhibition, due to rapid disease progression and poor performance status a significant proportion of patients do not receive immunotherapy and received best supportive care. Disease control with single agent PD-1 is short after BRAF/MEK inhibitors. These patients may have benefited from first line immunotherapy. This cohort, while small, suggests further data is needed about optimal sequencing of targeted and immunotherapy.
Mibefradil dihydrochoride with hypofractionated radiation for recurrent glioblastoma: A phase I dose expansion trial.
Authors: Nataniel Hernan Lester-Coll, Jeffrey G. Supko, Jeannie Kluytenaar, Kira F Pavlik, James B. Yu, Jennifer Moliterno, Joseph Piepmeier, Kevin Becker, Joachim M. Baehring, Anita Huttner, Alexander Vortmeyer, Joseph N. Contessa, Ramachandran Ramani, Rachel Lampert, Xiaopan Yao, Ranjit Bindra
Journal: Journal of Clinical Oncology (2018)

e14046 Background: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options. We performed a high-throughput screen for DNA repair inhibitors and identified mibefradil dihydrochloride, a T-type calcium channel blocker. We and others revealed that mibefradil acts as a glioma radiosensitizer. Recent studies in our laboratory indicate that mibefradil blocks non-homologous end joining. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and radiation therapy (RT), in a Phase I recurrent GBM study. Methods: The Primary objective was to determine mibefradil MTD with concurrent hypofractionated RT. Secondary objectives included safety, pharmacokinetics, progression-free survival (PFS) and overall survival (OS). A tertiary objective included assessing intra-tumoral drug concentrations. In this novel translational sub-study, patients were given mibefradil for 5 days prior to surgery, followed by a re-resection. Resected tissues were analyzed for the presence of drug in situ. Inclusion criteria included histologically proven GBM progressive following RT and temozolomide. Patients received mibefradil, dose escalated from 150mg/day using a 3 + 3 design. RT consisted of 5 fractions of 600 cGy each, delivered over 2 weeks. Results: Nineteen patients enrolled from 9/2014 - 12/2016. There were 4 DLTs; a final dose level of 200 mg/day was reached. Median PFS and OS were 3 months and 9 months, respectively. Four patients (22%) achieved a PFS interval of ≥4 months (longest 8 months). One patient had a complete radiographic response. Intriguingly, mibefradil was detected at micromolar levels in GBM tumor tissue in 2 patients enrolled in the translational sub-study. We detected drug levels in biopsies from T1-post contrast and FLAIR regions on MRI and these levels correlate with that required for tumor cell radiosensitization in vitro. Conclusions: Our data suggest mibefradil can be safely co-administered with RT over a 17 day period at 200 mg/day. Promising local control signals apparent in a selection of patients, and we have demonstrated that pharmacologically effective concentrations of the drug are achieved in resected brain tumor tissue. Clinical trial information: NCT02202993.
TCT-708 Influence of Hospital Characteristics on the Management and Outcomes of Cardiogenic Shock Complicating Acute Myocardial Infarction: A 15-Year National Study
Authors: Saraschandra Vallabhajosyula, Saarwaani Vallabhajosyula, Gregory Barsness, Shannon Dunlay, Chet Rihal, David Holmes, Abhiram Prasad
Journal: Journal of the American College of Cardiology (2018)
Identification of an actionable mutation of <i>KIT</i> in extraskeletal myxoid chondrosarcoma (EMC).
Authors: Milena Urbini, Valentina Indio, Annalisa Astolfi, Giuseppe Tarantino, Salvatore Lorenzo Renne, Silvana Pilotti, Angelo Paolo Dei Tos, Roberta Maestro, Alessandro Gronchi, Gianpaolo Dagrada, Paola Collini, Monica Brenca, Chiara Colombo, Anna Maria Frezza, Andrea Pession, Paolo Giovanni Casali, Silvia Stacchiotti, Maria A. Pantaleo
Journal: Journal of Clinical Oncology (2018)

e23547 Background: EMC is an extremely rare soft tissue sarcoma, marked by a translocation involving NR4A3 gene. EMC are usually indolent and generally are moderately sensitive to anthracycline-based chemotherapy; we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. In addition, there is still the need to identify alternative therapeutic strategies. To better characterize the molecular background of this disease we performed whole transcriptome sequencing (WTS) in a small series of EMC identifying a case carrying an activating KIT mutation. Methods: Five EMC, positive for EWSR1-NR4A3 in FISH, were collected for WTS analysis. KIT phosphorylation was evaluated through Western Blot. KIT hotspot exons were sequenced through Sanger method in these cases and in an additional cohort of 15 EMC FFPE samples. Results: Presence of the chimeric EWSR1-NR4A3 mRNA was confirmed in all cases by WTS and no additional fusion event was identified. In concordance with previous reports, exon12/exon3 EWSR1-NR4A3 fusion was the most frequent breakpoint detected (sample #2, #3 and #5). While exon7/exon2 and exon13/exon3 were detected respectively in sample #1 and #4. Pathogenic SNV and INDEL were searched starting from WTS data. Peculiarly, in sample #1 an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of KIT. The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. Sample #1 showed a marked high expression of KIT at mRNA level (9.8 fold greater than in the other 4 cases) and a mild phosphorylation of the receptor. KIT p.D579del is known to predict response to TKI treatment in GIST. However, Sanger sequencing of KIT in additional 15 FFPE EMC did not show any other mutated cases. Conclusions: Exon 11 KIT mutation has been detected in one out of 20 EMC cases analyzed, indicating that KIT alteration is not a recurrent event in EMC and thus it could not explain the sensitivity of these tumors to sunitinib. Its role in the pathogenesis of EMC is left to be determined. No additional unknown fusion and/or mutation were detected.