tbuckley/cabot-search huggingface dataset:
Ovarian cancer treatment: Is the standard of care met in a public hospital system?
Authors: Katherine LaVigne, Woojin Chong, Merieme Klobocista, Mark H. Einstein, John Patrick Curtin, Leslie R. Boyd
Journal: Journal of Clinical Oncology (2014)

e16524 Background: Women who are economically disadvantaged or are members of under-represented minority groups have worse ovarian cancer outcomes. Public hospitals, which serve patients regardless of their ability to pay for care, are likely to have an over-representation of disadvantaged women. It has been hypothesized that one of the reasons for poor outcomes in economically disadvantaged women is an inability to obtain quality care. We sought to evaluate outcomes at two urban public hospital centers with active gynecologic oncology divisions. Methods: Information was abstracted from patients’ records at two urban public hospitals which serve mostly under- or uninsured women. Cases were identified from years 2001 – 2009, and women who underwent primary treatment at one of these hospitals were included. NCCN guidelines were used as standard of care. Results: 49 patients were identified: 23/49 non-white Latinas, 12/49 Caucasians, 11/49 Asians, and 3/49 African-Americans. 15/49 patients were born outside of the United States. 43 patients underwent primary surgery, with a median surgical wait-time of 21 days. 6 patients had neoadjuvant chemotherapy. 27 patients were stage III or greater, of these 9/27 (30%) had a suboptimal debulking. Median time from surgery to chemotherapy was 30 days. Of 12 patients meeting criteria for IP port placement, 5 ports (42%) were placed. All patients who met criteria for adjuvant therapy were prescribed combination platinum/taxane. 23 patients with stage III or IV disease were evaluable for completion of adjuvant therapy, of these 13 achieved CR (56%). 12/23 (52%) were platinum sensitive (at least 6 months disease free). 46 patients with stage III or IV disease were evaluable for follow up with a median of 41 months. At last contact, 8/46 were NED, 17/46 were AWD, 7/46 were DOD, and 1/46 were DOC. Conclusions: Patients at public hospitals had a high rate of suboptimal resection, and fewer patients achieved complete response after standard therapy, when compared to historical ovarian cancer controls. This was despite availability of gynecologic oncologists. This data, while tempered by a small sample size, may point to other institutional or patient-related barriers faced by economically disadvantaged patients.
Longitudinal Adverse Event Assessment of the Combination of Ipilimumab, Nivolumab and Brentuximab Vedotin in Relapsed / Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412: Arms A-F)
Authors: Fangxin Hong, Gita Thanarajasingam, Stephen M. Ansell, Richard F Ambinder, Jonathon B. Cohen, Michael Robertson, Kevin A. David, Ranjana H Advani, Timothy S. Fenske, Stefan Klaus Barta, Neil Palmisiano, Jakub Svoboda, David Morgan, Reem Karmali, Thomas E. Witzig, Amylou C. Dueck, Paul Novotny, Brad S Kahl, Catherine Diefenbach
Journal: Blood (2018)
Does the side of surgery and treatment have an effect on cardiovascular measurements in breast cancer survivors?
Authors: John R. Keyserlingk, David H. Jones, Melisa Nestore, Sara Henophy, Julia Cousin, Alain Steve Comtois
Journal: Journal of Clinical Oncology (2014)

e17674 Background: Determine if the surgery side and treatment side for a patient has an impact on cardiovascular measurements. Specifically if surgery/treatment on the left side (L) is associated with elevated blood pressure values compared to patients receiving surgery/ treatment on the right side (R). Methods: Measurements were taken on 723 Cancer survivor (CS) patients that had an intervention on the L side, 672 CS that had an invention on the R side and 53 CS patients that an intervention on both sides. Blood pressure (BP) was measured in all. CS patients were stratified into 8 different groups according to treatment and results presented in Table below: G1 surgery-only (n= 32(R), n= 50(L)), , G2- surgery and chemotherapy (n= 12(R), n=14(L)), G3 - surgery and radiotherapy(n= 45(R), n=48(L)), G4- surgery and hormone therapy(n= 54(R), n=61(L)), G5- surgery, chemotherapy, radiotherapy and hormone therapy(n= 215(R), n=246(L)), G6- surgery, radiotherapy and hormone(n= 204(R), n=191(L)), G7- surgery chemotherapy and radiotherapy(n= 71(R), n=84(L)), G8- surgery chemotherapy and hormone therapy(n= 35(R), n= 27(L)). A one-way ANOVA was performed followed by Dunnet’s post-hoc analysis, significance was set at P < .05. Results: (See Table.) Conclusions: Patients that had surgical and treatment interventions on their L side tended to have poorer outcome measures than patients that had similar interventions on their R side. Right diastolic BP mmHg Left diastolic BP mmHg Right systolic BP mmHg Left systolic BP mmHg Right MAP mmHg Left MAP mmHg G1 75.56± 13.07 76.64± 7.33 128.18± 20.42 129.96± 16.96 93.63 ±14.68 94.31 ± 9.43 G2 74.25± 9.62 76.79± 7.62 126.33± 14.25 129.14± 12.24 91.49 ± 8.36 94.11 ± 8.33 G3 73.17± 9.74 75.47± 7.98 122.98 ± 16.30 124.66± 13.97 89.65 ± 10.55 89.84 ± 15.88 G4 76.48± 9.61 75.70± 10.82 129.00 ± 16.30 128.26± 16.29 93.87 ± 9.74 93.12 ± 11.21 G5 76.71± 10.63 78.05± 10.11 126.73 ± 17.32 127.42± 16.36 92.85 ± 13.38 93.65± 13.89 G6 76.84± 11.03 76.58± 8.81 132.88 ± 18.79 131.31± 14.74 94.46 ± 15.45 94.20± 12.18 G7 75.68 ± 9.53 77.35± 9.88 127.63 ± 20.05 128.79± 17.13 92.88 ± 11.76 94.37± 11.22 G8 75.20 ± 9.62 81.33± 12.28 124.26 ± 14.39 131.92± 21.62 91.46 ± 9.39 98.09± 14.23 Abbreviations: MAP, mean arterial pressure.
PRMT5 Inhibition Selectively Targets Acute Myeloid Leukemia Stem Cells Though a p53-Dependent Mechanism
Authors: Emma Toulmin, Stefan Sonderegger, Loretta Cerruti, Andrej Terzic, Feng Yan, Nicholas Wong, Ian Street, Paul Stupple, Stephen Jane, Andrew H Wei, Rachel Altura, Benjamin Nicholson, David J. Curtis
Journal: Blood (2018)
Mutations in NSCLC.
Authors: Åslaug Helland, Odd Terje Brustugun, Sigve Nakken, Ann Rita Halvorsen, Jinchang Sun, Susanne. Lorenz, Daniel Vodak, Ola Myklebost, Eivind Hovig, Leonardo A. Meza-Zepeda
Journal: Journal of Clinical Oncology (2014)

e18516 Background: Lung cancer has a poor prognosis, with 15-20% five-years survival rate. However, lung cancer treatment has in the last years taken advantage of newly developed targeted therapies. EGFR-mutations and ALK-translocations are druggable alterations used in treatment decisions. There are several additional druggable mutations in cancers, especially among kinases, but their frequency in lung cancer is not fully elucidated. Methods: Blood samples and tumour tissue were obtained from 100 operated early stage lung cancer patients admitted to Oslo University Hospital-Rikshospitalet in the period 2006-2011. 48 were women, 21 squamous cell carcinomas, 77 adenocarcinomas and two large cell carcinomas. DNA was isolated from both tumour and corresponding blood sample according to standard procedures. Targeted resequencing was performed using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons for all known kinases, and selected cancer related genes and their associated UTRs, in total 612 genes. Targeted regions were sequenced at 50-60x coverage, allowing the detection of subpopulations down to 20%. The derived sequence was analysed based on a pipeline including calling variations, somatic mutations, DNA copy number changes, indels and genomic rearrangements, as well as functional annotations. Results: There were significant differences in the number of somatic mutations detected, ranging from 0 to 57, with a median of 12 mutations. Over 1200 mutations were identified among all the samples analysed, with recurrent mutations identified in specific pathways like the PI3K- and CHEK2/ATM-pathways. The TP53-gene was mutated in 52% of the samples, and these mutations have been validated by Sanger sequencing. The second most frequent mutated gene was KRAS, observed in 27% of the samples. Interestingly, the tumours with mutations in the ATM gene, revealed a significantly higher number of mutations than the ATM-wild-type tumours (p=0.028). Conclusions: In this pilot study, we have analysed 100 lung carcinomas by next generation sequencing, focusing on the kinome. We have identified several interesting mutational events, and analyses on different clinical subgroups are ongoing.
Ibrutinib therapy for patients with relapsed or refractory mantle cell lymphoma: A budget impact analysis from a U.S. payer perspective.
Authors: Mekre Senbetta, Akash Dandappanavar, R. Scott McKenzie, Lorie Ellis, Ken O'Day
Journal: Journal of Clinical Oncology (2014)

e19553 Background: In the US approximately 4,000 incident cases of mantle cell lymphoma (MCL) and 1,000 attributed deaths occur annually. Management of relapsed/refractory (R/R) MCL is challenging, as responses to second- and third-line chemotherapies are often incomplete and not durable due to the highly toxic regimens. Ibrutinib is FDA-approved for the treatment of MCL in patients who have received at least one prior therapy. Due to increased health care costs, health plans are interested in the budget impact of new treatments. The objective of this analysis was to estimate the budget impact of adding ibrutinib to a US health plan formulary over a 1-year time horizon. Methods: A model was developed to evaluate the budget impact of ibrutinib in a hypothetical 1-million member US health plan. Comparators included NCCN-recommended, commonly prescribed regimens for R/R MCL patients (bortezomib, lenalidomide, bendamustine, rituximab, and combinations). Dosing, administration, mean duration of therapy (DOT) and adverse event (AE) rates were based on package inserts for approved drugs and published literature for other regimens. Drug, administration, and AE costs were considered. The estimated treatment-eligible population was based on epidemiologic data and a database analysis. Market share was estimated for each treatment with and without ibrutinib. The incremental cost per-member-per-month (PMPM) was calculated. One-way sensitivity analysis was performed. Results: The model estimated a treated population of 17 R/R MCL patients in a 1-million member health plan. Based on the comparators and assumptions listed above, the incremental budget impact of adopting ibrutinib for R/R MCL patients treated with ibrutinib for duration of 8.3 months and 12 months is estimated to be $0.010 and $0.027 PMPM, respectively. The model results were most sensitive to ibrutinib DOT, followed by ibrutinib market share, and health plan population ≥ 65 years. Conclusions: The model results indicate that the budget impact of ibrutinib is estimated to be minimal from a US health plan perspective. This is relevant considering the efficacy and safety benefits for this orphan disease with high unmet need.
Correlation of high levels of HER2 measured by multiplex mass spectrometry with increased overall survival in patients treated with anti-HER2-based therapy.
Authors: Paolo Nuciforo, Sheeno P Thyparambil, Ana Christina Garrido-Castro, Vicente Peg, Ludmila Prudkin, Jose Jimenez, William Arthur Hoos, Jon Burrows, Todd A. Hembrough, Jose Manuel Perez-Garcia, Javier Cortes, Maurizio Scaltriti
Journal: Journal of Clinical Oncology (2014)

649 Background: There is evidence that increased absolute levels of the HER2 receptor in breast cancer positively correlates with a clinical benefit from anti-HER2 therapies. The current method of HER2 evaluation, immunohistochemistry (IHC), does not allow for absolute HER2 quantification and is prone to false-positives. Thus, a significant portion of patients classified as HER2-positive actually express low levels of the receptor. We quantitated absolute levels of HER2 using a mass spectrometry-based assay and correlated expression levels with the anti-HER2 therapy benefit. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor sections were microdissected and proteins were solubilized and digested by trypsin in Liquid Tissue buffer. After digestion, internal standards were added and absolute quantitation for multiple proteins was performed using selected reaction monitoring (SRM) mass spectrometry. Results: 26 HER2-positive (IHC 3+) breast cancer samples from patients treated with anti-HER2 therapy were obtained from Vall d´Hebron Hospital. Nineteen patients were treated with trastuzumab-based therapy; six were treated with a combination of anti-Her2 therapies. HER2 quantitation by SRM revealed receptor level ranges from 283 to 12840 amol/µg. Based on the median HER2 expression of the trastuzumab-only treated patients, the patients were divided into two subgroups. The subgroup with high expression levels of HER2 protein (average of 7461 amol/µg) had an overall survival time of 82.8 months whereas the subgroup with low levels of HER2 (average of 1823 amol/µg) had a significantly shorter survival time of 55.3 months. Conclusions: We used a non-antibody based assay to quantify absolute levels of HER2 in samples from patients treated with anti-HER2 therapy. We found high variability in HER2 expression within a patient population that had been homogenously classified as 3+ by IHC. High levels of HER2 correlated with increased overall survival following anti-HER2 therapy. This study demonstrates the need for improved quantitation of HER2 protein levels prior to initiating anti-HER2 therapy.
Mutation-Enhanced International Prognostic Systems for Essential Thrombocythemia (MIPSS-ET) and Polycythemia Vera (MIPSS-PV)
Authors: Ayalew Tefferi, Paola Guglielmelli, Terra L. Lasho, Giacomo Coltro, Christy Finke, Giuseppe Gaetano Loscocco, Mythri Mudireddy, Benedetta Sordi, Natasha Szuber, Giada Rotunno, Rangit Vallapureddy, Annalisa Pacilli, Maura Nicolosi, Domenico Penna, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat, Alessandro M. Vannucchi
Journal: Blood (2018)
PD-L1 specific tumor infiltrating lymphocytes occur frequently in melanoma and HNSCC patients.
Authors: Niels Junker, Marco Donia, Rikke Andersen, Mads Hald Andersen, Inge Marie Svane
Journal: Journal of Clinical Oncology (2014)

11083 Background: Emerging immunotherapeutic strategies targeting the potent immune inhibitory PD-1/PD-L1 pathway in patients with advanced melanoma and squamous cell carcinoma of the lung, and TIL based adoptive therapy of patients with advanced melanoma are very promising. In order to identify relevant tumor associated targets of TIL based therapy our study aimed to identify the occurrence of PD-L1 specific T-cells in ex vivo expanded TIL from 30 patients, six of which were head and neck squamous cell carcinoma (HNSCC) patients and 24 were melanoma patients. The latter include 18 melanoma patients from our ongoing phase II trial NCT00937625. Methods: Upon PD-L1 peptide stimulation, TILs were screened for IFNgamma secretion using direct Elispot assays (Mabtech). In addition, PD-L1:tetramer (in house) analysis of TIL from selected patients was performed identifying PD-L1 specific cytotoxic T-cells. A standard 51Cr-release assay was used to assess killing of T2 cells presenting PD-L1 peptide. Results: In five of six HNSCC patients and in 17 of 24 melanoma patients, respectively, functional PD-L1 specific T-cells were identified in ex vivo expanded TIL, as determined by IFNgamma release. Moreover, it should be noted, PD-L1 responses were detected in four of five clinical responders (PR/CR), but in only two of five non-responders (SD/PD). Sequential analysis of specific binding to PD-L1:tetramers and the killing of PD-L1 presenting T2 cells confirmed the PD-L1 derived epitopes as a valid immunogenic target. Conclusions: These data demonstrate that counter immune inhibitory effector T-cells are present in tumors of different origin, and that they have the potential to effectively engage PD-L1, a known potent antitumor immune inhibitor. These findings may lead to the notion that effective immunotherapeutic approaches rely on the presence of effector T-cells specifically targeting both tumor and endogenous immune inhibitory pathways.
Reduction of Tumor Burden Rather Than Off-Target Effects Drives Changes in T-Cell Number and Profile during Prolonged Ibrutinib Treatment in Relapsed or Refractory Chronic Lymphocytic Leukemia Patients
Authors: Marzia Palma, Kia Heimersson, Tom A. Mulder, Barbro Näsman-Glaser, Anders Österborg, Håkan Mellstedt
Journal: Blood (2018)
The utility of HTS TCR analyses in the management of patients with T-cell malignancies.
Authors: Ilan Lanny Kirsch, Anna Sherwood, David Williamson, Wen-Kai Weng, Rachael Clark, Thomas Seth Kupper, David Wu, Harlan Robins
Journal: Journal of Clinical Oncology (2014)

8565 Background: We have pioneered a method to sequence the diversity of the TCR CDR3 rearrangements that exploits the capacity of high-throughput sequencing (HTS) to document the diverse repertoire of TCR CDR3 chains. Methods: These assays can describe both the breadth of T-cell repertoire diversity and quantify individual clones. This technology thus provides an opportunity to identify and then track the presence and frequency of clones in lymphoid malignancies. Results: HTS improves the detection and monitoring of minimal residual disease in precursor acute T lymphoblastic leukemias over other available methods. We have also sequenced the TCRB repertoire in a morphologic mix of T-cell lymphoma specimens. HTS of TCRB was concordant with flow cytometry or PCR-based evaluation of TCRG rearrangement in 46 of 59 samples with recognition of residual disease based on the previously identified diagnostic index clones. However, 5 samples were only positive for recurrent disease based on HTS. We have also demonstrated the ability of HTS to detect malignant cells beneath the level of detection of flow cytometry in a cohort of patients with Sezary Syndrome and have also demonstrated the utility of this assay for early detection of relapse and for providing potential useful information that distinguishes among drug toxicity, GVHD, or clinical relapse in skin lesions from this same patient population following allogeneic transplant. In an analysis of skin biopsies from patients with CTCL in which data from flow cytometry, qPCR, and HTS were performed comparatively, HTS was able to identify a significantly greater number of trackable diagnostic clones in the suspect lesions and distinguish malignant from non-malignant lesions. Conclusions: HTS TCR repertoire profiling is the most sensitive and accurate method for clonal detection and monitoring in T-cell malignancies. The assay is now being incorporated into clinical management in CTCL.
Nanosuspension-based formulation development for the first-in-class PLK2 inhibitor, GBO-006, toward IND-enabling studies.
Authors: Srinivas Rao Maddi, Seetaraju Gembali, Jeyaraj Duraiswamy Athisayamani, Arnab Roy Chowdhury
Journal: Journal of Clinical Oncology (2014)

e13529 Background: GBO-006-1 (ON 1231320) was shown to be a highly selective PLK2 inhibitor that promoted mitotic arrest of various cancer cell lines, subsequently resulting in their apoptotic death. Although this compound has many desirable attributes, it is poorly water soluble with low oral bioavailability in rodents. Intraperitoneal alternate day dosing of GBO-006 using 100% DMSO as formulation caused significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies underscored the need to develop a biocompatible parenteral formulation for additional IND enabling studies. We explored several technologies, including co-solvency, complexation and micelle solubilization approaches but failed to improve the aqueous solubility. However, a nanosuspension was successfully devised. Methods: Crystalline and lipid-based nanosuspensions using different surfactants were developed and evaluated for both solubility and long-term stability. Nanosuspensions were prepared by Ultra-Turrax homogenization followed by bead milling and microfluidics and subsequently evaluated for particle size reduction and morphology. Results: Nanosuspensions prepared by bead milling were stable for more than two weeks and showed reduced particle size of 0.26-0.3 microns. Mouse IV and IP pharmacokinetic studies showed a great improvement in Cmax, AUC and bio-distribution properties of the compound. Conclusions: We have developed a biologically compatible parenteral formulation for a first-in-class, novel anti-cancer agent that will be progressed towards IND enabling studies.
Phase II trial of bevacizumab, cisplatin, and pemetrexed in Japanese patients with advanced nonsquamous non-small cell lung cancer.
Authors: Noriko Yanagitani, Fumiyoshi Ohyanagi, Hironari Nishizawa, Hiroshi Gyotoku, Takeshi Uenami, Hiroshi Kobayashi, Keita Kudo, Yuichi Tambo, Atsushi Horiike, Sachiko Hagiwara, Takeshi Horai, Makoto Nishio
Journal: Journal of Clinical Oncology (2014)

e19135 Background: The treatment protocol using bevacizumab, pemetrexed (PEM) and cisplatin (CDDP) is considered to one of the strongest regimens for advanced non-squamous (Nsq) non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination has not yet been well examined in Japan. We therefore conducted this phase II study. Methods: All eligibility patients had either histologically or cytologically confirmed Nsq-NSCLC, with clinical stage IIIB, IV, or recurrent disease, no prior cytotoxic chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an adequate organ function. Patients with unstable brain metastases, uncontrolled pleural effusion or ascites, active infection, active concomitant malignancy or interstitial pneumonia were excluded. Bevacizumab 15mg/m2, CDDP (75 mg/m2) and PEM (500 mg/m2) on day 1 every 3 weeks were administered in four cycles and maintenance therapy with bevacizumab 15mg/m2once every 3 weeks was continued until either disease progression or unacceptable toxicity. The primary endpoint was the response rate. Results: From July 2011 to June 2013, 45 patients were enrolled. All 45 patients were evaluated for the efficacy and safety of the treatment. The median age was 61 years (range 35–73), consisting of 20 (44%) males and 25 (55%) females. Thirty patients had PS 0 and 15 patients had PS 1. All patients had adenocarcinoma. The partial response and stable disease were obtained in 27 patients and 18 patients, respectively. Toxicities of this regimens were generally mild (grade 3/4 neutropenia were observed in 5 patients, grade 3 pneumonia was observed in 2 patients, and grade 3 elevations of the serum creatinine levels were observed in 1 patient). However, grade 3 pulmonary embolisms were observed in 3 patients (6.7%), grade 3 hypertensions in 8 (17.8%) and grade 2 deep vein thrombosis in 1 patient (2.2%). Conclusions: The Bevacizumab/PEM/CDDP regimen was therefore found to be effective and well tolerated in Japanese Nsq-NSCLC patients. Clinical trial information: R000006702.
Phase 1 Studies Assessing the Safety and Clinical Activity of Multiple Doses of a NKG2D-Based CAR-T Therapy, Cyad-01, in Acute Myeloid Leukemia
Authors: Jason B. Brayer, David A Sallman, Tessa Kerre, Xavier Poire, Violaine Havelange, Philippe Lewalle, Eunice S. Wang, Dominik Selleslag, Sebastien Anguille, Yves Beguin, Enkhtsetseg Purev, Ahmad-Samer Al-Homsi, Doreen Dekker, Eytan Breman, Panagiota A. Sotiropoulou, Sarah Snykers, Nathalie Braun, Caroline Lonez, Bikash Verma, Frédéric F. Lehmann, Marco L. Davila
Journal: Blood (2018)