tbuckley/cabot-search huggingface dataset:
Pooled analysis of onapristone extended release (ONA ER) in metastatic cancer patients (pts): A review of liver safety.
Authors: Paul H. Cottu, Anuradha Jayaram, Antoine Italiano, Simon Pacey, Alexandra Leary, Robert J Jones, Mario Campone, Anne Floquet, Dominique Berton Rigaud, Catherine Lhomme, Marie-Paule Sablin, Alice Susannah Bexon, Jacques Bonneterre, Gerhardt Attard, Paul B Watkins
Journal: Journal of Clinical Oncology (2019)

e14647 Background: ONA, a type I progesterone receptor (PR) antagonist, prevents PR activation by disrupting PR dimerization and DNA binding, and inhibits tumor progression. ONA (immediate release) has efficacy comparable to other endocrine therapies in pts with metastatic breast cancer (BC). The only notable toxicity was transient elevation in liver chemistries in some pts. In 2 clinical trials, ONA ER was given to 88 cancer pts who underwent frequent liver chemistry monitoring. Methods: We pooled and reviewed all liver safety data from 2 trials. A hepatologist (PBW) reviewed all pts with either a hepatobiliary SOC AE or who experienced an elevation &gt; ULN of any liver-related laboratory test. Results: Of 88 pts who received ONA ER for a median 8 weeks (3-51), 59% were female, median age 68 (36-89), 99% Caucasian, 28% had liver metastases (mets), 48% bone mets and 17% also took abiraterone (ABI), which has liver toxicity. 54 pts (61%) experienced any ONA ER-related AE. More AEs were seen in ABI pts (67%), those with liver mets (72%) and BC (76%).. In terms of liver-related TEAEs, overall 10% of pts had ALT and 13% AST elevations, while 20% pts with liver mets had raised ALT/AST and 29% of BC pts. Overall 15% pts had G3 TEAEs, compared to 28% pts with liver mets, mostly due to increased GGT (24%), which has unclear clinical impact. There were no discontinuations for LFT elevations. A relationship between the liver events and ONA ER was judged to be unlikely in each subject, except one. This event was detected at day 29 of treatment and consisted of a marked rise in serum GGT and alkaline phosphatase with only a moderate rise in serum ALT (peak – 262). These abnormalities improved quickly after stopping ONA but recurred on reintroduction: these events are not serious by international criteria and the pt was able to continue ONA at a lower dose for 40 weeks without recurrence Conclusions: The safety experience for ONA ER has been reassuring but must continue to be characterized. For new ONA ER studies, weekly liver chemistry monitoring is planned for the first 4 weeks with Q2W monitoring thereafter. The occasional G3 elevations in serum AST, ALT or bilirubin will prompt interruption, but re-starting treatment at a lower dose should be possible for most pts. Clinical trial information: NCT02052128 and NCT02049190.
Identification of prognostic variables in advanced ovarian cancer based on real-world patients from big data analytics.
Authors: Jesús García-Donas, Elena Sevillano, Sergio Muñoz, Luis Bote, Monica Yagüe, Nuria Lainez, Eva Mª Guerra, Maria Garrido, Teresa Garcia-Donas, Sandra Amarilla, Paloma Navarro, Sergio Ruiz, MD Fenor, Juan Francisco Rodriguez-Moreno, Jose Luis Rojo
Journal: Journal of Clinical Oncology (2019)

e17104 Background: Prognosis of advanced ovarian cancer is dismal with most cases recurring after initial surgery. Current factors able to predict the evolution of the disease are limited to BRCA status and platinum sensitivity. We aim to explore the potential of different clinical variables as prognostic factors using big data analytics in currently available hospitalary departmental information systems. Methods: An observational study with two cohorts (one prospective and one retrospective) was designed. Inclusion criteria were adult patients ( &gt; 18 years old) diagnosed with epithelial ovarian cancer stage IC or superior.Clinical and histological data were recorded by a central data manager to ensure homogeneity in data collection. Big data analytics consisted on building an approximation to the statistical distribution of the tests to distinguish different kinds of features (metric, categorical, free text). Bootstrap resampling allowed to characterize the confidence regions for proportion differences, average differences, and text-profile differences in exitus vs in non-exitus groups. Results: Up to 265 patients in four different hospitals were recruited. Median age was 59 years (range 20-87), stage distribution was 48 (18%) I, 20 (8%) II, 122 (46%) III, 41 (15%) IVand 34 (13%) NA. Histology distribution was 158 (60%) papillary serous, 31 (12%) endometrioid, 18 (7%) clear cell, 11 (4%) mucinous and 47 (18%) NA. 152 (58%) patients underwent upfront surgery, 76 (29%) interval surgery and 10 (4%) no surgical intervention, 27 (10%) NA. 207 (78%) achieved optimal cytoreduction. 232 (88%) received adjuvant chemotherapy, most with carboplatin plus paclitaxel 180 (68%) and 48 (18%) also with bevacizumab. Median follow up was 81.4 months (CI95% 64.1-98.7) The proposed Big Data analytics identified a higher frequency of upfront surgery (vs interval surgery) and bevacizumab administration (vs chemotherapy alone) in the non-exitus group. Conclusions: Our results point to the notion that performance of upfront surgery and bevacizumab administration could have a long term impact in ovarian cancer. Simple Big Data analytics can contribute to identify new prognostic factors and to assess their real impact on patients managed in daily practice.
Genomic correlates of response to adjuvant trastuzumab (H) and pertuzumab (P) in HER2+ breast cancer (BC): Biomarker analysis of the APHINITY trial.
Authors: Ian E. Krop, Joseph Paulson, Christine Campbell, Astrid Christina Kiermaier, Fabrice Andre, Debora Fumagalli, Sanne de Haas, Roberto Salgado, Carsten Denkert, Sibylle Loibl, Andrew Bailey, Gail Lewis Phillips, Elizabeth Frank, Martine Piccart, Giuseppe Viale, Sherene Loi
Journal: Journal of Clinical Oncology (2019)

1012 Background: We conducted a comprehensive genomic and immune-marker based analysis to identify prognostic and predictive biomarkers beyond clinical parameters (eg nodal status) in the setting of HP-based therapy. Methods: APHINITY, a phase III study, randomized 4805 pt with HER2+ BC to adjuvant chemo/H, plus P or placebo. Tumor Infiltrating Lymphocytes (TILs) were analysed using published methods. A nested case-control design with 1023 pt samples (3 controls matched to 1 distant relapse) underwent DNA (targeted) and RNA sequencing. Inverse probability weighting with Kaplan-Meier estimator weights, and models adjusted for treatment, hormone receptor, nodal status, age and chemotherapy type were used. Results are reported descriptively with 95% CIs. Interaction p-values are unadjusted for multiplicity. Results: DNA-seq, RNA-seq and TIL analyses were successful in 940/1023 (92%), 974/1023 (95%), and 4313/4804 (90%) samples, respectively. Prognosis (arms pooled): PI3K/PTEN/AKT alterations (HR 1.35; CI 1.01-1.79), MYC (HR 1.61; CI 1.16-2.23) or ZNF703 amplification (HR 1.62; CI 1.07-2.47) suggest poorer prognosis while TOP2A amplification (HR 0.49; CI, 0.32-0.74) suggests better prognosis independent of anthracycline use. Higher mRNA expression of an immune signature (IFNG, PD-L1, CXCL9 (HR 0.68; CI 0.52-0.89)) and TILs (HR 0.91; CI 0.86-0.96) also suggest better outcomes. Predictive effects: Table shows the HR for H+P benefit versus H for selected markers. PAM50 subtype did not predict benefit. Conclusions: In this comprehensive biomarker analysis, higher levels of immune markers and HER2 appeared to be associated with better prognosis and greater H+P benefit. Clinical trial information: NCT01358877. [Table: see text]
Clinical utility and reimbursement for expanded genomic panel testing in adult oncology.
Authors: Susan Jean Hsiao, Anthony Sireci, Danielle Pendrick, Christopher Freeman, Jessica Yang, Gary K. Schwartz, Mahesh M. Mansukhani, Richard D. Carvajal, Jennifer A. Oberg
Journal: Journal of Clinical Oncology (2019)

6593 Background: The routine use of large next generation sequencing (NGS) cancer panels is required to identify the increasing number of, but often uncommon actionable alterations present across multiple tumor histologies to guide therapy. Inconsistent coverage and variable payment is hindering adoption of these tests into clinical practice. A review of clinical utility, coverage and reimbursement was conducted in a cohort of adult oncology patients who received expanded genomic panel testing as part of their clinical care. Methods: The Columbia Combined Cancer Panel (CCCP), a 467 gene panel designed to detect single nucleotide variants, indels, and copy number variations in solid and liquid tumors was performed in a CLIA-certified laboratory at Columbia University Irving Medical Center. Clinical utility categories included: immediate change in management; informed future treatment options; provided diagnostic/prognostic information; and other impact. Claims were submitted between 1/1/17 and 4/30/18. Carriers were categorized into commercial, managed-government, and government plans. Results: 300 tumors underwent NGS. Reimbursement data were available for 258 cases. 57% of testing was performed for a treatment-resistant, recurrent, or high stage cancer, or for a cancer of rare/mixed histology (21%). Findings were clinically actionable in 183 cases (61%). Results led to an immediate change in management (n = 6, 2%), informed future treatment options (n = 140, 47%), and provided diagnostic/prognostic information (n = 29, 10%). Only 57 tests (22%) received coverage. In 59% of denials (118/201), a clinically-actionable result was found. Commercial plans reimbursed 29/119 tests (24%) and managed-government plans reimbursed 28/54 tests (52%). Government plans provided no coverage for 85 tests. On average, insurers reimbursed 10% of the total CCCP service charges: 12.5% for commercial and 22% for managed-government plans. Conclusions: Expanded genomic testing identified clinically-impactful alterations in 61% of cases. Limited coverage and low reimbursement remain a barrier and broader reimbursement policies are needed to adopt expanded genomic testing that benefits patients into clinical practice.
Omission of adjuvant therapy in stage I clear cell ovarian cancer: Review of the British Columbia (BC) cancer experience.
Authors: Shiru Lucy Liu, Anna Tinker
Journal: Journal of Clinical Oncology (2019)

5536 Background: Standard guidelines recommend adjuvant chemotherapy for stage I clear cell ovarian cancer (CCOC), despite data demonstrating excellent outcomes. Since 2012, the BC Cancer provincial treatment guidelines for surgically staged stage IA/B and IC1 (defined by intraoperative rupture only) CCOC has been to offer observation only. We reviewed the clinical outcomes of stage I CCOC patients since policy implementation. Methods: A retrospective, population-based cohort study of all stage I CCOC patients operated on between April 2012 and December 2017 was conducted. Patient, tumor, surgical and clinical outcome data were collected. Survival analysis was conducted using Kaplan-Meier methods. Results: 78 patients with stage I disease were identified (see Table). Among stage IC1 patients, 9 received adjuvant therapy despite provincial policy, 6 of which were due to sharp dissection. 40 patients with stages IA/B and IC1, who underwent post-operative observation, were included in the analysis. Median duration of follow-up was 36 months. Median age at diagnosis was 55 years and &gt;50% patients had a Charlson Comorbidity Index of 0 (N= 26) and an Eastern Cooperative Oncology Group performance status of 0 (N=28) prior to diagnosis. Lymph node dissection was not performed in 20 patients. All 16 cases tested immunohistochemically for mismatch repair were intact, and 2 of 6 cases with tumour genomic sequencing had an AURKA aberration. There were 4 recurrences (10%), 3 of which were metastatic. 5-year disease-free survival is 90%, and 5-year overall survival is 95% for stage IA/B and 90% for stage IC1 (p=0.645). In comparison, 5-year overall survival for stage IC2 (surface involvement) and IC1 with sharp dissection (all received chemotherapy) is 82% and for stage IC3 (positive washings) is 23% (p&lt;0.001). Conclusions: Outcomes of patients with stage I A/B and C1 CCOC remain excellent. Adjuvant therapy can be safely omitted, with low recurrence rates and survival over 90% at 5 years. Consideration of disease substage is valuable in predicting the clinical outcomes of stage I CCOC. [Table: see text]
Summary of the International Conference on Onco-Nephrology: an emerging field in medicine
Authors: Anna Capasso, Ariella Benigni, Umberto Capitanio, Farhad R. Danesh, Vincenzo Di Marzo, Loreto Gesualdo, Giuseppe Grandaliano, Edgar A. Jaimes, Jolanta Malyszko, Mark A. Perazella, Qi Qian, Pierre Ronco, Mitchell H. Rosner, Francesco Trepiccione, Davide Viggiano, Carmine Zoccali, Giovambattista Capasso, Ariga Akitaka, Amit Alahoti, Todd R. Alexander, Lucia Altucci, Hatem Amer, Vincenzo Barone, Ariela Benigni, Luigi Biancone, Joseph V. Bonventre, Giovanni Camussi, Anna Capasso, Fortunato Ciardiello, Umberto Capitanio, Michele Caraglia, Giacomo Cartenì, Andrés Cervantes, Franco Citterio, Laura Cosmai, Farhad R. Danesh, Bruno Daniele, Antonietta D’Errico, Ferdinando De Vita, Vincenzo Di Marzo, Antonio Ereditato, Geppino Falco, Denis Fouque, Renato Franco, Maurizio Gallieni, Giovanni Gambaro, Loreto Gesualdo, Giuseppe Grandaliano, Calvin Kuo, Edgar A. Jaimes, Vincent Launay-Vacher, Evaristo Maiello, Francesca Mallamaci, Jolanta Malysxko, Gennaro Marino, Erica Martinelli, Giuseppe Matarese, Takeshi Matsubara, Piergiorgio Messa, Carlo Messina, Vincenzo Mirone, Floriana Morgillo, Alessandro Nanni Costa, Michele Orditura, Antonello Pani, Mark Anthony Perazella, Alessandra Perna, Claudio Pisano, Todd Pitts, Camillo Porta, Giuseppe Procopio, Qi Qian, Giuseppe Remuzzi, Pierre Ronco, Mitchell H. Rosner, Domenico Russo, Lilian L. Siu, Walter Stadler, Francesco Trepiccione, Teresa Troiani, Davide Viggiano, Alessandro Weisz, Andrzej Więcek, Ding Xiaoqiang, Ortensio Zecchino, Carmine Zoccali
Journal: Kidney International (2019)
Radiomics features to identify distinct subtypes of triple-negative breast cancers.
Authors: Haruka Itakura, Debra M. Ikeda, Satoko Okamoto, Shu-Tian Chen, Blaine Rister, Dev Gude, Sarah A. Mattonen, Emel Alkim, Julia Todderud, Emil Schueler, Daniel Rubin, George W. Sledge, Allison W. Kurian
Journal: Journal of Clinical Oncology (2019)

3069 Background: We sought to gain new insight into triple-negative breast cancer (TNBC), an aggressive, clinically distinct subgroup of breast cancers, by applying a sequence of computational approaches to tumor segmentation, three-dimensional anatomic characterization, and tumor subtyping. We extracted algorithmically-derived quantitative imaging (radiomics) features from each TNBC lesion in breast magnetic resonance imaging (MRI) to identify underlying subtypes. Methods: We evaluated tumors on pre-treatment, post-contrast MRI from 90 patients with non-metastatic TNBC. We employed active contour segmentation and semi-automated identification of tumor regions-of-interest. We extracted 900 radiomics features from each segmented tumor using an algorithm that characterizes the size, shape, texture, and edge sharpness of tumors at the voxel level. We applied k-means consensus clustering, a statistical tool for unsupervised discovery, and performed 1000 bootstraps with resampling on the feature vectors to examine all resulting clusters from k=2 to 10. Based on two diagnostic metrics of consensus stability, we selected the optimum cluster number. We performed Significance Analysis of Microarrays to identify statistically significant radiomics features for each cluster. Results: We identified three distinct image-based clusters in 117 tumors from 90 TNBC patients (multifocal lesions in n=13). Cluster 1 (n=97) was distinguished by 330 radiomics features (False Discovery Rate [FDR] &lt;5%) and Cluster 2 (n=13) by 85 features (FDR&lt;5%), whereas Cluster 3 (n=7) was not significantly associated with features. Clinical characteristics did not differ across the three clusters, with mean age (49.1±11.7) and clinical stage distributions (stage I: 20.7%, II: 55.4%, III: 23.9%) for the cohort mirroring those of individual clusters. Among those who received neoadjuvant therapy, we observed pathologic complete response in 50% (23 of 46, 95% CI, 0.36-0.64) of patients in Cluster 1, 83% (5 of 6, 95% CI, 0.54-1.0) in Cluster 2, and 0% (0 of 3) in Cluster 3. Conclusions: Radiomics features providing voxel-level characteristics of tumor morphology differentiated TNBC into three distinct subtypes. These subtypes, defined by radiomics biomarkers, may be associated with clinical response to neoadjuvant therapy.
Phase II randomized trial of afatinib with or without cetuximab as first-line treatment for EGFR mutated non-small cell lung cancer (NSCLC) patients (IFCT-1503 ACE-Lung).
Authors: Alexis B. Cortot, Anne Madroszyk, Etienne Giroux Leprieur, Olivier Molinier, Elisabeth A. Quoix, Henri Berard, Josianne Otto, Isabelle Rault, Judith Raimbourg, Jose Hureaux, Lionel Moreau, Didier Debieuvre, Hugues Morel, Marc G. Denis, Elodie Amour, Franck Morin, Denis Moro-Sibilot, Jacques Cadranel
Journal: Journal of Clinical Oncology (2019)

9079 Background: First-line treatment of metastatic EGFR-mutated NSCLC relies on EGFR-TKIs. However, all patients (pts) eventually develop progression. Dual inhibition of EGFR with afatinib (A), an irreversible pan-erbB TKI, and cetuximab (C), an EGFR monoclonal antibody, has shown activity in EGFR-mutated pts with acquired resistance to TKIs, regardless of the T790M status. Methods: We conducted a phase II randomized trial in advanced NSCLC pts harboring an activating EGFR mutation, who had not received prior therapy. Pts were treated with A (40 mg/d) until progression alone or with C 500 mg/m² every 2 weeks during 6 months (mos) (beginning at D15 at 250 mg/m²). Primary endpoint was time-to-treatment failure (TTF) at 9 mos for pts with del19 and L858R mutations. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS). Prospective monitoring of the T790M mutation was performed on circulating tumoral DNA (ctDNA) by digital PCR. Results: Trial was stopped early due to futility analysis after 118 pts were enrolled (59 in each arm). Baseline characteristics were balanced between the 2 arms, and especially for the types of EGFR mutation (del19, 55.9 vs 50.8%; L858R, 39 vs 40.7%; others, 5.1 vs 8.5% in AC and A arms, respectively). Treatment-related AEs of any grades were similar, although there was an excess of grade 3 AEs in the AC arm (50 vs 37.3%), but no of grade 5. The excess in grade 3-5 AEs was essentially due to cutaneous (96.6 vs 81.4%), eyes (32.8 vs 27.1%), hematological (22.4 vs 15.3%) but not to digestive toxicities (89.7 vs 98.3%). Among the 117 pts included in the efficacy analysis, 9-months TTF was 63.3% (47.5-75.6) in arm A and 65.8% (50.1-77.66) in arm AC. Median TTF was 11.1 mos (8.3-not reached [NR]) and 10.8 mos (9.2-13.7) in arms A and AC, respectively. Median PFS was 11.1 mos (8.3-NR) and 12.8 mos (9.2-13.7), respectively. Median OS was 20.8 mos (17.5-NR) and NR (17-NR), respectively. Conclusions: Efficacy of AC was similar to that of A alone. These results don’t support further evaluation of this combination in this setting. Results of ctDNA monitoring will be reported during the meeting. Clinical trial information: NCT02716311.
Monorchism
Authors: George K. Kawaichi, Philip Cooper, Harold F. O'Donnell
Journal: New England Journal of Medicine (1949)

CONGENITAL absence of one testis or both testes is still considered rare. Since the advent of surgical treatment for "cryptorchidism," however, an increasing number of cases of monorchism or anorchism have been reported. Gruber,1 in 1878, reviewed the literature for a period of three hundred years and was able to verify only 23 cases of monorchism and 7 cases of anorchism. In the more recent literature, Thorek and Thorek2 reported, in 1933, a case of monorchism. Rea,3 in 1938, reviewed the literature and found 40 reported cases of anorchism or monorchism. Of these, 11 were bilateral, and 29 unilateral. He . . .
Measuring T-cell avidity and enrichment using acoustic force-based technology.
Authors: Leif Stefan Anderson, Rens Braster, Gerrit Sitters, Andrea Candelli, Ton N. Schumacher, Wouter Scheper
Journal: Journal of Clinical Oncology (2019)

e14010 Background: The key driver for effective immune cell therapies is the overall binding strength of the immune cell and the target cell (e.g. tumor cells). The overall strength is known as ‘avidity’, a parameter reflecting interaction efficiency. The key to success for immune cell therapies is generating effective and long-lasting immune responses. The avidity of an immune cell to its target is predicative of its function, but current techniques to measure avidity are low-throughput and ineffective. Herein, we describe the use of acoustic forces to discriminate immune cells based on their avidity to tumor cells. The force required to separate a cell from its target is called the ‘rupture force’, and in this study, we were able to identify the rupture forces of tumor specific and non-specific T cells and enrich these different populations for downstream characterization. Methods: T cells from a healthy donor were transduced with either a non-relevant, or a melanoma recognizing T cell receptor and selected with puromycin resistance. Melanoma cells were seeded in the flow cell and allowed to adhere overnight to form a monolayer. For confocal experiments CFSE and Cell Trace far red stained T cells were mixed in a 1:1 ratio before co-culturing them in the flow cell. An acoustic force ramp was applied within the flow cell and cell detachment was monitored. Results: T cells engineered with a melanoma antigen-recognizing T-cell receptor needed 6 times more force than non-specific T cells to be separated from the melanoma target cells. Furthermore, 1.4 to 3.6-fold enrichment of high-avidity T cells was obtained from a mixed population of specific and non-specific T cells using acoustic forces. Conclusions: These findings indicate that melanoma-specific T cells bind with a higher avidity than non-specific T cells and that they can be separated with this approach. In conclusion, we demonstrate a novel method to measure cell avidity and sort cells by utilizing acoustic forces.