tbuckley/cabot-search huggingface dataset:
Nivolumab in renal cancer: French evaluation of use, current practices and medico economic approach.
Authors: Francoise Grude, Gildas Appéré, Fanny Marhuenda, Delphine Deniel Lagadec, Elouen Boughalem, Friederike Schlurmann, Muriel Travers, Claude El Kouri
Journal: Journal of Clinical Oncology (2019)

e16093 Background: Since April 2016 (EMA approval), Nivolumab could be prescribed in advanced renal carcinoma after prior treatment. The Brittany and Pays de la Loire Cancer Observatory has collected data on their real-life indications, current management, safety, efficacy and medico-economics. Methods: All non opposing adult patients with renal carcinoma initiated nivolumab (3 mg/kg q2w) in 2016 and 2017 were included. Minimum follow-up for survival was 12 months. Sex, age, performans status PS ECOG, toxicities, response rate, Progression Free Survival (PFS) and Overall Survival (OS) have been studied. Results: 141 pts were treated by nivolumab in 2016 and 2017 with a median age of 68 years old [39-94] and with 26% aged at least 75 years. The median number of courses was 7 [1-47]. 68 pts (48%) had 1 to 6 courses, 16 pts (11%) 7 to 12 courses, 25 pts (18%) 13 to 24 courses and 32 pts (23%) more than 25 courses. 81 (58%) pts were treated in 2 nd line, 34 (24%) in 3 rd line, and 25 (18%) in further lines. All lines combined, Complete Response (CR) was observed for 3 pts (2%), Partial Response (PR) for 26 pts (18%), Stable Disease (SD) for 36 pts (26%) (disease control DC : 46%) and disease progression for 51 pts (36%). For 25 pts (18%), nivolumab treatment has been stopped before first medical imaging. PS ECOG was 0-1 for 88 pts (62%), 2 for 21pts (15%), 3-4 for 8 pts (6%) and unknown for 24 pts. Median OS and PFS were 18.2 months and 3.2 months, respectively. No difference on survival has been noticed according to gender, treatment line, age (cut-off 70 or 75 yo) and grade III/IV toxicity. However, OS and PFS were significantly influenced by general health (p &lt; 0.0001). PFS for PS 0-1 pts was 6.5 months, for PS2 2.3 months and for PS3-4 0.8 months. OS was not reached for PS0-1 pts, 3.8 months for PS2 pts and 0.8 months for PS3-4 pts. OS for patients with DC (RC+RP+SD) has not reached and PFS was 14.9 months respectively. 17% of patients presented grade III/IV toxicities. Nivolumab courses during the 2 years costed 5.1 millions of euros (drug, hospitalisation and transportation). 80% of this costs were dedicated to pts who experienced DC. Conclusions: In real life setting, survival outcomes and toxicities with nivolumab in advanced renal carcinoma are comparable to literature’s data. ECOG PS≥2 pts presented shorter survival than PS0-1 pts. Interestingly, 80% of the cost incurred for these treatments benefited to pts with DC. Updated survival data will be available be shown at the meeting.
Progress and challenges in HER2-positive gastroesophageal adenocarcinoma
Authors: Dan Zhao, Samuel J. Klempner, Joseph Chao
Journal: Journal of Hematology & Oncology (2019)

HER2 expression remains an important biomarker to guide the addition of the monoclonal antibody trastuzumab to first-line systemic chemotherapy in unresectable, metastatic gastroesophageal adenocarcinomas (GEA). However, in contrast to breast cancer, other HER2-targeted strategies to date have not improved outcomes in this molecular subtype of GEA. Since the initial development of HER2 biomarker testing guidelines, significant spatial intratumoral heterogeneity of HER2 overexpression has been recognized as a major characteristic of this disease. In this review, we aim to survey the seminal positive and negative trials investigating HER2-targeted agents for GEA. We also highlight emerging data on the genomic and temporal heterogeneity of molecular resistance alterations that have yielded further insight into the heterogeneity of therapeutic responses. We conclude with an overview of promising novel agents and strategies which may refine the therapeutic landscape.
Assessment of the Appropriateness of Antibiotic Prescriptions for Infection Prophylaxis Before Dental Procedures, 2011 to 2015
Authors: Katie J. Suda, Gregory S. Calip, Jifang Zhou, Susan Rowan, Alan E. Gross, Ronald C. Hershow, Rose I. Perez, Jessina C. McGregor, Charlesnika T. Evans
Journal: JAMA Network Open (2019)

Antibiotics are recommended before certain dental procedures in patients with select comorbidities to prevent serious distant site infections.To assess the appropriateness of antibiotic prophylaxis before dental procedures using Truven, a national integrated health claims database.Retrospective cohort study. Dental visits from 2011 to 2015 were linked to medical and prescription claims from 2009 to 2015. The dates of analysis were August 2018 to January 2019. Participants were US patients with commercial dental insurance without a hospitalization or extraoral infection 14 days before antibiotic prophylaxis (defined as a prescription with ≤2 days' supply dispensed within 7 days before a dental visit).Presence or absence of cardiac diagnoses and dental procedures that manipulated the gingiva or tooth periapex.Appropriate antibiotic prophylaxis was defined as a prescription dispensed before a dental visit with a procedure that manipulated the gingiva or tooth periapex in patients with an appropriate cardiac diagnosis. To assess associations between patient or dental visit characteristics and appropriate antibiotic prophylaxis, multivariable logistic regression was used. A priori hypothesis tests were performed with an α level of .05.From 2011 to 2015, antibiotic prophylaxis was prescribed for 168 420 dental visits for 91 438 patients (median age, 63 years; interquartile range, 55-72 years; 57.2% female). Overall, these 168 420 dental visits were associated with 287 029 dental procedure codes (range, 1-14 per visit). Most dental visits were classified as diagnostic (70.2%) and/or preventive (58.8%). In 90.7% of dental visits, a procedure was performed that would necessitate antibiotic prophylaxis in high-risk cardiac patients. Prevalent comorbidities include prosthetic joint devices (42.5%) and cardiac conditions at the highest risk of adverse outcome from infective endocarditis (20.9%). Per guidelines, 80.9% of antibiotic prophylaxis prescriptions before dental visits were unnecessary. Clindamycin was more likely to be unnecessary relative to amoxicillin (odds ratio [OR], 1.10; 95% CI, 1.05-1.15). Prosthetic joint devices (OR, 2.31; 95% CI, 2.22-2.41), tooth implant procedures (OR, 1.66; 95% CI, 1.45-1.89), female sex (OR, 1.21; 95% CI, 1.17-1.25), and visits occurring in the western United States (OR, 1.15; 95% CI, 1.06-1.25) were associated with unnecessary antibiotic prophylaxis.More than 80% of antibiotics prescribed for infection prophylaxis before dental visits were unnecessary. Implementation of antimicrobial stewardship in dental practices is an opportunity to improve antibiotic prescribing for infection prophylaxis.
The effects of Wnt inhibition on tumor progression and the tumor microenvironment in a syngeneic mouse model of ovarian cancer.
Authors: Whitney Goldsberry, David W Doo, Selene Meza-Perez, Ashwini A. Katre, Lyse Norian, Troy Randall, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2019)

e17078 Background: Alterations in the Wnt/β-catenin pathway have been associated with tumor progression in multiple cancers. Gene expression profiling in ovarian cancer has correlated Wnt upregulation to patterns of immune evasion in the tumor microenvironment (TME). We investigated effects of in vitro Wnt inhibition in a murine ovarian cancer cell line with p53 knocked out as a model to mimic human ovarian carcinoma. Methods: We used a small molecule inhibitor, CGX-1321, in C57Bl6 mice, an immunocompetent mouse model, injected intraperitoneally with either ID8 cells, a murine ovarian cancer cell line, or ID8-p53 -/- cells. Mouse omentums were collected and weighed for evaluation of tumor growth. Representative histology slides were stained for H&amp;E. Western blots for β-catenin baseline levels were performed on the cell lines. TopFlash Assays with WNT3A stimulation were used for analysis of cell line nuclear β-catenin levels. Flow cytometry was performed on mouse omentums for TME evaluation. Results: Treatment with CGX-1321 decreased tumor size via omentum weight with both cell lines, p = 0.0098 with ID8 cells and p = 0.0855 with ID8-p53 -/- cells. H&amp;E slides revealed a decreased tumor progression. Western blots confirmed a difference in baseline β-catenin levels between these two cell lines. However, TopFlash assays showed a response to stimulation. Changes in the TME between treated samples with ID8-p53 -/- cells did now show significant differences via flow cytometry. Conclusions: In the syngeneic mouse model with a murine ovarian cancer cell line, with p53 knocked out, tumor size and proliferation were decreased with treatment with Wnt inhibition. Surprisingly, the TME changes were inconclusive via flow cytometry. Perhaps these cells do not rely upon the Wnt/ β-catenin pathway as heavily, as seen in changes to baseline β-catenin levels, or perhaps tumors progress quicker and the critical time point of TME change is being overlooked. More investigation needs to be performed to further elucidate these differences.
Circulating tumor DNA (ctDNA) during and after neoadjuvant chemotherapy and prior to surgery is a powerful prognostic factor in triple-negative breast cancer (TNBC).
Authors: Luca Cavallone, Adriana Aguilar, Mohammed Aldamry, Josiane Lafleur, Susie Brousse, Cathy Lan, Najmeh Alirezaie, Eric Bareke, Jacek Majewski, Manuela Pelmus, Cristiano Ferrario, Elizabeth A. Marcus, Andre Robidoux, Federico Discepola, Mark Basik
Journal: Journal of Clinical Oncology (2019)

594 Background: TNBC, the most aggressive form of breast cancer, is treated primarily with chemotherapy, even before surgery (neoadjuvant chemotherapy or NAC). The prognosis and need for adjuvant therapy depends greatly on the tumor response assessed by pathology (pCR). Highly sensitive and specific ctDNA assays have been shown to be of prognostic value in the metastatic settingbut not yet in earlier settings. Methods: Tissue was collected from 26 Q-CROC-03 clinical trial TNBC patients before, during and after NAC, prior to surgery. Whole exome sequencing on tumor tissues was used to select single nucleotide variants with high allele frequency (VAF), prioritizing TP53, to generateindividual digital droplet PCR (ddPCR) assays. An average of 5 variants (range 1-12) per patient were tested, for a total of 121 variants. A detection threshold was defined for each variant from a pool of normal controls. Median follow-up was 55 months. Results: ctDNA was detectable in 96% of patients at baseline, but 20% of the 121 variants were not detectable at any time point. At baseline, the mean VAF of all analyzed variants, but not of TP53 variants alone, was significantly correlated (p &lt; 0.05) with tumor factors (tumor size, stage, grade, nodal status before and at surgery, RCB score) but not with patient age or BRCA1/2 mutation status. 87 variants (74%) were detected at baseline and their VAF fell by 86% after 1 cycle of chemotherapy (T1). The detection of ctDNA at T1 was associated with DFS (p = 0.027) while the detection of ctDNA at the last post-chemotherapy pre-surgery time point (T4) was strongly associated with pathological complete response (pCR) and both DFS (p = 0.013) and OS(p = 0.006). At this time point, 5 of 41 variants (12%) were detected in pCR patients vs 42 of 80 (53%) in non-pCR, while only 6 of the 15 (40%) non-pCR patients had detectable TP53 variants. Interestingly, for variants detected at baseline, the positive predictive value of T4 ctDNA for disease recurrence was 69%, similar to that of non-pCR, while the negative predictive value of no ctDNA at T4 was 89% for disease recurrence vs 80% for pCR. Conclusions: ctDNA detection after NAC prior to surgery is strongly predictive of disease-free survival and overall survival and is comparable to pCR as a prognostic factor in our cohort (NCT01276899).
Preoperative checkpoint inhibition (CPI) and cryoablation (Cryo) in women with early-stage breast cancer (ESBC).
Authors: Elizabeth Anne Comen, Yolanda Bryce, David B. Page, Stephen Barnett Solomon, Micaela Rodine, Christina DiLauro Abaya, Elizabeth Anne Morris, George Plitas, Mahmoud El-Tamer, Mary Gemignani, Lisa M. Sclafani, Monica Morrow, Edi Brogi, Sujata Patil, Teresa Ho, Phillip Wong, Sadna Budhu, Taha Merghoub, Larry Norton, Heather L. McArthur
Journal: Journal of Clinical Oncology (2019)

592 Background: Checkpoint inhibition (CPI) combined with local strategies that cause local tumor destruction, such as cryo may augment tumor specific immunity and improve survival. We previously demonstrated in 18 ESBC patients (pts) that pre-operative (pre-op) cryo with ipilimumab (ipi) is not only safe but also generates robust local and systemic immune responses (NCT01502592). Given the added activity of dual CPI in other tumors, we undertook a second pilot study of pre-op ipi/nivolumab (nivo)/cryo to confirm the safety of this combination and the impact on immune biomarkers. Methods: In both pilot studies, eligible pts had operable ≥1.5cm invasive HER2 negative ESBC. CPI was administered 8-15d prior to, and cryo was performed 7-10d prior to, standard-of-care (SOC) surgery. Toxicity evaluation continued for 12wks after drug administration. Blood for immune correlates was obtained at baseline, cryo, surgery and 2-4 weeks thereafter. Tumor samples were obtained at cryo and surgery. Flow-cytometry of peripheral lymphocytes was compared to previously reported ipi/cryo responses. Results: After a median follow-up of 66 months all 18 ESBC ipi/cryo pts, including 3 TNBC pts, are recurrence free. In the ipi/nivo/cryo study, the safety primary endpoint was met when 5 pts underwent SOC surgery without delay. Ipi/nivo/cryo was well tolerated overall. One pt on an aromatase inhibitor had grade 4 liver toxicity 8 weeks after surgery. One pt, 3 weeks after her SOC surgery, developed grade 1 hyperthyroidism, preventing a secondary axillary dissection from proceeding as scheduled. Robust activation of peripheral CD4+ and CD8+ T cells peaked at week 2 post ipi/nivo with the majority of activated CD8+ T cells expressing PD1. Comparing the correlatives of the ipi/nivo/cryo study with the prior ipi/cryo study, we observed higher expression of activation markers (Ki-67, ICOS, CTLA-4, LAG-3) on peripheral T cells and downregulation of suppressor cells. Conclusions: Ipi/cryo-treated pts, including 3 TNBC pts, remain recurrence free after &gt; 5y. Combining cryo with ipi/nivo preop is feasible, safe, and associated with greater T cell activation than ipi/cryo alone. These results informed an ongoing randomized phase 2 study of pre-op ipi/nivo/cryo versus SOC in women with residual TNBC after neoadjuvant chemotherapy (NCT03546686). Clinical trial information: NCT02833233.
Response to Wollschläger, Blettner, and Pokora
Authors: Johanna M Meulepas, Cecile M Ronckers, Anne M J B Smets, Rutger A J Nievelstein, Patrycja Gradowska, Choonsik Lee, Andreas Jahnen, Marcel van Straten, Marie-Claire Y de Wit, Bernard Zonnenberg, Willemijn M Klein, Johannes H Merks, Otto Visser, Flora E van Leeuwen, Michael Hauptmann
Journal: JNCI Journal of the National Cancer Institute (2019)
Case 7-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Neil W. Kowall, Raymond A. Sobel
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 27-year-old man was admitted to the hospital because of headache, confusion, and a possible seizure.He was well until five months earlier, when acute myelomonocytic leukemia was found. After induction a complete remission was achieved after the administration of cytarabine (cytosine arabinoside [araC]) and asparaginase in high doses. The patient's course was complicated by prolonged neutropenia, an intermittent high fever, questionable allergy to piperacillin, klebsiella sepsis, mild renal failure, pancreatitis, and mild adult respiratory distress syndrome. Three months before entry the patient was discharged from the hospital without medications. He did well, gained 15.9 kg in . . .
ARTIST 2: Interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/III gastric cancer (GC).
Authors: Se Hoon Park, Dae Young Zang, Boram Han, Jun Ho Ji, Tae Gyu Kim, Sung Yong Oh, In Gyu Hwang, Jung Hoon Kim, Dongbok Shin, Do Hoon Lim, Kyoung Mee Kim, Ji Yeong An, Min-Gew Choi, Jun-Ho Lee, Tae Sung Sohn, Jae-Moon Bae, Sung Kim, Seung Kim, Jeeyun Lee, Won Ki Kang
Journal: Journal of Clinical Oncology (2019)

4001 Background: Adjuvant chemotherapy and/or chemoradiotherapy have been the standard of care in GC for years, supported by randomized trials. We compared the efficacy of different chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II/III, node-positive GC. Methods: From Feb 2013 through Nov 2018, we randomly assigned, in a 1:1:1 ratio, patients with pathologically-staged II or III, node-positive, D2-resected GC, to receive adjuvant S-1 (40-60 mg twice daily 4-weeks-on/2-weeks-off) for one year, S-1 (2-weeks-on/1-week-off) plus oxaliplatin 130 mg/m2 (SOX) for six months, or SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to the type of surgery (total or subtotal gastrectomy), stage (II or III), and Lauren histologic classification (diffuse or intestinal). The primary endpoint was disease-free survival (DFS). A total of 900 patients had to be enrolled to demonstrate superiority of SOX or SOXRT to S-1 (hazard ratio [HR] 0.667), with 90% power at a two-sided significance level of 5%. Results: A total of 538 patients were included for this interim efficacy analysis. Median age was 58 years, men constituted 65%, and stage II and III were 31% and 69%, respectively. Baseline tumor and patient characteristics were balanced between treatment arms. Adverse events were as anticipated in each arm, generally well-tolerated and manageable. DFS in the control arm (S-1) were significantly shorter than in SOX and SOXRT arms (stratified HR for recurrence): S-1 vs. SOX, 0.617 (P = 0.016) and S-1 vs. SOXRT, 0.686 (P = 0.057). The DFS at 3-years was found to be 65%, 78% and 73% in S-1, SOX and SOXRT arms, respectively. No difference in DFS between SOX and SOXRT was found (HR 0.910, P = 0.667). Based on the results after the observation of 145 recurrence events at the cutoff date of Dec 27, 2018, the independent data monitoring committee considered the results sufficient to meet the endpoint of the trial and recommended early stopping of the trial. Conclusions: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared to S-1 monotherapy. Clinical trial information: NCT0176146.
Simple and rapid enrichment of circulating tumor cells (CTCs) for RNAseq in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Gareth Morrison, Alexander Cunha, Nita Jojo, Zarko Manojlovic, Yucheng Xu, Peggy S. Robinson, Tanya B. Dorff, David I. Quinn, Amir Goldkorn
Journal: Journal of Clinical Oncology (2019)

e16587 Background: CTCs have the potential to reflect not only genomic alterations but also cancer-relevant transcriptomic phenotypes. However, CTC gene expression has been hampered by signal-to-noise: rare CTC-derived transcripts are drowned out by abundant leukocyte-derived RNA. To date, a few specialized labs have achieved CTC RNAseq by capturing and analyzing single cells, a laborious and expensive approach not suitable for routine analysis of numerous samples. To address this need, we developed and validated a simple, rapid method for enrichment of live CTCs for RNAseq. Methods: Blood was drawn with informed consent under an IRB-approved protocol. Prostate cancer cell line spike-in samples were used to optimize live CTC enrichment by sequential leukocyte depletion (RosetteSep, Stem Cell Technologies) and size-based enrichment (Parsortix, Angle). Cancer-specific gene expression was first measured by multiplexed prostate specific qRT-PCR and subsequently by whole transcriptome amplification (WTA, SMARTer V2, Clontech) and RNAseq. Four patient samples were similarly analyzed by enrichment and RNAseq, along with spike-in positive controls and matched unenriched buffy coat negative controls. Results: Processing “from patient to RNA” took &lt; 3 hrs. and achieved mean CTC recovery of 30% (range 28-33%) and mean leukocyte background of 100 (range 47-179), a 100,000-fold enrichment. Prostate specific genes (AR, PSA, PSMA) were consistently detected by qRT-PCR from enriched samples but not from unenriched samples. When analyzed by RNAseq, patient samples clustered with spike-in positive controls and away from matched buffy coat controls by principle component analysis and by unsupervised hierarchical clustering. Differential gene expression (enriched vs. matched buffy coat) identified prostate cancer-relevant transcripts. Conclusions: We developed a simple and efficient method for live CTC enrichment and expression profiling, applicable to large numbers of patient samples. This approach can be used serially over time to detect known cancer-specific transcripts and to discover new gene expression signatures that reflect tumor biology and inform disease management.
Dynamic contrast-enhanced MRI to predict intratumoral molecular heterogeneity in clear cell renal cell carcinoma.
Authors: Durga Udayakumar, Ze Zhang, Durgesh Dwivedi, Yin Xi, Tao Wang, Payal Kapur, Qurratulain Yousuf, Allison Joyce, Asghar Hajibeiji, Michael Fulkerson, Alberto Diaz de Leon, Matthew Lewis, Ananth J Madhuranthakam, Jeffrey A Cadeddu, Aditya Bagrodia, Vitaly Margulis, James Brugarolas, Ivan Pedrosa
Journal: Journal of Clinical Oncology (2019)

4580 Background: Mutation/inactivation of VHL in clear cell renal cell carcinoma (ccRCC) leads to upregulation of hypoxia inducible factors ( HIFs) and angiogenesis. However, ccRCC is characterized by high intra-tumor heterogeneity (ITH). Random small samples such as those in percutaneous biopsies are likely limited for characterization of molecular alterations in heterogeneous ccRCCs. We hypothesize that whole-tumor dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is useful to noninvasively identify ITH in ccRCC. Methods: This IRB-approved, prospective, HIPAA-compliant study, included 62 ccRCCs. 3T DCE MRI was obtained prior to nephrectomy. Surgical specimens were sectioned to match MRI acquisition plane. 182 snap frozen samples (49 tumors) and adjacent uninvolved renal parenchyma (URP) were collected. RNA isolations, cDNA library preparation and mRNA sequencing were performed using standard protocols. RNA expression in 81 tumor samples were correlated (Spearman ranked) with % enhancement in a region of interest (ROI) drawn in the same location of the tumor on pre- and 3 different post-contrast DCE MRI phases. Gene function overrepresentation (OR) analyses were done on top positively and negatively correlated genes. False discovery rate (FDR) &lt; 0.1 was considered statistically significant. Results: Principal component analysis of &gt; 20,000 genes indicated distinct gene expression in tumors from URP. Unsupervised clustering showed enrichment of ccA samples (better prognosis) compared to ccB samples (worse prognosis). Importantly, ccA and ccB samples coexisted in 25% of tumors. DCE-MRI % enhancement correlated with expression of &gt; 300 genes (p &lt; 0.003, FDR &lt; 0.1). OR analyses placed angiogenic pathway gene processes and the immune/inflammatory response processes within the top 5 positively- and negatively-correlated gene functions, respectively. HIF2 target genes correlated positively with % enhancement. Conclusions: DCE MRI detects specific molecular signatures and may help overcome the challenges of ITH in ccRCC. Further research is needed to explore the potential role of DCE MRI to assess response to antiangiogenic and immune-based therapies.