tbuckley/cabot-search huggingface dataset:
Plasma ctDNA mutation anaysis for identification of initial and acquired resistance to HER2-targeted therapy in advanced gastric cancer patients
Authors: E. Gaye, B. Bellosillo Paricio, L. Visa, M. Iglesias Coma, F.J. Sanchez Martin, A. Sampera Borràs, C. Montagut Viladot
Journal: Annals of Oncology (2018)

Background: Primary or acquired resistance to trastuzumab limits targeted treatment efficacy. Circulating tumor (ct)DNA is a potential surrogate to tissue that overcomes intratumoral heterogeneity with a minimal invasive approach. We assessed genomic alterations (GAs) of ctDNA and demonstrated molecular changes during trastuzumab therapy. Methods: Prospective genomic profiling of longitudinal plasma samples from seven HER2-positive metastatic gastric cancer (GC) patients treated with trastuzumab-based chemotherapy, using the AVENIO ctDNA Surveillance targeted gene panel and specifically assessing ERBB2 and MET copy number variations (CNVs) status. Results: ctDNA sequencing data was available for four patients both at baseline and progression. At baseline, 75% of GAs identified were single nucleotide variations (SNVs), including common mutated genes such as TP53 (12.5%), PIK3CA (12.5%), KRAS (12.5%), and MET (12.5%). Twenty-five per cent were copy number variations (CNVs), specifically ERBB2 amplification. At progression, almost the majority of GAs were acquired (45.5%). MET amplification was the most frequently detected GA (26.7% of cases). ERBB2 amplification (13.3%), MET (13.3%), TP53 (6.7%), PIK3CA (6.7%), and ERBB2 (6.7%) mutations were other co-occurring GAs. Conclusions: Follow-up ctDNA profiling during trastuzumab treatment identifies emergence of MET amplification and mutations, as a potential biomarker of resistance. Legal entity responsible for the study: Research Ethics Committee of Hospital del Mar. Funding: Roche. Disclosure: All authors have declared no conflicts of interest.
A phase 2 study of hyper-CVAD plus ofatumumab as frontline therapy in CD20+ acute lymphoblastic leukemia (ALL): Updated results.
Authors: Abdul Hamid Bazarbachi, Musa Yilmaz, Farhad Ravandi, Deborah A. Thomas, Maria Khouri, Guillermo Garcia-Manero, Rebecca S. Garris, Jorge E. Cortes, Nicholas James Short, Koji Sasaki, Ghayas C. Issa, Paul B. Koller, Tapan M. Kadia, Srdan Verstovsek, Naval Guastad Daver, Nitin Jain, Marina Konopleva, Susan Mary O'Brien, Elias Jabbour, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2018)

7041 Background: In vitro studies showed that ofatumumab (O), a type I human antibody that targets a different CD20 epitope compared to rituximab, induces more potent antibody-dependent and complement mediated cell death. We hypothesized that substituting rituximab with ofatumumab, as part of Hyper-CVAD (HCVAD) regimen, may further improve outcomes in pts with Philadelphia chromosome (Ph) negative CD20+ ALL. Methods: Pts received 4 cycles (cy) of HCVAD [cy 1, 3, 5, 7 consisted of cyclophosphamide, doxorubicin, vincristine, and dexamethasone] alternating with 4 cy of methotrexate-cytarabine (MTX-ara-C, even cy 2, 4, 6, 8). Ofatumumab was infused on day 1 and 11 of cy 1 and 3; and day 1 and 8 of cy 2 and 4. For maintenance, pts received POMP, and late intensification with MTX/PEGylated asparaginase and O-HCVAD. Intrathecal MTX-Ara-C was used for CNS prophylaxis. Minimal residual disease (MRD) was assessed using multiparameter flow cytometry. Results: A total of 68 pts were enrolled (Table) and 65 were evaluable for response. Sixty-four pts (98%) achieved CR/CRp, 39/62 (63%) achieved negative MRD at time of CR, and 62/67 pts (93%) achieved negative MRD overall. Time to negative MRD was median 0.7 mo (range, 0.4-7.8). Pts received one to eight (median: 8) cy of intensive phase chemotherapy. The most common non-hematologic grade 3/4 toxicitiy was infection; occurred in 37 (56%) and 55 (81%) pts during induction and consolidation, respectively. At median 27 mo of follow-up (range 4-73), 51 pts (75%) are alive; 17 pts (25%) are receiving maintenance, 15 pts (22%) have relapsed, 14 pts (21%) have completed maintenance, and 12 pts (18%) have received ASCT in CR1. The 2-year CRD and OS were 79% and 81%, respectively. The 2-yr OS was 80% in both pts with <20% and ≥20% CD20 expression. Conclusions: O-HCAVD is highly effective and safe combination regimen in pts with CD20+ Ph-negative ALL. Clinical trial information: NCT01363128.Clinical Characteristics (n=68) N (%)/ Median [Range] Age, years 41 [18-71] ECOG PS > 1 7 (11) CNS disease 2 (3) CRFL2+ 8/34 (24) TP53+ 10/42 (24) CD20 expression > 20 % 42 (62) 10-20 % 7 (10) 1-10 % 19 (28) Cytogenetics Diploid 24 (35) Low hypodiploidy/near-triploidy 6 (9) High hyperdiploidy 5 (7) Complex 3 (5) Misc. 30 (44)
ADAPT therapy vs capecitabine bevacizumab in stage IV colorectal cancer: Pooled 10-year survival experience and a phase II study update.
Authors: Edward H. Lin, Edward Y. Kim, Ling Wang, Chirstine Fong, Veena Shankaran, Xifeng Wu, Douglas E. Wood, Raymond Sze Yeung, Qiang Tian
Journal: Journal of Clinical Oncology (2016)

e15046 Background: COX-2 inhibition or aspirin use increase colorectal cancer survival by affecting tumor microenvironment through PD-1/PDL-1 pathway. Optimal use of these agents in cancer is unknown. We reported that maintenance ADAPT with capecitabine and celecoxib ± radiation following first-line chemotherapy results in higher complete response (CR) rate and prolong survival in stage IV colorectal cancer patients and we updated ten-year survival outcomes from two major cancer centers. Methods: IRB approved this UW study. We pooled MDACC database with theUW database constructed by searching Clinical Data Repository using Amalga. Cases and controls were found in the note. Clinical data elements were extracted from various data sources within the repository. Automated parsing of notes and reports was employed to extract several key variables to match the data from earlier MDACC database. Independent manual quality control was also conducted and records verified. Results: Pooled database included 437 patients treated with (A) capecitabine and celecoxib (N = 195) including 28 pts enrolled ongoing phase II trial (NCT01729923), (B) capecitabine bevacizumab (N = 241) and 93/195 in the capecitabine and celecoxib were deemed to have achieved complete responses with or without surgery whereas 63 of 241 patients had achieved complete responses. Median Survival from CRC diagnosis date was 74.9 months (A) versus 33 months (B) (p < 0.001). Median Survival from stage IV was 57.8 months (A) versus 24 months (B) and 21 months (C) (p < 0.001). Median survival of 93 complete responders from no surgery (N = 51) versus surgical (N = 42) was 75 vs 57 months from stage IV onset and 87 vs 68 months from CRC diagnosis respectively. Our omics models suggest that ADAPT therapy boost immune surveillance by up-regulating PDL-1 which paradoxically improved CRC survival. Conclusions: Capecitabine and celecoxib after first-line chemotherapy demonstrated durable complete response and significant better survival noted in none surgical CR patients versus surgically resected patients. Abscopal effects of radiation may contribute to CR and survival. Further randomized studies on the ADAPT strategy are warranted. Clinical trial information: NCT01729923.
Clinical evidence from two phase 3 trials supporting statistical adjustment methods to assess confounding impact of treatment crossover on overall survival (OS).
Authors: Christian Kappeler, Andrea Wagner, Joachim Kalmus, Marcia S. Brose, Martin Schlumberger, George D. Demetri
Journal: Journal of Clinical Oncology (2017)

e22509 Background: In controlled trials that allow patients to crossover from placebo (PBO) to active treatment (ACT) after progression, OS in PBO patients is confounded by ACT. Statistical methods to adjust OS for crossover rely on an assumption of common treatment effect (i.e. PBO to ACT crossover after progression has the same impact as ACT started at randomization). This exploratory analysis of two phase 3 trials (PBO-controlled and allowing crossover) with regorafenib in GIST and sorafenib in thyroid cancer provides evidence to support this assumption. Methods: Target lesions were assessed at baseline and at regular intervals post baseline. Progression-free survival (PFS) was assessed during double-blind (DB) treatment and secondary PFS (SPFS) in PBO patients during open-label (OL) treatment. Changes in target lesion diameter over time were estimated by a parametric model. Early tumor growth rate (TGR), defined as percent change from baseline/month in the sum of target lesion diameters, was calculated as the model curve slope at earliest time on the TGR curve. Results: SPFS during OL in PBO patients is closer to DB PFS in ACT patients than to DB PFS in PBO patients (Table). Early TGR during OL in PBO patients is closer to DB early TGR in ACT patients than to DB early TGR in PBO patients. Conclusions: Currently available statistical methods to adjust for the impact of treatment crossover are supported by clinical results from two independent randomized, controlled phase 3 studies. These results provide validity to crossover correction analyses. Clinical trial information: NCT01271712; NCT00984282. [Table: see text]
Circulating tumor DNA as a potential indicator of tumor load during interventional therapy of unresectable hepatocellular carcinoma.
Authors: Yong Li, Xudong Chen, Meixiao Zhan, Lige Qiu, Wei Zhang, Yongjie Xin, Xu He, Qiyang Li, Jing Bai, Lianpeng Chang, Aiwei Wu, Rongrong Chen, Yan-Fang Guan, Xin Yi, Ligong Lu
Journal: Journal of Clinical Oncology (2018)

12036 Background: Hepatocellular carcinoma (HCC) is a common malignant tumor, causing high morbidity and mortality. Interventional treatments have improved survival in unresectable hepatocellular carcinoma. Imageology and serologic biomarkers are major methods to evaluate therapeutic efficacy but limited in radiation exposure and accuracy. This study aims to assess feasibility of ctDNA as a potential biomarker to monitor therapeutic response during interventional treatments of HCC. Methods: We enrolled 30 HCC patients from 2016 to 2017. Tumor biopsies and matched pretreatment peripheral blood samples were collected. We implemented target capture NGS to identify somatic variants with a panel of 1021 cancer related genes. Blood tumor mutation burden (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥0.5 %. Results: Somatic genomic alterations were identified in 29 of 30 tumour biopsies (96.7%). TP53 (%), TERT (37.9%), CTNNB1 (13.8%) mutated most frequently in this cohort. Mutations in TP53 was commonly detected at codon 249(R249S). In matched plasma samples, we identified 28 of 30 (93.3%) patients to be positive before interventional treatment. A consistence of detected mutation between ctDNA and tumors is 90% and presented positive relation with tumour load (Pearson r = 0.48, p = 0.01). Compared with AFP, ctDNA abundance showed a positive correlation with tumour load (r = 0.61, p = 0.0005). In addition, TP53-mutated samples showed higher bTMB than TP53-wild samples ( 5.5 vs 2.4 mut/Mb, p = 0.03), suggesting a potential better effect when received treatment of immune checkpoint inhibitors. Conclusions: Liquid biopsy can reveal the mutation profile of patients of HCC. CtDNA can be used as a potential tool to reflect the tumor load and guide more precise interventional treatments.
Evaluation and validation issues in the development of transgenic mouse carcinogenicity bioassays.
Authors: R W Tennant
Journal: Environmental Health Perspectives (1998)

Transgenic mouse models have emerged as plausible alternatives to long-term bioassays for carcinogenicity. Three transgenic lines evaluated to date have shown a clear capability to discriminate between carcinogens and noncarcinogens, using long-term bioassay results as the standard. The data also suggest that the transgenic lines will not fully duplicate long-term bioassay results. It is proposed that these models do not respond to chemicals that have induced highly restricted species or strain-specific tumor responses in mice or rats. Rather, the value of the transgenic models is predicated on a preferential response to transspecies carcinogens (i.e., those positive in both rats and mice, often including tumors in the same tissues). Thus, although results in transgenic models may not be completely concordant with long-term bioassays, the data can be used effectively in chemical and drug safety assessments. Further, it is proposed that validation of the models is readily achievable via ongoing studies. Validation of any alternative model is best achieved by sufficient mechanistic understanding of the model to reasonably predict the outcome of bioassays conducted in the models and use all available information on the drug or chemical. This goal can now be met with the transgenic mouse lines.
Abstract 14702: Elevated Left Ventricular Diastolic Filling Pressure by Tissue Doppler Imaging and Silent Brain Infarction in Patients With Nonvalvular Atrial Fibrillation
Authors: Sera Ishikawa, Kenichi Sugioka, Shinichi Iwata, Naoki Norioka, Shinichi Nonin, Yu Kawai, Suwako Fujita, Asahiro Ito, Masahiko Takagi, Minoru Yoshiyama
Journal: Circulation (2016)

Introduction: Left atrial (LA) abnormalities detected by transesophageal echocardiography (TEE) are well known risk factors for thromboembolism in patients with nonvalvular atrial fibrillation (NVA...
NAP-CAPABIL: Pilot study of NAB-paclitaxel in combination with capecitabine as second line treatment of advanced biliary cancer.
Authors: Morteza Aghmesheh, Daniel Brungs, Carley Leighton, Katrin Marie Sjoquist
Journal: Journal of Clinical Oncology (2018)

e16156 Background: Advanced biliary tract cancer (ABTC) is highly aggressive malignancy, with 5 year overall survival of < 10%. While first-line chemotherapy improves survival and quality of life (QOL) in patients with ABCT, in the second-line setting evidence is limited to non-randomised phase II trials and retrospective reviews, with best supportive care the current standard of care. As this has been a traditionally difficult patient population to recruit for clinical trials, we undertook a pilot study to assess the feasibility of a phase II trial using capecitabine with nab-paclitaxel in patients with ABTC after failure of gemcitabine and cisplatin. Methods: Patients were eligible if they had histologically proven, unresectable biliary tract cancer, with good performance status (ECOG0-1), and had progressed on gemcitabine and a platinum. This is a single arm, open label, multicentre trial, with all patients receiving capecitabine (825mg/m2 bd PO D1-14 q21d) and nab-paclitaxel (125mg/m2 IV D1,8 q21d) until progression or unacceptable toxicity. The primary endpoint of the pilot study was feasibility of delivering the proposed regimen, measured by recruitment rate and treatment safety. Secondary objectives were disease control measures and and QOL outcomes Results: 10 patients were enrolled within the planned 18 month recruitment period from 4 cancer centres in NSW. Treatment was generally well tolerated with grade III toxicities in 5 patients (including infection, cholangitis, obstruction and intestinal perforation) and no episodes of grade IV toxicity. Median treatment duration was 4.3 months. Early efficacy signals are promising, with a disease control rate of 80% (8/10), and median progression free and overall survival of 5.7 and 12.1 months respectively. Comprehensive QOL data and specimens for translational research have been collected. Conclusions: Our pilot study demonstrates that combination of capecitabine and nab-paclitaxel is feasible as a second-line treatment in ABTC. A formal phase II, with embedded translational sub-study, is planned to assess efficacy. Clinical trial information: ACTRN12615000504516.
Assessment of Perfusion and Oxygenation of the Human Renal Cortex and Medulla by Quantitative MRI during Handgrip Exercise
Authors: Bryan Thomas Haddock, Susan T. Francis, Henrik B.W. Larsson, Ulrik B. Andersen
Journal: Journal of the American Society of Nephrology (2018)

Renal flow abnormalities are believed to play a central role in the pathogenesis of nephropathy and in primary and secondary hypertension, but are difficult to measure in humans. Handgrip exercise is known to reduce renal arterial flow (RAF) by means of increased renal sympathetic nerve activity.To monitor medullary and cortical oxygenation under handgrip exercise-reduced perfusion, we used contrast- and radiation-free magnetic resonance imaging (MRI) to measure regional changes in renal perfusion and blood oxygenation in ten healthy normotensive individuals during handgrip exercise. We used phase-contrast MRI to measure RAF, arterial spin labeling to measure perfusion, and both changes in transverse relaxation time (T2*) and dynamic blood oxygenation level-dependent imaging to measure blood oxygenation.Handgrip exercise induced a significant decrease in RAF. In the renal medulla, this was accompanied by an increase of oxygenation (reflected by an increase in T2*) despite a significant drop in medullary perfusion; the renal cortex showed a significant decrease in both perfusion and oxygenation. We also found a significant correlation (R2=0.8) between resting systolic BP and the decrease in RAF during handgrip exercise.Renal MRI measurements in response to handgrip exercise were consistent with a sympathetically mediated decrease in RAF. In the renal medulla, oxygenation increased despite a reduction in perfusion, which we interpreted as the result of decreased GFR and a subsequently reduced reabsorptive workload. Our results further indicate that the renal flow response's sensitivity to sympathetic activation is correlated with resting BP, even within a normotensive range.
Five-fraction stereotactic body radiotherapy (SBRT) in concert with chemotherapy for treatment of inoperable pancreatic adenocarcinoma.
Authors: Christen R Elledge, Jonathan W. Lischalk, Marie Kate Gurka, Michael J. Pishvaian, Brandon George Smaglo, Aiwu Ruth He, John Marshall, Sean P. Collins, Keith Robert Unger
Journal: Journal of Clinical Oncology (2016)

e15670 Background: The role of radiotherapy in the management of inoperable pancreatic cancer continues to be nebulous. SBRT has emerged as an attractive treatment option due to its short treatment duration, minimal chemotherapy disruption, and acceptable side effect profile. Here we report the clinical outcomes from a large single institutional cohort treated definitively with SBRT. Methods: This retrospective analysis examines 75 patients who were all pathologically diagnosed with pancreatic adenocarcinoma who were ineligible for resection. Inoperability was defined as those patients with borderline resectability who did not undergo surgery, locally advanced disease, medically inoperability, or those who refused surgery. SBRT was delivered in 5 fractions to a total dose of 25 to 30 Gy. Chemotherapy was concurrently administered if it was given within one week of the start of SBRT treatment. Toxicities were scored using the Common Terminology Criteria for Adverse Events version 3. Local control was determined with radiological follow up utilizing RECIST criteria. Both local control and overall survival were calculated using the Kaplan-Meier method. Results: A total of 75 patients with a median age of 69 years (45 to 90) were treated at Georgetown University Hospital from January 2009 to May 2015. Median pre-treatment ECOG was 1 (0 to 3) and the majority of patients were female (53%). The majority of tumors were localized to the pancreatic head (81%) and the most common reason for inoperability was locally advanced disease (75%). Concurrent chemotherapy was delivered in 55 (73%) patients. FOLFOX and gemcitabine were the most common concurrent systemic agents utilized in 47% and 40% of cases, respectively. Fifteen patients were excluded from RECIST local control analysis due to lack of radiological follow up. Kaplan-Meier 6- and 12-month local control was 88% and 72%, respectively. Kaplan-Meier 1-year and median survival was 55% and 12.26 months, respectively. Conclusions: Five-fraction SBRT can be practically delivered in concert with chemotherapy and achieves excellent local control in this cohort of patients with inoperable pancreatic cancer.
The impact of a positive cognitive impairment screen on conversations between patients, caregivers, and oncologists: A UR NCORP randomized study.
Authors: Allison Magnuson, Lianlian Lei, Michelle Christine Janelsins, Eva Culakova, Feng Vankee Lin, Maxence Gilles, Arti Hurria, William Dale, Paul Duberstein, Marsha Wittink, Megan Wells, Nikesha Gilmore, Lauren M. Hamel, Mark Allen O'Rourke, Adedayo A. Onitilo, Thomas Paul Bradley, Mary Ingraham Whitehead, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2018)

10048 Background: The prevalence of CI and the utility of CI screening for community oncology practices are not well established. We used two tools to screen for CI in older patients (pts) enrolled onto a cluster randomized controlled trial and explored how CI screening influences conversations about cognition (CAC) between older pts, their caregivers, and oncologists. Methods: Pts aged ≥70 with advanced cancer were recruited (URCC 13070; PI: Mohile). CI screen, including Mini-Cog (MC) (normal/abnormal) and Blessed Orientation Memory Concentration Test (BOMC) (scored 0-28), were included in a Geriatric Assessment (GA). Practices were randomized to usual care (UC) vs GA intervention (GA summary provided to oncologists). Audio-recorded clinical encounters were transcribed by 2 blinded coders who coded CAC with a priori scheme as follows: cognition discussed (Y/N), type of concern, who initiated. MC and BOMC were compared and receiver operating characteristic (ROC) analyses identified BOMC score that best predicted abnormal MC. Results: Mean age was 77 (range 70-93); 2.2% screened positive by BOMC using standard score of ≥11 and 33.5% had abnormal MC. Pts with abnormal MC were more likely to have impaired activities of daily living (ADL) (34 vs 24%), Instrumental ADL (64 vs 52%), Timed Up and Go (47 vs 34%) and positive depression screen (28 vs 19%), (p < 0.05 for all). CAC occurred in 22% of encounters and were more common in the intervention arm (OR 4.64, 95%CI: 2.98- 7.21, p < 0.001). Differences in CACs were most notable for pts with abnormal MC (71% in intervention group vs 16% in UC, p < 0.001). Oncologists were more likely to be the initiator of CACs in the intervention arm (90% vs 57%, p < 0.001). The most common concerns were memory (54%) and comprehension (15%). A BOMC cutoff ≥4 was optimal for predicting abnormal MC (AUC = .73, sensitivity 59%, specificity 74%). Conclusions: In community oncology practices, 1/3 of older pts screen positive for CI and were more likely to have other GA impairments. Providing oncologists with results of a CI screen increases CACs. A lower BOMC cutoff predicted abnormal MC, consistent with studies in non-cancer pts where lower BOMC score predicted more mild CI.