tbuckley/cabot-search huggingface dataset:
Additional metabolic effects at the neoadjuvant chemotherapy (NCT) of locally advanced breast cancer (LABC).
Authors: Natalya A Abramova, Liubov Yu Vladimirova, Alla I Shikhliarova, Anna E Storozhakova, Valeriya S Myagkova
Journal: Journal of Clinical Oncology (2014)

1070 Background: Dissociation of cellular respiration and oxidative phosphorylation (OF) in the mitochondria promotes activation of regulatory cascades of apoptosis and necrosis. Probably the local impact of drugs that block the various stages of the Krebs cycle - diphenhydramine (D) (NAD↔NADH transformations) or ATF (aerobic ATF resynthesis inhibition due to feedback)- may result in increased the damaging action of cytostatics. Coordination of key Krebs cycle enzymes activity when peritumoral injected D/ATF with clinical efficacy on LABC NCT was investigated. Methods: Elegibility criteria included measurable histologically verified LABC T3-4N0-3M0, ECOG≤1. 2 cycles of NCT (FAC) were combined with injection of D/ATF in peritumoral zone 30 minutes before the start of NCT in the test group. Tumor response was assessed and compared to control group. OF processes activity was evaluated by the method of measuring of succinate dehydrogenase (SDH) and α-glycerophosphate (α-GPDH) in blood peritumoral lymphocytes before and 30 minutes after D/ATF injection, prior to administration of NCT (test group). Results: 60 pts were recruited (30- test and 30- control group). Test group tumor response was: CR 16,7%(5),PR 66,6%(20),SD16,7%(5). Control group tumor response was PR 66,6%(20),SD 30,0%(7),PD 3,4%(1). Differences are valid for CR (p=0.014) and SD(p=0.019). Decrease in the activity of LDH after ATF was observed in 62.5% of the samples (p=0.021), after D- in 57.9% of the samples (p=0.024), the increase in α-GPDH after D/ATF- in 41.6% of samples (p=0.022). The data showed a decrease in intensity of the OF in peritumoral area by injection of D/ATF. Conclusions: Changes in the activity of key Krebs cycle dehydrogenases in peritumoral lymphocytes with injections of D/ATF corresponds to clinical data on significant improvement in tumor response NCT LABC pts.
Preliminary results of a phase II trial of pazopanib in patients with advanced non-small cell lung cancer with non-squamous histology (NSCLC-NS) with disease progression after a bevacizumab (bev) containing therapy.
Authors: Thomas E. Stinchcombe, Jared Weiss, Liza Cosca Villaruz, Anastasia Ivanova, Juneko E. Grilley-Olson, Nirav Suresh Dhruva, Mark A. Socinski
Journal: Journal of Clinical Oncology (2014)

e19070 Background: Bev-containing therapy is a standard for stage IIIB/IV NSCLC-NS. Mechanisms of resistance to bev are unclear and may involve increase VEGF signaling or increased activation of VEGF receptors. Pazopanib, a multi-targeted VEGF receptor tyrosine kinase, has activity in advanced NSCLC. Patients who have previously tolerated and/or benefited from bev may be more likely to benefit from second-line anti-angiogenic therapy. Methods: Pts were required to have stage IIIB or IV NSCLC-NS, to have progressed on a bevacizumab containing therapy < 9 weeks prior, and to have adequate organ function. The primary end-point was disease control rate (DCR), defined as partial or complete responses, or stable disease for ≥ 12 weeks. Pts were assessed radiographically every 2 cycles (6 weeks). A Simon 2-stage design was used; if ≤ 4 of 17 pts experienced disease control, the trial would be stopped for futility; if ≥5 experienced disease control the trial would then proceed to enroll to a total of 36 pts. An unplanned analysis was performed due to slow accrual. Results: Between 12/2010 and 11/2013, 15 pts were treated on the trial. Median age was 61 yrs (range 39-74), 8 pts were women, and all pts had stage IV disease. Of the 15 pts, 4 discontinued therapy prior to cycle 2 evaluation due to adverse events (n=3) and medical illness (n=1), 5 pts had progressive disease, 4 patients had stable disease for < 12 weeks, and 2 patients had stable disease for ≥ 12 weeks. No responses were observed. The DCR observed was 13% (2/15). Progression-free survival and overall survival data will be presented. The reasons for treatment discontinuation were disease progression (n=9), adverse events (n=4), and medical illness (n=2). Episodes of grade 3 treatment related toxicities observed include increase ALT (n=2), AST (n=1), anorexia (n=3), fatigue (n=3), hypertension (n=1), infection (n=1), mucositis (n=2), nausea (n=3), pericardial effusion (n=1), vomiting (n=1). Conclusions: Preliminary data suggest pazopanib has limited activity in NSCLC-NS in patients who have experienced disease progression after bevacizumab.
Evaluation of 167 Gene Expression Classifier (GEC) and ThyroSeq v2 Diagnostic Accuracy in the Preoperative Assessment of Indeterminate Thyroid Nodules: Bivariate/HROC Meta-analysis
Authors: Martyna Borowczyk, Ewelina Szczepanek-Parulska, Michał Olejarz, Barbara Więckowska, Frederik A. Verburg, Szymon Dębicki, Bartłomiej Budny, Małgorzata Janicka-Jedyńska, Katarzyna Ziemnicka, Marek Ruchała
Journal: Endocrine Pathology (2018)

The objective of this meta-analysis was to evaluate the performance of the Gene Expression Classifier (GEC) and ThyroSeq v2 (ThyroSeq) in the preoperative diagnosis of thyroid nodules with indeterminate fine-needle aspiration biopsy results. We searched literature databases from January 2001 to April 2018. The bivariate model analysis was performed to estimate pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), positive predictive value (PPV), and negative predictive value (NPV). Pooled data from 1086 nodules with histopathologic confirmation from 16 GEC studies enabled calculation of diagnostic parameters (95% confidence interval): sensitivity 98% (96-99%), specificity 12% (8-20%), PPV 45% (37-53%), and NPV 91% (85-96%). Pooled data from five ThyroSeq studies assessing 459 nodules showed sensitivity of 84% (74-91%), specificity 78% (50-92%), PPV 58% (31-81%), and NPV 93% (89-97%). When both tools were compared, GEC had a significantly higher sensitivity (p = 0.003), while ThyroSeq had a significantly higher specificity (p < 0.001) and accuracy (p = 0.015). Pooled LR+ was higher for ThyroSeq: 3.79 (1.40-10.27) vs. 1.12 (1.05-1.20). Pooled LR- was higher for GEC, 0.20 (0.10-0.39) vs. 0.13 (0.05-0.31). The bivariate summary estimates of sensitivity and specificity for GEC and ThyroSeq and their pooled accuracy showed a superiority of the ThyroSeq test. The GEC with a high sensitivity and NPV may be helpful in ruling out malignancy in cases of indeterminate thyroid nodule cytology. ThyroSeq has a significantly higher specificity and accuracy with an acceptable sensitivity so that it has the potential for use as an all-round test of malignancy of thyroid nodules.
Immunotherapy with T-Cells Engineered with a Chimeric Antigen Receptor Bearing a Human CD19-Binding Single Chain Variable Fragment for Relapsed or Refractory Acute Lymphoblastic Leukemia and B-Cell Non-Hodgkin Lymphoma
Authors: Jordan Gauthier, Alexandre V. Hirayama, Kevin A. Hay, Alyssa Sheih, Barbara S. Pender, Reed M. Hawkins, Aesha Vakil, Tinh-Doan Phi, Rachel N. Steinmetz, Aude G. Chapuis, Brian G. Till, Hans-Peter Kiem, Mazyar Shadman, Ryan D. Cassaday, Utkarsh H. Acharya, Stanley R. Riddell, David G. Maloney, Cameron J. Turtle
Journal: Blood (2018)
Abstract 15608: Deficiency of Tlr4 Homologue Rp105 Aggravates Outward Remodelling in a Murine Model of Arteriovenous Fistula Failure
Authors: Taisiya Bezhaeva, ChunYu Wong, Margreet R. de Vries, Eric P. van der Veer, Carla M.A. van Alem, Joris I. Rotmans, Paul H.A. Quax
Journal: Circulation (2016)

Introduction: Arteriovenous access dysfunction is still the Achilles’ heel of hemodialysis in patients with end-stage renal disease (ESRD) with a 1-year primary patency of only 60%.The pathophysiology of arteriovenous fistula (AVF) maturation failure is unknown but impaired outward remodeling and intimal hyperplasia are both considered to contribute. Radio protective (RP)105 is an important regulator of inflammatory TLR4 signalling, expressed on numerous cell types. In the present study, we defined cell specific effects of RP105-/- on vascular smooth muscle cells (VSMCs) and macrophages (mφ) in vitro and in vivo effects of RP105-/- on AVF maturation in a murine model of AVF failure. Methods: All in vitro experiments were performed on primary cells isolated from RP105-/- and wild type (WT) mice. AVFs were created in an end-to-side manner between v.jugularis and carotid a. in RP105-/- (n=13) and WT (n=11) mice. AVFs were harvested at day 14 and processed for morphometric analysis and immunohistochemistry. M...
Neoadjuvant chemotherapy in very locally advanced technically unresectable oral cavity cancers.
Authors: Kumar Prabhash, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Sachin Dhumal, Vamshi Krishna Muddu, S Juvekar, Supreeta Arya, Pankaj Chaturvedi, Devendra Chaukar, P. S. Pai, Anil D'Cruz
Journal: Journal of Clinical Oncology (2014)

e17033 Background: Median survival of technically unresectable oral cavity cancers (T4a and T4b) with non surgical therapy is 2-12 months. We hypothesized that neoadjuvant chemotherapy (NACT) might sufficiently reduce the tumor size and result in successful resection and improved outcomes. We present a retrospective analysis of consecutive patients who received NACT at our centre between January 2008 and August 2012. Methods: All patients were assessed in a multidisciplinary clinic. Buccal mucosa primary extending above zygomatic arch, tongue primary extending below hyoid or into vallecula, any tumor invading high infratemporal fossa or with extensive skin infiltration were considered unresectable as these factors impact the achievement of negative margins. After 2 cycles of NACT, patients were reassessed and planned for surgery and subsequent CT/RT or nonsurgical therapy including CT-RT, RT or palliation.The results were analysed for differences in locoregional control ( chi square test) and overall survival (OS). Results: 721 patients with stage IV oral cavity cancer received NACT. The median age was 45 years. NACT consisted of 2-drug regimen of taxane-platinum in 647 (89.8%) patients and 3-drug regimen wth additional fluorouracil in 74 (10.2%). 310 patients (43%) had sufficient reduction in tumor size and underwent surgical resection. More patients achieved resection with 3 drug regimen (62%) compared to 2 drug regimen (40%) (p=0.011). Of the remaining patients, 167 received chemoradiation, 3 radical radiation and 241 palliative treatment alone The locoregional control rate at 24 months was 20.6 % for the overall cohort, 32% in patients undergoing surgeryand 15% in patients undergoing non surgical treatment (p=0.0001). The median estimated OS in patients undergoing surgery was 19.6 months (95% CI, 9.59- 25.21 months) and 8.16 months (95%, CI 7.57-8.76) in patients treated with non surgical treatment (p=0.0001) Conclusions: Several stage 4 oral cavity cancers are considered unresectable due to anatomical spread and are treated wth nonsurgical modality with poor outcomes. In our analysis, NACT led to successful resection and improved overall survival in a significant proportion of such patients
New therapeutic perspectives to manage refractory immune checkpoint-related toxicities
Authors: Filipe Martins, Gerasimos P Sykiotis, Michel Maillard, Montserrat Fraga, Camillo Ribi, Thierry Kuntzer, Olivier Michielin, Solange Peters, Georges Coukos, Francois Spertini, John A Thompson, Michel Obeid
Journal: The Lancet Oncology (2019)
Circulating Tumor DNA Dynamics during Therapy Predict Outcomes in Mantle Cell Lymphoma
Authors: Rahul Lakhotia, Christopher Melani, Stefania Pittaluga, Kieron Dunleavy, Nakhle S. Saba, A. Nicole Lucas, Allison Jacob, Erik Yusko, Seth M. Steinberg, Elaine S. Jaffe, Adrian Wiestner, Wyndham H. Wilson, Mark Roschewski
Journal: Blood (2018)
Phase 1 dose-finding study of cabozantinib (cabo) plus abiraterone (abi) combination therapy in castration resistant prostate cancer (CRPC): An investigator-sponsored study.
Authors: Christopher Sweeney, Kathryn P. Gray, Lauren Christine Harshman, Aymen Elfiky, Toni K. Choueiri, Mark Pomerantz, Kathryn Dumas, Amanda Fredericks, Mary-Ellen Taplin, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2014)

5027^ Background: Abi (CYP17A1 and lyase inhibitor) and cabo (multi-tyrosine kinase inhibitor including MET and VEGFRs) have complementary mechanisms of action. Both have single agent activity in CRPC. Preclinical in vivo work with LAPC4-CR (castration and abi resistant cell line) has shown the combination has enhanced activity. Methods: A phase 1 dose escalation trial using a 3 + 3 design with a fixed dose of abi 1,000 mg daily and prednisone 5mg BID with escalating daily doses of cabo (20mg, 40mg, 60mg) in pts with progressive metastatic CRPC (pre or post chemo). Cycles were 28 days. The dose expansion cohorts alternated between the 20 and 40mg doses. Results: 21 patients were enrolled. Median age was 60 yrs. All had ECOG PS 0 or 1. 6 pts had prior docetaxel for CRPC. 3 patients were enrolled at each dose level. No DLTs were observed in the first 4 week cycle. The 60 mg cabo cohort had grd 2 adverse events (AEs) of myalgias (2), fatigue (2) and DVT (1) in cycles 2 and 3 necessitating a dose reduction to 40 mg (no change to abi). Due to a preferable tolerability profile over the 60mg dose, the 20mg and 40mg cohorts were expanded (9 pts each). See Table for key activity data. At time of report, 9 patients had >8 mos of combination therapy. The most common grd 1/2 AEs (n≥2) in the 20mg cohort were myalgias (5), nausea (2) , fatigue (3), edema (2), and hypertension (htn, 2). At the 40mg dose, grd 1/2 AEs (n≥2) included nausea (2), diarrhea (2), fatigue (4), mylagias (2), hand-foot syndrome (2), and htn (2). 6 pts had cabo-related grd 3 AEs (20mg: diarrhea, anemia, increased AST/ALT; 40mg: HTN, low phosphate, increased lipase). Five 40mg cohort pts required dose reductions but none were needed in the 20mg cohort. Conclusions: Cabo at either 20mg or 40 mg is tolerable when combined with standard dose abi/prednisone. The long term tolerability and preliminary efficacy data support the investigation of this combination for further clinical development in metastatic CRPC. A phase 2 study is underway. Clinical trial information: NCT01574937. 20 mg N=9 40 mg N=9 Median baseline PSA 21 14 PSA decline > 90% > 75% (n=8) 50% 63% (n=8) 13% 13% Median time on therapy (n=9) (n=9) Months (min, max) - 13 pts still on combination 7.3 (0.6+,20.3+) 5.3 (0.5, 15.5+)
Early [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic non-small cell lung cancer (NSCLC).
Authors: Carole Helissey, Denis Metivier, Claire Rousseau, Eric Gontier, Lionel Vedrine, Bernard Ceccaldi, francois-Regis Ferrand, Gerald Bonardel, Sylvestre Le Moulec
Journal: Journal of Clinical Oncology (2014)

e19154 Background: Management of NSCLC patients may be guided by 18F-FDG-PET/CT for diagnostic, staging, prognostic value at diagnostic in stage I-IIIA, but its indication in the metastatic NSCLC is still unclear. The aim of this study is to identify early 18F-FDG-PET/CT as a predictor of response and outcome in metastatic NSCLC. Methods: We retrospectively reviewed all patients who were treated for metastatic NSCLC in first line chemotherapy, and a restaging with 18F-PET/CT after 2 cycles only at Val de Grace Hospital. For each patient, we collected demographic characteristics, histological, site and number of metastases, mutational status and protocol of chemotherapy. The endpoints were PET metabolic response, RECIST response, progression-free (PFS) and overall survival (OS). Results: Between July 2008-November 2012, 63 patients were included. There were 41 men (65%) and the median age was 62 years (35-84). The principal histology was adenocarcinoma (80%). The principal site of metastasis was bone (46%). All patients received a chemotherapy based on platinum salt. After 2 cycles, 47 patients (76%) had a control disease (DC) and 16 patients (24%) had a progressive disease (PD). The median OS of the DC and PD group was respectively 17,9 months and 8 months (HR= 0.43, 95%CI (0.19-0.96), p=0.04). The median PFS of the DC and PD group was respectively 7.2 months and 2.3 months (HR= 0.12, 95%CI (0.04-0.33), p<0.001). Conclusions: PET response might confer an independent prognostic impact on PFS and OS in first line chemotherapy metastatic NSCLC. Absence of response on follow-up PET scan was associated with a shorter OS. Our results warrant a validation study.
Effect of the addition of temsirolimus to cetuximab in cetuximab-resistant head and neck cancers: Results of the randomized PII MAESTRO study.
Authors: Apoorva Chawla, Douglas Adkins, Francis P. Worden, Krishna A. Rao, H. Shawn Hu, Katharine Andress Rowe Price, Jose D Zavala, Theodore Karrison, Walter Michael Stadler, Victoria Meucci Villaflor, Yves A. Lussier, Everett E. Vokes, Ezra E.W. Cohen, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2014)

6089 Background: Patients with cetuximab resistant HNC have a median PFS of only 1.8 months (deSouza 2012). Preclinical/computational modelling suggests synergy between mTOR and EGFR, and potential to overcome resistance and aberrations in the PI3K-MTOR pathway occur in ≥30% of HNC. A previous trial of erlotinib+everolimus was terminated early due to toxicity (Bauman 2013). Methods: Eligibility was PS≤1, metastatic HNC with documented progression on cetuximab. Pts were randomized to temsirolimus (T) 25 mg +/-cetuximab (C) 400/250 mg/m2 weekly. Primary endpoint was PFS with a target of 80 pts to detect a 2 months increase. 2nd endpoints were RR, OS, toxicity. Results: 80 pts (40 TC, 40 T) started treatment via the Univ. of Chicago, and Mayo Phase II CTEP networks. Median age was 63 yrs; 69M, 11F. Median PFS was 89 days (TC) vs 93.5 days (T), NS. Median overall survival was 205/181 days, NS. Treatment was tolerable with fatigue, skin and hematologic toxicities being common. Hyperglycemia was seen in 17/80 patients (11 TC, 6 T). Grade 3-4 toxicities included metabolic abnormalities (17/40 TC, 10/40 T), hematologic toxicity (7/40 TC, 13/40 T), infection (4/40 TC, 3/40 T), and pulmonary toxicity (2/40 TC, 2/40 T). 5 responses (1 CR, 4 PR) were observed in the TC arm (RR 12.5%) (TC) vs 1 PR (2.5%) on T arm (one-sided P=0.1). Of note, all TC responders had disease control from prior C treatment (response/prolonged SD) with subsequent acquired resistance. In responders the mean interval between C failure and start of trial treatment was 3.4 months (1.1 – 6.5). In TC responders, median duration of response was 7.2 months (5.1 – 15.3). Interestingly, TC responses were maintained for up to 15 months exceeding prior benefit from C in several pts. TC responders had a median PFS of 231 days. The sole T alone response was short (89 days). Conclusions: T+C is safe and tolerable. The addition of T to C appears to overcome acquired C resistance in 12.5% of pts despite an overall negative trial. Responses are durable and clinically meaningful in this otherwise poor prognosis population. Single agent T is ineffective. Prior benefit from cetuximab is a candidate predictive biomarker for benefit from TC. Clinical trial information: NCI 8692.
A Novel HCK Inhibitor Kin-8193 Blocks BTK Activity in BTKCys481 Mutated Ibrutinib Resistant B-Cell Lymphomas Driven By Mutated MYD88
Authors: Guang Yang, Jinhua Wang, Li Tan, Xia Liu, Manit Munshi, Jiaji G Chen, Lian Xu, Nickolas Tsakmaklis, Maria Demos, Amanda Kofides, Maria Luisa Guerrera, Gloria G Chan, Zachary R Hunter, Christopher Patterson, Jorge J. Castillo, Sara J Buhrlage, Nathanael S. Gray, Steven P Treon
Journal: Blood (2018)
Glomerular Hypertrophy and Alterations in Renin-Angiotensin System Activation Are Associated with Diminished Systemic Blood Pressure in Aging Mice with Sickle Cell Anemia
Authors: Pamela L. Brito, Erica M.F. Gotardo, Hanan Chweih, Wilson A. Ferreira, Flavia C. Leonardo, Carla F. Franco-Penteado, Mariana Gonçalves Oliveira, Edson Antunes, Fernando F. Costa, Nicola Conran
Journal: Blood (2018)
Assessing the feasibility and safety of serial core needle biopsies in multiple early-phase clinical trials.
Authors: Brian Ball, Hongkun Wang, Ion Cotarla, Lisa Ley, Karen Dorsch-Vogel, Filip Banovac, Thomas Chang, Alexander Y Kim, Nina Gabelia, Lana Kapanadze, Anna Coffey, Deborah Berry, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2014)

e22100 Background: The value of early phase clinical trials of novel therapeutics is greatly enhanced through serial tumor biopsies to assess pharmacodynamic markers of drug activity. However, the optimal biopsy and target tumor characteristics have yet to be defined for core needle biopsies. Methods: We analyzed core needle tumor biopsies obtained from patients enrolled in our early phase clinical trials. At the time of each biopsy 3-5 core specimens were obtained, with at least one placed in formalin and embedded in paraffin (FFPE). “Paired biopsies” were those obtained from the same patient tumor on at least two different time points. H and E sections of individual FFPE specimens were prepared and scored for the presence or absence of tumor cells. Tumor samples were categorized by the primary tumor type, method of biopsy, biopsy site, and needle gauge. Results: 235 core needle specimens were obtained from 150 biopsies of 88 patients (including 39 patients who underwent paired biopsies) enrolled in 1 of 6 trials from 10/2010 to 11/2013. Primary tumor types included colorectal (60%), pancreatic (20%), sarcoma (10%), and other (14%). Tissue samples were obtained from multiple sites, including liver (59%), abdominal mass (14%), lung (10%), lymph node (6%), thoracic mass (5%), and pelvic mass (4%). The method of biopsy was CT (85%) and US (15%). Core needle sizes were 18-gauge (15%), 19-gauge (5%), and 20-gauge (77%). Evidence of tumor was found in 192 total specimens (82%). For paired biopsies, all but 7 patients had at least 1 core specimen with tumor cells. There was no significant difference among the initial core specimens between primary tumor type, biopsy site, biopsy method, and needle gauge. Of the 150 biopsies, only 7 had complications: pneumothorax (n= 1), blood loss requiring transfusion (n=1), vasovagal (n=2), post operative hypotension (n=1), and hematoma (n=3). Conclusions: Core needle biopsies, including paired biopsies can safely and successfully obtain sufficient tumor tissue from any site, tumor type, biopsy method, or needle gauge. As tumor tissue analyses for molecular characterization become more commonplace, core needle biopsies can successfully provide the tumor tissue that is required.