tbuckley/cabot-search huggingface dataset:
The genomic landscape of metastatic non-clear cell renal cell carcinoma.
Authors: Maria Isabel Carlo, Nabeela Khan, Yingbei Chen, James Hsieh, A. Ari Hakimi, Chung-Han Lee, Darren R. Feldman, Robert J. Motzer, Martin Henner Voss
Journal: Journal of Clinical Oncology (2017)

474 Background: Non-clear cell renal cell carcinoma (nccRCC) encompasses about 20% of RCC cases and includes a number of subtypes that vary clinically and molecularly. Compared to ccRCC, these tumors have more limited sensitivity to conventional anti-VEGF agents and mTOR inhibitors, and there is clear need for better therapies. Analysis of genomic alterations in potentially targetable pathways may lead to novel therapeutic development strategies. Methods: We retrospectively analyzed tumors from 112 patients with metastatic nccRCC with targeted next-generation sequencing (NGS) across a panel of &gt;340 cancer-relevant genes. Matched tumor and normal was used to facilitate somatic calling. We report on recurrent alterations observed for nccRCC variants. Results: Median age was 53 years (range 12-77), 67% were male; 47% presented with metastatic disease and 53% with localized disease that later metastasized. NGS was performed on tissue from primary tumors (57%) or metastatic sites (43%). Subtype classifications included unclassified (44%), papillary (21%), chromophobe (13%), translocation (12%), and other (9%). The most frequently altered genes by subtype are included in table. 36% of unclassified or papillary tumors had a mutation in a putative driver gene amenable to targeted therapies, including MET, NOTCH1, SMARCB1, TSC1, TSC2, PIK3CA, and FGFR3. 3 chromophobe tumors and 1 translocation tumor had a mutation in a potentially targetable pathway. Conclusions: The mutation profiles of metastatic nccRCC vary by papillary, chromophobe, and translocation subtype, with unclassified tumors most approximating papillary subtype. Unclassified and papillary subtypes harbor frequent mutations in potentially targetable pathways that merit further investigation. [Table: see text]
Radium-223 (Ra-223) in asymptomatic metastatic castration-resistant prostate cancer (mCRPC) patients treated in an international early access program (iEAP).
Authors: Axel Heidenreich, Silke Gillessen, Daniel Heinrich, Daniel Keizman, Joe M. O'Sullivan, Joan Carles, Manfred Wirth, Kurt Miller, Liping Huang, Monica Seger, Sten Nilsson, Fred Saad
Journal: Journal of Clinical Oncology (2017)

158 Background: Ra-223, a targeted alpha therapy, is currently used to treat mCRPC patients (pts). To investigate Ra-223 when used early in the disease course, we analyzed safety and efficacy in mCRPC pts with no symptoms at baseline treated in an iEAP. Methods: This was a prospective, single-arm phase 3b study of mCRPC pts (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded). Pts received Ra-223, 55 kBq/kg IV, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival (OS). Post hoc analyses were performed according to asymptomatic or symptomatic disease status at baseline. Asymptomatic was defined as no pain and no opioid use at baseline. Results: 708 pts received ≥1 Ra-223 injection: 548 (77%) were defined as symptomatic and 135 (19%) were defined as asymptomatic. Asymptomatic pts had more favorable baseline characteristics than symptomatic pts (table). Fewer asymptomatic pts had received prior abiraterone (34 pts, 25% vs 190, 35%), enzalutamide (5 pts, 4% vs 43, 8%) and prior docetaxel (70 pts, 52% vs 339, 62%). More asymptomatic pts received 6 cycles of Ra-223 (96, 71% vs 300, 55%). Adverse events (AEs) were reported for fewer pts with asymptomatic vs symptomatic disease: any grade, 61% vs 79%; grade 3/4, 29% vs 40% and serious AEs, 22% vs 38%. OS was longer in asymptomatic pts and ALP normalization was more common (table). Conclusions: Asymptomatic pts were more likely to have a better prognosis and to complete all 6 cycles of Ra-223. Ongoing first-line combination studies (ERA-223: NCT02043678 and PEACE-3: NCT02194842) may show whether Ra-223 administered early in the disease course will lead to better outcomes. Clinical trial information: NCT01618370. [Table: see text]
Is gemcitabine effective for pancreatic cancer after progression to FOLFIRINOX?
Authors: Bruno Melo Fernandes, Rafael Caparica Bitton, Jorge Sabbaga, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2017)

489 Background: Cytotoxic chemotherapy with FOLFIRINOX (5-Fluoracil + Irinotecan + Oxaliplatin) is considered the standard treatment for fit patients (pts) with pancreatic adenocarcinoma. Disease progression after FOLFIRINOX invariably occurs, and there is no definition on the optimal strategy for the second-line treatment of these pts. Gemcitabine is effective for advanced pancreatic cancer as first-line treatment, but its role after FOLFIRINROX progression is unknown. The present study aims to assess the efficacy of gemcitabine for treatment of advanced pancreatic cancer after progression to FOLFIRINOX. Methods: Single-institution, retrospective analysis of all pts consecutively diagnosed with advanced pancreatic cancer between January/2010, and October/2015, who received Gemcitabine as second line chemotherapy after progression to first line chemotherapy with FOLFIRINOX. Tumor responses were assessed through RECIST 1.1. PFS and OS were calculated using Kaplan Meier method. Results: 28 pts were included in our analysis. Median age was 55 years (38-75), and 19 pts (67%) were male. The median ECOG was 1 (0-2). Pts received a median of 9 cycles of FOLFIRINOX as first line treatment (1-27), with an objective (ORR) response rate of 39%. The median number of second-line Gemcitabine cycles was 3 (1-8), with an ORR of 3%, and a 17% rate of disease control (stable disease + partial response). Five patients (18%) discontinued second line Gemcitabine due to toxicities and the remaining 23 (82%) due to disease progression. Median overall survival was 5.6 months (0,36-11,5) and median progression-free survival was 2 months (0.2-7.7). Grade ≥ 3 toxicities with Gemcitabine were experienced by 18% of the patients. No treatment-related deaths were reported. Conclusions: Gemcitabine after progression to FOLFIRINOX presented a modest activity on the present study, with prospective trials being necessary to further assess this issue. Due to the palliative goal of the treatment, with the objective of improving patient´s quality of life, the significant risk of treatment-related adverse events and the low efficacy of Gemcitabine should be considered before prescribing Gemcitabine routinely as a second-line treatment for pancreatic cancer.
Autophagic cell death with hydroxychloroquine in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer.
Authors: Mridula Annette George, Tina M. Mayer, Dirk Moore, Chunxia Chen, Eileen White, Robert S. DiPaola, Chandrika Jeyamohan, Mark N. Stein
Journal: Journal of Clinical Oncology (2017)

102 Background: For patients who have a rising prostate-specific antigen value after definitive local therapy, androgen deprivation is a commonly employed option. However, immediate hormonal therapy has not been shown to alter the progression of the disease. Prior studies showed the dependence of early tumor growth and progression on anaerobic metabolism through glycolysis. Autophagy is conserved, genetically controlled catabolic response to starvation and stress whereby cells self-digest intracellular proteins and organelles by targeting them for degradation in lysosomes to generate energy and mitigate damage, thereby supporting cancer cell survival. Our hypothesis was that the autophagic inhibitor, hydroxychloroquine, when utilized in prostate cancer, would interfere with defective autophagy such that tumor growth will be slowed or stopped. Methods: Patients had rising PSA after primary therapy for PC, no radiographic evidence of metastasis, no (neo)adjuvant ADT within 3 months of enrollment and testosterone &gt; 150 ng/dL. Hydroxychloroquine was dosed at 400 mg/day (cohort 1) or 600 mg/day (cohort 2). Endpoints were PSA response (change in slope of PSA rise by at least 25%, when log (PSA) is plotted vs. time). Results: 64 patients (36 cohort 1; 28 patients cohort 2) with median age 71(55-94) and baseline PSA was 3.25ng/ml (0.24- 45.69ng/ml) were enrolled in the study. 39 patients completed 6 months of hydroxychloroquine therapy and 44 patients completed 5 months of treatment. Out of 64 patients, 52 had at least 5 PSA measurements after the start of treatment, and we restrict our analysis to these patients. In 33 patients of these 52 (63%), the doubling time decreased after treatment began. In 12 of these 52 (23%), the “doubling time” turned negative, consistent with decreasing PSA value. Most common adverse events were diarrhea (26%), nausea (12%) and rash (12%). Conclusions: Hydroxychloroquine appears to have some activity in PSA progression after localized therapy with minimal toxicity. Given that hydroxychloroquine has limited side effects, this drug has the potential to augment responses to hormonal therapy or chemotherapy. Clinical trial information: NCT00726596.
Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001–2013: a Clinical Practice Research Datalink study
Authors: Simon M Collin, Inger J Bakken, Irwin Nazareth, Esther Crawley, Peter D White
Journal: Journal of the Royal Society of Medicine (2017)

Objective Trends in recorded diagnoses of chronic fatigue syndrome (CFS, also known as 'myalgic encephalomyelitis' (ME)) and fibromyalgia (FM) in the UK were last reported more than ten years ago, for the period 1990-2001. Our aim was to analyse trends in incident diagnoses of CFS/ME and FM for the period 2001-2013, and to investigate whether incidence might vary by index of multiple deprivation (IMD) score. Design Electronic health records cohort study. Setting NHS primary care practices in the UK. Participants Participants: Patients registered with general practices linked to the Clinical Practice Research Datalink (CPRD) primary care database from January 2001 to December 2013. Main outcome measure Incidence of CFS/ME, FM, post-viral fatigue syndrome (PVFS), and asthenia/debility. Results The overall annual incidence of recorded cases of CFS/ME was 14.8 (95% CI 14.5, 15.1) per 100,000 people. Overall annual incidence per 100,000 people for FM was 33.3 (32.8-33.8), for PVFS 12.2 (11.9, 12.5), and for asthenia/debility 7.0 (6.8, 7.2). Annual incidence rates for CFS/ME diagnoses decreased from 17.5 (16.1, 18.9) in 2001 to 12.6 (11.5, 13.8) in 2013 (annual percent change -2.8% (-3.6%, -2.0%)). Annual incidence rates for FM diagnoses decreased from 32.3 (30.4, 34.3) to 27.1 (25.5, 28.6) in 2007, then increased to 38.2 (36.3, 40.1) per 100,000 people in 2013. Overall annual incidence of recorded fatigue symptoms was 2246 (2242, 2250) per 100,000 people. Compared with the least deprived IMD quintile, incidence of CFS/ME in the most deprived quintile was 39% lower (incidence rate ratio (IRR) 0.61 (0.50, 0.75)), whereas rates of FM were 40% higher (IRR 1.40 (0.95, 2.06)). Conclusion These analyses suggest a gradual decline in recorded diagnoses of CFS/ME since 2001, and an increase in diagnoses of fibromyalgia, with opposing socioeconomic patterns of lower rates of CFS/ME diagnoses in the poorest areas compared with higher rates of FM diagnoses.
Evaluation of proteomic profiles of normal mucosa, Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC) obtained from humans and the Levrat’s rat model of BE/EAC.
Authors: Michael K. Gibson, Ali H Zaidi, Xuemei Zeng, Jon M. Davison, Tyler Foxwell, Toshitaka Hoppo, Yoshihiro Komatsu, Katie Sue Nason, Christina Rotoloni, Astha Bhatt, Juliann Kosovec, Cornelia Smith, William L Bigbee, James D. Luketich, Blair A Jobe
Journal: Journal of Clinical Oncology (2012)

e14689 Background: EAC from BE is increasing, and prognosis is poor. Representative models are critical to understanding BE/EAC and developing therapies. We refined the Levrat’s model of BE/EAC and showed that a SMO inhibitor prevented BE/EAC (Proc ASCO 2012). To validate the rat model as representative of human and explore differentially expressed proteins/pathways, we evaluated the proteomic profiles of nl/BE/EAC from humans and rats. Methods: GE reflux was induced in 6-8 wk old male Sprague–Dawley rats by the Levrat’s procedure--approved by the IACUC. Incidence of BE/EAC at 28 wks was 90%/70%. Human nl/BE/EAC samples were obtained from the PENG database--IRB approved. Histology confirmed by a single pathologist (JD). Following LCM from paraffin, digests were analyzed in triplicate by nanoflow LC-MS/MS with a hybrid linear ion trap-Orbitrap Velos mass spectrometer followed by online nanoflow LC. Mass spectral data representing ~ 20-30,000 CID spectra were searched, and a quantitative estimate of relative abundance was obtained. Kruskal-Wallis non-parametric ANOVA was employed, and clusters were compared within and between humans and rats. Results: Data is available for rat tissues, 10 samples each for nl/BE/EAC. Heirarchical clustering of 410 features yielded 3 statistically significantly distinct groups corresponding to normal, BE and EAC (ANOVA p &lt; 0.001). Pair-wise comparison between groups yielded statistically significant (p &lt; 0.05) differential protein expression as follows: nl vs BE~550; nl vs EAC~450; BE vs EAC~150. For EAC, proteins were differentially expressed in pathways including: protein degradation/synthesis, cell death, growth and proliferation (NF-kB, EIF4A, Akt, b-tubulin). Analysis of human tissues and comparison to rat will be presented at the meeting. Conclusions: Proteomic evaluation of normal/BE/EAC tissues from the Levrat’s model of BE/EAC yielded distinct protein patterns for nl/BE/EAC. Proteins differentially expressed in EAC vs normal/EAC are involved in cancer related pathways. Differentially expressed proteins may provide targets for therapy, which could be tested in the Levrat’s model.
Factors associated with referral to medical oncology (MO) and subsequent use of adjuvant chemotherapy (ACT) among patients with resected non-small cell lung cancer (NSCLC): A population-based study.
Authors: Janarthanan Kankesan, Frances A. Shepherd, Yingwei Peng, Gail Elizabeth Darling, Gavin Li, Weidong Kong, William J. Mackillop, Christopher M. Booth
Journal: Journal of Clinical Oncology (2012)

1583 Background: ACT for NSCLC is associated with improved survival in the general population but may be underutilized. Underutilization may relate to lack of referral from surgeon to MO, MO not offering ACT, or patient declining ACT. Here we explore factors associated with referral to MO and use of ACT among patients with resected NSCLC in Ontario Canada. Methods: The Ontario Cancer Registry was used to identify all incident cases of NSCLC diagnosed in Ontario 2004-2006. We linked electronic records of treatment to identify surgery, ACT, and MO consultation. Co-morbidity was classified using the Charlson Comorbidity Index modified for administrative data. A multivariate logistic regression model was used to evaluate factors associated with referral to MO and use of ACT. Results: 3354 cases of NSCLC were resected in Ontario 2004-2006, 1830 (55%) were seen post-operatively by MO and 1032 (31%) were treated with ACT. Cases younger than 70 were more likely to have MO consultation (age 60-69 OR 1.6; 50-59 OR 2.3; 20-49 OR 2.2, p&lt;0.001) as were cases with stage II/III (ORs 2.7 and 2.0, p&lt;0.01) compared to stage I disease. There was substantial geographic variation in the proportion of surgical cases referred to MO (range 32-88%, p&lt;0.001). Among cases seen by MO, patients younger than 70 were more likely to have ACT (age 60-69 OR 3.1; 50-59 OR 4.7; 20-49 OR 6.7, p&lt;0.001) as were cases with stage II/III (ORs 2.7 and 3.0, p&lt;0.001) compared to stage I disease. Less co-morbidity (OR 2.1, p=0.02) and shorter post-operative stay (OR 1.4, p=0.001) were also associated with use of ACT. Among cases seen by MO, there was some geographic variation (range 46-63%, p&lt;0.001) in rates of ACT utilization. Conclusions: The upstream decision to refer to MO is associated with age and stage of disease and these factors have an even greater effect on ACT utilization once patients are seen by MO. While co-morbidity and post-operative length of stay are not associated with referral to MO, they are associated with use of ACT among cases seen by MO. There is substantial geographic variation in referral patterns to MO and less variation in ACT utilization once patients are seen by MO.
Hypoxia, angiogenic markers, and response to neoadjuvant radiotherapy in soft-tissue sarcomas.
Authors: Jeremy Lewin, Kenneth Khamly, Catherine Mitchell, Rodney J Hicks, Guy C. Toner, Sam Ngan, Gerard Powell, Jayesh Desai, Peter Choong, Steven Stacker, John Slavin, David Morgan Thomas
Journal: Journal of Clinical Oncology (2013)

10567 Background: Hypoxia is common in soft-tissue sarcomas (STS) and may correlate with radiotherapy (RT) resistance and worse outcomes. We aimed to quantify intratumoral hypoxia with 18-fluoroazamycin arabinoside (FAZA)-PET in resectable STS and correlate this to 18-fluorodeoxyglucose (FDG)-PET, tumour response, angiogenesis biomarkers and patient (pt) outcomes. Methods: This phase II prospective study enrolled pts with resectable STS prior to neoadjuvant RT. Pts underwent FDG-PET and FAZA-PET prior to RT. Circulating and immunohistochemical (IHC) markers of hypoxia and vessel architecture were measured weekly. Response to RT was measured by surgically resected pathologic necrosis (PN), radiological response and relapse-free survival. Results: 23 pts were recruited. 47% (8/17) demonstrated hypoxia on FAZA-PET with a possible association between hypoxia and enhanced metabolic activity on FDG-PET (FDG SUVmax=15.33 with hypoxia; SUVmax=5.86 without hypoxia p=.08). FDG-PET response to RT correlated with PN (good/equivocal FDG-PET response: 59% PN; poor FDG-PET response: 19%PN p=.008). All relapses were distant (n=10) at average follow up of 5 years. Relapse was associated with higher FAZA-PET SUV (1.94 vs 1.28 p=0.02), FDG-PET SUVmax (14.4 vs 6.2 p=0.05), and poorer response to RT (PN 36% vs 66%, p=0.04). Baseline VEGF-C (531±82pg/ml, mean±SEM) were higher than VEGF-A (35±8pg/ml) and VEGF-D (131±17pg/ml), and correlated with protein expression on IHC staining. Hypoxia on FAZA-PET correlated with lower baseline VEGF-A/C (VEGF-C: (292pg/ml vs 688pg/ml p=0.16) and VEGF–A (14pg/ml vs 46pg/ml p=0.13). Low VEGF-C correlated with resistance to RT assessed by FDG-PET. In hypoxic tumors after 1 week of RT, VEGF-A and C levels were significantly increased (VEGF-A 80pg/ml vs 14pg/ml; VEGF-C 541ng/ml vs 292ng/ml). Response to RT correlated with less induction of VEGF-A/C. Relapse was associated with lower baseline VEGF and higher IHC levels of other hypoxic markers (GLUT-1, CA 9). Conclusions: In STS, hypoxia is common, measurable, predicts poorer response to RT and is associated with adverse outcomes. Circulating levels of VEGF-C, the dominant isoform, inversely correlated with hypoxia and is induced by RT.
Antibody-dependent cell-mediated cytotoxicity (ADCC) evolution under treatment by cetuximab and links with treatment outcome in colorectal cancer (CRC) patients.
Authors: Marco Carlo Merlano, Martino Monteverde, Giuliana Strola, Jerome Barriere, Marie-Christine Etienne-Grimaldi, Emanuela Miraglio, Laura Lattanzio, Daniela Vivenza, Francesca Messa, Cristiana Lo Nigro, Gerard A. Milano
Journal: Journal of Clinical Oncology (2012)

2600 Background: ADCC plays a role in antitumor activity of IgG1 mAb by inducing immune cell-mediated lysis of tumor cells. We evaluated ADCC ability before and under cetuximab-based treatment and examined its impact on treatment outcome. Methods: 29 patients (17 men, 12 women, median age 72, range 51-84) with metastatic wild-type KRAS CRC treated with chemotherapy (irinotecan or Folfiri) plus cetuximab were prospectively enrolled. ADCC ex-vivo was measured before starting treatment and every 2 months during treatment (1 to 7 measurements/patient, 12 patients with &gt;2 measurements). 400 000 purified Natural Killer cells (CD3- CD56+) from patients were incubated with 10 000 target cells (CAL166 cancer cell line expressing EGFR) and 10 µg/ml cetuximab (triplicates). Cytotoxicity was measured by the LDH-release assay. ADCC was expressed as the % of lyzed target cells. Gene polymorphisms of Fcγ receptors FCGR2a (131Arg&gt;His) and FCGR3a (158Phe&gt;Val) were analyzed (Allelic Discrimination assay). Results: The feasibility rate of ADCC measurement was 88%. ADCC basal values ranged between 30% and 100% (mean 62%, median 66%). Basal ADCC was not influenced by patient gender. A tendency for an increased ADCC basal value was observed in younger patients: median was 76% in the 6 patients ≤ 60 vs 56% in the 23 patients over 60 years-old (p = 0.031). FCGR2A and FCGR3A gene polymorphisms were not linked to basal ADCC. The evolution of individual ADCC ability before treatment and 2 months later revealed a significant drop in ADCC following treatment initiation (intra-patient comparison, n=18, p=0.006), with an absolute median drop of 19%. This decrease was not sustained over time and intra-patient comparison between basal value and 4-month measurement was not significant. 25 patients were assessable for survival (11 deaths). Basal ADCC values were not related to survival. Conclusions: A new generation of mAb is currently being developed with the aim to amplify ADCC. Present data illustrate the feasibility of ADCC measurement in mAb-treated patients and reveal an initial drop in ADCC under treatment that may reflect the variable chemotherapy-induced impact on host immunity.