tbuckley/cabot-search huggingface dataset:
Mortality Following Cardiovascular and Bleeding Events Occurring Beyond 1 Year After Coronary Stenting
Authors: Eric A. Secemsky, Robert W. Yeh, Dean J. Kereiakes, Donald E. Cutlip, David J. Cohen, P. Gabriel Steg, Christopher P. Cannon, Patricia K. Apruzzese, Ralph B. D’Agostino, Joseph M. Massaro, Laura Mauri
Journal: JAMA Cardiology (2017)

Early cardiovascular and bleeding events after coronary stenting are associated with high risk of morbidity and mortality.To assess the prognosis of cardiovascular and bleeding events occurring beyond 1 year after coronary stenting.This secondary analysis is derived from data from the Dual Antiplatelet Therapy (DAPT) Study, a multicenter trial involving 220 US and international clinical sites from 11 countries. The study dates were August 2009 to May 2014. Individuals who underwent coronary stenting and completed 12 months of thienopyridine plus aspirin therapy without ischemic or bleeding events remained on an aspirin regimen and were randomized to continued thienopyridine therapy vs placebo for 18 additional months. Individuals were then followed up for 3 additional months while receiving aspirin therapy alone. The analysis began in August 2015.Ischemic events (myocardial infarction not related to stent thrombosis, stent thrombosis, and ischemic stroke) and bleeding events (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries [GUSTO] classification moderate or severe bleeding).Ischemic events (myocardial infarction not related to stent thrombosis, stent thrombosis, and ischemic stroke) and bleeding events (GUSTO classification moderate or severe bleeding). Death at 21 months after randomization (33 months after coronary stenting).In total, 25 682 individuals older than 18 years with an indication for coronary stenting were enrolled, and 11 648 (mean age, 61.3 years; 25.1% female) were randomized. After randomization, 478 individuals (4.1%) had 502 ischemic events (306 with myocardial infarction, 113 with stent thrombosis, and 83 with ischemic stroke), and 232 individuals (2.0%) had 235 bleeding events (155 with moderate and 80 with severe bleeding). Among individuals with ischemic events, 52 (10.9%) died. The annualized mortality rate after an ischemic event was 27.2 (95% CI, 20.3-35.7) per 100 person-years. The cumulative incidence of death after an ischemic event among the total randomized study population was 0.5% (0.3% with myocardial infarction, 0.1% with stent thrombosis, and 0.1% with ischemic stroke). Among individuals with bleeding events, 41 (17.7%) died. The annualized mortality rate after a bleeding event was 21.5 (95% CI, 15.4-29.1) per 100 person-years. The cumulative incidence of death after a bleeding event among the total randomized study population was 0.3% (0.1% with moderate and 0.2% with severe bleeding).In patients treated with dual antiplatelet therapy for at least 1 year after coronary stenting, ischemic events were more frequent than bleeding events, and both events were associated with high risk of mortality.clinicaltrials.gov Identifier: NCT00977938.
Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial
Authors: Bengt C Fellström, Jonathan Barratt, Heather Cook, Rosanna Coppo, John Feehally, Johan W de Fijter, Jürgen Floege, Gerd Hetzel, Alan G Jardine, Francesco Locatelli, Bart D Maes, Alex Mercer, Fernanda Ortiz, Manuel Praga, Søren S Sørensen, Vladimir Tesar, Lucia Del Vecchio
Journal: The Lancet (2017)
Targeting RET in Patients With <i>RET</i>-Rearranged Lung Cancers: Results From the Global, Multicenter <i>RET</i> Registry
Authors: Oliver Gautschi, Julie Milia, Thomas Filleron, Juergen Wolf, David P. Carbone, Dwight Owen, Ross Camidge, Vignhesh Narayanan, Robert C. Doebele, Benjamin Besse, Jordi Remon-Masip, Pasi A. Janne, Mark M. Awad, Nir Peled, Chul-Cho Byoung, Daniel D. Karp, Michael Van Den Heuvel, Heather A. Wakelee, Joel W. Neal, Tony S.K. Mok, James C.H. Yang, Sai-Hong Ignatius Ou, Georg Pall, Patrizia Froesch, Gérard Zalcman, David R. Gandara, Jonathan W. Riess, Vamsidhar Velcheti, Kristin Zeidler, Joachim Diebold, Martin Früh, Sebastian Michels, Isabelle Monnet, Sanjay Popat, Rafael Rosell, Niki Karachaliou, Sacha I. Rothschild, Jin-Yuan Shih, Arne Warth, Thomas Muley, Florian Cabillic, Julien Mazières, Alexander Drilon
Journal: Journal of Clinical Oncology (2017)

Purpose In addition to prospective trials for non–small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data—clinical, pathologic, and molecular features—were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.
Analysis of topoisomerase (TOP) expression in peripheral blood mononuclear cell (PBMCs) from patients (PTS) undergoing chemotherapy (CHT) for solid tumors( ST)
Authors: F. Zustovich, G. Cartei, A. Trestin, G. Palù, M. Palumbo, L. Barzon, E. Franchin, M. Mattiazzi, S. Binato, S. Zovato
Journal: Journal of Clinical Oncology (2004)

2124 Background: Clinical experience demonstrated the efficacy of combined drug regimens, including inhibitors of DNA replication and anti-TOP. Aim of this study was the time-course evaluation of TOP mRNA expression in PBMCs from PTS undergoing CHT for histologically proven ST in order to optimise combination regimens including TOP inhibitors. Methods: We analysed TOP1, TOP2A, TOP2B mRNA levels in PBMCs from 33 PTS (18 M and 15 F, median age 63) by quantitative real-time RT-PCR. Measurements were performed at 0 h, before the beginning of the first CHT dose administration, and at +2, +3, +6 and +24 h. Drugs included gemcitabine, oxaliplatin, 5-fluorouracile and methotrexate, either alone or in combination. Results: 28 PTS showed a significant increase of TOP expression at 2–3 h from the beginning of treatment with a subsequent restoration of baseline values at 6 h. In particular, TOP1 mRNA levels increased from 120% to 1,400% of baseline values, TOP2A increased 200%–730% from baseline and TOP2B increased from 130%–12,000% of baseline. Among the variety of drugs tested, 5-fluorouracile (in monotherapy or in association with oxaliplatin or methotrexate) and gemcitabine were the most effective in inducing TOP expression. Conclusions: we demonstrated that anti-tumour drugs acting on cell replication and/or metabolism induce TOP1, TOP2A, TOP2B expression with a pick at 2–3 h from treatment. These results are of interest in the designing combined chemotherapy schedules including topoisomerase inhibitors. No significant financial relationships to disclose.
Longer-term quality of life following ACL injury and reconstruction
Authors: Stephanie R Filbay
Journal: British Journal of Sports Medicine (2017)

My PhD aimed to generate a detailed picture of longer-term quality of life (QOL) following ACL injury and reconstruction.1 I wanted to summarise everything that was known on the topic before exploring QOL in greater detail and identifying factors related to poor QOL 5–20 years after ACL reconstruction. I also wanted to speak with people who have had an ACL reconstruction to find out from their perspective, how ACL injury has impacted their QOL and whether it continues to do so 5–20 years after ACL reconstruction.



Figure 1 
Stephanie receiving her PhD at The University of Queensland, December 2016



When I first ruptured my ACL as a 17-year-old, I (like a majority of people who rupture their ACL) expected to return to sport with minimal difficulties after completing rehabilitation. What I now know is that return-to-sport rates are low, re-injury …
Usefulness of cytological samples (CS) for the assessment of ALK rearrangements in non-small cell lung cancer (NSCLC).
Authors: Maria D. Lozano, Tania Labiano, Maria I. Zudaire, Alfonso Gurpide, Javier Zulueta, José María López-Picazo, Jose Ignacio Echeveste, Luis Miguel Seijo, Miguel A. Idoate, Salvador Martin-Algarra, Jose Luis Perez-Gracia
Journal: Journal of Clinical Oncology (2012)

e18008 Background: ALK gene rearrangements define a new molecular subtype of NSCLC with response to Crizotinib, a dual MET and ALK inhibitor. Analysis of ALK rearrangements has been performed in biopsies or surgical specimens. However, advanced NSCLC is often diagnosed by FNA cytology obtained through minimally invasive techniques, and frequently CS are the only tumour sample available. We assessed the feasibility of determining ALK rearrangements in CS. Methods: We studied prospectively ALK rearrangements in 53 CS from 53 NSCLC patients (30 M/23 F) by FISH (Vysis dual colour break apart probe). We considered positive for ALK rearrangement when &gt; 15% of cells show splits signals. Tumor samples were obtained by bronchoscopy -FNA in 26 cases (49.1%), EBUS-FNA in 7 (13.2%), EUS-FNA in 3 cases (5.7%), CT-FNA in 3 (5.7%), and direct FNA in 6 cases (11.3%). Two cavity fluids (3.8%), 4 imprints (7.5%), and 2 cellblocks received for consultation (3.8%) were also studied. FISH was performed on non-stained ThinPrep in 28 cases (52.8%), Papanicolau stained smears in 15 cases (28.3%), cell block in 9 cases (17%), and 1 stained ThinPrep. All cases were tested for EGFR and KRAS mutations. Correlation cytological/paraffin embedded samples was performed in 4 paired cases. Results: Thirty-seven samples(69.8%) were adequate for FISH analysis. Three cases (8.1%) had ALK rearrangements: non-smoker women with adenocarcinoma, two of them with signet ring cells. One case had a concurrent EGFR mutation in exon 21. FISH study was unsuccessful in 16 cases (30.2%):10 Papanicolau stained smears (62.5%), 5 unstained ThinPrep (31.3%), and 1 cell block. Nineteen ThinPrep slides were adequate for FISH analysis (86.4%) as well as 8 out of 9 cell blocks. Concordance rate in paired cases were 100%. Conclusions: Determination of ALK gene rearrangements in CS is feasible. It is mandatory an exquisite management and care of the samples to preserve quality. ThinPrep and cell blocks are the most suitable samples for FISH analysis, while Papanicolau stained smears provide poor results. Coexistence of ALK gene rearrangements and EGFR mutations was observed in one case, indicating that such alterations are not necessarily mutually exclusive.
Second-line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.
Authors: Antonin Levy, Jean Menard, Laurence Albiges, Mario Di Palma, Karim Fizazi, Bernard J. Escudier
Journal: Journal of Clinical Oncology (2012)

e15049 Background: Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. Methods: Data from all mRCC patients treated at the IGR from 2005 to 2009 with first-line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mTOR)) were analyzed. Only patients with subsequent follow up have been included in this analysis. Patients were defined as “non eligible” for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response), or (iii) if they refused a second line treatment. Results: 251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median OS of 25.8 months. Median OS with SU (127), SO (60) or B (61) were respectively 26.3, 16.4 and 32.5 months respectively. Only 3 patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. MSKCC classification (p = 0.02) and first line agent (p = 0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of PS = 0 compared to SO (53%) and SU (48%) (p = 0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a TKI (n=98; 75%) and 16.6 months for an mTOR (n=32; 42%) (p = 0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. Conclusions: The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for 2 nd line treatment.
Functional age and tolerance to radiotherapy: A prospective study of a Comprehensive Geriatric Assessment.
Authors: Noam Avraham VanderWalde, Allison Mary Deal, Elizabeth Comitz, Lori Stravers, Hyman B. Muss, Bhishamjit S. Chera
Journal: Journal of Clinical Oncology (2015)

e20534 Background: Comprehensive geriatric assessments (CGA) have been shown to predict for toxicity from chemotherapy (CT) and surgery. This study’s purpose is to evaluate associations between CGA components and poor tolerance to radiotherapy (RT) or Chemoradiotherapy (CRT) in patients with lung or head and neck cancer (HNC). Methods: From 2012 to 2014, consent was obtained on 50 patients undergoing curative intent RT or CRT for this prospective, institutionally approved study. Patients completed a pre-treatment CGA. During treatment and 4-8 weeks post treatment, quality of life and toxicity measures were obtained. Poor tolerance to treatment was defined by hospitalization, > 3 day treatment delay, change in RT or CT regimen, and death. The primary outcome was to assess the association between instrumental activities of daily living (I-ADL) scores and poor tolerance to treatment. Associations of other patient variables were also evaluated. Fisher’s exact test was used to test associations. Results: Of the 50 patients accrued, 46 had evaluable data. Mean age was 72.5 (range 65-92). Thirty nine percent had lung cancer, 61% had HNC. Forty six percent received CRT. At baseline, 37% had a deficiency in an I-ADL and 38% were considered pre-frail or frail. Thirty five percent required G-tube. Thirty nine percent had poor tolerance to RT or CRT. There was no association between either I-ADL deficiency or frailty index and tolerance. Receipt of CT was associated with poor tolerance (57% v 24%, p = .03) and G-tube requirement (53% v 21%, p = 0.05). Lung cancer patients with no I-ADL deficiency experienced poor tolerance less often than those with deficiencies (25% v 40%, p = 0.6), as did those with self-reported KPS ≥ 80 (23% v 60%, p = 0.27). HNC patients with I-ADL deficiency required g-tube more often than those with no I-ADL deficiency (86% v 45% p = .09). Conclusions: In this small cohort study of older patients, pre-treatment function, as measured by an abbreviated CGA, did not predict for poor tolerance to RT or CRT. However, trends were apparent among lung cancer patients. Larger cohorts may be needed to identify the true predictive value of the CGA. Toxicity and quality of life associations are being investigated. Clinical trial information: NCT01752751.
Role of genetic polymorphisms in CCL5/CCR5 axis to predict efficacy of regorafenib in patients with refractory metastatic colorectal cancer.
Authors: Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Federica Marmorino, Francesca Bergamo, Carlotta Antoniotti, Daniele Rossini, Yan Ning, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Roel Gopez, Diana L. Hanna, Afsaneh Barzi, Tetsuo Mashima, Toshiharu Yamaguchi, Fotios Loupakis, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2017)

596 Background: CCL5/CCR5 pathway is known to mediate VEGF-A production. A recent study reported that serum VEGF-A and CCL5 levels predict efficacy of regorafenib in metastatic colorectal cancer (mCRC). We tested whether genetic polymorphisms in the CCL5/CCR5 pathway are associated with outcomes in patients with refractory mCRC treated with regorafenib. Methods: We analyzed genomic DNA extracted from 229 samples of two cohorts receiving regorafenib: an evaluation cohort of 79 patients (median age 62 years, male 47%, median follow-up time 15.3 months); and a validation cohort of 150 patients (median age 62 years, male 54%, median follow-up time 36.4 months). Nine single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway ( CCL5, CCR5, PRCKD, CCL3, CCL4, KLF13, HIF1A) were analyzed by PCR-based direct sequencing. Associations between SNPs with progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Multivariable analyses including SNP and baseline characteristics were performed using the Cox proportional hazard regression model. Results: In the evaluation cohort, patients with any A allele in CCL4 rs1634517 had a significant shorter PFS compared to those with the C/C variant (2.0 vs. 2.5 months, HR 1.54, P= 0.043). Patients carrying any A allele in CCL3 rs1130371 had marginally significant shorter PFS (2.0 vs. 2.5 months, HR 1.48, P= 0.064) than those with the G/G variant. In the validation cohort, Patients with any A allele in CCL4 rs1634517 had a shorter PFS (1.8 vs. 2.3 months, HR 1.74, P= 0.001) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) compared to those with the C/C variant. It remained significant in multivariable analysis for PFS and OS ( P= 0.012 and 0.041). Patients carrying any A allele in CCL3 rs1130371 had a shorter PFS (1.8 vs. 2.3 months, HR 1.66, P= 0.002) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) than those with the G/G variant; these effects were significant in multivariable model (PFS: P= 0.027; OS: P= 0.047). Conclusions: Genetic variants in the CCL5/CCR5 pathway, CCL4 rs1634517 and CCL3 rs1130371, may serve as predictive and prognostic markers in refractory mCRC patients receiving regorafenib.
Midkine and pleiotrophin concentrations in biopsy needle washout of breast masses.
Authors: Nicole Michelle Giamanco, Youn Hee Jee, Craig D. Shriver, Thomas A. Summers, Anton Wellstein, Jeffrey Baron
Journal: Journal of Clinical Oncology (2014)

e22104 Background: The primary preoperative diagnostic method for distinguishing malignant from benign breast masses is core biopsy histology, but this approach can be inconclusive. Midkine (MDK) and pleiotrophin (PTN) are two closely related heparin-binding growth factors which are overexpressed in a wide variety of human cancers. Concentrations of both growth factors were found to be greater in washout of fine needle aspiration biopsies of malignant thyroid nodules compared to benign nodules. Because MDK and PTN are also overexpressed in breast cancer, we hypothesized that concentrations of these factors in washout of biopsy needles would be higher in breast cancer than in benign lesions and thus might aid in the preoperative diagnosis of breast masses. Methods: We plan to study 70 subjects. Here we report early findings from initial subjects enrolled (n=11, age 50 ± 12 y, mean ± SD, all female). Subjects underwent ultrasound-, MRI- or mammogram-guided core needle biopsies of breast masses (n=15). Needle contents were used for histology, and the needle was then washed with buffer for immunoassays. MDK and PTN were measured by high-sensitivity sandwich ELISAs, and DNA concentration was used to normalize the data. Samples with DNA < 50 ng/mL were excluded on the assumption of insufficient tissue sampling. Results: The MDK/DNA ratio was 0.32 ± 0.31 ng/ng (mean ± SD) in benign lesions (n = 11). The MDK/DNA ratio was 0.15 ± 0.41 ng/ng in the 2 malignant lesions sampled to date (1 estrogen receptor positive (ER+), progesterone receptor positive (PR+), HER2 negative invasive ductal carcinoma, 1 lobular carcinoma in situ), similar to benign lesions. The PTN/DNA ratio was 1.03 ± 1.19 ng/ng in benign lesions (n = 13). In one malignant lesion (ER+, PR+, HER2 negative invasive ductal carcinoma), the PTN/DNA ratio was 0 ng/ng, similar to benign lesions, but in the other malignant lesion (lobular carcinoma in situ), the ratio was substantially higher, 19.0 ng/ng. Conclusions: Preliminary findings indicate that both MDK and PTN are readily measurable in washout of needle biopsy samples from breast masses. Study of additional subjects is needed to determine whether specific types of breast cancer have higher MDK and/or PTN concentrations than benign masses.