tbuckley/cabot-search huggingface dataset:
High dose Interleukin2 (HD IL2) in metastatic renal cell carcinoma (mRCC) after prior therapy: A single centre experience.
Authors: Shien Chow, Rebecca Leach, Andrea Spencer-Shaw, Fadhel Shaheen, Fiona C. Thistlethwaite, Robert E. Hawkins
Journal: Journal of Clinical Oncology (2018)

e16558 Background: HD IL2 as 1st line therapy in mRCC can produce durable complete remission in significant proportion of patients when selected for favourable pathological and clinical features1. However, its utility following prior treatment particularly VEGF tyrosine kinase inhibitor (TKI) is less well known. We evaluated the outcomes of patients treated in our centre and the predictive role of our pathology criteria in this setting. Methods: 72 patients who received HD IL2 after prior therapy (2002 – 2015) were retrospectively reviewed. Patient selection using Christie IL2 pathology criteria started in 2006. Suitable candidates were classified in to Favourable (F) or Other (O) pathology group . HD IL2 was preferentially offered, but not exclusively, to patients with Favourable pathology. Outcomes of interest are efficacy, survival and tolerance. Results: Prior lines (L) of treatment: 1L 58%, 2L 31%, 3-4L 11%. N = 55 (74%) had prior Sunitinib. N = 62 in‘F’ group (ORR 35.5%; CR n = 10, PR n = 12, SD n = 16) and n = 10 in ‘O’ group (CR n = 0, PR n = 1, SD n = 5). Median PFS for CR, PR, SD are NE, 11.1, 5.8 months respectively. Progression-free rate at 5 year is ~18%. OS is 60%, 40%, 38% at 2, 4, and 8 year respectively. 70% of CR are relapse-free. 83% (5/6) of patients with PR who achieved complete resection of oligometastatic disease remained disease-free. Median C1 dose is 18. Acute toxicities were as expected in majority. There were 2 ITU admissions for inotropic support and 5 had myocarditis (~ 7%). One death likely related to cardiac complication. Conclusions: HD IL2 was well tolerated in post-TKI patients but a higher tendency of cardiac toxicity was observed than in treatment-naïve patients. mRCC patients with favourable pathology criteria can derive impressive and durable benefit from HD IL2 even after development of disease resistance to targeted therapy. Benefits of this treatment must be balanced against its potential risks, but with careful patient selection and treatment based in experienced centres, it remains an option for those who progressed after other therapy. Ref: 1. Chow, S. et al., 2016. High dose IL2 – a 10-year single-site experience in treatment of metastatic renal cell carcinoma. JITC, 4(1), p.67.
Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosis
Authors: Elham E. Amin, Ingrid M. Bistervels, Karina Meijer, Lidwine W. Tick, Saskia Middeldorp, Guy Mostard, Marlène van de Poel, Erik H. Serné, Hans M. Otten, Edith M. Klappe, Manuela A. Joore, Hugo ten Cate, Marije ten Wolde, Arina J. ten Cate-Hoek
Journal: Blood (2018)
ECOG score analysis as a proxy for health-related quality of life assessment in patients with poor or intermediate risk metastatic renal cell carcinoma from the CABOSUN trial (Alliance A031203).
Authors: Darren R. Feldman, Marion Feuilly, Jie Meng, Johanna Lister, Florence Marteau, Michael J. Morris, Daniel J. George, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2018)

e18690 Background: CABOSUN, a randomized and open-label phase II trial, demonstrated significant improvement in progression-free survival (PFS) with cabozantinib versus sunitinib in the first-line treatment of patients with intermediate- or poor-risk clear cell advanced renal cell carcinoma. To mitigate the lack of health-related quality of life (HRQoL) data collected in the original study, a post hoc analysis was conducted using Eastern Cooperative Oncology Group (ECOG) performance status scores as a proxy for HRQoL. The aim was first to understand if ECOG scores differed by health states, specifically pre-progression (PRE) versus post-progression (POST), and secondly if the time to ECOG deterioration differed by treatment arm. Methods: Performance status was assessed through ECOG score at each study visit over the treatment period; collection was not mandatory for the post-treatment follow-up period. Mean ECOG scores PRE and POST were computed and frequencies of ECOG score (0, 1, 2, 3) summarized regardless of treatment arm. A time-to-event analysis of time to poor performance status by treatment arm was conducted. Poor performance status was defined by deterioration of ECOG score from 0 to 2, 1 to 3 or 2 to 3. Results: 119 and 55 ECOG scores were available during the PRE and POST time periods, respectively, from 137/157 and 21/157 of the intention-to-treat population. Patients had significantly better performance status during the PRE versus POST (0.69 versus 0.91) period. ECOG scores of 0, 1, 2 and 3 comprised 40%, 51%, 8% and 0% of PRE observations. After progression, the proportion of ECOG 0 scores dropped to 25% while ECOG 2 and 3 scores almost doubled from 8% to 15%. Additionally, cabozantinib reduced the risk of deterioration to poor performance status by 66% compared with sunitinib (HR = 0.44; 95%CI [0.16-1.26]). Conclusions: The pre-progression period was associated with better HRQoL, as measured by ECOG score, and cabozantinib delayed its deterioration. Support: U10CA180821, CER-1503-29220; Clinical trial information: NCT01835158.
Clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with a post-treatment circulating tumor cell (CTC) of 0 vs CTC &gt; 0: Post hoc analysis of COU-AA-301.
Authors: Howard I. Scher, Glenn Heller, Margaret K. Yu, Thian Kheoh, Weimin Peng, Johann S. De Bono
Journal: Journal of Clinical Oncology (2017)

5015 Background: Assessment of radiographic response by RECIST in the majority of mCRPC pts is limited by the lack of measurable disease. Changes in CTC counts (CTCs) enumerated using Veridex CellSearch from unfavorable at baseline (BL [≥ 5 cells/7.5 mL]) to favorable (≤ 4) are prognostic for survival, and the test is FDA cleared as an aid in the monitoring of metastatic PC. The CTC cutpoint of ≥ 5 excludes many pts from response assessment. Examining CTCs alone and in combination with other biomarkers as a potential surrogate for clinical benefit was a secondary objective of COU-AA-301, a phase 3 trial of abiraterone acetate + prednisone vs prednisone alone in mCRPC. Methods: Pts from both treatment (tmt) groups with BL CTC &gt; 0 were combined to assess CTC = 0 as a response criterion. Association between CTC response, defined as BL CTC &gt; 0 and post-BL CTC = 0, and clinical outcomes was assessed. CTCs were determined at BL and 4, 8, and 12 wks. Pts with BL CTC &gt; 0 and missing post-tmt CTCs were considered nonresponders. Radiographic response was first assessed at Wk 12. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: Among739 pts with BL CTC &gt; 0, 141 had measurable disease. At Wk 12, 19% (141/739) of pts were CTC responders and 81% (598/739) were CTC nonresponders. Among CTC responders, 74% (104/141) had stable disease or better by RECIST; 26% (37/141) were either not evaluable or had disease progression by RECIST. Median OS was 23.8 and 10.0 mos for CTC responders (n = 141) and nonresponders (n = 598), respectively. Among pts with liver and/or lung metastases, 86% (24/28) of CTC responders at Wk 12 had stable disease or better by RECIST; 14% (4/28) had disease progression by RECIST. Median OS was 19.9 and 7.1 mos for CTC responders (n = 28) and nonresponders (n = 127), respectively. Similar results were observed in Wk 8 CTC responders. Conclusions: For mCRPC pts with BL CTC &gt; 0, CTC response on tmt (CTC = 0) is associated with longer survival and could be considered a response criterion. Additional analysis is required to fully characterize the relationship between CTC = 0 and objective response by RECIST in pts with measurable disease. Clinical trial information: NCT00638690.
Interference between mutational load, immune signatures and outcome in patients with head and neck cancer treated with definitive chemoradiation: A multicenter study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Authors: Inge Tinhofer, Theresa Eder, Anne-Katrin Hess, Vanessa Fleischer, Panagiotis Balermpas, Claus Rödel, Annett Linge, Mechthild Krause, Michael Baumann, Martin Stuschke, Daniel Zips, Henning Sebastian Schafer, Anca Grosu, Amir Abdollahi, Juergen Debus, Claus Belka, Steffi Pigorsch, Gabriele Multhoff, Stephanie Combs, Volker Budach
Journal: Journal of Clinical Oncology (2018)

6047 Background: Mutational load and immune expression signatures have previously been established as efficacy biomarkers in immune checkpoint inhibitor (ICI) trials. It is important to know the value of these biomarkers for predicting outcome after concurrent chemoradiation (cCRTX), for defining patient subgroups likely to benefit from ICI/cCRTX combinations. Methods: FFPE tumor samples from 101 patients with locally advanced SCCHN from a retrospective DKTK-ROG biomarker trial were available for this study. All patients had been treated with standard definitive cCRTX. Mutation profiling was performed using a large gene panel targeting the complete coding sequence of 327 genes. Mutational load was calculated based on the number of somatic non-synonymous mutations per megabase (Mb). Immune mRNA profiles were determined using the nanoString PanCancer Immune panel. Mutational load was correlated with immune profile and outcome. Results: The mean number of somatic mutations per Mb was 4.9 (range 0-36), in line with previous reports from TCGA/ICGC studies. No association was found between mutational load and HPV status. Univariate Cox regression analysis revealed a significant correlation of high mutational load with reduced OS (HR for death: 1.9; 95%-CI: 1.1-3.3, P= 0.028). Conversely, detection of immune profiles linked to T-cell functions was associated with improved OS (HR: 0.3; 95%-CI: 0.1-0.9, P= 0.033). There was a significant interaction between mutational load and immune profiles in their effects on outcome (Pinteraction= 0.03). High mutational load was associated with low T-cell infiltration, IFN-gamma signature scores and expression of genes involved in T-cell functions including PD-L1 and LAG3, indicative of immune dysfunctions in neoantigen-rich tumors. Conclusions: We established mutational load and T-cell immune signatures as interdependent predictors of the efficacy of cCRTX, thereby providing first evidence that both parameters might serve for selection of patients with benefit from combined cCRTX/ICI regimens.
Abstract 9744: Effect of High-intensity Statin Therapy on Strut Coverage After Drug-eluting Stent Implantation, Serial Follow-up Optical Coherence Tomographic Analysis
Authors: Jeong Hun Kim, Jung-Sun Kim, Dong-Ho Shin, Byeong-Keuk Kim, Young-Guk Ko, Donghoon Choi, Yangsoo Jang, Myeong-Ki Hong
Journal: Circulation (2015)

Introduction: Using optical coherence tomography (OCT), the impact of high-intensity statin therapy on stent strut coverage was evaluated in drug-eluting stent (DES)-treated patients. Hypothesis: The influence of high-intensity statin therapy on the serial stent healing process was not fully investigated Methods: Sixty patients were randomly assigned to two groups according to the statin dose (atorvastatin 40 mg as high-intensity statin therapy [n=29] vs. pravastatin 20 mg as low- intensity statin therapy [n=31]). Serial OCT evaluation at post-procedure, and at the 3- and 12-month follow-up was performed in 50 patients with 54 stents (23 atorvastatin-treated patients vs. 27 pravastatin-treated patients). The percentage of uncovered struts was defined as the ratio of uncovered struts to total struts. The primary endpoint was the percentage of uncovered struts at the 12-month follow-up. The secondary endpoint was the percentage of uncovered struts at the 3-month follow-up, and the comparative percentage change (Δ) of uncovered struts at the 3- and 12-month follow-up between the different intensity statin therapies. Results: The percentage of uncovered struts was 7.4% (range: 4.3-10.4%) in atorvastatin- treated patients vs. 10.6% (range: 5.7-22.6%) in pravastatin-treated patients at the 3-month follow-up (p=0.13), and 1.3% (0.3–3.8%) vs. 2.5% (0.9–9.7%), respectively, at the 12-month follow-up (p=0.01). The percentage Δ of uncovered struts from 3 to 12 months follow-up was -7.9±8.5% in atorvastatin-treated patients vs. -9.3±12.5% in pravastatin-treated patients (p=0.67). Conclusions: This study suggested that high-intensity statin therapy might provide beneficial effect for the vascular healing process after DES implantation.
Impact of pharmacogenomics on imatinib toxicity in gastrointestinal stromal tumors.
Authors: Wei Zhuang, Haibo Qiu, Xueding Wang, Shuang Xin, Min Huang, Zhiwei Zhou
Journal: Journal of Clinical Oncology (2017)

11043 Background: Imatinib-induced side effects are common, although most of these side effects are mild, some will be severe and lead to disruption of Imatinib treatment in gastrointestinal stromal tumor (GIST). It is necessary to explore a biological predictors to predict and optimal therapeutic strategy. But there were few studied conducted to explore the mechanisms of Imatinib-induced side effects. The present study comprehensively investigated the effects of genetic polymorphisms of cytokines involved in cell proliferation and metabolic enzymes and transporters involved in Imatinib metabolism on these side effects. Methods: A total of 154 GSIT patients treated with Imatinib were enrolled. 22 SNPs (single nucleotide polymorphisms) in KIT/ PDGFRA/ PDGFRB/ SHC1/ FLT1/ MAPK1/ EGFR/ CCL5/ CXCL14were detected using Agena Massarray matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) platform. Logistic regression analyses were performed to evaluate their effects on Imatinib-induced toxicities. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: Imatinibdose, FLT1 rs9951465, MAPK1 rs13515, PDGFRB rs55712339 and SHC1 rs3766920 were found to be correlated with the incidence of myelosuppression ( P= 0.027, 0.009, 0.002, 0.008, &lt; 0.001, respectively), moreover, FLT1 rs9554314 was correlated with severe myelosuppression (Grade 0,1 vs. 2+, P= 0.009, OR (95%CI) = 3.042 (1.314-7,042)). Meanwhile, EGFR rs10228436 was found to be correlated with the incidence of skin rash ( P= 0.027), moreover, CCL5 rs4796120 and CXCL14 rs7716492 were correlated with severe skin rash (Grade 0,1 vs. 2+), with OR (95%CI) and p value were 8.542 (0.934-78.107), 13.504 (2.308-79.004) and 0.057, 0.020, respectively. Conclusions: This is the first comprehensive report on the biomarkers for Imatinib toxicities. These biomarkers might be able to distinguish patients with mild or more severe forms of Imatinib toxicities, thus enabling the optimization of Imatinib therapy and lead patients benefit from Imatinib treatment in a long-term.
A&amp;E attendances in England are growing twice as fast as population
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

Doctors have warned that the NHS needs to expand capacity to prevent services collapsing, as new figures show that demand on emergency services in England has reached a record level.

Last year saw nearly 24 million attendances in hospital accident and emergency departments across the country, an increase of 22% since 2008-09 and of 2% from 2016 to 17, while the population rose by 1% from last year, show data from NHS Digital.1

Rob Harwood, chair of the BMA’s Consultants Committee, described as “unacceptable” the 1.4% of patients in A&E who waited more than 12 hours before being admitted or discharged. Any …
The rate of tumor growth during treatment accurately predicts the FDA gold standard of overall survival [OS] in a broad range of malignancies.
Authors: Julia Wilkerson, Krastan B. Blagoev, Wilfred Donald Stein, Elizabeth Hecht, John A. Chabot, Edward Espinal Dominguez, Montserrat Blanco-Codesido, Martin J. Murphy, Antonio Tito Fojo, Susan Elaine Bates
Journal: Journal of Clinical Oncology (2018)

2545 Background: Novel clinical trial endpoints that predict overall survival (OS) are needed to streamline anticancer drug development. Methods: We used a novel mathematical approach to estimate simultaneously occurring exponential rates of tumor growth [g] and regression [d] using data stored for > 10,000 patients [pts] enrolled in clinical trials. Data were provided by investigators, pharmaceutical companies, or were downloaded from Project Data Sphere [PDS], a publicly available data sharing warehouse; and included imaging measurements and serum tumor markers [eg. PSA, CA19-9 and M-spikes]. Pts with multiple myeloma, prostate, pancreas, colorectal, breast, renal, and neuroendocrine (NET) cancers undergoing cytotoxic, targeted, or immune therapies were included in this analysis. Results: In 85-90% of pts enrolled in a clinical trial, g and d could be estimated with p-values for fits < 0.1 in all and < 0.001 in the majority. Greater than 95% of the data fit the exponential equations, with 14 other equations describing models of tumor growth from the literature unable to fit > 5% of the data. Regression (d) rates are 3-4x faster than growth (g) but do not correlate with OS. g can estimate doubling time (dt), and is highly predictive of progression free survival (PFS) and OS even when analyzing combined data from disparate studies. Straightforward modeling shows g can distinguish whether an experimental therapy is associated with OS gain in as few as 30 pts. Estimated median g values ranged from 0.0057d-1 (dt 0.3y) for pancreatic adenocarcinoma to 0.00046d-1 (dt 4.1yr) for NETs on therapy. Conclusions: Estimates of g accurately predict OS in a broad range of cancers and g should be considered a valuable surrogate in assessing trial outcomes. g can be compared easily across settings and allows large clinical trials to serve as benchmarks for estimating efficacy of experimental therapy. Development of this valuable assessment tool has been made possible by the sharing of clinical trial data by pharmaceutical companies directly or through PDS. Housing both the data and soon the benchmark analyses in PDS will offer investigators new strategies for clinical trial assessment.
Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy.
Authors: Mohammed M. Milhem, Georgina V. Long, Christopher J. Hoimes, Asim Amin, Christopher D. Lao, Robert Martin Conry, Jason Hunt, Gregory A. Daniels, Mohammed Almubarak, Montaser F. Shaheen, Theresa Michelle Medina, Minal A. Barve, Sarwan K. Bishnoi, Ehtesham A. Abdi, Michael Jon Chisamore, Biao Xing, Albert Candia, Erick Gamelin, Robert Janssen, Antoni Ribas
Journal: Journal of Clinical Oncology (2019)

9534 Background: SD-101 is a synthetic CpG TLR9 agonist. Pembrolizumab is a PD-1 inhibitor. SYNERGY-001/KEYNOTE-184 assesses the safety and preliminary efficacy of the combination of SD-101 and pembrolizumab in patients naïve to anti-PD-1/L1 therapy with unresectable stage IIIC-IV melanoma. Methods: SD-101 was evaluated as 2 mg/lesion injected into 1 to 4 lesions and 8 mg/lesion in 1 lesion as 4 weekly doses followed by 7 doses Q3W. Pembrolizumab was administered as 200 mg IV Q3W. CT scans were performed every 9 weeks. Responses were assessed per investigator using RECIST v1.1. Responses and post-hoc Kaplan-Meier analyses of PFS in the ITT population were compared for patients who received 2 mg/lesion with 8 mg/lesion. Results: 86 patients (2 mg: N = 45; 8 mg: N = 41) have been enrolled with similar baseline characteristics: median age = 66 years; male = 67%; ECOG stage 0 = 67%; disease stage: IIIC = 21%; IVM1a/b = 50%; IVM1c = 28%; LDH ≤ ULN = 71%; treatment naïve = 73%. Median follow up to date is 8.1 months in 2 mg group and 8.3 months in 8 mg group. SD-101 safety profile comprises flu-like symptoms with most frequent grade ≥3 SD-101-related AEs of headache (7%), fatigue (7%), malaise (5%), myalgia (4%), and chills (4%). Immune-related AEs were reported in 19%. ORR in 2 mg group = 71% (95% CI: 57, 82) (CR: 13%) and in 8 mg group = 49% (95% CI: 33, 65) (CR: 7%) with responses in both injected and non-injected lesions, including visceral. DOR = not reached (NR) in either group. ORR by baseline PD-L1 expression in 62 patients, 53% of whom were PD-L1 positive: 2 mg = 80%/79% (PD-L1 positive/negative); 8 mg = 62%/40% (PD-L1 positive/negative). PFS was higher in 2 mg group with median PFS in 2 mg = NR (95% CI: Not estimable [NE], NE) and in 8 mg = 10.4 months (95% CI: 4.2, NE), HR = 0.45 (95% CI: 0.21, 0.98), p = 0.036. 6 month PFS rate in 2 mg = 81% and in 8 mg = 60%. 6 month OS rate in 2 mg = 98% and in 8 mg = 92%. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab has been well-tolerated, and is showing promising high response rates and PFS, regardless of PD-L1 expression, particularly in patients who received 2 mg SD-101. Clinical trial information: NCT02521870.
Hematopoietic stem cell transplantation (HSCT) compared to consolidation chemotherapy (CT) to increase leukemia free survival (LFS) in acute myelogenous leukemia (AML) patients between 60 and 75 years irrespective of genetic risk: Report from the AML 2004 of the East German Study Group (OSHO).
Authors: Dietger Niederwieser, Haifa Kathrin Al-Ali, Rainer Krahl, Christoph Kahl, Hans-Heinrich Wolf, Ute Kreibich, Vladan Vucinic, Ute Hegenbart, Carsten Hirt, Norma Peter, Bernhard Opitz, Axel Florschütz, Antje Schulze, Sebastian Scholl, Christian Jakob, Christian Junghanss, Herbert Sayer, Andreas Hochhaus, Thomas Fischer, Georg Maschmeyer
Journal: Journal of Clinical Oncology (2016)

e18501 Background: HSCT has been reported to be a treatment option for elderly patients with AML. Here we analyze the outcome of CT compared to HSCT in elderly AML patients according to genetic risk groups defined by the European Leukemia Net. Methods: By May 2015, 492 of 789 eligible patients (62%) from the AML 2004 study group entered CR and were assigned to CT (n = 205), matched (n = 119) or one antigen/allele mismatched HSCT (n = 31) depending on donor availability. Median age was higher (68 vs 66 years; p < 0.0005) and intermediate risk (IR) II and high risk (HR) cytogenetics were less frequent (p = 0.002) in CT than in HSCT. The interval CR - CT was significantly shorter than CR - HSCT (43 vs 65 days; p < 0.0005]. AML type, NPM1 and FLT3 status were comparable. Results: Patients receiving matched HSCT had longer LFS than those receiving CT (25±5% vs. 14±3% at 9 years; p < 0.001). As expected, RI was lower (42±5% vs 78±3%; p < 0.0001) and NRM was higher (34±5% vs 8±2%; p < 0.0001) at 9 years in HSCT than in CT patients. LFS differed between HSCT and CT for IR I (28±8% vs. 16±4% at 9 years; p = .007), IR II (30±10% vs. 4±4% at 7 years; p = .08) and HR patients (12±7% vs. 0±0% at 7 years; p < .05). RI was decreased in HSCT vs. CT for IR I (35±7% vs. 74±4% at 9 years; p < .0001), IR II (38±10% vs. 96±5% at 7 years; p < .0001) and HR (59±11% vs. 96±7% at 9 years; p < .004). These effects outweigh the higher NRM in HSCT for IR I (37±9% vs. 10±3% at 9 years; p = .0005), IR II (33±10% vs. 0% at 7 years; p = .003) and HR (29±10% vs. 4±4% at 9 years; p = .11). HSCT was an independent prognostic factor for NRM (p < 0.005), LFS and RI (both p < 0.0005). Genetic risk group (p < 0.01) was the only factor associated with OS. Conclusions: HCT improves LFS in AML CR1 patients between 60 and 75 years of age in genetic risk groups from IR I to HR. Clinical trial information: NCT01497002.