tbuckley/cabot-search huggingface dataset:
TCT-415 Transcatheter Aortic Valve Implantation using Symetis ACURATE in bicuspid aortic valve stenosis: insights from a multicenter experience
Authors: Antonio Mangieri, Alaide Chieffo, Won-Keun Kim, Giulio Stefanini, Marco Barbanti, Corrado Tamburino, Andreas Rück, Stefan Toggweiler, Matteo Montorfano, Antonio Colombo
Journal: Journal of the American College of Cardiology (2018)
68Ga-DOTATATE PET/CT to predict response to peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NETs).
Authors: Rohini Sharma, Wai Meng Wang, Joanne Evans, Siraj Yusuf, Adil Al-Nahhas, Francesco Mauri, Tara Barwick, Eric Aboagye
Journal: Journal of Clinical Oncology (2017)

4093 Background: PRRT represents a step change in NET management, significantly improving survival. However, objective response to PRRT, approximately 20%, is poor. There are no predictive biomarkers of response. Uptake on 68 Ga-DOTATATE PET/CT imaging is used to assess patient suitability for PRRT, highlighting the presence of somatostatin receptors (SSTR) to which PRRT selectively binds. We hypothesise that the density of SSTRs, as defined by a minimum SUV uptake, predicts for response to PRRT. Methods: 54 patients underwent PRRT. Modified PERCIST assessment was performed: up to 2 target lesions per organ were identified and volume of interest drawn. Maximum 5 targets were counted. Average SUV (SUVave) was calculated by dividing sum of SUVmax of target lesions by number of lesions. Response was determined by RECIST 1.1. Ki67 and SSTR2 expression were assessed on tumour samples and compared with SUVave. Results: Response to PRRT: partial response (PR) 26%, stable disease (SD) 40% progressive disease (PD) 12%. Response to PRRT predicted progression free survival (PFS) with patients experiencing PR having a PFS 2.5x that of those with SD, and almost 20x as long as PD. Using ROC curve analysis, SUVave of 21.6 predicted for tumour response with high sensitivity (0.74) and specificity (1.0), p = 0.15, 95% CI 0.71-3.96. No association between baseline SUVave and SSTR2 or Ki-67 was observed. SUVave &gt; 21.6 was an independent predictor of clinical outcome. Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.
First-in-human phase I study of JPH203, L-type amino acids transporter 1 inhibitor, in patients with advanced solid tumors.
Authors: Naohiro Okano, Kirio Kawai, Takaaki Kobayashi, Fumio Nagashima, Hitoshi Endou, Junji Furuse
Journal: Journal of Clinical Oncology (2018)

2519 Background: The uptake of amino acids is essential for cancer growth. The L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers, and the LAT1-mediated uptake of plasma-free amino acids (PFAA) plays a critical role in cancer growth. JPH203 is a novel, selective LAT1 inhibitor. Methods: A first-in-human phase I study of JPH203 was designed to determine the safety, maximum-tolerated dose (MTD), and recommended phase II dose (RP2D) of JPH203. This study evaluated the anti-tumor effects, progression-free survival, pharmacokinetics (PK), and pharmacodynamics (PD) of JPH203 and analyzed PFAA levels. JPH203 was administered intravenously for seven days, at planned doses ranging from 12–110 mg/m2, followed by a 21-day rest, in patients with advanced solid tumors that were refractory to standard therapies. Before treatment, we confirmed the safety of a single dose of JPH203. Dose-limiting toxicity was evaluated during the first cycle, using a 3+3 design. Results: Seventeen patients were enrolled. One patient discontinued JPH203 after a single dose because of tumor progression. Grade 3 liver dysfunction occurred in one of six patients who received 60 mg/m2 and the first patient received 85 mg/m2. Although we determined that the MTD was 60 mg/m2, the PK/PD profile and anti-tumor effects supported an RP2D of 25 mg/m2. Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension, and grade 1 or grade 2 fevers. A partial response was achieved in a patient with biliary tract cancer (BTC) who continued JPH203 for two years without disease progression. Disease control was observed in three of five patients with BTC, and in two of six with colorectal cancer. LAT1 substrates, PFAA and branched-chain amino acids (BCAA), were higher in patients with BTC than in those with other cancers. All patients with disease control had a body mass index (BMI) greater than the median BMI of 20.5 kg/m2. Furthermore, BCAA levels were associated with BMI. Conclusions: At the RP2D of 25 mg/m2, JPH203 was well tolerated and showed promising results against BTC. This phase I study also suggests that BMI and BCAA might predict the efficacy of targeted cancer chemotherapy. Clinical trial information: UMIN000016546.
Glioblastoma in the era of bevacizumab: An epidemiological study in the Canton of Zurich, Switzerland, 2010-2014.
Authors: Dorothee Gramatzki, Patrick Roth, Elisabeth Jane Rushing, Jonathan Weller, Nicolaus Andratschke, Silvia Hofer, Dimitri Korol, Luca Regli, Athina Pangalu, Miklos Pless, Joachim Oberle, René Bernays, Holger Moch, Sabine Rohrmann, Michael Weller
Journal: Journal of Clinical Oncology (2018)

e14062 Background: The vascular endothelial growth factor antibody, bevacizumab (Avastin), received approval for the treatment of recurrent glioblastoma in Switzerland in 2009. Here we explored the hypothesis that the approval of bevacizumab improved outcome with glioblastoma on a population Level. Methods: The prognostic significance of epidemiological, molecular genetic, and clinical data including treatment for glioblastoma patients diagnosed from 2010 - 2014 in the Canton of Zurich, Switzerland, was retrospectively analyzed using log rank test and Cox proportional hazards models. Data were compared to results for the 2005 - 2009 cohort. Results: 310 glioblastoma patients were identified in the years 2010 - 2014. Median overall survival (OS) was 13.5 months for patients with known isocitrate dehydrogenase (IDH) wildtype (wt) (IDH1R132H-non-mutant) tumors (N = 248), compared with 11.3 months for IDH wt patients (P = 0.761) before (2005 - 2009). In the IDH wt cohort, bevacizumab use increased from 19% to 49%, from 2005 - 2009 to 2010 - 2014. Patients who received bevacizumab at first recurrence were more likely to have a lower Karnofsky performance status (KPS) and tumors without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation than patients who received a bevacizumab-free salvage treatment. Multivariate analysis demonstrated young age, high KPS, greater extent of resection, methylated MGMT promoter, or first-line chemoradiotherapy, but not bevacizumab exposure to be independently associated with survival. Conclusions: OS did not improve at the population level between the 2005 - 2009 and the 2010 - 2014 cohorts in the Canton of Zurich, Switzerland. The strong increase of bevacizumab use did not translate into a statistically significant impact on survival.
Pandemrix vaccine: why was the public not told of early warning signs?
Authors: Peter Doshi
Journal: BMJ (2018)

Eight years after the pandemic influenza outbreak, a lawsuit alleging that GlaxoSmithKline's Pandemrix vaccine caused narcolepsy has unearthed internal reports suggesting problems with the vaccine's safety. <b>Peter Doshi</b> asks what this means for the future of transparency during public health emergencies
Clinical utility of androgen-receptor splice variant 7 (AR-V7) determinations in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Danilo Piana, Jun Luo, Mark Christopher Markowski, Eugene Shenderov, Emmanuel S. Antonarakis, Mario A. Eisenberger
Journal: Journal of Clinical Oncology (2018)

e17067 Background: Detection/dynamics of AR-V7 in circulating tumor cells (CTCs) is a determinant of resistance to novel AR-targeted treatment (NART) in mCRPC (Antonarakis et al. NEJM 2014 & Markowski et al. JCO Precis Oncol 2017). Methods: Eligible mCRPC had ≤12 months progression to initial androgen deprivation treatment (ADT) and/or ≥1 NART [enzalutamide, abiraterone, TAK-700, galeterone, apalutamide, bipolar androgen treatment (BAT)]. CTC assay used a modified AdnaTest with RT-PCR to detect mRNA for full-length AR (AR-FL) and AR-V7, reported as a ratio of AR-V7 to AR-FL (Antonarakis et al NEJM 2014). Treatment selection was prospective, based on AR-V7 results. Pts with AR-V7- or CTC- received NART; AR-V7-received docetaxel, cabazitaxel, radium223, sipuleucel-T, or a clinical trial. Clinical benefit is measured by ≥50% PSA decline in ≥ 1 month.The data presented is retrospectively assessed and statistics are descriptive. Results: 87 eligible pts had 137 AR-V7 determinations [74/137 (54%) CTC+; 33/74 (44.5%) AR-V7+; 41/74 (55.5%) AR-V7-; and 63/137(46%) CTC-]. Upon inadequate response to NART (progression < 6 months), assays were repeated. 87 pts were tested x1, 33x2, 12x3, 5x4. 54/87 (62%) pts were AR-V7- or CTC- and 51/54 received NART: 29/51 had ≥ 50% PSA decline for ≥ 1 month (57%), including 7/9 (78%) NART-naïve, 14/20 (70%) 1 NART, and 8/22 (36%) ≥ 2 NART (Table). Of the 33 AR-V7+ pts, 21 (51%), 27 (82%), 29 (88%), and 33 (100%) were positive upon 1, 2, 3, and 4 determinations respectively, and were offered non-ART treatments or clinical trials. Conclusions: In the clinical setting, serial interrogations of AR-V7 status are feasible, facilitate therapy selection, and potentially enhance NART therapeutic benefit in AR-V7- pts. Repeated testing reliably determines decisions on continuation of NART therapy. Biomarker-driven designs are required to further evaluate the predictive value of AR-V7 in mCRPC. Total No. of Pts No. AR-V7 Tests 1 No. AR-V7 +2 Pts No. AR-V7-/CTC-2 Pts No. AR-Targeted Treatment PSA Decline/Treated ( > 1month) NART naïve 20 27 7 13 9 7/9 (78%) 1 NART 37 57 16 21 20 14/20 (70%) ≥2 NART 30 53 10 20 22 8/22 (36%) TOTAL # 87 137 33 54 51 29/51 (57%)
DLBCL outcomes in Malawi: Effect of HIV and derivation of a simplified prognostic score.
Authors: Matthew Painschab, Edwards Kasonkanji, Takondwa Zuze, Bongani Kaimila, Tamiwe Tomoka, Bal Dhungel, Maurice Mulenga, Maria Chikasema, Blessings Tewete, Asekanadziwa Mtangwanika, Sarah Chiyoyola, Wilberforce Mhango, Fred Chimzimu, Coxcilly Kampani, Robert Krysiak, Thomas C. Shea, Nathan Montgomery, Yuri Fedoriw, Satish Gopal
Journal: Journal of Clinical Oncology (2018)

7565 Background: Prognostic factors for diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa (SSA) are unknown. We report mature data from one of the first prospective DLBCL cohorts treated under real-world conditions in SSA. Methods: Patients ≥18 years with newly diagnosed DLBCL were enrolled in Malawi from 2013 to 2017. Participants were treated with CHOP chemotherapy, and concurrent antiretroviral therapy (ART) if HIV+. Results: 86 participants were enrolled with mean age 47 (SD 13). 54 (63%) were male, and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 113 cells/mL (IQR 62-227) and 25 (49%) had an HIV viral load < 400 copies/mL. HIV+ participants were younger and more urban, but otherwise similar to HIV-. 10 (12%) participants died before chemotherapy. Participants received a median 6 CHOP cycles (IQR 4-6). 28% of cycles were delayed or reduced for toxicity, more commonly in the HIV+ group, typically for neutropenia. No patients were lost to follow-up with median follow up 24 months (IQR 16-40) for patients still alive at administrative censoring. 2-yr overall survival (OS) was 38% (95% CI 28-49), and 42% (95% CI 30-53) for patients surviving to CHOP initiation. For those receiving CHOP, 13/43 (30%) deaths were treatment-related, and occurred primarily in patients with adverse baseline DLBCL characteristics. In multivariate analyses, only ECOG performance status (PS) ≥2 and lactate dehydrogenase (LDH) > 2x upper limit of normal (ULN) were associated with mortality. HIV was not associated with OS, but for HIV+ patients, being on ART prior to lymphoma diagnosis was associated with mortality. A simplified prognostic model of LDH > 2x ULN and PS≥2 outperformed the traditional age-adjusted IPI. Conclusions: DLBCL can be successfully treated in SSA and outcomes were not different for HIV+ and HIV- patients, although OS was worse than resource-rich settings. For HIV+ participants, those developing DLBCL on ART had worse OS, suggesting possible effects of the immunologic environment on tumor biology. A simplified prognostic model utilizing only PS and LDH may be optimal in resource-limited settings, where staging is imprecise, but requires additional validation.
Myeloid-derived suppressor cell (MDSC) kinetics following acalabrutinib and pembrolizumab treatment in platinum-resistant metastatic urothelial carcinoma (mUC).
Authors: Kristen A Batich, Janet S. Staats, Cliburn Chan, Cecile Krejsa, Daniel J. George, Kent J. Weinhold, Tian Zhang
Journal: Journal of Clinical Oncology (2018)

e16519 Background: Immunotherapy checkpoint inhibitors (CPIs) have improved outcomes for mUC, but response rates are low (15-21%) in platinum-resistant cases. Better biomarkers of CPI treatment response and resistance are needed. Monocytic (m)MDSC have been described as negative biomarkers in tumors, abrogating the effect of CPIs. Outcomes may be improved when CPIs are used in combination with agents that alter the tumor microenvironment, such as Bruton tyrosine kinase inhibitors (BTKi). We recently completed a trial (NCT02351739) combining pembrolizumab with a selective BTKi, acalabrutinib, in patients (pts) with platinum-resistant mUC. Methods: A phase 2 randomized study enrolled 78 pts with mUC with either pembrolizumab (200mg IV every 3 weeks, P) monotherapy or combined with acalabrutinib (100mg twice daily, PA). Clinical responses, evaluated as complete (CR), partial (PR), stable disease (SD), and progressive disease (PD), did not differ between treatments. Immunophenotyping of peripheral blood mononuclear cells (PBMCs) was performed at baseline, 4, 7, and 10 weeks (wk). mMDSC were identified in a 14-color flow cytometry panel that excluded NK cell (CD16, CD56), B cell (CD19, CD20), and T cell lineages (CD3, CD25, CD127); mMDSC were defined as CD14+HLA-DRLo/- and expressed as counts (cells/µL) in peripheral blood (PB). Results: mMDSC were monitored in 61 pts. The median count at baseline was 45/µL; the 75% percentile was 93/µL. Elevated baseline counts ( > 200/µL) were noted in 9 pts, with sharp decreases by wk 4 or 7 in some; however, most pts with high baseline mMDSC remained above 75% percentile. Elevated mMDSC were noted in 4/19 pts with CR or PR (2 P and 2 PA), in 2/18 pts with SD (2 PA), and in 3/28 pts with PD as best response (1 P and 2 PA). Conclusions: In this study, correlative immune monitoring of PBMCs of mUC pts showed variable mMDSC and identified a subset of pts with high baseline counts. Associations between mMDSC counts and clinical endpoints were not observed. In many of these pts, decreased mMDSC were observed with treatment, suggesting that biological effects of P and PA may be detected in the peripheral blood and monitored over time.
Peritoneal carcinomatosis (PC) in well differentiated small intestinal neuroendocrine tumors (SI-NET).
Authors: Satya Das, Chanjuan Shi, Tatsuki Koyama, Yi Huang, Jordan Berlin
Journal: Journal of Clinical Oncology (2018)

e16164 Background: Although patients with well differentiated SI-NET generally have good prognoses, those who develop PC fare worse [1]. PC is thought to be a rare occurrence in lower grade patients however few published series have assessed its frequency and associated factors [2]. Methods: We performed a retrospective analysis of 208 consecutive SI-NET patients at Vanderbilt University Medical Center diagnosed between 1994-2015. Pathology slides were reviewed by our neuroendocrine pathologists who used Ki-67% and mitoses to classify tumors as G1, G2 or G3 by 2017 WHO NET criteria. We tested whether WHO grade, mesenteric mass size ( > or < 2 cm), R1/R2 resection and other variables were associated with PC using the Pearson chi-squared test and Wilcoxon rank-sum test. Kaplan-Meier estimates were used to assess the impact of these factors on progression free survival (PFS) and overall survival (OS). Results: 147, 50 and 7 patients had G1, G2 and G3 SI-NET, respectively. 29% of G1 patients and 31% of all patients developed PC. Features of patients who developed PC are described in Table 1. Among all analyzed patients, those with G1 tumors, R0 resections and T1/T2 primaries had significantly longer OS than patients with G2/G3 tumors, R1/2 resections and T3/T4 primaries, respectively. Conclusions: PC was a more common finding in G1 SI-NET patients at our institution than expected. Among all SI-NET patients, those who developed PC had bulkier mesenteric masses, more advanced T stage, larger sized (or numbers of) involved nodes, greater likelihood of metastases at other sites and less complete resections compared to patients who did not. Factors that impacted OS in SI-NET patients seemed to be associated with intrinsic tumor aggressiveness (WHO grade, T-stage) and surgical completeness. Table 1: PC & Patient Features Patient Variables (N = number of samples available) PC(%) No PC(%) P-Value Gender (208) 0.15 Male 55 51 Female 45 49 WHO Grade (204) 0.29 G1 69 73 G2 24 25 G3 6 2 Nodal Stage (201) 0.017 N0 2 14 N1 32 33 N2 66 53 Resection Status (206) < .001 R0 31 63 R1 2 2 R2 67 35 T-Stage (192) 0.002 T1 0 6 T2 9 22 T3 47 51 T4 44 21 Other Metastases at Diagnosis (207) < .001 Yes 67 38 No 33 63 Ki-67% (113) 0.98 Group 1 ( < 2%) 62 64 Group 2 (3-20%) 36 34 Group 3 ( > 20%) 2 2
Lung clinical trials and access to molecular markers in a small, low-income city in Brazil.
Authors: Sabina B. Aleixo, Jose Zago Pulido, Jose A. G. Aleixo, Narelle Jesus Parmanhani
Journal: Journal of Clinical Oncology (2018)

e18680 Background: Lung cancer still remains one of the deadliest cancer types in the world. Both the incidence and mortality are still high, equally among male and female patients, in practically all parts of the world. Participation and access to cancer treatment clinical trials (CCTs) is a key measure for delivery of quality cancer care in the world. In low-income cities in Brazil out of the state capitals where the majority of the population is treated by the public health insurance the situation is worst because there is no acess to new molecular tests and treatments. One strategy to overcome it is to have patients enrolled in international, industry-sponsored clinical trials. Methods: We retrospectively reviewed our database between 04/11/2010 and 12/12/2017 to know the number of lung cancer clinical trials that we participated and reviewed the charts of 85 patients that were enrolled in clinical observational and interventional studies. Results: We participated in 8 lung cancer clinical trials: 1 study did not open for accrual, 1 was an observational study and 6 were interventional studies. A total of 85 patients participated: 72 patients were screened with lung cancer, 39 patients had molecular testing (54%) and 13 patients were randomized (18%). There were 11 patients receiving 3 lines of treatment(15%) and median time of life varied from 1 month for up to 62 months. Conclusions: Participating in CCTS improves quality of medical assistance and gives an opportunity for more patients from the public health service accessing new molecular tests besides better and more lines of treatment. Industry-sponsored clinical trials can be a way do ameliorate outcomes in low and middle income countries and should be encouraged.
5-Year Outcomes of Self-Expanding Transcatheter Versus Surgical Aortic Valve Replacement in High-Risk Patients
Authors: Thomas G. Gleason, Michael J. Reardon, Jeffrey J. Popma, G. Michael Deeb, Steven J. Yakubov, Joon S. Lee, Neal S. Kleiman, Stan Chetcuti, James B. Hermiller, John Heiser, William Merhi, George L. Zorn, Peter Tadros, Newell Robinson, George Petrossian, G. Chad Hughes, J. Kevin Harrison, John V. Conte, Mubashir Mumtaz, Jae K. Oh, Jian Huang, David H. Adams
Journal: Journal of the American College of Cardiology (2018)
Utility of <sup>11</sup>C choline PET CT and MRI in relapsed prostate cancer (PC).
Authors: Thomas H Tarter, Benjamin Esparaz, David Lieber, Adam Zorn, Jon Locke, Mark Muscato, Thomas Rashid, Mindy Whisnant, James Lloyd Wade
Journal: Journal of Clinical Oncology (2017)

e16586 Background: Choline intracellular transport is upregulated in PC, and it is phosphorylated by choline kinase and becomes trapped within PC cells. 11 C Choline has t½ life of 20.4 minutes and emits positrons detectable by PET. Retrospective studies of 11 C choline PET CT in (PC) have been reported. In this original prospective study, we calculated the performance of 11 C choline with whole body PET CT and pelvic PET MRI in patients (pts) with biochemical PC relapse. Methods: From November 2014- June 2016, 101 pts with biochemical PC relapse underwent 11 C choline PET CT and pelvic PET MRI. Scans were read in blinded fashion. Tissue was obtained from area of 11 C Choline positivity and correlated with scan results. Results: Sixty-two pts (61%) were included in the analysis. 49 pts were excluded due to non-compliance with protocol. 11 C choline PET CT and pelvic MRI showed a sensitivity of 92.5%, specificity of 45.5%, positive predictive value of 75.5%, and negative predictive value of 76.9%. Of 37 pts with positive 11 C choline PET scans and confirmation of PC, 12 (32%) had positive 11 C choline PET scans and negative CT and MRI scans; 7 (18%) had positive C11 choline and CT scans and negative MRI scans; 12 (32%) had positive 11 C choline and MRI scans and negative CT scans, and 9 (24%) had positive 11 C choline, CT and MRI scans. Mean PSA level in this group of 37 pts was 9.86 ng/mL (range 0.4 – 107.9 ng/mL), and 7 (19%) of the pts had PSA levels &lt; 2 ng/mL. Conclusions: 11 C choline PET improves detection of relapsed PC over CT and MRI scans. 11 C choline PET pelvic MRI improves detection over 11 C choline PET CT.