tbuckley/cabot-search huggingface dataset:
An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma
Authors: Renata Sano, Kateryna Krytska, Colleen E. Larmour, Pichai Raman, Daniel Martinez, Gwenda F. Ligon, Jay S. Lillquist, Ulisse Cucchi, Paolo Orsini, Simona Rizzi, Bruce R. Pawel, Diego Alvarado, Yael P. Mossé
Journal: Science Translational Medicine (2019)

ALK is a tractable antibody-drug conjugate target in neuroblastoma.
Circulating tumor cell (CTC) enumeration in patients (pts) with metastatic genitourinary (mGU) tumors treated in a phase I study of cabozantinib and nivolumab (CaboNivo) +/- ipilimumab (CaboNivoIpi).
Authors: Andrea B. Apolo, Amir Mortazavi, Zishuo Ian Hu, Joseph Schonhoft, Lincy Chu, Amanda K. L. Anderson, Yipeng Wang, Ryan Dittamore, Sumanta K. Pal, Primo Lara, Mark N. Stein, Seth M. Steinberg, Christian Mayfield, Lisa M. Cordes, Marissa Mallek, Rene Costello, Carlos Diaz, Jane B Trepel, Donald P. Bottaro
Journal: Journal of Clinical Oncology (2019)

4555 Background: CTCs may serve as biomarkers for clinical outcomes in GU tumor pts. We examined the association between baseline CTC enumeration, CTC heterogeneity, CTC morphologic subtypes, and progression-free-survival, overall survival and response to therapy with combination CaboNivo or CaboNivoIpi. Methods: 123 samples from 52 pts with mGU tumors treated with CaboNivo (38 pts) or CaboNivoIpi (14 pts) drawn at Baseline, Cycle (C) 2 Day (D) 1, and C3D1 were processed using the Epic Sciences platform. CTCs were defined as cytokeratin (CK)+, CD45-, distinct morphology, intact nucleus. PD-L1 expression was also assessed. Results: From 07/20/2016-09/01/2018, 52 pts [urothelial carcinoma (UC) N = 33; plasmacytoid N = 1; Clear cell renal cell carcinoma N = 4; bladder adenocarcinoma N = 8; bladder squamous cell carcinoma N = 2; bladder small cell N = 2; renal medullary N = 2] were treated. Median age was 61.5 years (range 20-82); 35 (67%) were male. N = 37 (71%) had visceral involvement, N = 15 (29%) with liver involvement, N = 11 (21%) with bone involvement. CTCs were found in the peripheral blood of 26/40 (65%) pts at baseline. 1/40 pts (bladder adenocarcinoma) had PDL1+ CTCs at Baseline. Median CTC/mL at Baseline, C2D1, C3D1, were not significantly different. CTC counts of &gt; 2 and &gt; 4 at C2D1 were potentially associated with shorter OS (p = 0.071 and p = 0.045 without adjustment for multiple cutoffs for evaluation). PFS results exhibited similar trends. Unsupervised clustering of CTC images identified 5 main CTC subtypes, of which the presence of one was significantly associated with shorter OS (p = 0.0014, not adjusted for multiple testing). Additionally, we observed a trend towards patients with higher CTC heterogeneity at C2D1 having longer OS, when adjusting for the risk associated with CTC enumeration (p = 0.084). Conclusions: CTC were detected in pts with mGU tumors treated with CaboNivo and CaboNivoIpi. CTC values were somewhat but not statistically lower in responders vs. non-responders. On treatment lower CTCs and the absence of aggressive CTC subtypes were associated with better clinical outcomes. Ongoing analyses include single cell genomics, and analysis of T-cell populations. Clinical trial information: NCT02496208.
Towards precision medicine: CCL2, another brick in the wall?
Authors: Andriani Charpidou, Elias Kotteas, Mina Gaga
Journal: European Respiratory Journal (2019)

The introduction of targeted treatment in lung cancer has substantially changed the outcome of disease and the lives of lung cancer patients. Having biomarkers that can identify the right candidates and that predict the response to a specific treatment is very important and currently, research focuses on the identification of reliable molecular markers. In this issue of the European Respiratory Journal , Lu et al. [1] provide insight into the mechanisms of action of a new medication, anlotinib, and propose a new, predictive biomarker, the C-C motif ligand 2 (CCL2). Research for predictive biomarkers that are crucial to decisions for targeted treatments is very important; the data should be validated in large studies <http://ow.ly/mzis30neEA6>
Mortality from outpatients chemotherapy (CTx) in patients (pts) with solid tumors.
Authors: Anke Muetherig, Katja Sockel, Anke Rentsch, Gunnar Folprecht
Journal: Journal of Clinical Oncology (2015)

e17676 Background: Outpatient care is the common concept for most pts with solid tumors. In contrast to surgical treatment, only few data are available on the risk of outpatient chemotherapy of non-study pts. We analyzed data related to safety of cancer pts with outpatient CTx. Methods: The database was searched for all pts who received i.v. CTx for solid tumors at the outpatient CTx unit between Jan 2008 and Dec 2012. Follow-up were completed by database informations and manual search. All pts who died less than 60 days after the last dose of CTx were reviewed for the cause of death according to CTx toxicity, radiological or clinical disease progression (PD), comorbidity (CM), and others by pre-specified rules. For pts who did not fulfill the pre-specified rules, the files were reviewed by a board of three Medical oncologists. Results: From 2008 to 2012, 1623 pts received outpatient CTx for colorectal (264, 16.3%) and non-colorectal (331, 20.4%) gastrointestinal, lung (266, 16.4%), head and neck (128, 7.9%) and other (602, 37.1%) malignancies. 378 pts (23.3%) were > 70 years, 145 pts (8.9%) > 75 years old. In total, 317 pts (19.5%) died within 60 days of last dose of CTx. In 268 pts, the cause of death could be identified according to the pre-specified rules. The files of the remaining 49 pts underwent the review board. Fourteen pts (0.9%) died certainly and further 16 (1%) likely from chemotherapy-related side-effects. Ten pts (0.6%) had a sudden death at home. The death of one patient remained unclear, so in 41 pts (2.5%) chemotherapy could not be excluded as cause of death. CM was cause of death in 14 pts (0.9%) CM, radiologic documented and clinically specified PD in 115 pts (7.1%) and 147 pts (9%), respectively. The most frequent toxicities leading to death were infections w/o neutropenia (9 pts certain CTx related deaths and 12 pts with likely CTx related death) or diarrhea (four patients with certain CTx related death). In elderly pts, the rates of CTx associated death were 0.7% ( > 70 y) and 0.3% ( > 75 y) and did not differ from the general patient population. Conclusions: Outpatient CTx has a low, but not negligible mortality with infections and diarrhea as most frequent lethal toxicities.
Safety and tolerability of the olaparib tablet formulation in Japanese patients (pts) with advanced solid tumors (ASTs).
Authors: Yasuo Takahashi, Koshi Fujikawa, Tamotsu Sagawa, Kan Yonemori, Kenji Tamura, Makoto Kodaira, Taito Esaki, Tsuyoshi Shirakawa, Fumihiko Hirai, Yuki Yokoi, Toshio Kawata, Ben Hatano
Journal: Journal of Clinical Oncology (2015)

e13553 Background: A prior study using the tablet formulation of the oral PARP inhibitor olaparib (Lynparza) showed that 300 mg twice daily (bid) was tolerable in Western pts with ASTs (Mateo et al ECC 2013). This study evaluated olaparib tablets in Japanese pts with ASTs. Methods: In this Phase I multicenter study (NCT01813474), ptsreceived a single dose of olaparib before a 1-day washout, then bid dosing. A ‘rolling 6’ dose-escalation design (3–6 pts per cohort) was used, starting with a 200 mg single dose then 200 mg bid multiple dosing (cohort 1); the dose was escalated in subsequent cohorts until the maximum tolerated dose (MTD; dose where < 2 pts had a dose-limiting toxicity [DLT]) was reached. To obtain extra data, an expansion cohort was permitted for the most appropriate dose. Adverse events (AEs) were graded by CTCAE v4.0. Secondary and exploratory endpoints were PK and tumor response by RECIST v1.1, respectively. Results: Of 28 pts enrolled, 23 received olaparib (Table). The most common tumor types were: breast, n = 5 [22%]; ovarian, n = 4 [17%]. The median number of prior chemotherapy regimens was 3. No DLTs were recorded and 300 mg bid was chosen for expansion. The most common AEs were nausea (n = 10), decreased appetite (n = 7), anemia (n = 6 [grade ≥ 3, n = 1]), constipation (n = 6). Two pts each had AEs leading to olaparib interruption (platelet count decreased [cohort 2]; pneumonia [cohort 3]) and discontinuation (ileus [cohort 1]; neutrophil and WBC counts decreased [cohort 2]). Absorption of olaparib was relatively rapid with median tmax of ~2 hours. Plasma concentrations declined with a mean t1/2λz of 9–13 hours. No objective responses were seen; 25, 33 and 33% of pts in cohorts 1, 2 and 3, respectively, had stable disease (≥ 8 wks). Conclusions: Olaparib 200 and 300 mg bid tablet doses were well tolerated in Japanese pts with ASTs. The MTD was not reached but, for consistency with the global program, 300 mg bid was selected as the recommended dose for future studies. Clinical trial information: NCT01813474. Cohort 1 200 mg bid n = 4 2 300 mg bid n = 7 3 300 mg bid expansion n = 12 Median treatment duration, days (range) 72 (6-492) 30 (11-113) 56 (39-289) AEs, n (%) All grades 4 (100) 7 (100) 10 (83) Grade ≥ 3 1 (25) 3 (43) 1 (8) Serious 1 (25)* 0 0 *Ileus
Genomic analysis and clinical outcomes of Primary Gleason Pattern 5 (PG5) prostate cancer (PCa) treated with radical prostatectomy (RP).
Authors: Pedro Isaacsson Velho, Tamara L. Lotan, Mark Christopher Markowski, Emmanuel S. Antonarakis, Michael Anthony Carducci, Samuel R. Denmeade, Hao Wang, David Lim, Colin Pritchard, Mario A. Eisenberger
Journal: Journal of Clinical Oncology (2019)

54 Background: PG5 (5+5 and 5+4) PCa is historically associated with poor clinical outcomes such as progression to metastatic disease, poor response to androgen deprivation therapy (ADT) and short survival. To characterize the clinical features and biology of this aggressive type of PCa, we studied patients with PG5 who underwent a RP. Methods: Patients with surgical PG5 who underwent RP for localized PCa at Johns Hopkins Hospital were retrospectively studied. Pathological staging, tumor genomic data by Next Generation Sequencing (NGS), and PTEN and TP53 by IHC were correlated with clinical outcomes, such as biochemical relapse (BCR), metastasis-free survival (MFS), time to castration-resistance (TCR) and overall survival (OS). Fisher’s test and Kaplan-Meier were used for statistical analysis. Results: 60 pts, 90% pT3-4, 26% pN1, 46% R+, 90% seminal vesicle invasion (SVI) had a median follow up of 9 years. Overall median survival estimates: BCR: 17.4 months (m), MFS:86.4m and OS:111m. 26 patients developed metastasis (bone 77%, visceral 31%) with a median time to metastasis of 21.8m and TCR of 12m. On multivariate analysis, ductal/intraductal histology (HR 4.5, p&lt;0.01) and SVI (HR 4.4, p&lt;0.01) were associated with poor prognosis. Of 49 pts with NGS, 22% had Homologous recombination (HR) and 12% mismatch repair (MMR) alterations. In addition, 32% had TP53 mutation and 51% PTEN loss. Genomic event frequencies and outcomes are in Table. Conclusions: Patients with PG5 have adverse pathological features, short BCR, MFS and resistance to ADT, but outcomes are variable, suggesting heterogeneity. TP53 mutations and PTEN loss are associated with poor outcomes in univariate analysis, while ductal/intraductal and SVI are associated with poor outcomes in multivariate analysis. Although genomic data were not independently associated with outcomes, the high incidence of HR and MMR alterations provides the rationale for the design of adjuvant clinical trials. [Table: see text]
The Growing Development of DNA Nanostructures for Potential Healthcare‐Related Applications
Authors: Divita Mathur, Igor L. Medintz
Journal: Advanced Healthcare Materials (2019)

DNA self-assembly has proven to be a highly versatile tool for engineering complex and dynamic biocompatible nanostructures from the bottom up with a wide range of potential bioapplications currently being pursued. Primary among these is healthcare, with the goal of developing diagnostic, imaging, and drug delivery devices along with combinatorial theranostic devices. The path to understanding a role for DNA nanotechnology in biomedical sciences is being approached carefully and systematically, starting from analyzing the stability and immune-stimulatory properties of DNA nanostructures in physiological conditions, to estimating their accessibility and application inside cellular and model animal systems. Much remains to be uncovered but the field continues to show promising results toward developing useful biomedical devices. This review discusses some aspects of DNA nanotechnology that makes it a favorable ingredient for creating nanoscale research and biomedical devices and looks at experiments undertaken to determine its stability in vivo. This is presented in conjugation with examples of state-of-the-art developments in biomolecular sensing, imaging, and drug delivery. Finally, some of the major challenges that warrant the attention of the scientific community are highlighted, in order to advance the field into clinically relevant applications.
Sorafenib plus intra-arterial cisplatin versus sorafenib alone in patients with advanced hepatocellular carcinoma: A randomized phase II trial.
Authors: Masafumi Ikeda, Satoshi Shimizu, Tosiya Sato, Manabu Morimoto, Yoshitaka Inaba, Yasushi Kojima, Atsushi Hagihara, Masatoshi Kudo, Shoji Nakamori, Shuichi Kaneko, Rie Sugimoto, Toshiyuki Tahara, Takumi Ohmura, Kohichiroh Yasui, Keiko Sato, Hiroshi Ishii, Junji Furuse, Takuji Okusaka
Journal: Journal of Clinical Oncology (2015)

4076 Background: Intra-arterial cisplatin therapy for advanced hepatocellular carcinoma (HCC) has been reported a favorable tumor-shrinking effect and long-term survivals even in pts with highly advanced HCC. The aim of this trial was to evaluate the efficacy and safety ofsorafenib plus intra-arterial cisplatin (SP) vs. sorafenib alone (S) for advanced HCC. Methods: In this multicenter open-labeled randomized phase II trial, advanced HCC pts with no prior chemotherapy and Child Pugh A or B7 were randomly assigned 2:1 to receive SP (sorafenib: 800 mg, twice daily; intra-arterial cisplatin: 65 mg/m2, day 1, every 4 to 6 weeks up to a maximum of 6 cycles) or S (800 mg, twice daily) with portal vein tumor thrombosis and extrahepatic metastasis as dynamic allocation factors. The primary endpoint was overall survival. If the median survival of S is assumed as 7.0 months and that of SP as 9.5 months, the hazard ratio (HR) is 0.74. SP would be judged as favorable if HR is 0.74 or lower. A total of 105 pts was needed to estimate the 1-year survival rate with an accuracy of ±10%. Results: From June 2011 to December 2013, 108 pts were randomized (SP, n = 66; S, n = 42) and followed up to December 2014. In the full analysis set of 106 pts, the patient characteristics were well-balanced, except for portal vein tumor thrombosis and hepatitis C viral infection. The median survivals in the SP and the S arms were 10.6 and 8.7 months, respectively (crude HR [95% CI], 0.68 [0.44-1.04], p = 0.073; and stratified HR by the allocation factors [95% CI], 0.60 [0.38-0.96], p = 0.031). The median time to progression was 3.1 and 2.8 months in the SP and S arms (HR [95% CI], 0.78 [0.52-1.16], p = 0.212; stratified HR [95% CI], 0.78 [0.59-1.21]). The following adverse events were more frequent in the SP arm than in the S arm, (percentage in the SP/S arms): neutropenia, 60.0/43.9; leukocytopenia, 75.4/43.9; hemoglobin, 89.2/73.2; thrombocytopenia, 89.2/80.5; hyponatremia, 81.5/53.7; nausea, 41.4/19.5; and hiccups, 9.2/0.0, respectively. Conclusions: According to the prespecified HR of 0.74, SP yielded favorable overall survival as compared to S in pts with advanced HCC. A further phase III trial is warranted to confirm these results. Clinical trial information: UMIN000005703.
Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients?
Authors: Metin Ozkan, Oktay Bozkurt, Ilhan Hacibekiroglu, Muhammet Ali Kaplan, Yakup Duzkopru, Mukremin Uysal, Halit Karaca, Veli Berk, Mevlude Inanc, Ayse Ocak Duran, Ersin Ozaslan, Mahmut Ucar
Journal: Journal of Clinical Oncology (2015)

e15624 Background: The main goal of this study was to examine whether the occurrence of hypothyroidism during sunitinib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated with a better outcome. Methods: The study enrolled81 patients with pathologically proven mRCC who were treated with sunitinib between March 2008 and June 2013. Thyroid function evaluation comprised (free-thyroxine) FT4 and thyroid-stimulating hormone (TSH) before treatment and at day 1 of each 6-week cycle. Survival analysis was performed using the Kaplan–Meier method, and the differences among the groups were determined using the log-rank test. Results: Hypothyroidism occurred in thirty (37%) of 81 patients within a median 3 months (range 1–18) of treatment initiation. There was a statistically significant correlation between the occurrence of hypothyroidism during treatment and the rate of objective remission (ORR) (hypothyroid patients vs euthyroid patients: 46.7% vs 13.7%, respectively; p = 0.001). Median progression-free survival (PFS) was 10 (95% CI 6.13-13.8) months in the euthyroid patients, and 17 (95% CI 9.33-24.6) months in the hypothyroid patients (p = 0.001). The median overall survival (OS) was 39 (95% CI 25.4-52.5) months in the hypothyroid patients, and 20 (95% CI 14.7-25.2) months in the euthyroid patients (p = 0.019). Conclusions: The occurrence of hypothyroidism during treatment in patients was significantly associated with longer PFS, OS and better ORR in the current study.
Abstract MP04: Mean Heart Rate and Brain Morphology in Elderly Women Without a History of Cardiovascular Disease
Authors: Bernhard Haring, Jingmin Liu, Daijchi Shimbo, Claudia B Padula, Wenjun Li, Khyobeni Mozhui, Steve Rapp, Mark Espeland, Sylvia Wassertheil-Smoller
Journal: Circulation (2019)

Background: Low resting heart rate (RHR) has been shown to be predictive of a lower risk for cardiovascular events. Accumulating evidence suggests that RHR may also be related to cognition later in life. To this point, data on the relationship with brain morphology in populations with none or few modifiable cardiovascular risk factors are largely missing. The aim of this study was to assess the associations between mean RHR and brain volumes in elderly postmenopausal women without a history of cardiovascular disease. Methods: The study sample consisted of postmenopausal women without a history of diabetes, coronary heart disease, stroke, atrial fibrillation and hypertension who were enrolled in the MRI ancillary study of the Women’s Health Initiative Memory Study (WHIMS-MRI). Women with very low (&lt;40 bpm) or very high (&gt;120 bpm) heart rate, suffering from any cancer, emphysema, history of pulmonary embolism or current smokers were excluded. Heart rate readings were taken at baseline (WHI enrollment, 1996-1998) and each annual follow-up visit. Brain MRI scans were performed between 2004-2006. Our final sample consisted of 493 women with a mean age of 69 years who were followed over a median of 8 years with an average of 8 RHR assessments. Results: In multivariate regression models adjusting for age, education, WHI Hormone Trial Randomization assignment (HTR arm), depression, physical activity, alcohol intake, coffee intake, presence of ApoE4 allele, mean systolic blood pressure over time, anti-hypertensive medication use over time and incident cardiovascular disease over time, women in the highest tertile of mean RHR (71-92/min) exhibited significantly higher lesion volumes compared to women in the lowest tertile (51-66/min). Conclusion: In postmenopausal women without a history of cardiovascular disease, high mean RHR was associated with higher white and grey matter lesion volumes later in life reflecting higher volumes of neuronal dysfunction and degeneration.
Therapy and prevention for mental health: What if mental diseases are mostly not brain disorders?
Authors: John P. A. Ioannidis
Journal: Behavioral and Brain Sciences (2019)

Abstract Neurobiology-based interventions for mental diseases and searches for useful biomarkers of treatment response have largely failed. Clinical trials should assess interventions related to environmental and social stressors, with long-term follow-up; social rather than biological endpoints; personalized outcomes; and suitable cluster, adaptive, and n-of-1 designs. Labor, education, financial, and other social/political decisions should be evaluated for their impacts on mental disease.
A Randomized Controlled Trial of Executive Functioning Training Compared With Perceptual Training for Schizophrenia Spectrum Disorders: Effects on Neurophysiology, Neurocognition, and Functioning
Authors: Michael W. Best, Melissa Milanovic, Felicia Iftene, Christopher R. Bowie
Journal: American Journal of Psychiatry (2019)

Cognitive remediation is an efficacious treatment for schizophrenia. However, different theoretical approaches have developed without any studies to directly compare them. This is the first study to compare the two dominant approaches to cognitive remediation (training of executive skills and training of perceptual skills) and employed the broadest assessment battery in the literature to date.Outpatients with schizophrenia spectrum disorders were randomly assigned to receive either executive training or perceptual training. Electrophysiological activity, neurocognition, functional competence, case manager-rated community functioning, clinical symptoms, and self-report measures were assessed at baseline, immediately after treatment, and at a 12-week posttreatment follow-up assessment.Perceptual training improved the EEG mismatch negativity significantly more than executive training immediately after treatment, although the effect did not persist at the 12-week follow-up. At the follow-up, executive training improved theta power during an n-back task, neurocognition, functional competence, and case manager-rated community functioning to a greater extent than perceptual training. These effects were not observed immediately after treatment.Both perceptual training and executive training improved neurophysiological mechanisms specific to their domains of intervention, although only executive training resulted in improvement in neurocognition and functioning. Improvements in favor of executive training did not appear immediately after treatment but emerged 12 weeks after the end of active treatment. Thus, short-term intervention targeting higher-order cognitive functions may prime further cognitive and functional improvement.