tbuckley/cabot-search huggingface dataset:
First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma
Authors: Richard D. Kim, Debashis Sarker, Tim Meyer, Thomas Yau, Teresa Macarulla, Joong-Won Park, Su Pin Choo, Antoine Hollebecque, Max W. Sung, Ho-Yeong Lim, Vincenzo Mazzaferro, Joerg Trojan, Andrew X. Zhu, Jung-Hwan Yoon, Sunil Sharma, Zhong-Zhe Lin, Stephen L. Chan, Sandrine Faivre, Lynn G. Feun, Chia-Jui Yen, Jean-Francois Dufour, Daniel H. Palmer, Josep M. Llovet, Melissa Manoogian, Meera Tugnait, Nicolas Stransky, Margit Hagel, Nancy E. Kohl, Christoph Lengauer, Cori Ann Sherwin, Oleg Schmidt-Kittler, Klaus P. Hoeflich, Hongliang Shi, Beni B. Wolf, Yoon-Koo Kang
Journal: Cancer Discovery (2019)

Abstract Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7–not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. Significance: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection. See related commentary by Subbiah and Pal, p. 1646. This article is highlighted in the In This Issue feature, p. 1631
Multicenter phase I trial of trastuzumab emtansine (T-DM1) in combination with non-pegylated liposomal doxorubicin (NPLD) in HER2[+] metastatic breast cancer (MBC). THELMA study
Authors: E. López-Miranda, S. Di Cosimo, E. Brain, M. Ravnik, S. Escrivá-de-Romaní, M. Vidal, J. Gligorov, S. Borstnar, L. Calabuig, M. Sampayo, J.M. Pérez-García, F. Riva, A. Malfettone, A. Llombart Cussac, T. Suter, J. Cortés
Journal: Annals of Oncology (2019)
Construct validity and responsiveness of Skindex‐29‐Colombia
Authors: D. Vasquez, D.‐C. Aguirre, G. Sanclemente
Journal: British Journal of Dermatology (2019)

Until three decades ago, the understanding of disease and treatment effects on patients’ daily lives was very poor. More recently, and due to the fact that international scientific collaboration has increased, patient-reported outcomes (PRO) and quality-of-life (QOL) in particular, have become essential tools to evaluate the effect of any medication according to the patient´s perspective. However, as most QOL scales have been developed in English, there is a growing need to adapt them for use across different cultures but to make sure that the original instrument (scale) and the adapted scale are equivalent, a process that has been called “validation”. As QOL is a complex concept in which the precise meaning of questions can vary between individuals of different countries and cultures, so establishing its validity is quite difficult. In this respect, construct validity (instrument ability to measure a construct or concept), convergent/discriminant validity (correlation/lack of correlation of the instrument in comparison to another instrument), and responsiveness (instrument ability to detect change over time) are all crucial properties that test the instrument's accuracy. Therefore, this study aimed to assess these properties in the Colombian version of Skindex-29, which is a QOL scale. Validity and responsiveness were tested in 209 dermatology patients and 56 people without skin disease. Patients had either inflammatory or non-inflammatory skin diseases. Construct validity was assessed through a test called confirmatory factor analysis, which shows the relationship between all questions (items) of the instrument, and how they cluster around the QOL concept. The convergent/discriminant validity was evaluated by a test called the Spearman correlation coefficient, and responsiveness was tested through the standardized response mean. The authors found that the Colombian version of Skindex-29 is a valid and clinically sensitive instrument that can be used for clinical practice (e.g. by doctors treating patients) and for research, to measure the impact of skin diseases on quality-of-life in dermatology patients.
Reovirus oncolysis of breast cancer
Authors: Chandini Thirukkumaran, Zhong-Qiao Shi, Jason Spurrell, Ponnampalam Thirukkumaran, Don Morris
Journal: Cancer Research (2007)

1929  Introduction: Reovirus is an oncolytic double stranded RNA virus that is not associated with significant human disease. Phase II reovirus intralesional clinical trials have shown encouraging results and PhaseI systemic trials are ongoing. Despite this clinical activity little is known about the pathways/mechanism (s) of oncolysis in malignant cells. Utilizing microarray analysis we have previously shown that reovirus infection of breast cancer cells leads to the upregulation of several apoptotic genes including TNF-αIP, TRAILR2, TNFR6, TNF member 1, FAS associated factor as well as NF-kB, STAT5 and PUMA. The objectives of the present study were to validate these findings and assess whether NF-kB, PUMA and STAT5 are pivotal molecules in reovirus mediated apoptosis in breast cancer.  Methods: The breast carcinoma cell lines HTB 133, HTB132, HTB 30 and MCF-7 were incubated with live or UV-inactivated reovirus at a multiplicity of infection of 40 for 2,4, 6,8,10,12 and 24 hours respectively and nuclear and cytosolic proteins were prepared. Western blotting and/or EMSA analysis were performed against NF-kB, PUMA and STAT5. Total RNA was extracted from these breast cancer cells post reovirus infection with or without chemical inhibition of NF-kB at 12, 24 and 48 hours and real time PCR was performed. PUMA and NF-kB gene expression in HTB 133 and MCF-7 cells was down regulated using siRNA oligos and/ or vectors containing mutant PUMA BH3 domains or mutant Ik-B. Reovirus oncolytic protection was monitored using flow cytometry and Trypan blue exclusion.  Results: Real time PCR analysis indicated a 1.2-2.6 fold increase in NF-kB p65 message levels post reovirus infection of HTB 133 and MCF7 cells. Nuclear translocation of NF-kB p56 protein was significantly increased (3.4-54.8 fold) in all 4 breast cancer cell lines post reovirus treatment. Nuclear translocation of NF-kB correlated well with enhanced DNA binding as revealed by EMSAs. Significant upregulation of PUMA message levels (9-159 fold) and protein (3.6-63.6 fold) was detected in HTB 133 and MCF7 cells following virus infection. Chemical inhibition of NF-kB significantly down regulated PUMA message levels in these breast cancer cells. Mutant Ik-B expression showed a 22-49% inhibition of reovirus induced apoptosis. In addition, PUMA down regulation through siRNA methodology or mutant gene expression evidenced reovirus protection in these cells. STA5 protein was upregulated in both MCF7 and HTB 133 cell lines.  Conclusions: NF-kB and PUMA appear to be pivotal molecules in reovirus induced cell death of breast cancer. Ongoing research with generating stable transfectants of mutant Ik-B and PUMA and PUMA promoter deletion analysis will help confirm the importance of these molecules during reovirus breast cancer oncolysis.
Post-hoc analyses of a subgroup of patients with advanced biliary tract cancer (BTC) who crossed over to treatment with etoposide toniribate (EDO-S7.1) in a randomized phase II study
Authors: U.-F. Pape, S. Kasper, J. Meiler, M. Sinn, A. Vogel, L. Mueller, O. Burkhard, K. Caca, S. Heeg, V. Rodriguez Laval, A.A. Kuhl, R. Arsenic, H. Jansen, T. Mehrling, K. Hilgier, I. Wagner, N. Utku
Journal: Annals of Oncology (2019)
Ramucirumab in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): An exposure-response analysis
Authors: J. Llovet, M. Kudo, Y.-K. Kang, C.-J. Yen, R.S. Finn, P.R. Galle, E. Assenat, K. Motomura, T. Okusaka, T. Berg, C.-H. Hsu, M. Ikeda, Y. Hsu, K. Liang, R. Widau, W. Schelman, L. O’Brien, L. Gao, A.X. Zhu
Journal: Annals of Oncology (2019)
Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias
Authors: Riikka H. Hämäläinen, Juan C. Landoni, Kati J. Ahlqvist, Steffi Goffart, Sanna Ryytty, M. Obaidur Rahman, Virginia Brilhante, Katherine Icay, Sampsa Hautaniemi, Liya Wang, Marikki Laiho, Anu Suomalainen
Journal: Nature Metabolism (2019)
Author Correction: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
Authors: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini V. Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Juhi R. Kuchroo, Jeffrey J. Ishizuka, Jenna L. Collier, Gabriel K. Griffin, Seth Maleri, Dawn E. Comstock, Sarah A. Weiss, Flavian D. Brown, Arpit Panda, Margaret D. Zimmer, Robert T. Manguso, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining
Journal: Nature Immunology (2019)
Molecular profiling and prognostic significance of TP53 mutations in diffuse large b cell lymphoma: Identifying a high-risk subgroup
Authors: Y.-K. Shi, S. Jiang, Y. Qin, H. Jiang, B. Liu, J. Shi, F. Meng, P. Liu, J. Yang, S. Yang, X. He, S. Zhou, L. Gui, H. Liu, J. Lin
Journal: Annals of Oncology (2019)
Abstract 18017: The Modified History in Young Patients With Repaired Tetralogy of Fallot: A Longitudinal Magnetic Resonance Study
Authors: Tamadhir Gazzaz, Bernadette Elders, Cedric Manlhiot, Shi-Joon Yoo, Mike Seed, Brian Mccrindle, Lars Grosse-Wortmann
Journal: Circulation (2015)

Introduction: No large scale longitudinal information is available on the change of ventricular size and function as well as of exercise tolerance in survivors after Tetralogy of Fallot (TOF) repair during childhood and adolescence. Objective: The objective of this study was to assess the rate of progression of right ventricular (RV) size and pulmonary regurgitation (PR) in relationship to clinical status and outcomes in pediatric TOF patients from a contemporary surgical era. Methods: We analyzed 429 cardiac magnetic resonance (CMR) studies (from 2001-2014) of 267 patients (age at CMR 13.5 +/-2.8 years) after TOF repair prior to any pulmonary valve replacement (PVR), including 96 patients with serial CMRs. Measurements of biventricular volumes, mass, function, and PR were performed by a single observer. Serial ECGs, Holters, echocardiograms, and exercise tests were reviewed. Results: No deaths occurred in our cohort. Three patients (1.1%) had non-sustained ventricular tachycardia and 4 (1.5%) had supraventricular tachycardia. Sixty seven (25%) patients underwent PVR at a mean age15.5 +/- 2.3 years.There was a linear progression of BSA-indexed RV end-diastolic volume (EDVi) at 3 ml/m2 per year (p.a., p&lt;0.001). PR volume changed only minimally over time while PR fraction progressed at a rate of 0.7% p.a. (p&lt;0.001). RV and LV ejection fractions (EFs) deteriorated over time (0.5% p.a., p&lt;0.001 and 0.4% p.a., p=0.001, respectively). RV and LV EDVi increased (p=0.02 and p=0.001, respectively) and RV EF (p&lt;0.001) decreased more rapidly in boys than in girls. Right atrial (RA) length correlated inversely with VO2max (% predicted, p=0.02). In a multivariable analysis, worsening PR fraction, RV EF, RA length, and LV EDVi were all predictors of PVR in the future. Conclusions: This study describes the rate and dynamic of progression of biventricular size and function in children after TOF repair in the hitherto largest cohort, with apparent differences between boys and girls. RA length was inversely correlated with exercise intolerance.The need for PVR is predicted by the degree of RV dysfunction as well as LV and RA enlargement. The latter may deserve routine assessment in patients after TOF repair.
TCT-387 Morphological Correlates of Symptomatic Progression After Coronary Computed Tomography Angiography-derived High Risk Lesions Are Assessed by Optical Coherence Tomography
Authors: Mitsuaki Matsumura, Rafal Wolny, Akiko Fujino, Gary Mintz, Eisuke Usui, Tetsumin Lee, Masahiro Hoshino, Taishi Yonetsu, Tsunekazu Kakuta, Akiko Maehara
Journal: Journal of the American College of Cardiology (2018)
Pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment for Egyptian patients with malignant pleural mesothelioma
Authors: M.O. Alorabi, H.M. El Wakil, M.M. El-Mahdy, D.A. Salem, A.E. Essa, A.M. Gaballah
Journal: Annals of Oncology (2019)
Impact of the IDEA study on clinical practice for stage III colon cancer patients: A French GERCOR - FFCD - GI UNICANCER national survey
Authors: K. Ouali, R. Cohen, A. Turpin, C. Neuzillet, B. Rousseau, M.-L. Garcia-Larnicol, C. Tournigand, E. Samalin, J. Taieb, T. André
Journal: Annals of Oncology (2019)
Safety of new androgen receptor inhibitors (ARi) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC): A network meta-analysis of randomized controlled trials (RCT)
Authors: A. Altavilla, M Di Maio, M. Tucci, C. Lolli, G. Schepisi, C. Buttigliero, F. Vignani, U. De Giorgi
Journal: Annals of Oncology (2019)
A window of opportunity trial of preoperative nivolumab with or without tadalafil in squamous cell carcinoma of the head and neck (SCCHN): Safety, clinical, and correlative outcomes
Authors: A.J. Luginbuhl, J.M. Johnson, L. Harshyne, M. Tuluc, S. Mardekian, B.E. Leiby, J.M. Curry, D.M. Cognetti, Y. Kim, K. Mannion, U. Rodeck, A. Argiris
Journal: Annals of Oncology (2019)
Integrated safety analysis of the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with ovarian cancer in the treatment and maintenance settings
Authors: R.S. Kristeleit, A.M. Oza, A. Oaknin, C. Aghajanian, A.V. Tinker, O. Tredan, D.M. O’Malley, A. Leary, G.E. Konecny, D. Lorusso, J.I. Weberpals, S. Goble, L. Maloney, T. Cameron, E. Swisher, I.A. McNeish, R. Shapira-Frommer, J.A. Ledermann, R.L. Coleman
Journal: Annals of Oncology (2019)
Prognostic Impact of MRD in the Bone Marrow of Children at First Isolated Extramedullary Relapse of ALL.
Authors: Nikola Hanzsch, Cornelia Eckert, Cecile Acquaviva, Eva Fronkova, Arend von Stackelberg, Udo zur Stadt, Andre Schrauder, Jan Trka, Karl Seeger, Guenter Henze, Helene Cave
Journal: Blood (2004)
Patient-reported outcomes associated with switching to rivaroxaban for the treatment of venous thromboembolism (VTE) in patients with active cancer
Authors: A.T. Cohen, A. Maraveyas, J. Beyer-Westendorf, A.Y.Y. Lee, L.G. Mantovani, K. Folkerts, M. Bach, Y. De Sanctis, K. Abdelgawad
Journal: Annals of Oncology (2019)
Association between transit-amplifying signature and outcomes of patients treated with anti-epidermal growth factor receptor (EGFR) therapy in colorectal cancer
Authors: E. Fontana, G. Nyamundanda, D. Cunningham, D.J. Jonker, L.L. Siu, D. Tu, F. Sclafani, K.V. Eason, C. Ragulan, S. Hulkki-Wilson, J.M. Loree, M. Giordano, P.V. Lawrence, J. Shapiro, C. Cremolini, N. Starling, F. Pietrantonio, L. Trusolino, C. O’Callaghan, A. Sadanandam
Journal: Annals of Oncology (2019)
Burden of CKD and Cardiovascular Disease on Life Expectancy and Health Service Utilization: a Cohort Study of Hong Kong Chinese Hypertensive Patients
Authors: Eric Yuk Fai Wan, Esther Yee Tak Yu, Weng Yee Chin, Daniel Yee Tak Fong, Edmond Pui Hang Choi, Eric Ho Man Tang, Cindy Lo Kuen Lam
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The relative effects of the burdens of CKD and cardiovascular disease on risk of mortality, direct medical costs, and life expectancy in people with hypertension are unknown. In this retrospective cohort study of 506,849 patients with hypertension in Hong Kong, co-occurrence of these conditions was associated with significant incrementally elevated mortality risk, direct medical costs, and reduced life expectancy. The authors found extremely high mortality risk and cost increases for severe CKD, exceeding the combined effects from heart disease and stroke. Moderate CKD, heart disease, and stroke had burdens that were similar individually and roughly multiplicative for any combination. These findings suggest that CKD prevention and intervention to reduce mortality and health care costs in people with hypertension should be given priority equal to that for cardiovascular disease. Background The relative effects of combinations of CKD, heart disease, and stroke on risk of mortality, direct medical costs, and life expectancy are unknown. Methods In a retrospective cohort study of 506,849 Chinese adults in Hong Kong with hypertension, we used Cox regressions to examine associations between all-cause mortality and combinations of moderate CKD (eGFR of 30–59 ml/min per 1.73 m 2 ), severe CKD (eGFR of 15–29 ml/min per 1.73 m 2 ), heart disease (coronary heart disease or heart failure), and stroke, and modeling to estimate annual public direct medical costs and life expectancy. Results Over a median follow-up of 5.8 years (2.73 million person-years), 55,666 deaths occurred. Having an increasing number of comorbidities was associated with incremental increases in mortality risk and medical costs and reductions in life expectancy. Compared with patients who had neither CKD nor cardiovascular disease, patients with one, two, or three conditions (heart disease, stroke, and moderate CKD) had relative risk of mortality increased by about 70%, 160%, and 290%, respectively; direct medical costs increased by about 70%, 160%, and 280%, respectively; and life expectancy at age 60 years decreased by about 5, 10, and 15 years, respectively. Burdens were higher with severe CKD. Conclusions This study demonstrated extremely high mortality risk and medical cost increases for severe CKD, exceeding the combined effects from heart disease and stroke. Mortality risks and costs for moderate CKD, heart disease, and stroke were similar individually and roughly multiplicative for any combination. These findings suggest that to reduce mortality and health care costs in patients with hypertension, CKD prevention and intervention merits priority equal to that of cardiovascular disease.
FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma
Authors: S. Yamamoto, K. Kato, H. Daiko, T. Kojima, H. Hara, T. Abe, Y. Tsubosa, K. Nagashima, Y. Kitagawa
Journal: Annals of Oncology (2019)
Editor's Note: LOX-Mediated Collagen Cross-linking Is Responsible for Fibrosis-Enhanced Metastasis
Authors: Thomas R. Cox, Demelza Bird, Ann-Marie Baker, Holly E. Barker, Melisa W.-Y. Ho, Georgina Lang, Janine T. Erler
Journal: Cancer Research (2019)

The editors were made aware of concerns regarding this article (1). An internal review by the editors determined that lanes 2–4 of the pSMAD2 Western blot image in Supplementary Fig. S3C are identical to the LOX Western blot image in Supplementary Fig. S3D.
Elevated driver mutational burden or number of perturbed pathways and poor response to abiraterone or enzalutamide in metastatic castration-resistant prostate cancer
Authors: B. De Laere, A. Crippa, C. Ghysel, P. Ost, P. Rajan, M. Eklund, L. Dirix, H. Grönberg, J. Lindberg
Journal: Annals of Oncology (2019)
Maternal Bacterial Infection During Pregnancy and Offspring Risk of Psychotic Disorders: Variation by Severity of Infection and Offspring Sex
Authors: Younga H. Lee, Sara Cherkerzian, Larry J. Seidman, George D. Papandonatos, David A. Savitz, Ming T. Tsuang, Jill M. Goldstein, Stephen L. Buka
Journal: American Journal of Psychiatry (2019)

Previous studies suggest that prenatal immune challenges may elevate the risk of schizophrenia and related psychoses in offspring, yet there has been limited research focused on maternal bacterial infection. The authors hypothesized that maternal bacterial infection during pregnancy increases offspring risk of psychotic disorders in adulthood, and that the magnitude of this association varies as a function of severity of infectious exposure and offspring sex.The authors analyzed prospectively collected data from 15,421 pregnancies among women enrolled between 1959 and 1966 at two study sites through the Collaborative Perinatal Project. The sample included 116 offspring with confirmed psychotic disorders. The authors estimated associations between maternal bacterial infection during pregnancy and psychosis risk over the subsequent 40 years, stratified by offspring sex and presence of reported parental mental illness, with adjustment for covariates.Maternal bacterial infection during pregnancy was strongly associated with psychosis in offspring (adjusted odds ratio=1.8, 95% CI=1.2-2.7) and varied by severity of infection and offspring sex. The effect of multisystemic bacterial infection (adjusted odds ratio=2.9, 95% CI=1.3-5.9) was nearly twice that of less severe localized bacterial infection (adjusted odds ratio=1.6, 95% CI=1.1-2.3). Males were significantly more likely than females to develop psychosis after maternal exposure to any bacterial infection during pregnancy.The study findings suggest that maternal bacterial infection during pregnancy is associated with an elevated risk for psychotic disorders in offspring and that the association varies by infection severity and offspring sex. These findings call for additional investigation and, if the findings are replicated, public health and clinical efforts that focus on preventing and managing bacterial infection in pregnant women.
Checkpoint inhibitor therapy, with and without radiation, in diffuse large B cell lymphoma: A single-center analysis.
Authors: Stephanie Yoon, Mohammad Zahid, Pooja Phull, Jordan Senchak, Richard I. Fisher, Essel Dulaimi, Eric A. Ross, Jian Qin Yu, Mohan Doss, Nadia Khan
Journal: Journal of Clinical Oncology (2019)

e19059 Background: Single agent checkpoint inhibitors (CPI) in NHLs have resulted in modest successes. Exceptions include RT, PCNS and testicular lymphomas, where higher activity is seen. As a single agent, CPI response rates range from 10-40% in relapsed refractory (RR) DLBCL, with few CRs and short response durations. In a cohort of RR DLBCL patients at our institution, we sought to identify clinical features that defined responders and non-responders. Methods: Between 9/2016 and 7/2018, 13 pts with DLBCL/RT, treated with a CPI, either on trial or as off-label therapy, with at minimum 1 infusion/cycle were included. Pathology specimens confirming DLBCL/RT were reviewed at FCCC. All pts had measurable disease by CT or PET/CT prior to CPI and had an evaluable response. Cell of origin was determined by Hans IHC. Results: Almost half (6/13) of pts achieved a response to CPI. Notably all responders had either concurrent or pre-treatment XRT. All 3 RT patients responded to CPI and continued to allo transplant. P3 and P6 both developed GVHD post allo, resulting in a demise in P3. No GC subtype pts responded nor had prior/ concurrent XRT with CPI. In 2 pts responses are ongoing, &gt; 1 yr, and 1 RT pt remains in CR. Conclusions: XRT, prior or concurrent with CPI , was associated with durable responses in RR DLBCL. Patients with bulky ( &gt; 7cm), rapidly progressive disease (8/13 cases) may require a 'debulking' strategy for CPI efficacy. An abscopal effect achieved with XRT/CPI combinations, may be impactful RR NHL. Analysis of PDL1/2 and MHC I/II, with other biomarkers, are underway. These clinical results warrant validation in a larger cohort, therefore a prospectively designed study is planned for 2019 in RR DLBCL/RT. [Table: see text]