tbuckley/cabot-search huggingface dataset:
Focal adhesion kinase (FAK) inhibitors VS-6063 and VS-4718 target cancer stem cells.
Authors: Qunli Xu, Vihren N Kolev, Quentin G Wright, Irina M Shapiro, Christian M. Vidal, Mahesh Padval, Mitchell Keegan, Daniel Paterson, Joanna Horobin, Jonathan A Pachter
Journal: Journal of Clinical Oncology (2013)

e13523 Background: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that orchestrates cellular signaling through integrins and growth factor receptors and functions in multiple steps of tumorigenesis. Both VS-6063 and VS-4718 are potent, selective, and orally active FAK inhibitors. In a phase I clinical trial, VS-6063 was well tolerated and demonstrated preliminary clinical activity. VS-4718 is in late stage preclinical development and has been shown to inhibit tumor growth and metastasis in tumor models. We report here that the FAK inhibitors VS-6063 and VS-4718 effectively abrogate cancer stem cells (CSCs). Methods: VS-6063 and VS-4718 were evaluated in the ALDEFLUOR and Side Population (SP) CSC assays in vitro and in xenograft tumors in vivo. Results: Treating SUM159 breast cancer cells with FAK inhibitors reduced the percentage of ALDEFLUOR + and SP CSCs. Similar inhibitory effects on CSCs were observed in the ovarian cancer cell lines OVCAR-5 and OVCAR-8 and the mesothelioma cell line H2052. In direct contrast, cytotoxic agents paclitaxel, carboplatin and pemetrexed increased the percentage of CSCs, suggesting that these agents do not effectively target CSCs. Importantly, combination of either VS-6063 or VS-4718 with cytotoxic agents blocked induction of CSCs by these agents. The effect of a FAK inhibitor on CSCs in vivo was evaluated in an MDA-MB-231 human breast cancer orthotopic model. Oral administration of FAK inhibitor substantially reduced the number of ALDH1- positive cells in tumors as assessed by immunofluorescence. Following dissociation of cells from tumors, CSCs were found to be reduced in FAK inhibitor-treated tumors as measured by multiple assays. Furthermore, cells isolated from FAK inhibitor-treated tumors showed reduced tumor-initiating capability upon re-implantation into immunodeficient mice. FAK inhibitor also decreased ALDH1-positive CSCs in an orthotopic MM87 mesothelioma model. Conclusions: Our results provide clear demonstration that FAK inhibitors target cancer stem cells both in vitro and in xenograft tumors in vivo and support the planned clinical development of VS-6063 and VS-4718 to achieve durable clinical responses for cancer patients.
Advanced cancer patients’ changes in terminal illness understanding (TIU) and their psychological well-being.
Authors: Login S. George, Megan Johnson Shen, Paul K. Maciejewski, Andrew S. Epstein, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2019)

11617 Background: Although accurate TIU is necessary for informed treatment decision-making, clinicians worry that patients’ recognition of the terminal nature of their illness may lower psychological well-being. This study examines if such recognition is associated with lowered psychological well-being, that persists over time. Methods: Data came from 87 advanced cancer patients, with a life expectancy of less than 6 months. Patients were assessed pre and post an oncology visit to discuss cancer restaging scan results, and again one month later (follow-up). TIU was assessed at pre and post as the sum of four indicator variables — understanding of terminal nature of illness, curability, stage, and life-expectancy — and a TIU change score was computed (post minus pre). Psychological well-being (psychological symptoms subscale, McGill questionnaire) was assessed at pre, post, and follow-up, and two change scores were computed (post minus pre; follow-up minus post). Results: Changes toward more accurate TIU was associated with a corresponding decline in psychological well-being ( r = -0.33, p &lt; .01), but thereafter was associated with subsequent improvements in psychological well-being ( r = .40, p &lt; .001). This pattern persisted even after adjustment for relevant demographic factors, prognostic discussion, scan results, and physical well-being change. TIU change scores ranged from positive to negative, with some participants showing improvements in TIU ( n = 19), some showing decrements in TIU ( n = 14), and others showing stable TIU ( n = 54). Among patients with improved TIU, psychological well-being initially decreased, but subsequently recovered [7.03 (2.23) to 6.30 (1.80), to 7.63 (2.08)]; the stable TIU group showed relatively unchanged well-being [7.34 (2.37) to 7.45 (2.32), to 7.36 (2.66)], and the less accurate TIU group showed an initial improvement followed by a subsequent decline [6.30 (2.62) to 7.36 (2.04), to 5.63 (3.40)]. Conclusions: Improved TIU may be associated with initial decrements in psychological well-being, followed by patients rebounding to baseline levels. Concerns about psychological harm may not need to be a deterrent to having prognostic discussions with patients.
Cancer targeting by TCR gene-engineered T cells directed against Kita-Kyushu Lung Cancer Antigen-1
Authors: Bridget Marcinkowski, Sanja Stevanović, Sarah R. Helman, Scott M. Norberg, Carylinda Serna, Benjamin Jin, Nikolaos Gkitsas, Tejas Kadakia, Andrew Warner, Jeremy L. Davis, Lisa Rooper, Christian S. Hinrichs
Journal: Journal for ImmunoTherapy of Cancer (2019)

T cell receptor (TCR) gene-engineered T cells have shown promise in the treatment of melanoma and synovial cell sarcoma, but their application to epithelial cancers has been limited. The identification of novel therapeutic TCRs for the targeting of these tumors is important for the development of new treatments. Here, we describe the preclinical characterization of a TCR directed against Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1, encoded by <i>CT83</i>), a cancer germline antigen with frequent expression in human epithelial malignancies including gastric cancer, breast cancer, and lung cancer. Gene-engineered T cells expressing the KK-LC-1 TCR (KK-LC-1 TCR-Ts) demonstrated recognition of <i>CT83</i>+ tumor lines in vitro and mediated regression of established <i>CT83+</i> xenograft tumors in immunodeficient mouse models. Cross-reactivity studies based on experimental determination of the recognition motifs for the target epitope did not demonstrate cross-reactivity against other human proteins. <i>CT83</i> gene expression studies in 51 non-neural tissues and 24 neural tissues showed expression restricted exclusively to germ cells. <i>CT83</i> was however expressed by a range of epithelial cancers, with the highest expression noted in gastric cancer. Collectively, these findings support the further investigation and clinical testing of KK-LC-1 TCR-Ts for gastric cancer and possibly other malignancies.
Tandem Transplant for High-Risk Neuroblastoma
Authors: Rochelle Bagatell, Meredith S. Irwin
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Prevalence of early-stage prostate and estrogen receptor positive (ER+) breast cancer patients receiving primary androgen deprivation therapy (ADT) and aromatase inhibitors (AIs) in the United States (U.S.)
Authors: A. Barlev, M. Yong, G. Cherkowski, K. Cetin, J. Fryzek
Journal: Journal of Clinical Oncology (2009)

e22126 Background: AIs and ADT are used to prevent recurrence of breast and prostate cancers but have been shown to accelerate bone loss. We estimated the prevalence of early-stage ER+ breast and prostate cancer patients on hormone therapy in the U.S., as this is not well-described in the literature. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) Program, published literature, clinical practice, and a large claims database were used. We began with the American Cancer Society's estimated number of new breast and prostate cancer cases for the year 2008. We then assessed the number of patients with localized/regional disease and ER+ tumors and those receiving primary ADT (both chemical and surgical) or AI therapy by applying proportions from SEER, published literature, clinical practice, and the claims database. Using these incident case counts, we calculated the 5-year prevalence using appropriate cohort-specific survival rates to sum the number of new and surviving cases over a 5-year period. Results: The estimated 5-year prevalence of early-stage ER+ breast cancer for women aged ≥50 years in the U.S. was 607,411, of which 293,904 (48.4%) were on AI therapy based on the claims database. However, because this data source was limited to women aged &lt;65 years, we also used estimates from clinical practice to capture AI use for women of all ages. Based on clinical practice, 402,637 (66.3%) to 460,156 (75.8%) of early-stage ER+ breast cancer patients were on AI therapy. For early-stage prostate cancer, the estimated 5-year prevalence for all ages was 1,024,238, of which 141,451 (13.8%) were on primary ADT. However, these figures may underestimate current usage of hormone therapies, as our data and the literature show increasing trends in ADT and AI use for early-stage disease. Conclusions: Based on a combination of population-based data and the published literature, approximately half of all early-stage ER+ breast cancer patients and a modest proportion of early-stage prostate cancer patients are on hormone therapy in the U.S. [Table: see text]
Which needle and technique should we use for endoscopic ultrasound-guided liver biopsy? A work in progress
Authors: Alberto Larghi
Journal: Endoscopy (2019)

See also: Reply to Mok et al.Endoscopy 2020; 52(02): 158-158DOI: 10.1055/a-1041-3188 See also: The 22-gauge core needle is not optimal for endoscopic ultrasound-guided liver biopsyEndoscopy 2020; 52(02): 157-157DOI: 10.1055/a-1031-9504
Nelfinavir and lenalidomide/dexamethasone in patients with lenalidomide-refractory multiple myeloma. A phase I/II Trial (SAKK 39/10)
Authors: F. Hitz, M. Kraus, T. Pabst, D. Hess, L. Besse, T. Silzle, U. Novak, K. Seipel, S. Rondeau, S. Stüdeli, S. Berardi Vilei, P. Samaras, U. Mey, C. Driessen
Journal: Blood Cancer Journal (2019)

Abstract The antiretroviral agent nelfinavir has antimyeloma activity and can overcome resistance to bortezomib. Our phase I/II trial investigated whether adding nelfinavir to lenalidomide–dexamethasone can overcome lenalidomide resistance in lenalidomide-refractory multiple myeloma (MM). Twenty-nine patients were included (high-risk cytogenetic aberrations 31%; ≥2 prior therapy lines 93%; lenalidomide–bortezomib double-refractory 34%). Twenty-four patients (83%) had prior bortezomib and 10 (34%) were lenalidomide–bortezomib double-refractory. They received four cycles of nelfinavir 2500 mg/day with standard-dose lenalidomide (25 mg days 1–21) and dexamethasone (40/20 mg days 1, 8, 15, 22). Minor response or better was achieved in 16 patients (55%; 95% CI 36–74%), including 40% of those who were lenalidomide–bortezomib double-refractory, and partial response or better in nine patients (31%; 95% CI 15–51%). Median progression-free survival was 3.4 (95% CI 2.0–4.9) months and median overall survival 21.6 (13.0–50.1) months. Lenalidomide-related pneumonitis, pneumonia, and neutropenic fever occurred, but there were no unexpected adverse events. Peripheral blood mononuclear cells showed a 45% (95% CI 40–51%) reduction in total proteasome activity from baseline and significant induction of unfolded protein response and autophagy. Thus, nelfinavir–lenalidomide–dexamethasone is an active oral combination in lenalidomide-refractory MM.
L1-CAM as a predictor of survival in endometrial cancer: An analysis of The Cancer Genome Atlas (TCGA).
Authors: Thanh Hue Dellinger, Charles Warden, Ernest Soyoung Han, Mark Tsuneo Wakabayashi
Journal: Journal of Clinical Oncology (2013)

5599 Background: Despite a good survival rate for early-stage endometrial cancers (ECs), the prognosis for advanced-stage ECs remains poor, with no biomarkers and few therapeutic options currently in existence. L1-cell adhesion molecule (L1-CAM), a glycoprotein which functions in adhesion and migration of tumor cells, has been associated with a poor prognosis in Type I endometrial cancer (ASCO 2011 Abstract #5091). We evaluated the role of L1-CAM among both Type I and II ECs in TCGA. Methods: Partek Genomics Suit was used to define differentially expressed genes with p-values for clinical associations (ANOVA with linear contrast for discrete variables and linear regression for continuous variables). Differences in survival between “high” and “low” expression groups (defined by median expression) were compared using Cox regression analysis, with p-values calculated via log-rank test, using the ‘survival’ package in R. Results: Of 451 downloadable tumor samples, 335 tumors with both clinical and gene expression data were analyzed. Median age was 63 yrs. (range 31-90 yrs.). Stage I, II, III, and IV comprised 65%, 7%, 23%, and 5%, respectively. 82% were endometrioid; 16% (n = 52) serous. Grade 1, 2, and 3 comprised 24%, 27%, and 49%, respectively. Median follow-up was 19.5 months. High L1-CAM expression was found in older (p = 0.0005), suboptimally debulked (p=0.002), and African-American patients (p = 0.0003), and those with high grade (p = 0.008), serous histology (p &lt;0.00001), higher stage (p = 0.0004), positive peritoneal cytology (p = 0.007), deep myometrial invasion (p = 0.02), and positive pelvic (p = 0.003) and para-aortic lymph nodes (p = 0.002). High L1-CAM expression was associated with poor survival with a median overall survival of 17.2 months compared to 21.3 months for low L1-expressing endometrial tumors (HR= 3.1, CI=1.3 -7.3, p = 0.007). Conclusions: L1-CAM expression is associated with poorer survival and high-risk clinicopathologic factors in endometrial cancer. Its prevalence in Type II ECs, such as high-grade, serous ECs, makes it a particularly attractive target for both novel biomarker discovery and therapeutic targeting.
Transplantation of Human Umbilical Cord Blood–Derived Cellular Fraction Improves Left Ventricular Function and Remodeling After Myocardial Ischemia/Reperfusion
Authors: Lin Zhao, Guangming Cheng, Kashyap Choksi, Anweshan Samanta, Magdy Girgis, Rupal Soder, Robert J. Vincent, Michael Wulser, Matt De Ruyter, Patrick McEnulty, Jeryl Hauptman, Yanjuan Yang, Carl P. Weiner, Buddhadeb Dawn
Journal: Circulation Research (2019)

Rationale: Human umbilical cord blood (hUCB) contains diverse populations of stem/progenitor cells. Whether hUCB-derived nonhematopoietic cells would induce cardiac repair remains unknown. Objective: To examine whether intramyocardial transplantation of hUCB-derived CD45-Lin- nonhematopoietic cellular fraction after a reperfused myocardial infarction in nonimmunosuppressed rats would improve cardiac function and ameliorate ventricular remodeling. Methods and Results: Nonhematopoietic CD45-Lin- cells were isolated from hUCB. Flow cytometry and quantitative polymerase chain reaction were used to characterize this subpopulation. Age-matched male Fischer 344 rats underwent a 30-minute coronary occlusion followed by reperfusion and 48 hours later received intramyocardial injection of vehicle or hUCB CD45-Lin- cells. After 35 days, compared with vehicle-treated rats, CD45-Lin- cell-treated rats exhibited improved left ventricular function, blunted left ventricular hypertrophy, greater preservation of viable myocardium in the infarct zone, and superior left ventricular remodeling. Mechanistically, hUCB CD45-Lin- cell injection favorably modulated molecular pathways regulating myocardial fibrosis, cardiomyocyte apoptosis, angiogenesis, and inflammation in postinfarct ventricular myocardium. Rare persistent transplanted human cells could be detected at both 4 and 35 days after myocardial infarction. Conclusions: Transplantation of hUCB-derived CD45-Lin- nonhematopoietic cellular subfraction after a reperfused myocardial infarction in nonimmunosuppressed rats ameliorates left ventricular dysfunction and improves remodeling via favorable paracrine modulation of molecular pathways. These findings with human cells in a clinically relevant model of myocardial ischemia/reperfusion in immunocompetent animals may have significant translational implications.Visual Overview: An online visual overview is available for this article.
Saphenous vein grafts in contemporary coronary artery bypass graft surgery
Authors: Etem Caliskan, Domingos Ramos de Souza, Andreas Böning, Oliver J. Liakopoulos, Yeong-Hoon Choi, John Pepper, C. Michael Gibson, Louis P. Perrault, Randall K. Wolf, Ki-Bong Kim, Maximilian Y. Emmert
Journal: Nature Reviews Cardiology (2019)
Sarcopenia (SMI(+)) in patients (pts) with advanced or metastatic soft tissue sarcoma (a/mSTS): Potential parameter for risk prediction during multimodal therapy (MT)?
Authors: Dennis Strassmann, Bennet Hensen, Viktor Gruenwald, Katharina Stange, Hendik Eggers, Florain Länger, Martin Panzica, Patrick Zardo, Hans Christiansen, Christoph W. Reuter, Frank Wacker, Arnold Ganser, Philipp Ivanyi
Journal: Journal of Clinical Oncology (2019)

11069 Background: Objective parameters identifying ideal pts for MT from pts with a/mSTS remain scarce. Here, we analysed the impact of sacropenia in a/mSTS pts on treatment outcome of MT, retrospectively. Methods: Pts. with a/m STS treated at our centre (12/98-5/16ere identified. 89/181 pts were evaluable for analysis (CT-scans: -14 days before MT onset). Lumbar skeletal muscle index (SMI) was measured with MeVisLab 2.7 by manually segmentation of preinterventional CTs. SMI cut-off were defined through optimal fitting method (sarcopenia = SMI(+) in male: &lt; 44 , in female: 38). Progression was defined by clinical or radiological judgment. Descriptive statistics, Kaplan-Meier-analysis and Cox-regression were administered. Results: At MT onset 28/89 pts (31%) suffered from sarcopenia, and SMI(+) pts were older than SMI(-) pts (p = 0.025). SMI(+) pts tends to receive lower numbers of medical treatments, received less often surgery, and more frequently radiotherapy, although differences were not significant. Further on, SMI(+) pts tends to profit less from first line medical treatment, compared to SMI(-) pts (objective responses: 14,3% vs. 27.9%, p = .161, clinical benefit rate: 25% vs. 65.6%, p = .032, PFS: 1 (95%-CI:.35-1.65) vs. 16 (95%CI:8.8-23.2) months, p = .002). OS was inferior in SMI(+) compared to SMI(-) pts. (4 (95%CI:2-6) vs. 16 (95%CI:8.8-23.2), p = .002). Multivariable analysis showed a trend for SMI(+) to be associated with PFS (HR: 1.7 (95%CI: 0.9-2.8), p = .067) and were independently associated with OS (HR: 2.53 (95%CI: 1.5-4.2), p &lt; .001). Conclusions: In our cohort sarcopenia tends to be associated with less aggressive therapy in a/mSTS pts. However, sarcopenia tends to be associated with inferior PFS and was identified as independent risk factor for inferior OS. Although this analysis is limited due to its sample size sarcopenia might offer an attractive tool as guidance for treatment intensity modulation in a/mSTS patients, avoiding overtreatment in this cohort with dismal prognosis.
Outcome and prognostic factors in localized primitive neuroectodermal tumors with uniform chemotherapy protocol: A single center experience of 224 cases.
Authors: Bivas Biswas, Shishir Rastogi, Shah Alam Khan, Sandeep Agarwala, B. K. Mohanti, N. K. Shukla, S. V. S. Deo, Dayanand Sharma, Mehar C Sharma, Sreenivas Vishnubhatla, Sameer Bakhshi
Journal: Journal of Clinical Oncology (2013)

10527 Background: Data on localized PNET with uniform protocol is minimal. Methods: This is single institutional patient review treated between June 2003-Nov 2011, and evaluated on intent-to-treat analysis. All patients received uniform chemotherapy (VAC/IE) as follows: neo-adjuvant chemotherapy (NACT), surgery and/or radiotherapy as local treatment followed by ACT. Results: 224/374 (60%) PNET patients were localized with median age 15 years (range: 0.1–55), tumor diameter 8 cm (range: 1.6-25) and symptom duration 4 months (range: 0.5-30). Regions were extremities 40%, thorax 25% and head &amp; neck 14%. Post-NACT, CR was 32(14%); PR 152(68%) with ORR 82%. Ninety-nine patients underwent surgery (50/99 received adjuvant radiotherapy); 80 received radical radiotherapy as local therapy. There were no adverse tumor characteristics or poor NACT response in radical radiotherapy group versus surgery group. At median follow-up of 31.1 months (range: 1.3–113.4), 5-year EFS, OS and local control rate (LCR) were 34±3.5%, 52.5±4.7% and 59.5±4.8%, respectively. Multivariate analysis of prognostic factors is shown in the Table. Conclusions: This is largest data of localized PNET from Asia which identified unique prognostic factors. Localized PNET constituted 60% of entire cohort with delayed presentation. High WBC may be a marker of micrometastatic disease or an adverse paraneoplastic response. Skeletal primary and tumor diameter &gt;8 cm predicted inferior OS and LCR; additionally radical radiotherapy predicted inferior LCR. All efforts should be made to resect primary tumor post-NACT as radical radiotherapy alone despite good NACT response results in inferior LCR. [Table: see text]
Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction
Authors: Scott D. Solomon, John J.V. McMurray, Inder S. Anand, Junbo Ge, Carolyn S.P. Lam, Aldo P. Maggioni, Felipe Martinez, Milton Packer, Marc A. Pfeffer, Burkert Pieske, Margaret M. Redfield, Jean L. Rouleau, Dirk J. van Veldhuisen, Faiez Zannad, Michael R. Zile, Akshay S. Desai, Brian Claggett, Pardeep S. Jhund, Sergey A. Boytsov, Josep Comin-Colet, John Cleland, Hans-Dirk Düngen, Eva Goncalvesova, Tzvetana Katova, Jose F. Kerr Saraiva, Małgorzata Lelonek, Bela Merkely, Michele Senni, Sanjiv J. Shah, Jingmin Zhou, Adel R. Rizkala, Jianjian Gong, Victor C. Shi, Martin P. Lefkowitz
Journal: New England Journal of Medicine (2019)

The angiotensin receptor–neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor–neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear.