tbuckley/cabot-search huggingface dataset:
Tyrosine kinase inhibitors and QTc intervals: A class effect.
Authors: Jacqueline S.L. Kloth, Anna Pagani, Michiel C. Verboom, Alberto Malovini, Carlo Napolitano, Willem H.J. Kruit, Stefan Sleijfer, Neeltje Steeghs, Alberto Zambelli, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2014)

2590 Background: Tyrosine kinase inhibitors (TKIs) are reported to be associated with prolongation of the QTc interval on the ECG. QTc interval prolongation increases the risk for life threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and consist of small patient numbers. Methods: We screened all patients from 4 centers in the Netherlands and Italy, who were treated with TKIs. To evaluate the effects of TKIs on the QTc interval we investigated ECGs prior to and during treatment with sunitinib, vemurafenib, sorafenib, pazopanib, imatinib, erlotinib, lapatinib or gefitinib. All ECGs were reviewed by a single cardiologist (CN). Outcomes of this study were quantitative change in QTc interval (ΔQTc) after start of TKI treatment and chance of becoming a high risk individual, defined as QTc ≥ 470 milliseconds (ms), adjusted for risk factors such as for K+/Ca2+levels, co-medication, age, gender and co-morbidity. Results: A total of 363 patients had ECGs taken prior to and during TKI treatment and were therefore eligible for the analyses (see Table). In the entire group, start of TKI resulted in a significant increase in QTc interval (QTcbaseline = 401 ms vs QTctreatment= 415 ms, p < 0.0001). After correction for possible confounders (site, tumor type, ethnicity, TKI, time between ECGs), sunitinib, vemurafenib, sorafenib, imatinib and erlotinib showed a significant increase in QTc interval after start of treatment (p < 0.01). Especially patients treated with vemurafenib are at increased risk of having QTc ≥ 470 ms (p < 0.05). Conclusions: These observations show that most TKIs give rise to a significant increase in QTc interval. In vemurafenib treated patients, the incidence of patients who are at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, frequent ECG controls in patients treated with TKIs are required. TKI N QTc (ms) p-value N QTc ≥ 470 ms ΔQTc ≥ 30 ms Baseline Treatment Baseline Treatment N Whole 363 401 415 0.0001 6 21 76 Sunitinib 110 393 406 0.0001 1 3 22 Vemurafenib 67 401 427 0.0001 1 8 23 Sorafenib 52 400 410 0.0015 1 2 11 Pazopanib 46 402 412 0.0792 1 2 6 Imatinib 41 410 425 0.002 1 1 8 Erlotinib 21 412 421 0.0043 0 2 3 Lapatinib 16 413 414 0.9822 1 1 1 Gefitinib 10 403 409 0.92 0 2 2
Results of the first-in-human phase I trial assessing MSC2156119J (EMD 1214063), an oral selective c-Met inhibitor, in patients (pts) with advanced solid tumors.
Authors: Gerald Steven Falchook, David S. Hong, Hesham M. Amin, Siqing Fu, Sarina Anne Piha-Paul, Filip Janku, J. Gabrielle Granda, Hongxia Zheng, Manfred B. Klevesath, Karola Köhler, Friedhelm Bladt, Andreas Johne, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2014)

2521^ Background: MSC2156119J, a selective c-Met inhibitor, suppresses tumor growth in preclinical models. Methods: Primary endpoint of this dose-escalation study (3+3 design; NCT01014936): to assess an MTD; secondary endpoints: antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (Pd). Pts received 1x/d oral MSC2156119J (21-d cycles; 3 regimens [R]): d1–14 followed by 7-d rest (R1); 3x/wk (R2); or d1–21 (R3). An optimized formulation (OF) was introduced in Aug 2011. Results: Up to Nov 25, 2013,126 pts were analyzed (R1=42; R2=45; R3=39). On the initial formulation, doses were escalated from 30–230 mg/d in R1 and 30–115 mg/d in R2; on the OF (R1–3): 30–400 mg/d, 60–315 mg/d, and 300–1400 mg/d. AUC and Cmax increased with dose; bioavailability was higher with OF. An MTD was not reached. Six pts reported dose-limiting toxicities: asymptomatic G4 lipase and G3 amylase increase (R1; 115 mg/d), G3 nausea and vomiting (R2; 130 mg/d; OF), asymptomatic G3 lipase increase (R2; 60 + 100 mg/d; OF), G3 fatigue (R3; 1400 mg/d; OF), and G3 ALT elevation (R3; 1000 mg/d; OF). Other ≥G3 treatment-related adverse events (trAEs) were G3 peripheral edema (1 pt; R3; 300 mg/d; OF) and G3 AST elevation (1 pt; R3; 1000 mg/d; OF). Most frequent G2 trAEs (R1–3): fatigue (n=8), peripheral edema (n=3), vomiting (n=3), nausea (n=2), asymptomatic lipase increase (n=2), and neutropenia (n=2). 79% of pts had no trAE >G1. Pre- and on-therapy tumor biopsies showed phospho-c-Met inhibition in 19/21 evaluable pts. One pt (esophageal adenocarcinoma) had confirmed partial response (PR); 2 pts (nasopharyngeal and colorectal carcinoma) had unconfirmed PRs. Stable disease (SD) ≥4 mo was seen in 18 pts, incl. 1 pt with SD >32 mo. Based on preclinical PK/Pd models and clinical Pd data, 500 mg was considered biologically active and sufficient to reach ≥95% target inhibition. Conclusions: MSC2156119J was well tolerated and showed antitumor activity. Recommended phase II dose (RP2D) is 500 mg 1x/d. Dose escalation was stopped at 2.8xRP2D (1400 mg/d). An MTD was not reached. Additional Pd and biomarker data (c-Met status by immunohistochemistry [IHC] and in situ hybridization) will be presented. Clinical trial information: NCT01014936.
Cherry Angiomas—Further Expanding the Phenotype With Somatic <i>GNAQ</i> and <i>GNA11</i> Mutations
Authors: Dawn H. Siegel
Journal: JAMA Dermatology (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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Dermatology journal
Development of First-in-Class Histone Acetyltransferase (HAT) Activators for Precision Targeting of Epigenetic Derangements in Lymphoma
Authors: Yuxuan Liu, Jole Fiorito, Yulissa Gonzalez, Elisa Zuccarello, Elisa Calcagno, Adolfo Mazzeo, Nebiyu Ali Abshiru, Jeannie Camarillo, Neil L Kelleher, Changhong Qiao, Renu Nandakumar, Cremers Serge, Shixian Deng, Donald Landry, Owen A. O'Connor, Ottavio Arancio, Jennifer E Amengual
Journal: Blood (2018)
Meta-analysis of public microarray databases for prognostic and predictive gene signatures of late-stage ovarian cancer.
Authors: Michael J. Birrer, Markus Riester, Wei Wei, Levi Waldron, Aedin Culhane, Lorenzo Trippa, Esther Oliva, Sunghoon Kim, Franziska Michor, Curtis Huttenhower, Giovanni Parmigiani
Journal: Journal of Clinical Oncology (2014)

5531 Background: Numerous gene signatures of patient prognosis for late-stage, high-grade ovarian cancer have been published, but diverse data and methods have made these difficult to compare objectively. However, the corresponding large volume of publicly available expression data creates an opportunity to validate previous findings and to develop more robust signatures. Methods: We built a database of uniformly processed and curated public ovarian cancer microarray data and clinical annotations, and re-implemented and validated 14 prognostic signatures published between 2007 and 2012. Results: For the microarray datasets investigated, twelve published models performed better than 97.5% of randomized risk scores, and six out-performed 97.5% of random signatures of the same size trained on the same data. The most accurate prognostic model was that of The Cancer Genome Atlas Consortium. By meta-analysis and “leave-one-dataset-out cross-validation” of 1,622 samples we generated and tested a prognostic signature that improved on all previously published signatures. In addition, we established a predictive signature for suboptimal surgical debulking which was 90% accurate and validated by immunohistochemistry. The debulking signature reveals activated TGF-beta pathway which promotes tumor migration, invasion and progression. Conclusions: The debulking signature, if further validated, has the potential to change clinical practice by identifying women for triage to alternative adjuvant therapy and interval debulking.
Effects of iron nanoparticles on the growth of Pliss's lymphosarcoma.
Authors: Irina Aleksandrovna Goroshinskaya, Polina Sergeevna Kachesova, Ludmila Anatolievna Nemashkalova, Oleg Evgenevich Polozhentsev, Oleg Eduardovich Losev, Vladimir Borisovich Borodulin
Journal: Journal of Clinical Oncology (2014)

e14011 Background: The study of the anticancer activity of iron nanoparticles (Fe NPs) measuring 70-75 nm in rats transplantable tumors Methods: Experiments were carried out on white outbreed male rats with transplanted Pliss’s lymphosarcoma (Pliss). In 6 days after tumors transplantation the animals began to receive Fe NPs four times a week during two weeks with a week's break. Nanoparticles in 0.9% w/v of NaCl were injected intratumorally (group 1) or intraperitonially (group 2). In control group rats with lymphosarcoma received intraperitonially 0.3 ml of saline only. Fe NPs were spherical in shape and had an oxide film on its surface. The investigation by X-ray absorption near edge spectroscopy showed that used nanoparticles represented metal iron and weren't oxidized in physiological solution. Effect on tumor growth of Fe NPs was determined by tumor size and mass. Results: 8-fold administration of the iron nanoparticles at a dose of 1.25 mg/kg body weight to Pliss rats independently of injection way led to tumor regression in the most of animals. Thus at 10 animals from 20 ones the volume and mass of a tumor were equal to zero, at 2 animals averaged 0.16 cm3 and 0.03 g (that also belongs to full regression), at 2 animals – 14 cm3 and 27 g (decrease in the sizes of a tumor relatively average values of control group for 82.2% on volume and for 71.5% on mass) and only at 6 animals tumor growth (the average volume of 83.5 cm3, average mass of 120.2 g) was recorded. In general, the percentage of tumor growth inhibition was 66.3% for the tumor volume and 59.1% for the mass of the tumor nodule. The index of efficiency of influence of iron nanoparticles was equal 2.45. It was accompanied by decrease in level of molecules of average weight for 13% and increase in effective concentration of albumine at 77% that led to decrease in an index of toxicity by 11 times and intoxication coefficient for 57%. Conclusions: Introduction of Fe NPs to Pliss rats leads to full or partial regression of a tumor at 70% of animals and at all studied animals promotes considerable decrease in endogenous intoxication, characteristic for tumoral process that represents potential interest for antineoplastic therapy. The reported study was supported by RFBR, research project No. 14-04-32046 мол_a.
Physician communication on cost of cancer care under the Affordable Care Act.
Authors: Laura LaNiel Tenner, Paul R. Helft
Journal: Journal of Clinical Oncology (2014)

6554 Background: The steeply rising cost of cancer care in the United States adversely impacts the economy as well as patient emotional well-being and financial stability. The aim of this study was to assess U.S,oncologists’ attitudes and perceptions about the cost of cancer care in the wake of ACA implementation. Methods: From June through August 2013, a survey instrument was emailed to practicing oncologists in 50 states. Survey items included assessments of self-reported practices concerning communication of cost of therapy as well as influences of the ACA. Other survey items assessed oncologists’ perceptions of cost effectiveness data. Results: The electronic survey response rate was 16% with respondents from 35 states. Respondents were more likely to strongly or somewhat agree that it was important to discuss out-of-pocket costs [OPC] (89%) and healthcare system costs [HSC] (66%) with patients, p<0.0001. 70% reported that OPC of therapy influence their treatment decisions. 60% agreed that OPC and HSC of cancer treatments were likely or extremely likely to have a larger effect on their decisions regarding which cancer treatments to recommend to patients in the future under the ACA. While 4% agreed the government should play a role in determining the value of a cancer therapy, 53% of respondents thought that government price controls for cancer drugs were needed. A large majority agreed that physician education on the use of cost-effectiveness data (91%) and communicating cost of therapies with patients (85%) was needed. Conclusions: U.S. oncologists reported that they desire more cost and comparative effectiveness research as well as more education on how to communicate with patients about costs of therapy. Respondents perceived that both OPC and HSC will play a larger role in their cancer treatment decisions over the next five years, and that they will need to increase their communication with patients about both OPC costs as well as HSC. Respondents appeared divided on the topic of government intervention on pharmaceutical price controls and unified in their resolve to maintain control of decisions on the value of therapy.
Abstract 19131: Stent-Based Vascular Cell Delivery for Therapeutic VEGF-Induced Angiogenesis
Authors: Noel M Caplice, Brendan Doyle, Arun H Kumar, Kenneth Martin, Mohammed T Ali, Kimberley A Skelding, Shaohua Wang, Birgitta Gleeson, Erik L Ritman, Stephen J Russell
Journal: Circulation (2013)

Site specific targeting remains an elusive goal for stem cell and gene therapies in the cardiovascular field. One promising option involves use of modified 3D stent designs that deliver larger cell/gene payloads to specific disease sites using the versatility of percutaneous vascular access. Here, we engineered smooth muscle cells (SMCs) placed in a 3D metallic stent scaffold to deliver high local concentrations of an angiogenic gene (VEGF165) in a porcine model of chronic total occlusion involving ameroid placement on the proximal left circumflex (LCx) artery(n≥8 per group). Engineered SMCs were retained within the mesh stent structure (479 ± 47.4 SMC/mm2) and were competent for VEGF production in vitro (8.8 ± 1.8 ng/ml in media). Following implantation, micro CT analyses revealed that stents loaded with VEGF producing SMCs significantly enhanced vasa vasora microvessel density (5.43 ± 0.46 vs 2.14 ± 0.19 vessels/mm2, p&lt;0.001) with a concomitant increase in tissue VEGF protein levels (277.9 ± 85.7 vs 18.8 ± 4.4 pg/mg protein, p&lt;0.0001). Formation of endothelial cell colonies from peripheral blood mononuclear cells was significantly increased with the implantation of VEGF-secreting cells suggesting increased angiogenic potential (7.0 ± 2.0 versus 41.6 ± 4.5, EC:CFU p&lt;0.0001). VEGF secreting mesh stent placement enhanced regional blood flow analyses determined by microsphere analyses as well as improving regional wall motion in the LCx-related territory (p&lt;0.05) as well as left ventricular function assessed in terms of ejection fraction (34.2 ± 6.7% vs 61.2 ± 5.2% P&lt;0.001) and dp/dt (p&lt;0.001) Our data indicate robust clinically relevant angiogenesis can be achieved in a human scale porcine chronic vascular occlusion model following stent based delivery of angiogenic cells. This may have implications for percutaneous delivery of stem cells, genes and secreted therapeutic factors in cardiovascular disease in general and in creation of percutaneous microvascular bypass networks in the setting of chronic vaso-occlusive disease in particular.
The comparison diameter-axial-polar nephrometry with R.E.N.A.L nephrometry score in patients with cT1a renal cell carcinoma who underwent laparoscopic surgery.
Authors: Yoshio Naya, Fumiya Hongo, Masakatsu Oishi, Takashi Ueda, Hiroyuki Nakanishi, Terukazu Nakamura, Kazumi Kamoi, Koji Okihara, Tsuneharu Miki
Journal: Journal of Clinical Oncology (2014)

e15592 Background: In this study, we compared Diameter-Axial-Polar nephrometry (DAP) with R.E.N.A.L. nephrometry score (R.E.N.A.L-NS) for decision-making in surgical treatment for cT1a RCC patients and proposed optimal cut-off of DAP. Methods: A retrospective review of our institution’s prospectively maintained and Institutional Review Board-approved database (January 2003 to February 2010) was performed. 142 patients with cT1aN0M0 lesions who underwent treatment were identified. Treatment methods were 68 laparoscopic nephrectomies (LRN), 74 laparoscopic partial nephrectomies (LPN). The clinicopathological characteristics including R.E.N.A.L-NS and DAP were retrospectively analyzed for the entire cohort. Statistical analyses were calculated using SAS. Results: In the LRN group, the tumor size was larger than that in LPN (30mm vs. 20mm, p<0.0001). The R.E.N.A.L-NS and DAP in the LRN group was significantly higher than that in the PN group (R.E.N.A.L.-NS; 9 vs. 7, DAP; 7 vs. 5, p<0.0001 respectively). A multivariate logistic regression analysis for election of PN showed that tumor size (<2cm), R.E.N.A.L-NS, DAP, and imperative condition (solitary kidney) were independent factors. DAP is a strongest independent factor for decision making for performing LPN. The ROC-AUC of DAP and R.E.N.A.L NS for performing LPN were 0.897 and 0.825, respectively. Based on ROC analysis, when DAP was 6 or less, or R.E.N.A.L.-NS was 8 or less, LPN should be considered and when DAP was 7 or more, or R.E.N.A.L.- NS was 9 or more, OPN should be considered. Conclusions: Both R.E.N.A.L.-NS and DAP are useful for decision-making for performing LPN. DAP is a strongest independent factor for decision-making of surgical treatment. OR P value Age (≧ 71) 2.185 0.142 Period (last 58 months) 5.263 0.023 R.E.N.A.L score 55.855 <0.0001 DAP score 101.215 <0.0001 Imperative 4.090 0.045 eGFR<60ml/min 0.867 0.353 Charlson score 0.604 0.438
Tumorspheres cultured from circulating epithelial tumor cells (CETCs) as diagnostic marker in patients with solid cancers.
Authors: Katharina Pachmann, Monika Pizon, Dorothea Zimon, Ulrich A. Pachmann
Journal: Journal of Clinical Oncology (2014)

11043 Background: Metastatic disease is a serious threat and the most common cause of cancer-associated death in patients with solid tumors. The presence of CETCs is closely related to tumor metastasis, but it is still unclear whether all CETCs are capable to proliferate and generate metastasis. Therefore we investigated their proliferative capacity by analyzing the frequency of tumorsphere formation with subsequent phenotypic characterization of the tumorspheres arising in patients with solid tumors. Methods: 37 patients with solid cancer and early metastatic disease and detectable CETCs were enrolled in the present study. 10 patients had breast, 10 colorectal, 10 prostate and 7 lung cancer. CETCs were determined using the maintrac method and the CETCs were cultured in suspension culture in the context of the other white blood cells allowing for epithelial sphere formation. Cell viability, stem cell marker expression and ALDH 1 activity was evaluated by fluorescence scanning microscope (Olympus Scan R). Results: Sphere formation was observed in 90 %, 90 %, 80 % and 85.7 % of patients with breast, colorectal, prostate and lung cancer, respectively. Among solid cancer patients the number of tumor spheres increased significantly with tumor progression, especially with development of distant metastasis. The selectivity for distant metastasis of the area under ROC curve for the number of tumorspheres was 0.72 (p < 0.02). Five or more tumorspheres grouped metastatic disease with a sensitivity and specificity of 88.2 % and 75 %, respectively. Analysis of surface marker expression profile of tumorspheres showed that tumorspheres cultured from CETCs had typical phenotype of cancer stem cells and tumorspheres in patients with breast cancer possessed a high enzymatic activity for ALDH 1 with the ALDEFLUOR assay. There was no sphere formation in 20 healthy donors. Conclusions: Here, we describe for the first time the identification of CETCs which are capable of forming tumorspheres with proliferative activity and stem cell characteristics. This may contribute to the design of tools for early detection of progression and treatment in solid cancer.
Efficacy and toxicity of FOLFOX-4 as a second-line chemotherapy in locally advanced unresectable and metastatic carcinoma gall bladder: A prospective observational study.
Authors: Chandragouda Dodagoudar, Anupam Mahanta, Vikas Goswami, Varun Goel, Dinesh C Doval, Vineet Talwar, Ullas Batra, Sajjan Singh, Deepika Chauhan
Journal: Journal of Clinical Oncology (2014)

e15101 Background: There is no standard second-line chemotherapy after progression on 1st line therapy Gemcitabine and platinum combination chemotherapy, in locally advanced (unresectable) and metastatic Gall bladder cancer (LA/MGBC) patients. So this study was undertaken to assess the efficacy and safety of FOLFOX-4 regimen in this setting. Methods: In this prospective study, patients of LA/MGBC, with performance status ≤2, who progressed on first line therapy, were randomly enrolled from May 2012 to June 2013. FOLFOX-4 based treatment was administered until progression, unacceptable toxicity or up to 12 cycles. The response rates(RR), time to tumour progression(TTP) and overall survival (OS) were analyzed. Toxicity profile was recorded as per common toxicity criteria version 4. Results: Total 50 patients were enrolled. The median age of patients was 52 yrs (32yrs – 66yrs), out of which 16 (32%) were males and 34 (68%) were females. The median no. of cycles could be given were 11 (2-12). Only 50% patients in this study completed full twelve cycles of chemotherapy. 12 patients (24%) in this study required the dose reduction at least in one cycle of chemotherapy due to toxicities. Disease control rate was seen in 31(62%) patients, with CR in none, PR in 12 (24%), SD in 19 (38%) and PD in 19 (38%) patients. The median TTP was 3.8 months, median OS was 6 months. The main grade 3/4 side effects seen were hematological in 28% (n=14) and gastrointestinal in 26% (n=13) patients. Majority of patients (44%) had grade 1/2 peripheral neuropathy. Conclusions: FOLFOX-4 is an effective and well tolerated regimen as a second line treatment in LA/MGBC patients.