tbuckley/cabot-search huggingface dataset:
Metastasectomy for Abdominal Visceral Oligometastatic Melanoma
Authors: Danielle K. DePeralta, Jonathan S. Zager
Journal: JAMA Surgery (2017)

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 Surgery 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 Surgery journal
Expression of the double-strand RNA activated protein kinase (PKR) and its prognostic significance in patients with locally advanced rectal cancer
Authors: H.-J. Kim, H.-C. Kwon, M. S. Roh, S.-H. Kim, J.-S. Kim, H.-S. Lee, K.-J. Park, H.-J. Choi
Journal: Journal of Clinical Oncology (2004)

3643 Background: The interferon induced, dsRNA-activated, protein kinase, PKR is a key regulator of translational initiation, playing an important role in the regulation of cell proliferation, apoptosis, and transformation. Increased expression of PKR has been shown to correlate with better patient prognosis in head and neck cancer ( Haines et al. Arch. Otolaryngol. Head Neck Surg. 1993). The aim of this study is to identify the prognostic significance of PKR in locally advanced rectal cancer. Methods: One hundred nine patients had potentially curative surgical resection and were treated with chemoradiation therapy followed by 5-fluorouracil based chemotherapy. Paraffin embedded tumor tissue was collected and evaluated in 92 patients. Samples were immunohistochemically stained with the monoclonal antibody TJ4C4. Overall scores for PKR expression were calculated based on staining intensity and percentage of immunoreactive tumor cells. Clinical information including tumor grade, stage, carcinoembryonic antigen (CEA), disease-free survival (DFS), and overall survival (OS) was evaluated and compared by PKR expression. Results: The median follow-up duration was 30 months. The PKR score was not related to the tumor grade, stage, CEA level. The relapse rate was lower in high PKR score group (>7.0) than low PKR score group, though statistically insignificant (27.5% vs. 41.5% p=0.158). There was no significant difference in 5-year DFS (70.2% vs. 47.1%, p=0.3575) and 5- year OS (74.3% vs. 53.9%, p=0.9283) between the two groups. Cox regression multivariate analyses showed that new AJCC stage and tumor differentiation were significant independent prognostic factors in both DFS and OS. Conclusions: The levels of PKR expression were not associated with clinical outcome in locally advanced rectal cancer patients. No significant financial relationships to disclose.
<i>NRAS</i> and <i>BRAF</i> mutations in atypical melanocytic lesions arising in melanoma patients treated with vemurafenib.
Authors: Emily Y. Chu, Melissa Wilson, Joseph Sobanko, Christopher Miller, EunRan Suh, Wei Xu, Richard Letrero, Rosalie Elenitsas, Giorgos Karakousis, Xiao wei Xu, David Elder, Ravi K. Amaravadi, Lynn Mara Schuchter, Katherine L. Nathanson
Journal: Journal of Clinical Oncology (2013)

9017 Background: BRAF inhibition with targeted therapy has demonstrated improved overall survival in patients with BRAF mutant melanoma. The use of the selective BRAF inhibitors vemurafenib and dabrafenib are associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas often associated with RAS mutations. Preclinical evidence indicates that BRAF inhibitors may give rise to non-melanoma tumors by promoting MAPK activation in the tissues that lack mutant BRAF. Here we report atypical melanocytic lesions arising in patients treated with the BRAF inhibitor vemurafenib. Methods: To characterize the mutations of both the melanoma tumors and the atypical melanocytic lesions arising in patients with BRAF V600E/K melanoma treated with vemurafenib, a custom Sequenom panel designed to detect 74 mutations in 12 genes known to play a role in the pathogenesis of melanoma was applied to both melanoma and atypical melanocytic lesions for each patient. Results: We observed a total of six atypical melanocytic lesions (melanoma in situ and severely dysplastic nevi) in three patients undergoing treatment with vemurafenib. Mutations analysis in both pre-treatment tumor samples and on-treatment melanocytic lesions was feasible in two of the three patients. One patient with BRAF V600E metastatic melanoma developed two new melanoma in situ lesions while on vemurafenib, diagnosed 10 and 23 weeks after starting vemurafenib. Both on-treatment melanoma in situ lesions were found by Sequenom analysis to be BRAF wild-type, with a NRAS Q16R detected in one of the two lesions. Another patient’s pre-treatment primary melanoma demonstrated synchronous BRAF kinase domain mutations V600K and G466A, and CTNNB1 D32E mutation; a severely dysplastic nevus which arose after 25 weeks on vemurafenib in this patient showed only a BRAFG466A mutation. Conclusions: We identified an NRAS mutation and a rare BRAF kinase domain mutation in atypical melanocytic lesions that arose in patients treated with vemurafenib. Further studies are warranted to demonstrate a causal relationship between BRAF inhibition and the development or accelerated growth of atypical melanocytic lesions.
Prognostic significance of Bcl-xL in human hepatocelluler carcinoma
Authors: J. Watanabe, F. Kushihata, K. Honda, N. Kobayashi
Journal: Journal of Clinical Oncology (2004)

9731 Background: Proliferation and apoptosis of liver cancer cells are closely related phenomena. We investigated the correlation between overexpression of Bcl-xL, an anti-apoptosis-related protein of the Bcl-2 family, and the clinical course of hepatocellular carcinoma (HCC). Methods: Specimens from seven HCC patients were used for western blotting and immuno-electron microscopy. Samples from 33 HCC patients who had undergone hepatectomies were used for immunohistochemical staining. The degrees of Bcl-xL expression and Ki-67 as an index of HCC mitosis severity were each classified into two groups. Results: Using western blotting, enhanced immunoreactivity of Bcl-xL was found in cancerous specimens. Bcl-xL overexpression was found in cancer specimens in 21 of 33 patients (63.6%). The overall survival (p=0.019) and disease-free survival (p=0.030) rates of the group overexpressing Bcl-xL were definitely poorer. The Ki-67 higher labeling index (L.I.>10) group had a poorer survival rate (p=0.016). There were significant correlations between Bcl-xL and overall and disease-free survival. Multivariate analysis revealed that Bcl-xL, tumor size, histological portal invasion, and histological metastatic foci were independent prognostic factors for overall and disease-free survival. Conclusions: These results showed that Bcl-xL in HCC specimens, suggesting that Bcl-xL was a significant prognostic factor for disease progression in human HCC. No significant financial relationships to disclose.
All <b><i>trans</i></b>-retinoic acid modulates survival signaling in dormant breast cancer cells
Authors: R. Wieder, V. Joseph
Journal: Journal of Clinical Oncology (2004)

654 Background: At the time of diagnosis, early stages of breast cancer already have microscopic metastases in the bone marrow. These metastases are resistant to adjuvant chemotherapy. The mechanisms of this resistance are not understood. In a model we developed, fibroblast growth factor 2 (FGF-2), present in large deposits in the bone marrow stroma, inhibits proliferation of well-differentiated breast cancer cells and induces a state of dormancy. In turn, FGF-2 also induces an increased expression of integrins α5 and β1. Through these integrins, the cells bind fibronectin and activate survival signaling through the PI3 kinase/Akt pathway. Disruption of this signaling may induce cell death in the dormant cells or render them susceptible to cytotoxic therapy. Retinoids, that have reported activity against cancer cells, have been shown to modulate Akt phosphorylation. Methods: We investigated the role of all trans-retinoic acid (ATRA) in inhibiting Akt activation in dormant clones and their survival. Two well-differentiated breast cancer cell lines, MCF-7 and T-47D were used in the studies. Cells were incubated with FGF-2 10 ng/ml in fibronectin-coated tissue culture plates at clonogenic densities and ATRA was added at variable concentrations after three days in culture for an additional three or six days. Colonies of 2–10 cells (dormant clones) were counted and lysates were analyzed by Western blot. Results: FGF-2 upregulated the expression of integrins α5 and β1 on Western blots after three and six days and increased the phosphorylation of Akt and its downstream target GSK-3alpha/beta. Incubation of the dormant cells with ATRA 10-9, 10-8 and 10-7 M resulted in the inhibition of FGF-2-induced Akt phosphorylation. ATRA did not affect the increased expression of integrins α5 and β1 suggesting that this was not the mechanisms of inhibition of Akt phosphorylation. ATRA also inhibited the survival of dormant clones in a dose dependent manner and induced a distressed appearance in the remaining cells. Conclusions: These data suggest that ATRA, which is currently being tested in clinical trials in breast cancer, may have a potential value in the treatment of resistant micrometastases. No significant financial relationships to disclose.
PROPERTIES OF THE CAUSATIVE AGENT OF A CHICKEN TUMOR
Authors: James B. Murphy, Ernest Sturm
Journal: The Journal of Experimental Medicine (1932)

Water extracts of desiccates of certain relatively slow-growing strains of Chicken Tumors I and X, or the exudates from such tumors, definitely inhibited the growth of a mouse sarcoma (Crocker 180), and were without effect on a mouse carcinoma (Bashford 63) or Mouse Tumor S/37, a rapidly growing sarcoma derived from the stroma of a carcinoma. Extensive control tests with extracts from rapidly growing chicken tumors, and from tissues of normal and immune chickens showed no inhibiting action. There was no demonstrable action on the mouse tumors of sera from immunized rabbits, which neutralize the chicken tumor agent, nor of the sera from chickens highly immune to the chicken tumors.
Abstract 103: Mechanisms Underlying Mitochondrial Translocation Of GSK-3β, A Crucial Inducer Of Mitochondrial Permeability Transition: GSK-3β Activity, Interaction With VDAC2 And A Mitochondrial Targeting Sequence.
Authors: Masaya Tanno, Atsushi Kuno, Satoko Ishikawa, Makoto Ogasawara, Toshiyuki Tobisawa, Hiromichi Murase, Tatsuya Sato, Hidemichi Kouzu, Takayuki Miki, Tetsuji Miura
Journal: Circulation Research (2013)

Background: Although glycogen synthase kinase-3β (GSK-3β) is mainly localized in the cytosol in cardiomyocytes, mitochondrial GSK-3β has been shown to trigger permeability transition and cell death. In this study, we examined molecular mechanisms of the mitochondrial translocation of GSK-3β. Methods and Results: H9c2 cells were transfected with EGFP-tagged GSK-3β (WT) or kinase-deficient GSK-3β (K85R) and stained with MitoTracker Red. Observation by time-lapse microscopy (Eclipse Ti-E, Nikon) revealed that WT, but not K85R, translocated from the cytosol to mitochondria and induced cell death after exposure to H2O2. Two-dimensional gel electrophoresis of anti-GSK-3β-immunoprecipitates obtained from H9c2 cell lysates indicated that exposure to H2O2 down-regulated 4 spots and up-regulated 9 spots. LC/MS analysis revealed that one of the up-regulated spots contained voltage-dependent anion channel (VDAC) 2. Transfection of H9c2 cells with VDAC2-siRNA attenuated mitochondrial translocation of WT in response to H2O2 challenge (% of GSK-3β-positive mitochondria to total mitochondria =36±3% vs. 76±3%, p&lt;0.05). Furthermore, observation with a super-resolution microscope (N-SIM, Nikon) revealed that knockdown of VDAC2 reduced mitochondrial swelling and fragmentation caused by repetitive laser exposure compared with control cells (78±3% vs. 53±12%, p&lt;0.05). Based on similarities to known mitochondrial targeting sequences (MTSs), we hypothesized that GSK-3β contains an MTS consisting of N-terminal 15 amino acid residues dotted with positively charged amino acid residues, R4, R6 and K15. To test this hypothesis, one of these amino acid residues was replaced with alanine. R6A and K15A, but not R4A, showed significant attenuation in mitochondrial translocation after exposure to H2O2 compared with WT (51±5%, 45±5%, 75±7% vs. 76±3%, respectively). Conclusion: Kinase activity of GSK-3β and interaction with VDAC2 significantly promote translocation of GSK-3β to mitochondria, contributing to cell death. An N-terminal domain of GSK-3β, possibly as an MTS, mediates its mitochondrial translocation in response to oxidative stress.
Prognostic role of histological regression in primary cutaneous melanoma: a systematic review and meta-analysis
Authors: M.R. Gualano, S. Osella-Abate, G. Scaioli, E. Marra, F. Bert, E. Faure, E.S. Baduel, E. Balagna, P. Quaglino, M.T. Fierro, R. Siliquini, S. Ribero
Journal: British Journal of Dermatology (2017)

The prognostic significance of histological regression in primary melanoma has been debated for many years. We aim to review the evidence to see how histological regression may affect prognosis. A systematic review was performed by searching in MEDLINE, Scopus and the Cochrane Library from 1 January 1966 to 1 August 2015. All studies reporting hazard ratios or data on survival and histological regression were included. Primary random‐effects meta‐analyses were used to summarize outcome measures. Heterogeneity was assessed using the χ2‐test and I2‐statistic. To assess the potential bias of small studies we used funnel plots and the Begg and Mazumdar adjusted rank correlation method. Summaries of survival outcomes were measured as hazard ratios or relative risk of death at 5 years according to the presence of histological regression of primary melanoma. In total, 183 articles were reviewed out of 1876 retrieved. Ten studies comprising 8557 patients were included. Patients with histological regression had a lower relative risk of death (0·77, 95% confidence interval 0·61–0·97) than those without. Examination of the funnel plot did not provide evidence of publication bias. The results showed that histological regression is a protective factor for survival.
Targeting therapy based on preclinical analysis of clinical, molecular, and functional characteristics of individual high-grade serous ovarian cancers.
Authors: Monique Topp, Lynne Hartley, Michele Cook, Dariush Etemadmoghadam, Laura Galleta, Jan Pyman, Orla McNally, Paul Haluska, Elizabeth M. Swisher, Scott H Kaufmann, Matthew Wakefield, David Bowtell, Clare L. Scott
Journal: Journal of Clinical Oncology (2012)

5073 Background: Recent molecular exploration of high-grade epithelial ovarian cancer (OC) has revealed potential targets for novel therapy based on altered DNA repair function, deregulated pathways and recurrent amplifications (Cancer Genome Atlas Research Network. 2011. Nature 474). Improved pre-clinical models allowing analysis of specific molecular subsets of ovarian cancer are urgently required to test novel treatment strategies. Methods: We have generated a novel xenograft model of human high-grade serous OC (HG-SOC). Histologic, functional and molecular analysis of the novel xenograft cohort (at baseline and following xenotransplantation) allows stratification of individual HG-SOC for testing with appropriate targeted therapy. We perform functional analysis of in vitro Homologous Recombination (HR) DNA repair and drug response capabilities on fresh human HG-SOC immediately following surgical resection. Molecular classification (similar to Tothill [Clin Canc Res. 2008;14]); analysis of NHEJ pathway (Proc Natl Acad Sci. 2011;108) and other DNA repair genes (Proc Natl Acad Sci USA 2011;108) is performed. In vivo drug response is studied in murine xenografts. Results: Sixteen chemotherapy-naive potentially HG-SOC samples and associated clinical data have been collected. Functional evidence of DNA repair (HR) capability and response to DNA damaging agents will be presented, including IHC for markers of DNA damage (gH2AX), DNA repair (RAD51AP1) and apoptosis (capsase 3 cleavage). Molecular classification, DNA repair gene and DNA repair pathway analyses are underway. Twelve HG-SOC have been transplanted and 6 of the first 8 have successfully xenografted, with serial transplantation and phenotyping of xenograft derivatives underway. In vivo drug response will be presented. Conclusions: This xenograft model will enable us to address hypotheses generated by recent molecular analyses of human HG-SOC (Cancer Genome Atlas Research Network. 2011. Nature 474; Clin Canc Res. 2008;14). Clinical, functional and molecular annotation will allow pre-clinical drug testing based on the plausible hypothesis approach.
Design of Y-shaped targeting material for liposome-based multifunctional glioblastoma-targeted drug delivery
Authors: Zakia Belhadj, Man Ying, Xie Cao, Xuefeng Hu, Changyou Zhan, Xiaoli Wei, Jie Gao, Xiaoyi Wang, Zhiqiang Yan, Weiyue Lu
Journal: Journal of Controlled Release (2017)
Phase I study of the anti-neovascular agent MBT-0206 to evaluate safety and efficacy in patients with metastatic or advanced unresectable gastrointestinal cancer (GI cancer)
Authors: K. Ridwelski, E. Kettner, J. Fahlke, K. Bartelheim, M. Hitzl, B. Schulze, R. Koeber, U. Michaelis, K. Naujoks, M. R. Clemens
Journal: Journal of Clinical Oncology (2004)

3163 Background: MBT-0206 is a highly innovative anti-neovascular cytostatic compound designed to target and destroy newly formed tumor blood vessels. Its superior anti-tumor activity based on this new concept has been shown in several animal models. A phase I clinical study was conducted to determine dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and to explore anti-tumor activity. Methods: MBT-0206 was administered as intravenous short infusion at 4 dose levels (lipid-complexed paclitaxel mg/kg body weight (b.w.): 0.28 (n=8), 0.55 (n=8), 1.1 (n=10) and 1.65 (n=5)) on day 1, 3, 5 of a 4 week cycle. Up to 3 cycles were administered to patients with metastatic, unresectable GI cancer and tumor progression after standard chemotherapy. Safety was assessed on the basis of reported adverse events and efficacy was measured as objective tumor response according to WHO criteria. The studies were accompanied by quantitative analysis (LC-MS/MS) of paclitaxel and the main cationic lipid compound. Results:Non-haematological DLTs were observed in a dose dependent manner with the strongest incidence in the highest dose group. The main DLTs were fatigue and hypersensitivity. Other side effects commonly occurring with conventional chemotherapy were not observed. Haematological DLTs were detected only in the highest treatment group. The MTD was defined as 1.1 mg/kg b.w. lipid-complexed paclitaxel on a 3 times a week schedule. The overall assessment of tumor response performed at the first follow-up examination resulted in 13% stable disease. Conclusions: MBT-0206 showed a very good tolerability and low levels of mild side-effects. Therefore MBT-0206 will be suitable for prolonged treatment regimens and also for treatment in combination with conventional chemotherapeutics. There is no indication for paclitaxel accumulation and prolonged circulation of paclitaxel due to lipid complexation. The lipid compound showed a lower clearance, however only 2–5% remained in circulation after 24h. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Munich Biotech AG Munich Biotech Munich Biotech
Retrospective analysis of health care resource utilization in patients (pts) with ipilimumab-refractory (IPI-R) melanoma covered in a large U.S. claims database.
Authors: Eric D. Whitman, Xiting Cao, Kendall Lee Stevinson, Ashwini Arunachalam, Panagiotis Mavros
Journal: Journal of Clinical Oncology (2015)

e20056 Background: IPI represents a major advance in melanoma treatment. However, not all pts respond to IPI, and they may become IPI-R after an initial response or disease stabilization. We investigated the health care resource utilization of IPI-R pts in the community oncology setting. Methods: Subjects eligible for inclusion in this retrospective analysis of the Truven Health MarketScan commercial and Medicare supplemental database had a confirmed melanoma diagnosis, were aged ≥ 18 y, had ≥ 1 claim with a National Drug Code (NDC) or J code for IPI between Mar 1, 2011, and Mar 31, 2013, and were continuously enrolled in the database during the 6-month period before the earliest NDC or J code for IPI. Pts were followed until Dec 31, 2013. IPI-refractory melanoma was defined as receipt of ≥ 2 IPI doses followed by a claim for a different anticancer therapy within 24 wk after the last IPI dose. Health care resource utilization included inpatient admissions, outpatient visits, imaging procedures, therapeutic interventions, and diagnostic procedures. Codes associated with known complications of IPI were also examined before and after pts became IPI-R. Results: Of the 805 pts who met the inclusion criteria, 108 (13%) had IPI-refractory melanoma. The most common initial therapies given after IPI were vemurafenib (30%), temozolomide (26%), carboplatin + paclitaxel (23%), dacarbazine (6%), and paclitaxel (6%). Among refractory pts, 52% had an inpatient admission, 24% visited the emergency department, 32% entered a nursing facility or hospice, and 40% underwent surgery. The proportion of pts with claims associated with managing known immune-related complications before and after becoming IPI-R are shown (Table). Conclusions: In this real-world melanoma population, 13% of pts were IPI-R (ie, received ≥ 2 IPI doses followed by another anticancer therapy). Health care resource utilization and known IPI complications were frequent. This analysis likely underestimates the proportion of pts whose disease becomes refractory to IPI. Complication Before Refractory, % After Refractory, % Gastrointestinal 51 54 Pulmonary 40 52 Dermatologic 28 39 Hepatic 16 19 Endocrine 22 13