tbuckley/cabot-search huggingface dataset:
Correlation of homologous recombination deficiency in head and neck cancer with sensitivity to PARP inhibition.
Authors: Jana Heitmann, Zhixiang Zuo, Paul Geeleher, Michaela K. Keck, Arun Khattri, Mark W. Lingen, Jonas DeSouza, Victoria Meucci Villaflor, Michael Beckett, Ralph R. Weichselbaum, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2014)

6094 Background: Cancers deficient in homologous recombination (HR) exhibit synthetic lethality when treated with poly (ADP-ribose) polymerase (PARP) inhibitors and may be more sensitive to platinum based therapies. While BRCA1/2 mutations are uncommon in head and neck cancer (HNC), we hypothesized that other mechanisms of HR deficiency occur frequently. Methods: We employed three methods to determine homologous recombination deficiency (HRD): (1) HRD-score, (2) Large-scale chromosomal breaks (Popova et al), (3) BRCA-like CN profile (Schouten et al) using HNC TCGA and Chicago HNC Genomic cohort (CHGC) data. We furthermore screened for HR pathway mutations in both genomic cohorts. Single agent activity of three PARP inhibitors (veliparib (non-locking), olaparib and rucaparib (locking)) was evaluated in a panel of 10 HNC cell lines (colony formation, viability) and compared with a BRCA deficient breast cancer cell line. Immunofluorescent staining for γH2AX and RAD51 was performed. A gene signature of HRD deficiency was developed. Results: HR deficiency was present in 25% of HNC, and was largely concordant between all three methods (1. and 2. had the highest correlation), but were not related to BRCA1/2 mutations in HNC TCGA. BRCA1/2 mutations were rare (<1%) and of unclear significance. In a panel of HNC cell lines rucaparib showed the highest potency as a single agent with three cell lines exhibiting sensitivity (IC50: 7.0µM, 10.3µM and 11.7µM), comparable or superior to a BRCA deficient breast cancer cell line (IC50value: 8.9µM). Seven HNC cell lines were more resistant to single agent PARP inhibition. Foci formation of the HR marker RAD51 did not serve as a reliable biomarker in those cell lines, but our newly developed gene expression signature was applicable. Conclusions: In conclusion, we discover that HR-deficiency is present in 25% of HNC tumors, and benefit of single agent PARP inhibition is present in pre-clinical HNC models, despite the general absence of BRCA mutations in this tumor type. HRD-score is a candidate biomarker to identify patients that may benefit from PARP inhibition, including combinations with cytotoxic chemotherapies or radiation in the future.
TREAT-ME 1: Treatment of advanced gastrointestinal cancer in a clinical phase I/II trial with genetically modified mesenchymal stem cells.
Authors: Jobst C. von Einem, Hanno Niess, Marlies Michl, Peter J Nelson, Christine Guenther, Ralf Huss, Volker Heinemann, Christiane Bruns
Journal: Journal of Clinical Oncology (2014)

TPS3122^ Background: Next generation somatic cell-based therapies are at the edge to add another therapeutic modality to clinical oncology particular for malignancies with still high medical need. Based on a vast number of preclinical data, we have initiated a phase I/II clinical trial for the treatment of advanced adenocarcinoma of the gastrointestinal tract applying genetically-modified mesenchymal stem cells (MSC) from the patients' own bone marrow (TREAT-ME 1). Methods: Autologous MSC have the capability to home to any (inflammatory) tumor site or metastasis to deliver therapeutic gene products in a highly effective way. Our pharmaceutical product (IND) is a genetically modified somatic cell suspension. The stable integration of the therapeutic gene (here HSV-TK) under the control of a tumor specific promoter (based on the molecular tumor tissue profile) is accomplished through the use of a gamma-retroviral, replication incompetent and self-inactivating (SIN) vector system. The manufactured MSC cell-suspension is applied intravenously for three consecutive weeks, followed by the administration of the prodrug which is activated only in the context of the tumor environment. The study has started to recruit (Oct 2013) and the first patient cohorts are designed to define the optimal cell dose and feasibility. Safety and tolerability will be evaluated and as secondary variables TTP and OS up to one year. Interim results of the phase I safety phase are expected in 2014. In this trial we have already demonstrated that the genetic modification of autologous MSCs from cancer patients and their manufacturing as an IND is feasible and does not alter the typical biological properties of MSCs. The therapeutic administration of genetically modified MSCs as a principle mechanism of a cell-based gene therapy respectively a gene product delivery tool holds promise for the clinical application of a patient-tailored combination of cell- and suicide gene therapy. We expect this innovative medicinal product will provide high local therapeutic activity and low (off-target) toxicity resulting in a positive safety profile.
Impact from primary and recurrent treatment on survival of FIGO IIIc epithelial ovarian cancer patients.
Authors: Witold Szczesny, Ingvild Vistad, Janne Kaern, Jakob Nakling, Leiv Sandvik, Claes Trope, Torbjørn Paulsen
Journal: Journal of Clinical Oncology (2014)

e16511 Background: To investigate the impact of hospital level on 8-year survival in recurrent advanced epithelial ovarian cancer (EOC) treatment. Methods: Survival in months from primary/secondary/tertiary treatment through first- and second recurrence till death in three following time intervals (TI-1, TI-2, TI-3) was observed in a cohort derived from the Norwegian Cancer Registry. 174 women with EOC FIGO stage IIIC diagnosed during 2002 underwent primary surgery either in teaching (TH) (n=84) or non–teaching hospitals (NTH) (n=90). Results: TI-1: Significantly more extensive surgery at TH resulted in longer survival to the first recurrence or death vs. NTH (10.3 vs. 7.2, HR 1.44, P=0.02). Beyond TI-1 no difference in survival were noticed between TH– and NTH–groups. TI-2: 99 out of 109 recurrent patients were eligible for second line treatment (TH, n=54; NTH, n=45) and 71 platinol sensitive had better survival compared to 28 platinol resistant patients (10.9 vs. 4.3 months, p <0.01, HR=2.07 CI [1.3 – 3.4]. Platinol-based chemotherapy given to platinol sensitive improved survival compared to non-platinol/platinol-resistant patients (11.4 vs. 6.8 months, p<0.01). TI-3: 54 of 66 recurrent patients received chemotherapy. The majority had good performance status, mean age 60 and, received primary extensive surgery followed by 6 cycles of platinol/taxane chemotherapy. Conclusions: The difference in survival between hospital levels lasts to first recurrence due to extensive primary surgery at TH. Platinol sensitive patients had better 2nd line survival. Extensive primary surgery at TH, platinol sensitivity, age and performance status were predictors of survival in this cohort.
The proteolytic cleavage of EGFR is mediated by metalloproteases
Authors: Blanca L. Valle, Marianela Pérez-Torres, Elsa M. Cora
Journal: Cancer Research (2006)

75  We have detected a soluble isoform of the epidermal growth factor receptor (EGFR) in the conditioned culture media (CCM) of the breast adenocarcinoma cell line MDA-MB-468. This isoform is generated by proteolytic cleavage of the full length EGFR. We have demonstrated that the shedding of EGFR is stimulated by phorbol esters, such as PMA and that this shedding is mediated, in part, by activation of the ERK MAP kinase signaling cascade. In addition, the shedding of EGFR is stimulated by its ligands, EGF and TGF-α. To determine whether metalloproteases mediate the shedding of EGFR, the breast adenocarcinoma cell line MDA-MB-468 was incubated in the presence of metalloprotease inhibitors of different specificity: TAPI-2, EDTA, TIMP-1, TIMP-2, and TIMP-3. The levels of soluble EGFR were measured in the CCM by immunoblot analysis using an antibody specific for the extracellular domain of EGFR. The results of these studies shown that the broad spectrum hydroxamate-based inhibitor TAPI-2 and the metal chelator EDTA decreased significantly the constitutive and PMA-induced shedding of EGFR. The matrix metalloprotease inhibitor TIMP-1 decreased the constitutive and PMA-induced shedding to a lesser degree when compared to treatment with TAPI-2 and EDTA. However, TIMP-2 and TIMP-3 had no effect on the shedding of EGFR. These results strongly suggest that the shedding of EGFR in MDA-MB-468 cells is mediated by metalloproteases. We hypothesize that a member of the matrix metalloprotease family might mediate the shedding of EGFR. Current efforts are focused in the identification of the metalloprotease(s) involved in the shedding of EGFR. Supported by the NIH/NCI (CA73859 and CA85133), NIH/MBRS-SCORE (2-S06 GM 08224), NIH-COBRE (P200RR016439) and MDACC/PRCC (U54-CA096297)
Surveillance for asymptomatic recurrence in resected stage III colon cancer (CC): Does it result in a more favorable outcome?
Authors: Martin Smoragiewicz, Howard John Lim, Renata D'Alpino Peixoto
Journal: Journal of Clinical Oncology (2014)

3612 Background: Evidence supports a modest survival benefit for intensive post-treatment surveillance following potentially curative resection of CC. However, no studies so far included only patients with stage III CC, who have the highest risk of recurrence. Methods: Medical records of patients who initiated adjuvant chemotherapy (AC) with either 5-FU or capecitabine plus oxaliplatin for stage III CC between 2007 and 2011 at the BC Cancer Agency were reviewed. Kaplan-Meier and log rank test were generated to investigate whether diagnosis of recurrence based on symptoms was associated with worse OS. OS1 was considered from date of recurrence to date of death or last FU. OS2 was considered time from surgery (sg) to date of death or last follow-up (FU). Results: Of635 pts who received oxaliplatin-based AC for stage III colon cancer, 176 patients (27.7%) have recurred and 118 (18.6%) have died at a median FU of 57.9 months. Recurrence was detected based on CEA elevation (G1) in 72 (41.1%) pts, abnormal imaging (G1) in 77 (44%) and symptoms (G2) in 26 (14.9%). Median time from sg to recurrence was shorter in G1 as compared to G2 (18.5 vs 25.7 months, p=0.003, HR 0.501). Median OS1 was significantly prolonged in G1 as compared to G2 (26.7 vs 6.5 months, p<0.001, HR 0.393). However, median OS2 was not statistically different between G1 and G2 (49.8 vs 40.1, p=0.327, HR 0.776). Patients with surveillance detected recurrence underwent significantly more potentially curative metastasectomy than patients with recurrence detected due to symptoms (33% vs 8%, p= 0.014). Conclusions: In our population-based study, patients who were symptomatic at the time of recurrence were diagnosed later than those detected by abnormal CEA or imaging and had shorter OS1. However, OS2 was similar in both groups adjusting for the effect of lead time bias. Surveillance for asymptomatic recurrence may still provide an opportunity for curative metastasectomy but the overall survival impact is unclear.
PHF6 Mutations Are Mutually Exclusive to TP53 Mutations, and Define a Distinct Subgroup of Secondary Acute Myeloid Leukemia Associated with a Primitive Stem/Progenitor Immunophenotype, Absent Complex Karyotype and Relatively Better Outcomes
Authors: Wenbin Xiao, Aaron D Goldberg, Brian Ball, Christopher Famulare, Friederike Pastore, Martin S. Tallman, Yanming Zhang, Maria E Arcila, Elli Papaemmanuil, Ross L. Levine, Mikhail Roshal
Journal: Blood (2018)
Direct Binding of BCOR, but Not CBX8, to MLL-AF9 Is Essential for MLL-AF9 Leukemia Via Regulation of the EYA1/SIX1 Gene Network
Authors: John H. Bushweller, Charles Schmidt, Nicholas Achille, Aravinda Kuntimaddi, Adam Boulton, Benjamin Leach, Shubin Zhang, Nancy J. Zeleznik-Le
Journal: Blood (2018)
Effect of extracellular matrix metalloproteinase inducer emmprin on ß1 integrin-mediated adhesion through a new partner, the kindlin-3, in human melanoma cells.
Authors: Julie Delyon, Samia Mourah, Farah Khayati, Suzanne Menashi, Celeste Lebbe
Journal: Journal of Clinical Oncology (2014)

e22011 Background: Extracellular matrix metalloproteinase inducer (EMMPRIN) is a membrane glycoprotein overexpressed in many cancer tissues including malignant melanoma cells, and is implicated in tumor progression and dissemination. EMMPRIN is known for its ability to promote the invasiveness of tumor cells by stimulating the extracellular matrix (ECM) degradation, and to stimulate tumor angiogenesis. In tumor cells EMMPRIN co-localizes with integrins, the major adhesion molecules, and particularly with ß1 integrin, involved in promoting metastasis. Kindlin-3 is an integrin partner in hematopoietic cells, which was shown to regulate cell adhesion to the ECM. In this study, we evaluated the potential role of EMMPRIN in melanoma cell adhesion. Methods: The effects of EMMPRIN were evaluated after inhibition of EMMPRIN using siRNA in the human melanoma cell line M10 Results: The inhibition of EMMPRIN in melanoma cells decreased cell invasion, and significantly increased cell adhesion and spreading. A morphological change from a round to a polygonal shape was observed associated with enhanced phalloidin-labeled actin staining. In situ proximity ligation assay and co-immunoprecipitation revealed that kindlin-3 interacts with ß1 integrin and with EMMPRIN in melanoma cells. Silencing EMMPRIN highly stimulated the kindlin-3/ß1 integrin interaction. Moreover, the kindlin-3 expression was inversely regulated by EMMPRIN as assessed by qRT-PCR and western blotting analysis. Through in vivo analysis of miRNA-mediated reduced EMMPRIN expression in xenograft tumors in nude mice, we confirmed that EMMPRIN inhibition up-regulates the kindlin-3/ß1 integrin interaction and the kindlin-3 expression. Conclusions: Our results reveal a new role of EMMPRIN in the invasion process of tumor cells, through the ß1 integrin/kindlin-3 mediated adhesion pathway.
Alterations in two oncogenic drivers: Impact of concurrent <i>PIK3CA</i> or <i>AKT1</i> mutations in patients with oncogene-driven lung adenocarcinomas.
Authors: Juliana Eng, Matthew David Hellmann, Kaitlin Woo, Camelia S. Sima, Helena Alexandra Yu, Maria E. Arcila, Marc Ladanyi, Mark G. Kris, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2014)

8074 Background: Little is known of prognosis and the efficacy of targeted therapies in patients whose lung adenocarcinomas harbor two oncogenic drivers. Methods: We identified patients treated at MSKCC from 2009-2013 whose lung adenocarcinomas harbored two oncogenic drivers. Molecular diagnostic testing was performed via an institutional algorithm involving ≥1 of the following: mutational hotspot testing (91 mutations in EGFR, HER2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA and AKT1), multiplex sizing assays (insertions/deletions in EGFR and HER2), and break apart FISH tests (fusions involving ALK, ROS1 and RET). Overall survival (OS) and duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy (EGFR-mutant subgroup) were assessed using Kaplan-Meier estimates. Outcomes were compared between double-driver and single-driver stage-matched control groups from the Lung Cancer Mutation Consortium study (log-rank test). Results: 49 patients (55% KRAS-mutant, 39% EGFR-mutant, 2% BRAF-mutant, 2% MAP2K1-mutant, 2% ALK fusion-positive) were found to have a driver in a second gene (PIK3CA 94% or AKT1 6%). In patients with advanced disease (stage IIIB/IV), the median OS was worse if their tumors harbored a concurrent PIK3CA or AKT1 mutation (n=31, 11 mo, 95%CI 8.9-23.1) vs a single-driver (n=87, 24 mo, 95%CI 16.2-31.1, p=0.017). Median OS in subgroups (concurrent PIK3CA or AKT1 vs not) were as follows: KRAS-mutant (8 vs 12 mo, p=0.032), EGFR-mutant (18 vs 34 mo, p=0.066), and PIK3CA-mutant (concurrent driver vs not; 14 vs 21 mo, p=0.840). In patients with EGFR-mutant lung cancers who received single-agent EGFR TKIs, while the median duration of therapy was similar between groups (15 vs 15 mo, single vs double, p=0.157), 33% (95% CI 19-59%) of patients with EGFR-mutant-only tumors versus 0% with concurrent PIK3CA or AKT1-mutated tumors remained on therapy at 2 and 3 years. Conclusions: In patients with metastatic oncogene-driven lung adenocarcinomas, the presence of a concurrent PI3KCA or AKT1 mutation is a negative prognostic factor for OS. In EGFR-mutant lung cancers, continued EGFR TKI benefit at ≥2 yrs was observed only in patients without concurrent PIK3CA or AKT1 mutations.
Leveraging the Right Technology in Health Care—Having a Cow
Authors: Sima Pendharkar, Tiffany Leung, Sanjeev J. Suratwala
Journal: JAMA Surgery (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 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
Abstract 17973: Possible Roles of Myocardial Infiltration of Inflammatory Cells for the Development of Ventricular Fibrosis in Patients With DCM
Authors: Takafumi Nakayama, Yasuo Sugano, Tetsuro Yokokawa, Toshiyuki Nagai, Hideaki Kanzaki, Keiko O Ogo, Taka-aki Matsuyama, Yoshihiko Ikeda, Hatsue I Ueda, Nobuyuki Ohte, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai
Journal: Circulation (2017)

Background: Heart failure, arrhythmia and other clinical cardiac complications with dilated cardiomyopathy (DCM) are considered to be associated with the severity of ventricular fibrosis regardless...
Misconceptions in colorectal cancer among a community-based population and CRC screening adherence.
Authors: Thomas Guerrero, Mobeen Rehman, Mary Roberts, Joseph Diaz
Journal: Journal of Clinical Oncology (2014)

6578 Background: Colorectal cancer (CRC) screening rates among Latinos are lower than those of non-Latinos. Prior research suggests that a higher proportion of Latinos have erroneous understandings of cancer and many have misperceptions about cancer that may negatively impact their preventive behavior. The goal of this study was to estimate the prevalence of previously identified CRC misconceptions among a sample of primary care patients. Methods: Cross-sectional survey of primary care primary care patients with an oversampling of Spanish-speaking patients. The survey included items specifically developed to assess participants’ knowledge regarding previously identified misconceptions of CRC risk factors: (1) constipation increases risk of developing CRC, (2) constipation increases the risk of developing polyps, (3) polyps consist of excess cholesterol, and (4) rectal sex increases the risk of developing CRC. Individual misconceptions and a composite misconception score were calculated based on these items and compared across race, ethnicity, and language of survey respondent (English vs. Spanish). Results: Of 1,600 surveys mailed, the response rate was 41.1% with 346 responding in English and 311 responding in Spanish. Mean age for the sample was 59 years, 60% of respondents were female, and 40% had less than high school education. For each individual misconception item, Spanish-speaking Latinos had rates of endorsing the misconception that were nearly twice those of non-Latinos: 76% vs. 38% for constipation increases risk of developing CRC; 63% vs. 32% for constipation increases the risk of developing polyps: 20% vs. 9% for polyps consist of excess cholesterol; and 38% vs. 21% for rectal sex increases the risk of developing CRC (p<0.001 for all comparisons). Ninety percent of Latino respondents vs. 64% of non-Latino respondents endorsed 2 or more misconceptions. Conclusions: In this sample of primary care patients, Latinos are more likely to hold misconceptions about CRC risk. While it is uncertain whether these beliefs negatively impact actual screening rates, it provides an opportunity for education.
Systemic rituximab immunotherapy in the management of primary ocular adnexal lymphoma: Single institution experience.
Authors: Samuray Tuncer, Mert Basaran, Burak Tanyildiz, Nesimi Buyukbabani, Gul Basaran, Oner Dogan
Journal: Journal of Clinical Oncology (2014)

e19503 Background: To evaluate the efficacy of systemic rituximab immunotherapy in the management of primary ocular adnexal lymphomas (OAL). Methods: Clinical records of 10 consecutive patients (11 eyes) with biopsy-proven OAL managed with systemic anti-CD 20 monoclonal antibody (rituximab; 375 mg/m2 intravenously once every three weeks for 6-8 cycles) between June 2008-March 2013 were evaluated retrospectively. Orbital magnetic resonance imaging and positron emission tomography were performed to evaluate any orbital and systemic involvement, respectively. Clinical response was classified as complete or partial. Results: The age of patients ranged between 27-85 (median, 55) years. Nine patients (90%) presented with unilateral and one (10%) with bilateral conjunctival involvement. Orbit was affected in 4 patients (40%), one of which had also choroidal involvement (10%). None of the patients had systemic involvement at initial presentation. All patients received an average of 7 cycles (range, 6-8) of systemic immunotherapy. After a median follow-up of 31 months (range, 10- 61 months), complete response was achieved in 5 eyes (45%) with rituximab monotherapy. Recurrence was noted in one of these five eyes (20%) 8 months after completion of therapy. No systemic or ocular side effects were observed in any patient. Additional radiotherapy was required in remaining 5 patients (6 eyes; 55%) with partial response. Conclusions: Complete regression of primary OALs without recurrence was observed in about one-third of eyes after systemic rituximab monotherapy. Adjunctive radiotherapy was required in remaining two-thirds of the cases to achieve complete response. Thus, considering the balance between high rate of local control and potential ocular complications of radiotherapy, systemic rituximab can be considered as a first-line therapeutic option in the management of primary OAL.