tbuckley/cabot-search huggingface dataset:
Microarray genomic expression (MAGE)-based therapy for heavily pretreated patients with metastatic solid tumors.
Authors: Joseba Rebollo, Manuel Sureda Gonzalez, Francisco Jose Fernandez-Morejon, Pere Bretcha, Severino Rey, Ramon Gonzalez, Jose Farre, A. Brugarolas
Journal: Journal of Clinical Oncology (2012)

3064 Background: Oligonucleotide-MAGE assay to identify tumor targets and potential active drugs based on molecular profiling in chemotherapy resistant/refractory (R/R) patients with metastatic solid tumors. A potential clinical benefit has been observed by Von Hoff et al (JCO 2010;20:4877-83). Methods: Patients (pts) with R/R metastatic solid tumors were included in the study. Pathology confirmed fresh-frozen biopsies were obtained and molecular profiling oligonucleotide-MAGE (Agilent Whole Human Genome 4x44K) results, confirmed whenever possible by IHC, were used to identify potential therapy targets. Results were discussed and offered to pts and the response evaluated using RECIST criteria. OS and PFS were measured from the beginning of therapy. All pts signed informed consent. Results: From August 2010 we performed 70 procedures in 69 pts. No complications derived from the biopsy were observed. Thirty pts did not follow therapeutic recommendations and 9 pts are too early to evaluate. Thirty procedures from 29 pts are clinically evaluable. Ten pts were male and 19 female, with a median (M) age of 57 years (range 41-70). Seven pts had breast cancer, 5 NSCLC, 5 pancreas, 4 CRC, 2 ovary and one each of gastric, parotid gland, biliary tree, head and neck, esophagus and gallbladder cancers, respectively. The M previous treatments were 3 (range 1 to &gt;6). Oligonucleotide-MAGE assay confirmed resistance in 82% of drugs previously used. A M of 3 conventional (range 0-5) and 2 experimental (range 0-4) potentially active drugs were identified. Partial response was observed in 7 (26.9%), stable disease &gt;2 months in 12 (46.1%) and progression in 7 (26.9%) pts. Four pts were not evaluable. MPFS was 4 months (95%CI: 1.815-6.185), MOS was 6 months (95%CI: 3.4-8.6) and 1-year projected OS was 21%. Conclusions: We confirmed that it is possible to identify new potentially active drugs in heavily pretreated solid tumor pts with oligonucleotide-MAGE assay. Therapy based on these drugs showed to be active in one fourth of treated pts. These assays might be also integrated in early tumor stages to aid in the selection of chemotherapy drugs, and for this reason deserve further studies. Updated results will be presented.
Heterogeneity of colorectal cancer (CRC) in reference to KRAS proto-oncogene utilizing wave technology.
Authors: Kimberly Perez, Robert Walsh, Kate E. Brilliant, Leila Nobel, Evgeny Yakirevich, Virginia Breese, Cynthia Jackson, Devasis Chatterjee, Victor Pricolo, Leslie Roth, Nishit Shah, Thomas Cataldo, Howard Safran, Douglas Hixson, Peter J. Quesenberry
Journal: Journal of Clinical Oncology (2013)

e14637 Background: The use of Epidermal growth factor receptor (EGFR) inhibitor monotherapy in patients that have KRAS wild type has produced response rates of only 10-20%. We propose two possible explanations to explain these low response rates; 1) levels of resistant CRC cells carrying mutated KRAS are below the sensitivity of standard direct sequencing modalities (&lt;5%) or 2) the standard practice of analyzing a single area within a heterogeneous tumor is a practice that can overlook areas with mutated KRAS. Methods: In a collaborative effort with Lifespan Pathology Department and the Molecular Pathology Core of the COBRE for Cancer Research Development, 3 FFPE tissue blocks of human CRC were obtained. The three specimens previously demonstrated KRAS mutations detected by the Applied Biosystems Kit. The Wave system 4500 (High performance ion-pairing liquid chromatography (IP-HPLC)) was utilized to evaluate tissue for presence of KRAS proto-oncogene mutations at codon 12 and 13. Results: Initially, sensitivity of WAVE technology was compared with direct sequencing by evaluating a dilutional series. WAVE detected mutant alleles at levels of 2.5% compared to 20% performed with standard direct sequencing. Samples from 3 patients were evaluated by WAVE technology. 8 samples from patient 1 were analyzed. In 2 of 8 samples, no mutations were detected at concentrations as low as 5%. In one sample a mutation was noted by WAVE and not by direct sequencing. All 4 samples from patient 2 tested positive for Exon 12/13 mutations. Of the 7 samples from patient 3, 5 were positive for Exon 12/13 mutations and 2 were negative for Exon 12/13 mutations. Conclusions: Results demonstrated a greater degree of sensitivity in mutation detection when compared to standard sequencing. These studies also demonstrated heterogeneity of expression of KRAS mutations between areas of the tissue samples at a genomic level. The low clinical response rates to EGFR inhibition might be explained by the variation in mutation presence, which was dependent upon the region examined. The heterogeneity demonstrated in these studies provides another phenotypic variant that will impact clinical care.
Antimetastatic activity of ganetespib: Preclinical studies and assessment of progressions due to new lesions in the GALAXY-1 NSCLC trial.
Authors: David A Proia, Masazumi Nagai, John-Paul Jimenez, Chaohua Zhang, Jim Sang, Wei Guo, Kristin Beebe, Min-Jung Lee, Manuel Sequeira, Donald Smith, Jaime Acquaviva, Suqin He, Jane B. Trepel, Len Neckers, Safi R. Bahcall, Vojislav M. Vukovic
Journal: Journal of Clinical Oncology (2013)

e19097 Background: Heat shock protein 90 (Hsp90) maintains the stability and activity of numerous signaling proteins involved in metastasis including FAK (tumor cell adhesion), MET and MMP9 (cell motility), VEGFR and PDGFR (angiogenesis), and HIF-1α (metabolism, proliferation, motility, angiogenesis). In the GALAXY–1 trial in advanced non-small cell lung cancer (NSCLC) patients, docetaxel (D) plus ganetespib (G), an Hsp90 inhibitor, showed encouraging improvement in overall survival compared to D alone. We evaluated the antimetastatic activity of ganetespib in preclinical models, and compared radiological disease progression due to new lesion formation in the two arms of the GALAXY–1 trial. Methods: Effects of ganetespib were investigated on the: (1) migration of cancer cells under normoxic and hypoxic conditions via scratch assay, (2) expression of metastatic signaling factors using immunoblotting and reverse phase array, (3) architecture of NSCLC tumor xenografts including micro-vasculature, hypoxia, and apoptosis by immunostaining, and (4) metastasis to the lung in both tail vein and orthotopic breast cancer in vivo mouse models. In the GALAXY–1 trial, development of new metastatic lesions was evaluated using serial computed tomography scans. Results: In vitro, ganetespib blocked the migration of cancer cells and reduced the expression of key drivers of metastasis including P-AKT, FAK, HER2, IGF-1R, MET, HIF-1α, and VEGF. In vivo, ganetespib significantly reduced tumor angiogenesis and proliferation. In patients, in the population in the GALAXY–1 trial that exhibited the strongest survival improvement (diagnosis of advanced disease &gt;6 months, N=175), radiologic progressions due to new lesion formation were 19 (50%) vs. 5 (17%), for D vs. D+G, respectively, at time of abstract submission. Updated results will be presented. Conclusions: Ganetespib inhibits multiple processes involved in tumor metastasis. Preliminary data from the GALAXY–1 study support reduced frequency of progression due to new metastatic lesion formation in advanced NSCLC patients treated with ganetespib.
PREVALENCE, CAUSES, AND PREDICTORS OF 30-DAY READMISSIONS FOLLOWING LEFT ATRIAL APPENDAGE OCCLUSION: ANALYSIS FROM 2016 NATIONAL READMISSION DATABASE
Authors: Lingling Wu, Bharat Narasimhan, Hieu Huynh, Kirtipal Bhatia, Yifeng Yang, Claire Huang Lucas, Catherine Teng, Davendra Mehta
Journal: Journal of the American College of Cardiology (2020)
Updated results of the GEST study: Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer in Japan and Taiwan.
Authors: Akira Fukutomi, Takuji Okusaka, Kazuya Sugimori, Hideki Ueno, Tatsuya Ioka, Shinichi Ohkawa, Narikazu Boku, Kenji Yamao, Kazuhiro Mizumoto, Junji Furuse, Akihiro Funakoshi, Takashi Hatori, Taketo Yamaguchi, Shinichi Egawa, Atsushi Sato, Yasuo Ohashi, Ann-Lii Cheng, Masao Tanaka
Journal: Journal of Clinical Oncology (2012)

4035 Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) demonstrated the non-inferiority of S-1 to GEM with respect to the primary endpoint of overall survival (OS) in patients with pancreatic cancer (PC). We now report the updated results of this study. Methods: The GEST study was a randomized, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, and adequate organ functions were randomly assigned to receive GEM (1000 mg/m 2 , iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m 2 , iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was OS, used to assess the non-inferiority of S-1 and the superiority of GS to GEM. Patient information was updated in July 2011. Results: At the time of this follow-up analysis, median follow-up was 29.8 months with 795 OS events, compared with 18.4 months with 710 OS events out of 832 patients at the previous analysis. Median OS was 8.8 months (95% CI: 8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 group (HR=0.96, 97.5% CI: 0.79-1.17, p&lt;0.001 for non-inferiority), which is consistent with prior results (HR=0.96, 97.5% CI: 0.78-1.18, p&lt;0.001). In the GS group, median OS was 9.9 months (95% CI: 9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p=0.28 for superiority versus the GEM group). On subgroup analysis, GS was associated with a non-statistically significant trend toward better OS compared with GEM among patients with locally advanced disease and those with a PS of 1. Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 15.9 months (95% CI: 13.0-19.7) in the GS group (HR=0.72, 95% CI: 0.51-1.03) among patients with locally advanced disease, and 6.2 months (95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) in the GS group (HR=0.62, 95% CI: 0.46-0.83) among patients with a PS of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one of the standard treatments for advanced PC. As for GS therapy, there is room for further investigation.
SEX-BASED DIFFERENCES IN LONG-TERM OUTCOMES AFTER EARLY-ONSET MYOCARDIAL INFARCTION
Authors: Maddalena Ardissino, Adam J. Nelson, Giuseppe Maglietta, Guidantonio Malagoli Tagliazucchi, Caterina Disisto, Umberto Canosi, Carlo Cernetti, Piera Angelica Merlini, Carlo Berzuini, Elisabetta Ponte, Raffaella Fetiveau, Silvia Buratti, Elvezia Paraboschi, Stefano Duga, Domenico Tuttolomondo, Antonio Crocamo, Federico Barocelli, Serena Bricoli, Andrea Botti, Rosario Bonura, Giulia Magnani, Andrea Biagi, Giorgia Paoli, Emilia Solinas, Diego Ardissino
Journal: Journal of the American College of Cardiology (2020)
Phase I trial of weekly docetaxel and carboplatin in patients with recurrent squamous carcinoma of the cervix after chemoradiation
Authors: B. E. Miller, D. L. Tait
Journal: Journal of Clinical Oncology (2006)

15023 Background: Treatment for recurrent cervical cancer is palliative; therefore a low side effect profile is important. The combination of docetaxel and carboplatin has been used for the initial treatment of cervical cancer with success. We assessed the tolerance of a weekly schedule in patients with recurrent cervical cancer after chemoradiation. Methods: Patients with advanced recurrent squamous carcinoma of the cervix with a performance status of 2 or better were enlisted in a phase I study evaluating carboplatin at an AUC of 2 and docetaxel at the following dose levels: L1, 25 mg/m 2 ; L2, 30 mg/m 2 ; L3, 35 mg/m 2 ; and L4, 40 mg/m 2 i.v. for 3 consecutive weeks of a 4 week cycle. Results: So far 9 patients have been completely evaluated. The median age is 55 years. The median time to recurrence is 13 months. Previous treatment included chemoradiation and in 2 patients additional platinum based chemotherapy. Areas of metastasis included the lung, lymphnodes, abdomen, liver and the pelvis. Dose levels 1 to 3 are completed. A total of 34 courses were administered, an average of 3.6 per patient. One patient received 8 courses. Treatment was discontinued due to progressive disease in 7 patients and due to toxicity in 2 patients one with grade 3 onycholysis and another with a grade 3 allergic reaction to carboplatin. There were no treatment delays due to hematologic toxicity, no grade 2 or higher granulocytopenia, no thrombocytopenia. The mean hemoglobin level dropped from 12 g/dl prior to course 1 to 10.6 g/dl prior to course 3 and 10.2 g/dl prior to course 5. No grade 3 anemia was seen. The main non-hematologic side effects were fatigue, nausea and alopecia, none of which reached grade 3. Accrual on the L4 cohort is still ongoing. Conclusions: The combination of docetaxel and carboplatin given on a weekly schedule is well tolerated in patients with recurrent cervical cancer after chemoradiation. Dose levels similar to those reported for initial treatment can be reached. [Table: see text]
DEFINING ECHOCARDIOGRAPHIC REFERENCE VALUES OF LEFT VENTRICULAR VOLUMES, EF, STROKE VOLUME AND LV AND RV STRAIN IN OBESE PATIENTS WITH NORMAL CARDIAC GEOMETRY: A SINGLE CENTER STUDY
Authors: Mohamed Badawy, Malcolm Anastasius, Vaibhav Jain, Jeremy Thaden, Sorin Pislaru, Garvan Kane, Patricia Pellikka, Hector Villarraga
Journal: Journal of the American College of Cardiology (2020)
CONTEMPORARY TRENDS IN SURGICAL RHEUMATIC VALVE DISEASE IN A CARIBBEAN NATION: A MULTICENTER EXPERIENCE
Authors: Nicola Pradegan, Juan Leon Wyss, Melvin Berroa, Jose Iribarren, Espedy Garcia, Wascar Roa, Pedro Corniel, Walid Elias, Leonel Lembert, Oneyda Ramirez, Rafael Alba, Malquiel Quezada, Victor Cuello, Santiago Garcia, Miguel Reyes, Dario Veras Sanchez, Miguel Guerrero, Maribel Almonte Casado, Ysaac Heredia, Cesar Herrera
Journal: Journal of the American College of Cardiology (2020)
Cytidine deaminase status as a predictive marker in patients with hematologic malignancies treated with azacytidine or cytarabine.
Authors: Cedric Mercier, Raphaelle Fanciullino, Cindy Serdjebi, Joseph Ciccolini, Bertrand Pourroy, Gerard Milano, Regis Costello, L'houcine Ouafik
Journal: Journal of Clinical Oncology (2013)

7117 Background: Cytarabine and azacytidine are mainstays for treating haematological malignancies. As most nucleosidic analogs, both azacytidine and cytarabine are metabolized in the liver by an exclusive enzymatic step driven by cytidine deaminase (CDA). CDA is highly polymorphic and dysregulations have been repeatedly associated with poor clinical outcome with gemcitabine. Methods: We have used a test to determine, on a phenotype basis, CDA status in patients. This test was used prospectively in a subset of 39 adult patients (16F, 23M, mean age 77 years), all treated for various haematological malignancies (i.e., CML, AML, lymphomas, myelodysplastic syndromes) with either aza-cytidine or a cytarabine-containing regimen. Response and treatment-related toxicities were monitored following current standards. In addition, impact of CDA status on azacytidine tolerance was evaluated in mice with or without CDA deficiency, as a proof of concept for the actual implication of metabolic deregulations in the toxicities observed in patients. Results: In patients, mean CDA activity was 3.7 +/-2.8 U/mg (min: 1, max: 14.8 U/mg). Ten out of 39 patients (i.e., 25%) showed low CDA activities and were considered as PM. Conversely, 8 patients (i.e., 20%) displayed CDA activities particurlary elevated (i.e., &gt; 6U/mg) and were considered as UM patients. Of note, PM patients all showed severe toxicities, including two toxic-deaths. Conversely, UM patients showed little efficacy when treated with either azacytidine or cytarabine. In mice with CDA-deficiency, standard azacytidine led to profound and long-lasting neutropenia, as compared with normal mice. Drug monitoring confirmed that individuals with low CDA activity and toxicities showed higher concentrations of azacytidine as compared with normal individuals. Conclusions: Overall this pilot study strongly suggests that CDA status could be a relevant marker for predicting clinical outcome in patients treated with either azacytidine or cytarabine. CDA status could be further used as a covariate to tailor drug dosage so as to ensure an optimal efficacy/toxicity balance in patients with haematological malignancies.
B cell–intrinsic TLR9 expression is protective in murine lupus
Authors: Jeremy S. Tilstra, Shinu John, Rachael A. Gordon, Claire Leibler, Michael Kashgarian, Sheldon Bastacky, Kevin M. Nickerson, Mark J. Shlomchik
Journal: Journal of Clinical Investigation (2020)

Toll-like receptor 9 (TLR9) is a regulator of disease pathogenesis in systemic lupus erythematosus (SLE). Why TLR9 represses disease while TLR7 and MyD88 have the opposite effect remains undefined. To begin to address this question, we created 2 alleles to manipulate TLR9 expression, allowing for either selective deletion or overexpression. We used these to test cell type–specific effects of Tlr9 expression on the regulation of SLE pathogenesis. Notably, Tlr9 deficiency in B cells was sufficient to exacerbate nephritis while extinguishing anti–nucleosome antibodies, whereas Tlr9 deficiency in dendritic cells (DCs), plasmacytoid DCs, and neutrophils had no discernable effect on disease. Thus, B cell–specific Tlr9 deficiency unlinked disease from autoantibody production. Critically, B cell–specific Tlr9 overexpression resulted in ameliorated nephritis, opposite of the effect of deleting Tlr9. Our findings highlight the nonredundant role of B cell–expressed TLR9 in regulating lupus and suggest therapeutic potential in modulating and perhaps even enhancing TLR9 signals in B cells.
Τhe modulatory role of psychological distress in the relationship between illness perception and quality of life in patients with breast cancer.
Authors: Daniela Gercovich, Pablo Lopez, Diego Bortolato, Patricia Margiolakis, Mirta Morgenfeld, Laura Rosell, Claudia Lorena Acuna, Ernesto Gil Deza
Journal: Journal of Clinical Oncology (2013)

e20657 Background: In a previous study (Gercovich et al., 2011) we found that several dimensions of Illness Perception predicted some aspects of Quality of Life. The present study introduces Psychological Distress as a variable to assess the modulatory role it plays in the association between Illness Perception dimensions and Quality of Life in patients with breast cancer, identifying which of these two variables explain further variability in the different aspects of Quality of Life. Methods: A cohort of seventy-five patients was evaluated with the Brief Illness Perception Questionnaire, the Hospital Anxiety and Depression Scale and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-30). We calculated bivariate and partial correlations to evaluate the associations between the illness perception dimensions and different aspects of quality of life, controlling these associations by the psychological distress measure. Subsequently, we performed linear regression analysis to evaluate which of these two variables better explains the variability in the quality of life scores. Results: Although significant associations between subscales of perception of illness and quality of life were found, most of them lost their significance when controlled by distress. In the regression models, variables that predicted the variability in the quality of life best were psychopathological diagnostic and distress. Conclusions: According to the study results, psychological distress and psychopathological diagnostic were the two variables that better explained the variability in the quality of life. For this reason it is essential to learn more about the role these variables play on the quality of life and on the morbidity and mortality associated to them.
Response to: ‘Correspondence on: ‘Dupilumab as a novel steroid-sparing treatment for IgG4-related disease’ by Simpson <i>et al</i>’ by Ebbo <i>et al</i>
Authors: Rachel S Simpson, Jason K Lee
Journal: Annals of the Rheumatic Diseases (2020)

We thank Ebbo et al for their interest in our case report1 and for providing their case of a patient with IgG4-related disease (IgG4-RD) whom they have also treated with dupilumab.2 Notably, Ebbo et al reported variability in the response to dupilumab compared with our patient. Our patient did have different clinical manifestations than that of Ebbo et al ’s patient, as our patient had profound retroperitoneal and genitourinary fibrosis along with atopic dermatitis, asthma, allergic rhinoconjunctivitis, parotitis, and sinusitis while Ebbo et al ’s patient presented with dacryoadenitis and sialadenitis in conjunction with allergic manifestations such as chronic rhinosinusitis with nasal polyps, asthma and urticaria. We are curious also to ask if the relationships between the variables presented in Figures C, D and …
High level analysis of genomic data reveals complex predictors of response to trastuzumab (T) and chemotherapy for early stage breast cancer
Authors: L. N. Harris, S. Carter, F. You, A. Eklund, S. Hilsenbeck, Z. Szallasi, J. Chang
Journal: Journal of Clinical Oncology (2006)

544 Background: Trastuzumab (T) with chemotherapy has been shown to improve survival in breast cancer patients but de novo resistance is common. Identifying predictors of response to T in primary cancers may lead to an understanding of mechanisms of resistance. We investigated whether combined microarray datasets from patients with early breast cancer treated with preoperative T and chemotherapy could predict for response to therapy. Methods: Two cohorts of patients with HER2 3+/FISH+, stage II-III breast cancer were included in this analysis: trial 1- T and docetaxel (n=38), trial 2 -T and vinorelbine (n=48), both for 12 weeks. Frozen tissue core biopsies were available and successfully amplified in 41 patients (trial 1: 20, trial 2: 21 patients), with standard sample processing, RNA extraction, amplification and hybridization to Affymetrix U133 chips. Differential expression of genes and chromosomal regions, (defined as &gt;10 genes in a given chromosomal cytoband), between patients with pathologic complete response (pCR) vs. those with residual invasive disease were examined. A measure of total functional aneuploidy (tFA) was calculated by summing net deviation in expression of all chromosomal regions and a gene expression signature of genomic instability (CIN) was derived by the identification of genes showing a high level of correlation with tFA . Results: By unsupervised hierarchical analysis, both datasets interdigitated suggesting no inherent bias. Gene expression patterns of individual genes showed weak associations with pCR. However, distinct statistically significant chromosomal regions, Chr2p23 Chr6q24 Chr7q33 Chr2p2 Chr12q21.31 Chr14q32.2 Chr1p34.2 Chr8q21.3, were associated with pCR to T therapy (p&lt;0.005), and were confirmed in more than 50% samples by SNP analysis. In addition, resistant tumors showed higher levels of the CIN signature (p&lt;0.005). Conclusions: We have shown that gene expression data can be merged and used for discovery predictive chromosomal regions associated T response. In addition, chromosomal instability was associated with T resistance. If validated, these distinct dysregulated chromosomal regions may serve as predictive markers of response to trastuzumab therapy. [Table: see text]