tbuckley/cabot-search huggingface dataset:
Phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin’s lymphoma (NHL): Southwest Oncology Group Study S0108
Authors: A. T. Stopeck, W. Bellamy, J. Unger, L. Rimsza, M. Iannone, R. I. Fisher, T. P. Miller
Journal: Journal of Clinical Oncology (2005)

6592 Background: VEGF is overexpressed in a number of malignancies. We previously found high expression of VEGF and its receptors in a sample of aggressive NHL specimens. Based on these results, we initiated this trial. Methods: Patients (pts) were treated every 2 weeks with bevacizumab (BV), a recombinant monoclonal antibody against VEGF, at a dose of 10mg/kg IV. Eligibility was limited to advanced stage aggressive NHL histologies in 1st or 2nd relapse. Results: 51 pts were registered (5 ineligible). Median age was 70 yrs (range: 36–87). 44 pts have been evaluated for toxicity. One died of pulmonary emboli and another died of probable progressive disease (possible causal relationship to drug could not be ruled out). 15 pts had grade 3 toxicities. The most common were cytopenias (10); fatigue, malaise, or lethargy (5); dyspnea (3); hypertension (2); hyponatremia (2); and dehydration (2). 40 eligible pts were evaluated for best response. There were 2 PR for an overall response rate of 5% (95% C.I. 1–17%). Eight pts had SD as their best response. The non-progression rate (PR + SD) was 25%. The median TTP was 5 months, range 4–18 months, in non-progressing pts. In all pts, 6-month PFS estimate was 14% (95% C.I.: 4–24%). The 6-month OS was 58% (95% C.I.: 43–73%). IHC was performed on diagnostic tumor for VEGF and its receptors. 19 samples were adequate for analysis with 14 (74%) expressing VEGF and 13 expressing one or both receptors. Additional studies included baseline, week 8, and at-time-of-progression measurements of circulating endothelial cells (CEC), and plasma and urine angiogenic markers (VEGF, VCAM, and bFGF). Over the course of therapy, CEC (p=.12) and plasma VEGF (p<.001) levels decreased while plasma VCAM (p=.02) levels increased. Conclusions: Therapy with BV was well-tolerated in this pre-treated group of pts with prolonged stabilization of disease seen in a small, but significant subset. The high rate of concordance between expression of VEGF and receptors suggests an autocrine pathway may play an important role in NHL pathogenesis. These results provide a strong rationale for studying the addition of BV to standard chemotherapy in the treatment of aggressive NHL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech
ECG Response: March 25, 2014
Authors: Philip Podrid
Journal: Circulation (2014)

ECG Challenge: A 72-year-old man with a history of chronic obstructive pulmonary disease presents with an increase in shortness of breath that began 2 weeks ago after experiencing an upper respiratory infection presenting with a cough productive of yellowish sputum, pleuritic chest pain, and a low grade fever with temperatures of up to 100°.He did not seek medical attention, but because of worsening shortness of breath he presented to the emergency room.On physical examination he has bilateral rhonchous sounds and wheezing.A chest x-ray showed evidence of chronic obstructive pulmonary disease with hyperaeration and fibrous streaking.His O 2 saturation was 88% on room air.He was placed on supplemental O 2 via a nasal cannula at 4 L/min.He received albuterol therapy via a nebulizer.Shortly after his first treatment he was noted to have a transient increase in heart rate and an ECG was obtained.
Concordance to National Comprehensive Cancer Network (NCCN) clinical practice guideline (GL) drug therapy recommendations for metastatic breast cancer: An analysis from the commercial managed care claims database PharMetrics (PM).
Authors: E. M. Lepisto, K. Tangirala, J. L. Vandergrift, J. S. McClure, D. L. McNally, C. D. Mullins, B. S. Seal
Journal: Journal of Clinical Oncology (2010)

1032 Background: The NCCN GLs provide the standard of care for the treatment of women with metastatic breast cancer (mBC). The primary aim of the current project is to assess concordance between the NCCN GL recommendation for drug therapy and care received using the PM database (DB). The PM is a patient (pt) care DB that incorporates medical and pharmaceutical claims data for younger managed-care patients. Methods: Claims for pts diagnosed with metastatic breast cancer from 2002 to 2008 were examined. Overall, 26,476 women with metastatic breast cancer were identified. Median age was 40 years. Results: 26,260 (99%) patients were identified as premenopausal with 7,005 (28%) receiving antiestrogen (AE) therapy. Until 2005, the NCCN GLs recommended luteinizing hormone-releasing hormone (LHRH) agonists as an optional compliment to AE therapy for mBC. Prior to 2005, 37 of 2,838 pts (1%) received LHRH agonists. After 2005, 3% received nonconcordant therapy with LHRH agonists. After 2005, the NCCN GLs recommend bevacizumab therapy only with paclitaxel for treatment of mBC. 9,378 pts received antineoplastic therapy after 2005. Of this, 2.1% of pts were treated with bevacizumab therapy, 75% of which received therapy per NCCN GL recommendations. The use of bisphosphonates for pts with bone metastases is a category 1 recommendation in the NCCN GLs. Only 44% of patents with bone disease received GL concordant care. Additional drug therapy measures are in development. Comparisons with SEER/Medicare are being analyzed. Conclusions: Less than half of mBC pts with bone disease received care concordant with the NCCN GLs. Few patients received bevacizumab therapy with moderate concordance. Almost all patients receiving AE therapy did not receive LHRH agonists as per NCCN GL recommendations. PT cohort Recommended therapy Total (n) Concordant (n [%]) Time period Premenopausal pts on AE therapy No LHRH agonist 4,172 4,042 (97%) 2005-2008 Pts on bevacizumab therapy Only with paclitaxel 195 146 (75%) 2005-2008 Pts with bone metastases Bisphosphonates 16,596 7,268 (44%) 2002-2008 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NCCN, sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis, Smith Hanley sanofi-aventis Pfizer, sanofi-aventis GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis
Compound Heterozygosity for Hb S and a Novel Deletion of Dnase I Hypersensitivity Sites HS3 and HS4 of β-Globin Locus Control Region Results in Hb S/β+-Thalassemia Phenotype
Authors: Ali Amid, Barry Eng, Betty-Ann Hohenadel, Meredith Hanna, Lisa N. Nakamura, Lynda Walker, Melina Cheong, Melanie Kirby-Allen, John S. Waye
Journal: Blood (2014)
Optimizing measurement of EGFR mutation status in NSCLC.
Authors: M. Nicolson, C. Clark, C. Bell, A. Osborne, J. Tracey, R. D. Petty, K. M. Kerr
Journal: Journal of Clinical Oncology (2010)

e18120 Background: Improved clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) in non-small cell cancer (NSCLC) patients (pts) with sensitizing mutations (mu) of the EGFR, along with European licence prescribing restrictions, make it important to optimize the accuracy of mu analysis. The association of TKI resistance with KRAS mu at codons 12, 13 and 61, and their mutual exclusion with activating EGFR mutations, make it appropriate to measure both in the usually small samples where tumour content has been evaluated and maximised. Methods: EGFR and KRAS mu status are sought on all nonsquamous NSCLC diagnosed in our Cancer Centre and samples referred from other UK institutions. Formalin fixed paraffin embedded tumour samples are assessed by one specialist thoracic pathologist and macro-dissected to enrich for tumour content. Mu screening by direct sequencing has been the core analytical technique employed but lacks the required sensitivity to detect mu in samples with low mu content. Earlier work established pyrosequencing as a robust and sensitive method for KRAS testing. We are currently assessing more sensitive methods for EGFR testing including Cold PCR, WAVE Surveyor (WS), and fragment length analysis (FLA). Results: To date, 63 pt tumour samples (44 females, 19 males) from Aberdeen and five other UK sites have been analysed and EGFR/KRAS mu status established. Histology: 62 adenocarcinoma, 1 squamous. Partial results only were available in 4 pt due to poor/insufficient samples. Mu were found in both males and females, never and ex-smokers. The % tumour ranged from < 5% to 100% (average 58%). It is acknowledged that tumour % is not always a reliable indicator of % mu. Twelve pts were EGFR mu positive: 4 Exon 19 deletions, 4 L858R substitutions, 1 exon 20 insertion, 1 exon G719A substitution and 2 previously uncharacterised. FLA - for exon 19 deletions - and/or WS are run on all samples double negative on sequencing with estimated sensitivity 3-5%. Cold PCR will further increase sensitivity of these methods. Conclusions: This reported experience is from a single centre NHS/University institution where the issues with tissue size/quality and mu analysis are representative of other centres. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Roche AstraZeneca, Roche AstraZeneca, Roche AstraZeneca
Genetic polymorphism associated with chronic neurotoxicity and recurrence in curatively-resected colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy.
Authors: S. Lee, H. Won, E. Son, J. Lee, S. Park, J. Park, Y. Park, H. Lim, W. Kang
Journal: Journal of Clinical Oncology (2010)

3583 Background: We performed a genome-wide association analyses in a cohort of curatively- resected colon cancer patients receiving fluorouracil, folinic acid and oxaliplatin (FOLFOX) adjuvant chemotherapy in order to determine association with chronic neurotoxicity and recurrence. Methods: This was a prospective study in which DNA was purified from peripheral blood of colon cancer patients starting FOLFOX adjuvant chemotherapy. Genotypic analysis was performed using the Affymetrix Genome-Wide Human SNP Array 6.0 which includes > 906,600 SNPs. Neurotoxicity was assessed in accordance with NCI CTCAE v3. Primary endpoint was the development of severe (grade ≥ 2) neuropathy. Recurrence was the secondary endpoint. Fisher's exact test was used to evaluate allelic association with the development of severe neurotoxicity as well as recurrence. Results: For the 96 registered patients, 1113 FOLFOX cycles were delivered (median 12, range 6-12). All patients received > 500 mg/m2 of oxaliplatin (median 935 mg/m2, range 510-1020 mg/m2). Chronic neurotoxicity was noted in 83 (87%) patients: grade 1 in 42 patients, grade 2 in 36 patients and grade 3 in 3 patients. Severe neurotoxicity was related to genotypes, and the highest peak was observed in the chromosome 4p15.33 (p = 8.53E-07). As of December 2009, recurrence was noted in 30 patients (31%), and found to be related with DDX18 and NRP2 genes. Conclusions: We found suggestive loci associated with the development of severe neuropathy and recurrence after FOLFOX adjuvant chemotherapy. Final results from the validation in an independent patient cohort (n > 100) will be presented. No significant financial relationships to disclose.
Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCd) in Newly Diagnosed Multiple Myeloma Patients: A Phase I- II Study
Authors: Antonio Palumbo, Davide Rossi, Sara Bringhen, Alessandra Larocca, Fabiana Gentilini, Lorenzo De Paoli, Paola Omedè, Stelvio Ballanti, Federica Cavallo, Roberto Passera, Anna Marina Liberati, Mario Boccadoro, Gianluca Gaidano, Pieter Sonneveld, Paolo Corradini
Journal: Blood (2014)
A new mechanism of trastuzumab resistance in gastric cancer: MACC1 promotes the Warburg effect via activation of the PI3K/AKT signaling pathway
Authors: Jing Liu, Changqie Pan, Lihong Guo, Mengwan Wu, Jing Guo, Sheng Peng, Qianying Wu, Qiang Zuo
Journal: Journal of Hematology & Oncology (2016)

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. However, recurrent therapeutic resistance presents revolutionary claims. Warburg effect and AKT signaling pathway was involved in the resistance to trastuzumab. Our previous studies have demonstrated that overexpression of metastasis associated with the colon cancer 1 (MACC1) predicted poor prognosis of GC and promoted tumor cells proliferation and invasion. In this study, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 reversed this resistance.The effect of trastuzumab and glycolysis inhibitor combination on cell viability, apoptosis, and cell metabolism was investigated in vitro using established trastuzumab-resistant GC cell lines. We assessed the impact of trastuzumab combined with oxamate on tumor growth and metabolism in an established xenograft model of HER2-positive GC cell lines.Here, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 in trastuzumab-resistant cells reversed this resistance. Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effects of MACC1 on resistance and glycolysis were diminished. Our findings indicated that MACC1 promoted the Warburg effect mainly through the PI3K/AKT signaling pathway, which further enhanced GC cells trastuzumab resistance.Our results indicate that co-targeting of HER2 and the Warburg effect reversed trastuzumab resistance in vitro and in vivo, suggesting that the combination might overcome trastuzumab resistance in MACC1-overexpressed, HER2-positive GC patients.
Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8 + T Cell-Mediated Immunity in Colorectal Cancer
Authors: Nupur Bhattacharya, Robert Yuan, Tyler R. Prestwood, Hweixian Leong Penny, Michael A. DiMaio, Nathan E. Reticker-Flynn, Charles R. Krois, Justin A. Kenkel, Tho D. Pham, Yaron Carmi, Lorna Tolentino, Okmi Choi, Reyna Hulett, Jinshan Wang, Daniel A. Winer, Joseph L. Napoli, Edgar G. Engleman
Journal: Immunity (2016)
Preoperative blood parameters as biomarkers for high-grade gliomas.
Authors: M. Rosenthal, K. M. Field, P. Gibbs, T. Wohlers, K. Drummond
Journal: Journal of Clinical Oncology (2010)

2077 Background: High-grade gliomas are the most common malignant brain tumors. Identification of biomarkers may assist in directing therapy in these patients (pts). This study examined the prognostic significance of several blood parameters in pts with high-grade gliomas, purported to be of prognostic significance in previous small studies. Methods: A retrospective review was undertaken of pts with high grade gliomas treated at two institutions. BioGrid Australia linked pt clinical details, histopathology, blood parameters and death data. Univariate and multivariate Cox regression analyses were undertaken to determine the relationship between preoperative blood results (albumin, platelet count and monocyte count) and multiple clinical parameters including age, gender, performance status (PS), extent of surgery, tumor size, and overall survival (OS). Results: Of 431 pts, 14 (3.2%) had thrombocytopenia (< 150 × 109/L) and 24 (5.6%) had thrombocytosis (> 400 × 109/L). Of 221 pts, 32 (14.5%) had hypoalbuminaemia (< 35 g/L). Pts with thrombocytosis were significantly older (median age 67 y vs. 63 y, p = 0.04) and more frequently female (71% vs. 40%, p = 0.0045). Hypoalbuminaemia was more common in pts with GBM (16.5%) than AA (5.1%), p = 0.08. Pts with hypoalbuminaemia were significantly older (median age 68 y vs. 63 y, p = 0.0485), more frequently female (60% vs. 38%, p = 0.02) and of poorer PS (47% ECOG 3-4 vs. 23% with normal albumin, p = 0.03). Blood parameters did not significantly correlate with tumor size or extent of surgery. Cox regression analysis showed that thrombocytosis was a significant predictor for inferior OS (HR 2.495, p = 0.0486) but hypoalbuminaemia was not (HR 1.14, p = 0.63). Monocyte count was not predictive of overall survival. Conclusions: For pts withhigh-grade gliomas the association of selected preoperative blood parameters with both clinical features, and inferior survival (thrombocytosis), confirms results seen in previous smaller studies. As thrombocytosis and hypoalbuminemia are both markers of inflammation this may represent a common mechanism for these associations. Further research is required to determine how to integrate this data into the routine management of pts with high-grade gliomas. No significant financial relationships to disclose.
Integrative Genome-Scale Analysis Identifies Epigenetic Mechanisms of Transcriptional Deregulation in Unfavorable Neuroblastomas
Authors: Kai-Oliver Henrich, Sebastian Bender, Maral Saadati, Daniel Dreidax, Moritz Gartlgruber, Chunxuan Shao, Carl Herrmann, Manuel Wiesenfarth, Martha Parzonka, Lea Wehrmann, Matthias Fischer, David J. Duffy, Emma Bell, Alica Torkov, Peter Schmezer, Christoph Plass, Thomas Höfer, Axel Benner, Stefan M. Pfister, Frank Westermann
Journal: Cancer Research (2016)

The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. Cancer Res; 76(18); 5523-37. ©2016 AACR.
Trends in histology of newly diagnosed prostate cancer subsequent to USPSTF PSA screening recommendation.
Authors: Carl A. Olsson, Ann E. Anderson, Deepak A. Kapoor
Journal: Journal of Clinical Oncology (2016)

68 Background: Reports on impact of the United States Preventive Services Task Force (USPSTF) Grade D recommendation against PSA screening have been short-term and contradictory. We sought to assess whether changes in prostate biopsy (PBx) pathology reporting had occurred in our large urology practices and if such changes persisted over time. Methods: We reviewed prostate histology in the 2 years prior to the USPSTF publication in 2012, and 3 years subsequent to this recommendation. All men (3,429) undergoing PBx in years 2010/11 were combined, creating a baseline against which similar reviews of 2013-August 2015 (2,773, 2,577 and 1,767 patients, respectively) were compared. Analysis of PBx results was the same in all years; we focused only on patients with a cancer diagnosis. Each PBx core was studied for both primary Gleason pattern and score and each patient was assigned a Weighted Gleason Index (WGI) wherein each positive core was multiplied by its own Gleason score, resulting in a single number representing both score and number cores positive. Results: The percent positive PBx increased over time, from the combined rate of 39% (1,338) in 2010/11 to 41.4% (1,147) in 2013, 42.6% (1,097) in 2014 and 46% (813) in 2015 (p&lt;.001). Of 16,271 cores in 2010/11, 5,097 or 31.3% were positive; 14.8% had Gleason 8-10 scores. Of 13,960 cores in 2013, 4,415 or 31.6% were positive; 19.7% had Gleason 8-10 scores. Of 13,577 cores in 2014, 4,694 or 34.6% were positive; 26.1% had Gleason 8-10 scores. Of 10,380 cores in 2015, 3,396 or 32.7% were positive; 25.4% had Gleason 8-10 scores. Gleason 6 scores were stable over time; Gleason 7 scores "lost" 10% over time to higher scores. WGI for 2010/11 was 25.5, compared to 26.0 in 2013 (p=.60), 29.8 in 2014 (p&lt;.001) and 29.2 in 2015 (p=.001). There was no significant difference in WGI from 2014-15. Conclusions: The combined Gleason 6 score stability and decreased biopsies suggest that fewer low risk patients are undergoing PBx- a favorable outcome. However, there has been a persisting increase in both numbers of positive cores as well as cores found with higher Gleason scores. This increases patients presenting with higher risk disease and portends a possible reversal of gains made in reducing prostate cancer mortality.
PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models
Authors: Nesrin Sabha, Jonathan R. Volpatti, Hernan Gonorazky, Aaron Reifler, Ann E. Davidson, Xingli Li, Nadine M. Eltayeb, Claudia Dall’Armi, Gilbert Di Paolo, Susan V. Brooks, Ana Buj-Bello, Eva L. Feldman, James J. Dowling
Journal: Journal of Clinical Investigation (2016)

Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets.
Hypertension in the Elderly: Correction and Clarification-Reply
Authors: Cynthia D. Mulrow
Journal: JAMA (1995)

<h3>In Reply.</h3> —Thank you for pointing out the error in the legend to Figure 1. "HTN Coop" refers to the Hypertension-Stroke Cooperative Study Group. Data in Figure 1 are derived from the HTN Coop study (as is indicated in the legend to the figure) and not from the HDFP study. No data in Figure 1 are given for the HDFP because cause-specific morbidity and mortality data for elderly persons that were not adjusted for other factors such as race and sex were not found. Figure 2 references are correct with the right panel relevant to younger adults citing original reference 31 (overall HDFP results) and the left panel relevant to older adults citing original reference 4 (HDFP total mortality data for older subjects). Thank you for also citing HDFP data relating to stroke. We agree that this trial showed that stepped care treatment resulted in greater reductions in both fatal