tbuckley/cabot-search huggingface dataset:
Impact of <scp>SNP</scp> array karyotyping on the diagnosis and the outcome of chronic myelomonocytic leukemia with low risk cytogenetic features or no metaphases
Authors: Laura Palomo, Blanca Xicoy, Olga Garcia, Mar Mallo, Vera Ademà, Marta Cabezón, Montse Arnan, Helena Pomares, María José Larrayoz, María José Calasanz, Jaroslaw P. Maciejewski, Dayong Huang, Lee‐Yung Shih, Seishi Ogawa, Jose Cervera, Esperanza Such, Rosa Coll, Javier Grau, Francesc Solé, Lurdes Zamora
Journal: American Journal of Hematology (2015)

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for ∼80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. We hypothesized that single nucleotide polymorphism arrays (SNP-A) karyotyping could detect cryptic chromosomal alterations with prognostic impact in these subgroup of patients. SNP-A were performed at diagnosis in 128 CMML patients with low risk karyotypes or uninformative results for conventional G-banding cytogenetics (CC). Copy number alterations (CNAs) and regions of copy number neutral loss of heterozygosity (CNN-LOH) were detected in 67% of patients. Recurrent CNAs included gains in regions 8p12 and 21q22 as well as losses in 10q21.1 and 12p13.2. Interstitial CNN-LOHs were recurrently detected in the following regions: 4q24-4q35, 7q32.1-7q36.3, and 11q13.3-11q25. Statistical analysis showed that some of the alterations detected by SNP-A associated with the patients' outcome. A shortened overall survival (OS) and progression free survival (PFS) was observed in cases where the affected size of the genome (considering CNAs and CNN-LOHs) was >11 Mb. In addition, presence of interstitial CNN-LOH was predictive of poor OS. Presence of CNAs (≥1) associated with poorer OS and PFS in the patients with myeloproliferative CMML. Overall, SNP-A analysis increased the diagnostic yield in patients with low risk cytogenetic features or uninformative CC and added prognostic value to this subset of patients.
Germline Mutations in <i>BRCA1 </i> and <i> BRCA2 </i> in Breast-Ovarian Families From a Breast Cancer Risk Evaluation Clinic
Authors: A.-M. Martin, M.A. Blackwood, D. Antin-Ozerkis, H.A. Shih, K. Calzone, T.A. Colligon, S. Seal, N. Collins, M.R. Stratton, B.L. Weber, K.L. Nathanson
Journal: Journal of Clinical Oncology (2001)

Data from the Breast Cancer Linkage Consortium suggest that the proportion of familial breast and ovarian cancers linked to BRCA1 or BRCA2 may be as high as 98% depending on the characteristics of the families, suggesting that mutations in BRCA1 or BRCA2 may entirely account for hereditary breast and ovarian cancer families. We sought to determine what proportion of families with both breast and ovarian cancers seen in a breast cancer risk evaluation clinic are accounted for by coding region germline mutations in BRCA1 and BRCA2 as compared to a linkage study group. We also evaluated what clinical parameters were predictive of mutation status.Affected women from 100 families with at least one case of breast cancer and at least one case of ovarian cancer in the same lineage were screened for germline mutations in the entire coding regions of BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis, a polymerase chain reaction-based heteroduplex analysis, or direct sequencing.Unequivocal deleterious mutations were found in 55% (55 of 100) of the families studied. Mutations in BRCA1 and BRCA2 accounted for 80% and 20% of the mutations overall, respectively. Using multivariate analysis, the strongest predictors of detecting a mutation in BRCA1 or BRCA2 in this study group were the presence of a single family member with both breast and ovarian cancer (P <.0009; odds ratio [OR], 5.68; 95% confidence interval [CI], 2.04 to 15.76) and a young average age at breast cancer diagnosis in the family (P <.0016; OR, 1.69; 95% CI, 1.23 to 2.38).These results suggest that at least half of breast/ovarian families evaluated in a high-risk cancer evaluation clinic may have germline mutations in BRCA1 or BRCA2. Whether the remaining families have mutations in noncoding regions in BRCA1, mutations in other, as-yet-unidentified, low-penetrance susceptibility genes, or represent chance clustering remains to be determined.
High-dose induction chemotherapy of metastatic breast cancer in protected environment: a prospective randomized study.
Authors: G N Hortobagyi, A U Buzdar, G P Bodey, S Kau, V Rodriguez, S S Legha, H Y Yap, G R Blumenschein
Journal: Journal of Clinical Oncology (1987)

To test the hypothesis of whether high doses of chemotherapy in combination achieve higher response rates and longer durations of response and survival, we treated 33 pre- and perimenopausal patients with good performance status in a prospective trial with escalating doses of fluorouracil, doxorubicin and cyclophosphamide (FAC). Patients were randomly assigned to be treated within a protected environment (laminar air flow room), with prophylactic antibiotics, or in a standard hospital room. Important patient characteristics were equally distributed in the two treatment arms. A major objective response was observed in 27 of the 32 evaluable patients (84%), and 11 (34%) achieved a complete remission (CR). There was no significant difference in overall and complete response rates between the two treatment arms, nor was there a substantial difference in times to progression or survival between the groups treated in or out of the protected environment. Comparison of the results of this study with previously reported programs of FAC chemotherapy in patients with metastatic breast cancer shows that this study achieved higher overall and complete response rates. However, neither the time to progression, nor the survival of responders or the entire patient group was different from our previous experience with standard FAC chemotherapy. When the study was initiated in 1976, the proposed dose escalation represented high-dose chemotherapy. In retrospect, even the "high" doses used in this study represent only a modest increase over standard doses of chemotherapy. Much steeper dose escalations will be needed to evaluate the efficacy of high-dose chemotherapy in breast cancer, as well as the protective value of the protected environment and prophylactic antibiotics in metastatic breast cancer.
A robust in vivo model for B cell precursor acute lymphoblastic leukemia
Authors: Terry J. Fry, Peter D. Aplan
Journal: Journal of Clinical Investigation (2015)

B cell precursor acute lymphoblastic leukemia (BCP ALL) is the most common malignancy in children. While treatments have improved remarkably over the past four decades, resistant disease and late effects that result from cytotoxic chemotherapy remain serious problems for individuals with BCP ALL. Improved genetic tools have led to the discovery of numerous somatic mutations associated with BCP ALL, leading to a framework for the genetic classification of BCP ALL. In this issue of the JCI, Duque-Afonso et al. develop an accurate in vivo model for BCP ALL that recapitulates the key features of human disease, including acquired mutations in genes encoding PAX5 and components of the JAK/STAT pathway. The authors further show, as proof of principle, that this model can be used to evaluate the efficacy of drugs designed to target specific acquired mutations in patients with BCP ALL.
Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group
Authors: Brenda J. Weigel, Elizabeth Lyden, James R. Anderson, William H. Meyer, David M. Parham, David A. Rodeberg, Jeff M. Michalski, Douglas S. Hawkins, Carola A.S. Arndt
Journal: Journal of Clinical Oncology (2015)

Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer.Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites).One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies.Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.
Different markers of lung mechanics in pulmonary rehabilitation
Authors: Zsuzsanna Balogh, Maria Kerti, Janos Varga
Journal: European Respiratory Journal (2014)

Rationale:  Lung mechanics and chest wall kinematics including rib cage distortion has relationship with breathlessness and exercise capacity as well. Change of chest expansion as an indirect marker may have relationship with lung mechanics in patients with COPD.   Materials and methods:  97 patients with COPD (FEV 1 : 44±19 %pred, GOLD stage II:35, III:31, IV:31, age: 65±9 years) participated in this study. Patients performed a complex pulmonary rehabilitation program with chest wall-stretching, controlled breathing techniques and training, and personalized exercise training 2-3 times for 20-30 minutes per day by cycling and treadmill. Intensity increased between 60-80% of maximal exercise capacity based on symptoms for 6 weeks. 6 minutes walking distance (6MWD), Modified Medical Research Dyspnea Scale (mMRC), lung function and chest wall expansion were measured.   Results:  Rehabilitation resulted improvement in six minutes walking distance (6MWD: 357±65 vs. 417±62m, p 1  did not change significantly (44±19 vs. 47±21 %pred). The change of chest expansion, inspiratory- (IRV) and expiratory reserve volume (ERV) did correlate with change of 6 minute walking distance (CE: R 2 =21, IRV: R 2 =0,29, ERV: R 2 =0,25; p   Conclusion:  Chest expansion as a simple measurement may add valuable information in terms of lung mechanics and rib cage distortions. Strength of correlations showed the importance of other factors compared to lung mechanics to contribute to exercise tolerance as well.
Regression of Paravalvular Aortic Regurgitation and Remodeling of Self-Expanding Transcatheter Aortic Valve
Authors: Jae K. Oh, Stephen H. Little, Sahar S. Abdelmoneim, Michael J. Reardon, Neal S. Kleiman, Grace Lin, David Bach, Linda Gillam, Biswajit Kar, Joseph Coselli, Partho P. Sengupta, Kanny Grewal, James Chang, Yanping Chang, Mike Boulware, David H. Adams, Jeffrey J. Popma
Journal: JACC. Cardiovascular imaging (2015)
Abstract 627: Pro-Angiogenic Properties are Impaired in Bone Marrow (BM)-Derived Stem or Progenitor Cells in Diabetes and Diabetic Hindlimb Ischemia was Effectively Repaired by Non-Diabetic Stem or Progenitor Cells
Authors: Juyong Lee, Mejeong Lee, Jiyoon Lee, Marcy Silver, Aaron Burg, Shanu Mehta, Andrea Wecker, Jin-Ok Jeong, Hyun-Jai Cho, Yong-Pil Cho, Young-sup Yoon
Journal: Circulation (2006)

Background: Recent studies reported that angiogenesis and endothelial progenitor cells (EPCs) were dysfunctional in diabetes (DM). However, there have been no investigations on the pro-angiogenic characteristics of BM-derived cells in diabetes. Accordingly, we investigated angiogenic defects in BM-derived mononuclear cells (BM-MNCs), EPCs and mesenchymal stem cells (MSCs) and sought to determine whether hindlimb ischemia can be repaired by non-DM cells. Method & Results: Studies were performed with C57Bl mice 3 months after the induction of diabetes with streptozotocin. Gene profiling analysis with Angiogenesis Microarray Kit (GEArray) and real-time RT-PCR showed that multiple angiogenic factors were significantly down-regulated in DM cells compared to non-DM control cells (Table 1). We also compared cell functions between DM and non-DM cells. DM-EPCs revealed decreased adhesion to laminin (non-DM vs DM, 78 vs 40/mm2, P<0.05) and vitronectin(320 vs 140/mm2, P<0.05), decreased migration to VEGF-A (210 vs 8...
Abstract 81: Sphingosine 1-phosphate Signaling Contributes To Cardiac Inflammation, Remodeling And Dysfunction Following Myocardial Infarction.
Authors: Fuyang Zhang, Yunlong Xia, Wei Wang, Wenjun Yan, Lu Yang, Yan Li, Fen Zhou, Ling Tao
Journal: Circulation Research (2014)

Sphingosine 1-phosphate (S1P) generated by sphingosine kinases (SphK) regulates multiple pathophysiological processes in cardiovascular system. The study was designed to investigate the role of SphK/S1P axis in myocardial infarction (MI) induced heart failure and the underlying mechanisms. Male C57BL/6J mice were subjected to permanent left coronary artery occlusion for 4 weeks. The infarcted heart showed increased SphK1 expression and increased S1P content. S1PR1, the predominant type of S1P receptors expressed in left ventricle, was upregulated by 3-fold in cardiac tissue following MI (n=6, all P&lt;0.05). Further, we observed that S1P significantly activated NF-κB/STAT3 signaling and upregulated pro-inflammatory cytokines (TNF-α and IL-6) expression in a dose-dependent manner in cultured neonatal rat ventricular cardiomyocytes (n=3, all P&lt;0.01), all of which were almost blocked by pretreatment with S1PR1 siRNA or FTY720, a functional S1PR1 inhibitor (n=3, all P&lt;0.01). In vivo, administration of FTY720 (3mg/kg, i.p. daily for 4 weeks) decreased SphK1/S1P/S1PR1 axis, inhibited persistent NF-κB/STAT3 signaling activation and blocked pro-inflammatory cytokines production in post-MI heart. Accordingly, FTY720 remarkably alleviated cardiac fibrosis and dysfunction (ejection fraction: 35.5±3.0% vs. 29.4±2.7% , P&lt;0.05). Intriguingly, administration of SphK2 inhibitor ABC294640 (5mg/kg, i.p. daily for 4 weeks) amplified cardiac SphK1/S1P/S1PR1 axis, augmented NF-κB/STAT3 signaling activation and increased inflammatory cytokines expression. Consequently, SphK2 inhibition reduced survival rate (68.4% vs. 83.3%, P&lt;0.05) and exacerbated cardiac maladaptive structural changes and ventricular dysfunction induced by MI (ejection fraction: 25.4±2.3% vs. 30.4±3.2%, P&lt;0.05). Our results provide the evidence that upregulated SphK1/S1P/S1PR1 axis links persistent NF-κB/STAT3 activation, chronic cardiac inflammation and heart failure progression following MI, whereas SphK2 serves as an endogenous suppressor of pathological S1P signaling. Targeting SphK1/S1P/S1PR1 axis by FTY720 treatment or enhancing SphK2 activity might be a potential therapeutic strategy for ischemic heart failure.
Cardiac disease following treatment of Hodgkin's disease in children and adolescents.
Authors: S L Hancock, S S Donaldson, R T Hoppe
Journal: Journal of Clinical Oncology (1993)

PURPOSE Cardiac disease is second only to neoplastic disease as a cause of death after treatment for Hodgkin's disease. This study evaluates the risks of cardiac disease following treatment of Hodgkin's disease during childhood and adolescence. PATIENTS AND METHODS We reviewed records of 635 patients treated for Hodgkin's disease before 21 years of age at Stanford University between 1961 and 1991. Mean age was 15.4 years; mean follow-up duration was 10.3 years, representing 6,564 person-years of observation. Relative risks (RRs) of death from cardiac diseases were calculated by comparison with age-, sex-, and race-matched general population rates from United States decennial life-tables. RESULTS Twelve patients have died of cardiac disease (RR, 29.6; 95% confidence interval [CI], 16.0 to 49.3), including seven deaths from acute myocardial infarction ([AMI] RR, 41.5; 95% CI, 18.1 to 82.1), three from valvular heart disease, and two from radiation pericarditis/pancarditis. Thus far, the risk of AMI death was comparable after radiation alone (RO) or after chemotherapy and radiation (CM) (RO-AMI RR, 52.2; 95% CI, 21.1 to 108.7; CM-AMI RR, 21.1; 95% CI, 0.0 to 104.4; P = .6). The risk for other cardiac death (CD) tended to be higher after combined treatment (RO-non-AMI RR, 7.4; 95% CI, 0.0 to 36.5; CM-non-AMI RR, 45.8; 95% CI, 14.4 to 110.6; P = .1). Deaths occurred 3 to 22 years after patients received 42 to 45 Gy to the mediastinum between 9 and 20 years of age. There have been no deaths among patients treated to lower mediastinal radiation doses or without mediastinal radiation. There are no clear trends in the latency of risk. One hundred six nonfatal abnormalities have also been diagnosed. CONCLUSION Mediastinal radiation of 40 to 45 Gy increases the risk of death from coronary artery and other cardiac diseases. The risk increases within 5 years of irradiation. These observations support combined-modality, low-dose irradiation regimens in children and adolescents and suggest the need for careful cardiac screening of treated patients.
Phase II study of combination cetuximab and weekly paclitaxel in patients with metastatic/recurrent squamous cell carcinoma of head and neck (SCCHN): Spanish Head and Neck Cancer Group (TTCC)
Authors: R. Hitt, A. Irigoyen, J. Nuñez, J. Grau, J. Garcia Saenz, M. Pastor, C. Jara, C. Garcia Giron, M. Hidalgo, J. Cruz Hernandez
Journal: Journal of Clinical Oncology (2007)

6012 Background: Cetuximab and paclitaxel have shown to be active in SCCHN pts and preclinical data has demonstrated a possible synergy for the combination. In a variety of tumor types, weekly paclitaxel has demonstrated an improved safety profile and activity as compared to every 3 weeks paclitaxel, providing the rationale to study the combination of cetuximab and weekly paclitaxel in metastatic/recurrent SCCHN. Methods: Pts were required to have a y performance status (KPS) = 70%, measurable disease using RECIST criteria, and may have received one regimen of induction and/or concomitant chemotherapy, but not within the recurrent/metastatic setting. Treatment included weekly paclitaxel 80 mg/m 2 and cetuximab (initial dose of 400 mg/m 2 , followed by a weekly infusion of 250 mg/m 2 ). Biopsies of tumors and samples of blood are being analyzed for correlative markers including EGFR gene copy number -FISH-, polymorphisms of intron 1 of the EGFR, and downstream EGFR pathway markers and mutations. Results: 46 planned pts were enrolled from Ap-2006 to Sep-2006. Median age is 60 years (range 42–78). Median KPS is 80% (range 70–100%). 35 pts are evaluable for response. Complete responses have been observed in 7 pts, partial responses in 18 pts, and stable disease in 6 pts for an overall response rate of 71% and disease control rate of 88%. 44 pts are evaluable for safety. Main grade 3/4 toxicities(NCI): 8 pts had acne- like rash; 7 neutropenia but only 1 febrile neutropenia; 6 asthenia; 3 mucositis; 2 infusion related reactions to paclitaxel and 1 to cetuximab; 2 peripheral neuropathies; 1 diarrhea; 1 vomiting; and 1 conjunctivitis. Conclusions: This trial shows that the combination of cetuximab and weekly paclitaxel is well tolerated and provides very encouraging activity in advanced/recurrent SCCHN. The full data, including biomarker results, will be presented at the annual meeting. No significant financial relationships to disclose.
Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: a novel and effective method for delivering multiple courses of dose-intensive therapy.
Authors: T C Shea, J R Mason, A M Storniolo, B Newton, M Breslin, M Mullen, D M Ward, L Miller, M Christian, R Taetle
Journal: Journal of Clinical Oncology (1992)

PURPOSE The trial was undertaken to study the effect of administering granulocyte-macrophage colony-stimulating factor (GM-CSF) with and without peripheral-blood progenitor cells (PBPC) on the hematologic and nonhematologic toxicity observed with multiple cycles of high-dose carboplatin chemotherapy. PATIENTS AND METHODS Eighteen patients with a variety of solid tumors received a total of 40 cycles of carboplatin, 1,200 mg/m2 per cycle, administered by continuous infusion over 96 hours. All 40 courses were administered with a daily 4-hour intravenous (IV) infusion of either 5 or 10 micrograms/kg/d of recombinant human Escherichia coli-derived GM-CSF. The first 20 courses were administered without PBPC support (treatment A). Because of severe neutropenia and thrombocytopenia, the next 20 courses of therapy were administered with GM-CSF, PBPC, and oral antibiotic prophylaxis (treatment B). RESULTS The addition of PBPC support led to a significant reduction in the duration of neutropenia (10.5 v 7.5 days; P = .027) and thrombocytopenia (12.4 v 5.2 days; P = .001), number of RBC transfusions (six v three; P = .01) and platelet transfusions (10.3 v 3.7; P = .013), number of hospital days (12.6 v 2.9; P = .01), and days of IV antibiotics (11.8 v 2.4; P = .007) per cycle. Significant increases in the weekly dose intensity (206 v 285 mg/m2/wk; P = .014) and total dose (2,287 v 3,600 mg/m2; P = .018) of carboplatin delivered were also observed with treatment B. The overall response rate in this study was 70%, with 11 of 16 assessable patients achieving either a complete (three patients) or partial (eight patients) remission. CONCLUSION This combination of GM-CSF and PBPC infusion represents an effective method for delivering multiple cycles of high-dose carboplatin chemotherapy and may serve as a model for the administration of high-dose chemotherapy in future trials.