tbuckley/cabot-search huggingface dataset:
Update of Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene Therapy for Beta-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex-Vivo with a Lentiviral Beta AT87Q-Globin Vector (LentiGlobin BB305 Drug Product)
Authors: Mark C. Walters, John Rasko, Suradej Hongeng, Janet Kwiatkowski, Gary J Schiller, Morris Kletzel, P. Joy Ho, Elliott Vichinsky, Christof von Kalle, Marina Cavazzana, Philippe Leboulch, Alexandria Petrusich, Sandeep Soni, Alexis A. Thompson
Journal: Blood (2015)
Deficiency of the Sialyltransferase <i>St3Gal4</i> Reduces Ccl5-Mediated Myeloid Cell Recruitment and Arrest
Authors: Yvonne Döring, Heidi Noels, Manuela Mandl, Birgit Kramp, Carlos Neideck, Dirk Lievens, Maik Drechsler, Remco T.A. Megens, Pathricia V. Tilstam, Marcella Langer, Helene Hartwig, Wendy Theelen, Jamey D. Marth, Markus Sperandio, Oliver Soehnlein, Christian Weber
Journal: Circulation Research (2014)

Sialylation by α2,3-sialyltransferases has been shown to be a crucial glycosylation step in the generation of functional selectin ligands. Recent evidence suggests that sialylation also affects the binding of chemokines to their corresponding receptor.Because the chemokine receptors for Ccl5 and Ccl2 are important in atherogenic recruitment of neutrophils and monocytes, we here investigated the role of α2,3-sialyltransferase IV (ST3Gal-IV) in Ccl5- and Ccl2-mediated myeloid cell arrest and further studied its relevance in a mouse model of atherosclerosis.St3Gal4-deficient myeloid cells showed a reduced binding of Ccl5 and an impaired Ccl5-triggered integrin activation. Correspondingly, Ccl5-induced arrest on tumor necrosis factor-α-stimulated endothelium was almost completely abrogated, as observed in flow chamber adhesion assays and during ex vivo perfusion or intravital microscopy of carotid arteries. Moreover, Ccl5-triggered neutrophil and monocyte extravasation into the peritoneal cavity was severely reduced in St3Gal4(-/-) mice. In contrast, St3Gal4 deficiency did not significantly affect Ccl2 binding and only marginally decreased Ccl2-induced flow arrest of myeloid cells. In agreement with the crucial role of leukocyte accumulation in atherogenesis, and the importance of Ccl5 chemokine receptors mediating myeloid cell recruitment to atherosclerotic vessels, St3Gal4 deficiency drastically reduced the size, stage, and inflammatory cell content of atherosclerotic lesions in Apoe(-/-) mice on high-fat diet.In summary, these findings identify ST3Gal-IV as a promising target to reduce inflammatory leukocyte recruitment and arrest.
Effects of Antineoplastic Drugs on Plateau-Phase Cultures of Mammalian Cells. I. Description of the Plateau-Phase System2
Authors: F. Mauro, B. Falpo, G. Briganti, R. Elli, G. Zupi
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article Effects of Antineoplastic Drugs on Plateau-Phase Cultures of Mammalian Cells. I. Description of the Plateau-Phase System Get access F. Mauro, F. Mauro 3Laboratorio di Radiobiologia Animale, C. S. N. Casaccia, Comitato Nazionale Energia Nucleare, Rome, Italy. Search for other works by this author on: Oxford Academic PubMed Google Scholar B. Falpo, B. Falpo 3Laboratorio di Radiobiologia Animale, C. S. N. Casaccia, Comitato Nazionale Energia Nucleare, Rome, Italy. Search for other works by this author on: Oxford Academic PubMed Google Scholar G. Briganti, G. Briganti 3Laboratorio di Radiobiologia Animale, C. S. N. Casaccia, Comitato Nazionale Energia Nucleare, Rome, Italy. Search for other works by this author on: Oxford Academic PubMed Google Scholar R. Elli, R. Elli 4Istituto di Biologia Generale, Facoltà di Medicina, Università di Roma, Rome. Search for other works by this author on: Oxford Academic PubMed Google Scholar G. Zupi G. Zupi 5Istituto Regina Elena per 10 Studio e la Cura del Tumori, Viale Regina Elena, Rome. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 52, Issue 3, March 1974, Pages 705–713, https://doi.org/10.1093/jnci/52.3.705 Published: 01 March 1974 Article history Received: 13 June 1973 Accepted: 11 October 1973 Published: 01 March 1974
High-dose therapy with autologous stem cell rescue in patients with breast cancer at high risk for relapse
Authors: S. Farjami, R. Kancherla, Z. Qureshi, A. Hoang, C. Puccio, A. Mittelman, K. Seiter, T. Ahmed
Journal: Journal of Clinical Oncology (2005)

824 Background: One of the potential drawbacks of high-dose chemotherapy (HD-CT) in breast cancer is transplant related mortality and long term complications associated with conditioning regimens. Hence, the optimum conditioning regimen is yet to be defined. We evaluated the efficacy and safety of combination thiotepa, mitoxantrone and carboplatin (TMJ) as a standard conditioning regimen. Methods: Hundred seventeen patients with stage II or IIIA with four or more positive lymph nodes were consecutively enrolled in this study. Following initial staging patients received three cycles of modified CAF chemotherapy (cyclophosphamide 500 mg/m2 day 1, Doxorubicin 50 mg/m2 day 1 and 5-FU 600 mg/m2 on day 1 and day 8). Peripheral blood stem cell collection was performed following mobilization with cyclophosphamide 2gm/m2 on day 1 and 2 (total dose of 4gms/m2), etoposide 150mg/m2 on days 1, 2 and 3 (total dose of 450mg/m2) and cytokines. Following stem cell collection patients received HD-CT with thiotepa 250mg/m2 daily on days 1, 2 & 3(total dose of 750mg/m2), mitoxantrone 40mg/m2 on day 1 and carboplatin 333mg/m2 on days 1, 2 & 3 (total dose of 1gm/m2). Stem cells were infused on seventh day of HD-CT chemotherapy. Eligible patients received radiation to chest wall and tamoxifen for 5 years. Results: With median duration of follow-up of 77.16 months (range 6.9–158.16) the median overall survival (OS) and progression free survival (PFS) were 67.5 months (range 6.9–138.2) and 59.87 months (range 7.3–130.7), respectively. The subgroup analysis showed a significantly better OS in patient who received more that two millions CD34+ cells with P value of 0.04 and hazard ratio of 0.40. Mucositis and Infection were the most severe non-hematological toxicities. Grade four cardiac and pulmonary toxicities developed in one patient. There was one transplant related mortality (TRM) secondary to severe infection. One patient developed myelodysplastic syndrome (MDS). Conclusions: Our study suggest that combination thiotepa, mitoxantrone and carboplatin (TMJ) is a relatively safe and efficacious regimen and could be considered as a standard conditioning regimen in HD-CT in patients with breast cancer. No significant financial relationships to disclose.
Prediction equations for carbon monoxide diffusing capacity of the lung (TL,CO) in healthy Bulgarian children aged 7 to 18 years
Authors: Stoilka Mandadzhieva, Blagoi Marinov, Stefan Kostianev
Journal: European Respiratory Journal (2014)

Introduction: The diagnosis of lung function impairments in childhood is highly dependent on reference values used. Previous studies for carbon monoxide diffusing capacity of the lung (TL,CO) in children have limited use because they were done by different methods and with small number of participants.

Aim : The aim of this study was to derive prediction equations and normal reference values for carbon monoxide diffusing capacity of the lung (TL,CO) in healthy Bulgarian children in the age span 7-18 years.

Methods : Five hundred forty nine healthy children (254 boys/295 girls) took part in the study. Study protocol included comprehensive anthropometric, spirometric and measurements for carbon monoxide diffusing capacity of the lung (TL,CO).

Results : Prediction equations were calculated separately for boys and girls. There were significantly higher values for single breath TL,CO in boys compared to girls - 7.19±2.47 vs. 6.51±1.71 mmol.min-1kPa-1 (p‹0.001). Alveolar volume (VA) in both genders shows similar values. TL,CO and VA showed close correlations with height (r2 between 0.82 and 0.90). With increasing height all children presented a faster increase in TL,CO than in VA. Height (Ht) explained the maximum variance for TL,CO parameters and the best-fit regression equation relating functional parameters and body height was the exponential function Y=b0ˆ(eˆˆ(b1ˆht)).

Conclusions : The developed prediction equations can be used in clinical practice. Compared with reference equations based on other populations, regional reference values are biologically more suitable for the interpretation of spirometric data.
Elimination of clonogenic malignant human T cells using monoclonal antibodies in combination with 2'-deoxycoformycin.
Authors: C L Schwartz, C P Minniti, P Harwood, S Na, M L Banquerigo, L C Strauss, J Kurtzberg, S D Smith, C I Civin
Journal: Journal of Clinical Oncology (1987)

2'Deoxycoformycin (dCF) specifically inhibits adenosine deaminase (ADA) and causes selective cytotoxicity of normal and malignant T cells. In clinical trials, dCF caused rapid lysis of malignant T lymphoblasts. Although dCF has been associated with dose-limiting nonhematopoietic toxicities, myelosuppression has not been observed. Since dCF is relatively nontoxic to hematopoietic stem cells, we tested dCF for utility in the ex vivo purging of malignant T lymphoblasts from remission leukemic bone marrow for autologous bone marrow transplantation. We found that T lymphoblast cell lines were sensitive to dCF (plus deoxyadenosine [dAdo]) under conditions that did not ablate human hematopoietic colony-forming cells. Moreover, combined pharmacologic (dCF plus dAdo) and immunologic (anti-T cell monoclonal antibodies [McAb] plus complement) purging resulted in additive reduction in clonogenic T lymphoblasts. These results provide the basis for a clinical trial of bone marrow transplantation using combined pharmacologic/immunologic purging of T lymphoblasts from patients' harvested autologous marrow.
Primary Chemotherapy for Operable Breast Cancer: Incidence and Prognostic Significance of Ipsilateral Breast Tumor Recurrence After Breast-Conserving Surgery
Authors: Roman Rouzier, Jean-Marc Extra, Mathieu Carton, Marie-Christine Falcou, Anne Vincent-Salomon, Alain Fourquet, Pierre Pouillart, Edwige Bourstyn
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine the incidence and the prognostic value of ipsilateral breast tumor recurrence (IBTR) in patients treated with primary chemotherapy and breast-conserving surgery. PATIENTS AND METHODS: Between January 1985 and December 1994, 257 patients with invasive T1 to T3 breast carcinoma were treated with primary chemotherapy, lumpectomy, and radiation therapy. The median follow-up time was 93 months. To evaluate the role of IBTR in metastase-free survival, a Cox regression multivariate analysis was performed using IBTR as a time-dependent covariate. RESULTS: The IBTR rates were 16% (± 2.4%) at 5 years and 21.5% (± 3.2%) at 10 years. Multivariate analysis showed that the probability of local control was decreased by the following independent factors: age ≤ 40 years, excision margin ≤ 2 mm, S-phase fraction more than 4%, and clinical tumor size more than 2 cm at the time of surgery. In patients with excision margins of more than 2 mm, the IBTR rates were 12.7% at 5 years and 17% at 10 years. Nodal status, age ≤ 40 years, and negative estrogen receptor status were predictors of distant disease in the Cox multivariate model with fixed covariates. The contribution of IBTR was highly significant (relative risk = 5.34) when added to the model, whereas age ≤ 40 years was no longer significant. After IBTR, 31.4% (± 7.0%) of patients developed metastases at 2 years and 59.7% (± 8.1%) at 5 years. Skin involvement, size at initial surgery, and estrogen receptor status were predictors of metastases after IBTR. CONCLUSION: IBTR is a strong predictor for distant metastases. There are implications for conservative surgery after downstaging of the tumor and therapy at the time of IBTR.
Pulmonary apoptosis in fetal Down syndrome
Authors: Martijn Bruijn, Jan von der Thüsen, Chris van der Loos, Ronald de Krijger, Rhiannon van Loenhout, Albert Bos, Job van Woensel
Journal: European Respiratory Journal (2011)

Background:  Increased levels of apoptosis have been implied in various non-pulmonary conditions frequently found in Down syndrome (DS). Children with DS are at increased risk for acute lung injury and fetal lung development is disrupted in DS. In both processes, apoptosis plays a key role. Nevertheless, pulmonary apoptosis has not been studied in DS.   Aim:  We hypothesized that the amount of apoptotic epithelial cells in fetal lungs of DS is increased compared to controls.   Methods:  We compared lung tissue sections from autopsies of 21 fetuses with DS and 12 controls (16-24 weeks gestational age (GA)). Sections were double stained with antibodies against pan-cytokeratin (CK) and activated caspase-3 (C3), markers for epithelium and apoptosis. Per section, 7 random photographs were taken at 200x magnification. Spectral imaging software was used to quantify the mean number of pixels that showed colocalization of CK and C3. All sections were H&E stained to determine the presence of canalicular or saccular morphology.   Results:  The mean (SD) percentage of CK-positive pixels was equal between DS and controls (27.2% (4.7) versus 27.1% (6.2), p=0.97). The median percentage (IQR) of CK-positive pixels that showed colocalization of C3 was 0.16% (0.18) in DS compared to 0.27% (0.24) in controls (p=0.45). This was independent of GA. The mean (SD) number of CK-positive pixels increased from 22.5% (5.2) to 30.4% (4.6) with the appearance of saccular morphology in controls but not in DS (p=0.01).   Conclusion:  The number of apoptotic epithelial cells in lungs of DS fetuses does not differ from controls. We did find a difference in the development of epithelial structures between DS and controls. This might explain anomalies in alveolar development found at birth in DS.
Should the elderly receive chemotherapy for node-negative breast cancer? A cost-effectiveness analysis examining total and active life-expectancy outcomes.
Authors: C E Desch, B E Hillner, T J Smith, S M Retchin
Journal: Journal of Clinical Oncology (1993)

PURPOSE This study determines the survival benefit and cost-effectiveness of adjuvant chemotherapy in elderly women with breast cancer. In addition, the analysis measures the impact of substituting active life expectancy for survival in the clinical decision. PATIENTS AND METHODS Two cohorts of women with estrogen receptor (ER)-negative, stage I breast cancer from age 60 to 80 years were monitored using a Markov process. One group received standard chemotherapy following primary therapy, and the other had no postoperative treatment. Data were derived from recently published clinical trials and a major meta-analysis. Outcome included the average survival, active life-expectancy, and incremental cost/quality-adjusted life-year (cost/QALY). RESULTS Adjuvant chemotherapy prolongs survival in older women, but to a lesser extent compared with younger women. The average gain in quality-adjusted months was 1.8 months in a 75-year-old cohort at a cost/QALY of $4,400. These small benefits were not substantially altered when univariate changes were made in toxicity, recurrence risk, or effectiveness of chemotherapy. When active life expectancy replaced survival as an end point, the benefit for 75-year-old women decreased to 2 weeks at a cost of more than $96,000/QALY. CONCLUSION There is a small survival benefit for adjuvant chemotherapy in elderly patients. The cost of this benefit is high, but within the range of commonly reimbursed procedures until a point between 75 and 80 years old. The use of active life expectancy as the primary outcome reduces the benefit and adds to the cost. If physicians and policymakers agree that active life expectancy is a relevant outcome, withholding chemotherapy for patients &gt; or = 70 years old is a reasonable approach.
A phase I study evaluating the relative bioavailability of S-1 capsules.
Authors: M. Abramov, L. S. Rosen, E. Borisova, C. Zergebel, M. Houghton, K. Saito, M. Lichinitser
Journal: Journal of Clinical Oncology (2010)

e13086 Background: S-1 is an oral, fixed-dose combination product comprised of tegafur (FT), a prodrug of 5-FU, and 2 modulators of 5-FU metabolism: gimeracil (CDHP) and oteracil (Oxo). S-1 is designed to provide oral delivery of 5-FU while reducing the rate of degradation of 5-FU and its conversion in the gastrointestinal tract to its toxic phosphorylated metabolite. The purpose of this study was to investigate the bioavailability of S-1 components and 5-FU after administration of standard S-1 capsules compared to an oral solution. Methods: Patients with advanced stage solid tumors received single oral doses of 50 mg S-1 capsule (2 × 25 mg capsules) or 50 mg S-1 oral solution (80 mL) on Day 1 and Day 8 in a randomized crossover fashion. Plasma samples were collected on Days 1 and 8 predose (0 hr) and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hrs postdose. Single-dose pharmacokinetic (PK) parameters (AUC and Cmax) were determined for FT, 5-FU, CDHP, and Oxo. Results: 14 patients (3 men, 11 women) were enrolled; median age was 55 years and median BSA was 1.72 m2. The mean plasma PK parameters were similar for the 2 formulations(Table). For 5-FU, FT, and CDHP, the point estimates and 90% confidence intervals (CIs) for the ratio of the geometric means (S-1 capsule: S-1 oral solution) for AUC and Cmax were contained entirely within the 0.8 to 1.25 boundary. For Oxo, the 90% CIs were just outside the limit, probably because of greater intrasubject variability. Conclusions: The bioavailability of S-1 components (FT, CDHP, and Oxo) and active metabolite (5-FU) obtained after administration of S-1 capsules was comparable to that obtained after S-1 oral solution. N=14 Cmax (ng/mL) AUC0-inf (ng*hr/mL) Geometric mean (CV) Ratio Geometric mean (CV) Ratio Capsule Solution (95% CI) Capsule Solution (95% CI) 5-FU 163 (33) 163 (31) 1.00 (0.94, 1.07) 804 (30) 759 (28) 1.06 (1.00, 1.12) FT 1,732 (16) 1,735 (22) 0.99 (0.91, 1.10) 13,833 (30) 13,717 (32) 1.01 (0.93, 1.09) CDHP 435 (23) 391 (24) 1.11 (1.02, 1.21) 1,789 (34) 1,639 (31) 1.09 (1.01, 1.18) Oxo 102 (46) 101 (61) 1.01 (0.77, 1.31) 542 (51)a 525 (60)a 1.03 (0.75, 1.42) Abbreviation: CV, coefficient of variation. a n = 11 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Taiho Pharmaceutical
Clinical utility of blood-borne markers of epithelial cell death in pancreatic cancer
Authors: S. St. George-Smith, R. A. Smith, W. Greenhalf, N. Smith, P. Ghaneh, J. P. Neoptolemos, C. Dive
Journal: Journal of Clinical Oncology (2008)

22056 Background: Cytokeratin 18 (CK18) is a cytoskeletal protein expressed in epithelial cells but not haematopoietic cells. As epithelial cells die they shed CK18 into the periphery where it has clinical potential as a serological biomarker of carcinoma cell death. The M30 ELISA measures caspase-cleaved CK18 and the M65 ELISA detects both full length and caspase-cleaved CK18 reporting caspase-dependent and caspase-independent epithelial cell deaths. Comparison of M65 and M30 data thus informs on the mode of epithelial cell death. No previous studies have characterised plasma levels of these biomarkers in pancreatic cancer. Methods: Patients with resectable and unresectable pancreatic ductal adenocarcinoma were identified from a prospectively maintained database. Plasma samples were collected on the day prior to surgery and the GCLP validated M65 and M30 ELISA assays were performed. The resultant data were correlated with tumor resectability, serum CA19–9 and the circulating lymphocyte count. Results: 107 evaluable patients were identified (71 resectable, 36 unresectable). Preoperative M65 levels were available for 106 and M30 levels in 102 patients. Median M65 levels were significantly greater in unresectable cases (907 [IQR = 569–1544] U/l) than in resected cases (578 [321–988] u/l, p=0.005). A positive predictive value of 85% and specificity of 86% was determined using a M65 cut-off value of 430 U/l to predict tumour resectability at laparotomy. Levels of M65 were correlated with CA19–9 (p=0.025) and inversely correlated with the lymphocyte count (p<0.001). No significant correlation between plasma M30 levels and either CA19–9, lymphocyte count or tumor resectability were recorded, however, M30 levels ≥250 U/l were associated with a shorter median survival in unresectable cases (3.7 months) compared with cases with M30 levels <250 u/l (6.1 months - log rank, p=0.052). Conclusions: Preoperative plasma concentrations of CK18 represent a potential biomarker for both tumor resectability and prognosis in pancreatic cancer. These results suggest that levels of caspase-independent epithelial cell death are also significantly associated with the systemic host inflammatory response. No significant financial relationships to disclose.
PTH-334 Cost-effectiveness of warm humidified co2 to reduce surgical site infections in laparoscopic colorectal surgery: a cohort study
Authors: SE Mason, JM Kinross, D Reynecke, J Hendricks, TH Arulampalam
Journal: Gut (2015)

<h3>Introduction</h3> Surgical Site Infections (SSI) are a common complication which negatively impact on patient quality of life and constitute a financial burden to healthcare providers. The objective of this study is to evaluate whether using warmed, humidified carbon dioxide for peritoneal insufflation decreases the incidence of SSIs, improves patient safety and provides value for money. <h3>Method</h3> A retrospective cohort study of patients undergoing elective laparoscopic colorectal resection for both benign and malignant disease was performed at a single UK specialist centre from September 2012 to July 2014. The control group (n = 126) received peritoneal insufflation with standard cold, dry carbon dioxide whereas the intervention group (n = 126) received peritoneal insufflation with warmed, humidified carbon dioxide (using HumiGard<sup>TM</sup>, Fisher&amp;Paykel Healthcare). All patients had standard prophylactic antibiotic therapy on induction. The primary outcome measures were incidence of SSI and costs (standard-of-care costs, intervention costs and SSI treatment costs incurred at an average cost of £2000 per SSI). The intervention was assessed by calculating the Risk Ratio (RR), Odds Ratio (OR) and incremental cost-effectiveness ratio (ICER) per infection-free patient gained. <h3>Results</h3> Median age was 68 (20–87). The median BMI was 27 (SD 5.98). The mean operation time was 211 min (SD 92.7), M:F ratio was 1:1. The primary diagnoses were as follows: cancer n = 174, diverticulitis n = 31, Crohn’s n = 15, ulcerative colitis n = 10, other n = 22. There was no significant variation in age, BMI, sex, smoking status, operation time or conversion rates between groups. Introduction of warmed, humidified carbon dioxide for peritoneal insufflation reduced the incidence of SSI from 12% to 4.7% (RR = 0.40; p = 0.049; 95% CI: 0.160 – 0.997 and OR = 0.37; p = 0.047; 95% CI = 0.138 – 0.987). Treatment costs including SSI costs for patients in the control group amounted to approximately £31000 compared to £21500 in the intervention group. The ICER for the intervention is -£1226, the negative number indicating a net reduction in costs in addition to decreased SSI incidence. It costs on average £1226 less to generate each additional infection-free patient using the intervention. <h3>Conclusion</h3> This study indicates that warmed, humidified carbon dioxide is superior to cold, dry carbon dioxide for peritoneal insufflation in laparoscopic colorectal surgery. The intervention appears to be cost-effective whilst decreasing surgical morbidity. <h3>Disclosure of interest</h3> None Declared.