tbuckley/cabot-search huggingface dataset:
Resolving the Optimal Timing of Radiotherapy After Radical Prostatectomy: The Need for Further Research
Authors: Christopher Parker, Matthew R. Sydes
Journal: Journal of Clinical Oncology (2008)

TO THE EDITOR: Van der Kwast and colleagues recently provided an excellent summary of the published randomized controlled trials of postoperative radiotherapy after radical prostatectomy. They highlight remaining areas of uncertainty and, in particular, the ongoing doubt concerning the optimum timing of postoperative treatment. The possibility of a second wave of metastases arising from residual local disease, before elevation of serum prostate-specific antigen (PSA) levels is detected, is a strong argument for immediate (adjuvant) radiotherapy. In contrast, the financial cost and the morbidity of radiotherapy, together with the pattern of failure analysis of the Southwest Oncology Group 8794 trial, argue for a policy of deferred (salvage) radiotherapy at the time of PSA failure. Given the large number of men treated with radical prostatectomy and the trend towards surgical treatment of men with high-risk and locally advanced disease, the optimum timing of postoperative radiotherapy is an important and unresolved issue. The completed randomized trials described by Van der Kwast et al, although valuable, do little to resolve this issue because they compared immediate radiotherapy with a policy of deferring radiotherapy until clinical (and not biochemical) progression. A large-scale randomized controlled trial is required to study the timing of postoperative radiotherapy with respect to long-term clinical outcomes. The recently opened Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial is an Intergroup phase III trial, run by the Medical Research Council Clinical Trials Unit in the United Kingdom, and by the National Cancer Institute Clinical Trials Group in Canada, that aims to recruit over 4,000 patients (ISRCTN40814031). The trial has a pragmatic design: men who have had a radical prostatectomy, and for whom there is uncertainty regarding the optimum timing of postoperative radiotherapy, may be randomly assigned to either adjuvant radiotherapy or early salvage radiotherapy at PSA failure. This is the Radiotherapy Timing Randomisation and will recruit around 2,700 patients. In addition, all men receiving postoperative radiotherapy, whether in the adjuvant or salvage setting, may also be randomized between radiotherapy alone, radiotherapy plus 6 months of hormone therapy, or radiotherapy plus 24 months of hormone therapy (Hormone Duration Randomisation). The RADICALS recruitment target is ambitious but achievable. We are grateful to Van der Kwast and his colleagues for highlighting the uncertainty regarding the optimum timing of postoperative radiotherapy following radical prostatectomy. This uncertainty can only be resolved by appropriately designed phase III trials. Centers or trial groups that would be interested in taking part in the RADICALS trial are invited to contact the Medical Research Council’s Clinical Trials Unit by visiting their Web site.
Procarbazine and Infertility in Low-Grade Gliomas in Children
Authors: Helen Toledano, Myriam Ben-Arush, Isaac Yaniv
Journal: Journal of Clinical Oncology (2012)

TO THE EDITOR: We read with interest the publication by Ater et al on the comparison between two different chemotherapy regimens for low-grade glioma in children. The primary aim was to compare the event-free survival but the stated secondary aims included a comparison of toxicity of the two regimens. The discussion mentions the fear that the TPCV (thioguanine, procarbazine, CCNU, vincristine) regimen may increase the risk of secondary neoplasms however there is no mention of the risk of infertility from procarbazine in TPCV. The protocol includes procarbazine 200 mg/m/cycle for a total of eight cycles giving a cumulative dose of 1,600 mg/m. The TPCV protocol was based on the TPDCV (thioguanine, procarbazine, dibromodulcitol, CCNU, vincristine) regimen with the exclusion of the dibromodulcitol but even a recent publication on 15 years follow-up of pediatric patients with low-grade hypothalamic/chiasmatic glioma treated with this regimen makes no mention of fertility or folliclestimulating hormone measurements. It is well known from the literature on Hodgkin lymphoma in children that there is a relationship between the cumulative doses of gonadotoxic drugs, especially procarbazine, and the extent of testicular damage and the azoo/hypospermia is usually irreversible. With an overall survival for low-grade gliomas of 85% and the likelihood that the majority of these patients will reach adulthood, lasting testicular damage with severely impaired spermatogenesis could be particularly distressing to the many young adults cured of their glioma. In addition, the vast majority of these patients will be too young for fertility preservation techniques such as sperm banking. This issue needs to be addressed in the decision making process regarding treatment options together with the family of a child with a low-grade glioma and should be documented in long-term follow-up studies of TPCV and similar procarbazine-containing regimens. Considering the morbidity of gonadal dysfunction, efforts are needed to test alternative treatment regimens with less gonadotoxic chemotherapeutic agents or hopefully new biologic targeted therapies for low-grade gliomas in children.
PEDIATRIC RESOURCE EXPENDITURES IN CARDIAC SPECIALTY ENCOUNTERS (PRECISE): DEVELOPMENT OF A COST ADJUSTMENT MODEL FOR CONGENITAL HEART SURGERY
Authors: Lisa Bergersen, Kimberlee Gauvreau, Jean Connor, Melvin Almodovar, James DiNardo, John Triedman, Puja Banka, Dionne Graham, Sitaram Emani, John Mayer
Journal: Journal of the American College of Cardiology (2013)
Expansion of HIV-specific CD4+ and CD8+ T cells by dendritic cells transfected with mRNA encoding cytoplasm- or lysosome-targeted Nef
Authors: Daniel G. Kavanagh, Daniel E. Kaufmann, Sherzana Sunderji, Nicole Frahm, Sylvie Le Gall, David Boczkowski, Eric S. Rosenberg, David R. Stone, Mary N. Johnston, Bradford S. Wagner, Mohammad T. Zaman, Christian Brander, Eli Gilboa, Bruce D. Walker, Nina Bhardwaj
Journal: Blood (2005)
Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of <i>TP53</i>: Final Results of the National Cancer Research Institute CLL206 Trial
Authors: Andrew R. Pettitt, Richard Jackson, Stacey Carruthers, James Dodd, Susanna Dodd, Melanie Oates, Gillian G. Johnson, Anna Schuh, Estella Matutes, Claire E. Dearden, Daniel Catovsky, John A. Radford, Adrian Bloor, George A. Follows, Stephen Devereux, Anton Kruger, Julie Blundell, Samir Agrawal, David Allsup, Stephen Proctor, Earnest Heartin, David Oscier, Terry J. Hamblin, Andrew Rawstron, Peter Hillmen
Journal: Journal of Clinical Oncology (2012)

Purpose In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. Patients and Methods Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m 2 for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). Results The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. Conclusion Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.
Rituximab Added to First-Line Mitoxantrone, Chlorambucil, and Prednisolone Chemotherapy Followed by Interferon Maintenance Prolongs Survival in Patients With Advanced Follicular Lymphoma: An East German Study Group Hematology and Oncology Study
Authors: Michael Herold, Antje Haas, Stefanie Srock, Sabine Neser, Kathrin Haifa Al-Ali, Andreas Neubauer, Gottfried Dölken, Ralph Naumann, Wolfgang Knauf, Mathias Freund, Robert Rohrberg, Klaus Höffken, Astrid Franke, Thomas Ittel, Erika Kettner, Ursula Haak, Ulrich Mey, Christian Klinkenstein, Michael Aβmann, Ullrich von Grünhagen
Journal: Journal of Clinical Oncology (2007)

Purpose Rituximab has been shown to be active in follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. We conducted a randomized trial comparing mitoxantrone, chlorambucil, and prednisolone (MCP) chemotherapy plus rituximab with MCP alone. Patients and Methods Previously untreated patients with stage III or IV CD20 + indolent or mantle cell lymphoma were randomly assigned to either eight 28-day cycles of MCP plus rituximab (R-MCP; n = 181) or eight cycles of MCP alone (n = 177). All patients who achieved a complete or partial remission were treated with interferon maintenance until relapse. Herein, we report the results from the primary analysis population of patients with FL, who constituted the majority of patients (56%) recruited to the trial (n = 201; R-MCP, n = 105; MCP, n = 96). Results Rates of overall and complete response were significantly higher in the R-MCP arm than the MCP arm (overall response, 92% v 75%, respectively; P = .0009; complete response, 50% v 25%, respectively; P = .004). With a median follow-up time of 47 months, median event-free survival (EFS) and progression-free survival (PFS) times were significantly prolonged with R-MCP compared with MCP (EFS, not reached v 26 months, respectively; P &lt; .0001; PFS, not reached v 28.8 months, respectively; P &lt; .0001), and overall survival (OS) was significantly improved with R-MCP compared with MCP (4-year OS rate, 87% v 74%, respectively; P = .0096). Conclusion The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.
INFLUENZA VIRUS AND ITS MUCOPROTEIN SUBSTRATE IN THE CHORIOALLANTOIC MEMBRANE OF THE CHICK EMBRYO
Authors: R. Walter Schlesinger, H. Valerie Karr
Journal: The Journal of Experimental Medicine (1956)

The fate of heat-stable inhibitors (HI) of hemagglutination by influenza viruses in the infected chorioallantoic membrane has been studied. The amount of soluble HI extractable from the normal CAM is taken as a measure of the total mucoprotein substrate derived from the allantoic cells. It has been shown that a decrease in HI is demonstrable when all or nearly all cells of the allantois are involved in the infectious process. Once this condition is fulfilled, viral multiplication in the CAM is associated with stepwise breakdown and partial restoration of HI. The periodicity of these steps is in close agreement with earlier reports by others on the duration of primary and secondary cycles of viral multiplication. Periodicity of viral multiplication and of HI breakdown with subsequent restoration is particularly pronounced in eggs pretreated with metaperiodate or with mixtures of periodate and glucose or glycerol. The stepwise nature of the HI breakdown indicates that it is in some way related to intracellular phases of viral reproduction, and that individual cells produce virus in cycles rather than continuously. A possible mechanism of this process is proposed.
Plasma or serum from patients with systemic sclerosis alters behaviour of normal erythrocytes.
Authors: I B Kovacs, M H Rustin, R H Thomas, C Ridler, S O Sowemimo-Coker, J D Kirby
Journal: Annals of the Rheumatic Diseases (1985)

Incubation of washed normal erythrocytes with fresh or frozen plasma or serum from patients with systemic sclerosis (SS) significantly decreased the filterability of the cells, whereas the incubation of homologous normal serum or plasma with washed erythrocytes did not alter the filterability of these cells. The endothelial cell adherence of normal erythrocytes was increased by 3.5- and 2.6-fold (p less than 0.01) respectively when plasma or serum from patients with SS rather than that from normal controls was added to the incubation medium. Further investigation and isolation of the reactive material(s) present in the serum and plasma of patients with SS, which affect the deformability and endothelial cell adherence of erythrocytes, may be helpful in understanding the pathogenesis of the disease.
Prognostic Value of Total Serum Bilirubin/γ-Glutamyl Transpeptidase Ratio in Cirrhotic Patients
Authors: Thierry Poynard, Othar Zourabichvili, Gerard Hilpert, Sylvie Naveau, Alain Poitrine, Clarisse Benatar, Jean-Claude Chaput
Journal: Hepatology (1984)

The aim of this study was to assess the prognostic value of total serum bilirubin (TSB), γ-glutamyl transpeptidase (GGT) and the TSB/GGT ratio in 129 consecutive cirrhotic patients, and to determine how seven other clinical and biochemical variables affect the prognostic value of these measurements. The Cox model and log rank test were used to compare survival rates at 1 year. Considered alone, encephalopathy, ascites, TSB, prothrombin time, serum albumin, GGT and the TSB/GGT ratio (TSB expressed in /imoles per liter and GGT in IU per liter were associated to the 1-year survival (p &lt; 0.10). The estimated per cent surviving at the end of 1 year was 20% for those with encephalopathy and 59% for those without, 46% and 62% for those with and without ascites, 28% for those with TSB ± 3.0 mg per dl, 68% for those with TSB ± 3.0 mg per dl, 44% for those with GGT ± 100 IU per liter, 60% for those with GGT ± 100 IU per liter, and 12% for those with TSB/GGT ± 1, 66% for those with TSB/GGT ± 1. With the Cox model, which was used to assess the combined effect of several prognostic variables, GGT was the only biochemical variable which added significant prognostic value to TSB. The combination of TSB and GGT added significant prognostic value to encephalopathy and ascites.
Optimal Definitions for Abdominal Obesity and the Metabolic Syndrome in Andean Hispanics: The PREVENCION Study
Authors: Josefina Medina-Lezama, Catherine A. Pastorius, Humberto Zea-Diaz, Antonio Bernabe-Ortiz, Fernando Corrales-Medina, Oscar Leopoldo Morey-Vargas, Diana Andrea Chirinos, Edgar Muñoz-Atahualpa, Julio Chirinos-Pacheco, Julio Alonso Chirinos
Journal: Diabetes Care (2010)

OBJECTIVE We aimed to establish optimal definitions for abdominal obesity and metabolic syndrome (MetS) among Andean adults. RESEARCH DESIGN AND METHODS Among 1,448 Andean adults, we assessed the relationship between waist circumference and subclinical vascular disease assessed by carotid intima-media thickness (cIMT) and manifest cardiovascular disease (M-CVD). RESULTS Optimal waist circumference cutoffs to classify individuals with abnormal cIMT or M-CVD were &amp;gt;97 and &amp;gt;87 cm in men and women, respectively. With these cutoffs, there was substantial disagreement between the original American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) and the recently updated MetS definition, particularly among men (κ = 0.85). Subjects with MetS identified by the updated definition but not meeting the original AHA/NHLBI MetS criteria demonstrated significantly increased cIMT (P &amp;lt; 0.001) compared with subjects who did not meet the MetS criteria by either definition. CONCLUSIONS Our findings support the use of ethnic-specific waist circumference cutoffs and the updated MetS definition in Andean adults.
INTERACTIONS OF THE COMPLEMENT SYSTEM WITH ENDOTOXIC LIPOPOLYSACCHARIDE: CONSUMPTION OF EACH OF THE SIX TERMINAL COMPLEMENT COMPONENTS
Authors: H. Gewurz, H. S. Shin, S. E. Mergenhagen
Journal: The Journal of Experimental Medicine (1968)

Large amounts of each C'3, C'5, C'6, C'7, C'8, and C'9 were consumed when guinea pig serum was incubated with endotoxic lipopolysaccharide, zymosan, or preformed immune complexes. Since these C' components subserve several of the biological activities which follow the injection of endotoxins into experimental animals, these experiments support the hypothesis that certain biological effects induced by endotoxins may be mediated via the C' system, and may account for some of the known similarity in the reactivities evoked by endotoxins and immune complexes in vivo.
The Cyclin-Dependent Kinase Inhibitor Flavopiridol Potentiates Doxorubicin Efficacy in Advanced Sarcomas: Preclinical Investigations and Results of a Phase I Dose-Escalation Clinical Trial
Authors: Jason J. Luke, David R. D'Adamo, Mark A. Dickson, Mary Louise Keohan, Richard D. Carvajal, Robert G. Maki, Elisa de Stanchina, Elgilda Musi, Samuel Singer, Gary K. Schwartz
Journal: Clinical Cancer Research (2012)

Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas.Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion.Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m(2) bolus; 50 mg/m(2) bolus + 40 mg/m(2) infusion) both in combination with doxorubicin (60 mg/m(2)). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing C(max) with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks.The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified.
Features and Trend of Loss of Promoter-Associated CpG Islands in the Human and Mouse Genomes
Authors: Cizhong Jiang, Leng Han, Bing Su, Wen-Hsiung Li, Zhongming Zhao
Journal: Molecular Biology and Evolution (2007)

CpG islands (CGIs) are often considered as gene markers, but the number of CGIs varies among mammalian genomes that have similar numbers of genes. In this study, we investigated the distribution of CGIs in the promoter regions of 3,197 human-mouse orthologous gene pairs and found that the mouse genome has notably fewer CGIs in the promoter regions and less pronounced CGI characteristics than does the human genome. We further inferred CGI's ancestral state using the dog genome as a reference and examined the nucleotide substitution pattern and the mutational direction in the conserved regions of human and mouse CGIs. The results reveal many losses of CGIs in both genomes but the loss rate in the mouse lineage is two to four times the rate in the human lineage. We found an intriguing feature of CGI loss, namely that the loss of a CGI usually starts from erosion at the both edges and gradually moves towards the center. We found functional bias in the genes that have lost promoter-associated CGIs in the human or mouse lineage. Finally, our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated. Our study provides a detailed view of the evolution of promoter-associated CGIs in the human and mouse genomes and our findings are helpful for understanding the evolution of mammalian genomes and the role of CGIs in gene function.
Comparison of alpha5(IV) collagen chain expression in skin with disease severity in women with X-linked Alport syndrome.
Authors: K Nakanishi, K Iijima, N Kuroda, Y Inoue, Y Sado, H Nakamura, N Yoshikawa
Journal: Journal of the American Society of Nephrology (1998)

X-Linked Alport syndrome is caused by mutations in the type IV collagen alpha5 chain gene. Male patients usually develop end-stage renal disease, whereas female patients have more variable phenotypes from asymptomatic hematuria to end-stage renal disease. The variable phenotypes in female patients may be attributable to different X-chromosome inactivation patterns. Therefore, the correlation between disease severity and the degree of alpha5 chain expression in the epidermal basement membrane of female patients with X-linked Alport syndrome was examined. To estimate the disease severity in X-linked Alport syndrome, the ratios of protein to creatinine in single voided urine samples were used. Expression of the alpha5 chain in the epidermal basement membrane was examined by an indirect immunofluorescence method using an anti-alpha5 chain monoclonal antibody. A total of 25 female patients with X-linked Alport syndrome from 17 families was examined. Multiple regression analysis using disease severity as the response variable, and age, family history of nephritis, female and male family history of end-stage renal disease, serum creatinine concentration, and alpha5(IV) expression ratio in the epidermal basement membrane as explanatory variables showed that only alpha5(IV) expression ratio was a significant factor, and that it showed a highly significant negative association with disease severity (adjusted r2=0.71, P=0.0001). These findings suggest that variable alpha5 chain expression, possibly caused by different X-inactivation patterns, is responsible for the variable disease severity in female patients with X-linked Alport syndrome, and that immunohistochemical examination of alpha5 chain expression in the epidermal basement membrane may be a simple and useful method for predicting patient outcome.