bluuebunny/crossref_metadata_2025_split huggingface dataset:
Docetaxel Plus Prednisone or Mitoxantrone Plus Prednisone for Advanced Prostate Cancer: Updated Survival in the TAX 327 Study
Authors: Berthold Dominik R. , Pond Gregory R. , Soban Freidele , de Wit Ronald , Eisenberger Mario , Tannock Ian F. 
Published: January 2008

Purpose The TAX 327 study compared docetaxel administered every 3 weeks (D3), weekly docetaxel (D1), and mitoxantrone (M), each with prednisone (P), in 1,006 men with metastatic hormone-resistant prostate cancer (HRPC). The original analysis, undertaken in August 2003 when 557 deaths had occurred, showed significantly better survival and response rates for pain, prostate-specific antigen (PSA), and quality of life for D3P when compared with MP. Here, we report an updated analysis of survival. Methods Investigators were asked to provide the date of death or last follow-up for all participants who were alive in August 2003. Results By March 2007, data on 310 additional deaths were obtained (total = 867 deaths). The survival benefit of D3P compared with MP has persisted with extended follow-up (P = .004). Median survival time was 19.2 months (95% CI, 17.5 to 21.3 months) in the D3P arm, 17.8 months (95% CI, 16.2 to 19.2 months) in the D1P arm, and 16.3 months (95% CI, 14.3 to 17.9 months) in the MP arm. More patients survived ≥ 3 years in the D3P and D1P arms (18.6% and 16.6%, respectively) compared with the MP arm (13.5%). Similar trends in survival between treatment arms were seen for men greater than and less than 65 years of age, for those with and without pain at baseline, and for those with baseline PSA greater than and less than the median value of 115 ng/mL. Conclusion The present analysis confirms that survival of men with metastatic HRPC is significantly longer after treatment with D3P than with MP. Consistent results are observed across subgroups of patients.
Bendamustine in Patients With Rituximab-Refractory Indolent and Transformed Non-Hodgkin's Lymphoma: Results From a Phase II Multicenter, Single-Agent Study
Authors: Friedberg Jonathan W. , Cohen Philip , Chen Ling , Robinson K. Sue , Forero-Torres Andres , La Casce Ann S. , Fayad Luis E. , Bessudo Alberto , Camacho Elber S. , Williams Michael E. , van der Jagt Richard H. , Oliver Jennifer W. , Cheson Bruce D. 
Published: January 2008

Purpose Bendamustine hydrochloride is an alkylating agent with novel mechanisms of action. This phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell non-Hodgkin's lymphoma (NHL) refractory to rituximab. Patients and Methods Patients received bendamustine 120 mg/m2 intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression-free survival, and safety. Results Seventy-six patients, ages 38 to 84 years, with predominantly stage III/IV indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 months), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded 1 year. The most frequent nonhematologic adverse events included nausea and vomiting, fatigue, constipation, anorexia, fever, cough, and diarrhea. Grade 3 or 4 reversible hematologic toxicities included neutropenia (54%), thrombocytopenia (25%), and anemia (12%). Conclusion Single-agent bendamustine produced durable objective responses with acceptable toxicity in heavily pretreated patients with rituximab-refractory, indolent NHL. These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population.
What Is the Role for the Circumferential Margin in the Modern Treatment of Rectal Cancer?
Authors: Nagtegaal Iris D. , Quirke Phil 
Published: January 2008

Purpose Treatment of rectal cancer has changed dramatically over the last decade. The worldwide introduction of total mesorectal excision in combination with the increasing use of radio(chemo)–therapy has led to an improved prognosis. One of the main prognostic factors in rectal cancer is the circumferential resection margin (CRM). Since the initial description of its clinical importance in 1986, the involvement of this margin (also called lateral or radial resection margin) has been associated with a poor prognosis. Methods In the current review, the evidence for the importance of the CRM in more than 17,500 patients is reviewed, and the relevance of this assessment to modern treatment is assessed. Results We demonstrate that, after neoadjuvant therapy (both radiotherapy and radiochemotherapy), the predictive value of the CRM for local recurrence is significantly higher than when no preoperative therapy has been applied (hazard ratio [HR] = 6.3 v 2.0, respectively; P < .05). Furthermore, involvement of the CRM is a powerful predictor of both development of distant metastases (HR = 2.8; 95% CI, 1.9 to 4.3) and survival (HR = 1.7; 95% CI, 1.3 to 2.3). In addition to the prognostic data, this review describes different modes of margin involvement, exact definitions, and factors influencing its presence. Conclusion CRM involvement is one of the key factors in rectal cancer treatment.
Shortening the Timeline of Pediatric Phase I Trials: The Rolling Six Design
Authors: Skolnik Jeffrey M. , Barrett Jeffrey S. , Jayaraman Bhuvana , Patel Dimple , Adamson Peter C. 
Published: January 2008

Purpose To shorten the study conduct timeline of pediatric phase I oncology trials by employing a novel trial design. Methods A comparison of the traditional 3 + 3 patients per cohort, phase I trial design with a novel, rolling six design was performed by using discrete event simulation. The rolling six design allows for accrual of two to six patients concurrently onto a dose level based on the number of patients currently enrolled and evaluable, the number experiencing dose-limiting toxicity (DLT), and the number still at risk of developing a DLT. Clinical trial simulations (n = 1,000) were based on historical data and were performed using SAS 9.1.3 (SAS Institute, Cary, NC). Study timelines and patient numbers were determined for each design, and safety was assessed as a function of the number of DLTs observed. Results In twelve completed historical studies, the median time to study completion was 452 days (range, 220 to 606 days); number of evaluable participants enrolled was 22 (range, 11 to 33), and DLTs occurring per study was three (range, 0 to 5). In 1,000 study simulations, in which the average time to new patient accrual was 10 days, the average ± standard deviation (SD) time to study completion was 294 ± 75 days for the rolling six design versus 350 ± 84 days for the 3 + 3 design, whereas the number of DLTs per study was the same (average ± SD, 3.3 ± 1.1 v 3.2 ± 1.1 for the rolling six and 3 + 3 designs, respectively). Conclusion The rolling six design may significantly decrease the duration of pediatric phase I studies without increasing the risk of toxicity. The design will be tested prospectively in upcoming Children's Oncology Group phase I trials.
Nodal Stage Classification for Breast Carcinoma: Improving Interobserver Reproducibility Through Standardized Histologic Criteria and Image-Based Training
Authors: Turner Roderick R. , Weaver Donald L. , Cserni Gabor , Lester Susan C. , Hirsch Karen , Elashoff David A. , Fitzgibbons Patrick L. , Viale Giuseppe , Mazzarol Giovanni , Ibarra Julio A. , Schnitt Stuart J. , Giuliano Armando E. 
Published: January 2008

Purpose Reliable pathologic stage classification of axillary lymph nodes is an important determinant of prognosis and therapeutic decision making for patients with invasive breast cancer. Pathologists' distinction between micrometastasis (pN1mi) and isolated tumor cells [ITC; pN0(i+)] is variable using the American Joint Committee on Cancer (AJCC) Staging Manual (Sixth Edition). We sought to determine whether a set of clearly defined histologic criteria could lead to reproducible nodal classification by pathologists. Patients and Methods Digital images of sentinel lymph node biopsies from 56 patients with small-volume nodal metastases were examined by six experienced breast pathologists (MDs), first as a pre-test, and again as a post-test after studying a training program that outlined and illustrated the classification criteria. Results Post-test results, after study of the training program, were significantly improved. Compared with the reference MD, agreement improved from 76.2% (pre-test κ = 0.575; standard deviation [SD], 0.25) to 97.3% (post-test κ = 0.947; SD, 0.049). Multirater analysis of agreement among the six MDs improved from 71.5% (pre-test κ = 0.487; ASE, 0.039) to 95.7% (post-test κ = 0.915; ASE, 0.037). Agreement on lobular carcinoma metastasis classification improved from 55% (23 of 42; pre-test) to 100% (42 of 42; post-test) (P < .001), and agreement on ITC classification in nodal parenchyma improved from 67.6% (69 of 102; pre-test) to 98.0% (100 of 102; post-test; P < .001). Conclusion Application of current definitions for classification of small-volume nodal metastases are inconsistent, leading to variable classification of ITC and micrometastases. Reproducibility of pathologic nodal stage classification is achievable through study of a training set to clarify the AJCC criteria.
High Viral Load and Hepatitis B Virus Subgenotype Ce Are Associated With Increased Risk of Hepatocellular Carcinoma
Authors: Chan Henry Lik-Yuen , Tse Chi-Hang , Mo Frankie , Koh Jane , Wong Vincent Wai-Sun , Wong Grace Lai-Hung , Lam Chan Stephen , Yeo Winnie , Sung Joseph Jao-Yiu , Mok Tony Shu-Kam 
Published: January 2008

Purpose We aimed to investigate the impact of hepatitis B virus (HBV) DNA and HBV genotypes/subgenotypes on the risk of hepatocellular carcinoma (HCC). Patients and Methods A prospective cohort of patients infected with chronic HBV in a surveillance program for HCC since 1997 was studied. Ultrasound and alpha-fetoprotein evaluation were regularly performed to detect HCC. Risk factors for HCC and the relationship between HBV DNA and HBV genotypes were determined. Results Among 1,006 patients with a median follow-up of 7.7 years, 86 patients (8.5%) developed HCC. With reference to the low HBV DNA stratum (log HBV DNA ≤ 4.5 copies/mL), the hazard ratio for HCC of the intermediate HBV DNA stratum (log HBV DNA > 4.5 to 6.5 copies/mL) was 1.62 (95% CI, 1.05 to 2.48; P = .027) and that of the high HBV DNA stratum (log HBV DNA > 6.5 copies/mL) was 2.73 (95% CI, 1.76 to 4.25; P < .001). Among patients with genotyping results, 330 patients had HBV genotype B and 439 patients had HBV genotype C (94 subgenotype Ce and 345 subgenotype Cs). With reference to HBV genotype B, HBV subgenotype Ce has the highest risk of HCC (hazard ratio = 2.75; 95% CI, 1.66 to 4.56; P < .0001) and HBV subgenotype Cs has intermediate risk (hazard ratio = 1.70; 95% CI, 1.09 to 2.64; P = .020). On multivariate analysis, HBV DNA, HBV genotypes, liver cirrhosis, male sex, older age, and lower serum albumin were independent risk factors of HCC. Conclusion High HBV DNA level and HBV genotype C, particularly subgenotype Ce, increased the risk of HCC in chronic hepatitis B.
Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers
Authors: Guix Marta , de Matos Granja Nara , Meszoely Ingrid , Adkins Theresa B. , Wieman Bobbye M. , Frierson Kerek E. , Sanchez Violeta , Sanders Melinda E. , Grau Ana M. , Mayer Ingrid A. , Pestano Gary , Shyr Yu , Muthuswamy Senthil , Calvo Benjamin , Krontiras Helen , Krop Ian E. , Kelley Mark C. , Arteaga Carlos L. 
Published: January 2008

PurposeTo administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity.Patients and MethodsNewly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ERα.ResultsIn drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade ≤ 2 rash and diarrhea were the main toxicities. Erlotinib inhibited tumor cell proliferation (Ki67), P-EGFR, and P-HER-2. The inhibition of proliferation occurred in estrogen receptor (ER) –positive but not in human epidermal growth factor receptor 2 (HER-2) –positive or triple-negative cancers. Treatment was associated with a significant reduction of P-MAPK, P-Akt, P-S6, and S118 P-ERα in hormone receptor–positive cancers.ConclusionA presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer. EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2–positive or triple-negative breast cancers.
Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107
Authors: Grothey Axel , Hedrick Eric E. , Mass Robert D. , Sarkar Somnath , Suzuki Sam , Ramanathan Ramesh K. , Hurwitz Herbert I. , Goldberg Richard M. , Sargent Daniel J. 
Published: January 2008

Purpose In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. Patients and Methods For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. Results Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. Conclusion In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.
Citizen Participation and Health Care: Problems of Government Induced Participation
Authors: Lipsky Michael , Lounds Morris 
Published: January 2008

In this paper we trace the implications of some common contradictions in government-inspired efforts to increase citizen participation in health care delivery. We cover general problems of generating citizen participation, specific difficulties in community organization resulting when issues of health are the organizing focus, and the benefits that were thought to result from efforts to increase citizen participation in social programs in the 1960's.
When programs focused on increased citizen participation were initiated program administrators attempted to maximize citizen involvement quickly by: projecting an image of maximal social impact; minimizing or ignoring questions of long-term fiscal uncertainty; projecting an image of maximal control by citizens; and projecting images of institutional solidarity and of experimentation and innovation. They tended to recruit to the staff social activists taken to be representative of the community (although they might not be), promising opportunities for upward mobility. They also tended to adopt conciliatory administrative styles in keeping with their experimental non-elitist orientations.
These tendencies characteristic of the initiation phase of projects conflicted with the demands placed upon programs in later phases of program implementation. These demands resulted from later perceived needs to: evaluate programs; limit spending; counter internal organizational opposition; and respond to sponsors' shifting interests. Paraprofessionals recruited to the staff tended to lose their “community” orientation, and administrative style tended to focus considerably more on program accountability.
These shifting program demands substantially account for what otherwise appears to be the failure of efforts to increase citizens' participation in health delivery programs, and, by extension, in other areas where the impetus for increased citizen participation comes from government initiatives.
The American Medical Economy: Problems and Perspectives
Authors: Rice Dorothy P. , Wilson Douglas 
Published: January 2008

Federal initiatives during the last decade have resulted in considerable changes in the American medical economy. Large sums of money have been infused into the system under Medicare and Medicaid, substantially improving access to care for the aged and the poor. At the same time, the improvements in knowledge and medical technology that have occurred have been largely underwritten by the tremendous increases in third-party payment mechanisms. These costly new technologies have contributed significantly to the high cost of hospital care and to the increased specialization of physician's services.
The chronic inflation in medical expenditures and the explosive increases in Federal subsidization of medical care have led to questions concerning the efficacy of medical care for improving health status. There is a considerable lack of evidence for a causal relationship between what is done to the patient and the outcome of the medical care process as measured by mortality, disability, and capacity to carry on activities.
Various attempts have been made to control the chronic inflation of medical expenditures, but success is uneven and elusive. Alternatives in financing medical care services currently under debate include various provisions to control costs and utilization, but attention should be directed to organizing American medical care services in general, toward the more rational use of our resources.
Abortion and the Law: The Impact on Hospital Policy of the Roe and Doe Decisions
Authors: Kemp Kathleen A. , Carp Robert A. , Brady David W. 
Published: January 2008

The purpose of the article is to analyze the effect of the U.S. Supreme Court's abortion decisions upon the policies of hospitals in Harris County (Houston), Texas. The study attempts to determine the variables associated with the hospitals' policies prior to and following the Roe and Doe decisions and which variables best explain the change (or lack of change) from the first period to the other.
The principal data source is a series of in-depth personal interviews with 68 key decision-makers in 36 general hospitals in Harris county. Critical data about the hospitals' economic status were obtained from the American Hospital Association 's HospitaIs: Guide Issue, 1972.
The major findings of the study are as follows: (1) the Roe and Doe decisions did affect hospital policy in that within a year after the High Court's rulings, hospitals evidenced a dramatic shift toward more permissive abortion policies; (2) economic variables, while not having much explanatory power for pre-Roe and Doe abortion policies, were important predictors of hospital policy and of the propensity for hospitals to liberalize their abortion standards after the Supreme Court decisions; and (3) the values, attitudes, and attributes of the individual decision-makers had much to do with explaining their respective hospitals' abortion policies before and after the Supreme Court decisions and accounted for changes in abortion policy from the first to the second period.
The Worker's Right-to-Know: Obstacles, Ambiguities and Loopholes
Authors: Richter Elihu D. 
Published: January 2008

Telling the worker about exposure to occupational hazards and their potentially adverse health effects has been established as an ethical principle of occupational health and safety. Situations or issues that may result in incomplete application or nonapplication of this principle include: (1) the employee's need to initiate the disclosure process; (2) medical reluctance to disclose exposure data; (3) long latency periods between exposure and effect; (4) problems of quality control; (5) the use of monitoring methods with low predictive value; (6) statutory secrecy provisions; (7) doctor-patient communication difficulties; (8) serious social and health problems not related to work environment; (9) the nonspecific nature of most work-related morbidity; and (10) the absence of any monitoring whatsoever. Obligatory disclosure of exposure information is hypothesized to spur preventive measures, environmental and personal, for both short- and long-term hazards. Where the foregoing problems interfere with full disclosure, this norm's full preventive role may not be fulfilled. Evaluation of the effect of disclosure requirements on promoting occupational health and safety must include attention to this possibility.
“You shall not put a stumbling block before the blind.”
Leviticus 19:14.
“Publicity is … a remedy for social and industrial diseases. Sunlight is said to be the best disinfectant.”
Louis Brandeis, Other People's Money.
Exo Selective Cycloaddition Reactions of α-Hydroxy Cyclic Nitronates to Allylic Alcohols in the Presence of Magnesium Ions Leading to Isoxazolidines and Isoxazolines
Authors: Nishiuchi Masaki , Sato Hiroyasu , Umemoto Nao , Murakami Sayoko 
Published: January 2008

Abstract
The reaction of 4-hydroxy-2-isoxazoline N-oxides, as α-hydroxy cyclic nitronates, bearing an ester substituent at 3-position with allylic alcohols is highly activated in the presence of magnesium ions to give exclusively regio- and exo-selective bicyclic isoxazolidine cycloadducts at room temperature. The resulting bicyclic isoxazolidines undergo regioselective ring-opening fragmentation to give 2-isoxazoline derivatives having a 3-ester substituent. Thus, 4-hydroxy-2-isoxazoline N-oxides act as synthetic equivalents of nitrile oxides.