bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying Pediatric Neuro-oncology Risk Factors: Development of the Neurological Predictor Scale
Authors: Micklewright Jackie L. , King Tricia Z. , Morris Robin D. , Krawiecki Nicolas
Published: January 2008

Pediatric neuro-oncology researchers face methodological challenges associated with quantifying the influence of tumor and treatment-related risk factors on child outcomes. The Neurological Predictor Scale was developed to serve as a cumulative index of a child's exposure to risk factors. The clinical utility of the Neurological Predictor Scale was explored in a sample of 25 children with heterogeneous brain tumors. Consistent with expectation, a series of regression analyses demonstrated that the Neurological Predictor Scale significantly predicted composite intellectual functioning ( r2 = 0.21, p < .05), short-term memory ( r2 = 0.16, p = .05), and abstract visual reasoning abilities ( r2 = 0.28, p < .05). With the exception of chemotherapy, the Neurological Predictor Scale accounted for a significant amount of the variance in child intellectual functioning above and beyond individually examined variables. The Neurological Predictor Scale can be used to quickly quantify the cumulative risk factors associated with pediatric brain tumor diagnoses.
Levetiracetam Versus Carbamazepine Monotherapy for Partial Epilepsy in Children Less Than 16 Years of Age
Authors: Perry Scott , Holt Philip , Benatar Michael
Published: January 2008

Newer antiepileptic drugs are reported to have better side-effect profiles than traditional antiepileptics, although the evidence to this effect and their efficacy is limited. We compare the efficacy and tolerability of levetiracetam and carbamazepine monotherapy in children with partial epilepsy ≤ 16 years of age. We identified 86 patients (66 levetiracetam, 20 carbamazepine) treated with initial monotherapy for partial epilepsy and followed for ≥ 6 months. Efficacy was based on the number of patients achieving seizure freedom of ≥ 6 months. Tolerability was based on parent-and patient-reported side effects. Forty-eight (73%) subjects on levetiracetam and 13 (65%) subjects on carbamazepine achieved 6 months of seizure freedom. A total of 70% of patients on carbamazepine and 45% of those on levetiracetam had at least 1 adverse event while on monotherapy ( P = .07). Levetiracetam and carbamazepine monotherapy demonstrate similar efficacy for treatment of partial epilepsy and are well tolerated in children.
Physicochemical characterization and biological activity of lipooligosaccharides and lipid A from Neisseria meningitidis
Authors: Zughaier Susu M. , Lindner Buko , Howe Jörg , Garidel Patrick , Koch Michel H.J. , Brandenburg Klaus , Stephens David S.
Published: January 2008

Meningococcal endotoxin is the major contributor to the pathogenesis of fulminant sepsis and meningitis of meningococcal disease and is a potent activator of the MyD88-dependent and MyD88-independent pathways via the MD-2/TLR4 receptor. To understand better the biological properties of meningococcal endotoxin that initiates these events, the physicochemical structure of Neisseria meningitidis lipopoly(oligo)saccharide (LOS) of the serogroup B wild-type strain NMB (NeuNAc-Galβ-GlcNAc-Galβ-Glcβ-Hep 2(GlcNAc,Glcα)PEA-Kdo2-lipid A, 1,4′-bisphosphorylated ± PEA, PEtN) and the genetically-defined mutants ( gmhB, Kdo2 -lipid A; kdtA, meningococcal lipid A; gmhB—lpxL1, Kdo2penta-acylated lipid A and NMB— lpx1, penta-acylated meningococcal LOS) were assessed in relation to bioactivity. Confirming previous work, Kdo2-lipid A was the minimal structure required for optimal activation of the MD-2/TLR4 pathway of human macrophages. Meningococcal lipid A alone was a very weak agonist in stimulating human macrophages, even at high doses. Penta-acylated LOS structures demonstrated a moderate reduction in TLR4/MyD88-dependent signaling and a dramatic decrease in TLR4-TRIF-dependent signaling. For a better understanding of these results, we have performed an analysis of physicochemical parameters of the LOS structures such as the gel-to-liquid crystalline phase transition of the acyl chains, the inclination angle of the diglucosamine backbone with respect to the membrane surface, and the aggregate structure, and have found a very significant correlation of these parameters with biological activities extending our concept of endotoxicity.
Decreased beating rate variability of spontaneously contracting cardiomyocytes after co-incubation with endotoxin
Authors: Schmidt Hendrik , Saworski Jana , Werdan Karl , Müller-Werdan Ursula
Published: January 2008

Decreased heart rate variability (HRV) in critically ill patients indicates a poor prognosis. In heart failure patients, there is an elevated sympathetic tone, reflected by a dominance of sympathetic parameters in HRV, whereas in critically ill patients sympathetic and parasympathetic modulation of heart rate is attenuated despite increased catecholamine blood levels. Thus, autonomic dysfunction in the critically ill cannot be causally related to an impairment at the level of neural transmission, but may be due to a derangement of signal transduction at the effector cell level. On the basis of our working hypothesis that endotoxin may be involved in this blunting of effector cell response to nerval input, we studied the spontaneous beating of cardiomyocytes under the influence of endotoxin. Applying the clinically established indices of HRV to the analysis of beating rate variability (BRV) of neonatal rat cardiomyocytes in serum-free medium, a narrowing of their BRV by endotoxin is demonstrated. We propose that the narrowing of HRV in critically ill patients does not only reflect the altered input from the central or peripheral neurons, but rather a remodeling of the cardiac pacemaker cells by endotoxin and inflammatory mediators.
Review: Human antimicrobial proteins — effectors of innate immunity
Authors: Harder Jürgen , Gläser Regine , Schröder Jens-Michael
Published: January 2008

We live in a world populated by an enormous number of micro-organisms. This necessitates the existence of highly effective mechanisms to control microbial growth. Through many research efforts, a chemical defense system based on the production of antimicrobial proteins (AMPs) has been identified. AMPs are endogenous, small proteins exhibiting antimicrobial activity against a wide variety of micro-organisms. The wide distribution of these molecules in the plant and animal kingdom reflects their biological significance. Various human AMPs show a potent effect on pathogenic micro-organisms including antibiotic-resistant bacteria. Thus, there is great interest in understanding the role of AMPs within innate immunity and evaluating their use and/or specific induction to fend off infections. In this review, we provide an overview of the characteristics of human AMPs and discuss examples where AMPs may be involved in the pathogenesis of infectious and inflammatory diseases.
The Partners in Prevention Program: Further Development of the Task-Centered Case Management Model
Authors: Colvin Julanne , Lee Mingun , Magnano Julienne , Smith Valerie
Published: January 2008

Based on the significant findings reported in the previous paper on academic progress and behavioral changes documented in annual evaluations, further study of the Partners in Prevention (PIP) Program was conducted. The PIP Program was compared to a school counseling approach through a quasi-experiment, which looked at how each approach influences change in academic achievement, the behaviors that present as barriers to academic success and the students', parents', teachers', and practitioners' perceptions of progress on intervention goals. While the PIP Program was found to have greater influence than the school counseling approach on overall grades and reading averages and on students' perception of their improvement on targeted goals, there were no differences between the two approaches in terms of improvements in behavior.
Does Early Bereavement Counseling Prevent Ill Health and Untimely Death?
Authors: Grimby Agneta , Johansson Åsa K.
Published: January 2008

Fifty elderly bereaved men and women, who received bereavement counseling by a physician and a psychologist at 3 separate occasions during the year after loss, were followed during another 10 years in regard to morbidity and mortality, as some earlier studies have indicated increased risk during widowhood. Days of hospital care and mortality rates during 5 and 8 years, respectively, were the primary outcome variables. A group of representative married subjects was used for comparison purposes. The results showed no difference between the groups in the number of days of care before loss, nor did the days of hospital care after the loss differ. The mortality rate was similar in both groups. This may suggest that bereavement counseling has a preventive effect regarding health and survival, but this should be further evaluated in controlled studies before counseling programs can be recommended.
Core Competencies in Palliative Care for Surgeons: Interpersonal and Communication Skills
Authors: Bradley Ciarán T. , Brasel Karen J.
Published: January 2008

Surgeons are an important part of the multidisciplinary approach to the care of terminally ill and dying patients. Some surgical residencies have recognized the need to incorporate palliative care—related topics into graduate surgical education. One core competency of utmost importance to palliative care is the effective use of interpersonal and communication skills. Four areas of surgical practice are identified where these communication skills are important: during preoperative counseling, when presenting a devastating diagnosis or poor prognosis, when discussing error, and when discussing death. Case examples and recommendations for the appropriate words and actions to use in these scenarios are offered. It is important for both surgeons in practice and those in training to achieve proficiency with these communication skills.
Using Patient Safety Indicators to Estimate the Impact of Potential Adverse Events on Outcomes
Authors: Rivard Peter E. , Luther Stephen L. , Christiansen Cindy L. , Shibei Zhao  , Loveland Susan , Elixhauser Anne , Romano Patrick S. , Rosen Amy K.
Published: January 2008

The authors estimated the impact of potentially preventable patient safety events, identi- fied by Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators (PSIs), on patient outcomes: mortality, length of stay (LOS), and cost. The PSIs were applied to all acute inpatient hospitalizations at Veterans Health Administration (VA) facil- ities in fiscal 2001. Two methods—regression analysis and multivariable case matching— were used independently to control for patient and facility characteristics while predicting the effect of the PSI on each outcome. The authors found statistically significant ( p < .0001) excess mortality, LOS, and cost in all groups with PSIs. The magnitude of the excess varied considerably across the PSIs. These VA findings are similar to those from a previously published study of nonfederal hospitals, despite differences between VA and non-VA systems. This study contributes to the literature measuring outcomes of medical errors and provides evidence that AHRQ PSIs may be useful indicators for comparison across delivery systems.
Medicaid 1915(c) Waiver Use and Expenditures for Persons Living With HIV/AIDS
Authors: Miller Nancy A. , Elder Keith T. , Kitchener Martin , Yu Kang  , Harrington Charlene
Published: January 2008

States' use of Medicaid 1915(c) waiver services for persons living with HIV/AIDS (PLWHA) has been limited. The authors examine state-level factors related to the decision to offer waiver services, as well as waiver use and expenditures in states offering waivers for PLWHA. They use fixed effects cross-sectional time series models to explore these state factors. States with Democratic governors were more likely to offer waiver services and were found to have higher rates of use and greater expenditures and to devote a larger share of long-term care dollars to waiver services for PLWHA. State supply of both institutional and residential care beds was negatively related to use and expenditures. Medicaid community-based care has been found to be related to improved outcomes and reduced costs of care. Ways to foster 1915(c) waiver expansion are important so as to increase access to care for PLWHA.
State Debt Policies and the Credit Ratings of Public Universities
Authors: Moody Michael J.
Published: January 2008

As public institutions have come to rely more heavily on borrowing, they have adopted many policies to govern debt issuance in an effort to bolster their credit rating and thus reduce the costs of borrowing. In many states, the implemented debt polices are applied not only to direct state agencies but also to the public entities such as universities that operate with some autonomy. The question of how these state policies affect various actors remains unanswered. Given that some states' debt policies with respect to public universities are more restrictive than others, how are these differences perceived in credit markets? This article looks at the impact of certain state policies and procedures on public university credit ratings.
Teens, Dating Violence, and Media Use
Authors: Manganello Jennifer A.
Published: January 2008

Dating violence is highly prevalent among adolescents. Of importance, dating violence has been associated with negative physical and mental health outcomes for teens and high-risk behaviors such as unsafe sex practices. Although a growing body of research has examined the extent and nature of this problem, little research has considered aspects of the media that might be associated with risk for teen dating violence, such as time spent using media and effects of media content. This article provides an overview of the prevalence of teen dating violence, describes the potential for assessing media use as a risk factor, offers a conceptual model, and suggests ideas for future research.
The Health Care Experiences of Adult Survivors of Child Sexual Abuse
Authors: Havig Kirsten
Published: January 2008

This systematic review analyzes empirically based medical literature relevant to the experiences of adult survivors of sexual abuse in the health care setting and what is known about providing sensitive care to this population. Effects of this trauma may impact the adult survivor's experience of care, health behaviors, and outcomes. The 10 articles reviewed in this study provide patient-based information on the experience of child sexual abuse and its impact on health and health care for patients. Suggestions are made for health care providers in two main areas: facilitation of communication and disclosure issues, and improving the experience of the health care encounter for survivors. Specific strategies are offered to assist in providing nonthreatening care encounters for adults who have been affected by childhood sexual trauma. Implications for research, practice, and policy for patients, health care providers, and social workers in the health care setting are discussed.
Use of Satiation Therapy in the Treatment of Adolescent-Manifest Sexual Interest in Male Children
Authors: Hunter John A. , Ram Nilam , Ryback Ralph
Published: January 2008

Satiation therapy was employed as an adjunctive therapy in the residential treatment of a 19-year-old male sexual offender with treatment-refractory sexual interest in prepubescent male children. Satiation therapy was administered on a 14-day cycle according to an “A-B-A-B” treatment design. Self-reported sexual interest, sexual fantasy, and emotion data were collected three times daily over the course of 64 days. Results support the effectiveness of the intervention in differentially reducing sexual interest in young males relative to interest in male peers. Concomitantly, the client evidenced a shift toward the predominance of sexual fantasies of male peers over those involving male children. Experienced anger proved to be a predictor of relative sexual interest in male children. Analyses suggested that diurnal changes in mood, sexual interest, and sexual fantasy made him more vulnerable to sexual acting-out in the evening or night. Implications for relapse prevention planning are discussed.
Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor
Authors: Acevedo Lisette M. , Barillas Samuel , Weis Sara M. , Göthert Joachim R. , Cheresh David A.
Published: January 2008

Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF- but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGF- but not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a function-blocking Nrp-1 antibody. While both Sema3A- and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF- but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.
Platelet-VWF complexes get the chop
Authors: Berndt Michael C. , Andrews Robert K.
Published: January 2008

In this issue of Blood, Shim and colleagues define a dual role for platelet glycoprotein (GP)Ibα (the major ligand-binding subunit of the GPIb-IX-V complex) in regulating ADAMTS13-mediated cleavage of von Willebrand factor (VWF) under shear: it alleviates an inhibitory effect of the VWF A1 domain on cleavage of the A2 domain,1 and it allows tensile force to be exerted on the A2 domain through at least 2 platelets binding per VWF multimer via the A1 domain (see figure).
Steel to heal? MPD surgical conundrums
Authors: Mesa Ruben A.
Published: January 2008

In this issue of Blood, Ruggeri and colleagues highlight the high risk of vascular events in patients with essential thrombocythemia and polycythemia vera undergoing operative procedures even with current “optimal” surgical prophylaxis.
Secreted thrombospondin-1 controls platelet sensitivity to NO
Authors: Mosher Deane F. , Maurer Lisa M. , Britt Carlson C.
Published: January 2008

Many functions have been suggested for the large amounts of thrombospondin-1 that are stored in α-granules of platelets. Isenberg et al describe a new role whereby thrombospondin-1 counteracts NO and allows platelet activation to take place in situations in which NO is being generated.
Persistence drives gene clustering in bacterial genomes
Authors: Fang Gang , Rocha Eduardo PC , Danchin Antoine
Published: January 2008

Background

Gene clustering plays an important role in the organization of the bacterial chromosome and several mechanisms have been proposed to explain its extent. However, the controversies raised about the validity of each of these mechanisms remind us that the cause of this gene organization remains an open question. Models proposed to explain clustering did not take into account the function of the gene products nor the likely presence or absence of a given gene in a genome. However, genomes harbor two very different categories of genes: those genes present in a majority of organisms – persistent genes – and those present in very few organisms – rare genes.

Results

We show that two classes of genes are significantly clustered in bacterial genomes: the highly persistent and the rare genes. The clustering of rare genes is readily explained by the selfish operon theory. Yet, genes persistently present in bacterial genomes are also clustered and we try to understand why. We propose a model accounting specifically for such clustering, and show that indispensability in a genome with frequent gene deletion and insertion leads to the transient clustering of these genes. The model describes how clusters are created via the gene flux that continuously introduces new genes while deleting others. We then test if known selective processes, such as co-transcription, physical interaction or functional neighborhood, account for the stabilization of these clusters.

Conclusion

We show that the strong selective pressure acting on the function of persistent genes, in a permanent state of flux of genes in bacterial genomes, maintaining their size fairly constant, that drives persistent genes clustering. A further selective stabilization process might contribute to maintaining the clustering.
Identification of cellular pathways affected by Sortin2, a synthetic compound that affects protein targeting to the vacuole in Saccharomyces cerevisiae
Authors: Norambuena Lorena , Zouhar Jan , Hicks Glenn R , Raikhel Natasha V
Published: January 2008

Background

Sortin2 is a low mass compound that interferes with vacuolar delivery of proteins in plants and yeast. The Sortin2 phenotype was tested in Arabidopsis thaliana and found to be reversible upon drug removal, demonstrating the ability of chemical genomics to induce reversible phenotypes that would be difficult to achieve using conventional genetics [1]. However, standard genetic methods can be used to identify drug target pathways in a high-throughput manner.

Results

In this study, we analyzed structure-function relationships of Sortin2 using structural analogues. The results show the key roles of sulphite substitution and a benzoic acid group. A Sortin 2 hypersensitivity screen for the induced secretion of a vacuolar cargo protein was done utilizing a yeast haploid deletion library. Using bioinformatics approaches, we highlighted functional information about the cellular pathways affected by drug treatment which included protein sorting and other endomembrane system-related processes.

Conclusion

Chemical, genomic and genetics approaches were used to understand the mode of action of Sortin2, a bioactive chemical that affects the delivery of a vacuolar protein. Critical features of Sortin2 structure necessary for bioactivity suggest a binding pocket that may recognize two ends of Sortin2. The genome-wide screen shows that Sortin2 treatment in yeast affects primarily components within the endomembrane system. This approach allowed us to assign putative functions in protein sorting for fifteen genes of previously unknown function.
Adherence to Initial Adjuvant Anastrozole Therapy Among Women With Early-Stage Breast Cancer
Authors: Partridge Ann H. , LaFountain Andrea , Mayer Erica , Taylor Brooke S. , Winer Eric , Asnis-Alibozek Aviva
Published: January 2008

Purpose

Previous research evaluating adherence to tamoxifen therapy among women with early-stage breast cancer has revealed adherence estimates ranging from 25% to 96%. No previous studies have focused on adherence to adjuvant aromatase inhibitors.

Methods

We used longitudinal claims data from three large commercial health programs to estimate adherence with anastrozole therapy among women with early-stage breast cancer. Adherence was defined as the proportion of days that patients had medication available over the observation period (ie, days covered); women with fewer than 80% of days covered were defined as nonadherent.

Results

More than 12,000 women in the databases were found to have new anastrozole prescription claims during the period of study: 1,498 women were classified as having early-stage disease in one commercial health program (Plan A) data set, 1,899 women in another program (Plan B) data set, and 8,994 women in MarketScan, a commercial data set made up of several health programs. Mean adherence over the first 12 months of therapy ranged from 82% to 88% in the three data sets. Between 19% and 28% of women had fewer than 80% of days covered. For women with 36 months of continuous eligibility, the mean adherence decreased each year, ranging from 78% to 86% in year 1 to 62% to 79% in year 3 within the three data sets.

Conclusion

A substantial proportion of women with early-stage breast cancer may be suboptimally adherent to adjuvant anastrozole therapy. Future research should focus on the identification of patients at risk for nonadherence with oral hormonal therapy for breast cancer and the development of interventions to improve adherence.
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

Purpose

To 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 Methods

Newly 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.

Results

In 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.

Conclusion

A 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.
The Medical Care System Under National Health Insurance: Four Models
Authors: McClure Walter
Published: January 2008

This paper presents a critical evaluation of four national health insurance models in light of their ability to counteract incentives in the present system that are dysfunctional in terms of costs and quality of care. The feasible models are labelled as: major risk insurance, alternative delivery systems under universal coverage; the public utility allocation model (alias the British system); and the public utility hospital model. It is concluded that substantial changes in the existing structure of the medical care system will be very difficult to achieve politically. Further, those models most politically feasible, the present medical care system with universal third party financing, and public utility process controls with universal third party financing, are the ones most likely to aggravate present cost-quality difficulties. Therefore, the recommended procedure for implementing national health insurance is unabashedly incremental: i.e.; to experiment with cost-sharing, alternative delivery systems, other provider incentive mechanisms and public utility regulation-budget allocation approaches, before wholesale adoption of national health insurance is entertained.
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.
The Challenge of Comparative Health Policy for Political Science
Authors: Falcone David J.
Published: January 2008

After a brief review of the literature and some reflection on the state of the art, this paper argues that more analyses of health policy in an explicitly comparative perspective are needed. This conclusion is based on a discussion of the largely unexploited benefits that could accrue from a welding of political science and health services research and a consideration of a research design illustrating the compatibility of these two endeavors.
Demographic Differences in Support for Government Measures to Control Health Care Costs
Authors: Weaver Jerry L.
Published: January 2008

This paper uses longitudinal data from representative samples of national and southern California populations in an analysis of public opinion regarding proposals for health care cost controls. After examining ethnicity in conjunction with sex, socioeconomic status, age and party identification, it appears that this variable has significant explanatory power. This suggests that community may be a more useful concept than class in assessing public support for various forms of national health insurance and regulatory policies.
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.