bluuebunny/crossref_metadata_2025 huggingface dataset:
Look Who's Coming to Dinner
Authors: Heberlig Eric S. , Larson Bruce A. , Smith Daniel A. , Soltis Kristen L.
Published: December 2007

House congressional campaign committees (CCCs) have increasingly relied on incumbents for financial support during the past decade. To raise money for their party's CCC, incumbents can (a) contribute to the CCC through their own principal campaign committee and/or leadership PAC or (b) broker contributions from donors. The authors argue that direct incumbent contributions make available to the party campaign committee broader contribution networks than do brokered incumbent contributions. One observable implication of this thesis is that ties to D.C. lobbyists should be a more powerful predictor of brokered than of direct contributions to the CCCs. Comparing Federal Election Commission data on direct member contributions to the National Republican Congressional Committee (NRCC) with unique data on member ticket sales to the 2005 NRCC March Gala, the authors find strong support for this expectation. Soliciting direct contributions from incumbents appears to be a better means for the CCCs to gain access to new campaign money.
Constituency Population and Representation in the U.S. House
Authors: Frederick Brian
Published: December 2007

The U.S. House of Representatives has remained frozen at 435 members for almost a century. House members on average represent more than 640,000 citizens, which is expected to continue to rise if the body remains constituted of close to 435 members. One assertion put forward by critics of this rise is that it leads to a less intimate relationship between the representative and the constituent. Yet there has not been empirical substantiation that the increase in constituency population size has interfered with the representational linkage in the House. This study employs a series of multivariate models using survey data from the American National Election Study to test whether citizens in more heavily populated House districts have less access to their representatives and are less likely to approve of their performance. Findings indicate that increases in House district population size reduce the accessibility and approval of U.S. House members.
The Development of Group Interaction Patterns: How Groups Become Adaptive, Generative, and Transformative Learners
Authors: London Manuel , Sessa Valerie I.
Published: December 2007

This article integrates the literature on group interaction process analysis and group learning, providing a framework for understanding how patterns of interaction develop. The model proposes how adaptive, generative, and transformative learning processes evolve and vary in their functionality. Environmental triggers for learning, the group's readiness to learn, stage of development, control mechanisms, and facilitation influence the interaction patterns that emerge, are reinforced, and repeated over time. The model has implications for research on the evolution of adaptive, generative, and transformative group learning and for diagnosing group conditions and implementing interventions that promote group learning.
Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial
Authors: Choudhury Aklak B , Dawson Carolyn M , Kilvington Hazel E , Eldridge Sandra , James Wai-Yee , Wedzicha Jadwiga A , Feder Gene S , Griffiths Chris J
Published: December 2007

Background

Guidelines recommend inhaled corticosteroids (ICS) for patients with severe chronic obstructive pulmonary disease (COPD). Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity. The effect of withdrawing ICS from COPD patients in primary care is unknown.

Methods

In a pragmatic randomised, double-blind, placebo-controlled trial in 31 practices, 260 COPD patients stopped their usual ICS (median duration of use 8 years) and were allocated to 500 mcg fluticasone propionate twice daily (n = 128), or placebo (n = 132). Follow-up assessments took place at three monthly intervals for a year at the patients' practice. Our primary outcome was COPD exacerbation frequency. Secondary outcomes were time to first COPD exacerbation, reported symptoms, peak expiratory flow rate and reliever inhaler use, and lung function and health related quality of life.

Results

In patients randomised to placebo, COPD exacerbation risk over one year was RR: 1.11 (CI: 0.91–1.36). Patients taking placebo were more likely to return to their usual ICS following exacerbation, placebo: 61/128 (48%); fluticasone: 34/132 (26%), OR: 2.35 (CI: 1.38–4.05). Exacerbation risk whilst taking randomised treatment was significantly raised in the placebo group 1.48 (CI: 1.17–1.86). Patients taking placebo exacerbated earlier (median time to first exacerbation: placebo (days): 44 (CI: 29–59); fluticasone: 63 (CI: 53–74), log rank 3.81, P = 0.05) and reported increased wheeze. In a post-hoc analysis, patients with mild COPD taking placebo had increased exacerbation risk RR: 1.94 (CI: 1.20–3.14).

Conclusion

Withdrawal of long-term ICS in COPD patients in primary care increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration. Patients with mild COPD may be at increased risk of exacerbation after withdrawal.

Trial Registration

ClinicalTrials.gov NCT00440687
Two or more enteropathogens are associated with diarrhoea in Mexican children
Authors: Paniagua Gloria Luz , Monroy Eric , García-González Octavio , Alonso Javier , Negrete Erasmo , Vaca Sergio
Published: December 2007

Background

Diarrhoeal diseases constitute a major public health problem, particularly in the developing world, where the rate of mortality and morbidity is very high. The purpose of this study was to conduct a 2 years and 3 months study in order to determine the prevalence of five enteropathogen diarrheogenic agents in Mexico City.

Methods

Faecal samples were obtained from 300 Mexican children diagnosed as positive for diarrhoea, aged > 2 to < 12 years old, and from 80 children matched for age but with no symptoms of the disease (control group). Two multiplex PCR were used to detect Escherichia coli, Salmonella spp., and Shigella spp. In addition, the two protozoan parasites Entamoeba histolytica/Entamoeba dispar and Giardia intestinalis were detected by conventional methods.

Results

All diarrhoeal samples were positive for one or more enteropathogens. The most common enteropathogens in diarrhoeal samples were E. histolytica/E. dispar (70.3%), Salmonella (ohio 28.3%; typhimurium 16.3%; infantis 8%; anatum 0.6%; Newport 0.3%), G. intestinalis (33%), E. coli (ETEC 13.3%; EPEC 9.3%; VTEC 8.6%; EIEC 1%) and Shigella spp. (flexneri 1.6%, sonnei 1%). Infections by two (24%) three (16%) and four (12%) pathogens were observed.

Conclusion

This study revealed that 52% of the patients were infected by more than one enteropathogen, notably E. histolitica/E. dispar and Salmonella ohio. These results are useful for clinicians to improve the empiric treatment used in such cases.
BGLAP is expressed in pancreatic cancer cells and increases their growth and invasion
Authors: Kayed Hany , Bekasi Sandor , Keleg Shereen , Michalski Christoph W , Giese Thomas , Friess Helmut , Kleeff Jörg
Published: December 2007

Background

Bone gamma-carboxyglutamate protein (BGLAP; osteocalcin) is a small, highly conserved molecule first identified in the mineralized matrix of bone. It has been implicated in the pathophysiology of various malignancies. In this study, we analyzed the expression and role of BGLAP in the normal human pancreas, chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) using quantitative RT-PCR, immunohistochemistry, immunocytochemistry and enzyme immunoassays, as well as cell proliferation and invasion assays. Gene silencing was carried out using specific siRNA molecules.

Results

Compared to the normal pancreas, BGLAP mRNA and protein levels were not significantly different in CP and PDAC tissues. BGLAP was faintly present in the cytoplasm of normal acinar cells but was strongly expressed in the cytoplasm and nuclei of tubular complexes and PanIN lesions of CP and PDAC tissues. Furthermore, BGLAP expression was found in the cancer cells in PDAC tissues as well as in 4 cultured pancreatic cancer cell lines. TNFalpha reduced BGLAP mRNA and protein expression levels in pancreatic cancer cell lines. In addition, BGLAP silencing led to reduction of both cell growth and invasion in those cells.

Conclusion

BGLAP is expressed in pancreatic cancer cells, where it potentially increases pancreatic cancer cell growth and invasion through autocrine and/or paracrine mechanisms.
Late aortic lymphocele and residual ovary syndrome after gynecological surgery
Authors: Pastore Maria , Manci Natalina , Marchetti Claudia , Esposito Francesca , Iuliano Marialetizia , Manganaro Lucia , Panici Pierluigi Benedetti
Published: December 2007

Background

Gynecological surgery, as radical hysterectomy or pelvic and aortic lymphadenectomy, accounts for more than 50% of iatrogenic injuries. In premenopausal women, an hysterectomy with ovarian sparing and concomitant lateral ovarian transposition is frequently performed. However, the fate of the retained ovary is complicated by the residual ovarian syndrome (ROS) and one of the most common postoperative complications of the lymphadenectomy procedure is the lymphocele, with an average incidence of 22–48.5%. The differential diagnosis of a postoperative fluid collection includes, in addition to a lymphocele, urinoma, hematoma, seroma or abscess and the computed tomography (CT) findings alone is not enough.

Case presentation

We describe a patient, affected by ROS concomitant with a asymptomatic lymphocele, initially confused with an aortic lymph nodes relapse, after abdominal radical hysterectomy. The patient was subjected to a surgical approach, included a diagnostic open laparoscopy and laparotomy with sovraombelico-pubic incision, wide opening of the pelvic peritoneum and retroperitoneum. Examination of the mass revealed, macroscopically, a ovary with multiloculated cystic masses filled with clear or yellow serous fluid and the layers were composed by flat or cuboidal mesothelial cells.

Conclusion

The tribute of this case illustrates the atypical appearance with uncertain aetiology after complex imaging. Gynecologist and radiologist should acquaint with the appearance of fluid collection (urinoma, lymphocele, seroma, hematoma, abscess) in gynecologic oncology follow-up to properly differentiated from tumor recurrence.
A three-arm randomised controlled trial comparing Gonadotrophin Releasing Hormone (GnRH) agonist long regimen versus GnRH agonist short regimen versus GnRH antagonist regimen in women with a history of poor ovarian response undergoing in vitro fertilisation (IVF) treatment: Poor responders intervention trial (PRINT)
Authors: Sunkara Sesh K , Coomarasamy Arri , Khalaf Yakoub , Braude Peter
Published: December 2007

Background

Poor response to ovarian stimulation with exogenous gonadotrophins occurs in 9–24% of women undergoing in vitro fertilisation (IVF) treatment, which represents an estimated 4000–10,000 women per year in the UK. Poor responders often have their treatment cycle cancelled because of expected poor outcome.

One treatment strategy that may influence outcome is the choice of pituitary suppression regimen prior to the initiation of ovarian stimulation. The three commonly used pituitary suppression regimens in IVF treatment are:

(1) the GnRH agonist long regimen,

(2) the GnRH agonist short regimen and

(3) the GnRH antagonist regimen.

A systematic review of randomised controlled trials of these pituitary suppression regimens has shown the evidence to be either inconclusive or inconsistent. We therefore designed a three arm randomised trial to evaluate the effectiveness of these regimens in women who had poor ovarian response in a previous IVF treatment cycle.

Methods/design

Consenting, eligible women will be randomised to one of the three regimens using an internet-based trial management programme that ensures allocation concealment and employs block randomisation and minimisation for prognostic variables. The primary outcome is the number of oocytes retrieved. Other outcomes include total dose of follicle stimulating hormone (FSH) used for ovarian stimulation, mature oocytes retrieved, embryos available for transfer, implantation rate and clinical pregnancy rate.

The sample size for this trial has been estimated as 102 participants with 34 participants in each of the three arms. Appropriate interim analysis will be conducted by a Data Monitoring and Ethics Committee (DMEC), and the final analysis will be by intention to treat.

Trial registration

ISRCTN27044628
Fractionation of the rice bran layer and quantification of vitamin E, oryzanol, protein, and rice bran saccharide
Authors: Schramm Rebecca , Abadie Alicia , Hua Na , Xu Zhimin , Lima Marybeth
Published: December 2007

Value-added processing with respect to rice milling has traditionally treated the rice bran layer as a homogenous material that contains significant concentrations of high-value components of interest for pharmaceutical and nutraceutical applications. Investigators have shown that high-value components in the rice bran layer vary from differences in kernel-thickness, bran fraction, rice variety, and environmental conditions during the growing season. The objectives of this study were to quantify the amount of rice bran removed at pre-selected milling times and to correlate the amount of rice bran removed at each milling time with the concentration of vitamin E, gamma-oryzanol, rice bran saccharide, and protein obtained. The ultimate goal of this research is to show that rice bran fractionation is a useful method to obtain targeted, nutrient-rich bran samples for value-added processing. Two long grain rice cultivars, Cheniere and Cypress, were milled at discrete times between 3 and 40 seconds using a McGill mill to obtain bran samples for analysis. Results showed that the highest oryzanol and protein concentrations were found in the outer portion of the rice bran layer, while the highest rice bran saccharide concentration was found in the inner portion of the bran layer. Vitamin E concentration showed no significant difference across the bran layer within a variety, though the highest magnitude of concentration occurs within the first 10 seconds of milling for both varieties. To extract the higher concentration of oryzanol and protein only the outer portion of the bran layer requires processing, while to extract the higher concentration of rice bran saccharide, only the inner portion of the bran layer requires processing. Rice bran fractionation allows for the selective use of portions of the bran layer and is advantageous for two reasons: (1) bran fractions contain higher concentrations of components of interest with respect to the overall bran layer average, and (2) less bran needs to be processed to obtain components of interest.
Recent breast cancer trends among Asian/Pacific Islander, Hispanic, and African-American women in the US: changes by tumor subtype
Authors: Hausauer Amelia K , Keegan Theresa HM , Chang Ellen T , Clarke Christina A
Published: December 2007

Background

Recently, unprecedented drops in breast cancer incidence have been reported for populations of mostly White European descent. Incidence patterns in non-White racial/ethnic groups are less described. Therefore, we examined population-based breast cancer incidence trends separately for US Asian/Pacific Islander, Hispanic, African-American, and non-Hispanic White women by etiologically relevant tumor subtype characteristics, including hormone receptor status, histology, size, and in situ behavior.

Methods

We obtained breast cancer data from 13 Surveillance, Epidemiology, and End Results (SEER) cancer registries to calculate age-adjusted incidence rates and trends, stratified by race/ethnicity and tumor subtype for the period 1992–2004. Detailed analyses were limited to women 50 years old or older. Joinpoint regression was used to assess incidence trends by annual quarter of diagnosis.

Results

Between 2001 and 2004, incidence rates of invasive breast cancer in women 50 years old or older declined appreciably among Asians/Pacific Islanders (-8.5%) and Hispanics (-2.9%) and were stable in African-Americans (+0.5%), reductions substantially lower than those observed among non-Hispanic Whites (-14.3%). In Asian/Pacific Islander women, perceptible but statistically nonsignificant decreases were observed for hormone receptor-positive, lobular, and small tumors only. Rates of hormone receptor-negative tumors increased among African-Americans (26.1%) and Hispanics (26.9%) during 2001–2004. Incidence trends in most groups, except African-American women, peaked between 1999 and mid-2002. Rates of in situ cancer remained stable in all groups.

Conclusion

Recently reported reductions in breast cancer incidence varied considerably by race/ethnicity. These patterns are consistent with documented racial/ethnic differences in the prevalence and discontinuation of hormone therapy (HT) after July 2002 but do not correspond as well to patterns of mammography use in these groups. The data presented in this analysis provide further evidence that population-level HT use is a major influence on population-level rates of particular breast cancer subtypes, especially receptor-positive tumors.
Effects of high-fat diet and/or body weight on mammary tumor leptin and apoptosis signaling pathways in MMTV-TGF-α mice
Authors: Dogan Soner , Hu Xin , Zhang Yan , Maihle Nita J , Grande Joseph P , Cleary Margot P
Published: December 2007

Introduction

Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened mammary tumor (MT) latency in MMTV-TGF-α mice with dietary-induced obesity. One link between obesity and breast cancer is the adipokine, leptin. Here, the focus is on diet-induced obesity and MT and mammary fat pad (MFP) leptin and apoptotic signaling proteins.

Methods

MMTV-TGF-α mice were fed low-fat or high-fat diets from 10 to 85 weeks of age. High-Fat mice were divided into Obesity-Prone and Obesity-Resistant groups based on final body weights. Mice were followed to assess MT development and obtain serum, MFP, and MT.

Results

Incidence of palpable MTs was significantly different: Obesity-Prone > Obesity-Resistant > Low-Fat. Serum leptin was significantly higher in Obesity-Prone compared with Obesity-Resistant and Low-Fat mice. Low-Fat mice had higher MFP and MT ObRb (leptin receptor) protein and Jak2 (Janus kinase 2) protein and mRNA levels in comparison with High-Fat mice regardless of body weight. Leptin (mRNA) and pSTAT3 (phosphorylated signal transducer and activator of transcription 3) (mRNA and protein) also were higher in MTs from Low-Fat versus High-Fat mice. Expression of MT and MFP pro-apoptotic proteins was higher in Low-Fat versus High-Fat mice.

Conclusion

These results confirm a connection between body weight and MT development and between body weight and serum leptin levels. However, diet impacts MT and MFP leptin and apoptosis signaling proteins independently of body weight.
Changeovers of vasoactive drug infusion pumps: impact of a quality improvement program
Authors: Argaud Laurent , Cour Martin , Martin Olivier , Saint-Denis Marc , Ferry Tristan , Goyatton Agnes , Robert Dominique
Published: December 2007

Background

Hemodynamic instability following the changeover of vasoactive infusion pump (CVIP) is a common problem in the intensive care unit. Several empiric methods are used to achieve CVIP. We hypothesized that the variation in these procedures could generate some morbidity. We sought to assess the effects of the standardization of practice, as a quality improvement program, on the CVIP-induced incidents.

Materials and methods

We performed a prospective before-and-after intervention study including all adult patients with a diagnosis of cardiovascular failure who received a continuous infusion of vasoactive drugs or inotropic drugs. After a baseline preimplementation period (phase 1), a standardized 'quick change method' of CVIP using two syringe drivers was implemented in our intensive care unit (phase 2). Endpoints (rate and distribution of incidents: variations of systolic blood pressure >20 mmHg or heart rate >20 beats/min, and arrhythmias) were registered in both 3-month phases.

Results

We studied a total of 913 CVIP events (phase 1, 435 events; phase 2, 478 events) from 43 patients. Patient characteristics were not significantly different among phases, with a majority of the patients having septic shock. The frequency of incidents was significantly (P < 0.0001) reduced in phase 2 (5.9%, n = 28) versus phase 1 (17.8%, n = 78). This effect was observed whichever catecholamine was used. More than 98% of incidents were blood pressure variations, with a similar distribution of the nature of incidents in both phases.

Conclusion

The present study illustrates that adverse events are common following CVIP, and illustrates the positive impact of a quality improvement program to enhance inpatient safety related to this current process of care.
Forward and inverse self-potential modeling in mineral exploration
Authors: Mendonça Carlos Alberto
Published: December 2007

Natural self-potential (SP) fields observed in the vicinity of conductive orebodies can be explained in terms of electrochemical reactions in which the conductors participate. Battery-like models assume that a buried conductor creates an anode-cathode pair by conveying a flow of electrons to oxidizing areas in the shallow subsurface from reducing areas at depth. For conductors with invariant composition (behaving as an inert electrode), a quantitative formulation is already available. Numerical Green’s functions are used to allow one-step evaluation of SP fields from an inert electrode model. The model is used to simulate geoelectric targets in mineral exploration and to test a procedure to obtain current source terms by inverting an SP data set. Data inversion is constrained by charge conservation and prescribes source terms at the target surface. A background resistivity model is assumed to be known and is used to recognize interfaces and evaluate numerical Green’s functions in forward and inverse modeling. The inversion procedure is applied to interpret 2D data from two gold deposits of the Yanacocha district, Peru.
Wave-equation angle-domain common-image gathers for converted waves
Authors: Rosales Daniel A. , Fomel Sergey , Biondi Biondo L. , Sava Paul C.
Published: December 2007

Wavefield-extrapolation methods can produce angle-domain common-image gathers (ADCIGs). To obtain ADCIGs for converted-wave seismic data, information about the image dip and the P-to-S velocity ratio must be included in the computation of angle gathers. These ADCIGs are a function of the half-aperture angle, i.e., the average between the incidence angle and the reflection angle. We have developed a method that exploits the robustness of computing 2D isotropic single-mode ADCIGs and incorporates both the converted-wave velocity ratio [Formula: see text] and the local image dip field. It also maps the final converted-wave ADCIGs into two ADCIGs, one a function of the P-incidence angle and the other a function of the S-reflection angle. Results with both synthetic and real data show the practical application for converted-wave ADCIGs. The proposed approach is valid in any situation as long as the migration algorithm is based on wavefield downward continuation and the final prestack image is a function of the horizontal subsurface offset.
Health-Related Quality of Life Results in Pathologic Stage C Prostate Cancer From a Southwest Oncology Group Trial Comparing Radical Prostatectomy Alone With Radical Prostatectomy Plus Radiation Therapy
Authors: Moinpour Carol M. , Hayden Katherine A. , Unger Joseph M. , Thompson Ian M. , Redman Mary W. , Canby-Hagino Edith D. , Higgins Betsy A. , Sullivan Jerry W. , Lemmon Dianne , Breslin Sheila , Crawford E. David
Published: December 2007

Purpose

To compare short- and long-term effects of adjuvant treatment versus observation after surgery on health-related quality of life (HRQL) of prostate cancer patients.

Patients and Methods

The Southwest Oncology Group (SWOG) intergroup trial compared radical prostatectomy (RP) plus observation versus RP plus adjuvant radiation therapy (RT). Two-hundred seventeen of 425 therapeutic trial patients were eligible and registered to the HRQL study. Patients completed the SWOG Quality of Life Questionnaire (emotional, physical, social, and role function; general symptom status; treatment/disease-specific symptoms; and global HRQL [GHRQL]) at baseline, 6 weeks, 6 months, and annually for 5 years. Prespecified outcomes were three genitourinary symptoms (bowel function tenderness, frequent urination, and erectile dysfunction [ED]) and measures of physical and emotional function. Adjustments were made for the baseline score.

Results

Patients receiving adjuvant RT reported worse bowel function (through approximately 2 years) and worse urinary function. There were no statistically significant differences for ED. GHRQL was initially worse for the RP+RT arm but improved over time and was better at the end of the period than the GHRQL reported for RP alone (treatment arm × time interaction, P = .0004). Symptom distress was significantly worse for the RP+RT arm compared with the RP alone arm, but the treatment arms did not differ with respect to other general measures of HRQL.

Conclusion

The addition of RT to surgery resulted in more frequent urination, as well as early report of more bowel dysfunction, although bowel function differences disappeared over the 5-year period. The addition of RT did not negatively impact ED.
Taxane-Based Combinations As Adjuvant Chemotherapy of Early Breast Cancer: A Meta-Analysis of Randomized Trials
Authors: De Laurentiis Michele , Cancello Giuseppe , D'Agostino Diego , Giuliano Mario , Giordano Antonio , Montagna Emilia , Lauria Rossella , Forestieri Valeria , Esposito Angela , Silvestro Lucrezia , Pennacchio Roberta , Criscitiello Carmen , Montanino Agnese , Limite Gennaro , Bianco Angelo Raffaele , De Placido Sabino
Published: December 2007

Purpose

We conducted a meta-analysis of randomized trials that evaluated the efficacy of incorporating taxanes into anthracycline-based regimens for early breast cancer (EBC). We aimed to determine whether this approach improves disease-free survival (DFS) and overall survival (OS) and whether benefits are maintained across relevant patient subgroups.

Methods

Studies were retrieved by searching the PubMed database and the proceedings of major conferences. We extracted hazard ratios (HR) and 95% CIs for DFS and OS from each trial and obtained pooled estimates using an inverse-variance model.

Results

Thirteen studies were included in the meta-analysis (N = 22,903 patients). The pooled HR estimate was 0.83 (95% CI, 0.79 to 0.87; P < .00001) for DFS and 0.85 (95% CI, 0.79 to 0.91; P < .00001) for OS. Risk reduction was not influenced by the type of taxane, by estrogen receptor (ER) expression, by the number of axillary metastases (N1 to 3 v N4+), or by the patient's age/menopausal status. Sensitivity analysis showed that taxanes given in combination with anthracyclines, unlike sequential administration, did not significantly improve OS. However, the test for interaction showed that HR did not differ between the two schedules (P = .54). Taxane administration resulted in an absolute 5-year risk reduction of 5% for DFS and 3% for OS.

Conclusion

The addition of a taxane to an anthracycline-based regimen improves the DFS and OS of high-risk EBC patients. The DFS benefit was independent of ER expression, degree of nodal involvement, type of taxane, age/menopausal status of patient, and administration schedule.
Effect of BRCA1/2 Mutations on Long-Term Survival of Patients With Invasive Ovarian Cancer: The National Israeli Study of Ovarian Cancer
Authors: Chetrit Angela , Hirsh-Yechezkel Galit , Ben-David Yehuda , Lubin Flora , Friedman Eitan , Sadetzki Siegal
Published: December 2007

Purpose

To evaluate the long-term survival of ovarian cancer (OvC) patients in total and by BRCA1/2 mutation status.

Patients and Methods

In a nationwide case-control study on OvC conducted in Israel between 1994 and 1999, 779 Jewish women with epithelial invasive OvC were tested for the three Ashkenazi Jewish founder mutations in BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) genes and followed for survival up to 2003. Of the 605 women of Ashkenazi origin, 213 (35.2%) carried a mutation in the BRCA1/2 genes. Clinical characteristics were abstracted from the patients' medical records. The Kaplan-Meier method, log-rank tests, and stepwise Cox regression model were used for survival analyses.

Results

The 5-year survival rate for the entire group was 39%. Median survival for carriers was significantly longer than for noncarriers (53.7 v 37.9 months, respectively; P = .002). This differential survival was pronounced among women diagnosed at stages III to IV (5-year survival rates of 38.1% and 24.5% for carriers and noncarriers, respectively; P < .001) and for women with poor grade (45.4% v 31.5%, for carriers and noncarriers, respectively; P < .001). These results remained significant after controlling for age at diagnosis, grade, and morphology. This benefit in prognosis was seen for both BRCA1 and BRCA2 carriers compared with noncarriers. During the study period (median follow-up, 6.2 years), being a BRCA1/2 mutation carrier decreased the mortality rate by 28%.

Conclusion

This study confirms that, among Ashkenazi OvC patients, BRCA1/2 mutations are associated with improved long-term survival. This may be due to distinct clinical behavior and/or to a better response to chemotherapy.
Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia
Authors: Garcia Agustin A. , Hirte Hal , Fleming Gini , Yang Dongyun , Tsao-Wei Denice D. , Roman Lynda , Groshen Susan , Swenson Steve , Markland Frank , Gandara David , Scudder Sidney , Morgan Robert , Chen Helen , Lenz Heinz-Josef , Oza Amit M.
Published: December 2007

Purpose

Vascular endothelial growth factor (VEGF) plays an important role in the biology of ovarian cancer (OC). Inhibitors of VEGF suppress tumor growth in OC models. Metronomic chemotherapy, defined as frequent administration of low doses of cytotoxic chemotherapy, suppresses tumor growth, possibly by inhibiting angiogenesis. A phase II trial was conducted to evaluate the antitumor activity and adverse effects of bevacizumab and metronomic oral cyclophosphamide in women with recurrent OC.

Patients and Methods

Patients with measurable disease and prior treatment with a platinum-containing regimen were eligible. Up to two different regimens for recurrent disease were allowed. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks and oral cyclophosphamide 50 mg/d. The primary end point was progression-free survival at 6 months. Plasma levels of VEGF, E-selectin, and thrombospondin-1 were obtained serially.

Results

Seventy patients were enrolled. The probability of being alive and progression free at 6 months was 56% (± 6% SE). A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. The most common serious toxicities were hypertension, fatigue, and pain. Bevacizumab-related toxicities included four episodes of gastrointestinal perforation or fistula, two episodes each of CNS ischemia and pulmonary hypertension, and one episode each of gastrointestinal bleeding and wound healing complication. There were three treatment-related deaths. Levels of VEGF, E-selectin, and thrombospondin-1 were not associated with clinical outcome.

Conclusion

The combination of bevacizumab and metronomic cyclophosphamide is active in recurrent OC. Further study of this combination is warranted.
Survival for Patients With Invasive Cutaneous Melanoma Among Ethnic Groups: The Effects of Socioeconomic Status and Treatment
Authors: Zell Jason A. , Cinar Pelin , Mobasher Mehrdad , Ziogas Argyrios , Meyskens Frank L. , Anton-Culver Hoda
Published: December 2007

Purpose

Although uncommon, melanoma is associated with poor survival characteristics among African Americans and Hispanics compared with non-Hispanic whites (NHWs). Low socioeconomic status (SES) is also associated with poor survival among patients with melanoma, but it is not known whether this is because of SES itself or because of treatment disparities. We set out to determine this by using the large, population-based California Cancer Registry (CCR) database as a model.

Patients and Methods

We conducted a case-only analysis of CCR data (1993 to 2003), including a descriptive analysis of relevant clinical variables and SES. The SES variable used has been derived from principle component analysis of census block-level CCR data that was linked to census data to address seven indicators of SES. Univariate analyses of overall survival (OS) were conducted using the Kaplan-Meier method. Multivariate survival analyses were performed using Cox proportional hazard ratios (HRs).

Results

A total of 39,049 incident patient cases of cutaneous melanoma, including 36,694 in NHWs; 127 in African Americans; 1,996 in Hispanics; and 262 in Asian-Americans, were analyzed. Higher SES was associated with an early stage at presentation (P < .0001), with treatment with surgery (P = .0005), and with prolonged survival (P < .0001). After adjustments for age, sex, histology, American Joint Committee on Cancer stage, anatomic site, treatment, and SES, a statistically significant increased risk of death was observed for African Americans compared with NHWs (HR, 1.60; 95% CI, 1.17 to 2.18); no survival differences were noted for Asians or Hispanics compared with NHWs in the adjusted analysis.

Conclusion

Low SES independently predicts poor outcome among patients with cutaneous melanoma. However, the poor OS observed for African American patients with melanoma is not explained by differences in treatment or SES.
Age and Comorbidity As Independent Prognostic Factors in the Treatment of Non–Small-Cell Lung Cancer: A Review of National Cancer Institute of Canada Clinical Trials Group Trials
Authors: Asmis Timothy R. , Ding Keyue , Seymour Lesley , Shepherd Frances A. , Leighl Natasha B. , Winton Tim L. , Whitehead Marlo , Spaans Johanna N. , Graham Barbara C. , Goss Glenwood D.
Published: December 2007

Purpose

This study analyzed patients enrolled in two large, prospectively randomized trials of systemic chemotherapy (adjuvant/palliative setting) for non–small-cell lung Cancer (NSCLC). The main objective was to determine if age and/or the burden of chronic medical conditions (comorbidity) are independent predictors of survival, treatment delivery, and toxicity.

Patients and Methods

Baseline comorbid conditions were scored using the Charlson comorbidity index (CCI), a validated measure of patient comorbidity that is weighted according to the influence of comorbidity on overall mortality. The CCI score (CCIS) was correlated with demographic data,(ie, age, sex, race), performance status (PS), histology, cancer stage, patient weight, hemoglobin, alkaline phosphatase, lactate dehydrogenase, outcomes of chemotherapy delivery (ie, type, total dose, and dose intensity), survival, and response.

Results

A total of 1,255 patients were included in this analysis. The median age was 61 years (range, 34 to 89 years); 34% of patients were elderly (at least 65 years of age); and 31% had comorbid conditions at randomization. Twenty-five percent of patients had a CCIS of 1, whereas 6% had a CCIS of 2 or greater. Elderly patients were more likely to have a CCIS equal to or greater than 1 compared with younger patients (42% v 26%; P < .0001), as were male patients (35% v 21%; P < .0001) and patients with squamous histology (36% v 29%; P = .001). Although age did not influence overall survival, the CCIS appeared prognostic (CCIS 1 v 0; hazard ratio 1.28; 95%CI, 1.09 to 1.5; P = .003).

Conclusion

In these large, randomized trials, the presence of comorbid conditions (CCIS ≥ 1), rather than age more than 65 years, was associated with poorer survival.
Outcomes for Elderly, Advanced-Stage Non–Small-Cell Lung Cancer Patients Treated With Bevacizumab in Combination With Carboplatin and Paclitaxel: Analysis of Eastern Cooperative Oncology Group Trial 4599
Authors: Ramalingam Suresh S. , Dahlberg Suzanne E. , Langer Corey J. , Gray Robert , Belani Chandra P. , Brahmer Julie R. , Sandler Alan B. , Schiller Joan H. , Johnson David H.
Published: December 2007

Purpose

Fit elderly patients with advanced non–small-cell lung cancer (NSCLC) benefit from platinum-based, two-drug chemotherapy. Bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P) improves survival for advanced, nonsquamous NSCLC, as evidenced in Eastern Cooperative Oncology Group (ECOG) 4599. We conducted a subset analysis of ECOG 4599 to determine the outcome for elderly patients.

Patients and Methods

ECOG 4599 randomly assigned patients with advanced nonsquamous NSCLC to PC or to PCB. We analyzed outcome in patients who were at least 70 years of age at the time of study entry. Patient characteristics, efficacy, and toxicity data were compared between PC and PCB for the elderly. Outcomes for elderly and younger patients (< 70 years) treated with PCB were also compared.

Results

Among elderly patients (n = 224; 26%), there was a trend towards higher response rate (29% v 17%; P = .067) and progression-free survival (5.9 v 4.9 months; P = .063) with PCB compared with PC, although overall survival (PCB = 11.3 months; PC = 12.1 months; P = .4) was similar. Grade 3 to 5 toxicities occurred in 87% of elderly patients with PCB versus 61% with PC (P < .001), with seven treatment-related deaths in the PCB arm compared with two with PC. Elderly patients had higher incidence of grade 3 to 5 neutropenia, bleeding, and proteinuria with PCB compared with younger patients.

Conclusion

In elderly NSCLC patients, PCB was associated with a higher degree of toxicity, but no obvious improvement in survival compared with PC. Data from this unplanned, retrospective analysis justify prospective evaluation of the therapeutic index of PCB regimen in elderly patients.
BRCA1 p.Val1688del Is a Deleterious Mutation That Recurs in Breast and Ovarian Cancer Families From Northeast Italy
Authors: Malacrida Sandro , Agata Simona , Callegaro Monia , Casella Cinzia , Barana Daniela , Scaini Maria C. , Manoukian Siranoush , Oliani Cristina , Radice Paolo , Barile Monica , Menin Chiara , D'Andrea Emma , Montagna Marco
Published: December 2007

Purpose

A growing number of sequence changes of unknown clinical significance are being identified in the BRCA1 gene. However, these variants cannot be used for identification and surveillance of at-risk individuals unless their pathogenic role can be demonstrated. The frequency of these variants makes research on this subject a relevant topic in the field of predisposition to breast and ovarian cancers. Herein, we investigate the pathogenicity of the BRCA1 p.Val1688del (c.5181_5183delGTT) variant, which recurs in our population.

Patients and Methods

Recent studies have drawn attention to different strategies that, if considered singly, do not usually provide sufficient power to firmly state for or against causality, thus forcing to a re-evaluation of the literature on each specific variant. To increase the power of our study, we used a recently described strategy that integrates data from multiple independent evidences. By this approach, we analyzed data from the comprehensive study of 12 breast/ovarian cancer families carrying p.Val1688del.

Results

We succeeded in integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data. Under this model, we obtained a final score of 349,000:1 in favor of disease causality. This result largely matches established cutoffs, and thus is readily translatable into a clear clinical message.

Conclusion

We show that p.Val1688del is a pathogenic mutation deriving from a common founder. Notably, this study alone increases by 15% the number of BRCA1-positive families in our patients’ cohort, thus substantially contributing to explain many of the families wherein prediction of a BRCA1 mutation contrasted with the absence of a molecular recognizable defect.
Long-Term Outcome of Complete Cytogenetic Responders After Imatinib 400 mg in Late Chronic Phase, Philadelphia-Positive Chronic Myeloid Leukemia: The GIMEMA Working Party on CML
Authors: Palandri Francesca , Iacobucci Ilaria , Martinelli Giovanni , Amabile Marilina , Poerio Angela , Testoni Nicoletta , Soverini Simona , Castagnetti Fausto , De Vivo Antonio , Breccia Massimo , Specchia Giorgina , Abruzzese Elisabetta , Martino Bruno , Cilloni Daniela , Saglio Giuseppe , Pane Fabrizio , Liberati Anna Marina , Rosti Gianantonio , Baccarani Michele
Published: December 2007

Purpose

Imatinib mesylate (IM) has rapidly become the front-line treatment of Philadelphia-positive (Ph-pos) chronic myeloid leukemia, but the number of patients who were treated and are being treated with IM second-line is still substantial.

Patients and Methods

We have monitored and analyzed the cytogenetic and molecular response to IM 400 mg/d in a cohort of 277 late chronic phase (LCP) patients who were resistant or intolerant to interferon-α and were observed for 48 to 79 months (median, 72 months).

Results

One hundred fifty-three patients (55%) achieved a complete cytogenetic response (CCgR). Seventy-seven percent of them were still in CCgR after 5 years. The rate of response loss did not increase over time. The 6-year progression-free survival and overall survival of these 153 complete cytogenetic responders were 90% and 91%, respectively. Molecular response was less than major in 21%, major in 78%, and complete in one patient only.

Conclusion

These data confirm that, in LCP the CCgR rate to IM is 50% to 60%, and show that CCgR is stable and is associated with a prolonged survival, even if leukemia continues to be molecularly detectable.
Efficacy of Sunitinib and Sorafenib in Metastatic Papillary and Chromophobe Renal Cell Carcinoma
Authors: Choueiri Toni K. , Plantade Anne , Elson Paul , Negrier Sylvie , Ravaud Alain , Oudard Stephane , Zhou Ming , Rini Brian I. , Bukowski Ronald M. , Escudier Bernard
Published: December 2007

Purpose

Sunitinib and sorafenib are novel tyrosine kinase inhibitors (TKIs) that have shown significant clinical activity in metastatic clear cell renal cell carcinoma (RCC). The activity of sunitinib and sorafenib in non–clear cell histologies has not been evaluated.

Patients and Methods

Clinical features at study entry and treatment outcomes were evaluated in patients with metastatic papillary RCC (PRCC) and chromophobe RCC (ChRCC) who received either sunitinib or sorafenib as their initial TKI treatment in five US and French institutions. Response rate and survival were documented. Fisher's exact test was used for categoric variables, and the Kaplan-Meier method was used to estimate survival.

Results

Fifty-three patients were included. The number of patients with papillary and chromophobe histologies was 41 (77%) and 12 (23%), respectively. Response rate, progression-free survival (PFS) time, and overall survival time for the entire cohort were 10%, 8.6 months, and 19.6 months, respectively. Three (25%) of 12 ChRCC patients achieved a response (two patients treated with sorafenib and one treated with sunitinib), and PFS was 10.6 months. Two (4.8%) of 41 PRCC patients achieved a response (both patients were treated with sunitinib). PFS for the whole cohort was 7.6 months. Sunitinib-treated PRCC patients had a PFS of 11.9 months compared with 5.1 months for sorafenib-treated patients (P < .001).

Conclusion

Patients with PRCC and ChRCC may have prolonged PFS from sunitinib and sorafenib, although clinical responses remain overall low in PRCC. Additional prospective trials with these agents in non–clear cell RCC will further clarify their use in the future.
Hypothalamic Prolactin Receptor Messenger Ribonucleic Acid Levels, Prolactin Signaling, and Hyperprolactinemic Inhibition of Pulsatile Luteinizing Hormone Secretion Are Dependent on Estradiol
Authors: Anderson Greg M. , Kieser David C. , Steyn Frederick J. , Grattan David R.
Published: December 2007

Hyperprolactinemia can reduce fertility and libido. Although central prolactin actions are thought to contribute to this, the mechanisms are poorly understood. We first tested whether chronic hyperprolactinemia inhibited two neuroendocrine parameters necessary for female fertility: pulsatile LH secretion and the estrogen-induced LH surge. Chronic hyperprolactinemia induced by the dopamine antagonist sulpiride caused a 40% reduction LH pulse frequency in ovariectomized rats, but only in the presence of chronic low levels of estradiol. Sulpiride did not affect the magnitude of a steroid-induced LH surge or the percentage of GnRH neurons activated during the surge. Estradiol is known to influence expression of the long form of prolactin receptors (PRL-R) and components of prolactin’s signaling pathway. To test the hypothesis that estrogen increases PRL-R expression and sensitivity to prolactin, we next demonstrated that estradiol greatly augments prolactin-induced STAT5 activation. Lastly, we measured PRL-R and suppressor of cytokine signaling (SOCS-1 and -3 and CIS, which reflect the level of prolactin signaling) mRNAs in response to sulpiride and estradiol. Sulpiride induced only SOCS-1 in the medial preoptic area, where GnRH neurons are regulated, but in the arcuate nucleus and choroid plexus, PRL-R, SOCS-3, and CIS mRNA levels were also induced. Estradiol enhanced these effects on SOCS-3 and CIS. Interestingly, estradiol also induced PRL-R, SOCS-3, and CIS mRNA levels independently. These data show that GnRH pulse frequency is inhibited by chronic hyperprolactinemia in a steroid-dependent manner. They also provide evidence for estradiol-dependent and brain region-specific regulation of PRL-R expression and signaling responses by prolactin.
Chronic Ethanol Consumption Leads to Disruption of Vitamin D3 Homeostasis Associated with Induction of Renal 1,25 Dihydroxyvitamin D3-24-Hydroxylase (CYP24A1)
Authors: Shankar Kartik , Liu Xiaoli , Singhal Rohit , Chen Jin-Ran , Nagarajan Shanmugam , Badger Thomas M. , Ronis Martin J. J.
Published: December 2007

Bone loss resulting from chronic ethanol (EtOH) abuse is frequently accompanied by altered vitamin D3 homeostasis. In the current study, we examined EtOH effects in a female rat model in which control or EtOH-containing diets were infused intragastrically. EtOH treatment reduced plasma 1,25-dihydroxycholecalciferol (1,25 (OH)2 D3) coincident with a decrease in renal CYP27B1 (25(OH)D3 1α-hydroxylase) mRNA and an increase in expression of renal CYP24A1 (1,25 (OH)2 D3- 24-hydroxylase). EtOH induction of CYP24A1 occurred as a result of increased transcription and was also observed in vitro in primary cultures of rat renal proximal tubule cells (RPTCs) and in NRK-52E cells. Synergistic induction of CYP24A1 by EtOH in combination with 1,25 (OH)2 D3 was observed. The major EtOH metabolizing enzymes, alcohol dehydrogenase-1 and CYP2E1, were induced by EtOH in RPTCs. Inhibition of EtOH metabolism by 4-methylpyrazole inhibited the induction of CYP24A1 mRNA. CYP24A1 mRNA induction in RPTCs was also inhibited by the protein synthesis inhibitor cycloheximide. CYP24A1 was also induced after hydrogen peroxide treatment, and EtOH treatment of RPTCs resulted in production of reactive oxygen species as measured by flow cytometry using the fluorescent probe dichlorofluorescin acetate. In addition, inhibition of MAPK signaling pathways with the MAPK kinase inhibitor U0126 or the p38 inhibitor SB203580 inhibited EtOH induction of CYP24A1. Our data suggest that EtOH reduces circulating 1,25 (OH)2 D3 concentrations as the result of CYP24A1 induction that is mediated via MAPK activation resulting from renal oxidative stress produced by local metabolism of EtOH via CYP2E1 and antidiuretic hormone-1.