bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Aggressive Surgery Only Benefit Patients With Less Advanced Ovarian Cancer? Results From an International Comparison Within the SCOTROC-1 Trial
Authors: Crawford Simon C. , Vasey Paul A. , Paul Jim , Hay Andrea , Davis Jo A. , Kaye Stan B.
Published: November 2005

Purpose

Studies indicate that ovarian cancer patients who have been optimally debulked survive longer. Although chemotherapy has been variable, they have defined standards of care. Additionally, it is suggested that patients from the United Kingdom (UK) have inferior survival compared with some other countries. We explored this within the context of a large, international, prospective, randomized trial of first-line chemotherapy in advanced ovarian cancer (docetaxel-carboplatin v paclitaxel-carboplatin; SCOTROC-1). The Scottish Randomised Trial in Ovarian Cancer surgical study is a prospective observational study examining the impact on progression-free survival (PFS) of cytoreductive surgery and international variations in surgical practice.

Patients and Methods

One thousand seventy-seven patients were recruited (UK, n = 689; Europe, United States, and Australasia, n = 388). Surgical data were available for 889 patients. These data were analyzed within a Cox model.

Results

There were three main observations. First, more extensive surgery was performed in non-UK patients, who were more likely to be optimally debulked (≤ 2 cm residual disease) than UK patients (71.3% v 58.4%, respectively; P < .001). Second, optimal debulking was associated with increased PFS mainly for patients with less extensive disease at the outset (test for interaction, P = .003). Third, UK patients with no visible residual disease had a less favorable PFS compared with patients recruited from non-UK centers who were similarly debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). This observation seems to be related to surgical practice, primarily lymphadenectomy.

Conclusion

Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.
Allele Imbalance, or Loss of Heterozygosity, in Normal Breast Epithelium of Sporadic Breast Cancer Cases and BRCA1 Gene Mutation Carriers Is Increased Compared With Reduction Mammoplasty Tissues
Authors: Larson Pamela S. , Schlechter Benjamin L. , de las Morenas Antonio , Garber Judy E. , Cupples L. Adrienne , Rosenberg Carol L.
Published: November 2005

Purpose

Normal-appearing breast epithelium can contain genetic abnormalities, including allele imbalance (AI), also referred to as loss of heterozygosity. Whether abnormalities are associated with cancer or cancer risk is unknown.

Patients and Methods

We performed a miniallelotype, using 20 microsatellites, on each of 460 histologically normal, microdissected breast terminal ducto-lobular units (TDLUs) from three groups of women: sporadic breast cancer patients (SP; n = 18), BRCA1 gene mutation carriers (BRCA1; n = 16), and controls undergoing reduction mammoplasty (RM; n = 18). We analyzed the results using Fisher's exact tests, logistic regression, and generalized estimating equations.

Results

AI was increased three-fold in SP and BRCA1 groups compared with RM. Both the number of TDLUs with AI increased (eight [5%] of 162 in the RM group compared with 24 [15%] of 162 in the SP and 22 [16%] of 136 in the BRCA1 groups; P = .0150), and the proportion of patients with AI increased (five [28%] of 18 in the RM group compared with 15 [83%] of 18 in the SP and 13 [81%] of 16 in the BRCA1 groups; P = .0007). The adjusted odds ratios (OR) for AI in TDLU increased in SP (OR = 15.5) and BRCA1 (OR = 13.7) patients compared with RM (P = .0025). This result was particularly evident on chromosome 17q (P = .0393), where more AI was seen in BRCA1 (OR = 12.4) than in SP (OR = 4.9) patients or RM controls.

Conclusion

Increased prevalence of AI in normal-appearing epithelium is associated with breast cancer and increased breast cancer risk. The increased prevalence may reflect dysregulation, even in normal-appearing epithelium, of genomic processes contributing to cancer development. The clinical significance of genetic alterations in the subset of controls remains to be determined.
Phase I Study of the Sequential Combination of Interleukin-12 and Interferon Alfa-2b in Advanced Cancer: Evidence for Modulation of Interferon Signaling Pathways by Interleukin-12
Authors: Eisenbeis Charles F. , Lesinski Gregory B. , Anghelina Mirela , Parihar Robin , Valentino Daniel , Liu Jing , Nadella Padma , Sundaram Poongothai , Young Donn C. , Sznol Mario , Walker Michael J. , Carson William E.
Published: November 2005

Purpose

To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-α-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-γ on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs).

Patients and Methods

Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN-α-2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN-α-2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN-γ production. Peripheral blood was drawn for measurement of plasma IFN-γ and the induction of Jak-STAT signal transduction in PBMCs.

Results

No IL-12–or IFN-α–related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN-γ by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN-γ achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021).

Conclusion

The combination of rhIL-12 and IFN-α-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-α–induced Jak-STAT signal transduction in patient PBMCs.
Health Behaviors of Cancer Survivors: Examining Opportunities for Cancer Control Intervention
Authors: Bellizzi Keith M. , Rowland Julia H. , Jeffery Diana D. , McNeel Timothy
Published: November 2005

Purpose

A population-based investigation was conducted to examine the prevalence of health behaviors (smoking, alcohol use, physical activity, and cancer screening) of cancer survivors by age, time since diagnosis, and cancer site. Understanding health behaviors of survivors is imperative, as many survivors are living longer and are at risk for cancer recurrence, second cancers, and complications from treatment.

Methods

Using the National Health Interview Survey, this study examined the prevalence of smoking and alcohol use as well as whether cancer survivors (n = 7,384) are meeting current recommendations for physical activity and cancer screening compared with noncancer controls (n = 121,347).

Results

Cancer survivors are similar to controls with respect to smoking status and alcohol consumption after adjusting for group differences. However, younger survivors (18 to 40 years) are at greater risk for continued smoking than controls. Survivors are 9% more likely to meet physical activity recommendations compared with controls. χ2 tests indicate no significant differences in smoking, alcohol consumption, and physical activity by time since diagnosis, but differences by cancer site exist. Female cancer survivors are 34% and 36% more likely to meet mammogram and Papanicolaou smear screening recommendations, respectively, compared with controls. Similar screening patterns were found for prostate-specific antigen screening in men.

Conclusion

This study provides benchmark approximations of the prevalence of risky health behaviors of survivors by time since diagnosis and cancer site. As part of the collective effort to reduce late effects of cancer treatment, oncologists may be in the best position to offer initial guidance for promoting healthy lifestyle behaviors among cancer survivors.
Wnt5a Expression Is Associated With the Tumor Proliferation and the Stromal Vascular Endothelial Growth Factor—An Expression in Non–Small-Cell Lung Cancer
Authors: Huang Cheng-long , Liu Dage , Nakano Jun , Ishikawa Shinya , Kontani Keiichi , Yokomise Hiroyasu , Ueno Masaki
Published: November 2005

Purpose

The Wnt gene family encodes the multifunctional signaling glycoproteins. We performed the present study to investigate the clinical significance of Wnt5a expression in non–small-cell lung cancer (NSCLC).

Patients and Methods

One hundred twenty-three patients with NSCLC who had undergone resection were investigated. Real-time quantitative reverse transcriptase polymerase chain reaction was performed to evaluate the Wnt5a gene expression. Immunohistochemistry was performed to investigate the Wnt5a protein expression, the Ki-67 proliferation index, tumor angiogenesis, and the expression of beta-catenin and vascular endothelial growth factor-A (VEGF-A).

Results

Wnt5a gene expression in squamous cell carcinoma was significantly higher than that in adenocarcinoma (P < .0001). There was a significant correlation between the normalized Wnt5a gene expression ratio and the intratumoral Wnt5a protein expression (r = 0.729; P < .0001). The intratumoral Wnt5a expression was significantly correlated with the Ki-67 proliferation index (r = 0.708; P < .0001). In contrast, no correlation was observed between the intratumoral Wnt5a expression and tumor angiogenesis. Furthermore, the intratumoral Wnt5a expression was significantly correlated with the stromal expression of beta-catenin (r = 0.729; P < .0001) and VEGF-A (r = 0.661; P < .0001). In addition, the stromal VEGF-A expression was also correlated with Ki-67 proliferation (r = 0.627; P < .0001). Cox regression analyses demonstrated Wnt5a status to be a significant prognostic factor for NSCLC patients (P = .0193), especially for patients with squamous cell carcinomas (P = .0491).

Conclusion

The present study revealed that an overexpression of Wnt5a could produce more aggressive NSCLC, especially in squamous cell carcinomas, during tumor progression.
Ixabepilone (Epothilone B Analogue BMS-247550) Is Active in Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer: A Southwest Oncology Group Trial S0111
Authors: Hussain Maha , Tangen Catherine M. , Lara Primo N. , Vaishampayan Ulka N. , Petrylak Daniel P. , Colevas A. Dimitrios , Sakr Wael A. , Crawford E. David
Published: November 2005

Purpose

The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC).

Methods

Eligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response.

Results

Forty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months).

Conclusion

Ixabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.
Chemotherapy and Cardiotoxicity in Older Breast Cancer Patients: A Population-Based Study
Authors: Doyle John J. , Neugut Alfred I. , Jacobson Judith S. , Grann Victor R. , Hershman Dawn L.
Published: November 2005

Purpose

Adjuvant chemotherapy, especially with anthracyclines, is known to cause acute and chronic cardiotoxicity in breast cancer patients. We studied the cardiac effects of chemotherapy in a population-based sample of breast cancer patients aged ≥ 65 years with long-term follow-up.

Patients and Methods

In the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we analyzed treatments and outcomes among women ≥ 65 years of age who were diagnosed with stage I to III breast cancer from January 1, 1992 to December 31, 1999. Propensity scores were used to control for baseline heart disease (HD) and other known predictors of chemotherapy, and Cox proportional hazards models were used to estimate the risk of cardiomyopathy (CM), congestive heart failure (CHF), and HD after chemotherapy.

Results

Of 31,748 women with stage I to III breast cancer, 5,575 (18%) received chemotherapy. Chemotherapy was associated with younger age, fewer comorbidities, hormone receptor negativity, multiple primary tumors, and advanced disease. Patients who received chemotherapy were less likely than other patients to have pre-existing HD (45% v 55%, respectively; P < .001). The hazard ratios for CM, CHF, and HD for patients treated with doxorubicin (DOX) compared with patients who received no chemotherapy were 2.48 (95% CI, 2.10 to 2.93), 1.38 (95% CI, 1.25 to 1.52), and 1.35 (95% CI, 1.26 to 1.44), respectively. The relative risk of cardiotoxicity among patients who received DOX compared with untreated patients remained elevated 5 years after diagnosis.

Conclusion

When baseline HD was taken into account, chemotherapy, especially with anthracyclines, was associated with a substantially increased risk of CM. As the number of long-term survivors grows, identifying and minimizing the late effects of treatment will become increasingly important.
Temporal and Geographic Variation in the Use of Hematopoietic Growth Factors in Older Women Receiving Breast Cancer Chemotherapy: Findings From a Large Population-Based Cohort
Authors: Du Xianglin L. , Lairson David R. , Begley Charles E. , Fang Shenying
Published: November 2005

Purpose

Hematopoietic growth factors have played a major role in preventing infection and shortening the duration of neutropenia in patients receiving cancer chemotherapy. Little information is available on how these growth factors are used in patients with cancer outside the clinical trial setting. We performed descriptive and exploratory analyses on the patterns and correlates of the use of hematopoietic growth factors in community-dwelling elderly patients.

Patients and Methods

We identified 5,843 women from the Surveillance, Epidemiology, and End Results (SEER)–Medicare-linked data cohorts who were diagnosed with breast cancer at age 65 or older in 1992 to 1999 from the 11 SEER areas and received chemotherapy.

Results

Overall, 17.3% of the elderly women with breast cancer chemotherapy received filgrastim and 6.8% received epoetin. The use of the growth factors increased significantly over time from 1992 to 1999 (P < .001 for trend). Compared with patients diagnosed in 1992 to 1994, patients diagnosed in 1998 to 1999 were more than five times and 65 times more likely to receive filgrastim and epoetin, respectively, after controlling for other factors such as age and comorbidity. There also was substantial geographic variation in the use of hematopoietic growth factors, ranging from 10.6% in Seattle to 22.9% in Atlanta. Significant predictors of growth factors included patient age, race, tumor stage, and comorbidity.

Conclusion

There were substantial temporal and geographic variations in the use of hematopoietic growth factors among patients receiving chemotherapy for breast cancer. The nationwide and population-based Medicare claims provide potential for examining the effectiveness, medical costs, and cost effectiveness of hematopoietic growth factors in the community.
Costs and Cost Effectiveness of a Health Care Provider–Directed Intervention to Promote Colorectal Cancer Screening Among Veterans
Authors: Wolf Michael S. , Fitzner Karen A. , Powell Eowyn F. , McCaffrey Kathryn R. , Pickard A. Simon , McKoy June M. , Lindenberg Julia , Schumock Glen T. , Carson Kenneth R. , Ferreira M. Rosario , Dolan Nancy C. , Bennett Charles L.
Published: November 2005

Purpose

Colorectal cancer screening is underused, particularly in the Veterans Affairs (VA) population. In a randomized controlled trial, a health care provider–directed intervention that offered quarterly feedback to physicians on their patients' colorectal cancer screening rates led to a 9% increase in colorectal cancer screening rates among veterans. The objective of this secondary analysis was to assess the cost effectiveness of the colorectal cancer screening promotion intervention.

Methods

Providers in the intervention arm attended an educational workshop on colorectal cancer screening and received confidential feedback on individual and group-specific colorectal cancer screening rates. The primary end point was completion of colorectal cancer screening tests. Sensitivity analyses investigated cost-effectiveness estimates varying the data collection methods, costs of labor and technology, and the effectiveness of the intervention.

Results

Rates of colorectal cancer screening for the intervention versus control arms were 41.3% v 32.4%, respectively (P < .05). The incremental cost-effectiveness ratio was $978 per additional veteran screened based on feedback reports generated from manual review of records. However, if feedback reports could be generated from information technology systems, sensitivity analyses indicate that the cost-effectiveness estimate would decrease to $196 per additional veteran screened.

Conclusion

An intervention based on quarterly feedback reports to physicians improved colorectal cancer screening rates at a VA medical center. This intervention would be cost effective if relevant data could be generated by existing information technology systems. Our findings may have broad applicability because a 2005 Medicare initiative will provide the VA electronic medical record system as a free benefit to all US physicians.
Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFRα, PDGFRβ, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung
Authors: Rossi Giulio , Cavazza Alberto , Marchioni Alessandro , Longo Lucia , Migaldi Mario , Sartori Giuliana , Bigiani Nazzarena , Schirosi Laura , Casali Christian , Morandi Uliano , Facciolongo Nicola , Maiorana Antonio , Bavieri Mario , Fabbri Leonardo M. , Brambilla Elisabeth
Published: November 2005

Purpose

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a relatively uncommon, high-grade neuroendocrine tumor sharing several features with small-cell lung carcinoma (SCLC) but currently considered as a variant of non-SCLC and accordingly treated with poor results. Little is known about the optimal therapy of LCNEC and the possible therapeutic molecular targets.

Patients and Methods

We reviewed 83 patients with pure pulmonary LCNEC to investigate their clinicopathologic features, therapeutic strategy, and immunohistochemical expression and the mutational status of the receptor tyrosine kinases (RTKs) KIT, PDGFRα, PDGFRβ, and Met.

Results

LCNEC histology predicted a dismal outcome (overall median survival, 17 months) even in stage I patients (5-year survival rate, 33%). LCNEC strongly expressed RTKs (KIT in 62.7% of patients, PDGFRα in 60.2%, PDGFRβ in 81.9%, and Met in 47%), but no mutations were detected in the exons encoding for the relevant juxtamembrane domains. Tumor stage and size (≥ 3 cm) and Met expression were significantly correlated with survival. At univariate and multivariate analysis, SCLC-based chemotherapy (platinum-etoposide) was the most important variable correlating with survival, both in the adjuvant and metastatic settings (P < .0001).

Conclusion

Pulmonary LCNEC represents an aggressive tumor requiring multimodal treatment even for resectable stage I disease, and LCNEC seems to respond to adjuvant platinum-etoposide–based chemotherapy. Patients who received this therapy had the best survival rate. Despite our failure in finding mutational events in the tested RTKs, the strong expression of KIT, PDGFRα, PDGFRβ, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.
Genomic and Protein Expression Profiling Identifies CDK6 As Novel Independent Prognostic Marker in Medulloblastoma
Authors: Mendrzyk Frank , Radlwimmer Bernhard , Joos Stefan , Kokocinski Felix , Benner Axel , Stange Daniel E. , Neben Kai , Fiegler Heike , Carter Nigel P. , Reifenberger Guido , Korshunov Andrey , Lichter Peter
Published: November 2005

Purpose

Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms.

Patients and Methods

We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival.

Results

Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02).

Conclusion

We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.
Adverse Effects of Preoperative Radiation Therapy for Rectal Cancer: Long-Term Follow-Up of the Swedish Rectal Cancer Trial
Authors: Birgisson Helgi , Påhlman Lars , Gunnarsson Ulf , Glimelius Bengt
Published: November 2005

Purpose

To analyze the occurrence of subacute and late adverse effects in patients treated with preoperative irradiation for rectal cancer.

Patients and Methods

The study population included 1,147 patients randomly assigned to preoperative radiation therapy or surgery alone in the Swedish Rectal Cancer Trial conducted 1987 through 1990. Patient data were matched against the Swedish Hospital Discharge Register to identify patients admitted to hospital after the primary treatment of the rectal cancer. Patients with known residual disease were excluded, and patients with a recurrence were censored 3 months before the date of recurrence. Relative risks (RR) with 95% CIs were calculated.

Results

Irradiated patients were at increased risk of admissions during the first 6 months from the primary treatment (RR = 1.64; 95% CI, 1.21 to 2.22); these were mainly for gastrointestinal diagnoses. Overall, the two groups showed no difference in the risk of admissions more than 6 months from the primary treatment (RR = 0.95; 95% CI, 0.80 to 1.12). Regarding specific diagnoses, however, RRs were increased for admissions later than 6 months from the primary treatment in irradiated patients for unspecified infections, bowel obstruction, abdominal pain, and nausea.

Conclusion

Gastrointestinal disorders, resulting in hospital admissions, seem to be the most common adverse effect of short-course preoperative radiation therapy in patients with rectal cancer. Bowel obstruction was the diagnosis of potentially greatest importance, which was more frequent in irradiated than in nonirradiated patients.
Prophylactic Oophorectomy Reduces Breast Cancer Penetrance During Prospective, Long-Term Follow-Up of BRCA1 Mutation Carriers
Authors: Kramer Joan L. , Velazquez Isela A. , Chen Bingshu E. , Rosenberg Philip S. , Struewing Jeffery P. , Greene Mark H.
Published: November 2005

Purpose

Breast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates.

Methods

Females from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy.

Results

Within this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers.

Conclusion

Differing rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.
Genetic Testing in Pheochromocytoma or Functional Paraganglioma
Authors: Amar Laurence , Bertherat Jérôme , Baudin Eric , Ajzenberg Christiane , Bressac-de Paillerets Brigitte , Chabre Olivier , Chamontin Bernard , Delemer Brigitte , Giraud Sophie , Murat Arnaud , Niccoli-Sire Patricia , Richard Stéphane , Rohmer Vincent , Sadoul Jean-Louis , Strompf Laurence , Schlumberger Martin , Bertagna Xavier , Plouin Pierre-François , Jeunemaitre Xavier , Gimenez-Roqueplo Anne-Paule
Published: November 2005

Purpose

To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl).

Patients and Methods

We studied 314 patients with a pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria.

Results

We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant.

Conclusion

Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.
Efficacy of Fractionated Stereotactic Reirradiation in Recurrent Gliomas: Long-Term Results in 172 Patients Treated in a Single Institution
Authors: Combs Stephanie E. , Thilmann Christoph , Edler Lutz , Debus Jürgen , Schulz-Ertner Daniela
Published: November 2005

Purpose

To evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) performed as reirradiation in 172 patients with recurrent low- and high-grade gliomas.

Patients and Methods

Between 1990 and 2004, 172 patients with recurrent gliomas were treated with FSRT as reirradiation in a single institution. Seventy-one patients suffered from WHO grade 2 gliomas. WHO grade 3 gliomas were diagnosed in 42 patients, and 59 patients were diagnosed with glioblastoma multiforme (GBM). The median time between primary radiotherapy and reirradiation was 10 months for GBM, 32 months for WHO grade 3 tumors, and 48 months for grade 2 astrocytomas. FSRT was performed with a median dose of 36 Gy in a median fractionation of 5 × 2 Gy/wk.

Results

Median overall survival after primary diagnosis was 21 months for patients with GBM, 50 months for patients with WHO grade 3 gliomas, and 111 months for patients with WHO grade 2 gliomas. Histologic grading was the strongest predictor for overall survival, together with the extent of neurosurgical resection and age at primary diagnosis. Median survival after reirradiation was 8 months for patients with GBM, 16 months for patients with grade 3 tumors, and 22 months for patients with low-grade gliomas. Only time to progression and histology were significant in influencing survival after reirradiation. Progression-free survival after FSRT was 5 months for GBM, 8 months for WHO grade 3 tumors, and 12 months for low-grade gliomas.

Conclusion

FSRT is well tolerated and may be effective in patients with recurrent gliomas. Prospective studies are warranted for further evaluation.
Recent Chemotherapy Reduces the Sensitivity of [18F]Fluorodeoxyglucose Positron Emission Tomography in the Detection of Colorectal Metastases
Authors: Akhurst Timothy , Kates Tara J. , Mazumdar Madhu , Yeung Henry , Riedel Elyn R. , Burt Bryan M. , Blumgart Leslie , Jarnagin William , Larson Steven M. , Fong Yuman
Published: November 2005

Purpose

[18F]2-fluoro-2-deoxyglucose (FDG) –positron emission tomography (PET) has become a useful tool in the assessment of patients with colorectal cancer. Patients often undergo chemotherapy as treatment for primary or metastatic colorectal malignancy. Because cytotoxic chemotherapy may decrease the cellular metabolic activity of tumor, we assessed the effects of chemotherapy on PET imaging.

Patients and Methods

This is a prospective study examining detection of hepatic colorectal metastases by FDG-PET as related to use of chemotherapy. Pathologic analysis of the liver resection specimens was used as gold standard.

Results

There was significantly decreased tumor FDG uptake (as measured by the maximal standardized uptake value) in patients treated preoperatively with chemotherapy, resulting in less efficient detection of cancerous lesions. One biologic basis of this change in accuracy of PET was a significant decrease in the activity of the key glycolytic enzyme hexokinase in tumors from patients treated with chemotherapy.

Conclusion

These results indicate that FDG-PET scanning should be interpreted in the context of concurrent cytotoxic therapy. FDG-PET scanning results may also be useful in assessment of response to such cytotoxic therapies.
Bmp2is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning
Authors: Ma Lijiang , Lu Mei-Fang , Schwartz Robert J. , Martin James F.
Published: November 2005

Cardiac cushion development provides a valuable system to investigate epithelial to mesenchymal transition (EMT), a fundamental process in development and tumor progression. In the atrioventricular (AV) canal,endocardial cells lining the heart respond to a myocardial-derived signal,undergo EMT, and contribute to cushion mesenchyme. Here, we inactivated bone morphogenetic protein 2 (Bmp2) in the AV myocardium of mice. We show that Bmp2 has three functions in the AV canal: to enhance formation of the cardiac jelly, to induce endocardial EMT and to pattern the AV myocardium. Bmp2 is required for myocardial expression of Has2, a crucial component of the cardiac jelly matrix. During EMT,Bmp2 promotes expression of the basic helix-loop-helix factor Twist1,previously implicated in EMT in cancer metastases, and the homeobox genes Msx1 and Msx2. Deletion of the Bmp type 1A receptor, Bmpr1a, in endocardium also resulted in failed cushion formation,indicating that Bmp2 signals directly to cushion-forming endocardium to induce EMT. Lastly, we show that Bmp2 mutants failed to specify the AV myocardium with loss of Tbx2 expression uncovering a myocardial, planar signaling function for Bmp2. Our data indicate that Bmp2 has a crucial role in coordinating multiple aspects of AV canal morphogenesis.
Molecular characterization of melanocyte stem cells in their niche
Authors: Osawa Masatake , Egawa Gyohei , Mak Siu-Shan , Moriyama Mariko , Freter Rasmus , Yonetani Saori , Beermann Friedrich , Nishikawa Shin-Ichi
Published: November 2005

Emerging evidence from stem cell (SC) research has strengthened the idea that SC fate is determined by a specialized environment, known as the SC niche. However, because of the difficulty of identifying individual stem cells and their surrounding components in situ, the exact mechanisms underlying SC regulation by the niche remain elusive. To overcome this difficulty, we employed melanocyte stem cells (MSCs), which allow the identification of individual SCs in the niche, the lower permanent portion of the hair follicle(HF). Here, we present molecular makers that can distinguish MSCs from other melanocyte (MC) subsets in the HF. We also describe a simple and robust method that allows gene expression profiling in individual SCs. After isolating individual MSCs from transgenic mice in which the MCs are marked by green fluorescence protein (GFP), we performed single-cell transcript analysis to obtain the molecular signature of individual MSCs in the niche. The data suggest the existence of a mechanism that induces the downregulation of various key molecules for MC proliferation or differentiation in MSCs located in the niche. By integrating these data, we propose that the niche is an environment that insulates SCs from various activating stimuli and maintains them in a quiescent state.
Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation
Authors: Zhu Yuan , Harada Takayuki , Liu Li , Lush Mark E. , Guignard Frantz , Harada Chikako , Burns Dennis K. , Bajenaru M. Livia , Gutmann David H. , Parada Luis F.
Published: November 2005

The gene responsible for neurofibromatosis type 1 (NF1) encodes a tumor suppressor that functions as a negative regulator of the Ras proto-oncogene. Individuals with germline mutations in NF1 are predisposed to the development of benign and malignant tumors of the peripheral and central nervous system(CNS). Children with this disease suffer a high incidence of optic gliomas, a benign but potentially debilitating tumor of the optic nerve; and an increased incidence of malignant astrocytoma, reactive astrogliosis and intellectual deficits. In the present study, we have sought insight into the molecular and cellular basis of NF1-associated CNS pathologies. We show that mice genetically engineered to lack NF1 in CNS exhibit a variety of defects in glial cells. Primary among these is a developmental defect resulting in global reactive astrogliosis in the adult brain and increased proliferation of glial progenitor cells leading to enlarged optic nerves. As a consequence, all of the mutant optic nerves develop hyperplastic lesions, some of which progress to optic pathway gliomas. These data point to hyperproliferative glial progenitors as the source of the optic tumors and provide a genetic model for NF1-associated astrogliosis and optic glioma.
The dissociation of the Fgf-feedback loop controls the limbless state of the neck
Authors: Lours Corinne , Dietrich Susanne
Published: November 2005

In tetrapods, limbs develop at two specific positions along the anteroposterior axis of the embryo, whereas other regions of the embryo, most prominently the neck and the flank, are limbless. However, the flank can generate an ectopic limb when the Fgf-feedback loop crucial for the initiation of limb budding is activated. Thus, despite its limblessness, the flank is a limb-competent area.

Using the chick embryo as model, we investigated whether the neck, as the flank, has the competence to form a limb, and what mechanism may regulate its limblessness. We show that forelimb lateral mesoderm plus ectoderm grafted into the neck can continue limb development, suggesting that the neck does not actively inhibit this process. However, neck tissues themselves do not support or take part in limb formation. Hence, the neck is limb-incompetent. This is due to the dismantling of Fgf signalling at distinct points of the MAPK signalling cascade in the neck lateral mesoderm and ectoderm.
LIF and BMP signaling generate separate and discrete types of GFAP-expressing cells
Authors: Bonaguidi Michael A. , McGuire Tammy , Hu Min , Kan Lixin , Samanta Jayshree , Kessler John A.
Published: November 2005

Bone morphogenetic protein (BMP) and leukemia inhibitory factor (LIF)signaling both promote the differentiation of neural stem/progenitor cells into glial fibrillary acidic protein (GFAP) immunoreactive cells. This study compares the cellular and molecular characteristics, and the potentiality, of GFAP+ cells generated by these different signaling pathways. Treatment of cultured embryonic subventricular zone (SVZ) progenitor cells with LIF generates GFAP+ cells that have a bipolar/tripolar morphology, remain in cell cycle, contain progenitor cell markers and demonstrate self-renewal with enhanced neurogenesis - characteristics that are typical of adult SVZ and subgranular zone (SGZ) stem cells/astrocytes. By contrast, BMP-induced GFAP+ cells are stellate, exit the cell cycle, and lack progenitor traits and self-renewal - characteristics that are typical of astrocytes in the non-neurogenic adult cortex. In vivo, transgenic overexpression of BMP4 increases the number of GFAP+ astrocytes but depletes the GFAP+ progenitor cell pool, whereas transgenic inhibition of BMP signaling increases the size of the GFAP+progenitor cell pool but reduces the overall numbers of astrocytes. We conclude that LIF and BMP signaling generate different astrocytic cell types,and propose that these cells are, respectively, adult progenitor cells and mature astrocytes.
Efficient Sonochemical Degradation of 4-Chlorophenol Catalyzed by Titanium Dioxide Hydrate
Authors: Dai Zhiming , Chen Aiping , Kisch Horst
Published: November 2005

A nanocrystalline anatase hydrate (Titanhydrat-0, TH) is a highly efficient catalyst for low intensity sonochemical degradation of 4-chlorophenol (4-CP). The initial disappearance rate of 4-CP increases by a factor of 95 under the TH dosage of 0.5 g dm−3. After 120 min of ultrasonic irradiation 63% of 4-CP is completely mineralized under the TH dosage of 0.5 g dm−3. However, in homogeneous sonochemical degradation, no mineralization at all occurs. Moreover, we deduce that the process of sonochemical mineralization mainly occurs at the interface region of TH. The process of sonocatalytic degradation is simple and inexpensive, and appears to be a potentially powerful method of remediation of contaminants in water.
Ge-1 is a central component of the mammalian cytoplasmic mRNA processing body
Authors: YU JIANG HONG , YANG WEI-HONG , GULICK TOD , BLOCH KENNETH D. , BLOCH DONALD B.
Published: November 2005

The mRNA processing body (P-body) is a cellular structure that regulates gene expression by degrading cytoplasmic mRNA. The objective of this study was to identify and characterize novel components of the mammalian P-body. Approximately 5% of patients with the autoimmune disease primary biliary cirrhosis have antibodies directed against this structure. Serum from one of these patients was used to identify a cDNA encoding Ge-1, a 1401-amino-acid protein. Ge-1 contains an N-terminal WD40 motif and C-terminal domains characterized by a repeating ψ(X2–3) motif. Ge-1 co-localized with previously identified P-body components, including proteins involved in mRNA decapping (DCP1a and DCP2) and the autoantigen GW182. The Ge-1 C-terminal domain was necessary and sufficient to target the protein to P-bodies. Following exposure of cells to oxidative stress, Ge-1-containing P-bodies were found adjacent to TIA-containing stress granules. During the recovery period, TIA returned to the nucleus while Ge-1-containing P-bodies localized to the perinuclear region. siRNA-mediated knock-down of Ge-1 resulted in loss of P-bodies containing Ge-1, DCP1a, and DCP2. In contrast, Ge-1-containing P-bodies persisted despite knock-down of DCP2. Taken together, the results of this study show that Ge-1 is a central component of P-bodies and suggest that Ge-1 may act prior to the 5′-decapping step in mRNA degradation.
Biochemical analysis of the EJC reveals two new factors and a stable tetrameric protein core
Authors: TANGE THOMAS Ø. , SHIBUYA TOSHIHARU , JURICA MELISSA S. , MOORE MELISSA J.
Published: November 2005

The multiprotein exon junction complex (EJC) is deposited on mRNAs upstream of exon–exon junctions as a consequence of pre-mRNA splicing. In mammalian cells, this complex serves as a key modulator of spliced mRNA metabolism. To date, neither the complete composition nor the exact assembly pathway of the EJC has been entirely elucidated. Using in vitro splicing and a two-step chromatography procedure, we have purified the EJC and analyzed its components by mass spectrometry. In addition to finding most of the known EJC factors, we identified two novel EJC components, Acinus and SAP18. Heterokaryon analysis revealed that SAP18 is a shuttling protein whereas Acinus is restricted to the nucleus. In MS2 tethering assays Acinus stimulated gene expression at the RNA level, while MLN51, another EJC factor, stimulated mRNA translational efficiency. Using tandem affinity purification (TAP) of proteins overexpressed in HeLa cells, we demonstrated that Acinus binds directly to another EJC component, RNPS1, while stable association of SAP18 to form the trimeric apoptosis and splicing associated protein (ASAP) complex requires both Acinus and RNPS1. Using the same methodology, we further identified what appears to be the minimal stable EJC core, a heterotetrameric complex consisting of eIF4AIII, Magoh, Y14, and MLN51.
Arginine-rich motifs present multiple interfaces for specific binding by RNA
Authors: BAYER TRAVIS S. , BOOTH LAUREN N. , KNUDSEN SCOTT M. , ELLINGTON ANDREW D.
Published: November 2005

A number of proteins containing arginine-rich motifs (ARMs) are known to bind RNA and are involved in regulating RNA processing in viruses and cells. Using automated selection methods we have generated a number of aptamers against ARM peptides from various natural proteins. Aptamers bind tightly to their cognate ARMs, with Kd values in the nanomolar range, and frequently show no propensity to bind to other ARMs or even to single amino acid variants of the cognate ARM. However, at least some anti-ARM aptamers can cross-recognize a limited set of other ARMs, just as natural RNA-binding sites have been shown to exhibit so-called “chameleonism.” We expand upon the number of examples of cross-recognition and, using mutational and circular dichroism (CD) analyses, demonstrate that there are multiple mechanisms by which RNA ligands can cross-recognize ARMs. These studies support a model in which individual arginine residues govern binding to an RNA ligand, and the inherent flexibility of the peptide backbone may make it possible for “semi-specific” recognition of a discrete set of RNAs by a discrete set of ARM peptides and proteins.
A consensus CaMK IV-responsive RNA sequence mediates regulation of alternative exons in neurons
Authors: XIE JIUYONG , JAN CALVIN , STOILOV PETER , PARK JENNIFER , BLACK DOUGLAS L.
Published: November 2005

Neurons make extensive use of alternative pre-mRNA splicing to regulate gene expression and diversify physiological responses. We showed previously in a pituitary cell line that the Ca++/calmodulin-dependent protein kinase CaMK IV specifically repressed splicing of the BK channel STREX exon. This repression is dependent on a CaMK IV-responsive RNA element (CaRRE) within the STREX 3′ splice site. Here, we report that similar Ca++ regulation of splicing, mediated by L-type calcium channels and CaM kinase IV, occurs in cultured neurons and in the brain. We identify a critical CaRRE motif (CACATNRTTAT) that is essential for conferring CaMK IV repression on an otherwise constitutive exon. Additional Ca++-regulated exons that carry this consensus sequence are also identified in the human genome. Thus, the Ca++/CaMK IV pathway in neurons controls the alternative splicing of a group of exons through this short CaRRE consensus sequence. The functions of some of these exons imply that splicing control through the CaMK IV pathway will alter neuronal activity.