bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized Phase II Trial of First-Line Trastuzumab Plus Docetaxel and Capecitabine Compared With Trastuzumab Plus Docetaxel in HER2-Positive Metastatic Breast Cancer
Authors: Wardley Andrew M. , Pivot Xavier , Morales-Vasquez Flavia , Zetina Luis M. , de Fátima Dias Gaui Maria , Reyes Douglas Otero , Jassem Jacek , Barton Claire , Button Peter , Hersberger Veronica , Torres Antonio Antón
Published: December 2009

Purpose

To evaluate trastuzumab (H) and docetaxel (T) with or without capecitabine (X) as first-line combination therapy for human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.

Patients and Methods

Patients with HER2-positive locally advanced or metastatic breast cancer were randomly assigned to H (8 mg/kg loading; 6 mg/kg every 3 weeks) plus T (75 mg/m2 in HTX arm, 100 mg/m2 in HT arm, every 3 weeks) with or without X (950 mg/m2 twice per day on days 1 to 14 every 3 weeks). The primary end point was overall response rate (ORR).

Results

In 222 patients, median follow-up was approximately 24 months. ORR was high with both regimens (70.5% with HTX; 72.7% with HT; P = .717); complete response rate was 23.2% with HTX compared with 16.4% with HT. HTX demonstrated significantly longer progression-free survival: median 17.9 months compared with 12.8 months with HT (hazard ratio, 0.72; P = .045), which translates to a gain of around 5 months. Two-year survival probability was 75% with HTX compared with 66% with HT. Febrile neutropenia (27% v 15%) and grade 3/4 neutropenia (77% v 54%) incidences were higher with HT than HTX. Treatment-related grade 3 hand-foot syndrome (17% v < 1%) and grade 3/4 diarrhea (11% v 4%) occurred more commonly with HTX than HT. One case of congestive heart failure occurred in each arm.

Conclusion

HTX is an effective and feasible first-line therapy for HER2-positive locally advanced or metastatic breast cancer, although it should be reserved for patients with good performance status who are not receiving long-term steroids.
Role of Axillary Clearance After a Tumor-Positive Sentinel Node in the Administration of Adjuvant Therapy in Early Breast Cancer
Authors: Straver Marieke E. , Meijnen Philip , van Tienhoven Geertjan , van de Velde Cornelis J.H. , Mansel Robert E. , Bogaerts Jan , Demonty Gaston , Duez Nicole , Cataliotti Luigi , Klinkenbijl Jean , Westenberg Helen A. , van der Mijle Huub , Hurkmans Coen , Rutgers Emiel J.T.
Published: December 2009

Purpose

The After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) phase III study compares axillary lymph node dissection (ALND) and axillary radiation therapy (ART) in early breast cancer patients with tumor-positive sentinel nodes. In the ART arm, the extent of nodal involvement remains unknown, which could have implications on the administration of adjuvant therapy. In this preliminary analysis, we studied the influence of random assignment to ALND or ART on the choice for adjuvant treatment.

Patients and Methods

In the first 2,000 patients enrolled in the AMAROS trial, we analyzed the administration of adjuvant systemic therapy. Multivariate analysis was used to assess variables affecting the administration of adjuvant chemotherapy. Adjuvant therapy was applied according to institutional guidelines.

Results

Of 2,000 patients, 566 patients had a positive sentinel node and were treated per random assignment. There was no significant difference in the administration of adjuvant systemic therapy. In the ALND and ART arms, 58% (175 of 300) and 61% (162 of 266) of the patients, respectively, received chemotherapy. Endocrine therapy was administered in 78% (235 of 300) of the patients in the ALND arm and in 76% (203 of 266) of the patients in the ART arm. Treatment arm was not a significant factor in the decision, and no interactions between treatment arm and other factors were observed. Multivariate analysis showed that age, tumor grade, multifocality, and size of the sentinel node metastasis significantly affected the administration of chemotherapy. Within the ALND arm, the extent of nodal involvement remained not significant in a sensitivity multivariate analysis.

Conclusion

Absence of knowledge regarding the extent of nodal involvement in the ART arm appears to have no major impact on the administration of adjuvant therapy.
Single Nucleotide Polymorphism in the Mutational Hotspot ofWT1Predicts a Favorable Outcome in Patients With Cytogenetically Normal Acute Myeloid Leukemia
Authors: Damm Frederik , Heuser Michael , Morgan Michael , Yun Haiyang , Großhennig Anika , Göhring Gudrun , Schlegelberger Brigitte , Döhner Konstanze , Ottmann Oliver , Lübbert Michael , Heit Wolfgang , Kanz Lothar , Schlimok Günter , Raghavachar Aruna , Fiedler Walter , Kirchner Hartmut , Döhner Hartmut , Heil Gerhard , Ganser Arnold , Krauter Jürgen
Published: December 2009

Purpose

We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers.

Patients and Methods

WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified.

Results

The minor allele of SNP rs16754 (WT1AG/GG) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations.

Conclusion

WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.
Randomized Phase III Trial of Platinum-Doublet Chemotherapy Followed by Gefitinib Compared With Continued Platinum-Doublet Chemotherapy in Japanese Patients With Advanced Non–Small-Cell Lung Cancer: Results of a West Japan Thoracic Oncology Group Trial (WJTOG0203)
Authors: Takeda Koji , Hida Toyoaki , Sato Tosiya , Ando Masahiko , Seto Takashi , Satouchi Miyako , Ichinose Yukito , Katakami Nobuyuki , Yamamoto Nobuyuki , Kudoh Shinzoh , Sasaki Jiichiro , Matsui Kaoru , Takayama Koichi , Kashii Tatsuhiko , Iwamoto Yasuo , Sawa Toshiyuki , Okamoto Isamu , Kurata Takayasu , Nakagawa Kazuhiko , Fukuoka Masahiro
Published: December 2009

Purpose

Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Chemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life.

Results

Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P < .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03).

Conclusion

This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.
Acupuncture Versus Venlafaxine for the Management of Vasomotor Symptoms in Patients With Hormone Receptor–Positive Breast Cancer: A Randomized Controlled Trial
Authors: Walker Eleanor M. , Rodriguez Alba I. , Kohn Beth , Ball Ronald M. , Pegg Jan , Pocock Jeffrey R. , Nunez Ramon , Peterson Ed , Jakary Susan , Levine Robert A.
Published: December 2009

Purpose

Vasomotor symptoms are common adverse effects of antiestrogen hormone treatment in conventional breast cancer care. Hormone replacement therapy is contraindicated in patients with breast cancer. Venlafaxine (Effexor), the therapy of choice for these symptoms, has numerous adverse effects. Recent studies suggest acupuncture may be effective in reducing vasomotor symptoms in menopausal women. This randomized controlled trial tested whether acupuncture reduces vasomotor symptoms and produces fewer adverse effects than venlafaxine.

Patients and Methods

Fifty patients were randomly assigned to receive 12 weeks of acupuncture (n = 25) or venlafaxine (n = 25) treatment. Health outcomes were measured for up to 1 year post-treatment.

Results

Both groups exhibited significant decreases in hot flashes, depressive symptoms, and other quality-of-life symptoms, including significant improvements in mental health from pre- to post-treatment. These changes were similar in both groups, indicating that acupuncture was as effective as venlafaxine. By 2 weeks post-treatment, the venlafaxine group experienced significant increases in hot flashes, whereas hot flashes in the acupuncture group remained at low levels. The venlafaxine group experienced 18 incidences of adverse effects (eg, nausea, dry mouth, dizziness, anxiety), whereas the acupuncture group experienced no negative adverse effects. Acupuncture had the additional benefit of increased sex drive in some women, and most reported an improvement in their energy, clarity of thought, and sense of well-being.

Conclusion

Acupuncture appears to be equivalent to drug therapy in these patients. It is a safe, effective and durable treatment for vasomotor symptoms secondary to long-term antiestrogen hormone use in patients with breast cancer.
Genotype-Driven Phase I Study of Irinotecan Administered in Combination With Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer
Authors: Toffoli Giuseppe , Cecchin Erika , Gasparini Giampiero , D'Andrea Mario , Azzarello Giuseppe , Basso Umberto , Mini Enrico , Pessa Sergio , De Mattia Elena , Lo Re Giovanni , Buonadonna Angela , Nobili Stefania , De Paoli Paolo , Innocenti Federico
Published: December 2009

Purpose

We aimed to identify the maximum-tolerated dose (MTD) of irinotecan in patients with cancer with UGT1A1*1/*1 and *1/*28 genotypes. We hypothesize that the patients without the *28/*28 genotype tolerate higher doses of irinotecan.

Patients and Methods

Patients undergoing first-line treatment for metastatic colorectal cancer (CRC) eligible for treatment with irinotecan plus infusional fluorouracil/leucovorin (FOLFIRI) were screened for the UGT1A1*28/*28 genotype and excluded from the study. Fifty-nine white patients with either the *1/*1 or the *1/*28 genotype were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 215 mg/m2 for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained.

Results

The dose of irinotecan was escalated to 370 mg/m2 in patients with the *1/*28 genotype and to 420 mg/m2 in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m2 and in two of three of *1/*1 patients at 420 mg/m2. No DLTs were observed in 10 *1/*28 patients at 310 mg/m2 and in 10 *1/*1 patients at 370 mg/m2; hence these dose levels were the MTD for each genotype group. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. The pharmacokinetics of irinotecan and SN-38 exhibit linear kinetics.

Conclusion

The recommended dose of 180 mg/m2 for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated when patients with the UGT1A1*28/*28 genotype are excluded. Prospective genotype-driven studies should test the efficacy of higher irinotecan doses in the FOLFIRI schedule.
Adverse Events Among the Elderly Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer
Authors: Chrischilles Elizabeth A. , Pendergast Jane F. , Kahn Katherine L. , Wallace Robert B. , Moga Daniela C. , Harrington David P. , Kiefe Catarina I. , Weeks Jane C. , West Dee W. , Zafar S. Yousuf , Fletcher Robert H.
Published: December 2009

Purpose

To describe chemotherapy use and adverse events (AEs) for advanced-stage, non–small-cell lung cancer (NSCLC) in community practice, including descriptions according to variation by age.

Methods

We interviewed patients with newly diagnosed, stages IIIB and IV NSCLC in the population-based cohort studied by the Cancer Care Outcomes Research and Surveillance Consortium, and we abstracted the patient medical records. AEs were medical events occurring during chemotherapy. Using logistic regression, we assessed the association between age and chemotherapy; with Poisson regression, we estimated event rate ratios and adjusted the analysis for age, sex, ethnicity, radiation therapy, stage, histology, and presence and grade of 27 comorbidities.

Results

Of 1,371 patients, 58% (95% CI, 55% to 61%) received chemotherapy and 35% (95% CI, 32% to 38%) had AEs. After adjustment, 72% (95% CI, 65% to 79%) of those younger than 55 years and 47% (95% CI, 42% to 52%) of those age 75 years and older received chemotherapy. Platinum-based therapies were less common in the older-age groups. Pretreatment medical event rates were 18.6% for patients younger than 55 years and were only 9.2% for those age 75 years and older (adjusted rate ratio, 0.49; 95% CI, 0.26 to 0.91). In contrast, older adults were more likely to have AEs during chemotherapy. The adjusted rate ratios compared with age younger than 55 years were 1.70 for 65- to 74-year-olds (95% CI, 1.19 to 2.43) and 1.34 for those age 75 years and older (95% CI, 0.90 to 2.00).

Conclusion

Older patients who received chemotherapy had fewer pretherapy events than younger patients and were less likely to receive platinum-based regimens. Nevertheless, older patients had more adverse events during chemotherapy, independent of comorbidity. Potential implicit trade-offs between symptom management and treatment toxicity should be made explicit and additionally studied.
HER2,TOP2A, and TIMP-1 and Responsiveness to Adjuvant Anthracycline-Containing Chemotherapy in High-Risk Breast Cancer Patients
Authors: Ejlertsen Bent , Jensen Maj-Britt , Nielsen Kirsten V. , Balslev Eva , Rasmussen Birgitte B. , Willemoe Gro L. , Hertel Pernille B. , Knoop Ann S. , Mouridsen Henning T. , Brünner Nils
Published: December 2009

Purpose

To evaluate whether the combination of HER2 with TIMP-1 (HT) or TOP2A with TIMP-1 (2T) more accurately identifies patients who benefit from cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) than these markers do when analyzed individually.

Patients and Methods

The Danish Breast Cancer Cooperative Group (DBCG) 89D trial randomly assigned 980 high-risk Danish breast cancer patients to CMF or CEF. Archival tumor tissue was analyzed TIMP-1, and HER2-negative and TIMP-1 immunoreactive tumors were classified as HT nonresponsive and otherwise HT responsive. Similarly, the 2T panel was constructed by combining TOP2A and TIMP-1; tumors with normal TOP2A status and TIMP-1 immunoreactivity were classified as 2T-nonresponsive and otherwise 2T-responsive.

Results

In total, 623 tumors were available for analysis, of which 154 lacked TIMP-1 immunoreactivity, 188 were HER2 positive, and 139 had a TOP2A aberration. HT status was a statistically significant predictor of benefit from CEF compared with CMF (Pinteraction= .036 for invasive disease–free survival [IDFS] and .047 for overall survival [OS]). The 269 (43%) patients with a 2T-responsive profile had a significant reduction in IDFS events (adjusted hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P < .001) and OS events (adjusted hazard ratio, 0.54; 95% CI, 0.38 to 0.77; P < .001). 2T status was a highly significant predictor of benefit from CEF compared with CMF (Pinteraction< .0001 for IDFS and .004 for OS).

Conclusion

The 2T profile is a more accurate predictor of incremental benefit from anthracycline-containing chemotherapy than HER2, TIMP-1, or TOP2A individually, and compared with these, 2T classifies a larger proportion of patients as sensitive to anthracyclines.
Molecular Predictors of Outcome With Gefitinib and Docetaxel in Previously Treated Non–Small-Cell Lung Cancer: Data From the Randomized Phase III INTEREST Trial
Authors: Douillard Jean-Yves , Shepherd Frances A. , Hirsh Vera , Mok Tony , Socinski Mark A. , Gervais Radj , Liao Mei-Lin , Bischoff Helge , Reck Martin , Sellers Mark V. , Watkins Claire L. , Speake Georgina , Armour Alison A. , Kim Edward S.
Published: December 2009

Purpose

In the phase III INTEREST trial, 1,466 pretreated patients with advanced non–small cell lung cancer (NSCLC) were randomly assigned to receive gefitinib or docetaxel. As a preplanned analysis, we prospectively analyzed available tumor biopsies to investigate the relationship between biomarkers and clinical outcomes.

Methods

Biomarkers included epidermal growth factor receptor (EGFR) copy number by fluorescent in situ hybridization (374 assessable samples), EGFR protein expression by immunohistochemistry (n = 380), and EGFR (n = 297) and KRAS (n = 275) mutations.

Results

For all biomarker subgroups analyzed, survival was similar for gefitinib and docetaxel, with no statistically significant differences between treatments and no significant treatment by biomarker status interaction tests. EGFR mutation–positive patients had longer progression-free survival (PFS; hazard ratio [HR], 0.16; 95% CI, 0.05 to 0.49; P = .001) and higher objective response rate (ORR; 42.1% v 21.1%; P = .04), and patients with high EGFR copy number had higher ORR (13.0% v 7.4%; P = .04) with gefitinib versus docetaxel.

Conclusion

These biomarkers do not appear to be predictive factors for differential survival between gefitinib and docetaxel in this setting of previously treated patients; however, subsequent treatments may have influenced the survival results. For secondary end points of PFS and ORR, some advantages for gefitinib over docetaxel were seen in EGFR mutation–positive and high EGFR copy number patients. There was no statistically significant difference between gefitinib and docetaxel in biomarker-negative patients. This suggests gefitinib can provide similar overall survival to docetaxel in patients across a broad range of clinical subgroups and that EGFR biomarkers such as mutation status may additionally identify which patients are likely to gain greatest PFS and ORR benefit from gefitinib.
Evaluation of Coronary Artery Disease by Computed Tomography Angiography in Patients Treated for Childhood Hodgkin's Lymphoma
Authors: Küpeli Serhan , Hazırolan Tuncay , Varan Ali , Akata Deniz , Alehan Dursun , Hayran Mutlu , Besim Aytekin , Büyükpamukçu Münevver
Published: December 2009

Purpose

To detect pathologies in coronary arteries by computed tomography angiography (CTA) in survivors of childhood Hodgkin's lymphoma who have been treated with radiotherapy and/or cardiotoxic agents.

Patients and Methods

Patients with HL who have been in remission for at least 2 years after completion of therapy were included. CBC, lipid profile, urine analysis, brain natriuretic peptide, troponin-T, creatinine kinase–myocardial band, ECG, telecardiography, echocardiography, and CTA of the patients were performed. Cardiac vascular abnormalities were noted.

Results

A total of 119 patients were included in the study. In 19 patients (16%), we found coronary artery abnormalities. There was a significant difference between the patients who received mediastinal radiotherapy and those who did not (P = .02). By multivariate analysis, in patients receiving mediastinal radiotherapy the risk of developing a coronary artery abnormality was found to increase 6.8 times compared with patients who did not receive mediastinal radiotherapy (P = .009). Stent implantation was performed in a 28-year-old patient because of critical stenosis in right coronary. In two patients some irregularities were detected both in CTA and conventional angiography, and they remained in close follow-up. A 22-year-old patient whose CTA showed critical stenosis in his left anterior descending artery refused the conventional angiography.

Conclusion

To our knowledge, this is the first large study using CTA for detection of coronary abnormalities in patients treated for HL in pediatric age group. Coronary CTA is a minimally invasive tool for early diagnosis of coronary artery disease in patients who were treated with mediastinal radiotherapy and/or cardiotoxic chemotherapy.
Patterns of Improved Survival in Patients With Multiple Myeloma in the Twenty-First Century: A Population-Based Study
Authors: Turesson Ingemar , Velez Ramon , Kristinsson Sigurdur Y. , Landgren Ola
Published: December 2009

Purpose

Randomized multiple myeloma (MM) studies show improved response rates and better progression-free survival for newer therapies. However, a less pronounced effect has been found for overall survival (OS). Using population-based data including detailed treatment information for individual patients, we assessed survival patterns for all patients diagnosed with MM in Malmö, Sweden from 1950 to 2005.

Patients and Methods

We identified 773 patients with MM (48% males). On the basis of the age limit used for treatment with high-dose melphalan with autologous stem-cell support (HDM-ASCT; ≤ 65 years old) in Sweden, we constructed Kaplan-Meier curves and used the Breslow generalized Wilcoxon test to evaluate OS patterns (diagnosed in six calendar periods) for patients 65 years old or younger and patients older than 65 years.

Results

Including all age groups, patients diagnosed from 1960 to 1969 had a better survival than patients diagnosed from 1950 to 1959. In subsequent 10-year calendar periods, median OS increased from 24.3 to 56.3 months (P = .036) in patients ≤ 65 years old. In contrast, OS did not improve among patients older than age 65 years (21.2 to 26.7 months, P = .7).

Conclusion

With the establishment of HDM-ASCT as the standard therapy for younger patients with MM, OS has improved significantly for this age group in the general MM population. With novel therapies being commonly used at disease progression, presumably it becomes increasingly difficult to confirm survival differences between defined induction, consolidation, and maintenance therapies in the future. Consequently, in the era of novel MM therapies, population-based studies will serve as a necessary complement to randomized trials.
Sources of Bias in Specimens for Research About Molecular Markers for Cancer
Authors: Ransohoff David F. , Gourlay Margaret L.
Published: December 2009

Claims about the diagnostic or prognostic accuracy of markers often prove disappointing when “discrimination” found between cancers versus normals is due to bias, a systematic difference between compared groups. This article describes a framework to help simplify and organize current problems in marker research by focusing on the role of specimens as a source of bias in observational research and using that focus to address problems and improve reliability. The central idea is that the “fundamental comparison” in research about markers (ie, the comparison done to assess whether a marker discriminates) involves two distinct processes that are “connected” by specimens. If subject selection (first process) creates baseline inequality between groups being compared, then laboratory analysis of specimens (second process) may erroneously find positive results. Although both processes are important, subject selection more fundamentally influences the quality of marker research, because it can hardwire bias into all comparisons in a way that cannot be corrected by any refinement in laboratory analysis. An appreciation of the separateness of these two processes—and placing investigators with appropriate expertise in charge of each—may increase the reliability of research about cancer biomarkers.
Physician Preferences and Knowledge Gaps Regarding the Care of Childhood Cancer Survivors: A Mailed Survey of Pediatric Oncologists
Authors: Henderson Tara O. , Hlubocky Fay J. , Wroblewski Kristen E. , Diller Lisa , Daugherty Christopher K.
Published: December 2009

Purpose

Little is known about physicians' attitudes and knowledge regarding the health care needs of childhood cancer survivors (CCS). We sought to obtain pediatric cancer physicians' self-reported attitudes and knowledge regarding this population.

Methods

A mailed survey was sent to 1,159 pediatric oncologists in the United States.

Results

A total of 655 surveys were returned (ie, 57% response rate). Median age of respondents was 47 years (range, 31 to 82 years); 57% were men. Respondents practiced for a median 14 years (range, 1 to 50 years) and reported seeing a median of 21 patients per week (range, 0 to 250 patients per week). When comfort levels in caring for CCS were described (ie, 1 = very uncomfortable; 7 = very comfortable), respondents were most comfortable with survivors ≤ 21 years (mean ± standard deviation, 6.2 ± 1.3 level), were less comfortable (5.0 ± 1.5 level) with those older than 21 years but less than 30 years old, and were uncomfortable with CCS ≥ 30 years (2.9 ± 1.7 level). In response to a clinical vignette of a 29-year-old woman treated with mantle radiation for Hodgkin's lymphoma at 16 years of age, and on the basis of available guidelines, 34% of respondents did not appropriately recommend yearly breast cancer surveillance; 43% of respondents did not appropriately recommend cardiac surveillance; and 24% of respondents did not appropriately recommend yearly thyroid surveillance. Those with greater self-reported familiarity with available long-term follow-up (LTFU) guidelines (odds ratio [OR], 1.33; 95% CI, 1.15 to 1.54) and with receipt of training in the care of CCS (OR, 1.73; 95% CI, 1.18 to 2.52) were more likely to have answered all three questions correctly.

Conclusion

Pediatric oncologists express a range of preferences with regard to LTFU of CCS. Many appear unfamiliar with LTFU surveillance guidelines.
Pattern formation in miniature: the female gametophyte of flowering plants
Authors: Sundaresan Venkatesan , Alandete-Saez Monica
Published: December 2009

Plant reproduction involves gamete production by a haploid generation, the gametophyte. For flowering plants, a defining characteristic in the evolution from the ‘naked-seed’ plants, or gymnosperms, is a reduced female gametophyte, comprising just seven cells of four different types – a microcosm of pattern formation and gamete specification about which only little is known. However, several genes involved in the differentiation, fertilization and post-fertilization functions of the female gametophyte have been identified and, recently, the morphogenic activity of the plant hormone auxin has been found to mediate patterning and egg cell specification. This article reviews recent progress in understanding the pattern formation, maternal effects and evolution of this essential unit of plant reproduction.
VEGF is required for dendritogenesis of newly born olfactory bulb interneurons
Authors: Licht Tamar , Eavri Ronen , Goshen Inbal , Shlomai Yael , Mizrahi Adi , Keshet Eli
Published: December 2009

The angiogenic factor vascular endothelial growth factor A (VEGF) has been shown to have a role in neurogenesis, but how it affects adult neurogenesis is not fully understood. To delineate a role for VEGF in successive stages of olfactory bulb (OB) neurogenesis, we used a conditional transgenic system to suppress VEGF signaling at the adult mouse sub-ventricular zone (SVZ), rostral migratory stream (RMS) and OB, which constitute the respective sites of birth, the migration route, and sites where newly born interneurons mature and integrate within the existing OB circuitry. Following the development of fluorescently tagged adult-born neurons, we show that sequestration of VEGF that is constitutively expressed by distinct types of resident OB neurons greatly impaired dendrite development in incoming SVZ-born neurons. This was evidenced by reduced dendritic spine density of granule cells and significantly shorter and less branched dendrites in periglomerular neurons. Notably, the vasculature and perfusion of the SVZ, RMS and OB were not adversely affected when VEGF suppression was delayed until after birth, thus uncoupling the effect of VEGF on dendritogenesis from its known role in vascular maintenance. Furthermore, a requirement for VEGF was specific to newly born neurons, as already established OB neurons were not damaged by VEGF inhibition. This study thus uncovered a surprising perfusion-independent role of VEGF in the adult brain, namely, an essential role in the maturation of adult-born neurons.
The transcriptional co-factor Chip acts with LIM-homeodomain proteins to set the boundary of the eye field in Drosophila
Authors: Roignant Jean-Yves , Legent Kevin , Janody Florence , Treisman Jessica E.
Published: December 2009

Development involves the establishment of boundaries between fields specified to differentiate into distinct tissues. The Drosophila larval eye-antennal imaginal disc must be subdivided into regions that differentiate into the adult eye, antenna and head cuticle. We have found that the transcriptional co-factor Chip is required for cells at the ventral eye-antennal disc border to take on a head cuticle fate; clones of Chip mutant cells in this region instead form outgrowths that differentiate into ectopic eye tissue. Chip acts independently of the transcription factor Homothorax, which was previously shown to promote head cuticle development in the same region. Chip and its vertebrate CLIM homologues have been shown to form complexes with LIM-homeodomain transcription factors, and the domain of Chip that mediates these interactions is required for its ability to suppress the eye fate. We show that two LIM-homeodomain proteins, Arrowhead and Lim1, are expressed in the region of the eye-antennal disc affected in Chip mutants, and that both require Chip for their ability to suppress photoreceptor differentiation when misexpressed in the eye field. Loss-of-function studies support the model that Arrowhead and Lim1 act redundantly, using Chip as a co-factor, to prevent retinal differentiation in regions of the eye disc destined to become ventral head tissue.
GFAPδ in radial glia and subventricular zone progenitors in the developing human cortex
Authors: Middeldorp Jinte , Boer Karin , Sluijs Jacqueline A. , De Filippis Lidia , Encha-Razavi Férechté , Vescovi Angelo L. , Swaab Dick F. , Aronica Eleonora , Hol Elly M.
Published: December 2009

A subpopulation of glial fibrillary acidic protein (GFAP)-expressing cells located along the length of the lateral ventricles in the subventricular zone (SVZ) have been identified as the multipotent neural stem cells of the adult mammalian brain. We have previously found that, in the adult human brain, a splice variant of GFAP, termed GFAPδ, was expressed specifically in these cells. To investigate whether GFAPδ is also present in the precursors of SVZ astrocytes during development and whether GFAPδ could play a role in the developmental process, we analyzed GFAPδ expression in the normal developing human cortex and in the cortex of foetuses with the migration disorder lissencephaly type II. We demonstrated for the first time that GFAPδ is specifically expressed in radial glia and SVZ neural progenitors during human brain development. Expression of GFAPδ in radial glia starts at around 13 weeks of pregnancy and disappears before birth. GFAPδ is continuously expressed in the SVZ progenitors at later gestational ages and in the postnatal brain. Co-localization with Ki67 proved that these GFAPδ-expressing cells are able to proliferate. Furthermore, we showed that the expression pattern of GFAPδ was disturbed in lissencephaly type II. Overall, these results suggest that the adult SVZ is indeed a remnant of the foetal SVZ, which develops from radial glia. Furthermore, we provide evidence that GFAPδ can distinguish resting astrocytes from proliferating SVZ progenitors.
Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development
Authors: Soyer Josselin , Flasse Lydie , Raffelsberger Wolfgang , Beucher Anthony , Orvain Christophe , Peers Bernard , Ravassard Philippe , Vermot Julien , Voz Marianne L. , Mellitzer Georg , Gradwohl Gérard
Published: December 2009

The transcription factor neurogenin 3 (Neurog3 or Ngn3) controls islet cell fate specification in multipotent pancreatic progenitor cells in the mouse embryo. However, our knowledge of the genetic programs implemented by Ngn3, which control generic and islet subtype-specific properties, is still fragmentary. Gene expression profiling in isolated Ngn3-positive progenitor cells resulted in the identification of the uncharacterized winged helix transcription factor Rfx6. Rfx6 is initially expressed broadly in the gut endoderm, notably in Pdx1-positive cells in the developing pancreatic buds, and then becomes progressively restricted to the endocrine lineage, suggesting a dual function in both endoderm development and islet cell differentiation. Rfx6 is found in postmitotic islet progenitor cells in the embryo and is maintained in all developing and adult islet cell types. Rfx6 is dependent on Ngn3 and acts upstream of or in parallel with NeuroD, Pax4 and Arx transcription factors during islet cell differentiation. In zebrafish, the Rfx6 ortholog is similarly found in progenitors and hormone expressing cells of the islet lineage. Loss-of-function studies in zebrafish revealed that rfx6 is required for the differentiation of glucagon-, ghrelin- and somatostatin-expressing cells, which, in the absence of rfx6, are blocked at the progenitor stage. By contrast, beta cells, whose number is only slightly reduced, were no longer clustered in a compact islet. These data unveil Rfx6 as a novel regulator of islet cell development.
vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis
Authors: Lokmane Ludmilla , Heliot Claire , Garcia-Villalba Pilar , Fabre Mélanie , Cereghini Silvia
Published: December 2009

Mouse metanephric kidney development begins with the induction of the ureteric bud (UB) from the caudal portion of the Wolffian duct by metanephric mesenchymal signals. While the UB undergoes branching morphogenesis to generate the entire urinary collecting system and the ureter, factors secreted by the UB tips induce surrounding mesenchymal cells to convert into epithelia and form the nephrons, the functional units of the kidney. Epithelial branching morphogenesis and nephrogenesis are therefore tightly orchestrated; defects in either of these processes lead to severe kidney phenotypes ranging from hypoplasia to complete aplasia. However, the underlying regulatory networks have been only partially elucidated. Here, we identify the transcription factor vHNF1 (HNF1β) as a crucial regulator of these early developmental events. Initially involved in timing outgrowth of the UB and subsequent branching, vHNF1 is also required for nephric duct epithelial maintenance, Müllerian duct formation and early nephrogenesis. Mosaic analyses further suggest a cell-autonomous requirement for vHNF1 in the acquisition of a specialized tip domain and branching morphogenesis. vHNF1 exerts these intricate functions at least in part through the direct control of key regulatory molecules involved in different aspects of early kidney development. Notably, vHNF1 acting directly upstream of Wnt9b appears to orchestrate Wnt signaling action in the mesenchymal-epithelial transitions underlying the initiation of nephrogenesis. These results demonstrate that vHNF1 is an essential transcriptional regulator that, in addition to the known later functions in normal duct morphogenesis, plays a crucial role during the earliest stages of urogenital development and provide novel insights into the regulatory circuits controlling events.
Nodal and BMP2/4 pattern the mesoderm and endoderm during development of the sea urchin embryo
Authors: Duboc Véronique , Lapraz François , Saudemont Alexandra , Bessodes Nathalie , Mekpoh Flavien , Haillot Emmanuel , Quirin Magali , Lepage Thierry
Published: December 2009

Nodal factors play fundamental roles in induction and patterning of the mesoderm and endoderm in vertebrates, but whether this reflects an ancient role or one that evolved recently in vertebrates is not known. Here, we report that in addition to its primary role in patterning the ectoderm, sea urchin Nodal is crucial for patterning of the endoderm and skeletogenic mesoderm through the regulation of the expression of key transcription factors and signalling molecules, including BMP2/4 and FGFA. In addition, we uncovered an essential role for Nodal and BMP2/4 in the formation and patterning of the non-skeletogenic mesoderm. By comparing the effects of misexpressing Nodal or an activated Nodal receptor in clones of cells, we provide evidence that Nodal acts over a long range in the endomesoderm and that its effects on the blastocoelar cell precursors are likely to be direct. The activity of Nodal and BMP2/4 are antagonistic, and although bmp2/4 is transcribed in the ventral ectoderm downstream of Nodal, the BMP2/4 ligand is translocated to the dorsal side, where it activates signalling in the dorsal primary mesenchyme cells, the dorsal endoderm and in pigment cell precursors. Therefore, correct patterning of the endomesoderm depends on a balance between ventralising Nodal signals and dorsalising BMP2/4 signals. These experiments confirm that Nodal is a key regulator of dorsal-ventral polarity in the sea urchin and support the idea that the ventral ectoderm, like the Spemann organiser in vertebrates, is an organising centre that is required for patterning all three germ layers of the embryo.
Regulation of cortical contractility and spindle positioning by the protein phosphatase 6 PPH-6 in one-cell stageC. elegansembryos
Authors: Afshar Katayoun , Werner Michael E. , Tse Yu Chung , Glotzer Michael , Gönczy Pierre
Published: December 2009

Modulation of the microtubule and the actin cytoskeleton is crucial for proper cell division. Protein phosphorylation is known to be an important regulatory mechanism modulating these cytoskeletal networks. By contrast, there is a relative paucity of information regarding how protein phosphatases contribute to such modulation. Here, we characterize the requirements for protein phosphatase PPH-6 and its associated subunit SAPS-1 in one-cell stage C. elegans embryos. We establish that the complex of PPH-6 and SAPS-1 (PPH-6/SAPS-1) is required for contractility of the actomyosin network and proper spindle positioning. Our analysis demonstrates that PPH-6/SAPS-1 regulates the organization of cortical non-muscle myosin II (NMY-2). Accordingly, we uncover that PPH-6/SAPS-1 contributes to cytokinesis by stimulating actomyosin contractility. Furthermore, we demonstrate that PPH-6/SAPS-1 is required for the proper generation of pulling forces on spindle poles during anaphase. Our results indicate that this requirement is distinct from the role in organizing the cortical actomyosin network. Instead, we uncover that PPH-6/SAPS-1 contributes to the cortical localization of two positive regulators of pulling forces, GPR-1/2 and LIN-5. Our findings provide the first insights into the role of a member of the PP6 family of phosphatases in metazoan development.
Drosophila Hey is a target of Notch in asymmetric divisions during embryonic and larval neurogenesis
Authors: Monastirioti Maria , Giagtzoglou Nikolaos , Koumbanakis Konstantinos A. , Zacharioudaki Evanthia , Deligiannaki Myrto , Wech Irmgard , Almeida Mara , Preiss Anette , Bray Sarah , Delidakis Christos
Published: December 2009

bHLH-O proteins are a subfamily of the basic-helix-loop-helix transcription factors characterized by an ‘Orange’ protein-protein interaction domain. Typical members are the Hairy/E(spl), or Hes, proteins, well studied in their ability, among others, to suppress neuronal differentiation in both invertebrates and vertebrates. Hes proteins are often effectors of Notch signalling. In vertebrates, another bHLH-O protein group, the Hey proteins, have also been shown to be Notch targets and to interact with Hes. We have studied the single Drosophila Hey orthologue. We show that it is primarily expressed in a subset of newly born neurons, which receive Notch signalling during their birth. Unlike in vertebrates, however, Hey is not expressed in precursor cells and does not block neuronal differentiation. It rather promotes one of two alternative fates that sibling neurons adopt at birth. Although in the majority of cases Hey is a Notch target, it is also expressed independently of Notch in some lineages, most notably the larval mushroom body. The availability of Hey as a Notch readout has allowed us to study Notch signalling during the genesis of secondary neurons in the larval central nervous system.
A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages
Authors: Pearson Bret J. , Alvarado Alejandro Sánchez
Published: December 2009

The functions of adult stem cells and tumor suppressor genes are known to intersect. However, when and how tumor suppressors function in the lineages produced by adult stem cells is unknown. With a large population of stem cells that can be manipulated and studied in vivo, the freshwater planarian is an ideal system with which to investigate these questions. Here, we focus on the tumor suppressor p53, homologs of which have no known role in stem cell biology in any invertebrate examined thus far. Planaria have a single p53 family member, Smed-p53, which is predominantly expressed in newly made stem cell progeny. When Smed-p53 is targeted by RNAi, the stem cell population increases at the expense of progeny, resulting in hyper-proliferation. However, ultimately the stem cell population fails to self-renew. Our results suggest that prior to the vertebrates, an ancestral p53-like molecule already had functions in stem cell proliferation control and self-renewal.
Midline crossing by gustatory receptor neuron axons is regulated byfruitless, doublesexand the Roundabout receptors
Authors: Mellert David J. , Knapp Jon-Michael , Manoli Devanand S. , Meissner Geoffrey W. , Baker Bruce S.
Published: December 2009

Although nervous system sexual dimorphisms are known in many species, relatively little is understood about the molecular mechanisms generating these dimorphisms. Recent findings in Drosophila provide the tools for dissecting how neurogenesis and neuronal differentiation are modulated by the Drosophila sex-determination regulatory genes to produce nervous system sexual dimorphisms. Here we report studies aimed at illuminating the basis of the sexual dimorphic axonal projection patterns of foreleg gustatory receptor neurons (GRNs): only in males do GRN axons project across the midline of the ventral nerve cord. We show that the sex determination genes fruitless (fru) and doublesex (dsx) both contribute to establishing this sexual dimorphism. Male-specific Fru (FruM) acts in foreleg GRNs to promote midline crossing by their axons, whereas midline crossing is repressed in females by female-specific Dsx (DsxF). In addition, midline crossing by these neurons might be promoted in males by male-specific Dsx (DsxM). Finally, we (1) demonstrate that the roundabout (robo) paralogs also regulate midline crossing by these neurons, and (2) provide evidence that FruM exerts its effect on midline crossing by directly or indirectly regulating Robo signaling.
A Drosophila model of Menkes disease reveals a role for DmATP7 in copper absorption and neurodevelopment
Authors: Bahadorani Sepehr , Bahadorani Peyman , Marcon Edyta , Walker David W. , Hilliker Arthur J.
Published: December 2009

Human Menkes disease is a lethal neurodegenerative disorder of copper metabolism that is caused by mutations in the ATP7A copper-transporting gene. In the present study, we attempted to construct a Drosophila model of Menkes disease by RNA interference (RNAi)-induced silencing of DmATP7, the Drosophila orthologue of mammalian ATP7A, in the digestive tract. Here, we show that a lowered level of DmATP7 mRNA in the digestive tract results in a reduced copper content in the head and the rest of the body of surviving adults, presumably owing to copper entrapment in the gut. Similar to Menkes patients, a majority of flies exhibit an impaired neurological development during metamorphosis and die before eclosion. In addition, we show that survival to the adult stage is highly dependent on the copper content of the food and that overexpression of the copper homeostasis gene, metal-responsive transcription factor-1 (MTF-1), enhances survival to the adulthood stage. Taken together, these results highlight the role of DmATP7-mediated copper uptake in the neurodevelopment of Drosophila melanogaster and provide a framework for the analysis of potential gene interactions influencing Menkes disease.