bluuebunny/crossref_metadata_2025 huggingface dataset:
The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma
Authors:   The ENFUMOSA Study Group
Published: August 2003

Since severe asthma is a poorly understood, major health problem, 12 clinical specialist centres in nine European countries formed a European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA).

In a cross-sectional observational study, a total of 163 subjects with severe asthma were compared with 158 subjects whose asthma was controlled by low doses of inhaled corticosteroids (median dose of beclomethasone equivalents 666 µg). Despite being treated with higher doses of inhaled corticosteroids (median dose 1773 µg) and for a third of the severe asthmatics also being treated with regular, oral-steroid therapy (median daily dose 19 mg), the subjects with severe asthma met the inclusion criteria. The criteria required subjects to have undergone at least one asthma exacerbation in the past year requiring oral steroid treatment. Females dominated the severe asthma group (female/male ratio 4.4:1versus1.6:1 in the controlled asthmatics), and compared with controlled asthmatics, they had a predominantly neutrophilic inflammation (sputum neutrophils, 36versus28%) and evidence of ongoing mediator release but less atopy.

From these findings and other physiological and clinical data reported in this paper, it is suggested that severe asthma might be a different form of asthma rather than an increase in asthma symptoms. The findings prompt for longitudinal studies and interventions to define the mechanisms in severe asthma.
Older Age Is an Adverse Prognostic Factor in Stage I, Favorable Histology Wilms’ Tumor Treated With Vincristine Monochemotherapy: A Study by the United Kingdom Children’s Cancer Study Group, Wilm’s Tumor Working Group
Authors: Pritchard-Jones K. , Kelsey A. , Vujanic G. , Imeson J. , Hutton C. , Mitchell C.
Published: August 2003

Purpose: To identify clinical prognostic factors in children with stage I, favorable histology (FH) Wilms’ tumor treated with vincristine monochemotherapy after immediate nephrectomy to define subgroups for consideration of further reduction in treatment intensity.

Patients and Methods: During two consecutive trials of the United Kingdom Children’s Cancer Study Group (UKW2 and UKW3, 1986 to 2001), 242 children with stage I FH Wilms’ tumor were treated with immediate nephrectomy followed by 10 weekly injections of vincristine 1.5 mg/m2. Event-free survival (EFS) and overall survival (OS) were compared by age group.

Results: The 4-year EFS rate was 93.2%, 87.2%, and 71.3% for children less than 2 years old, 2 to 4 years old, and 4 years old or older at diagnosis, respectively (log-rank, P = .001); the corresponding 4-year OS rate was 98.1%, 95.0%, and 87.2% (log-rank, P = .01). There were no toxicity- or procedure-related deaths. In multivariate analysis, specimen weight was not of independent prognostic value (P = .66). Among the 186 children younger than 4 years at diagnosis, there were 17 relapses and five deaths, compared with 16 relapses and eight deaths among the 56 children at least 4 years old at diagnosis. OS after relapse was surprisingly poor (61.6% at 4 years).

Conclusion: Treatment for stage I FH Wilms’ tumor is generally successful using vincristine monotherapy after immediate nephrectomy, and therefore, the risks of dactinomycin hepatopathy can be avoided. However, age at least 4 years is a significant adverse prognostic factor. This treatment schedule should be considered in any trial of treatment reduction in very young children with stage I FH Wilms’ tumor, regardless of tumor size, and we suggest that the upper age limit for the reduced therapy be set at 4 years.
Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic Melanoma
Authors: Hwu Wen-Jen , Krown Susan E. , Menell Jennifer H. , Panageas Katherine S. , Merrell Janene , Lamb Lynne A. , Williams Linda J. , Quinn Carolyn J. , Foster Theresa , Chapman Paul B. , Livingston Philip O. , Wolchok Jedd D. , Houghton Alan N.
Published: August 2003

Purpose: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases.

Patients and Methods: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m2/d × 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients < 70 years old, or 100 mg/d with dose escalation to 250 mg/d for patients ≥ 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred.

Results: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25+ months’ duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months.

Conclusion: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study.
Comparison of Gemcitabine Versus the Matrix Metalloproteinase Inhibitor BAY 12-9566 in Patients With Advanced or Metastatic Adenocarcinoma of the Pancreas: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group
Authors: Moore M.J. , Hamm J. , Dancey J. , Eisenberg P.D. , Dagenais M. , Fields A. , Hagan K. , Greenberg B. , Colwell B. , Zee B. , Tu D. , Ottaway J. , Humphrey R. , Seymour L.
Published: August 2003

Purpose: To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer.

Methods: Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. The planned sample size of the study was 350 patients. Two formal interim analyses were planned.

Results: The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the BAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P < .001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P < .001). Quality-of-life analysis also favored gemcitabine.

Conclusion: Gemcitabine is significantly superior to BAY 12-9566 in advanced pancreatic cancer.
Randomized, Double-Blind, Controlled Trial of Mitoxantrone/Prednisone and Clodronate Versus Mitoxantrone/Prednisone and Placebo in Patients With Hormone-Refractory Prostate Cancer and Pain
Authors: Ernst D.S. , Tannock I.F. , Winquist E.W. , Venner P.M. , Reyno L. , Moore M.J. , Chi K. , Ding K. , Elliott C. , Parulekar W.
Published: August 2003

Purpose: To compare the incidence of palliative response in patients with hormone-resistant prostate cancer (HRPC) treated with mitoxantrone and prednisone (MP) plus clodronate with that of patients treated with MP plus placebo.

Materials and Methods: Men with HRPC, bone metastases, and bone pain were randomly assigned to receive clodronate 1,500 mg administered intravenously (IV) or placebo every 3 weeks, in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid. Patients completed the present pain intensity (PPI) index and Prostate Cancer–Specific Quality-of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis. The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50% in analgesic intake, without increase in either.

Results: The study accrued 209 eligible patients over 44 months. One hundred sixty patients (77%) had mild PPI scores (1 or 2), and 49 (24%) had moderate PPI scores (3 or 4). The primary end point of palliative response was achieved in 46 (46%) of 104 patients on the clodronate arm and in 41 (39%) of 105 patients on the placebo arm (P = .54). The median duration of response, symptomatic disease progression-free survival, overall survival, and overall quality of life were similar between the arms. Subgroup analysis suggested possible benefit in patients with more severe pain.

Conclusion: MP provides useful palliation in symptomatic men with HRPC. Clodronate does not increase the rate of palliative response or overall quality of life. Clodronate may be beneficial to patients who have moderate pain, but this requires further confirmation.
Changes in the 2003 American Joint Committee on Cancer Staging for Breast Cancer Dramatically Affect Stage-Specific Survival
Authors: Woodward Wendy A. , Strom Eric A. , Tucker Susan L. , McNeese Marsha D. , Perkins George H. , Schechter Naomi R. , Singletary S. Eva , Theriault Richard L. , Hortobagyi Gabriel N. , Hunt Kelly K. , Buchholz Thomas A.
Published: August 2003

Purpose: To evaluate how implementation of the 2003 American Joint Committee on Cancer (AJCC) staging system will affect stage-specific survival of breast cancer patients.

Patients and Methods: Records of 1,350 patients treated on sequential institutional protocols with mastectomy and adjuvant doxorubicin-based chemotherapy were reviewed. Pathologic stage was assigned retrospectively according to the 1988 and the 2003 AJCC staging criteria. Overall stage-specific survival (OS) was calculated using the Kaplan-Meier method, and hypothetical differences were compared by the log-rank test.

Results: Six hundred five of 1,087 patients with stage II disease according to the 1988 classification system had stage II disease according to the 2003 system. The 10-year OS for patients with stage II disease was significantly improved using the 2003 system (76% [2003] v 65% [1988]; P < .0001). Two hundred eighty-nine of 633 patients with stage IIb disease using the 1988 system were stage IIb with the 2003 system, and 10-year OS was 58% (1988) versus 70% (2003; P = .003). The number of patients with stage III disease increased from 207 (1988) to 443 (2003), and the 10-year OS changed from 45% (1988) to 50% (2003; P = .077). Most of this difference resulted from changes within stage IIIa: OS, 45% (1988) versus 59% (2003; P < .0001).

Conclusion: Stage reclassification using the new AJCC staging system for breast cancer will result in significant changes in reported outcome by stage. It is imperative that careful attention is devoted to this effect so that accurate conclusions regarding the efficacy of new treatment strategies can be drawn.
Phase II Study of Pegylated Liposomal Doxorubicin in Combination With Gemcitabine in Patients With Metastatic Breast Cancer
Authors: Rivera Edgardo , Valero Vicente , Arun Banu , Royce Melanie , Adinin Rosni , Hoelzer Karen , Walters Ronald , Wade James L. , Pusztai Lajos , Hortobagyi Gabriel N.
Published: August 2003

Purpose: We conducted a phase II clinical trial to determine the clinical efficacy and safety of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer.

Patients and Methods: Patients were eligible if they had measurable disease, no prior chemotherapy for metastatic disease, and a performance status ≤ 2 on the Zubrod scale. Patients received pegylated liposomal doxorubicin 24 mg/m2 intravenously on day 1, plus gemcitabine 800 mg/m2 intravenously on days 1 and 8 of each 21-day cycle.

Results: Of 49 patients enrolled, 27 had received prior adjuvant chemotherapy (19 with an anthracycline). Prior median cumulative anthracycline dose was 240 mg/m2. In total, three complete responses and 21 partial responses were achieved in 46 assessable patients, for an overall response rate of 52% (95% confidence interval, 37% to 67%). Responses were observed in 11 (58%) of 19 patients with previous anthracycline exposure. Median response duration was 5.6 months, time to progression was 4.5 months, and overall survival was 16.1 months. Although the most common grade 3 to 4 toxicities were hematologic, few neutropenic complications resulted. The most frequent nonhematologic toxicities were nausea and vomiting, fatigue, stomatitis, and hand-foot syndrome. One patient previously treated with an anthracycline developed a transient decrease (21%) in the left ventricular ejection fraction, with cardiac function recovering within 2 months.

Conclusion: Pegylated liposomal doxorubicin in combination with gemcitabine is active and well tolerated in patients with metastatic breast cancer. Median overall survival was 16.1 months, and approximately 78% of patients derived clinical benefit from treatment. This regimen represents a therapeutic option for patients receiving front-line therapy for their metastatic breast cancer.
Phase I/II Study of Hepatic Arterial Therapy With Floxuridine and Dexamethasone in Combination With Intravenous Irinotecan As Adjuvant Treatment After Resection of Hepatic Metastases From Colorectal Cancer
Authors: Kemeny N. , Jarnagin W. , Gonen M. , Stockman J. , Blumgart L. , Sperber D. , Hummer A. , Fong Y.
Published: August 2003

Purpose: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection.

Patients and Methods: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen.

Results: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg × pump volume ÷ pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive.

Conclusion: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.
Postchemotherapy Retroperitoneal Surgery Remains Necessary in Patients With Nonseminomatous Testicular Cancer and Minimal Residual Tumor Masses
Authors: Oldenburg Jan , Alfsen G. Cecilie , Lien Hans H. , Aass Nina , Wæhre Håkon , Fosså Sophie D.
Published: August 2003

Purpose: To determine preoperative parameters that predict the histology of specimens obtained by retroperitoneal lymph node dissection (RPLND) in patients with nonseminomatous germ cell cancer (NSGCT) whose residual mass was ≤ 20 mm in diameter after modern cisplatin-based induction chemotherapy.

Patients and Methods: Eighty-seven patients with metastatic NSGCT underwent RPLND after having received cisplatin- or carboplatin-based induction chemotherapy. In all patients, the largest diameter of the residual mass on the transaxial plane was ≤ 20 mm, as assessed by abdominal computed tomography (CT) immediately before RPLND.

Results: Complete fibrosis or necrosis was found in 58 patients (67%), teratoma was found in 23 patients (26%), and vital malignant germ cell tumor was found in six patients (7%), including one patient with rhabdomyosarcoma in the RPLND specimen. In five of the six latter patients, the residual lesion was ≤ 10 mm at pre-RPLND CT. No pre- or postchemotherapy clinical or radiologic parameter was identified that significantly predicted the histology of the residual mass.

Conclusion: One third of retroperitoneal postchemotherapy lesions ≤ 20 mm contained residual vital tumor tissue, despite modern chemotherapy regimens. Therefore, postchemotherapy RPLND remains necessary in patients with minimal-size residual lesions to facilitate easy and safe follow-up and initiate additional therapy as early as possible, thus avoiding recurrences.
Neuro-Oncology Working Group 01 Trial of Nimustine Plus Teniposide Versus Nimustine Plus Cytarabine Chemotherapy in Addition to Involved-Field Radiotherapy in the First-Line Treatment of Malignant Glioma
Authors:   The Neuro-Oncology Working Group of the German Cancer Society
Published: August 2003

Purpose: The role of chemotherapy in the primary treatment of malignant glioma remains controversial. The results from the German-Austrian Glioma trial (GAG, 1983 to 1988) demonstrated a survival benefit for chemotherapy using carmustine (BCNU) plus teniposide (VM26) over BCNU alone in addition to radiotherapy in patients with a Karnofsky performance score (KPS) more than 60. The Neuro-Oncology Working Group (NOA) of the German Cancer Society therefore compared the efficacy of nimustine (ACNU) plus VM26 and ACNU plus cytarabine (Ara-C) chemotherapy in addition to standard radiotherapy in patients with newly diagnosed malignant glioma.

Patients and Methods: From 1994 to 2000, 375 patients were randomly assigned to receive radiotherapy and cycles of ACNU 90 mg/m2 intravenously (IV) on day 1 and VM26 60 mg/m2 IV on days 1 to 3 (n = 183), or ACNU 90 mg/m2 IV on day 1 and Ara-C 120 mg/m2 IV on days 1 to 3 (n = 179), in 6-week intervals. Thirteen patients were not eligible after central neuropathology review. The remaining 362 patients had glioblastoma (n = 301) or anaplastic glioma (n = 61).

Results: Median survival and 2-year survival rates were 17.3 months and 25% for ACNU plus VM26, and 15.7 months and 29% for ACNU plus Ara-C in glioblastoma, and 60 months and 88% for ACNU plus VM26 and 62.5 months and 72% for ACNU plus Ara-C in anaplastic glioma. Multivariate analysis revealed no survival advantage for either arm or for subpopulations defined by histology, age, or KPS. Hematologic toxicity was more prominent in the ACNU plus Ara-C arm.

Conclusion: The median survival times and 2-year survival rates for patients with anaplastic glioma and glioblastoma achieved in the NOA-01 trial compare favorably with historical trials and with the Radiation Therapy Oncology Group database. The toxicity profile favors ACNU plus VM26 for further evaluation.
Vaccination With Irradiated, Autologous Melanoma Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor by Adenoviral-Mediated Gene Transfer Augments Antitumor Immunity in Patients With Metastatic Melanoma
Authors: Soiffer Robert , Hodi F. Stephen , Haluska Frank , Jung Ken , Gillessen Silke , Singer Samuel , Tanabe Kenneth , Duda Rosemary , Mentzer Steven , Jaklitsch Michael , Bueno Raphael , Clift Shirley , Hardy Steve , Neuberg Donna , Mulligan Richard , Webb Iain , Mihm Martin , Dranoff Glenn
Published: August 2003

Purpose: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer.

Patients and Methods: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 × 106, 4 × 106, or 1 × 107tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals.

Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.

Conclusion: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.
New Classification Scheme for the Prognostic Stratification of Meningioma on the Basis of Chromosome 14 Abnormalities, Patient Age, and Tumor Histopathology
Authors: Maíllo Angel , Orfao Alberto , Sayagués José María , Díaz Pedro , Gómez-Moreta Juan Antonio , Caballero Marcelino , Santamarta David , Santos-Briz Angel , Morales Francisco , Tabernero María Dolores
Published: August 2003

Purpose: Meningiomas are usually considered benign tumors. However, relapses occur in 10% to 20% of all patients, including both histopathologically aggressive and benign tumors. This study explored the value of numerical abnormalities for 10 different chromosomes in meningiomas for predicting relapse-free survival (RFS).

Patients and Methods: This study prospectively analyzed the frequency of numerical abnormalities of chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y in 70 meningioma patients by fluorescence in situ hybridization and their relationship with disease characteristics at diagnosis and patients’ outcome.

Results: Results showed the presence of numerical abnormalities for one or more chromosomes in most patients (77%). Chromosome 22 in the whole series and chromosome Y in males were those more frequently altered, followed by chromosomes 1, 14, and X in females. Patients with abnormalities of chromosomes 1, 9, 10, 11, 14, 15, 17, the sex chromosomes, and gains of chromosome 22 were associated with adverse prognostic features, more frequent relapses, and shorter RFS. Multivariate analysis showed that tumor grade together with chromosome 14 status and age were the best combination of independent variables for predicting RFS. According to these variables, all patients with a score of two or more than two adverse prognostic factors had experienced relapse at 5 years, whereas none of those with a score of zero had experienced relapse 10 years after surgery.

Conclusion: In addition to age and histologic grade, abnormalities of chromosome 14 contribute to a better prognostic stratification of meningioma patients at diagnosis. Additional prospective studies in larger series of patients, also including larger numbers of patients who experienced relapse, are necessary to confirm the utility of the proposed predictive model.
Do Older Men Benefit From Curative Therapy of Localized Prostate Cancer?
Authors: Alibhai Shabbir M.H. , Naglie Gary , Nam Robert , Trachtenberg John , Krahn Murray D.
Published: August 2003

Purpose: Prior decision-analytic models are based on outdated or suboptimal efficacy, patient preference, and comorbidity data. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) associated with available treatments for localized prostate cancer in men aged ≥ 65 years, adjusting for Gleason score, patient preferences, and comorbidity.

Methods: We evaluated three treatments, using a decision-analytic Markov model: radical prostatectomy (RP), external beam radiotherapy (EBRT), and watchful waiting (WW). Rates of treatment complications and pretreatment incontinence and impotence were derived from published studies. We estimated treatment efficacy using three data sources: cancer registry cohort data, pooled case series, and modern radiotherapy studies. Utilities were obtained from 141 prostate cancer patients and from published studies.

Results: For men with well-differentiated tumors and few comorbidities, potentially curative therapy (RP or EBRT) prolonged LE up to age 75 years but did not improve QALE at any age. For moderately differentiated cancers, potentially curative therapy resulted in LE and QALE gains up to age 75 years. For poorly differentiated disease, potentially curative therapy resulted in LE and QALE gains up to age 80 years. Benefits of potentially curative therapy were restricted to men with no worse than mild comorbidity. When cohort and pooled case series data were used, RP was preferred over EBRT in all groups but was comparable to modern radiotherapy.

Conclusion: Potentially curative therapy results in significantly improved LE and QALE for older men with few comorbidities and moderately or poorly differentiated localized prostate cancer. Age should not be a barrier to treatment in this group.
ras Mutations Are Associated With Aggressive Tumor Phenotypes and Poor Prognosis in Thyroid Cancer
Authors: Garcia-Rostan Ginesa , Zhao Hongyu , Camp Robert L. , Pollan Marina , Herrero Agustin , Pardo Javier , Wu Ran , Carcangiu Maria Luisa , Costa Jose , Tallini Giovanni
Published: August 2003

Purpose: ras oncogenic activation has long been demonstrated in thyroid carcinomas of follicular cell derivation, but no consistent relationship has been shown between mutations and clinicopathologic features.

Materials and Methods: We analyzed H-, K-, and N-ras mutations by polymerase chain reaction–single-strand conformational polymorphism followed by DNA sequencing in 125 thyroid carcinoma specimens from 107 patients, to include tumors covering the entire spectrum of thyroid tumor differentiation.

Results: Mutations were identified in four (8.2%) of 49 well-differentiated carcinomas (WDCs; two [6.7%] of 30 of the tumors were papillary carcinomas, two [10.5%] of 19 of them were follicular carcinomas), in 16 (55.2%) of 29 poorly differentiated carcinomas (PDCs), and in 15 (51.7%) of 29 undifferentiated carcinomas, with a significant association between ras mutation and poorly or undifferentiated tumors (P < .001). Twenty-six (74.3%) of 35 patients with ras-mutated tumors died as a result of disease as opposed to 23 (31.9%) of 72 patients with tumors lacking the mutations. Among patients with differentiated thyroid carcinomas (WDC and PDC), 11 (55.0%) of 20 patients with mutated tumors died as a result of disease as opposed to nine (15.5%) of 58 patients with wild-type ras tumors, and the correlation was independent of tumor differentiation and stage (P = .016). K-ras codon 13 mutations (all with G-A nucleotide transitions resulting in Gly>Asp substitution) and single activating mutations in any of the ras genes were also independent predictors of poor survival in differentiated thyroid carcinomas (P = .027 and P = .007, respectively).

Conclusion: These findings demonstrate that ras mutations are a marker for aggressive cancer behavior and indicate a possible role of ras genotyping to identify thyroid carcinoma subsets associated with poor prognosis.
Patient Stratification Based on Prednisolone-Vincristine-Asparaginase Resistance Profiles in Children With Acute Lymphoblastic Leukemia
Authors: Den Boer M.L. , Harms D.O. , Pieters R. , Kazemier K.M. , Göbel U. , Körholz D. , Graubner U. , Haas R.J. , Jorch N. , Spaar H.J. , Kaspers G.J.L. , Kamps W.A. , Van der Does-Van den Berg A. , Van Wering E.R. , Veerman A.J.P. , Janka-Schaub G.E.
Published: August 2003

Purpose: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol.

Patients and Methods: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol.

Results: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate ± SE was 69% ± 7.0%, 83% ± 4.4%, and 84% ± 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P ≤ .05). Resistant patients were at increased risk of an early event (nonresponse or relapse within 2.5 years of diagnosis) compared with sensitive and intermediate-sensitive patients (P = .03). The profile did not identify patients at higher risk of late relapse, which was also observed for DCLSG ALL-VII/VIII patients now analyzed at a median of 7.5 years of follow-up (range, 4.4 to 10.8 years). Despite being nondiscriminative for late relapses, the resistant profile was still the strongest prognostic factor for COALL-92 patients in a multivariate analysis including known risk factors (P = .07).

Conclusion: Drug resistance profiles identify patients at higher risk of early treatment failures and may, therefore, be used to improve risk-group stratification of children with ALL.
TGFBR1*6A and Cancer Risk: A Meta-Analysis of Seven Case-Control Studies
Authors: Kaklamani Virginia G. , Hou Nanjiang , Bian Yiansong , Reich Jennifer , Offit Kenneth , Michel Loren S. , Rubinstein W.S. , Rademaker Alfred , Pasche Boris
Published: August 2003

Purpose: TGFBR1*6A is a hypomorphic polymorphic allele of the type I transforming growth factor beta receptor (TGFBR1). TGFBR1*6A is a candidate tumor susceptibility allele that has been associated with an increased incidence of various types of cancer. This study was undertaken to analyze all published case-control studies on TGFBR1*6A and cancer and determine whether TGFBR1*6A is associated with cancer.

Patients and Methods: All published case-control studies assessing the germline frequency of TGFBR1*6A were included. Studies assessing TGFBR1*6A in tumors were excluded. The results of seven studies comprising 2,438 cases and 1,846 controls were pooled and analyzed.

Results: Overall, TGFBR1*6A carriers have a 26% increased risk of cancer (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.07 to 1.49). Cancer risk for TGFBR1*6A homozygotes (OR, 2.53; 95% CI, 1.39 to 4.61) is twice that of TGFBR1*6A heterozygotes (OR, 1.26; 95% CI, 1.04 to 1.51). Analysis of various types of tumors shows that TGFBR1*6A carriers are at increased risk of developing breast cancer (OR, 1.48; 95% CI, 1.11 to 1.96), hematological malignancies (OR, 1.70; 95% CI, 1.13 to 2.54), and ovarian cancer (OR, 1.53; 95% CI, 1.07 to 2.17). Carriers of TGFBR1*6A who are from the United States are at increased risk of colorectal cancer (OR, 1.38; 95% CI, 1.02 to 1.86). However, Southern European TGFBR1*6A carriers have no increased colorectal cancer risk. There is no association between TGFBR1*6A and bladder cancer.

Conclusion: TGFBR1*6A is emerging as a highfrequency, low-penetrance tumor susceptibility allele that predisposes to the development of breast, ovarian, and colorectal cancer, as well as hematologic malignancies.
Cisplatin Plus Gemcitabine Versus a Cisplatin-Based Triplet Versus Nonplatinum Sequential Doublets in Advanced Non–Small-Cell Lung Cancer: A Spanish Lung Cancer Group Phase III Randomized Trial
Authors: Alberola V. , Camps C. , Provencio M. , Isla D. , Rosell R. , Vadell C. , Bover I. , Ruiz-Casado A. , Azagra P. , Jiménez U. , González-Larriba J.L. , Diz P. , Cardenal F. , Artal A. , Carrato A. , Morales S. , Sánchez J.J. , de las Peñas R. , Felip E. , López-Vivanco G.
Published: August 2003

Purpose: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non–small-cell lung cancer (NSCLC).

Patients and Methods: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV–VI).

Results: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV–VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV–VI, 27%; CG v GV–VI, P = .003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV–VI, 27%; P < .05); neutropenic fever (CG, 4%; CGV, 19%; GV–VI, 5%; P < .0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV–VI, 3%; P = .0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV–VI, 6%; P < .0001).

Conclusion: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.
Loss of p16 Expression Is of Prognostic Significance in Locally Advanced Prostate Cancer: An Analysis From the Radiation Therapy Oncology Group Protocol 86–10
Authors: Chakravarti A. , Heydon K. , Wu C.L. , Hammond E. , Pollack A. , Roach M. , Wolkov H. , Okunieff P. , Cox J. , Fontanesi J. , Abrams R. , Pilepich M. , Shipley W.
Published: August 2003

Purpose: The retinoblastoma (RB) cell cycle regulatory pathway is known to be deregulated in virtually all known human tumors. The protein product of the RB gene, pRB, and its upstream regulator, p16, are among the most commonly affected members of this pathway. We investigated the prognostic significance of both pRB and p16 expression in locally advanced prostate cancers, from patients treated on the Radiation Therapy Oncology Group (RTOG) protocol 86–10.

Materials and Methods: Sixty-seven cases from RTOG 86–10 had immunohistochemically stained slides, judged interpretable for both p16 and pRB, available for analysis. Median follow-up was 8.9 years (range, 6.0 to 11.8 years) for surviving patients. Staining for each marker was then correlated with overall survival, local progression, distant metastasis, and disease-specific survival.

Results: Loss of p16 expression, as defined by expression was significantly associated with reduced overall survival (P = .039), disease-specific survival (P = .006), and higher risk of local progression (P = .0007) and distant metastasis (P = .026) in the univariate analysis. In the multivariate analysis, loss of p16 was significantly associated with reduced disease-specific survival (P = .0078) and increased risk of local failure (P = .0035) and distant metastasis (P = .026). A borderline association with reduced overall survival (P = .07) was also evident. Loss of pRB was associated with improved disease-specific survival on univariate (P = .028) and multivariate analysis (P = .043), but carried no other significant outcome associations.

Conclusion: Loss of p16 is significantly associated with adverse clinical outcome in cases of locally advanced prostate cancer.
Identifying Psychosocial Risk Indicative of Subsequent Resource Use in Families of Newly Diagnosed Pediatric Oncology Patients
Authors: Kazak Anne E. , Cant M. Catherine , Jensen Merritt M. , McSherry Mary , Rourke Mary T. , Hwang Wei-Ting , Alderfer Melissa A. , Beele David , Simms Steven , Lange Beverly J.
Published: August 2003

Purpose: The primary purpose of this prospective study was to identify the level of risk for psychosocial distress in families of children newly diagnosed with cancer. Additional study aims were to examine concordance among family and staff reports of psychosocial risk, changes in risk status over time, and to predict the use of psychosocial resources during the first months of treatment.

Patients and Methods: Caregivers of 125 children newly diagnosed with cancer completed the Psychosocial Assessment Tool (PAT) at diagnosis (t1) and 3 to 6 months later (t2). Primary oncologists and nurses completed an analogous measure of perceived family psychosocial risk at t1 and t2. At t2, oncology social workers reported types and intensity of psychosocial interventions provided.

Results: The PAT identified three subsets of families who presented with increasing levels of psychosocial risk at diagnosis. In general, there was moderate concordance among family, oncologist, and nurse reports of psychosocial risk. PAT scores at t1 predicted t2 PAT scores and psychosocial resource use at t2 beyond demographic or disease factors.

Conclusion: A brief screening tool (PAT) is valuable in identifying psychosocial risk factors at diagnosis and is predictive of later use of psychosocial resources. As a next step in this research, the development of psychosocial interventions to match family risk level may be an effective and cost-efficient approach to working with families to address their concerns and promote short- and long-term adjustment.
A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field
Authors: Hochgreb Tatiana , Linhares Vania L. , Menezes Diego C. , Sampaio Allysson C. , Yan Chao Y. I. , Cardoso Wellington V. , Rosenthal Nadia , Xavier-Neto José
Published: September 2003

Establishment of anteroposterior (AP) polarity is one of the earliest decisions in cardiogenesis and plays an important role in the coupling between heart and blood vessels. Recent research implicated retinoic acid (RA) in the communication of AP polarity to the heart. We utilized embryo culture, in situ hybridization, morphometry, fate mapping and treatment with the RA pan-antagonist BMS493 to investigate the relationship between cardiac precursors and RA signalling. We describe two phases of AP signalling by RA,reflected in RALDH2 expression. The first phase (HH4-7) is characterized by increasing proximity between sino-atrial precursors and the lateral mesoderm expressing RALDH2. In this phase, RA signalling is consistent with diffusion of the morphogen from a large field rather than a single hot spot. The second phase (HH7-8) is characterized by progressive encircling of cardiac precursors by a field of RALDH2 originating from a dynamic and evolutionary-conserved caudorostral wave pattern in the lateral mesoderm. At this phase, cardiac AP patterning by RA is consistent with localized action of RA by regulated activation of the Raldh2 gene within an embryonic domain. Systemic treatment with BMS493 altered the cardiac fate map such that ventricular precursors were found in areas normally devoid of them. Topical application of BMS493 inhibited atrial differentiation in left anterior lateral mesoderm. Identification of the caudorostral wave of RALDH2 as the endogenous source of RA establishing cardiac AP fates provides a useful model to approach the mechanisms whereby the vertebrate embryo confers axial information on its organs.
Deformation Behavior of Aluminum Bicrystals
Authors: Kuo J.C. , Zaefferer S. , Zhao Z. , Winning M. , Raabe D.
Published: August 2003

Grain boundaries are natural obstacles to motion and dislocations during plastic straining of crystalline matter; therefore, they deserve closer investigation. Here, the deformation behavior of an aluminum bicrystal is described. The specimen was compressed in a channel die to 30 % engineering thickness reduction at room temperature. The crystal orientations were determined by electron backscatter diffraction (EBSD) and the plastic strain distribution was measured by photogrammetry. It was found that the two abutting crystals close to the grain boundary rotate towards each other, whereas the grain interiors increase their mutual misorientation during plastic loading.
High‐Resolution EBSD Investigation of Deformed and Partially Recrystallized IF Steel
Authors: Thomas I. , Zaefferer S. , Friedel F. , Raabe D.
Published: August 2003

The recrystallization behavior of titanium‐alloyed interstitial free steel has been investigated by means of high‐resolution ESBD measurements and TEM observations. The cold rolled material exhibits three types of microstructures characterized by their orientations and internal local misorientations, with nucleation starting from γ‐fiber but as well from other orientations. On comparison with TEM (see Figure for a TEM image of a 94 % cold‐rolled Fe‐36 % Ni sheet), the capability of ESBD for the observation of subgrain structures appears to be somewhat limited.
Automated Evaluation of Kikuchi Patterns by Means of Radon and Fast Fourier Transformation, and Verification by an Artificial Neural Network
Authors: Schwarzer R.A. , Sukkau J.
Published: August 2003

Automated crystal orientation measurement (ACOM) in the SEM by interpreting backscatter Kikuchi patterns (see Figure) has become a standard tool of quantitative texture analysis in materials science during the last decade. A Radon transformation of the diffraction pattern, in combination with a 1D fast Fourier transformation, enables the fast extraction of the positions of Kikuchi bands. The high‐frequency coefficients of the 1D FFT are used to define pattern quality as a measure of lattice imperfection and residual stress of the real crystal structure.
Measurement of In‐Grain Orientation Gradients by EBSD and Comparison with Finite Element Results
Authors: Delannay L. , Logé R.E. , Chastel Y. , Signorelli J.W. , Van Houtte P.
Published: August 2003

EBSD orientation mapping over large sample areas (see Figure for a close‐up of three grains extracted from an orientation map) gives the basis data for a statistical evaluation on orientation gradients developed within grains of a cold‐rolled aluminum plate. This data set serves as a counterpart for finite‐element simulations for checking whether the orientation gradients observed can be attributed to the interaction of adjacent grains. Although the tendency of the simulations fits the experiment, the amplitude of the orientation spread is always underestimated, whatever the initial orientation of grains.
Recrystallization and Texture in a Ferritic Stainless Steel: an EBSD Study
Authors: Sinclair C.W. , Robaut F. , Maniguet L. , Mithieux J.‐D. , Schmitt J.‐H. , Brechet Y.
Published: August 2003

The recrystallization behavior of laboratory‐processed AISI409 ferritic stainless steel sheet has been studied with a focus on texture inhomogeneity and “sluggish” recrystallization kinetics, mainly using EBSD in the scanning electron microscope. Pronounced texture gradients were observed in some grain orientations (see Figure for a TEM image of the α versus γ‐grain border region) and correlated to the deformation‐induced substructure. The strong pinning of some boundaries has been linked not only to textural effects, but also to the precipitation of fine titanium carbonitrides.
Texture and Microtexture Evolution in an Ultra‐Low Carbon Steel During Recrystallization
Authors: Novillo E. , Petite M.M. , Bocos J.L. , Iza‐Mendia A. , Gutiérrez I.
Published: August 2003

Recrystallization texture and microtexture in a cold‐rolled ultra‐low‐carbon steel was investigated using X‐ray diffraction and electron‐back‐scattered diffraction based orientation imaging microscopy (ESBD/OIM). Special emphasis was put on the grain coarsening of various texture components during recrystallization: grain selection with an excess in size and number of {111} recrystallized grains was observed (see Figure), generating in the final stages of recrystallization a strong γ‐fibre that results in good drawing properties.
Investigation of the Correlation between Texture and Microstructure on a Submicrometer Scale in the TEM
Authors: Zaefferer S.
Published: August 2003

In recent years the investigation of local texture and microstructure by analysis of electron backscatter diffraction patterns (EBSP) in the SEM has become a very powerful and popular method. With the introduction of SEM with field emission guns (FEG) the spatial resolution of EBSP measurements could be enhanced from 500 nm with a tungsten emitter to better than 50 nm. This evolution of SEM techniques raises the question whether transmission electron microscopy (TEM) still has fields of application in texture research. The present article answers this question with a clear “yes” and presents three examples of investigations where TEM is indispensable. The three examples comprise the investigation of the correlation between dislocation structure and deformation texture, a study on nucleation mechanisms of recrystallization in highly deformed metals and the investigation of microtexture and microstructure in nanocrystalline materials. Together with the presentation of these cases some of the necessary measurement techniques are described briefly. It is shown that TEM has to be applied when highest spatial resolution of orientation determination and imaging and high accuracy of orientation determination are to be reached, when the three‐dimensional and quantitative characterization of lattice defects is required or when materials with a high density of lattice defects are to be investigated.
Effects of a High Magnetic Field on Microstructure and Texture Evolution in a Cold‐rolled Interstitial‐Free (IF) Steel Sheet during Annealing
Authors: He C.S. , Zhang Y.D. , Zhao X. , Zuo L. , He J.C. , Watanabe K. , Zhang T. , Nishijima G. , Esling C.
Published: August 2003

Crystal nuclei with the {hkl}<110> orientations are energetically favored in annealing of cold‐rolled steel under a strong magnetic field. This might explain the enhancement of the α‐fiber in during this process at 650 °C (see Figure for a juxtaposition of microstructures obtained at 10T (top) and without a magnetic field (bottom). Texture evolution during recrystallization above 650 °C also appears to be influenced, yet not by a change in the recrystallization mechanism but rather by an additional orientation‐dependent nucleation and grain growth process.
Microstructural Characteristics by EBSD and ECC in ECAE Processed Pure Cu Samples
Authors: Wang G. , Wu S.D. , Esling C. , Li G.Y. , Zuo L. , Wang Z.G.
Published: August 2003

The preferred sites for nucleation of recrystallization grains on pure copper samples processed by equal‐channel angular extrusion (ECAE) are the intersections of shear bands. This was shown using EBSP and electron‐channeling contrast (ECC) techniques of scanning electron microscopy. The characteristics of the distribution of grain boundaries, GB properties in ultrafine polycrystals, and low melting point of Cu enable the growth of recrystallization nuclei at room temperature (see Figure for an example of orientation formation after two months at RT).