bluuebunny/crossref_metadata_2025 huggingface dataset:
Intensive Therapy With Growth Factor Support for Patients With Ewing Tumor Metastatic at Diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457—A Report From the Children's Oncology Group
Authors: Bernstein Mark L. , Devidas Meenakshi , Lafreniere Dominique , Souid Abdul-Kader , Meyers Paul A. , Gebhardt Mark , Stine Kimo , Nicholas Richard , Perlman Elizabeth J. , Dubowy Ronald , Wainer Irving W. , Dickman Paul S. , Link Michael P. , Goorin Allen , Grier Holcombe E.
Published: December 2005

Purpose

Prognosis is poor for Ewing sarcoma patients with metastasis at diagnosis. We intensified a five-drug therapy (ifosfamide, etoposide alternated with vincristine, doxorubicin, and cyclophosphamide) using filgrastim but not stem-cell support. We studied topotecan alone and combined with cyclophosphamide in therapeutic windows before the five-drug therapy. A randomly assigned proportion of patients received amifostine as a cytoprotective agent.

Patients and Methods

Eligible patients were ≤ 30 years old and had histologically proven Ewing sarcoma or primitive neuroectodermal tumor (PNET) and metastasis at diagnosis. Chemotherapeutic cycles began every 21 days, after recovery from toxicities.

Results

One hundred ten of the 117 patients enrolled were eligible. Thirty-six patients received initial topotecan. Three had partial responses (PRs), and 17 had progressive disease (PD). Thirty-seven patients were administered topotecan and cyclophosphamide; 21 of these patients achieved PR, and one patient had PD. In a randomly assigned group of 69 patients, amifostine did not provide myeloprotection, which was measured by absolute neutrophil count, platelet count, or cycle intervals. The best responses to the overall therapy included 45 complete responses, 41 PRs, stable disease in 14 patients, and PD in five patients. For all patients, the 2-year event-free survival (EFS) rate was 24% (± 4%), and the overall survival rate was 46% (± 5%). For the 39 patients with isolated pulmonary metastases, the 2-year EFS rate was 31% (± 7%) compared with 20% (± 5%) for patients with more widespread disease.

Conclusion

Topotecan had limited activity in patients with Ewing sarcoma or PNET metastatic at diagnosis. The topotecan-cyclophosphamide combination was active. Amifostine was not myeloprotective. Overall results showed no improvement compared with previous studies.
Successful Chemotherapeutic Modality of Doxorubicin Plus Dacarbazine for the Treatment of Desmoid Tumors in Association With Familial Adenomatous Polyposis
Authors: Gega Makoto , Yanagi Hidenori , Yoshikawa Reigetsu , Noda Masafumi , Ikeuchi Hiroki , Tsukamoto Kiyoshi , Oshima Tsutomu , Fujiwara Yoshinori , Gondo Nobuhisa , Tamura Kazuo , Utsunomiya Joji , Hashimoto-Tamaoki Tomoko , Yamamura Takehira
Published: December 2005

Purpose

Desmoid tumors are locally aggressive and can be fatal in familial adenomatous polyposis (FAP) patients if they are not suitable for surgery or radiation therapy. Here, we prospectively investigated the efficacy of a chemotherapeutic regimen involving doxorubicin (DOX) and dacarbazine (DTIC) for inoperable FAP-associated desmoid tumors.

Patients and Methods

From an initial group of 120 FAP patients, seven of the 11 individuals with symptomatic unresectable desmoid tumors that were unresponsive to conventional hormone therapy were enrolled onto this study. The general chemotherapy regimen comprised four or five cycles of DOX (20 mg/m2 daily) plus DTIC (150 mg/m2 daily) throughout 4 days of drip intravenous infusion (day 1 through 4) every 28 days, followed by the cyclooxygenase–2 inhibitor meloxicam (10 mg/m2). The primary end point was relapse-free survival. The secondary end points included toxicity, clinical improvement, and tumor regression according to computed tomography.

Results

Significant tumor regression was observed clinically and radiologically in all seven patients. Three patients showed a complete response. The average progression-free survival period was 74.0 months (range, 32.5 to 107.5 months). Three patients showed grade 3 adverse events with no treatment-related mortality. All seven patients survived and remained without tumor progression. An adenomatous polyposis coli germline–mutation analysis revealed no mutations in the specified regions.

Conclusion

A chemotherapeutic regimen of DOX plus DTIC followed by meloxicam is an effective and safe treatment for FAP-associated desmoid tumors. This modality should be considered for use as first-line chemotherapy in symptomatic desmoid tumors that are unresponsive to conventional medical therapy, due to the absence of useful presymptomatic markers.
ΔTAp73 Upregulation Correlates With Poor Prognosis in Human Tumors: Putative In Vivo Network Involving p73 Isoforms, p53, and E2F-1
Authors: Domínguez Gemma , García José M. , Peña Cristina , Silva Javier , García Vanesa , Martínez Lara , Maximiano Constanza , Gómez María E. , Rivera José A. , García-Andrade Carmen , Bonilla Felix
Published: December 2005

Purpose

Although full-length TAp73 variants largely mimic p53 suppressor activities, the transactivation-deficient transcripts ΔTAp73 exert an oncogenic effect by inactivating p53 and TAp73 suppressor properties. Additionally, ΔTAp73 may cooperate with oncogenic RAS to induce cell transformation, confer drug resistance, and induce the phosphorylation of phosphorylated Rb. Here, we study the expression of TAp73 and ΔTAp73 variants and assess possible associations with E2F-1, p53 and K-ras status. We address the possible clinical relevance of alterations in these genes.

Patients and Methods

We determine in 113 colon and 60 breast cancer patients (a) the expression levels of TAp73, ΔTAp73 (ΔEx2p73, ΔEx2/3p73, and ΔNp73), and E2F-1 transcripts by quantitative real-time reverse transcriptase polymerase chain reaction (PCR); (b) mutations in the first exon of K-ras by PCR–single-stranded confirmational polymorphism; and (c) p53 status by immunohistochemistry. Tumor characteristics were examined in each patient.

Results

Both suppressor and oncogenic isoforms of TP73 were significantly coupregulated in tumor tissues. Associations were observed between (a) p53 wild type status and upregulation of some TP73 variants; (b) overexpression of E2F-1 and some TP73 forms; and (c) upregulation of ΔTAp73 variants and advanced pathologic stage, lymph node metastasis, vascular invasion, presence of polyps, and tumor localization.

Conclusion

Overexpression of TP73 variants in tumor tissues indicates that they may be involved in colon and breast carcinogenesis. The association between upregulation of ΔTAp73 isoforms and poor prognosis features, specifically advanced tumor stage, suggests that they may be of practical clinical prognostic value. Interestingly, the in vivo associations identified here may indicate a functional network involving p73 variants, p53, and E2F-1.
Preliminary Results on Safety and Activity of a Randomized, Double-Blind, 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in Premenopausal Women
Authors: Guerrieri-Gonzaga Aliana , Robertson Chris , Bonanni Bernardo , Serrano Davide , Cazzaniga Massimiliano , Mora Serena , Gulisano Marcella , Johansson Harriet , Formelli Franca , Intra Mattia , Latronico Antuono , Franchi Dorella , Pelosi Giuseppe , Johnson Karen , Decensi Andrea
Published: December 2005

Purpose

To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety.

Patients and Methods

Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events.

Results

Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk ≥ 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms.

Conclusion

The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.
Radiotherapy As Primary Treatment for Stage IE and IIE Nasal Natural Killer/T-Cell Lymphoma
Authors: Li Ye-Xiong , Yao Bo , Jin Jing , Wang Wei-Hu , Liu Yue-Ping , Song Yong-Wen , Wang Shu-Lian , Liu Xin-Fan , Zhou Li-Qiang , He Xiao-Hui , Lu Ning , Yu Zi-Hao
Published: December 2005

Purpose

The optimal therapy remains unclear for nasal natural killer (NK)/T–cell lymphoma. The purpose of this study is to analyze the outcome of radiotherapy as the primary treatment for localized stage IE and IIE diseases.

Patients and Methods

One hundred five patient cases were reviewed. There were 83 stage IE and 22 stage IIE patients. All except three patients received radiotherapy (RT) alone or RT combined with chemotherapy (CT; combined-modality therapy [CMT]). Overall, 31 patients were treated with RT alone, 34 with RT followed by CT, 37 with CT followed by RT, and three with CT alone.

Results

Five-year overall survival (OS) and progression-free survival (PFS) for all patients were 71% and 59%, respectively. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. Complete response (CR) was achieved in 91 patients (87%) after RT and/or CT. Initial RT resulted in a superior CR as compared with initial CT, with 54 (83%) of 65 patients achieving CR with initial RT, versus only eight (20%) of 40 after initial CT. For 102 patients who received RT with or without CT, the outcome of primary treatment with RT alone was compared with that of CMT. Five-year OS and PFS was 66% and 61% for RT alone, and 76% and 61%% for CMT, respectively (OS, P = .6433; PFS, P = .8391).

Conclusion

RT as primary therapy resulted in good outcome in early-stage disease, and the addition of CT to RT was not accompanied by an improvement in survival.
Salvage Radioimmunotherapy With Murine Iodine-131–Labeled Antitenascin Monoclonal Antibody 81C6 for Patients With Recurrent Primary and Metastatic Malignant Brain Tumors: Phase II Study Results
Authors: Reardon David A. , Akabani Gamal , Coleman R. Edward , Friedman Allan H. , Friedman Henry S. , Herndon James E. , McLendon Roger E. , Pegram Charles N. , Provenzale James M. , Quinn Jennifer A. , Rich Jeremy N. , Vredenburgh James J. , Desjardins Annick , Guruangan Sri , Badruddoja Michael , Dowell Jeanette M. , Wong Terence Z. , Zhao Xiao-Guang , Zalutsky Michael R. , Bigner Darell D.
Published: December 2005

Purpose

To assess the efficacy and toxicity of intraresection cavity iodine-131–labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients.

Patients and Methods

In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy.

Results

With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis.

Conclusion

In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.
Antibody Pretargeting Advances Cancer Radioimmunodetection and Radioimmunotherapy
Authors: Goldenberg David M. , Sharkey Robert M. , Paganelli Giovanni , Barbet Jacques , Chatal Jean-François
Published: December 2005

This article reviews the methods of pretargeting, which involve separating the targeting antibody from the subsequent delivery of an imaging or therapeutic agent that binds to the tumor-localized antibody. This provides enhanced tumor:background ratios and the delivery of a higher therapeutic dose than when antibodies are directly conjugated with radionuclides, as currently practiced in cancer radioimmunotherapy. We describe initial promising clinical results using streptavidin-antibody constructs with biotin-radionuclide conjugates in the treatment of patients with malignant gliomas, and of bispecific antibodies with hapten-radionuclides in the therapy of tumors expressing carcinoembryonic antigen, such as medullary thyroid and small-cell lung cancers.
Neuroendocrine Neoplasms of the Lung: A Prognostic Spectrum
Authors: Asamura Hisao , Kameya Toru , Matsuno Yoshihiro , Noguchi Masayuki , Tada Hirohito , Ishikawa Yuichi , Yokose Tomoyuki , Jiang Shi-Xu , Inoue Takeshi , Nakagawa Ken , Tajima Kinuko , Nagai Kanji
Published: December 2005

Purpose

Neuroendocrine (NE) tumors of the lung include typical carcinoid (TC), atypical carcinoid (AC), large-cell NE carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). Their clinicopathologic profiles and relative grade of malignancy have not been defined.

Patients and Methods

From 10 Japanese institutes, 383 surgically resected pulmonary NE tumors were collected. The histologic diagnosis was determined by the consensus of a pathology panel consisting of six expert pathologists as TC, AC, LCNEC, or SCLC on the basis of the WHO classification, and its relationship to clinicopathologic profiles was analyzed.

Results

Of the 383 tumors, 18 were excluded because of an improper specimen. The pathology panel reviewed the remaining 366 tumors, and a diagnosis of NE tumor was made in 318 patients (87.4%); 55 patients had TC, nine had AC, 141 had LCNEC, and 113 had SCLC. The 5-year survival rates of patients with all stages were as follows: 96.2% for TC, 77.8% for AC, 40.3% for LCNEC, and 35.7% for SCLC. There was significant prognostic difference between TC and AC as well as between AC and LCNEC+SCLC. However, there was no difference between LCNEC and SCLC, and their survival curves were superimposed. The multivariate analysis indicated that histologic type, completeness of resection, symptoms, nodal involvement, and age were significantly prognostic.

Conclusion

The grade of malignancy of NE tumors was upgraded in the following order: TC, AC, LCNEC, and SCLC. No prognostic difference was noted between LCNEC and SCLC. The high-grade NE histology uniformly indicated poor prognosis regardless of its histologic type.
Extranodal Natural Killer T-Cell Lymphoma, Nasal-Type: A Prognostic Model From a Retrospective Multicenter Study
Authors: Lee Jeeyun , Suh Cheolwon , Park Yeon Hee , Ko Young H. , Bang Soo Mee , Lee Jae Hoon , Lee Dae Ho , Huh Jooryung , Oh Sung Yong , Kwon Hyuk-Chan , Kim Hyo Jin , Lee Soon Il , Kim Jung Han , Park Jinny , Oh Seok Joong , Kim Kihyun , Jung Chulwon , Park Keunchil , Kim Won Seog
Published: December 2005

Purpose

Patients with natural killer T (NK/T) -cell lymphomas have poor survival outcome, and for this condition there is no optimal therapy. The purpose of this study was to design a prognostic model specifically for extranodal NK/T-cell lymphoma, which can identify high-risk patients who need more aggressive therapy.

Patients and Methods

This multicenter retrospective study was comprised of 262 patients who were diagnosed with NK/T-cell lymphoma.

Results

After a median follow-up duration of 51.2 months, 5-year overall survival rate in 262 patients was 49.5%. Prognostic factors for survival were “B” symptoms (P = .0003; relative risk, 2.202; 95% CI, 1.446 to 3.353), stage (P = .0006; relative risk, 2.366; 95% CI, 1.462 to 3.828), lactate dehydrogenase (LDH) level (P = .0005; relative risk, 2.278; 95% CI, 1.442 to 3.598), and regional lymph nodes (P = .0044; relative risk, 1.546; 95% CI, 1.009 to 2.367). Of 262 patients, 219 had complete information on four parameters. We identified four different risk groups: group 1, no adverse factor; group 2, one factor; group 3, two factors; and group 4, three or four factors. The new model showed a superior prognostic discrimination as compared with the International Prognostic Index (IPI). Notably, the distribution of patients was balanced when a new model was adopted (group 1, 27%; group 2, 31%; group 3, 20%; group 4, 22%), whereas 81% of patients were categorized as low or low-intermediate risks using IPI.

Conclusion

The newly proposed model for extranodal NK/T-cell lymphoma demonstrated a more balanced distribution of patients into four groups with better prognostic discrimination as compared with the IPI.
Control of a Permanent Magnet Synchronous Motor Using a Second-Order Non-Linear Trajectory Smoother
Authors: Tsang K M , Wang J
Published: December 2005

A second-order non-linear discrete trajectory smoother is coupled with conventional control law for servo-control of permanent magnet synchronous motors (PMSMs). Conventional control relies on three closed loops with linear proportional-integral-derivative (PID) controllers and gives an undesirable performance under the mismatch. of system parameters and load conditions. To overcome this drawback, a discrete-time second-order non-linear trajectory smoother is applied for the control of a PMSM. The second-order non-linear trajectory smoother is a non-linear variable structure system (VSS) catering for smooth trajectory generation for a motion control system. The trajectory smoother guarantees robustness against a change of system parameters and load conditions. Simulation and experimental studies are included to demonstrate the effectiveness of the proposed control scheme.
Application of Robust Chattering-Reduction Sliding Mode Control Techniques for Position Control of a Vector-Controlled Induction Machine with Non-Linear Friction Dynamics
Authors: Goh K B , Dunnigan M W , Williams B W
Published: December 2005

Sliding mode control (SMC) methods possess several advantageous properties such as robustness against parameter variation, disturbance rejection, straightforward design, and are simple to implement. In this paper, a sliding mode control algorithm (which considers the non-linear friction dynamics) based on an equivalent control technique is designed and implemented on a non-linear induction machine system with non-linear friction dynamics such as Coulomb, windage, Stribeck, and static friction. The chattering phenomenon, which is inherent in the standard sliding mode algorithm, is discussed, as well as the techniques to reduce the chattering effect. A sixth-order non-linear induction machine model is employed for simulation analysis. The developed control algorithms are then tested for position control of a practical vector-controlled induction machine, in three different operating conditions (nominal load, high inertial load, and rotor resistance mismatch). The controller performance results are compared practically with several different sliding mode control algorithms as well as with a fixed-gain controller test.
Modified Bilinear Integration Algorithm Based on the Modulated Sine Function
Authors: Liu Fu-Hwa , Chen Cheun-Ming
Published: December 2005

This study presents a novel discretization method for converting an analogue controller into its corresponding counterpart for a discrete-time system. The proposed method is appropriate for the natural response curve and, thus, is more effective for certain digitally redesigned systems. Based on the mapping region of the transformation using the proposed method from the s-domain to the z-domain, a transformation involving a modulated parameter n is used to generate a corresponding stable discrete-time controller for a stable continuous-time controller. As a suitable modulated parameter in the proposed transformation is selected to digitalize an analogue-controlled system, the new sampled-data-controlled system achieves a precise discrete-time response, and can also tolerate a large sampling period for sample-data implementation. A simulated example is used to demonstrate the results.
Remote Control of a Moving Platform and Its Applications
Authors: Wang Ming-Shyan , Lee Jing , Chen Jian-Hao
Published: December 2005

The paper introduces a motion simulation, monitoring, and controlling system based on a three-degree-of-freedom (3DOF) motion platform, stereographic display, and network communication. Proportional-integral-derivative (PID) and fuzzy logic (FL) controllers are applied to control the motion platform and to compare their control qualities with each other. Two applications of the present system are demonstrated. One is a car simulator, in which the motion platform simulates the behaviour of a car running on the road. The other one is an animated virtual reality (VR) remote control system. By cooperating with real-time virtual scene reconstruction, users can remotely monitor and control the motion platform in real-time.
Active Control of Dynamic Platforms
Authors: Rieger K , Bouazza-Marouf K
Published: December 2005

The control of a dynamic platform system for offshore operations in adverse weather conditions is discussed in this paper. The aim is to control the deck of the dynamic platform system to remain stationary irrespective of displacement-type base disturbances and force/ torque-type deck disturbances. Two control schemes based on the principle of invariance are described. Open-loop control, with drift cancellation, is implemented for the heave (vertical) motion, which is not always possible to obtain in practical systems. An experimental rig has been used to investigate and validate simulation results. Good simulation and experimental results have been obtained.
Catatonic Schizophrenia and the Use of Memantine
Authors: Carpenter Stacey S , Hatchett A Daniel , Fuller Matthew A
Published: December 2005

Objective:

To report a case of catatonic schizophrenia treated with memantine that resulted in a rapid reduction of catatonic symptoms.

Case Summary:

A 68-year-old male with catatonic schizophrenia presented with bizarre and catatonic behavior manifested by mutism, waxy flexibility, immobility, staring, nonresponsiveness to verbal commands, grimacing, rigidity, and posturing. During the course of his hospitalization, he was treated with memantine up to 10 mg/day. The catatonia responded rapidly and significantly to memantine.

Discussion:

Few treatment options are available for the management of catatonia. Lorazepam is generally the agent that has been used most often and has had varying degrees of success. Our report adds to a recently published case that also suggested that memantine might be useful for the management of catatonic behaviors in a patient with schizophrenia. While its mechanism of action is unknown, it has been thought that glutamate antagonists, such as memantine, may be beneficial in catatonic schizophrenia due to a glutamatergic dysfunction present in catatonic patients. It also has been hypothesized that there is a decrease in γ-aminobutyric acid released to the supplementary motor areas, resulting in less glutamate inhibition. This results in a net effect of glutamatergic hyperfunction in the striatum, which may produce catatonia. Based on this hypothesis, memantine would be beneficial as an N-methyl-D-aspartic acid antagonist to decrease the amount of glutamate in the striatum and thereby relieve symptoms of catatonia. However, these potential benefits must be weighed against recently reported adverse reactions associated with memantine use, namely, psychosis and seizures.

Conclusions:

Memantine produced a rapid and significant reduction in catatonic symptoms in our patient with catatonic schizophrenia.
Analysis of Severe Adverse Events Related to the Use of Mifepristone as an Abortifacient
Authors: Gary Margaret M , Harrison Donna J
Published: December 2005

Background:

The systematic analysis of morbidity and mortality for the Food and Drug Administration (FDA)-approved medical abortion regimen using mifepristone is possible using data from the FDA's Adverse Event Reporting System.

Objective:

To assess mifepristone's mortality, morbidity, sentinel events, and quality of postmarketing surveillance using mifepristone adverse event reports (AERs).

Methods:

Six hundred seven unique mifepristone AERs submitted to the FDA over a 4 year span were coded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Coding was based only on data in AERs and may underestimate severity and treatment rendered. Two board-certified obstetrician/gynecologists, the authors, made individual evaluations, compared them, and agreed upon final coding.

Results:

The most frequent AERs were hemorrhage (n = 237) and infection (66). Hemorrhages included 1 fatal, 42 life threatening, and 168 serious cases; 68 required transfusions. Infections included 7 cases of septic shock (3 fatal, 4 life threatening) and 43 cases requiring parenteral antibiotics. Surgical interventions were required in 513 cases (235 emergent, 278 nonemergent). Emergent cases included 17 ectopic pregnancies (11 ruptured). Second trimester viability was documented in 22 cases (9 lost to follow-up, 13 documented fetal outcome). Of the 13 documented cases, 9 were terminated without comment on fetal morphology, 1 was enrolled in fetal registry, and 3 fetuses were diagnosed with serious malformations, suggesting a malformation rate of 23%.

Conclusions:

Hemorrhage and infection are the leading causes of mifepristone-related morbidity and mortality. AERs relied upon by the FDA to monitor mifepristone's postmarketing safety are grossly deficient due to extremely poor quality.
Evaluation of pituitary function in the fatigued patient: a review of 59 cases
Authors: Greenfield Jerry R , Samaras Katherine
Published: December 2005

Objective: The aim of this study was to review the results of dynamic pituitary testing in patients presenting with fatigue.

Methods: We reviewed clinical histories and insulin tolerance test (ITT) results of 59 patients who presented with fatigue and other symptoms of glucocorticoid insufficiency over a 4-year period. All patients referred for ITT had an early-morning cortisol level of <400 nM and a low or normal ACTH level.

Results: Peak cortisol and GH responses following insulin-induced hypoglycaemia were normal in only seven patients (12%). Median age of the remaining 52 patients was 47 years (range, 17–67 years); all but five were female. Common presenting symptoms were neuroglycopaenia (n= 47), depression (n= 37), arthralgia and myalgia (n= 28), weight gain (n= 25), weight loss (n= 9), postural dizziness (n= 15) and headaches (n= 13). Other medical history included autoimmune disease (n= 20; particularly Hashimoto’s thyroiditis, Graves’ disease and coeliac disease), postpartum (n= 8) and gastrointestinal (n= 2) haemorrhage and hyperprolactinaemia (n= 13). 31 subjects had peak cortisol levels of <500 nM (suggestive of ACTH deficiency; 18 of whom had levels < 400 nM) and a further six had indeterminate results (500–550 nM). The remaining 15 subjects had normal cortisol responses (median 654 nM; range, 553–1062 nM) but had low GH levels following hypoglycaemic stimulation (5.9 mU/l; 3–11.6 mU/l).

Conclusion: Our results suggest that patients presenting with fatigue and symptoms suggestive of hypocortisolism should be considered for screening for secondary adrenal insufficiency, particularly in the presence of autoimmune disease or a history of postpartum or gastrointestinal haemorrhage. Whether physiological glucocorticoid replacement improves symptoms in this patient group is yet to be established.
Adiponectin and the development of diabetes in patients with coronary artery disease and impaired fasting glucose
Authors: Knobler Hilla , Benderly Michal , Boyko Valentina , Behar Shlomo , Matas Zipora , Rubinstein Ardon , Raz Itamar , Wainstein Julio
Published: December 2005

Objectives: Adiponectin has insulin-sensitizing properties, and high adiponectin levels have been shown to be associated with reduced risk of developing diabetes. Patients with coronary artery disease (CAD) have relatively low adiponectin levels and high prevalence of glucose intolerance. The role of adiponectin in predicting the development of diabetes in this high-risk group has not been determined. The study aimed to determine whether baseline adiponectin levels predict the development of diabetes in a group of patients with CAD and impaired fasting glucose (IFG).

Methods: A total of 588 patients who participated in the Bezafibrate Infarction Prevention (BIP) study and who had at baseline fasting glucose of 100–125 mg/dl were included and followed for 6.2±1.3 years. Adiponectin was determined in frozen plasma samples taken at baseline.

Results: Of the patients with IFG at baseline, 256 (44%) developed diabetes during follow-up. The patients who developed diabetes had at baseline higher body-mass index, fasting glucose, C-reactive protein, triglycerides, homeostatic assessment of insulin resistance (HOMA-IR) and diastolic blood pressure than patients who did not develop diabetes. Adiponectin levels at baseline were significantly lower in patients who developed diabetes than in patients who did not develop diabetes (P = 0.009, nonparametric Kruskall–Wallis test). An increase of 1 unit of natural logarithm of adiponectin level was associated with a hazard ratio of 0.77 (95% CI, 0.61–0.96) for diabetes development.

Conclusion: Patients with CAD and IFG have a very high rate of conversion to type 2 diabetes. Even in this high-risk group, high adiponectin levels are associated with reduced risk of developing diabetes.
Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty
Authors: Carel Jean-Claude , Blumberg Joëlle , Seymour Christine , Adamsbaum Catherine , Lahlou Najiba , _ _
Published: December 2005

Objective: Depot GnRH agonists are commonly used in the treatment of central precocious puberty (CPP). The triptorelin 11.25 mg 3-month depot, currently used in adult indications, had not previously been evaluated in CPP.

Design: This was a multicenter, open-label, 12 month trial conducted in 64 CPP children (54 girls and 10 boys), treated quarterly.

Methods: Children with a clinical onset of pubertal development before the age of 8 years (girls) or 9 years (boys), pubertal response of LH to GnRH ≥7 IU/l, advanced bone age >1 year, enlarged uterus (≥36 mm) and testosterone level ≥0.5 ng/ml (boys), were included. Suppression of gonadotropic activation, as determined from serum LH, FSH, estradiol or testosterone, and pubertal signs were assessed at Months 3, 6 and 12.

Results: GnRH-stimulated peak LH ≤3 IU/l, the main efficacy criterion, was met in 53 out of 62 (85%), 60 out of 62 (97%) and 56 out of 59 (95%) of the children at Months 3, 6 and 12 respectively. Serum FSH and sex steroids were also significantly reduced, while pubertal development regressed in most patients. Mean residual triptorelin levels were stable from Month 3 through to Month 12. The triptorelin 3-month depot was well tolerated. Severe injection pain was experienced in only one instance. Five girls experienced mild-to-moderate or severe (one girl) withdrawal bleeding.

Conclusions: The triptorelin 3-month depot efficiently suppresses the pituitary–gonadal axis and pubertal development in children with CPP. This formulation allows a 3-fold reduction, over the once-a-month depot, in the number of i.m. injections required each year.
Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis of PCOS
Authors: Carmina E , Napoli N , Longo R A , Rini G B , Lobo R A
Published: December 2005

Objective: Metabolic syndrome (MBS) is a common disorder and is thought to be extremely prevalent in polycystic ovary syndrome (PCOS). In the USA the prevalence of MBS in PCOS has been reported to be as high as 43–46% using Adult Treatment Panel III (ATP-III) criteria. Because of differences in diet, lifestyle and genetic factors, we postulated that the prevalence of MBS might not be as high in Italian women. This study sought to determine the prevalence of MBS in Italian women using both the ATP-III and the World Health Organization (WHO) criteria and to determine whether the prevalence is influenced by the way in which PCOS is diagnosed.

Design: Assessment of the prevalence of MBS in 282 women with PCOS, aged 18–40 years, living in western Sicily. Eighty-five age- and weight-matched normal women served as controls.

Methods: Patients were divided into those with chronic anovulation and hyperandrogenism (classic PCOS; n = 225) and others with hyperandrogenism and polycystic ovaries but who were ovulatory (ovulatory PCOS; n = 57). A 75 g oral glucose tolerance test was carried out, as were lipid determinations; insulin resistance was assessed by the Quantitative Insulin-Sensitivity Check Index (QUICKI). We used ATP-III and WHO criteria to diagnose MBS.

Results: Using ATP-III criteria, the prevalence of MBS was 8.2% and using WHO criteria it was 16% in Italian women with PCOS. In controls, the prevalence was 2.4% using both methods. In classic PCOS patients, MBS was higher (8.9% by ATP-III, 17.3% by WHO) than in ovulatory PCOS (5% and 10.6% respectively). Body weight significantly modified prevalence rates.

Conclusion: MBS is substantially higher in women with PCOS than in the general population, and the prevalence is higher in those women diagnosed by classic criteria. However, the prevalence of MBS in PCOS appears to be much lower in Italy than in the USA.
Hormone replacement therapy and mortality in 52- to 70-year-old women: the Kuopio Osteoporosis Risk Factor and Prevention Study
Authors: Pentti Kati , Honkanen Risto , Tuppurainen Marjo T , Sandini Lorenzo , Kröger Heikki , Saarikoski Seppo
Published: December 2005

Objectives: To analyze prospectively the association between hormone replacement therapy (HRT) and mortality in women before old age.

Design and methods: A group of 11 667 women (91% of the age cohort of the area) aged 52–62 years from the population-based Kuopio Osteoporosis Risk Factor and Prevention Study were followed for 7 years in 1994–2001. Information about HRT use and health events was obtained from two repeated questionnaires in 1989 and 1994. Information about deaths and causes of death from the follow-up period was obtained from the Statistics Finland. Cox’s proportional-hazards models were used to calculate risk of death related to the use of HRT.

Results: At the start of follow-up, 2203 women had used HRT >5 years, 3945 women ≤5 years and 5519 women had never used it. During the follow-up, 361 deaths occurred. Compared with non-users of HRT, the adjusted hazard ratio (HR) of death from any cause was 1.05 (95% confidence interval (CI) 0.80–1.36) in women who used HRT ≤5 years and 1.06 (95% CI 0.78–1.46) in women who used HRT >5 years. The adjusted HR for coronary heart disease (CHD) mortality in women who used HRT ≤5 years was 0.79 (95% CI 0.36–1.73), and in women who used HRT >5 years, 2.16 (95% CI 0.93–4.98). For breast cancer mortality the adjusted HR for ≤5 years of HRT use was 0.96 (95% CI 0.32–2.82) and 2.62 (95% CI 0.98–7.00) for >5 years of HRT use.

Conclusions: History of HRT use does not affect overall or CHD mortality in women. More than 5 years of HRT use may increase the risk of breast cancer mortality.
The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins
Authors: Hansen Pia S , Brix Thomas H , Iachine Ivan , Kyvik Kirsten O , Hegedüs Laszlo
Published: December 2005

Objective: In euthyroid individuals, autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) are regarded as early markers of thyroid autoimmunity. Family and twin studies suggest that development of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is under genetic influence. We aimed to estimate the relative importance of genetic and environmental effects for the presence of thyroid autoantibodies in euthyroid subjects.

Methods: A representative sample of healthy twin pairs was identified through the Danish Twin Registry; 1372 individuals, divided into 283 monozygotic (MZ), 285 dizygotic same sex (DZ), and 118 opposite sex twin pairs were investigated. Serum TPOab and serum Tgab were measured. Proband-wise concordance and intraclass correlations were calculated, and quantitative genetic modelling was performed.

Results: Probandwise concordance and intraclass correlations were consistently higher for MZ than for DZ twin pairs indicating genetic influence. Genetic components (with 95% confidence intervals) accounted for 73% (46–89%) of the liability of being thyroid antibody positive. Adjusting for covariates (age, TSH and others), the estimate for genetic influence on serum TPOab concentrations was 61% (49–70%) in males and 72% (64–79%) in females. For serum Tgab concentrations, the estimates were 39% (24–51%) and 75% (66–81%) respectively.

Conclusions: Early markers of thyroid autoimmunity appear to be under strong genetic influence. The analyses suggest that it is the same set of genes that operate in males and females. However, complex mechanisms such as dominance and/or epistasis may be involved.
GH effect on enzyme activity of 11βHSD in abdominal obesity is dependent on treatment duration
Authors: Sigurjónsdóttir Helga Á , Koranyi Josef , Axelson Magnus , Bengtsson Bengt-Åke , Johannsson Gudmundur
Published: December 2005

Objective: In the past years the interaction of GH and 11βhydroxysteroid dehydrogenase (11βHSD) in the pathogenesis of central obesity has been suggested.

Design: We studied the effects of 9 months of GH treatment on 11βHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48–66 years, in a randomised, double-blind, placebo-controlled trial.

Methods: Urinary steroid profile was used to estimate 11βHSD type 1 and 2 (11βHSD1 and 11βHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic–hyperinsulinaemic glucose clamp was used to assess insulin sensitivity.

Results: In the GH-treated group the 11βHSD1 activity decreased transiently after 6 weeks (P< 0.01) whereas 11βHSD2 increased after 9 months of treatment (P< 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11βHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11βHSD1 and 11βHSD 2 and changes in GDR.

Discussion: The study demonstrates that short- and long-term GH treatment has different effects on 11βHSD1 and 11βHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11βHSD.
Androgen therapy in women
Authors: Arlt Wiebke
Published: December 2005

Androgens in women either derive from direct ovarian production or from peripheral conversion of the adrenal sex steroid precursor, dehydroepiandrosterone, towards active androgens. Therefore, loss of adrenal or ovarian function, caused by Addison’s disease or consequent to bilateral oophorectomy, results in severe androgen deficiency, clinically often associated with a loss of libido and energy. Importantly, physiological menopause does not necessarily lead to androgen deficiency, as androgen synthesis in the ovaries may persist despite the decline in estrogen production. However, the definition of female androgen deficiency, as recently provided by the Princeton consensus statement, is not precise enough and may lead to over-diagnosis due to the high prevalence of its diagnostic criteria: androgen levels below or within the lower quartile of the normal range and concurrent sexual dysfunction. Importantly, physiological menopause is not necessarily associated with androgen deficiency and therefore does not routinely require androgen therapy. Current replacement options include transdermal testosterone administration or dehydroepiandrosterone treatment, both of which have been shown to result in significant improvements, in particular in libido and mood, while effects on body composition and muscular function are not well documented. It is important to keep in mind that the number of randomized controlled trials is still limited and that currently none of the available preparations is officially approved for use in women. Currently, androgen replacement should be reserved for women with severe androgen deficiency due to an established cause and matching clinical signs and symptoms.
Graves’ disease and Hashimoto’s thyroiditis in monozygotic twins: case study as well as transcriptomic and immunohistological analysis of thyroid tissues
Authors: Aust G , Krohn K , Morgenthaler N G , Schröder S , Schütz A , Edelmann J , Brylla E
Published: December 2005

Objective: To report on the rare simultaneous occurrence of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) in monozygotic twins.

Design: We compared the pattern of thyroid tissue-derived cDNAs to gain insight into previous and ongoing immune destruction and reconstruction processes using microarrays. The results were confirmed by immunohistology and real-time PCR.

Results: Destruction of thyroid tissue in HT reduced levels of thyrocyte-related cDNAs and cDNAs encoding extracellular matrix components, but increased levels of proteases involved in extracellular matrix degradation compared with GD. Lymphocytic infiltrates forming ectopic follicles replaced the thyroid tissue almost completely in HT. Thus, lymphocyte-related cDNA levels were higher in HT than in GD. The same was true for many chemokines and their receptors, which not only enable migration towards the thyroid but also maintain the lymphocytic infiltrate. HT also showed increased levels of cDNAs encoding molecules related to apoptosis than did GD. Surprisingly, the Th1- and Th2-specific cytokine profiles suggested for HT and GD respectively could not be confirmed. cDNAs encoding factors and receptors involved in angiogenesis were increased in GD compared with HT.

Conclusions: Comparison of gene expression reflects the cellular differences between the two types of autoimmune thyroid disease in twins with identical genetic and similar environmental background.
Inflammation is a modulator of the insulin-like growth factor (IGF)/IGF-binding protein system inducing reduced bioactivity of IGFs in cystic fibrosis
Authors: Street Maria E , Ziveri Maria A , Spaggiari Cinzia , Viani Isabella , Volta Cecilia , Grzincich Gian Luigi , Virdis Raffaele , Bernasconi Sergio
Published: December 2005

Objective: In inflammatory bowel diseases, increased serum interleukin (IL)-6 levels are associated with high serum insulin-like growth factor-binding protein 2 (IGFBP-2) levels, and cytokines modify the insulin-like growth factor (IGF)/IGFBP system in models in vitro. In cystic fibrosis (CF) the IGF/IGFBP system has not been extensively studied, and relationships with proinflammatory cytokines have not been explored. The aim of this study was to investigate the IGF/IGFBP system and verify changes dependent on IL-1β, IL-6, tumour necrosis factor α (TNFα), and insulin.

Methods: Eighteen subjects with CF (mean age 26.6 ± 1.1 years) and 18 controls, comparable for age, sex, and body mass index, were enrolled. Serum IGF-I, IGF-II, IGFBP-2, IGFBP-3, IL-1β, IL-6, TNFα, insulin and C-peptide were measured. Different molecular forms of IGFBP-2 and IGFBP-3 were investigated by Western immunoblotting. The patients were analysed as a whole and as two subgroups depending on established clinical criteria (Swachman–Kulczycki score).

Results: Patients had higher serum concentrations of IL-1β, IL-6, TNFα and IGFBP-2 than controls. Serum concentrations of IGF-I and IGF-II were significantly lower and insulin and C-peptide levels significantly increased in CF compared with healthy controls whereas IGFBP-3 serum concentrations were similar, with comparable IGF-I/IGFBP-3 and decreased IGF-I/IGFBP-2 and IGF-II/IGFBP-2 molar ratios. From correlation analysis we detected a significant positive correlation between IGFBP-2 and IL-6 and a negative correlation between IGFBP-2 and IGFBP-3.

Conclusions: Our findings suggest that inflammation is an important modulator of the IGF/IGFBP system with an overall reduction in IGF bioactivity in CF.
Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study
Authors: Leão Lenora M Camarate S M , Duarte Mônica Peres C , Silva Dalva Margareth B , Bahia Paulo Roberto V , Coeli Cláudia Medina , de Farias Maria Lucia Fleiuss
Published: December 2005

Background: There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease.

Objective: We aimed to assess the effects of androgen replacement on cardiovascular risk factors.

Design: Thirty-seven postmenopausal women aged 42–62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo.

Methods: Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography.

Results: A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance.

Conclusion: This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease.