bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in gene expression during the development of mammary tumors in MMTV-Wnt-1transgenic mice
Authors: Huang Shixia , Li Yi , Chen Yidong , Podsypanina Katrina , Chamorro Mario , Olshen Adam B , Desai Kartiki V , Tann Anne , Petersen David , Green Jeffrey E , Varmus Harold E
Published: September 2005

Background

In human breast cancer normal mammary cells typically develop into hyperplasia, ductal carcinoma in situ, invasive cancer, and metastasis. The changes in gene expression associated with this stepwise progression are unclear. Mice transgenic for mouse mammary tumor virus (MMTV)-Wnt-1 exhibit discrete steps of mammary tumorigenesis, including hyperplasia, invasive ductal carcinoma, and distant metastasis. These mice might therefore be useful models for discovering changes in gene expression during cancer development.

Results

We used cDNA microarrays to determine the expression profiles of five normal mammary glands, seven hyperplastic mammary glands and 23 mammary tumors from MMTV-Wnt-1 transgenic mice, and 12 mammary tumors from MMTV-Neu transgenic mice. Adipose tissues were used to control for fat cells in the vicinity of the mammary glands. In these analyses, we found that the progression of normal virgin mammary glands to hyperplastic tissues and to mammary tumors is accompanied by differences in the expression of several hundred genes at each step. Some of these differences appear to be unique to the effects of Wnt signaling; others seem to be common to tumors induced by both Neu and Wnt-1 oncogenes.

Conclusion

We described gene-expression patterns associated with breast-cancer development in mice, and identified genes that may be significant targets for oncogenic events. The expression data developed provide a resource for illuminating the molecular mechanisms involved in breast cancer development, especially through the identification of genes that are critical in cancer initiation and progression.
The two tempos of nuclear pore complex evolution: highly adapting proteins in an ancient frozen structure
Authors: Bapteste Eric , Charlebois Robert L , MacLeod Dave , Brochier Céline
Published: September 2005

Background

The origin of the nuclear compartment has been extensively debated, leading to several alternative views on the evolution of the eukaryotic nucleus. Until recently, too little phylogenetic information was available to address this issue by using multiple characters for many lineages.

Results

We analyzed 65 proteins integral to or associated with the nuclear pore complex (NPC), including all the identified nucleoporins, the components of their anchoring system and some of their main partners. We used reconstruction of ancestral sequences of these proteins to expand the detection of homologs, and showed that the majority of them, present all over the nuclear pore structure, share homologs in all extant eukaryotic lineages. The anchoring system, by contrast, is analogous between the different eukaryotic lineages and is thus a relatively recent innovation. We also showed the existence of high heterogeneity of evolutionary rates between these proteins, as well as between and within lineages. We show that the ubiquitous genes of the nuclear pore structure are not strongly conserved at the sequence level, and that only their domains are relatively well preserved.

Conclusion

We propose that an NPC very similar to the extant one was already present in at least the last common ancestor of all extant eukaryotes and it would not have undergone major changes since its early origin. Importantly, we observe that sequences and structures obey two very different tempos of evolution. We suggest that, despite strong constraints that froze the structural evolution of the nuclear pore, the NPC is still highly adaptive, modern, and flexible at the sequence level.
Audit of clinicians' approach to patients' driving status in a dementia day hospital setting
Authors: Baker Philip , Rogers Tim
Published: September 2005

Aims and Method

To examine whether driving is discussed with patients attending a specialist day hospital for dementia and whether appropriate action is taken. Patients' notes were reviewed for evidence of such discussion. A questionnaire was implemented before the audit was repeated 6 months later.

Results

During the first cycle 44 patients' notes were assessed and 38 were assessed on repeat audit. The documentation of discussions regarding driving increased from 23 to 95% of notes following implementation of the questionnaire.

Clinical Implications

By discussing driving status, important legal, insurance and safety issues can be addressed. Routine use of a simple questionnaire dramatically improved the likelihood of such discussion. These findings apply for all conditions requiring Driver and Vehicle Licensing Agency notification.
Randomized Phase III Study of Cisplatin With or Without Raltitrexed in Patients With Malignant Pleural Mesothelioma: An Intergroup Study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada
Authors: van Meerbeeck Jan P. , Gaafar Rabab , Manegold Christian , Van Klaveren Rob J. , Van Marck Eric A. , Vincent Mark , Legrand Catherine , Bottomley Andrew , Debruyne Channa , Giaccone Giuseppe
Published: September 2005

Purpose

We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM).

Patients and Methods

Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2(arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13).

Results

Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048).

Conclusion

A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.
Preliminary Results of a Randomized Study on Therapeutic Gain by Concurrent Chemotherapy for Regionally-Advanced Nasopharyngeal Carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group
Authors: Lee Anne W.M. , Lau W.H. , Tung Stewart Y. , Chua Daniel T.T. , Chappell Rick , Xu L. , Siu Lillian , Sze W.M. , Leung T.W. , Sham Jonathan S.T. , Ngan Roger K.C. , Law Stephen C.K. , Yau T.K. , Au Joseph S.K. , O'Sullivan Brian , Pang Ellie S.Y. , O S.K. , Au Gordon K.H. , Lau Joseph T.
Published: September 2005

Purpose

This randomized study compared the results achieved by concurrent chemoradiotherapy (CRT) versus radiotherapy (RT) alone for nasopharyngeal carcinoma (NPC) with advanced nodal disease.

Patients and Methods

Patients with nonkeratinizing/undifferentiated NPC staged T1-4N2-3M0 were randomized to CRT or RT. Both arms were treated with the same RT technique and dose fractionation. The CRT patients were given cisplatin 100 mg/m2 on days 1, 22, and 43, followed by cisplatin 80 mg/m2 and fluorouracil 1,000 mg/m2/d for 96 hours starting on days 71, 99, and 127.

Results

From 1999 to January 2004, 348 eligible patients were randomly assigned; the median follow-up was 2.3 years. The two arms were well-balanced in all prognostic factors and RT parameters. The CRT arm achieved significantly higher failure-free survival (72% v 62% at 3-year, P = .027), mostly as a result of an improvement in locoregional control (92% v 82%, P = .005). However, distant control did not improve significantly (76% v 73%, P = .47), and the overall survival rates were almost identical (78% v 78%, P = .97). In addition, the CRT arm had significantly more acute toxicities (84% v 53%, P < .001) and late toxicities (28% v 13% at 3-year, P = .024).

Conclusion

Preliminary results confirmed that CRT could significantly improve tumor control, particularly at locoregional sites. However, there was significant increase in the risk of toxicities and no early gain in overall survival. Longer follow-up is needed to confirm the ultimate therapeutic ratio.
Intellectual and Functional Outcome of Children 3 Years Old or Younger Who Have CNS Malignancies
Authors: Fouladi Maryam , Gilger Elizabeth , Kocak Mehmet , Wallace Dana , Buchanan Gray , Reeves Cara , Robbins Nicole , Merchant Thomas , Kun Larry E. , Khan Raja , Gajjar Amar , Mulhern Raymond
Published: September 2005

Purpose

To evaluate the impact of tumor location, clinical parameters, and therapy on neurocognitive, neuroendocrine, and functional outcomes in children ≤ 3 years old with intracranial CNS malignancies who survived at least 2 years after diagnosis.

Patients and Methods

Records were retrospectively reviewed for 194 children diagnosed from 1985 to 1999 at St Jude Children's Research Hospital (Memphis, TN).

Results

The median age at diagnosis was 1.8 years (range, 0.1 to 3.5 years). Median follow-up was 7.64 years (2.0 to 19.4 years). Tumors were infratentorial (102), diencephalic (53), and hemispheric (39); 47% required ventriculoperitoneal shunts, 36% developed seizure disorders, and 20% developed severe ototoxicity. Therapy included no radiation therapy (RT) in 57 (30%), local RT in 87 (45%), and craniospinal irradiation (CSI) in 49 (25%). Overall survival at 10 years was 78 ± 4%. In a longitudinal analysis of 126 patients with at least one neurocognitive evaluation (NE), the mean rate of intelligence quotient (IQ) change for patients who received CSI (−1.34 points per year) and local RT (−0.51 points per year) was significantly different from the no RT group (0.91 points per year; P = .005 and P = .036, respectively). Patients with hemispheric tumors had a significantly greater IQ decline (−1.52 points per year) than those with midline tumors (0.59 points per year; P = .038). Among those with NE ≥ 5 years after diagnosis, 71.4% of CSI recipients compared with 23% of local RT recipients had IQ less than 70 (P = .021). Patients undergoing CSI were more likely to develop endocrinopathies (P < .0001) and to require special education (P = .0007).

Conclusion

In young children with CNS tumors, CSI and hemispheric location are associated with significant declines in IQ scores.
Predictors of Prostate Cancer–Specific Mortality After Radical Prostatectomy or Radiation Therapy
Authors: Zhou Ping , Chen Ming-Hui , McLeod David , Carroll Peter R. , Moul Judd W. , D’Amico Anthony V.
Published: September 2005

Purpose

We evaluated predictors of prostate cancer–specific mortality (PCSM) after prostate-specific antigen (PSA) failure after radical prostatectomy (RP) or radiation therapy (RT).

Patients and Methods

A total of 1,159 men with clinically localized prostate cancer treated with RP (n = 498) or RT (n = 661) developed PSA failure, and they formed the study cohort. Competing risk regression analyses were used to evaluate whether previously identified predictors of time to metastasis, including post-treatment PSA doubling time (PSA-DT), Gleason score, and interval to PSA failure, could also predict time to PCSM after PSA failure. The cumulative incidence method was used to estimate PCSM after PSA failure.

Results

A post-RP PSA-DT of less than 3 months (hazard ratio [HR], 54.9; 95% CI, 16.7 to 180), a post-RT PSA-DT of less than 3 months (HR, 12.8; 95% CI, 7.0 to 23.1), and a biopsy Gleason score of 8 to 10 (HR, 6.1; 95% CI, 3.4 to 10.7) for patients treated with RT were significantly associated with PCSM. Post-RP estimated rates of PCSM 5 years after PSA failure were 31% (95% CI, 17% to 45%) v 1% (95% CI, 0% to 2%) for patients with PSA-DT of less than 3 months v ≥ 3 months. Post-RT estimated rates of PCSM 5 years after PSA failure were 75% (95% CI, 59% to 92%) v 35% (95% CI, 24% to 47%) for patients with a biopsy Gleason score of ≥ 8 v ≤ 7, respectively, and PSA-DT of less than 3 months; these rates were 15% (95% CI, 0.8% to 28%) v 4% (95% CI, 1% to 6%), respectively, for patients with a PSA-DT ≥ 3 months.

Conclusion

Patients at high risk for PCSM after PSA failure can be identified based on post-RP PSA-DT or post-RT PSA-DT and biopsy Gleason score. These parameters may be useful in identifying patients for a randomized trial evaluating hormonal therapy with or without docetaxel.
Lack of CpG Island Methylator Phenotype Defines a Clinical Subtype of T-Cell Acute Lymphoblastic Leukemia Associated With Good Prognosis
Authors: Roman-Gomez Jose , Jimenez-Velasco Antonio , Agirre Xabier , Prosper Felipe , Heiniger Anabel , Torres Antonio
Published: September 2005

Purpose

To examine cancer genes undergoing epigenetic inactivation in a set of T-cell acute lymphoblastic leukemias (T-ALLs) to obtain the CpG island methylator phenotype (CIMP) in the disease and its possible correlation with clinical features and outcome of the patients.

Patients and Methods

Methylation-specific polymerase chain reaction was used to analyze methylation of the ADAMTS-1, ADAMTS-5, APAF-1, ASPP-1, CDH1, CDH13, DAPK, DIABLO, DKK-3, LATS-1, LATS-2, NES-1, p14, p15, p16, p57, p73, PARK-2, PTEN, sFRP1/2/4/5, SHP-1, SYK, TMS-1, and WIF-1 genes in samples from 50 consecutive T-ALL patients (19 children and 31 adults). Results were compared with results obtained in 286 B-cell acute lymphoblastic leukemias (B-ALLs).

Results

A total of 88% of the T-ALL samples had at least one gene methylated. According to the number of methylated genes observed in each individual sample, 12 patients (24%) were included in the CIMP− group (zero to two methylated genes), and 38 patients (76%) were included in the CIMP+ group (> two methylated genes). Clinical features and remission rate did not differ significantly among both groups of patients. Estimated disease-free survival (DFS) rate at 12 years and overall survival (OS) rate at 13 years were 100% and 91% for the CIMP− group and 20% and 17% for the CIMP+ group, respectively (P = .0006 and P = .003, respectively). Multivariate analysis demonstrated that methylation profile was an independent prognostic factor in predicting DFS (P = .05) and OS (P = .02). A group of five genes (SYK-1, ASPP-1, sFRP-2, sFRP-5, and WIF-1) showed specificity for T-ALL compared with B-ALL.

Conclusion

Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in T-ALL.
Postoperative Nomogram Predicting the 10-Year Probability of Prostate Cancer Recurrence After Radical Prostatectomy
Authors: Stephenson Andrew J. , Scardino Peter T. , Eastham James A. , Bianco Fernando J. , Dotan Zohar A. , DiBlasio Christopher J. , Reuther Alwyn , Klein Eric A. , Kattan Michael W.
Published: September 2005

Purpose

A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP.

Methods

Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy.

Results

The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < .0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = .030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79.

Conclusion

We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.
Acupuncture-Point Stimulation for Chemotherapy-Induced Nausea and Vomiting
Authors: Ezzo Jeanette , Vickers Andrew , Richardson Mary Ann , Allen Claire , Dibble Suzanne L. , Issell Brian , Lao Lixing , Pearl Michael , Ramirez Gilbert , Roscoe Joseph A. , Shen Joannie , Shivnan Jane , Streitberger Konrad , Treish Imad , Zhang Grant
Published: September 2005

Purpose

Assess the effectiveness of acupuncture-point stimulation on acute and delayed chemotherapy-induced nausea and vomiting in cancer patients.

Materials and Methods

Randomized trials of acupuncture-point stimulation by needles, electrical stimulation, magnets, or acupressure were retrieved. Data were provided by investigators of the original trials and pooled using a fixed-effects model.

Results

Eleven trials (N = 1,247) were pooled. Overall, acupuncture-point stimulation reduced the proportion of acute vomiting (relative risks [RR] = 0.82; 95% CI, 0.69 to 0.99; P = .04), but not the mean number of acute emetic episodes or acute or delayed nausea severity compared with controls. By modality, stimulation with needles reduced the proportion of acute vomiting (RR = 0.74; 95% CI, 0.58 to 0.94; P = .01), but not acute nausea severity. Electroacupuncture reduced the proportion of acute vomiting (RR = 0.76; 95% CI, 0.60 to 0.97; P = .02), but manual acupuncture did not; delayed symptoms were not reported. Acupressure reduced mean acute nausea severity (standardized mean difference = −0.19; 95% CI, −0.38 to −0.01; P = .03) and most severe acute nausea, but not acute vomiting or delayed symptoms. Noninvasive electrostimulation showed no benefit for any outcome. All trials used concomitant pharmacologic antiemetics, and all, except electroacupuncture trials, used state-of-the-art antiemetics.

Conclusion

This review complements data on postoperative nausea and vomiting, suggesting a biologic effect of acupuncture-point stimulation. Electroacupuncture has demonstrated benefit for chemotherapy-induced acute vomiting, but studies with state-of-the-art antiemetics as well as studies for refractory symptoms are needed to determine clinical relevance. Acupressure seems to reduce chemotherapy-induced acute nausea severity, though studies did not involve a placebo control. Noninvasive electrostimulation seems unlikely to have a clinically relevant impact when patients are given state-of-the-art pharmacologic antiemetic therapy.
Impact of Patient Distance to Radiation Therapy on Mastectomy Use in Early-Stage Breast Cancer Patients
Authors: Schroen Anneke T. , Brenin David R. , Kelly Maria D. , Knaus William A. , Slingluff Craig L.
Published: September 2005

Purpose

Treatment access underlies quality cancer care. We hypothesize that mastectomy rates in a rural state are independently influenced by distance to radiation therapy (XRT) and by changing XRT access through opening new facilities.

Patients and Methods

Early-stage breast cancer patients diagnosed from 1996 to 2000 were identified in the Virginia state registry. Distance from patient zip code to nearest XRT facility was calculated with geographical software. Distance to XRT facility (≤ 10, > 10 to 25, > 25 to 50, and > 50 miles), American Joint Committee on Cancer tumor stage, age, race, and diagnosis year were evaluated for influencing mastectomy rate. Mastectomy use within 15 miles of five new facilities was assessed before and after opening.

Results

Among 20,094 patients, 43% underwent mastectomy, 53% underwent lumpectomy, and therapy of 4% of patients is unknown. Twenty-nine percent of patients lived more than 10 miles from XRT facility. Mastectomy increased with distance to XRT facility (43% at ≤ 10 miles, 47% at > 10 to 25 miles, 53% at > 25 to 50 miles, and 58% at > 50 miles; P < .001). Among 11,597 patients with T1 (< 2 cm) tumors, mastectomy also varied by distance (31% at ≤ 10 miles, 36% at > 10 to 25 miles, 41% at > 25 to 50 miles, and 49% at > 50 miles; P < .001). In multivariate analysis, mastectomy use was independently influenced by XRT distance after adjusting for age, race, T stage, and diagnosis year. Over the study period, mastectomy rates declined from 48% to 43% across Virginia, and there were similar declines in a 15-mile area around four new radiation facilities in urban settings. However, mastectomies decreased from 61% to 45% around a new XRT facility in a rural setting.

Conclusion

Distance to XRT facility significantly impacts mastectomy use. Opportunities for increasing breast-conservation rates through improved XRT access exist.
OncoSurge: A Strategy for Improving Resectability With Curative Intent in Metastatic Colorectal Cancer
Authors: Poston Graeme J. , Adam René , Alberts Steven , Curley Steven , Figueras Juan , Haller Daniel , Kunstlinger Francis , Mentha Gilles , Nordlinger Bernard , Patt Yehuda , Primrose John , Roh Mark , Rougier Philippe , Ruers Theo , Schmoll Hans Joachim , Valls Carlos , Vauthey Nick Jean-Nicolas , Cornelis Marleen , Kahan James P.
Published: September 2005

Purpose

Most patients with colorectal liver metastases present to general surgeons and oncologists without a specialist interest in their management. Since treatment strategy is frequently dependent on the response to earlier treatments, our aim was to create a therapeutic decision model identifying appropriate procedure sequences.

Methods

We used the RAND Corporation/University of California, Los Angeles Appropriateness Method (RAM) assessing strategies of resection, local ablation and chemotherapy. After a comprehensive literature review, an expert panel rated appropriateness of each treatment option for a total of 1,872 ratings decisions in 252 cases. A decision model was constructed, consensus measured and results validated using 48 virtual cases, and 34 real cases with known outcomes.

Results

Consensus was achieved with overall agreement rates of 93.4 to 99.1%. Absolute resection contraindications included unresectable extrahepatic disease, more than 70% liver involvement, liver failure, and being surgically unfit. Factors not influencing treatment strategy were age, primary tumor stage, timing of metastases detection, past blood transfusion, liver resection type, pre-resection carcinoembryonic antigen (CEA), and previous hepatectomy. Immediate resection was appropriate with adequate radiologically-defined resection margins and no portal adenopathy; other factors included presence of ≤ 4 or > 4 metastases and unilobar or bilobar involvement. Resection was appropriate postchemotherapy, independent of tumor response in the case of ≤ 4 metastases and unilobar liver involvement. Resection was appropriate only for > 4 metastases or bilobar liver involvement, after tumor shrinkage with chemotherapy. When possible, resection was preferred to local ablation.

Conclusion

The results were incorporated into a decision matrix, creating a computer program (OncoSurge). This model identifies individual patient resectability, recommending optimal treatment strategies. It may also be used for medical education.
Social Support, Psychological Distress, and Natural Killer Cell Activity in Ovarian Cancer
Authors: Lutgendorf Susan K. , Sood Anil K. , Anderson Barrie , McGinn Stephanie , Maiseri Heena , Dao Minh , Sorosky Joel I. , De Geest Koen , Ritchie Justine , Lubaroff David M.
Published: September 2005

Purpose

Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL).

Patients and Methods

Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses.

Results

Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL.

Conclusion

Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.
Etiology of Solitary Extrapulmonary Positron Emission Tomography and Computed Tomography Findings in Patients With Lung Cancer
Authors: Lardinois Didier , Weder Walter , Roudas Marina , von Schulthess Gustav K. , Tutic Michaela , Moch Holger , Stahel Rolf A. , Steinert Hans C.
Published: September 2005

Purpose

The aim of this prospective study was to assess the incidence and the nature of solitary extrapulmonary [18F] fluorodeoxyglucose (FDG) accumulations in patients with non–small-cell lung cancer (NSCLC) staged with integrated positron emission tomography and computed tomography (PET/CT) and to evaluate the impact on management.

Patients and Methods

A total of 350 patients with NSCLC underwent whole-body PET/CT imaging. All solitary extrapulmonary FDG accumulations were evaluated by histopathology, further imaging, or clinical follow-up.

Results

PET/CT imaging revealed extrapulmonary lesions in 110 patients. In 72 patients (21%), solitary lesions were present. A diagnosis was obtained in 69 of these patients, including 37 (54%) with solitary metastases and 32 (46%) with lesions unrelated to the lung primary. Histopathologic examinations of these 32 lesions revealed a second clinically unsuspected malignancy or a recurrence of a previous diagnosed carcinoma in six patients (19%) and a benign tumor or inflammatory lesion in 26 patients (81%). The six malignancies consisted of carcinoma of the breast in two patients, and carcinoma of the orbit, esophagus, prostate, and non-Hodgkin's lymphoma in one patient each. Benign tumors and inflammatory lesions included eight colon adenomas, four Warthin's tumors, one granuloma of the lower jaw, one adenoma of the thyroid gland, one compensatory muscle activity due to vocal chord palsy, two occurrences of arthritis, three occurrences of reflux esophagitis, two occurrences of pancreatitis, two occurrences of diverticulitis, one hemorrhoidal inflammation, and one rib fracture.

Conclusion

Solitary extrapulmonary FDG accumulations in patients with newly diagnosed lung cancer should be analyzed critically for correct staging and optimal therapy, given that up to half of the lesions may represent unrelated malignancies or benign disease.
Factors Predictive of Distant Metastases in Patients With Breast Cancer Who Have a Pathologic Complete Response After Neoadjuvant Chemotherapy
Authors: Gonzalez-Angulo Ana M. , McGuire Sean E. , Buchholz Thomas A. , Tucker Susan L. , Kuerer Henry M. , Rouzier Roman , Kau Shu-Wan , Huang Eugene H. , Morandi Paolo , Ocana Alberto , Cristofanilli Massimo , Valero Vicente , Buzdar Aman U. , Hortobagyi Gabriel N.
Published: September 2005

Purpose

To identify clinicopathological factors predictive of distant metastasis in patients who had a pathologic complete response (pCR) after neoadjuvant chemotherapy (NC).

Methods

Retrospective review of 226 patients at our institution identified as having a pCR was performed. Clinical stage at diagnosis was I (2%), II (36%), IIIA (27%), IIIB (23%), and IIIC (12%). Eleven percent of all patients were inflammatory breast cancers (IBC). Ninety-five percent received anthracycline-based chemotherapy; 42% also received taxane-based therapy. The relationship of distant metastasis with clinicopathologic factors was evaluated, and Cox regression analysis was performed to identify independent predictors of development of distant metastasis.

Results

Median follow-up was 63 months. There were 31 distant metastases. Ten-year distant metastasis-free rate was 82%. Multivariate Cox regression analysis using combined stage revealed that clinical stages IIIB, IIIC, and IBC (hazard ratio [HR], 4.24; 95% CI, 1.96 to 9.18; P < .0001), identification of ≤ 10 lymph nodes (HR, 2.94; 95% CI, 1.40 to 6.15; P = .004), and premenopausal status (HR, 3.08; 95% CI, 1.25 to 7.59; P = .015) predicted for distant metastasis. Freedom from distant metastasis at 10 years was 97% for no factors, 88% for one factor, 77% for two factors, and 31% for three factors (P < .0001).

Conclusion

A small percentage of breast cancer patients with pCR experience recurrence. We identified factors that independently predicted for distant metastasis development. Our data suggest that premenopausal patients with advanced local disease and suboptimal axillary node evaluation may be candidates for clinical trials to determine whether more aggressive or investigational adjuvant therapy will be of benefit.
Long-Term Results of a Randomized Trial on Extended Use of High Dose l-Asparaginase for Standard Risk Childhood Acute Lymphoblastic Leukemia
Authors: Pession Andrea , Valsecchi Maria Grazia , Masera Giuseppe , Kamps Willem A. , Magyarosy Edina , Rizzari Carmelo , van Wering Elisabeth R. , Lo Nigro Luca , van der Does Anna , Locatelli Franco , Basso Giuseppe , Aricò Maurizio
Published: September 2005

Purpose

Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of high-dose l-asparaginase (HD-l-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy.

Patients and Methods

The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-l-ASP (25,000 IU/m2).

Results

The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome.

Conclusion

In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-l-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.
Communicating Quality of Life Information to Cancer Patients: A Study of Six Presentation Formats
Authors: Brundage M. , Feldman-Stewart D. , Leis A. , Bezjak A. , Degner L. , Velji K. , Zetes-Zanatta L. , Tu D. , Ritvo P. , Pater J.
Published: September 2005

Purpose

To determine which formats for presenting health-related quality of life (HRQL) data are interpreted most accurately and are most preferred by cancer patients. Patients often want a great deal of information about cancer treatments, including information relevant to HRQL. Clinical trials provide methodologically sound HRQL data that may be useful to patients.

Patients and Methods

In a multicenter study, 198 patients with previously treated cancer participated in a structured interview. Participants judged HRQL information presented in one textual and five graphical formats. Outcome measures included the accuracy of patients' interpretations and ease-of-use and helpfulness ratings for each format.

Results

Correct interpretations ranged from 85% to 98% across formats (F = 10.3, P < .0001) with line graphs of mean HRQL scores over time being interpreted correctly most often. Older patients and less-educated patients were less likely to interpret graphs accurately (F = 7.3, P = .008; and F = 10.6, P = .001, respectively), but all groups were most accurate on simple line graphs. Multivariate analysis revealed that format type, participant age and education were independent predictors of accuracy rates. Patients' ratings also varied across formats both for ease of understanding scores (F = 12.1, P < .0001) and for helpfulness scores (F = 13.2, P < .0001), with line graphs being rated highest on both outcomes.

Conclusion

Patients generally prefer a simple linear representation of group mean HRQL scores, and can accurately interpret data presented in this format more than 98% of the time irrespective of their age group and educational level. The findings have important implications for the communication of clinical trial HRQL results.
Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas
Authors: D'Adamo David R. , Anderson Sibyl E. , Albritton Karen , Yamada Jennifer , Riedel Elyn , Scheu Kelly , Schwartz Gary K. , Chen Helen , Maki Robert G.
Published: September 2005

Purpose

To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS).

Patients and Methods

Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2.

Results

A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related.

Conclusion

The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.
Cumulative Mutagenesis of the Basic Residues in the 201–218 Region of Insulin-Like Growth Factor (IGF)-Binding Protein-5 Results in Progressive Loss of Both IGF-I Binding and Inhibition of IGF-I Biological Action
Authors: Allan Gordon J. , Tonner Elizabeth , Szymanowska Malgorzata , Shand John H. , Kelly Sharon M. , Phillips Kirsten , Clegg Roger A. , Gow Iain F. , Beattie James , Flint David J.
Published: September 2005

We have reported previously that mutation of two conserved nonbasic amino acids (G203 and Q209) within the highly basic 201–218 region in the C-terminal domain of IGF-binding protein-5 (IGFBP-5) decreases binding to IGFs. This study reveals that cumulative mutagenesis of the 10 basic residues in this region, to create the C-Term series of mutants, ultimately results in a 15-fold decrease in the affinity for IGF-I and a major loss in heparin binding. We examined the ability of mutants to inhibit IGF-mediated survival of MCF-7 cells and were able to demonstrate that this depended not only upon the affinity for IGF-I, but also the kinetics of this interaction, because IGFBP-5 mutants with similar affinity constants (KD) values, but with different association (Ka) and dissociation (Kd) rate values, had markedly different inhibitory properties. In contrast, the affinity for IGF-I provided no predictive value in terms of the ability of these mutants to enhance IGF action when bound to the substratum. Instead, these C-Term mutants appeared to enhance the actions of IGF-I by a combination of increased dissociation of IGF-IGFBP complexes from the substratum, together with dissociation of IGF-I from IGFBP-5 bound to the substratum. These effects of the IGFBPs were dependent upon binding to IGF-I, because a non-IGF binding mutant (N-Term) was unable to inhibit or enhance the actions of IGF-I. These results emphasize the importance of the kinetics of association/dissociation in determining the enhancing or inhibiting effects of IGFBP-5 and demonstrate the ability to generate an IGFBP-5 mutant with exclusively IGF-enhancing activity.
Bone Morphogenetic Protein-4 Inhibits Corticotroph Tumor Cells: Involvement in the Retinoic Acid Inhibitory Action
Authors: Giacomini Damiana , Páez-Pereda Marcelo , Theodoropoulou Marily , Labeur Marta , Refojo Damian , Gerez Juan , Chervin Alberto , Berner Silvia , Losa Marco , Buchfelder Michael , Renner Ulrich , Stalla Günter K. , Arzt Eduardo
Published: September 2005

The molecular mechanisms governing the pathogenesis of ACTH-secreting pituitary adenomas are still obscure. Furthermore, the pharmacological treatment of these tumors is limited. In this study, we report that bone morphogenetic protein-4 (BMP-4) is expressed in the corticotrophs of human normal adenohypophysis and its expression is reduced in corticotrophinomas obtained from Cushing’s patients compared with the normal pituitary. BMP-4 treatment of AtT-20 mouse corticotrophinoma cells has an inhibitory effect on ACTH secretion and cell proliferation. AtT-20 cells stably transfected with a dominant-negative form of the BMP-4 signal cotransducer Smad-4 or the BMP-4 inhibitor noggin have increased tumorigenicity in nude mice, showing that BMP-4 has an inhibitory role on corticotroph tumorigenesis in vivo. Because the activation of the retinoic acid receptor has an inhibitory action on Cushing’s disease progression, we analyzed the putative interaction of these two pathways. Indeed, retinoic acid induces both BMP-4 transcription and expression and its antiproliferative action is blocked in Smad-4dn- and noggin-transfected Att-20 cells that do not respond to BMP-4. Therefore, retinoic acid induces BMP-4, which participates in the antiproliferative effects of retinoic acid. This new mechanism is a potential target for therapeutic approaches for Cushing’s disease.
Ventromedial Arcuate Nucleus Communicates Peripheral Metabolic Information to the Suprachiasmatic Nucleus
Authors: Yi Chun-Xia , van der Vliet Jan , Dai Jiapei , Yin Guangfu , Ru Liqiang , Buijs Ruud M.
Published: September 2005

The arcuate nucleus (ARC) is crucial for the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. The expression of receptors for metabolic hormones, such as insulin, leptin, and ghrelin, allows ARC to sense information from the periphery and signal it to the central nervous system. The ventromedial ARC (vmARC) mainly comprises orexigenic neuropeptide agouti-related peptide and neuropeptide Y neurons, which are sensitive to circulating signals. To investigate neural connections of vmARC within the central nervous system, we injected the neuronal tracer cholera toxin B into vmARC. Due to variation of injection sites, tracer was also injected into the subependymal layer of the median eminence (seME), which showed similar projection patterns as the vmARC. We propose that the vmARC forms a complex with the seME, their reciprocal connections with viscerosensory areas in brain stem, and other circumventricular organs, suggesting the exchange of metabolic and circulating information. For the first time, the vmARC-seME was shown to have reciprocal interaction with the suprachiasmatic nucleus (SCN). Activation of vmARC neurons by systemic administration of the ghrelin mimetic GH-releasing peptide-6 combined with SCN tracing showed vmARC neurons to transmit feeding related signals to the SCN. The functionality of this pathway was demonstrated by systemic injection of GH-releasing peptide-6, which induced Fos in the vmARC and resulted in a reduction of about 40% of early daytime Fos immunoreactivity in the SCN. This observation suggests an anatomical and functional pathway for peripheral hormonal feedback to the hypothalamus, which may serve to modulate the activity of the SCN.
Temporally controlled targeted somatic mutagenesis in embryonic surface ectoderm and fetal epidermal keratinocytes unveils two distinct developmental functions of BRG1 in limb morphogenesis and skin barrier formation
Authors: Indra Arup Kumar , Dupé Valérie , Bornert Jean-Marc , Messaddeq Nadia , Yaniv Moshe , Mark Manuel , Chambon Pierre , Metzger Daniel
Published: September 2005

Animal SWI2/SNF2 protein complexes containing either the brahma (BRM) or brahma-related gene 1 (BRG1) ATPase are involved in nucleosome remodelling and may control the accessibility of sequence-specific transcription factors to DNA. In vitro studies have indicated that BRM and BRG1 could regulate the expression of distinct sets of genes. However, as mice lacking BRM are viable and fertile, BRG1 might efficiently compensate for BRM loss. By contrast, as Brg1-null fibroblasts are viable but Brg1-null embryos die during the peri-implantation stage, BRG1 might exert cell-specific functions. To further investigate the in vivo role of BRG1, we selectively ablated Brg1 in keratinocytes of the forming mouse epidermis. We show that BRG1 is selectively required for epithelial-mesenchymal interactions in limb patterning, and during keratinocyte terminal differentiation, in which BRM can partially substitute for BRG1. By contrast, neither BRM nor BRG1 are essential for the proliferation and early differentiation of keratinocytes, which may require other ATP-dependent nucleosome-remodelling complexes. Finally, we demonstrate that cell-specific targeted somatic mutations can be created at various times during the development of mouse embryos cell-specifically expressing the tamoxifen-activatable Cre-ERT2 recombinase.
The novel Smad-interacting protein Smicl regulatesChordinexpression in theXenopusembryo
Authors: Collart Clara , Verschueren Kristin , Rana Amer , Smith James C. , Huylebroeck Danny
Published: September 2005

In this paper, we investigate the function of Smicl, a zinc-finger Smad-interacting protein that is expressed maternally in the Xenopusembryo. Inhibition of Smicl function by means of antisense morpholino oligonucleotides causes the specific downregulation of Chordin, a dorsally expressed gene encoding a secreted BMP inhibitor that is involved in mesodermal patterning and neural induction. Chordin is activated by Nodal-related signalling in an indirect manner, and we show here that Smicl is involved in a two-step process that is necessary for this activation. In the first, Smad3 (but not Smad2) activates expression of Xlim1 in a direct fashion. In the second, a complex containing Smicl and the newly induced Xlim1 induces expression of Chordin. As well as revealing the function of Smicl in the early embryo, our work yields important new insight in the regulation of Chordin and identifies functional differences between the activities of Smad2 and Smad3 in the Xenopus embryo.
The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity
Authors: Wallingford John B. , Habas Raymond
Published: September 2005

The Dishevelled protein regulates many developmental processes in animals ranging from Hydra to humans. Here, we discuss the various known signaling activities of this enigmatic protein and focus on the biological processes that Dishevelled controls. Through its many signaling activities,Dishevelled plays important roles in the embryo and the adult, ranging from cell-fate specification and cell polarity to social behavior. Dishevelled also has important roles in the governance of polarized cell divisions, in the directed migration of individual cells, and in cardiac development and neuronal structure and function.
Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane
Authors: Bouschet Tristan , Martin Stéphane , Henley Jeremy M.
Published: September 2005

The calcium-sensing receptor (CaSR) is a class III G-protein-coupled receptor (GPCR) that responds to changes in extracellular calcium concentration and plays a crucial role in calcium homeostasis. The mechanisms controlling CaSR trafficking and surface expression are largely unknown. Using a CaSR tagged with the pH-sensitive GFP super-ecliptic pHluorin (SEP-CaSR), we show that delivery of the GPCR to the cell surface is dependent on receptor-activity-modifying proteins (RAMPs). We demonstrate that SEP-CaSRs are retained in the endoplasmic reticulum (ER) in COS7 cells that do not contain endogenous RAMPs whereas they are delivered to the plasma membrane in HEK 293 cells that do express RAMP1. Coexpression of RAMP1 or RAMP3, but not RAMP2, in COS7 cells was sufficient to target the CaSR to the cell surface. RAMP1 and RAMP3 colocalised and coimmunoprecipitated with the CaSR suggesting that these proteins associate within the cell. Our results indicate that RAMP expression promotes the forward trafficking of the GPCR from the ER to the Golgi apparatus and results in mature CaSR glycosylation, which is not observed in RAMP-deficient cells. Finally, silencing of RAMP1 in the endogenously expressing HEK293 cells using siRNA resulted in altered CaSR traffic. Taken together, our results show that the association with RAMPs is necessary and sufficient to transfer the immature CaSR retained in the ER towards the Golgi where it becomes fully glycosylated prior to delivery to the plasma membrane and demonstrate a role for RAMPs in the trafficking of a class III GPCR.
Synthesis and Characterization of Novel Chiral 1,2-Diamines Derived from α-Pinene
Authors: Suzuki Toshiaki , Shibata Akira , Morohashi Naoya , Ohba Yoshihiro
Published: September 2005

Direct diazidation of α-pinene (1) followed by reduction gave two novel 1,2-diamines (2a and 2b) whose absolute configuration were determined by 2D 1H NMR and X-ray crystallography.