bluuebunny/crossref_metadata_2025 huggingface dataset:
Furin gene (fur) regulation in differentiating human megakaryoblastic Dami cells: involvement of the proximal GATA recognition motif in the P1 promoter and impact on the maturation of furin substrates
Authors: Laprise Marie-Hélène , Grondin Francine , Cayer Pauline , McDonald Patrick P. , Dubois Claire M.
Published: October 2002

The convertase furin is involved in the maturation of key growth/aggregation mediators synthesized by the platelet producers, megakaryocytes, but the regulation of furin in these cells remains unknown. Computer-assisted search of the furin promoter sequence revealed multiple potential binding motifs for GATA-1, suggesting that furin is expressed and regulated in these cells. Using megakaryoblastic Dami cells, we observed that fur mRNA expression increased gradually on phorbol 12-myristate 13-acetate–induced differentiation, reaching maximum levels (8.3-fold increase) at 10 days. Transient transfections with P1, P1A, or P1B fur-LUC–promoter constructs revealed that in Dami cells, the P1 promoter is the strongest and the most sensitive to forced expression of GATA-1. Coexpression of GATA-1 and its comodulator, Friend of GATA-1 (FOG-1), resulted in a cooperative increase in P1 activity. Deletion analysis indicated that important GATA-1–regulated sequences are located in the most proximal region of the P1 promoter. Further analysis revealed 2 potential GATA-binding motifs at positions −66 and +62. Point mutation of each of the 2 motifs indicated that the intactness of the first GATA site is required for full basal and GATA-1–stimulated promoter activity. Finally, the inhibition of furin activity through gene transfer of the inhibitor α1-AT-PDX led to a block in maturation of the furin substrates transforming growth factor-β1 and platelet-derived growth factor. Taken together, these results indicate that the most proximal GATA element in the P1 promoter is needed forfur gene expression in megakaryoblastic cells. They also suggest that proper regulation of the fur gene in megakaryocytes has an impact on the activation of furin substrates involved in megakaryocyte maturation and platelet functions.
Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-κB/Rel–regulated inhibitors of apoptosis
Authors: Munzert Gerd , Kirchner Dieter , Stobbe Heike , Bergmann Lothar , Schmid Roland M. , Döhner Hartmut , Heimpel Hermann
Published: October 2002

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a resistance toward apoptosis-inducing agents. Nuclear factor-κB (NF-κB)/Rel has been shown to regulate the expression of antiapoptotic genes, such as members of the inhibitor of apoptosis protein (IAP) and tumor necrosis factor receptor-associated factor (TRAF) gene families. Expression and regulation of NF-κB/Rel–dependent inhibitors of apoptosis have not been collectively studied in B-CLL. We examined expression of known NF-κB/Rel–regulated antiapoptotic genes by RNAse protection assay, real-time polymerase chain reaction, and immunoblotting in patients with B-CLL. TRAF1 and to a lesser extent TRAF2 were overexpressed in B-CLL lymphocytes as compared with normal CD19+ B cells. TRAF1 overexpression did not correlate with markers of disease progression or overall survival. Furthermore, we found high constitutive expression of the IAP genes c-IAP-1, c-IAP-2, and XIAP both in normal and B-CLL lymphocytes. Focusing on the regulation of TRAF1, NF-κB/Rel activity in B-CLL nuclear extracts was shown to bind to TRAF1 promoter elements. However, IκB kinase (IKK) activity was not increased in CLL lymphocytes as compared with normal CD19+ B cells. The known IKK inhibitor sulfasalazine did not compromise TRAF1 expression. Thus, although our study revealed a common expression pattern of NF-κB/Rel–regulated inhibitors of apoptosis, our findings indicate an IKK-independent regulation of TRAF1 in B-CLL.
A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with altered cell-cycle status of early erythroid progenitor cells
Authors: Melkun Edward , Pilione Mylisa , Paulson Robert F.
Published: October 2002

The Friend virus susceptibility gene 2 (Fv2) controls the polyclonal expansion of infected cells that occurs early during Friend erythroleukemia virus infection. Fv2 has recently been shown to encode a truncated form of the Stk receptor tyrosine kinase (Sf-Stk). This observation, coupled with earlier work, suggested that Sf-Stk drives the expansion of infected cells by forming a complex with the Friend virus envelope glycoprotein, gp55, and the erythropoietin receptor. Fv2 has also been implicated in the control of cell cycling in early erythroid progenitors (erythroid blast-forming units [BFU-Es]). Mouse strains that are homozygous for the resistant allele of Fv2 (Fv2rr) have few actively cycling BFU-Es. In this report, we demonstrate that the control of BFU-E cycling is encoded by a gene linked to, but distinct from, Fv2, and suggest that this gene is the dual-specific protein phosphatase Cdc25A, which regulates the G1- to S-phase transition of the cell cycle. We show that a naturally occurring allele of Cdc25A, which increases Cdc25A phosphatase activity and promotes cell-cycle progression, segregates in mouse strains that exhibit high levels of BFU-E cell cycling. In wild-type mice, this allele of Cdc25A does not overtly affect erythropoiesis; however, when this allele is combined with a mutation of the Kit receptor (KitWV), the anemia of the mice is enhanced. Furthermore, overexpression of Cdc25A in bone marrow cells causes a defect in the BFU-E colony formation. These results suggest that proper regulation of the cell cycle through Cdc25A is required for normal erythropoiesis.
Phenotypes and phosphatidylinositol glycan-class A gene abnormalities during cell differentiation and maturation from precursor cells to mature granulocytes in patients with paroxysmal nocturnal hemoglobinuria
Authors: Kai Tatsuyuki , Shichishima Tsutomu , Noji Hideyoshi , Yamamoto Tetsuo , Okamoto Masatoshi , Ikeda Kazuhiko , Maruyama Yukio
Published: October 2002

To define the phosphatidylinositol glycan-class A (PIG-A) gene abnormality in precursor cells and the changes of expression of glycosylphosphatidylinositol-anchored protein and contribution of paroxysmal nocturnal hemoglobinuria (PNH) clones with PIG-A gene abnormalities among various cell lineages during differentiation and maturation, we investigated CD59 expression on bone marrow CD34+ cells and peripheral granulocytes from 3 patients with PNH and the PIG-A gene abnormalities in the CD59−, CD59+/−, and CD59+ populations by nucleotide sequence analyses. We also performed clonogeneic assays of CD34+CD59+ and CD34+CD59− cells from 2 of the patients and examined the PIG-A gene abnormalities in the cultured cells. In case 1, the CD34+ cells and granulocytes consisted of CD59− and CD59+ populations and CD59−, CD59+/−, and CD59+populations, respectively. Sequence analyses indicated that mutation 1-2 was in the CD59+/− granulocyte population (20 of 20) and the CD34+CD59− population (2 of 38). In cases 2 and 3, the CD34+ cells and granulocytes consisted of CD59+ and CD59− cells. Sequence analyses in case 3 showed that mutation 3-2 was not in CD34+CD59− cells and was present in the CD59− granulocyte population. However, PIG-A gene analysis of cultured CD34+CD59− cells showed that they had the mutation. This analysis also revealed that there were some other mutations, which were not found in CD34+CD59− cells and CD59− or CD59+/− granulocytes in vivo, and that sometimes they were distributed specifically among different cell lineages. In conclusion, our findings suggest that PNH clones might contribute qualitatively and quantitatively differentially to specific blood cell lineages during differentiation and maturation of hematopoietic stem cells.
Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia
Authors: Laverdière Caroline , Chiasson Sonia , Costea Irina , Moghrabi Albert , Krajinovic Maja
Published: October 2002

Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of childhood acute lymphoblastic leukemia (ALL). Resistance to this drug may arise by, among other factors, altered cellular uptake that may hamper the efficacy of the treatment. Recently, a G80A polymorphism has been described in the reduced folate carrier gene (RFC1), which encodes the major MTX transporter. Here, we assessed the association between the genetic polymorphisms G80A and both MTX plasma levels and childhood ALL outcome. Children with the A80 variant had worse prognoses than patients with the GG genotype (P = .04), as shown by event-free survival estimates. Patients homozygous for A80 had higher levels of MTX (P = .004) than the other genotype groups. Possible explanations for observed associations are discussed; however, additional experiments are required to achieve understanding of the underlying mechanism.
Two distinct HLA-A0201–presented epitopes of the Wilms tumor antigen 1 can function as targets for leukemia-reactive CTL
Authors: Bellantuono Ilaria , Gao Liquan , Parry Suzanne , Marley Steve , Dazzi Francesco , Apperley Jane , Goldman John M. , Stauss Hans J.
Published: October 2002

Using the allo-restricted T-cell approach to circumvent tolerance, we have previously identified a cytotoxic T-lymphocyte (CTL) epitope in the transcription factor Wilms tumor antigen 1 (WT1) presented by HLA-A0201 (A2) class I molecules. Here we describe an additional A2-presented epitope and show that CTLs against both epitopes kill WT1-expressing leukemia cell lines. Colony-forming assays demonstrated that both types of CTL killed CD34+progenitor cells from A2+ leukemia patients, but not from A2+ healthy individuals. The long-term culture-initiating cell (LTC-IC) assay was used to analyze the killing activity of WT1-specific CTLs against the more immature fraction of CD34+ cells. The CTLs killed LTC-ICs of patients with chronic myelogenous leukemia (CML), whereas the function of normal CD34+ progenitor/stem cells was not inhibited. Together, the data show that CTLs specific for 2 distinct peptide epitopes of WT1 can discriminate between normal and leukemia LTC-ICs, suggesting that such CTLs have the potential to selectively kill CML progenitor/stem cells.
Clinical governance: breathing new life into clinical audit
Authors: Palmer Claire
Published: November 2002

The terms ‘clinical audit’ and ‘clinical governance’ elicit a variety of responses, including boredom, frustration, incomprehension and, rarely, enthusiasm. This paper sets out to persuade the reader that clinical audit, as an integral component of clinical governance, will be reborn as an activity that clinicians will find interesting, developmental and a useful part of their everyday clinical practice. Under clinical governance, clinical audit will at last be able to achieve important and measurable improvements in patient care as a matter of routine.
Randomized Trial of Influenza Vaccine With Granulocyte-Macrophage Colony-Stimulating Factor or Placebo in Cancer Patients
Authors: Ramanathan Ramesh K. , Potter Douglas M. , Belani Chandra P. , Jacobs Samuel A. , Gravenstein Stefan , Lim Felix , Kim Hyoung , Savona Steven , Evans Terry , Buchbarker Dianne , Simon Mary B. , Depee Jane K. , Trump Donald L.
Published: October 2002

PURPOSE: To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) would improve response to influenza vaccination in cancer patients.

PATIENTS AND METHODS: In a randomized, patient-blinded, placebo-controlled trial carried out in 1997 to 2000, 133 patients were stratified into five groups of treatment and disease. Single doses of standard split trivalent influenza vaccine and either placebo or 250 μg of GM-CSF were administered at the same time. Hemagglutination inhibition assay titers were measured before and 4 weeks after vaccination.

RESULTS: Standard analyses, which define response as at least a four-fold increase in titers, detect no effect of GM-CSF for any of the three influenza subtypes in the trivalent vaccines (P ≥ .12). Analysis that includes the magnitude of the change in titers and combines responses of the subtypes suggests that the placebo group had the greater response (P = .051), thus indicating that GM-CSF does not improve response. Ancillary analyses show that response declines both with increasing age and with higher initial titers. The fraction of patients with at least a four-fold increase in titers was 0.36 (95% confidence interval, 0.29 to 0.42)

CONCLUSION: A single 250-μg dose of GM-CSF administered with the influenza vaccine does not improve response to vaccination. Response in cancer patients is low and declines as age and initial titer increase.
Phase III Randomized Trial Comparing Three Platinum-Based Doublets in Advanced Non–Small-Cell Lung Cancer
Authors: Scagliotti G.V. , De Marinis F. , Rinaldi M. , Crinò L. , Gridelli C. , Ricci S. , Matano E. , Boni C. , Marangolo M. , Failla G. , Altavilla G. , Adamo V. , Ceribelli A. , Clerici M. , Di Costanzo F. , Frontini L. , Tonato M.
Published: October 2002

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 2 every 21 days (GC arm), or paclitaxel 225 mg/m2 (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL·min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m2/wk for 12 weeks then every other week plus cisplatin 100 mg/m2 day 1 every 28 days (VC arm).

RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P < .001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P < .001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P < .05).

CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.
Combination Therapy With Thalidomide Plus Dexamethasone for Newly Diagnosed Myeloma
Authors: Rajkumar S. Vincent , Hayman Suzanne , Gertz Morie A. , Dispenzieri Angela , Lacy Martha Q. , Greipp Philip R. , Geyer Susan , Iturria Nancy , Fonseca Rafael , Lust John A. , Kyle Robert A. , Witzig Thomas E.
Published: October 2002

PURPOSE: Multiple myeloma is a malignancy of plasma cells and is characterized by increased marrow angiogenesis. Thalidomide, an agent with antiangiogenic properties, is effective in relapsed myeloma. We report the results of a study combining thalidomide and dexamethasone as initial therapy for myeloma.

PATIENTS AND METHODS: Fifty patients with newly diagnosed myeloma were studied. Thalidomide was given at a dose of 200 mg/d orally. Dexamethasone was given at a dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and 40 mg/d on days 1 to 4 (even cycles), repeated monthly.

RESULTS: Of all 50 patients, a confirmed response was seen in 32 patients yielding a response rate of 64% (95% confidence interval, 49% to 77%). Thirty-one patients (62%) proceeded to stem-cell collection after four cycles of therapy including 26 who underwent stem-cell transplantation and five who chose stem-cell cryopreservation. Major grade 3 or 4 toxicities were observed in 16 patients (32%), and the most frequent were deep vein thrombosis (six patients), constipation (four patients), rash (three patients), and dyspnea (two patients). Three deaths occurred during active therapy because of a pancreatitis, pulmonary embolism, and infection.

CONCLUSION: We conclude that the combination of thalidomide plus dexamethasone is a feasible and active regimen in the treatment of multiple myeloma. It merits further study as an oral alternative to infusional chemotherapy with vincristine, doxorubicin, and dexamethasone and other intravenous regimens currently used as pretransplantation induction therapy for myeloma.
Pain and Quality of Life After Treatment in Patients With Locally Recurrent Rectal Cancer
Authors: Esnaola Nestor F. , Cantor Scott B. , Johnson Margo L. , Mirza Attiqa N. , Miller Alexander R. , Curley Steven A. , Crane Christopher H. , Cleeland Charles S. , Janjan Nora A. , Skibber John M.
Published: October 2002

PURPOSE: Because survival in patients with locally recurrent rectal cancer (LRRC) is limited, pain control and quality of life (QOL) are important parameters. The purpose of this study was to assess the prevalence of posttreatment pain and QOL of patients with LRRC treated with nonsurgical palliation or resection and identify predictors of poor outcome.

PATIENTS AND METHODS: Posttreatment pain severity and QOL were prospectively assessed in 45 patients with LRRC using the Brief Pain Inventory and Functional Assessment of Cancer Therapy–Colorectal questionnaire.

RESULTS: Fifteen patients received nonsurgical palliation, and 30 patients underwent resection of their pelvic tumors. There was a significant association between higher posttreatment pain scores and worse QOL (P < .001). Patients treated with nonsurgical palliation reported moderate to severe pain beyond the third month of treatment. Resected patients reported comparable levels of pain during the first 3 postoperative years, particularly after bony resections; long-term survivors (beyond 3 years), however, reported minimal pain and good QOL. Female sex, pelvic/sciatic pain at presentation, total pelvic exenteration, and bony resection were associated with higher rates of moderate to severe posttreatment pain (P = .04, P < .001, P = .04, and P = .02, respectively). Pain at presentation was an independent predictor of posttreatment pain (odds ratio, 7.4 [95% confidence interval, 1.8 to 30.3]; P = .006).

CONCLUSION: Patients with LRRC treated with nonsurgical palliation or resection experience significant levels of pain after treatment. Close posttreatment pain monitoring is warranted in patients presenting with pelvic pain, and more aggressive pain management strategies may improve posttreatment QOL.
Immunomagnetic Enrichment and Detection of Micrometastases in Colorectal Cancer: Correlation With Established Clinical Parameters
Authors: Weihrauch Martin R. , Skibowski Edmund , Koslowsky Thomas C. , Voiss Wilfried , Re Daniel , Kuhn-Regnier Ferdinand , Bannwarth Carolin , Siedek Michel , Diehl Volker , Bohlen Heribert
Published: October 2002

PURPOSE: Micrometastatic disease in bone marrow is of prognostic significance in colorectal cancer patients. However, detection rates of standard immunocytology are relatively low. We used magnetic activated cell sorting (MACS), a highly sensitive method, to increase detection rates and correlated the presence of cytokeratin (CK)-expressing cells with clinical parameters.

PATIENTS AND METHODS: Bone marrow was obtained from 51 consecutive patients with newly diagnosed colorectal adenocarcinoma who underwent primary surgery and 18 control subjects. International Union Against Cancer (UICC) stage I disease was diagnosed in 11 patients, stage II disease was diagnosed in 14 patients, stage III disease was diagnosed in 12 patients, and stage IV disease was diagnosed in 14 patients. CK-positive cells were enriched and stained with magnetically labeled CAM 5.2 antibodies directed to CK 7 and 8.

RESULTS: CK-positive cells were found in 33 (65%) patients and were absent in 18 (35%). Four of 11 (36%) patients with UICC stage I disease, nine of 14 (64%) with stage II diease, eight of 12 (67%) with stage III disease, and 12 of 14 (86%) with stage IV disease were CK-positive. Epithelial cells were more frequently found in pT3/4 (72%) than in pT1/2 (36%) tumors (P = .026), but there was no difference for lymph node status. CK-positive patients had a higher chance for elevated carcinoembryonic antigen (85% v 15%, P = NS) and CA 19-9 levels (92% v 8%, P = .019). There were no significant differences in CA 72-4, sex, age, tumor grading, or tumor localization regarding the presence of CK-positive cells. All control subjects were CK-negative.

CONCLUSION: In searching for micrometastases in colorectal cancer patients, we have achieved high detection rates by using MACS. The presence of these cells correlated significantly with tumor stage, tumor extension, and the tumor marker CA 19-9.
Phase I Safety, Pharmacokinetic, and Pharmacodynamic Trial of ZD1839, a Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Five Selected Solid Tumor Types
Authors: Baselga J. , Rischin D. , Ranson M. , Calvert H. , Raymond E. , Kieback D.G. , Kaye S.B. , Gianni L. , Harris A. , Bjork T. , Averbuch S.D. , Feyereislova A. , Swaisland H. , Rojo F. , Albanell J.
Published: October 2002

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types.

PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non–small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited.

RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway.

CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.
Dosage Adjustment and Pharmacokinetic Profile of Irinotecan in Cancer Patients With Hepatic Dysfunction
Authors: Raymond Eric , Boige Valérie , Faivre Sandrine , Sanderink Ger-Jan , Rixe Olivier , Vernillet Laurent , Jacques Christian , Gatineau Michel , Ducreux Michel , Armand Jean-Pierre
Published: October 2002

PURPOSE: To determine the recommended dose (RD) and the pharmacokinetic profile of irinotecan and its metabolites in cancer patients with hyperbilirubinemia.

PATIENTS AND METHODS: Patients were assigned to four treatment groups according to their baseline total bilirubin level. Patients in group I (bilirubin within normal range) and group II (bilirubin 1.0 to 1.5 times upper limit of normal [ULN]) received a dose of 350 mg/m2 every 3 weeks. Patients in groups III (bilirubin 1.51 to 3.0 times ULN) and IV (bilirubin > 3.1 times ULN) received starting doses of 175 and 100 mg/m2, respectively. RDs were defined according to the dose-limiting toxicity (DLT) experienced at cycle 1.

RESULTS: Thirty-three patients including 21 gastrointestinal cancers were included. Grade 4 febrile neutropenia and diarrhea were common DLTs in patients with hyperbilirubinemia. At a dose of irinotecan 350 mg/m2, DLTs were observed in two of seven and one of five patients in groups I and II, respectively. In group III, escalated doses of irinotecan 175, 200, and 240 mg/m2 were associated with DLTs in one of seven, one of five, and three of six patients, respectively. No DLT was observed in group IV. High bilirubin and alkaline phosphatase levels were associated with an exponential decrease in the clearance of irinotecan. Pharmacokinetic analysis showed that the relative increase in exposure was likely caused by reduced biliary excretion.

CONCLUSION: We showed that baseline total bilirubin level could be used to determine the appropriate dose of irinotecan in cancer patients with hepatic dysfunction. Doses of 350 mg/m2 and 200 mg/m2 were considered RDs in patients with bilirubin values ≤ 1.5 times ULN and 1.51 to 3.0 times ULN, respectively.
Quality of Breast Cancer Care: What Do We Know?
Authors: Malin Jennifer L. , Schuster Mark A. , Kahn Katherine A. , Brook Robert H.
Published: October 2002

PURPOSE: To critically review studies that describe patterns of care for breast cancer patients and to examine the data sources used for case identification and determining patterns of care.

METHODS: We searched the MEDLINE database (National Library of Medicine, Bethesda, MD) in August 2001 for studies of breast cancer care published from January 1985 to June 2001. Thirty-eight articles, describing 32 studies, met the inclusion criteria for this review.

RESULTS: According to the patterns of care literature, approximately 10% of women do not have an axillary lymph node dissection, 11% to 26% do not have their hormone receptor status reported, 20% do not receive radiation after breast-conserving surgery, and 30% to 70% of women with lymph node–positive breast cancer are not prescribed tamoxifen. Twenty-five (78%) of the studies relied on cancer registries for case identification. Cancer registries (47%) and the medical record (38%) were the most frequent sources of data on process of care. Twenty percent of the articles reported using more than one data source to determine patterns of care.

CONCLUSION: Although more patterns of care research has taken place in breast cancer than in any other oncologic condition, we found the available data had many limitations. These limitations highlight the challenges of quality-of-care research. To track changes in the quality of cancer care that may result from our rapidly transforming health care system, we need reliable data on the quality of current practice.
The Case Identification Challenge in Measuring Quality of Cancer Care
Authors: Pearson Marjorie L. , Ganz Patricia A. , McGuigan Kimberly , Malin Jennifer R. , Adams John , Kahn Katherine L.
Published: October 2002

PURPOSE: The delivery of quality care to all patients with cancer has been named as a national priority within the American health care system. This article addresses the issues critical to case identification in cancer quality measurement and recommends possible strategies for accurately identifying a population of cancer patients.

METHODS: We present the measurement issues associated with the basic challenges of case identification strategies for quality measurement. We discuss two basic challenges: (1) accurately identifying all patients with the defining characteristics (eg, a diagnosis of breast cancer), and (2) identifying only patients with these characteristics.

RESULTS: Possible options for identifying newly diagnosed patients include using claims or other administrative data, cancer registries, cancer registry rapid case ascertainment, pathology laboratories, and physicians’ offices. In the published literature, the sensitivity of claims varies from 75% to 95%, whereas central registries must have a 90% completeness rate to be certified. Most of these approaches, however, involve limitations to obtaining valid and comparable data across multiple settings.

CONCLUSION: Using an existing data collection system staffed by skilled data collectors and managers should result in substantially more accurate and timely data. Registry officials and the government agencies that provide their support should be encouraged to adopt quality-of-care analyses as an important purpose of the registry system and to enhance their capacity to rapidly ascertain cases, collect the appropriate identifying information needed for patient contact, and verify stage at diagnosis. In order to meet the growing demand for timely, accurate information about quality of care, registries are likely to require additional support so they can enhance their capacity to rapidly ascertain cases, collect the appropriate identifying information needed for patient contact, and verify stage at diagnosis.
Low Sensitivity of theki-rasPolymerase Chain Reaction for Diagnosing Pancreatic Cancer From Pancreatic Juice and Bile: A Multicenter Prospective Trial
Authors: Trümper Lorenz , Menges Markus , Daus Heiner , Köhler Daniel , Reinhard Jan-Olaf , Sackmann Michael , Moser Cornelius , Sek Alexandra , Jacobs Georg , Zeitz Martin , Pfreundschuh Michael
Published: October 2002

PURPOSE: Early detection of pancreatic cancer using molecular markers may improve outcome. Mutations of the ki-ras oncogene are detected in 70% to 90% of pancreatic adenocarcinomas. A prospective, partially blinded, multicenter diagnostic trial was performed to test the sensitivity and specificity of the ki-ras polymerase chain reaction (PCR) analysis of pancreatic juice and bile specimens.

PATIENTS AND METHODS: Specimens of pancreatic juice and bile were collected from 532 consecutive patients. Mutations in codon 12 of the ki-ras gene were identified by two independent enrichment PCRs and confirmed by direct sequencing.

RESULTS: One hundred seventy-four of 532 patients were excluded from the final analysis (reasons: no amplifiable DNA, no specimen or only duodenal juice sent, lost to follow-up). Sixty-three of 358 patients had ductal pancreatic cancer. In 24 (38.1%) of 63 patients, a mutated ki-ras gene was identified in pancreatic juice and/or bile. Ki-ras mutations were found in four (8%) of 50 cases of chronic pancreatitis, in 10 (18.7%) of 53 cases of other malignancies of the pancreaticobiliary tree, and in 14 (7.3%) of 192 cases of benign diseases or normal findings. Sensitivity and specificity of the ki-ras PCR analysis for the detection of pancreatic cancer was 38.1% and 90.5%, respectively.

CONCLUSION: In this prospective trial performed in nonselected patients, mutations of the ki-ras gene were detected in 38.1% of cases with pancreatic cancer. This test in its present form is not appropriate to confirm or screen for pancreatic cancer. More sensitive and/or quantitative PCR tests may improve the molecular diagnosis of pancreatic cancer.
Primary Adult Soft Tissue Sarcoma: Time-Dependent Influence of Prognostic Variables
Authors: Stojadinovic Alexander , Leung Denis H.Y. , Allen Peter , Lewis Jonathan J. , Jaques David P. , Brennan Murray F.
Published: October 2002

PURPOSE: To define prognostic factors for postrelapse survival and their time-dependent influence for adult soft tissue sarcoma (STS).

PATIENTS AND METHODS: We analyzed 2,123 patients with completely resected localized primary STS treated from 1982 to 1999. Variables studied included tumor site, size, depth, grade, and resection margin but not treatment other than resection. Landmark time frames were used to assess the influence of disease-free interval (DFI) on disease-specific survival (DSS). DSS was estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed using log-rank test and the Cox proportional hazards regression model. Time-dependent stepwise regression analysis evaluated the time-dependent influence of each variable.

RESULTS: Two thirds of recurrences developed within 2 years of initial resection. Tumor size (P < .001), grade (P < .001), and microscopic resection margin (P < .001) independently predicted DSS for all STS. Size and grade independently predicted early (DFI ≤ 3 years) and margin late (DFI > 3 years) DSS. Risk of tumor-related death was the same across all sites 3 years postresection and decreased significantly for extremity/trunk STS when DFI exceeded 3 years (P < .001). Influence of initial high-risk factors for tumor-related mortality in extremity/trunk STS decreased by 40% 3 years postresection, but their influence over DSS for non–extremity/trunk sites remained constant over time. Likelihood of complete resection after recurrence (all sites) increased with DFI (9% and 33% for DFI < 6 and > 36 months, respectively).

CONCLUSION: Tumor size, grade, and resection margin predict outcome for completely resected STS, and their influence for DSS is time- and site-dependent. The influence of prognostic factors changes over the natural history of extremity/trunk STS. Time to recurrence exerts significant influence over complete resection rates for recurrent disease.
Expression of CEACAM1 in Adenocarcinoma of the Lung: A Factor of Independent Prognostic Significance
Authors: Laack Eckart , Nikbakht Haleh , Peters Anja , Kugler Christian , Jasiewicz Yvonne , Edler Lutz , Brümmer Jens , Schumacher Udo , Hossfeld Dieter Kurt
Published: October 2002

PURPOSE: To evaluate the prognostic relevance of CEACAM1 and sialyl Lewis X expression in adenocarcinomas of the lung.

PATIENTS AND METHODS: Paraffin wax sections of 93 patients with adenocarcinomas of the lung who underwent surgery between 1990 and 1995 were immunohistochemically investigated using monoclonal anti-CEACAM1 and sialyl Lewis X antibodies. The clinical course of all patients was followed up for a minimum of 5 years.

RESULTS: Sixty-one tumors were classified as CEACAM1-positive, and 32 were classified as CEACAM1-negative. Patients with CEACAM1-positive tumors had a significantly poorer overall (P = .00025) and relapse-free (P = .00029) survival than those with CEACAM1-negative tumors. Only three patients did not express the sialyl Lewis X glycotope, whereas 90 tumors (97%) were sialyl Lewis X–positive. In multivariate Cox regression analysis, next to tumor stage and sex, only the expression of CEACAM1 was a significant independent prognostic factor for survival.

CONCLUSION: Expression of CEACAM1 was an independent prognostic factor in our patient population and can be used to stratify patients with adenocarcinomas of the lung into low-risk and high-risk groups. In contrast, the expression of sialyl Lewis X was of no prognostic relevance because it was expressed in 97% of all investigated tumors, and most likely has no influence on the function of CEACAM1 in this tumor entity.
Vascular Permeability Factor/Vascular Endothelial Growth Factor: A Critical Cytokine in Tumor Angiogenesis and a Potential Target for Diagnosis and Therapy
Authors: Dvorak Harold F.
Published: October 2002

ABSTRACT: Vascular endothelial growth factor A (VEGF-A), the founding member of the vascular permeability factor (VPF)/VEGF family of proteins, is an important angiogenic cytokine with critical roles in tumor angiogenesis. This article reviews the literature with regard to VEGF-A’s multiple functions, the mechanisms by which it induces angiogenesis, and its current and projected roles in clinical oncology. VEGF-A is a multifunctional cytokine that is widely expressed by tumor cells and that acts through receptors (VEGFR-1, VEGFR-2, and neuropilin) that are expressed on vascular endothelium and on some other cells. It increases microvascular permeability, induces endothelial cell migration and division, reprograms gene expression, promotes endothelial cell survival, prevents senescence, and induces angiogenesis. Recently, VEGF-A has also been shown to induce lymphangiogenesis. Measurements of circulating levels of VEGF-A may have value in estimating prognosis, and VEGF-A and its receptors are potential targets for therapy. Recognized as the single most important angiogenic cytokine, VEGF-A has a central role in tumor biology and will likely have an important role in future approaches designed to evaluate patient prognosis. It may also become an important target for cancer therapy.
Relevance of Bone Marrow Cell Dose on Allogeneic Transplantation Outcomes for Patients With Acute Myeloid Leukemia in First Complete Remission: Results of a European Survey
Authors: Rocha Vanderson , Labopin Myriam , Gluckman Eliane , Powles Ray , Arcese William , Bacigalupo Andrea , Reiffers Josy , Iriondo Arturo , Ringdén Olle , Ruutu Tapani , Frassoni Francesco
Published: October 2002

PURPOSE: Many attempts have been made to improve the results of allogeneic bone marrow transplantation (alloBMT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Bone marrow cell dose has been reported to be an important factor in alloBMT; however, its true impact on relapse incidence (RI), leukemia-free survival (LFS), and nonrelapse mortality (NRM) in a large cohort of patients is unknown.

PATIENTS AND METHODS: From January 1992 to December 1999, 572 bone marrow transplantation recipients reported to the European Blood and Marrow Transplantation (EBMT) registry underwent allografting from an HLA-identical sibling donor with an unmanipulated bone marrow for AML in CR1.

RESULTS: The median number of nucleated cells (NCs) infused was 2.6 × 108/kg. Estimated 5-year NRM, LFS, and RI for patients receiving more or less than 2.6 × 108NCs/kg were, respectively, 18% ± 5% v 30% ± 5% (P = .001), 68% ± 3% v 46% ± 3% (P < .00001), and 14% ± 4% v 24% ± 5% (P = .004). The association of cell dose with the above outcomes was confirmed in multivariate analyses for NRM (relative risk [RR], 0.53; P = .0007), for LFS (RR, 0.53; P = .00008), and for RI (RR, 0.57; P = .02). The cell dose was also an important factor for neutrophil (RR, 0.76; P = .009) and platelet (RR, 0.77; P = .03) recoveries; however, it did not statistically influence the incidence of acute graft-versus-host disease.

CONCLUSION: This study shows that marrow cell dose is one of the most important factors influencing relapse, NRM, and LFS after alloBMT for patients with AML in CR1. Therefore, increasing the marrow cell dose should substantially improve the survival of these patients.
Metal Ion-Assisted Weak Interactions Involving Biological Molecules. From Small Complexes to Metalloproteins
Authors: Yamauchi Osamu , Odani Akira , Hirota Shun
Published: November 2002

Noncovalent or weak interactions play important roles in molecular recognition and structual organization in chemical and biological systems. Hydrogen bonding and aromatic ring stacking are widely recognized for biomolecules, and these and other types of weak interactions are recently attracting much attention as a clue to understanding the efficiency and specificity of biological reactions. We studied weak interactions around the metal center as factors for mixed ligand (ternary) metal complex formation, molecular recognition, and construction of self-organized structures by potentiometric, spectroscopic, and crystallographic methods. We concluded the electrostatic ligand–ligand interactions within Cu(II) and Pd(II) complexes containing an acidic and a basic amino acid and aromatic ring stacking interactions between the aromatic rings of an aromatic amino acid and a coordinated aromatic ligand such as 2,2′-bipyridine. Selective adduct formation between Pt(II) complexes and uncoordinated mononucleotides were found to occur through stacking and hydrogen bonding. In the systems with aromatic ring stacking, a close metal–aromatic ring contact was revealed in the solid state, and the 195Pt NMR spectra indicated electron density decrease due to stacking. As an extension of such studies, we investigated metalloprotein–charged peptide electrostatic interactions and established the redox partner binding site of plastocyanin and its subtle structural change due to the interactions. The results demonstrated the use of charged oligopeptides as models for the studies on protein–protein binding. Weak interactions between [Cu(arginine)2]2+ and its counterions, such as benzene-1,3-dicarboxylate, led to controlled self-organization of the complex ion, giving crystalline products with handed single-helical or double-helical structures and layer structures, depending on the anions used.
Synthesis of β-d-Ribofuranosyl-(1→3)-α-l-rhamnopyranosyl-(1→3)-l-rhamnopyranose by in situ Activating Glycosylation Using 1-OH Sugar Derivative and Me3SiBr–CoBr2–Bu4NBr–Molecular Sieves 4A System
Authors: Hirooka Motoko , Mori Yoko , Sasaki Akiko , Koto Shinkiti , Shinoda Yoshika , Morinaga Aya
Published: November 2002

β-d-Ribofuranosyl-(1→3)-α-l-rhamnopyranosyl-(1→3)-l-rhamnopyranose, the trisaccharide repeating unit of the C. freundii O28,1c O-specific polysaccharide, was synthesized using in situ activating glycosylation of the 1-OH sugar derivatives and a reagent mixture of trimethylsilyl bromide, cobalt(II) bromide, tetrabutylammonium bromide, and molecular sieves 4A. Regioselective tritylation was useful for synthesizing the 3-OH derivatives of methyl, allyl, and benzyl α-l-rhamnosides.
Preparation and Characterization of Novel Activated Carbons with Antibacterial Function
Authors: Yamamoto Osamu , Sawai Jun
Published: November 2002

After ion-exchange resins were treated for 24 h by an aqueous solution of [Zn(NH3)4]2+ complex, the treated resins were carbonized for 10 min in nitrogen gas at each temperature. The activated carbons with ZnO were then prepared. The antibacterial activity on their carbon samples was studied without the presence of light. ZnO of hexagonal type was detected in the carbon samples, of which the amount decreased with an increase in the carbonization temperature. However, the specific surface areas of carbon samples increased with increasing the carbonization temperature of the resin. The antibacterial activity on carbon samples containing ZnO increased with a decrease of the carbonization temperature and an increase of the amount of ZnO in the samples. From a comparison of the antibacterial activity between Staphylococcus aureus and Escherichia coli, it was found that the activity for Staphylococcus aureus was stronger than that for Escherichia coli. The concentration of hydrogen peroxide increased linearly with an increase in the amount of carbon samples. The occurrence of antibacterial activity was found to be due to the generation of hydrogen peroxide from ZnO in activated carbons.
Direct Hydrogenation of Carboxylic Acids to Corresponding Aldehydes Catalyzed by Palladium Complexes
Authors: Nagayama Kazuhiro , Shimizu Isao , Yamamoto Akio
Published: November 2002

A variety of carboxylic acids can be directly hydrogenated into the corresponding aldehydes in high yields by using homogeneous catalysts such as [Pd(PPh3)4] or combination of Pd(OAc)2 with tertiary phosphines in the presence of an excess amount of 2,2-dimethylpropionic anhydride (pivalic anhydride). As a typical example, octanoic acid can be converted into octanal in 99% yield in 3 h at 80 °C under 3.0 MPa of H2 in acetone in the presence of pivalic anhydride and a catalyst system composed of Pd(OAc)2 + 5P(p-tol)3. Such hydrogenation is widely applicable to various aliphatic, aromatic, and heterocyclic carboxylic acids as well as to di- and tribasic carboxylic acids. The process allows the presence of other functional groups such as ketonic carbonyl, nitrile, and ester groups and even internal C=C bonds. Heterogeneous palladium catalyst such as palladium on carbon also showed some catalytic activities.
Inequality Among World Citizens: 1820–1992
Authors: Bourguignon François , Morrisson Christian
Published: October 2002

This paper investigates the distribution of well being among world citizens during the last two centuries. The estimates show that inequality of world distribution of income worsened from the beginning of the 19th century to World War II and after that seems to have stabilized or to have grown more slowly. In the early 19th century most inequality was due to differences within countries; later, it was due to differences between countries. Inequality in longevity, also increased during the 19th century, but then was reversed in the second half of the 20th century, perhaps mitigating the failure of income inequality to improve in the last decades.
The Returns to Entrepreneurial Investment: A Private Equity Premium Puzzle?
Authors: Moskowitz Tobias J , Vissing-Jørgensen Annette
Published: October 2002

We document the return to investing in U.S. nonpublicly traded equity. Entrepreneurial investment is extremely concentrated, yet despite its poor diversification, we find that the returns to private equity are no higher than the returns to public equity. Given the large public equity premium, it is puzzling why households willingly invest substantial amounts in a single privately held firm with a seemingly far worse risk-return trade-off. We briefly discuss how large nonpecuniary benefits, a preference for skewness, or overestimates of the probability of survival could potentially explain investment in private equity despite these findings.
Managing Dynamic Competition
Authors: Lewis Tracy R , Yildirim Huseyin
Published: October 2002

In many important high-technology markets, including software development, data processing, communications, aeronautics, and defense, suppliers learn through experience how to provide better service at lower cost. This paper examines how a buyer designs dynamic competition among rival suppliers to exploit learning economies while minimizing the costs of becoming locked in to one producer. Strategies for controlling dynamic competition include the handicapping of more efficient suppliers in procurement competitions, the protection and allocation of intellectual property, and the sharing of information among rival suppliers.
Rigidity, Discretion, and the Costs of Writing Contracts
Authors: Battigalli Pierpaolo , Maggi Giovanni
Published: October 2002

In this paper we model contract incompleteness “from the ground up,” as arising endogenously from the costs of describing the environment and the parties' behavior. Optimal contracts may exhibit two forms of incompleteness: discretion, meaning that the contract does not specify the parties' behavior with sufficient detail; and rigidity, meaning that the parties' obligations are not sufficiently contingent on the external state. The model sheds light on the determinants of rigidity and discretion in contracts, and yields rich predictions regarding the impact of changes in the exogenous parameters on the degree and form of contract incompleteness.
Contractual Structure and Wealth Accumulation
Authors: Mookherjee Dilip , Ray Debraj
Published: October 2002

Can historical wealth distributions affect long-run output and inequality despite “rational” saving, convex technology and no externalities? We consider a model of equilibrium short-period financial contracts, where poor agents face credit constraints owing to moral hazard and limited liability. If agents have no bargaining power, poor agents have no incentive to save: poverty traps emerge and agents are polarized into two classes, with no interclass mobility. If instead agents have all the bargaining power, strong saving incentives are generated: the wealth of poor and rich agents alike drift upward indefinitely and “history” does not matter eventually.