bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease
Authors: Jundt Franziska , Kley Katharina , Anagnostopoulos Ioannis , Schulze Pröbsting Kristina , Greiner Axel , Mathas Stephan , Scheidereit Claus , Wirth Thomas , Stein Harald , Dörken Bernd 
Published: October 2002

Abstract
Immunoglobulin transcription is impaired in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD). We recently demonstrated that defective immunoglobulin promoter transcription correlates with the down-regulation of the B-cell transcription factors Oct2 and BOB.1/OBF.1. These results prompted us to investigate whether immunoglobulin enhancer activity is also impaired in HRS cells and whether as yet unidentified factors could be necessary for immunoglobulin enhancer activity in HRS cells of cHD. Here we analyzed 30 cases of cHD for expression of the Ets family member PU.1 that is known to collaborate with multiple transcription factors and to regulate expression of immunoglobulin genes. We show that PU.1 is not expressed in primary and cultured HRS cells. Reintroduction of PU.1 and Oct2 in cultured HRS cells restored the activity of cotransduced immunoglobulin enhancer constructs. Our study identifies PU.1 deficiency as a recurrent defect in HRS cells that might contribute to their impairment of immunoglobulin transcription.
Adapting a transforming growth factor β–related tumor protection strategy to enhance antitumor immunity
Authors: Bollard Catherine M. , Rössig Claudia , Calonge M. Julia , Huls M. Helen , Wagner Hans-Joachim , Massague Joan , Brenner Malcolm K. , Heslop Helen E. , Rooney Cliona M. 
Published: October 2002

AbstractTransforming growth factor β (TGF-β), a pleiotropic cytokine that regulates cell growth and differentiation, is secreted by many human tumors and markedly inhibits tumor-specific cellular immunity. Tumors can avoid the differentiating and apoptotic effects of TGF-β by expressing a nonfunctional TGF-β receptor. We have determined whether this immune evasion strategy can be manipulated to shield tumor-specific cytotoxic T lymphocytes (CTLs) from the inhibitory effects of tumor-derived TGF-β. As our model we used Epstein-Barr virus (EBV)–specific CTLs that are infused as treatment for EBV-positive Hodgkin disease but that are vulnerable to the TGF-β produced by this tumor. CTLs were transduced with a retrovirus vector expressing the dominant-negative TGF-β type II receptor HATGF-βRII-Δcyt. HATGF-βRII-Δcyt– but not green fluorescence protein (eGFP)–transduced CTLs was resistant to the antiproliferative and anticytotoxic effects of exogenous TGF-β. Additionally, receptor-transduced cells continued to secrete cytokines in response to antigenic stimulation. TGF-β receptor ligation results in phosphorylation of Smad2, and this pathway was disrupted in HATGF-βRII-Δcyt–transduced CTLs, confirming blockade of the signal transduction pathway. Long-term expression of TGF-βRII-Δcyt did not affect CTL function, phenotype, or growth characteristics. Tumor-specific CTLs expressing HATGF-βRII-Δcyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF-β–secreting tumors and may be of value in treatment of these diseases.
Perturbation of B-cell development in mice overexpressing the Bcl-2 homolog A1
Authors: Chuang Peter I. , Morefield Samantha , Liu Chien-Ying , Chen Stephen , Harlan John M. , Willerford Dennis M. 
Published: October 2002

AbstractDecisions about cell survival or death are central components of adaptive immunity and occur at several levels in immune system development and function. The Bcl-2 family of homologous proteins plays an important role in these decisions in lymphoid cells. Bcl-2, Bcl-xL, and A1 are differentially expressed during B- and T-cell development, and they have shared and distinct roles in regulating cell death. We sought to gain insight into the role of A1 in immune system development and function. A murine A1-a transgene was expressed under the control of the Eμ enhancer, and mice with A1 overexpression in B- and T-cell lineages were derived. Thymocytes and early B cells in Eμ-A1 mice showed extended survival. B-lineage development was altered, with expansion of the pro–B cell subset at the expense of pre–B cells, suggesting an impairment of the pro– to pre–B-cell transition. This early B-cell phenotype resembled Eμ–Bcl-xL mice but did not preferentially rescue cells with completed V(D)J rearrangements of the immunoglobulin heavy chain. In contrast to Eμ–Bcl-2 transgenes, A1 expression in pro–B cells did not rescue pre–B-cell development in SCID mice. These studies indicate that A1 protects lymphocytes from apoptosis in vitro but that it has lineage- and stage-specific effects on lymphoid development. Comparison with the effects of Bcl-2 and Bcl-xL expressed under similar control elements supports the model that antiapoptotic Bcl-2 homologs interact differentially with intracellular pathways affecting development and apoptosis in lymphoid cells.
In situ localization of follicular lymphoma: description and analysis by laser capture microdissection
Authors: Cong Peijie , Raffeld Mark , Teruya-Feldstein Julie , Sorbara Lynn , Pittaluga Stefania , Jaffe Elaine S. 
Published: October 2002

AbstractFrom 1992 to 2000, we identified 23 lymph node biopsies with focal germinal centers (GCs) containing centrocytes staining strongly for bcl-2 protein, whereas most of the remaining lymph node showed bcl-2–negative follicular hyperplasia. We propose the designation in situ localization of follicular lymphoma (FL) for this phenomenon. In 2 additional cases, bcl-2+ follicles with features of in situ FL were identified in association with other low-grade B-cell lymphomas. To investigate the clonality of the bcl-2+follicles, we performed laser capture microdissection of bcl-2+ and bcl-2 follicles from the same lymph node in 5 cases, and analyzed them in parallel by polymerase chain reaction (PCR) amplification of immunoglobulin heavy chain (IgH) genes. In 4 of 5 cases the bcl-2+ follicles contained monoclonal IgH gene rearrangements, whereas the bcl-2− GCs exhibited a polyclonal ladder. A BCL2/JH gene rearrangement was detected in 6 of 14 (43%) evaluable cases. There were 5 patients with synchronous evidence of FL at another site. There were 13 patients who, without a prior diagnosis of FL, had clinical follow-up; one developed FL in an adjacent lymph node within one year, and 2 manifested FL at 13 and 72 months, respectively. There are 10 patients who have not yet shown other evidence of FL. These results suggest that at least close to half of these cases (8/18; 44%) represent homing to and early colonization of reactive GCs by FL. Other cases might represent FL at the earliest stage of development, or a preneoplastic event, requiring a second hit for neoplastic transformation. These findings provide insight into the pathophysiology of early FL, and illustrate the utility of immunohistochemistry for early diagnosis.
Derivation of a Termination‐of‐resuscitation Guideline for Emergency Medical Technicians Using Automated External Defibrillators
Authors: Verbeek P. Richard , Vermeulen Marian J. , Ali Fahim H. , Messenger David W. , Summers Jim , Morrison Laurie J. 
Published: October 2002

Abstractcardiac arrest and survival to hospital discharge following failed resuscitation by defibrillation‐trained emergency medical technicians (EMT‐Ds), and to propose an out‐of‐hospital termination‐of‐resuscitation (TOR) guideline for EMT‐Ds. Methods: A 22‐month retrospective review of 700 out‐of‐hospital primary cardiac arrest patients in a large emergency medical services (EMS) system who received exclusively EMT‐D care. Results: Seven hundred primary cardiac arrest patients were identified. Follow‐up was obtained in 662 cases (94.6%). Of these, 36 (5.4%) achieved a return of spontaneous circulation (ROSC) prior to transport. Among the 626 patients who failed to achieve ROSC at any time, two (0.3%) survived to discharge. Multivariate analysis showed that ROSC at any time had the strongest association with survival [odds ratio (OR) 45.5; 95% confidence interval (95% CI) = 8.5 to 243.7]. A shock prior to transport (OR 6.9; 95% CI = 1.2 to 40.3) and cardiac arrest witnessed by EMS personnel (OR 4.4; 95% CI = 1.0 to 18.5) were also independently associated with survival. These variables were incorporated into a TOR guideline. The guideline was 100% sensitive (95% CI = 99.1 to 100) in identifying survivors and had 100% negative predictive value (95% CI = 75.3 to 100) for identifying nonsurvivors of out‐of‐hospital cardiac arrest in the study population. Conclusions: In this EMS system, cardiac arrest patients may be considered for out‐of‐hospital TOR following EMT‐D resuscitation attempts when there has been no ROSC, no shock has been given, and the arrest was not witnessed by EMS personnel. These guidelines require prospective validation.
Survival of Patients With Newly Diagnosed Glioblastoma Multiforme Treated With RSR13 and Radiotherapy: Results of a Phase II New Approaches to Brain Tumor Therapy CNS Consortium Safety and Efficacy Study
Authors: Kleinberg L. , Grossman S.A. , Carson K. , Lesser G. , O’Neill A. , Pearlman J. , Phillips P. , Herman T. , Gerber M. 
Published: October 2002

PURPOSE: The objectives of this phase II study were to determine survival, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 2,4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid (RSR13, efaproxiral) 100 mg/kg per day administered with standard cranial radiotherapy (RT) for the treatment of glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin, is a radiation-enhancing agent that noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue. PATIENTS AND METHODS: Fifty patients with newly diagnosed GBM (Karnofsky performance status ≥ 60) were enrolled onto this multicenter phase II study. Patients received daily RSR13 100 mg/kg intravenously infused for 30 minutes immediately before cranial RT (60 Gy in 30 fractions). Supplemental oxygen was given during RSR13 infusion and continued until after the RT treatment was completed. RT was given within 30 minutes of the end of RSR13 infusion. PK and PD determinations were performed. RESULTS: The median survival for the RSR13-treated patients was 12.3 months with 1-year and 18-month survival rates of 54% and 24%, respectively. Twenty-four percent of patients had greater than grade 2 toxicity, which was generally transient and self-limited. A significant PD effect on hemoglobin-oxygen binding affinity was demonstrated for most patients. CONCLUSION: RSR13 (100 mg/kg) administered immediately before cranial RT is well tolerated and is pharmacodynamically active. Median survival in excess of 1 year is favorable.
Role of Chest Computed Tomography at Diagnosis in the Management of Wilms’ Tumor: A Study by the United Kingdom Children’s Cancer Study Group
Authors: Owens C. M. , Veys P. A. , Pritchard J. , Levitt G. , Imeson J. , Dicks-Mireaux C. 
Published: October 2002

PURPOSE: This study sought to determine whether the identification of minimal pulmonary metastatic disease by chest computed tomography (CT) performed at diagnosis in patients with Wilms’ tumor and normal chest x-rays (CXR) could predict a subgroup of children at increased risk of pulmonary relapse. PATIENTS AND METHODS: A retrospective analysis was carried out of the records of 449 children entered onto the United Kingdom Childrens’ Cancer Study Group Second Wilms’ Tumor Study between July 1986 and September 1991. The imaging protocol did not stipulate chest CT at diagnosis, but 141 children who had normal frontal and lateral CXRs and a chest CT scan performed at diagnosis were eligible for analysis. After surgery, children with stage I Wilms’ tumor received single-agent chemotherapy (vincristine), whereas children with stages II, III, and bilateral Wilms’ tumor received combination chemotherapy. Most children with stage III tumors were also treated with abdominal radiotherapy (20 Gy). RESULTS: In 31 patients (22%), pulmonary nodules were visible on chest CT; eight experienced relapse, four (15%) in the lungs. When only stage I patients were analyzed, there was a significant difference between the pulmonary relapse rate of 43% (three of seven) in the CT-positive group and 10% (five of 48) in the CT-negative group (P = .02). Four of eight patients with stage I disease with pulmonary relapse died. CONCLUSION: CT seemed to identify a subgroup of stage I patients who were at increased risk of pulmonary relapse. These children had received only single-agent chemotherapy. A prospective randomized trial is needed to clarify whether these children would benefit from combination chemotherapy.
Response to Neoadjuvant Chemotherapy Combined With Regional Hyperthermia Predicts Long-Term Survival for Adult Patients With Retroperitoneal and Visceral High-Risk Soft Tissue Sarcomas
Authors: Wendtner Clemens-M. , Abdel-Rahman Sultan , Krych Matthäus , Baumert Jens , Lindner Lars H. , Baur Andrea , Hiddemann Wolfgang , Issels Rolf D. 
Published: October 2002

PURPOSE: To determine the efficacy of neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for local tumor control and overall survival (OS) in adult patients with retroperitoneal or visceral (RP/V) high-risk soft tissue sarcomas (HR-STS).PATIENTS AND METHODS: From 1991 to 1997, 58 patients with HR-STS at RP/V sites were prospectively treated with four cycles of etoposide, ifosfamide, and doxorubicin combined with RHT followed by surgery, adjuvant chemotherapy, and radiation.RESULTS: Objective response rate assessable in 40 patients was 13% (five partial responses). Including minor responses (n = 8), the radiographic response rate was 33%. The pathologic response rate assessable in 26 patients after surgical resection was 42%. Median OS was 31 months. At a median observation time of 74 months, 5-year probability of local failure-free survival (LFFS), distant metastasis-free survival, event-free survival, and OS were 25%, 51%, 20%, and 32%, respectively. Averaged minimum temperatures (Tmin) and time-averaged temperatures achieved in 50% (T50) and 90% (T90) of all measured tumor sites differed significantly between responders and nonresponders (Tmin, 39.3°C v 38.0°C; P = .002; T50, 40.9°C v 40.3°C; P = .038; T90, 40.1°C v 39.3°C; P = .017). At 5-year follow-up, probability of LFFS (59% v 0%; P < .001) and OS (60% v 10%; P < .001) was significantly in favor of patients responding to neoadjuvant thermochemotherapy.CONCLUSION: Response to neoadjuvant chemotherapy combined with RHT is predictive for an improved local tumor control resulting in a long-term survival benefit for patients with HR-STS at unfavorable RP/V sites; however, the impact of RHT has to be defined in a randomized phase III trial.
Time to Progression in Metastatic Breast Cancer Patients Treated With Epirubicin Is Not Improved by the Addition of Either Cisplatin or Lonidamine: Final Results of a Phase III Study With a Factorial Design
Authors: Berruti Alfredo , Bitossi Raffaella , Gorzegno Gabriella , Bottini Alberto , Alquati Palmiro , De Matteis Andrea , Nuzzo Francesco , Giardina Giorgio , Danese Saverio , De Lena Mario , Lorusso Vito , Farris Antonio , Sarobba Maria Giuseppa , DeFabiani Enza , Bonazzi Giorgio , Castiglione Federico , Bumma Cesare , Moro Gregorio , Bruzzi Paolo , Dogliotti Luigi 
Published: October 2002

PURPOSE: To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer. PATIENTS AND METHODS: Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m2 on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m2 on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 × 2 factorial design of this study. RESULTS: The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P = .10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P = .47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P = .08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue. CONCLUSION: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug’s tolerability.
Interim Comparison of a Continuous Infusion Versus a Short Daily Infusion of Cytarabine Given in Combination With Cladribine for Pediatric Acute Myeloid Leukemia
Authors: Crews Kristine R. , Gandhi Varsha , Srivastava Deo Kumar , Razzouk Bassem I. , Tong Xin , Behm Fred G. , Plunkett William , Raimondi Susana C. , Pui Ching-Hon , Rubnitz Jeffrey E. , Stewart Clinton F. , Ribeiro Raul C. 
Published: October 2002

PURPOSE: To identify the optimal schedule for infusion of cytarabine (ara-C) given with cladribine (2-CdA) to pediatric patients with acute myeloid leukemia (AML), and to compare the effects of the two schedules on the pharmacokinetics of ara-C triphosphate (ara-CTP) in leukemic cells. PATIENTS AND METHODS: Forty-nine pediatric patients with newly diagnosed primary AML received a 5-day course of ara-C 500 mg/m2/d and 2-CdA 9 mg/m2/d. They were randomly assigned to receive ara-C as either a 2-hour daily infusion (arm A) or a continuous infusion (arm B). Cellular pharmacokinetics were studied on days 1 and 2. All patients then received two courses of remission induction chemotherapy with daunorubicin, ara-C, and etoposide (DAV). RESULTS: Thirty-two percent of patients (seven of 22) in arm A and 63% (17 of 27) in arm B entered complete remission (P = .045) after ara-C and 2-CdA therapy. Coadministration of 2-CdA increased the intracellular concentration of ara-CTP in 20 of 36 patients, although we found no statistically significant difference between the treatment arms in this effect (P = .63). The incidence of toxicity did not differ significantly between the two treatment arms (P = .53). After two courses of DAV, the rate of complete remission was 91% in arm A and 96% in arm B (P = .58). CONCLUSION: Intracellular accumulation of ara-CTP is increased when 2-CdA is given with ara-C, but no schedule-dependent differences in this effect were seen. The combination of 2-CdA and ara-C seems to be effective therapy for pediatric AML.
Hormonal influence on the release of endothelial nitric oxide: gender-related dimorphic sensitivity of rat aorta for noradrenaline
Authors: Calderone Vincenzo , Baragatti Barbara , Breschi Maria Cristina , Nieri Paola , Martinotti Enrica 
Published: October 2002

Abstract
Male gender shows a higher incidence of vascular disorders and this phenomenon could be explained by sexual dimorphic behaviour of vessels. Both gonadal hormones and endothelial nitric oxide (NO) are involved in the regulation of the vascular reactivity. This study aimed to evaluate a possible sexual dimorphic sensitivity of rat aorta for the catecholamine noradrenaline. To understand the role played by physiological concentrations of sex hormones, the experimental procedures were performed on isolated preparations from intact (sham-operated) and gonadectomized rats of both sexes. In parallel sets of experiments, the biosynthesis of NO was inhibited by Nω-nitro-l-arginine methyl ester (L-NAME) to reveal any potential involvement of the endothelial modulator and its possible link with the endocrinous factor. In aortae from intact male and female rats, noradrenaline induced contractile effects with different potencies (mean ± s.d. EC50 values 12.15 ± 5.25 nM and 84.10 ±18.68 nM, respectively). Gonadectomy resulted in an increased sensitivity for noradrenaline in female vessels and a decreased sensitivity for the agonist in male vessels (EC50 values 25.64 ± 5.04 nM and 21.70 ± 11.13 nM, respectively). In aortae from intact male rats, the inhibition of NO biosynthesis resulted in a weak increase in sensitivity for noradrenaline (EC50 value 6.08 ±4.53 nM), whereas the increase was higher in vessels from intact female rats (EC50 value 10.38 ± 8.40 nM). After treatment with L-NAME, aortae from gonadectomized male and female rats presented almost equivalent increases in sensitivity for the adrenergic agonist (EC50 values 6.02 ± 3.63 nM and 9.10 ± 9.63 nM, respectively), and no significant difference in sensitivity could be recorded between intact and orchidectomized male rats, or between intact and ovariectomized female rats. It was concluded that rat aorta showed a sexual dimorphic sensitivity for noradrenaline and the female sex was more protected against the adrenergic contractile stimulus because of a higher release of endothelial NO. The gender-related difference in NO release was influenced by gonadal hormones, with the female hormones inducing an increase and the male hormones causing a reduction.
Prognostic value of plasma interleukin‐6 levels in patients with chronic lymphocytic leukemia
Authors: Lai Raymond , O'Brien Susan , Maushouri Taghi , Rogers Anna , Kantarjian Hagop , Keating Micheal , Albitar Maher 
Published: October 2002

AbstractBACKGROUNDInterleukin 6 (IL‐6) is a B‐cell growth and differentiation factor, which may promote the growth of B‐cell neoplasms. In chronic lymphocytic leukemia (CLL) patients, IL‐6 plasma levels increased in a stage‐dependent manner, suggesting that IL‐6 may be a useful prognostic marker. The purpose of this study is to fully assess the prognostic value of IL‐6 in CLL patients.METHODSWe measured the plasma levels of IL‐6 in 100 CLL patients using an enzyme‐linked immunoassay method.RESULTSIncreasing levels of IL‐6 significantly correlated with patient age, severity of anemia, Rai stage, white cell count, and β‐2‐microglobulin (β‐2M). Although CLL patients did not differ significantly from the normal controls in the median IL‐6 plasma level (P = 0.38), patients with advanced diseases (defined by Rai stage III/IV or β‐2M > 3.5) had a significantly higher median IL‐6 plasma level than the normal controls (P < 0.05). Furthermore, in patients with advanced diseases, Cox regression hazards model showed that a higher IL‐6 level correlated with shorter survival (P = 0.0001). Using IL‐6 level of 3 pg/mL as a cutoff, patients with low IL‐6 levels had a significantly longer overall survival than those with high IL‐6 levels (log rank test, P = 0.002). In patients with CD38‐positive CLL, patients with high IL‐6 levels (> 3 pg/mL) had significantly shorter survival (P = 0.03). To conclude, IL‐6 is a particularly useful predictor for survival in CLL patients with advanced diseases.CONCLUSIONSOur findings suggest that patients with advanced‐stage CLL as well as high IL‐6 plasma levels may require aggressive therapeutic approaches and special consideration for experimental therapy. Cancer 2002;95:1071–5. © 2002 American Cancer Society.DOI 10.1002/cncr.10772