bluuebunny/crossref_metadata_2025 huggingface dataset:
Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia in first complete remission: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: Garderet Laurent , Labopin Myriam , Gorin Norbert-Claude , Polge Emmanuelle , Baruchel André , Meloni Giovanna , Ortega Juan , Vossen Jaak , Bunjes Donald , Leverger Guy , Blaise Didier , Ferrant Augustin , Brune Mats , Dore Eric , Gadner Helmut , Zintl Felix , Yaniv Isaac , Dini Giorgio , Frassoni Francesco
Published: June 2004

Acute megakaryoblastic leukemia (M7 AML) is a highly aggressive disease. We evaluated outcomes in 57 children (11 with Down syndrome) and 69 adults with M7 AML after first complete remission (CR1) following autologous or HLA-identical allogeneic transplantation. Characteristics of the recipients of autologous transplants (38 children, 37 adults) were, respectively: median age, 1.7 and 46 years; non-total body irradiation (non-TBI) conditioning regimen, 97% and 70%; bone marrow as stem cell source, 74% and 43%. Characteristics of the recipients of allogeneic transplants (19 children, 32 adults) were, respectively: median age, 2.8 and 37 years; non-TBI regimen, 63% and 42%; bone marrow as stem cell source, 95% and 69%. Autologous transplantation benefited children more; the relapse rate was high in adults. Results for autologous transplantation were (children and adults, respectively): engraftment, 90% and 100%; 3-year treatment-related mortality (TRM) rate, 3% and 8%; relapse rate, 45% and 64%; leukemia-free survival (LFS) rate, 52% and 27%; overall survival (OS) rate, 61% and 30%. After allogeneic transplantation, TRM was fairly low in children and adults, and relapse rates were lower than after autologous transplantation. Results for allogeneic transplantation were, respectively: engraftment, 95% and 90%; TRM, 0% and 26%; relapse rate, 34% and 28%; LFS, 66% and 46%; OS, 82% and 43%). We conclude that M7 AML patients in CR1 (except children with Down syndrome, who already have better outcomes) can benefit from transplantation. (Blood. 2005;105:405-409)
Marked elevations in N-terminal brain natriuretic peptide levels in septic shock
Authors: Chua Gerald , Kang-Hoe Lee
Published: June 2004

Introduction

N-terminal pro brain natriuretic peptide (NT-proBNP) is a cardiac biomarker that has recently shown to be of diagnostic value in a diagnosis of decompensated heart failure, acute coronary syndromes and other conditions resulting in myocardial stretch. We sought to study whether sepsis-induced myocardial dilation would result in an elevation of NT-proBNP.

Method

Serum NT-proBNP measurements were made in six consecutive patients with septic shock within 6 hours of admission to the intensive care unit.

Results

Markedly elevated levels of NT-proBNP were found in all six patients.

Conclusions

NT-proBNP levels can be markedly elevated in critically ill patients presenting with septic shock. An elevated NT-proBNP level in a critically ill patient is not specific for decompensated heart failure.
Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine
Authors: Seguí Joaquim , Gironella Meritxell , Sans Miquel , Granell Susana , Gil Fèlix , Gimeno Mercedes , Coronel Pilar , Piqué Josep M , Panés Julián
Published: June 2004

Oxidant stress has been implicated in the pathogenesis of inflammatory bowel disease. Antioxidant enzymes, such as superoxide dismutase (SOD), are candidate drugs for modulating this pathogenic factor. This study was designed to determine the therapeutic value of SOD in an experimental model of colitis and to study the mechanisms underlying its effects on intestinal inflammation. For that purpose, colitic (trinitrobenzene sulfonic acid-induced) and control rats were studied. Groups of colitic animals were treated with different doses of SOD (1, 4, or 13 mg/kg/day) or vehicle, starting after induction of colitis and during 7 days. Clinical and pathological markers of colitis severity and lipid peroxidation in colonic tissue were measured. Leukocyte-endothelial cell interactions in colonic venules and expression of vascular cell adhesion molecule 1 (VCAM-1) were determined. Development of colitis was associated with a significant loss in body weight, an increase in macroscopic and microscopic damage scores, and colonic myeloperoxidase activity. Administration of SOD significantly attenuated these changes in a dose-dependent manner and reduced lipid peroxidation in colonic tissue. The increase in leukocyte rolling and adhesion in colonic venules of colitic rats were significantly reduced by administration of SOD, 13 mg/kg/day. Development of colitis was associated with a marked increase in endothelial VCAM-1 expression, which was significantly reduced by treatment with SOD. In conclusion, treatment with SOD significantly reduces peroxidation reactions in the inflamed colon and affords significant amelioration of colonic inflammatory changes in experimental colitis. This effect is related to a reduction in VCAM-1 expression and leukocyte recruitment into the inflamed intestine.
Enrichment for a CD26hi SIRP− subset in lymph dendritic cells from the upper aero-digestive tract
Authors: Epardaud Mathieu , Bonneau Michel , Payot Fabrice , Cordier Corinne , Mégret Jérôme , Howard Chris , Schwartz-Cornil Isabelle
Published: June 2004

Dendritic cells (DC) have been reported to migrate in afferent lymph in the steady state. However, it is unknown whether DC traffic is modulated by the nature of the drained tissue. To analyze the influence of mucosal versus cutaneous microenvironments on the constitutive DC release, we exploited a novel technique of lymph cannulation in sheep, which allowed a comparison of afferent lymph DC migrating from the head mucosae [cervical DC (CerDC)] with DC migrating from skin [prescapular DC (PresDC)]. The migration rate was lower for CerDC than for PresDC. Compared with PresDC, CerDC contained a higher proportion of the CD26hi signal regulatory protein (SIRP)− DC subset. It is interesting that cytoplasmic apoptotic DNA as well as cytokeratin-positive inclusions were primarily detected among CD26hi SIRP− DC, an observation similar to that made in rats, which leads to the suggestion that this subset was involved in self-antigen presentation and tolerance induction. After the inoculation of cholera toxin (CT) onto the oro-nasal mucosae, migration of CD26hi SIRP− and CD26lo SIRP+ DC was accelerated in lymph, indicating that the effect of CT on DC mobilization is not subset-specific. Our results show that a mucosal environment influences DC output and the relative DC subset representation in lymph. This modulation of DC traffic to lymph nodes by mucosal surfaces is likely to affect the bias of the mucosal immune responses.
APC derived from donor splenocytes support retinal autoimmune disease in allogeneic recipients
Authors: Gregerson Dale S , Kawashima Hidetoshi
Published: June 2004

T cell adoptive transfer models of autoimmune disease have been used in conjunction with radiation/bone marrow chimeras to define the minimal requirements for antigen (Ag) recognition. In models with central nervous system Ags, major histocompatibility complex (MHC) class II compatibility achieved by grafting F1 bone marrow into parental recipients was reported to be necessary and sufficient for transfer of CD4 T cell-mediated experimental autoimmune encephalomyelitis. Bone marrow-derived, perivascular microglia are now widely regarded to play a critical role in the expression of experimental autoimmune diseases of the nervous system. Similar results might be expected in the experimental autoimmune uveoretinitis model, as retina is an extension of the brain. Using an allogeneic Ag-presenting cell (APC) adoptive transfer strategy, it was found that resident APC were not essential and that their replacement with MHC-compatible cells by bone marrow-grafting techniques was not necessary. Instead, APC were recruited from the circulation.
Human eosinophils produce the T cell-attracting chemokines MIG and IP-10 upon stimulation with IFN-γ
Authors: Dajotoy Terese , Andersson Pia , Bjartell Anders , Löfdahl Claes-Göran , Tapper Hans , Egesten Arne
Published: June 2004

Eosinophils participate in allergic inflammation, where expression of T helper cell type 2 (Th2) cytokines such as interleukin (IL)-4 and IL-5 are seen. However, eosinophils sometimes accumulate during disease with expression of Th1 cytokines [i.e., interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α), and IL-1β]. In this study, we investigated whether eosinophils can respond with expression of the IFN-inducible C–X–C chemokines monokine induced by IFN-γ [MIG; CXC chemokine ligand 9 (CXCL9)], IFN-γ-inducible protein (IP-10/CXCL10), and IFN-inducible T cell α chemoattractant (I-TAC/CXCL11). These chemokines share the ability to recruit and activate T cells and natural killer cells to sites of inflammation. We found that IFN-γ induced rapid and sustained gene expression of MIG, IP-10, and I-TAC in eosinophils, as detected by quantitative reverse transcriptase-polymerase chain reaction. During incubation, IFN-γ-stimulated eosinophils released MIG and IP-10, as detected by enzyme-linked immunosorbent assay, while I-TAC could not be detected in the medium. TNF-α but not IL-1β enhanced the IFN-γ-induced production of MIG and IP-10. Conversely, addition of the Th2 cytokine IL-4 down-regulated IFN-γ-induced synthesis of MIG and IP–10 in eosinophils. Crohn's disease is characterized by a Th1-polarized inflammation and presence of eosinophils. In lesions from this disease, MIG was detected in eosinophils by immunohistochemistry. Taken together, the results point to immunoregulatory roles for eosinophils during some diseases with Th1-polarized inflammation.
Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins
Authors: Moldenhauer Anja , Frank Richard C , Pinilla-Ibarz Javier , Holland Gudrun , Boccuni Piernicola , Scheinberg David A , Salama Abdulgabar , Seeger Karl , Moore Malcolm A S , Nimer Stephen D
Published: June 2004

Recurrent cytogenetic abnormalities in leukemic blasts make these an attractive source for dendritic cells (DC) to induce a leukemia-specific immune response. In this study, three leukemic cell lines were investigated: Kasumi-1 and SKNO-1 (two acute myeloid leukemia (AML) cell lines carrying the (8;21)-chromosomal translocation, resulting in the expression of the leukemia-specific fusion protein AML1-eight-twenty-one) and REH, an acute lymphoblastic leukemia cell line with the (12;21)-chromosomal translocation and expression of translocation ETS-like leukemia-AML1. These fusion proteins are implicated in the pathogenesis of the leukemic state by recruiting corepressors and histone deacetylases (HDAC), which interfere with normal cell differentiation. In vitro generation of DC was achieved using a cytokine cocktail containing tumor necrosis factor α, granulocyte macrophage-colony stimulating factor, c-kit ligand, and soluble CD40 ligand; yet, addition of the HDAC inhibitor (Hdi) trichostatin A enhanced DC differentiation with retention of the fusion transcripts. These leukemic DC showed high-level CD83 and human leukocyte antigen (HLA)-DR expression and had a high allostimulatory potential. Only DC generated from these cell lines after Hdi induced blast-specific cytotoxic T cell responses in HLA-A-matched T cells with a cytotoxicity of 42% in parental Kasumi-1 and 83% in parental REH cells, respectively. This model system suggests that the Hdi supports the in vitro differentiation of DC from leukemic blasts with AML1-containing fusion proteins.
GPI-defective monocytes from paroxysmal nocturnal hemoglobinuria patients show impaired in vitro dendritic cell differentiation
Authors: Ruggiero Giuseppina , Terrazzano Giuseppe , Becchimanzi Cristina , Sica Michela , Andretta Claudia , Masci Anna Maria , Racioppi Luigi , Rotoli Bruno , Zappacosta Serafino , Alfinito Fiorella
Published: June 2004

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic disorder characterized by a phosphatidylinositol (PI) glycan-A gene mutation, which impairs the synthesis of the glycosyl-PI (GPI) anchor, thus causing the absence of all GPI-linked proteins on the membrane of the clonal-defective cells. The presence of a consistent GPI-defective monocyte compartment is a common feature in PNH patients. To investigate the functional behavior of this population, we analyzed its in vitro differentiation ability toward functional dendritic cells (DCs). Our data indicate that GPI-defective monocytes from PNH patients are unable to undergo full DC differentiation in vitro after granulocyte macrophage-colony stimulating factor and recombinant interleukin (IL)-4 treatment. In this context, the GPI-defective DC population shows mannose receptor expression, high levels of the CD86 molecule, and impaired CD1a up-regulation. The analysis of lipopolysaccharide and CD40-dependent, functional pathways in these DCs revealed a strong decrease in tumor necrosis factor α and IL-12 production. Finally, GPI-defective DCs showed a severe impairment in delivering accessory signals for T cell receptor-dependent T cell proliferation.
Distinct and overlapping roles of CXCR5 and CCR7 in B-1 cell homing and early immunity against bacterial pathogens
Authors: Höpken Uta E , Achtman Ariel H , Krüger Kerstin , Lipp Martin
Published: June 2004

CXC chemokine receptor (CXCR)5 and CC chemokine receptor (CCR)7 are the major chemokine receptors required for B cell homing and microenvironmental localization during antigen-independent and -dependent B cell differentiation. Here, we show markedly decreased B-1 B cell numbers in the peritoneal cavity of CXCR5−/− and CXCR5−/−CCR7−/− double-deficient mice paralleled by reduced antigen-induced phosphorylcholine-specific immunoglobulin (Ig)M responses after intraperitoneal (i.p.) administration of streptococcal antigen. CCR7−/− mice lso revealed a partial reduction in peritoneal B-1 cell numbers combined with a reduced humoral response to i.p. injected bacterial antigen. However, opposite roles of CXCR5 and CCR7 were observed when the frequency of peritoneal B-2 cells was analyzed. CXCR5−/− mice almost completely lacked B-2 cells, whereas CCR7 deficiency engendered an increase in peritoneal B-2 cells. In addition, CCR7−/− mice had enhanced, splenic IgM+ plasma cell responses, whereas the extrafollicular B cell response of the CXCR5−/−mice was not significantly altered compared with wild-type controls. Thus, the two chemokine receptors exert divergent forces at multiple levels of the innate immune response. CXCR5 plays a dominant role in peritoneal B-1 B cell homing and body cavity immunity, but both chemokine receptors are needed for a proportional peritoneal B-2 cell homing and balanced development of an early splenic B cell response.
Privacy and Confidentiality Issues in Primary Care: views of advanced practice nurses and their patients
Authors: Deshefy-Longhi Terry , Dixon Jane Karpe , Olsen Douglas , Grey Margaret
Published: June 2004

Various aspects of the concepts of privacy and confidentiality are discussed in relation to health care information in primary health care settings. In addition, findings are presented from patient and nurse practitioner focus groups held to elicit concerns that these two groups have in relation to privacy and confidentiality in their respective primary care settings. The focus groups were held prior to the implementation of the Health Insurance Portability and Accessibility Act in the USA. Implications for advanced practice registered nurses in primary care practices are provided.
Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461
Authors: Marcucci Guido , Mrózek Krzysztof , Ruppert Amy S. , Archer Kellie J. , Pettenati Mark J. , Heerema Nyla A. , Carroll Andrew J. , Koduru Prasad R.K. , Kolitz Jonathan E. , Sterling Lisa J. , Edwards Colin G. , Anastasi John , Larson Richard A. , Bloomfield Clara D.
Published: June 2004

Purpose

As most patients with acute myeloid leukemia (AML) with morphologic complete remission (CR) ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as part of the criteria for CR. To our knowledge, ours is the first relatively large study evaluating the usefulness of CRc attained immediately following induction chemotherapy.

Patients and Methods

We included AML patients treated on Cancer and Leukemia Group B front-line studies with cytogenetic samples obtained at diagnosis and at the first day of documented CR following induction. Patients with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n = 103) were compared with those with abnormal cytogenetics both at diagnosis and at CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Cox proportional hazards models determined the prognostic significance of cytogenetics at CR, adjusting for other covariates.

Results

Clinical features were similar for both groups, with the exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at diagnosis, which was more frequent (P = .03) in the NCR group. Median follow-up was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter OS (P = .006) and DFS (P = .0001), and higher CIR (P = .0001). In multivariable models, the NCR and ACR groups were predictors for OS (P = .03), DFS (P = .02), and CIR (P = .05). The relative risk of relapse or death was 2.1 times higher for ACR patients than for NCR patients (95% CI, 1.1 to 3.9).

Conclusion

Our data suggest that converting to normal karyotype at the time of first CR is an important prognostic indicator and support the use of CRc as a criterion of CR in AML.
Randomized Controlled Trial of the Role of Positron Emission Tomography in the Management of Stage I and II Non-Small-Cell Lung Cancer
Authors: Viney Rosalie C. , Boyer Michael J. , King Madeleine T. , Kenny Patricia M. , Pollicino Christine A. , McLean Jocelyn M. , McCaughan Brian C. , Fulham Michael J.
Published: June 2004

Purpose

Positron emission tomography (PET) is a costly new technology with potential to improve preoperative evaluation for patients with non–small-cell lung cancer (NSCLC). There is increasing pressure for PET to be included in standard diagnostic work-up before decisions about surgical management of NSCLC. The resource implications of its widespread use in staging NSCLC are significant.

Methods

A randomized controlled trial was conducted to investigate the impact of PET on clinical management and surgical outcomes for patients with stage I-II NSCLC. The primary hypothesis was that PET would reduce the proportion of patients with stage I-II NSCLC who underwent thoracotomy by at least 10% through identification of patients with inoperable disease.

Results

One hundred eighty-four patients with stage I-II NSCLC were recruited and randomly assigned; 92% had stage I disease. Following exclusion of one ineligible patient, 92 patients were assigned to no PET and 91 to PET. Compared with conventional staging, PET upstaged 22 patients, confirmed staging in 61 and staged two patients as benign. Stage IV disease was rarely detected (two patients). PET led to further investigation or a change in clinical management in 13% of patients and provided information that could have affected management in a further 13% of patients. There was no significant difference between the trial arms in the number of thoracotomies avoided (P = .2).

Conclusion

For patients who are carefully and appropriately staged as having stage I-II disease, PET provides potential for more appropriate stage-specific therapy but may not lead to a significant reduction in the number of thoracotomies avoided.
The Use of Alternate, Non–Cross-Resistant Adjuvant Chemotherapy on the Basis of Pathologic Response to a Neoadjuvant Doxorubicin-Based Regimen in Women With Operable Breast Cancer: Long-Term Results From a Prospective Randomized Trial
Authors: Thomas Eva , Holmes Frankie A. , Smith Terry L. , Buzdar Aman U. , Frye Debra K. , Fraschini Giuseppe , Singletary S. Eva , Theriault Richard L. , McNeese Marsha D. , Ames Frederick , Walters Ronald , Hortobagyi Gabriel N.
Published: June 2004

Purpose

To evaluate the use of an alternate, non–cross-resistant adjuvant chemotherapy regimen in women with a poor pathologic response to a preoperative doxorubicin-based regimen.

Patients and Methods

Patients with locally advanced breast cancer received three cycles of vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP) every 21 days followed by surgery. Patients with less than 1 cm3 residual tumor at mastectomy received an additional five cycles of VACP. Those with more than 1 cm3 residual tumor were randomly assigned to receive an additional five cycles of VACP or five cycles of vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil (VbMF).

Results

One hundred ninety-three patients were evaluable. Overall clinical response was seen in 83.4% after three cycles of VACP, whereas the pathologic complete response was 12.2%. One hundred six patients were randomly assigned to VACP or VbMF. Those receiving VbMF achieved higher relapse-free survival (RFS) and overall survival (OS) than those who received additional VACP, although the differences did not reach statistical significance. Initial stage of tumor, clinical complete response, and pathologic complete response were all associated with statistically superior survival rates.

Conclusion

Clinical and pathologic response to preoperative doxorubicin-based chemotherapy predicted for improved survival in women with operable breast cancer. For those with a poor response to initial neoadjuvant chemotherapy, treatment with VbMF was associated with a trend toward improved RFS and OS compared with those continuing with the doxorubicin regimen.
An Eicosapentaenoic Acid Supplement Versus Megestrol Acetate Versus Both for Patients With Cancer-Associated Wasting: A North Central Cancer Treatment Group and National Cancer Institute of Canada Collaborative Effort
Authors: Jatoi Aminah , Rowland Kendrith , Loprinzi Charles L. , Sloan Jeff A. , Dakhil Shaker R. , MacDonald Neil , Gagnon Bruno , Novotny Paul J. , Mailliard James A. , Bushey Teresita I.L. , Nair Suresh , Christensen Brad
Published: June 2004

Purpose

Studies suggest eicosapentaenoic acid (EPA), an omega-3 fatty acid, augments weight, appetite, and survival in cancer-associated wasting. This study determined whether an EPA supplement—administered alone or with megestrol acetate (MA)—was more effective than MA.

Patients and Methods

Four hundred twenty-one assessable patients with cancer-associated wasting were randomly assigned to an EPA supplement 1.09 g administered bid plus placebo; MA liquid suspension 600 mg/d plus an isocaloric, isonitrogenous supplement administered twice a day; or both. Eligible patients reported a 5-lb, 2-month weight loss and/or intake of less than 20 calories/kg/d.

Results

A smaller percentage taking the EPA supplement gained ≥ 10% of baseline weight compared with those taking MA: 6% v 18%, respectively (P = .004). Combination therapy resulted in weight gain of ≥ 10% in 11% of patients (P = .17 across all arms). The percentage of patients with appetite improvement (North Central Cancer Treatment Group Questionnaire) was not statistically different: 63%, 69%, and 66%, in EPA-, MA-, and combination-treated arms, respectively (P = .69). In contrast, 4-week Functional Assessment of Anorexia/Cachexia Therapy scores suggested MA-containing arms experienced superior appetite stimulation compared with the EPA arm, with scores of 40, 55, and 55 in EPA-, MA-, and combination-treated arms, respectively (P = .004). Survival was not significantly different among arms. Global quality of life was not significantly different among groups. With the exception of increased impotence in MA-treated patients, toxicity was comparable.

Conclusion

This EPA supplement, either alone or in combination with MA, does not improve weight or appetite better than MA alone.
Interleukin-6, Interleukin-10, and Vascular Endothelial Growth Factor in Metastatic Renal Cell Carcinoma: Prognostic Value of Interleukin-6—From the Groupe Français d'Immunothérapie
Authors: Negrier Sylvie , Perol David , Menetrier-Caux Christine , Escudier Bernard , Pallardy Michel , Ravaud Alain , Douillard Jean-Yves , Chevreau Christine , Lasset Christine , Blay Jean-Yves
Published: June 2004

Purpose

Few clinical prognostic factors have been identified for patients with metastatic renal cell carcinoma (MRCC), and no biomarker is known in this disease. Several endogenous cytokines have demonstrated interesting and significant correlations with survival in these patients. Our objective was to analyze the prognostic value of circulating vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and interleukin-6 (IL-6).

Patients and Methods

Serum levels of IL-6, IL-10, and VEGF were measured in patients with MRCC. Their prognostic value for response to treatment and progression-free and overall survival was evaluated. Pretreatment samples were obtained from 138 patients of a large randomized multicentric trial. Endogenous cytokine levels were determined using immunoassays. Univariate and multivariate analyses were performed to evaluate the prognostic value of each factor further controlled by an internal validation test. Threshold values for serum IL-6 and VEGF were determined using the quartile method.

Results

Serum IL-6 was detectable in 70% of the patients. IL-10 and VEGF were elevated in 8% and 71% of the patients, respectively. None of these circulating factors was correlated with response to treatment. IL-10 was not significantly correlated with progression-free or overall survival. Despite significant correlation with survival, VEGF was not an independent prognostic factor in the multivariate analysis. Finally, IL-6 was significantly correlated with progression-free survival and overall survival, and has prognostic value for overall survival.

Conclusion

Circulating IL-6 level appears to be an important independent prognostic factor in patients with MRCC; if confirmed in further studies, it could be considered for treatment decisions in these patients.
Hematologic Toxicity of High-Dose Iodine-131–Metaiodobenzylguanidine Therapy for Advanced Neuroblastoma
Authors: DuBois Steven G. , Messina Julia , Maris John M. , Huberty John , Glidden David V. , Veatch Janet , Charron Martin , Hawkins Randall , Matthay Katherine K.
Published: June 2004

Purpose

Iodine-131–metaiodobenzylguanidine (131I-MIBG) has been shown to be active against refractory neuroblastoma. The primary toxicity of 131I-MIBG is myelosuppression, which might necessitate autologous hematopoietic stem-cell transplantation (AHSCT). The goal of this study was to determine risk factors for myelosuppression and the need for AHSCT after 131I-MIBG treatment.

Patients and Methods

Fifty-three patients with refractory or relapsed neuroblastoma were treated with 18 mCi/kg 131I-MIBG on a phase I/II protocol. The median whole-body radiation dose was 2.92 Gy.

Results

Almost all patients required at least one platelet (96%) or red cell (91%) transfusion and most patients (79%) developed neutropenia (< 0.5 × 103/μL). Patients reached platelet nadir earlier than neutrophil nadir (P < .0001). Earlier platelet nadir correlated with bone marrow tumor, more extensive bone involvement, higher whole-body radiation dose, and longer time from diagnosis to 131I-MIBG therapy (P ≤ .04). In patients who did not require AHSCT, bone marrow disease predicted longer periods of neutropenia and platelet transfusion dependence (P ≤ .03). Nineteen patients (36%) received AHSCT for prolonged myelosuppression. Of patients who received AHSCT, 100% recovered neutrophils, 73% recovered red cells, and 60% recovered platelets. Failure to recover red cells or platelets correlated with higher whole-body radiation dose (P ≤ .04).

Conclusion

These results demonstrate the substantial hematotoxicity associated with high-dose 131I-MIBG therapy, with severe thrombocytopenia an early and nearly universal finding. Bone marrow tumor at time of treatment was the most useful predictor of hematotoxicity, whereas whole-body radiation dose was the most useful predictor of failure to recover platelets after AHSCT.
Multivariate Prognostic Factor Analysis in Locally Advanced and Metastatic Esophago-Gastric Cancer—Pooled Analysis From Three Multicenter, Randomized, Controlled Trials Using Individual Patient Data
Authors: Chau Ian , Norman Andy R. , Cunningham David , Waters Justin S. , Oates Jacqui , Ross Paul J.
Published: June 2004

Purpose

To identify baseline prognostic factors and assess whether pretreatment quality of life (QoL) predicts survival in patients with locally advanced or metastatic esophago-gastric cancer.

Patients and Methods

Between 1992 and 2001, 1,080 patients were enrolled into three randomized, controlled trials assessing fluorouracil-based combination chemotherapy. All patients were required to complete the European Organization for Research and Treatment of Cancer core QoL questionnaire before random assignment.

Results

Of the 1,080 patients randomly assigned, 979 (91%) died. Four independent poor prognostic factors were identified by multivariate analysis: performance status ≥ 2 (hazard ratio [HR], 1.58; 99% CI, 1.25 to 1.98), liver metastases (HR, 1.41; 99%CI, 1.14 to 1.74), peritoneal metastases (HR, 1.33; 99%CI, 1.01 to 1.74) and alkaline phosphatase ≥ 100 U/L (HR, 1.41; 99% CI, 1.14 to 1.76). A prognostic index was constructed dividing patients into good (no risk factor), moderate (one or two risk factors) or poor (three or four risk factors) risk groups. One-year survival for good, moderate, and poor risk groups were 48.5%, 25.7%, and 11%, respectively, and the survival differences among these groups were highly significant (P < .00001). Compared with the good risk group, the moderate risk group had nearly twice the risk of death, and the poor risk group had 3.5-fold increased risk of death. Pretreatment physical (P = .003), role functioning (P < .001), and global QoL (P < .001) predicted survival.

Conclusion

Four poor prognostic factors were identified and a simple prognostic index was devised. Information from this analysis can be used to aid clinical decision-making, help individual patient risk stratification, and serve as benchmark for the planning for future phase III trials.
Improved Sphincter Preservation in Low Rectal Cancer With High-Dose Preoperative Radiotherapy: The Lyon R96-02 Randomized Trial
Authors: Gerard Jean-Pierre , Chapet Olivier , Nemoz Chantal , Hartweig Johannes , Romestaing Pascale , Coquard Regis , Barbet Nicolas , Maingon Philippe , Mahe Marc , Baulieux Jacques , Partensky Christian , Papillon Marc , Glehen Olivier , Crozet Bruno , Grandjean Jean-Paul , Adeleine Patrice
Published: June 2004

Purpose

The potential advantage of high-dose preoperative radiotherapy to increase tumor response and improve the chance of sphincter preservation for low rectal cancer remains controversial. The aim of this trial was to evaluate the role of escalating the dose of preoperative radiation to increase sphincter-saving procedures.

Patients and Methods

Patients with rectal carcinoma located in the lower rectum, staged T2 or T3, Nx, or M0 with endorectal sonography, and not involving more than two-thirds circumference, were randomly assigned to one of two groups: preoperative external-beam radiotherapy (EBRT; 39 Gy in 13 fractions over 17 days) versus the same EBRT with boost (85 Gy in three fractions) using endocavitary contact x-ray.

Results

Between 1996 and 2001, 88 patients were enrolled onto the study. A significant improvement was seen in favor of the contact x-ray boost for complete clinical response (24% v 2%) and for a complete or near-complete sterilization of the operative specimen (57% v 34%). A significant increase in sphincter preservation was observed in the boost group (76% v 44%; P = .004). At a median follow-up of 35 months, there was no difference in morbidity, local relapse, and 2-year overall survival.

Conclusion

A dose escalation with endocavitary irradiation provides increased tumor response and sphincter preservation with no detrimental effect on treatment toxicity and early clinical outcome.
Screening for Metastasis From Choroidal Melanoma: The Collaborative Ocular Melanoma Study Group Report 23
Authors: Diener-West Marie , Reynolds Sandra M. , Agugliaro Donna J. , Caldwell Robert , Cumming Kristi , Earle John D. , Green Donna L. , Hawkins Barbara S. , Hayman James , Jaiyesimi Ishmael , Kirkwood John M. , Koh Wui-Jin , Robertson Dennis M. , Shaw John M. , Thoma Jonni
Published: June 2004

Purpose

To describe the predictive value of liver function tests (LFTs), chest x-ray, and diagnostic imaging for detecting melanoma metastasis during routine follow-up after treatment for choroidal melanoma.

Materials and Methods

Prospective longitudinal follow-up of patients enrolled onto two randomized trials was conducted by the Collaborative Ocular Melanoma Study (COMS) Group. Baseline and annual or semiannual systemic and laboratory evaluations were performed according to a standard protocol for 2,320 patients enrolled on the COMS.

Results

COMS patients were screened annually for metastasis and new cancers using LFTs (alkaline phosphatase, AST, ALT, or bilirubin). Elevated findings (1.5 to 2 times upper limit of normal) on LFT prompted a diagnostic or imaging test to confirm or rule out cancer recurrence. Of 714 patients with clinical reports of metastasis, 675 patients died. Of these 675 patients, all but four had either histopathologically confirmed or clinically suspected metastatic melanoma present at the time of death. Among all patients, the 5-year cumulative diagnosis rate of metastatic melanoma was 24% (95% CI, 22% to 27%). Based on all patients with reported metastasis, the sensitivity, specificity, positive predictive value and negative predictive value associated with at least one abnormal LFT before first diagnosis of metastasis at any site was 14.7%, 92.3%, 45.7% and 71.0%, respectively.

Conclusion

Use of LFTs results followed by diagnostic tests has high specificity and predictive values but low sensitivity. Better tests are needed to identify earlier metastatic disease associated with choroidal melanoma.
Effects of a High-Fiber, Low-Fat Diet Intervention on Serum Concentrations of Reproductive Steroid Hormones in Women With a History of Breast Cancer
Authors: Rock Cheryl L. , Flatt Shirley W. , Thomson Cynthia A. , Stefanick Marcia L. , Newman Vicky A. , Jones Lovell A. , Natarajan Loki , Ritenbaugh Cheryl , Hollenbach Kathryn A. , Pierce John P. , Chang R. Jeffrey
Published: June 2004

Purpose

Diet intervention trials are testing whether postdiagnosis dietary modification can influence breast cancer recurrence and survival. One possible mechanism is an effect on reproductive steroid hormones.

Participants and Methods

Serum reproductive steroid hormones were measured at enrollment and 1 year in 291 women with a history of breast cancer who were enrolled onto a randomized, controlled diet intervention trial. Dietary goals for the intervention group were increased fiber, vegetable, and fruit intakes and reduced fat intake. Estradiol, bioavailable estradiol, estrone, estrone sulfate, androstenedione, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and sex hormone-binding globulin were measured.

Results

The intervention (but not the comparison) group reported a significantly lower intake of energy from fat (21% v 28%), and higher intake of fiber (29 g/d v 22 g/d), at 1-year follow-up (P < .001). Significant weight loss did not occur in either group. A significant difference in the change in bioavailable estradiol concentration from baseline to 1 year in the intervention (−13 pmol/L) versus the comparison (+3 pmol/L) group was observed (P < .05). Change in fiber (but not fat) intake was significantly and independently related to change in serum bioavailable estradiol (P < .01) and total estradiol (P < .05) concentrations.

Conclusion

Results from this study indicate that a high-fiber, low-fat diet intervention is associated with reduced serum bioavailable estradiol concentration in women diagnosed with breast cancer, the majority of whom did not exhibit weight loss. Increased fiber intake was independently related to the reduction in serum estradiol concentration.
Breast Conservation After Neoadjuvant Chemotherapy: The M.D. Anderson Cancer Center Experience
Authors: Chen Allen M. , Meric-Bernstam Funda , Hunt Kelly K. , Thames Howard D. , Oswald Mary Jane , Outlaw Elesyia D. , Strom Eric A. , McNeese Marsha D. , Kuerer Henry M. , Ross Merrick I. , Singletary S. Eva , Ames Fredrick C. , Feig Barry W. , Sahin Aysegul A. , Perkins George H. , Schechter Naomi R. , Hortobagyi Gabriel N. , Buchholz Thomas A.
Published: June 2004

Purpose

To determine patterns of local-regional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) among patients treated with breast conservation therapy after neoadjuvant chemotherapy.

Patients and Methods

Between 1987 and 2000, 340 cases of breast cancer were treated with neoadjuvant chemotherapy followed by conservative surgery and radiation therapy. Clinical stage at diagnosis (according to the 2003 American Joint Committee on Cancer system) was I in 4%, II in 58%, and III in 38% of patients. Only 4% had positive surgical margins.

Results

At a median follow-up period of 60 months (range, 10 to 180 months), 29 patients had developed LRR, 16 of which were IBTRs. Five-year actuarial rates of IBTR-free and LRR-free survival were 95% and 91%, respectively. Variables that positively correlated with IBTR and LRR were clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a multifocal pattern of residual disease, and lymphovascular space invasion in the specimen. The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. Initial T category (T1–2 v T3–4) correlated with LRR but did not correlate with IBTR (5-year IBTR-free rates of 96% v 92%, respectively, P = .19).

Conclusion

Breast conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of LRR and IBTR in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of LRR and IBTR.
Nonmyeloablative Allogeneic Hematopoietic Transplantation: A Promising Salvage Therapy for Patients With Non-Hodgkin's Lymphoma Whose Disease Has Failed a Prior Autologous Transplantation
Authors: Escalón Maricer P. , Champlin Richard E. , Saliba Rima M. , Acholonu Sandra A. , Hosing Chitra , Fayad Luis , Giralt Sergio , Ueno Naoto T. , Maadani Farzaneh , Pro Barbara , Donato Michele , McLaughlin Peter , Khouri Issa F.
Published: June 2004

Purpose

Allogeneic transplantation for patients with lymphoma who experience a recurrence after an autologous transplantation has been considered a hazardous therapeutic choice. We investigated the safety and efficacy of nonmyeloablative stem-cell transplantation in these patients.

Patients and Methods

Patients were required to have chemosensitive or stable disease. Twenty consecutive patients were treated in two sequential trials. Fifteen patients underwent a preparative regimen of fludarabine (30 mg/m2 daily for 3 days), intravenous cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab. For the remaining five patients, the conditioning regimen consisted of cisplatin (25 mg/m2 continuous infusion daily for 4 days), fludarabine (30 mg/m2 daily for 2 days), and cytarabine (1,000 mg/m2 daily for 2 days). Tacrolimus and methotrexate were used for graft-versus-host disease prophylaxis.

Results

All patients experienced engraftment of donor cells. One patient (5%) experienced grade 2 acute graft-versus-host disease, and no patients experienced a higher grade. One patient experienced disease progression at 115 days post-transplantation and responded to donor lymphocyte infusion. The remaining patients remained disease-free. One patient died at 10.5 months from a fungal infection. With a median follow-up time of 25 months, the estimated 3-year current progression-free survival rate was 95%.

Conclusion

These data suggest that nonmyeloablative allogeneic stem-cell transplantation is an effective option in lymphoma patients with chemosensitive or stable disease who experience disease recurrence following autologous transplantation.
Tumor-Specific Methylation in Bronchial Lavage for the Early Detection of Non-Small-Cell Lung Cancer
Authors: Kim Hojoong , Kwon Young Mi , Kim Jin Seuk , Lee Haengbyoung , Park Jung-Ho , Shim Young Mog , Han Joungho , Park Joobae , Kim Duk-Hwan
Published: June 2004

Purpose

The aim of this study was to identify tumor-specific methylation in bronchial lavage for the early detection of non-small-cell lung cancer (NSCLC) by differentiating the age-related methylation from the tumor-specific methylation in NSCLC.

Patients and Methods

Eighty-five NSCLC patients and 127 cancer-free subjects participated in this study. Aberrant methylation at the promoters of the p16, Ras association domain family 1A (RASSF1A), fragile histidine triad (FHIT), H-cadherin, and retinoic acid receptor β (RARβ) genes were evaluated in the resected tumor tissues and bronchial lavage samples of NSCLC patients and in the bronchial lavage samples of cancer-free subjects by methylation-specific polymerase chain reaction.

Results

Of the 127 cancer-free samples, methylation was detected in 6% for p16, 13% for RARβ, 3% for H-cadherin, 4% for RASSF1A, and 28% for FHIT. Hypermethylation of the p16, RARβ, H-cadherin, and RASSF1A genes was not associated with patient age and smoking, whereas hypermethylation of the FHIT promoter occurred more frequently in older patients (P = .02) and was associated with exposure to tobacco smoke (P = .001). A strong correlation between age and smoking was found in patients with hypermethylation of the FHIT gene (r = 0.36; P = .03). A total of 68% of the bronchial lavage samples from the 85 NSCLC patients showed methylation of at least one of p16, RARβ, H-cadherin, and RASSF1A genes.

Conclusion

Our study suggests that tumor-specific methylation of the p16, RASSF1A, H-cadherin, and RARβ genes may be a valuable biomarker for the early detection of NSCLC in bronchial lavage, and that the age-related methylation of FHIT gene in the normal bronchial epithelium is related to the exposure to tobacco smoke.
Thalidomide: Current Role in the Treatment of Non-Plasma Cell Malignancies
Authors: Kumar Shaji , Witzig Thomas E. , Rajkumar S. Vincent
Published: June 2004

Thalidomide, initially introduced as a sedative, was withdrawn from the market in the early 1960s after it was found to be a teratogen. However, it later found use as an investigational agent in the treatment of erythema nodosum leprosum, oral ulcers, graft versus host disease, and wasting associated with the human immunodeficiency syndrome. Its antiangiogenic properties were recognized in the early 1990s during a period where the importance of angiogenesis became increasingly apparent as a critical step in the in the proliferation and spread of malignant neoplasms. This led to the evaluation of thalidomide as an antiangiogenic agent in the treatment of several cancers. Thalidomide has already become part of standard therapy for the treatment of patients with relapsed and refractory multiple myeloma. It has also been found to have varying degree of benefit in various other malignancies. Although more clinical trials are needed, Kaposi's sarcoma and myelofibrosis represent other malignancies in which thalidomide has already demonstrated promising activity. The mechanism of action of thalidomide in cancer is still unclear, but do appear to be mediated by several other mechanisms in addition to its anti-angiogenic properties. This article reviews the current status of thalidomide for the treatment of non-plasma-cell malignancies.
Randomized Phase III Study of Gemcitabine and Vinorelbine Versus Gemcitabine, Vinorelbine, and Cisplatin in the Treatment of Advanced Non-Small-Cell Lung Cancer: From the German and Swiss Lung Cancer Study Group
Authors: Laack E. , Dickgreber N. , Müller T. , Knuth A. , Benk J. , Lorenz C. , Gieseler F. , Dürk H. , Engel-Riedel W. , Dalhoff K. , Kortsik C. , Graeven U. , Burk M. , Dierlamm T. , Welte T. , Burkholder I. , Edler L. , Hossfeld D.K.
Published: June 2004

Purpose

To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC).

Patients and Methods

Between September 1999 and June 2001, 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1 and 8 + cisplatin 75 mg/m2 on day 2 every 3 weeks). Primary end point of the study was overall survival.

Results

Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P = .73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P = .35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P = .004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed.

Conclusion

In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated.