Biomedical subjects

Lynette M Smith

Publications and source records attributed to Lynette M Smith.

At least 19 recordsLinked to original sources

PubMed2006

An age-related decrease in creatinine clearance is associated with an increase in number of falls in untreated women but not in women receiving calcitriol treatment.

CONTEXT: Decreased calcitriol production due to impaired renal function may be a significant risk factor for falls in normal aging population. OBJECTIVE: The objective of the study was to examine the association between creatinine clearance (CrCl) and the incidence of falls and fallers in groups treated with placebo, calcitriol, estrogen therapy (ET)/estrogen + progestin therapy (HT), and calcitriol + ET/HT. DESIGN: This was a 3-yr, double-blind, placebo-controlled study designed to test the efficacy of calcitriol and ET/HT on bone loss and falls with analysis by intention to treat and post hoc. SETTING: The study was conducted at an academic outpatient center. PARTICIPANTS: Four hundred eighty-nine normal elderly women aged 65-77 yr; 415 women completed the study. INTERVENTION: Subjects were randomized to placebo, calcitriol 0.25 mug twice a day, ET daily (conjugated equine estrogens 0.625 mg), HT (conjugated equine estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg) and calcitriol + ET/HT. MAIN OUTCOME MEASURES: Cumulative number of falls and fallers were compared between groups with 24-h urine CrCl less than 60 and 60 ml/min or greater. RESULTS: Calcitriol treatment decreased the number of fallers and falls. Low CrCl less than 60 ml/min was a predictor of the number of falls per person but not fallers in the placebo group (P = 0.007). In the low CrCl group (<60 ml/min), the rate of falls decreased on calcitriol by 53% [95% confidence interval (CI) -71% to -22%; P = 0.003], calcitriol + ET/HT by 61% (95% CI -76% to -37%; P = 0.001), and ET/HT by 25% (95% CI: -55% to +24%; not significant). Calcitriol reduced the rate of falls by 30% (95% CI -49% to -4%; P = 0.027) in the CrCl 60 ml/min or greater group. CONCLUSION: Calcitriol treatment decreases falls in all subjects but especially in elderly women with decreased renal function (<60 ml/min) and frequent fallers.

Accidental Falls↗

PubMed2006

A rationally designed agonist antibody fragment that functionally mimics thrombopoietin.

By using rational design, antibody fragments (Fabs) that mimic thrombopoietin (TPO) were created. A peptide with cMpl receptor-binding capability was grafted into different complementarity-determining regions of a fully human Fab scaffold. Functional presentation of the peptide was optimized by using phage display and cell-based panning. Select antibodies and fragments containing two grafted peptides were assayed for their ability to stimulate the cMpl receptor in vitro. Several candidates demonstrated agonist activity in an in vitro cMpl receptor signaling reporter assay, including Fab59, which was estimated to be equipotent to TPO. Fab59 additionally was able to effectively stimulate platelet production in normal mice. These rationally designed mimetic Fabs may provide a therapeutic intervention for thrombocytopenia while avoiding the potential generation of neutralizing antibodies to endogenous TPO. Furthermore, this study demonstrates a method by which short-lived linear peptides with binding activity may be converted to more stable and potent agonists capable of activating cell surface receptors.

Animals↗

PubMed2006

Neuropathologic and neuroinflammatory activities of HIV-1-infected human astrocytes in murine brain.

The balance between astrocyte and microglia neuroprotection and neurotoxicity defines the tempo of neuronal dysfunction during HIV-1-associated dementia (HAD). Astrocytes maintain brain homeostasis and respond actively to brain damage by providing functional and nutritive neuronal support. In HAD, low-level, continuous infection of astrocytes occurs, but the functional consequences of this infection are poorly understood. To this end, human fetal astrocytes (HFA) and monocyte-derived macrophages (MDM) were infected with HIV-1DJV and HIV-1NL4-3 (neurotropic and lymphotropic strains respectively) and a pseudotyped Vesicular Stomatitis Virus (VSV/HIV-1NL4-3) prior to intracranial injection into the basal ganglia of severe combined immunodeficient mice. Neuropathological and immunohistochemical comparisons for inflammatory and neurotoxic activities were performed amongst the infected cell types at 7 or 14 days. HIV-1-infected MDM induced significant increases in Mac-1, glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1, and proinflammatory cytokine RNA and/or protein expression when compared with HSV/HIV-1- and HIV-1-infected HFA and sham-operated mice. Levels of neuron-specific nuclear protein, microtubule-associated protein 2, and neurofilament antigens were reduced significantly in the brain regions injected with human MDM infected with HIV-1DJV or VSV/HIV-1. We conclude that HIV-1 infection of astrocytes leads to limited neurodegeneration, underscoring the early and active role of macrophage-driven neurotoxicity in disease.

Animals↗

PubMed2006

Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125).

Mucins are being implicated in diagnosis, prognosis, and as therapeutic targets due to their aberrant expression in a variety of carcinomas. Here, we have analyzed the expression of MUC4 and have compared its potential usefulness in early detection and prognosis of ovarian carcinoma alone and in combination with other mucin antigens, MUC1 and MUC16. Clinical significance of the differential mucin expression was evaluated by grouping the tumor samples in early (stage I and II) and advanced (stage III and IV) stage cases and histological subtypes (serous, mucinous, endometrioid and clear cell). Correlation of these mucins with patient's survival (n=63) was determined by Kaplan-Meier analysis in order to predict their prognostic value. MUC4 showed significant overexpression in tumor cases (P<0.0001) with highest incidence (92.0%) among all three mucins. A significant overexpression of MUC1 (P<0.018) and MUC16 (P<0.0001) was also observed in 83.0 and 79.0% of tumor samples, respectively. Notably, MUC4 expression was significantly higher (P</=0.004) compared to both MUC1 and MUC16 in early-stage ovarian tumor samples with 100% incidence. In advanced stage ovarian tumors, all the mucins displayed overall comparable expression, nonetheless, MUC4 had highest prevalence (88.0%) compared to MUC1 (84.0%) and MUC16 (81.0%). A combined panel of MUC4 with MUC16 detected 100% of the late-stage tumor cases without compromising the specificity. Among histological subtypes, only MUC4 displayed 100% (n=5) sensitivity in mucinous ovarian tumors, while MUC1 and MUC16 detected 40 and 20% cases, respectively. The expression of MUC4, however, did not significantly correlate with the survival of the ovarian cancer patient, while a significant correlation of MUC16 with poor prognosis was observed. In conclusion, our study demonstrates that MUC4 could be a potential candidate marker for early diagnosis of epithelial ovarian carcinoma and can be utilized in combination with MUC16 to achieve greater sensitivity for the detection of late-stage tumors.

Adenocarcinoma, Clear Cell↗

PubMed2006

Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas.

BACKGROUND: Mucins are considered important markers for early diagnosis and targeted therapy due to their aberrant and unique expression pattern during malignant progression of carcinomas. Recent findings have provided substantial evidence for the involvement of transmembrane mucins, MUC1 and MUC4, in altered cell signaling, tumor growth, and metastasis. METHODS: Immunohistochemical analyses were performed on prostate tumor tissues for expression profiling of the two transmembrane mucins, MUC1 and MUC4. In cancer cell lines, the expression was studied by RT-PCR and immunoblot analyses. Cells were treated with DNA-methylase and histone-deacetylase inhibitors to examine the implication of epigenetic mechanism(s) in MUC4 regulation. RESULTS: The expression of MUC4 was significantly down regulated in prostate cancer tissues (n=38, P=0.0026) compared to normal/benign prostatic hyperplastic regions. A faint to moderate staining was observed in 26.3% cases of cancer, while 84.2% cases of adjacent normal were positive for MUC4 with moderate to strong staining in most cases. Similar observations were made in immortalized normal prostate epithelial and cancer cell lines. MUC1 also showed a reduced expression in prostate tumor tissues; however, its expression was comparable in all normal prostate epithelial and cancer cell lines. Interestingly, we also found that epigenetic mechanism(s) might be implicated in MUC4 gene silencing. CONCLUSIONS: Our data suggest that MUC4 downregulation may be of significance for diagnostic applications in prostate cancer.

Antigens↗

PubMed2006

Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma.

Although mantle cell lymphoma (MCL) frequently harbors inactivated ataxia telangiectasia mutated (ATM) and p53 alleles, little is known about the molecular phenotypes caused by these genetic changes. We identified point mutations and genomic deletions in these genes in a series of cyclin D1-positive MCL cases and correlated genotype with gene expression profiles and overall survival. Mutated and/or deleted ATM and p53 alleles were found in 56% (40/72) and 26% (21/82) of the cases examined, respectively. Although MCL patients with inactive p53 alleles showed a significant reduction in median overall survival, aberrant ATM status did not predict for survival. Nevertheless, specific gene expression signatures indicative of the mutation and genomic deletion status of each gene were identified that were different from wild-type cases. These signatures were comprised of a select group of genes related to apoptosis, stress responses, and cell cycle regulation that are relevant to ATM or p53 function. Importantly, we found the molecular signatures are different between cases with mutations and deletions, because the latter are characterized by loss of genes colocalized in the same chromosome region of ATM or p53. This information on molecular phenotypes may provide new areas of investigation for ATM function or may be exploited by designing specific therapies for MCL cases with p53 aberrations.

Apoptosis↗

PubMed2006

N-cadherin switching occurs in high Gleason grade prostate cancer.

BACKGROUND: The inappropriate expression of non-epithelial N-(neural) cadherin by epithelial cells, called cadherin switching, has been suggested to play a role in prostate cancer (PC) progression. We explored the role of N-cadherin as a biomarker in PC by correlating the expression with clinical parameters. METHODS: Two pathologists blinded to patients' history independently reviewed and scored the intensity and extent of staining of N-cadherin expression in 44 randomly selected radical prostatectomy specimens. The expression was correlated with total Gleason grade, individual Gleason patterns, tumor stage, and preoperative serum prostate specific antigen (PSA) levels and P-values < 0.05 were considered statistically significant. RESULTS: Of the 44 PC specimens, 14 (32%), 23 (52%), 7 (16%) consisted of Gleason grade 5-6, 7, and 8-10, respectively and 20/44 (45%) demonstrated N-cadherin expression. N-cadherin was expressed in 1/14 (7%) of Gleason 5-6 compared to 15/23 (65%) of Gleason grade 7, and 4/7 (57%) of Gleason grade 8-10, demonstrating a significant correlation between N-cadherin switching and higher Gleason grade (P = 0.001). While only about a third of primary or secondary Gleason pattern 3 demonstrated N-cadherin expression, a majority of Gleason patterns of > or = 4 expressed N-cadherin (P > 0.05), further suggesting that N-cadherin switching occurs with higher Gleason pattern. However, N-cadherin expression did not significantly correlate with preoperative serum PSA levels or tumor stage in our study cohort. CONCLUSIONS: We have demonstrated for the first time that N-cadherin switching occurs in higher grade PC and correlates significantly with increasing Gleason patterns. N-cadherin may be as a useful biomarker of aggressive PC.

Antigens, CD↗

PubMed2006

Metallothioneins and resistance to cisplatin and radiation in prostate cancer.

OBJECTIVES: The metallothioneins (MTs) are a family of small molecular weight trace metal and free radical scavenging proteins well established to play a role in the resistance to chemotherapy and radiotherapy in human cancers. MT gene expression is upregulated in response to the presence of metal ions such as zinc. Because prostatic tissue has the greatest concentration of zinc in the human body, in this study we analyzed the effect of MT induction by zinc in prostate cancer (PCa). METHODS: The activation of MT gene expression in response to zinc treatment in LNCaP and C4-2 PCa cells was shown by Western blotting and DNA microarray analysis. Chemotherapy and radiation sensitivity assays of cells after treatment with cisplatin or radiation were performed in the presence, or absence, of 150 microM ZnSO4, and cell viability was measured after 72 hours by MTS viability and clonogenic and flow cytometry assays. The experiments were repeated three times and the data analyzed. RESULTS: Increasing concentrations of ZnSO4 upregulated MT expression in a dose-dependent manner. Microarray analysis demonstrated a specific increase in MT expression. Cells treated with zinc demonstrated a significantly decreased sensitivity to cisplatin and radiotherapy compared with controls (P <0.05). CONCLUSIONS: Our data have confirmed that treatment of PCa with zinc causes an increase in MT expression, which is significantly associated with resistance to cisplatin chemotherapy and radiotherapy in PCa. Therapeutic targeting of MT may therefore provide a means to overcome resistance to radiotherapy and cisplatin chemotherapy in PCa.

Antineoplastic Agents↗

PubMed2006

Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group.

Alveolar rhabdomyosarcoma (ARMS) is a soft tissue cancer in which chromosomal translocations generate PAX3-FKHR and PAX7-FKHR gene fusions. To improve the approach for fusion detection in archival samples, we developed a real-time reverse transcriptase-polymerase chain reaction assay for these fusion transcripts. By incorporating consensus primers and gene-specific probes, both presence and subtype of the fusion were determined in one assay. We applied this approach to a convenience sample of 78 formalin-fixed, paraffin-embedded ARMS tumors from the Intergroup Rhabdomyosarcoma Study (IRS)-III clinical trial and obtained satisfactory results in 59 (76%) cases. The distribution of fusion types was 35 (59%) PAX3-FKHR, 11 (19%) PAX7-FKHR, and 13 fusion-negative (22%). In a subsequent clinical analysis, we found that IRS-III ARMS cases analyzed for fusion status had a significantly improved outcome compared to IRS-III ARMS cases that were not available for fusion analysis. The basis of this outcome could not be explained by known prognostic clinical factors, and multivariate analysis confirmed that our convenience sample was not representative of the whole IRS-III cohort. In conclusion, although these robust assays provide new opportunities for correlative studies of archival material, our first application illustrates an important limitation of using a convenience sample for molecular-clinical correlative studies.

Child↗

PubMed2005

Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling.

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.

Cyclin D1↗

PubMed2005

Prognostic factors of chronic graft-versus-host disease after allogeneic blood stem-cell transplantation.

Allogeneic hematopoietic stem cells in peripheral blood transplantation (alloPBSCT) or bone marrow transplantation (alloBMT) have different biological characteristics which may affect differently prognostic factors for incidence and severity of chronic graft-versus-host disease (cGVHD). To determine the prognostic factors of cGVHD in patients receiving alloPBSCT, data on 87 patients who survived at least 100 days after matched related donor myeloablative transplantation were analyzed. Factors significantly associated with higher incidence of cGVHD after alloPBSCT included CMV-positive donor, acute skin GVHD, and diagnoses other than lymphoma. Factors predictive for poor survival following cGVHD diagnosis included platelet count < 100,000/mm3 and history of acute liver GVHD. Acute liver GVHD and etoposide in the preparative regimen significantly increased risk of death due to cGVHD after alloPBSCT. All alloPBSCT multivariate models were fit to an independent cohort of comparable matched related donor alloBMT patients (n=75). After alloBMT, only acute skin GVHD and diagnoses other than lymphoma retained prognostic significance for predicting cGVHD. Low platelet count was the only variable predictive for poor survival in cGVHD patients after alloBMT. Acute liver GVHD was the only factor that retained prognostic significance for risk of death due to cGVHD after alloBMT. These data suggest there are some cGVHD prognostic factors that may be unique to recipients of alloPBSCT. More studies are needed to determine whether cGVHD prognostic systems should be used interchangeably in patient populations receiving different stem-cell products.

Adolescent↗

PubMed2005

Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma.

We sought to determine whether identification of poor-risk subgroups of diffuse large B-cell lymphoma (DLBCL) using immunohistochemical stains would have practical utility with regard to prognosis and therapeutic decisions. Tissue microarray blocks were created using replicate samples of formalin-fixed, paraffin-embedded tissue from 200 cases of de novo DLBCL. The sections were stained with antibodies to proteins that are expressed by activated or proliferating B cells including MUM1, FOXP1, bcl-2, survivin, protein kinase C-beta (PKC-beta), cyclin D2, cyclin D3, and Ki-67. In univariate analysis, tumor expression of cyclin D2 (P = 0.025) or PKC-beta (P = 0.015) was associated with a worse overall survival, whereas none of the other markers was predictive of overall survival. Patients with DLBCL that expressed either cyclin D2 or PKC-beta had a 5-year overall survival of only 30% as compared to 52% for those who were negative for both markers (P = 0.0019). In multivariate analysis, the expression of cyclin D2 or PKC-beta was an independent predictor of poor overall survival (P = 0.035). Cyclin D2 and PKC-beta expression will be useful in designing a 'biological prognostic index' for patients with DLBCL.

Adult↗

PubMed2005

Unique gene expression and clinical characteristics are associated with the 11q23 deletion in chronic lymphocytic leukaemia.

Chromosome abnormalities influence prognosis and tumour progression in B-cell Chronic Lymphocytic Leukaemia (CLL). This study sought to determine whether these different disease subgroups were associated with unique gene expression patterns. Thirty-four cases of CLL were screened for the 11q23, 13q14, 17p13 deletions, and trisomy 12 by fluorescence in situ hybridization (FISH). Expression of 205 cell signalling and apoptosis genes were compared by cDNA array among cases with different chromosome abnormalities. A majority of the statistically differentially expressed genes were present in the 11q23 deletion group by hierarchical clustering. CDC2, a serine/threonine kinase, was overexpressed in the 11q23 deletion group (P = 0.0004) and confirmed by Taqman real-time polymerase chain reaction. Several other genes associated with cell signalling were overexpressed in the 11q23 deletion group. A strong overall correlation existed between the presence of different chromosome abnormalities and a number of prognostic factors including immunoglobulin heavy chain variable region mutation status (P = 0.011), time to treatment (P = 0.025) and lymphocyte doubling time (P = 0.034). This study confirmed the prognostic impact of chromosome abnormalities identified by FISH in CLL, particularly the 11q23 deletion and trisomy 12. In addition, the 11q23 deletion group was associated with a unique gene expression pattern involving cell signalling and apoptosis genes.

Adult↗

PubMed2004

Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: a report from the soft tissue sarcoma committee of the children's oncology group.

PURPOSE: More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome (3-year failure-free survival estimates, 55 to 76%). Dose intensification of known active agents may improve outcome. EXPERIMENTAL DESIGN: This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma. Induction therapy comprised four 3-week cycles of VAC: vincristine (V) 1.5 mg/m2 on days 0, 7, and 14; actinomycin D (A) 1.35 mg/m2 on day 0; and dose-intensified cyclophosphamide (C) on days 0, 1, and 2. The three cyclophosphamide dose levels tested were as follows: (a) 1.2 g/m2/dose; (b) 1.5 g/m2/dose; and (c) 1.8 g/m2/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m2/cycle of C. Radiotherapy was administered at week 0 (parameningeal tumors with intracranial extension) or week 12 or 15 (all others). RESULTS: Between October 1996 and August 1999, 115 eligible patients were enrolled. Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity (typhlitis +/- other severe toxicity). Dose level 1 was the maximum-tolerated dose, and 91 evaluable patients were treated at this level. The 3-year failure-free and overall survival estimates for patients treated at the maximum-tolerated dose were 52% (95% confidence interval, 41-64%) and 67% (95% confidence interval, 56-77%), respectively, at a median follow-up of 3 years. CONCLUSIONS: A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m2/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Prognostic factors influencing survival in patients with B-cell small lymphocytic lymphoma.

The term "B-cell small lymphocytic lymphoma" (B-SLL) is generally reserved for patients with lymph node masses that show the histology and immunophenotype of B-cell chronic lymphocytic leukemia (B-CLL) but who are not leukemic. The aim of our study was to define clinical factors that predict for survival in B-SLL. Thirty-nine patients with B-SLL and with less than 5,000 mature-appearing lymphocytes/microL in the peripheral blood were studied. The median follow-up of survivors was 6.6 years (range, 1.6-12.3 years). The estimated 5-year overall survival (OS) and failure-free survival (FFS) were 66% and 23%, respectively. In the univariate analysis, significant adverse predictors for OS were age > or =60 years, B symptoms, elevated serum LDH, low hemoglobin (<11 g/dL), and high International Prognostic Index (IPI) score (3-5). In multivariate analysis, the IPI score was the only significant predictor of OS. Anemia and B symptoms were additionally predictive of poor OS in patients with low IPI scores.

Adult↗

PubMed2004

Fluorescence in situ hybridization detection of cytogenetic abnormalities in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.

Routine cytogenetic analysis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) frequently fails to identify an abnormal clone due to the low rate of spontaneous mitoses and poor response to mitogen stimulation. Recent studies utilizing interphase fluorescence in situ hybridization (FISH) suggest that prognostically significant chromosomal abnormalities occur more frequently in B-CLL/SLL than has been previously recognized. The purpose of this study was to compare the chromosomal abnormalities detected by karyotyping and FISH in cases of B-CLL/SLL, and to correlate these with clinical features and survival. Seventy-two cases were studied for chromosome 3, 12 or 18 aneuploidy, and for rearrangements involving 11q13, 11q23, 13q14, 14q32 and 17p13. The median age of the patients was 54 years (range, 30-87 years). Clinical staging of B-CLL patients showed that 70% of the patients were Rai stage 0, 1, or 2, and 30% stage 3 or 4. Karyotyping identified chromosomal abnormalities in 31% of the cases, whereas FISH studies were abnormal in 72% of cases including 64% of the cases with normal karyotypes. The most common abnormalities were deletion 13q14 (46%), trisomy 12 (21%), and 14q32 rearrangements (21%). At diagnosis, patients with trisomy 12 were more likely to have a high LDH (P = 0.04), but no other significant differences in the clinical or laboratory features, Rai stage, or survival were found among patients with normal cytogenetics vs. those with chromosomal abnormalities. Univariate analysis showed that B-symptoms (P = 0.044), anemia (P = 0.0006), absolute lymphocytosis > or = 30,000/mm3 (P = 0.029), and Rai stage 3 or 4 (P = 0.0038) at initial presentation were associated with an increased risk of death, but only Rai stage 3 or 4 (P = 0.0038) was significant in multivariate analysis. Interphase FISH studies improve the cytogenetic diagnosis when performed in conjunction with karyotyping in B-CLL/SLL, but the prognostic relevance of various abnormalities could not be confirmed in this study.

Adult↗

PubMed2003

Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.

Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important subgroups with germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3 gene expression profiles using a cDNA microarray. Tissue microarray (TMA) blocks were created from 152 cases of DLBCL, 142 of which had been successfully evaluated by cDNA microarray (75 GCB, 41 ABC, and 26 type 3). Sections were stained with antibodies to CD10, bcl-6, MUM1, FOXP1, cyclin D2, and bcl-2. Expression of bcl-6 (P <.001) or CD10 (P =.019) was associated with better overall survival (OS), whereas expression of MUM1 (P =.009) or cyclin D2 (P <.001) was associated with worse OS. Cases were subclassified using CD10, bcl-6, and MUM1 expression, and 64 cases (42%) were considered GCB and 88 cases (58%) non-GCB. The 5-year OS for the GCB group was 76% compared with only 34% for the non-GCB group (P <.001), which is similar to that reported using the cDNA microarray. Bcl-2 and cyclin D2 were adverse predictors in the non-GCB group. In multivariate analysis, a high International Prognostic Index score (3-5) and the non-GCB phenotype were independent adverse predictors (P <.0001). In summary, immunostains can be used to determine the GCB and non-GCB subtypes of DLBCL and predict survival similar to the cDNA microarray.

Adolescent↗

PubMed2003

Lymphodepleting effects and safety of pentostatin for nonmyeloablative allogeneic stem-cell transplantation.

Nonmyeloablative allogeneic stem-cell transplantation (alloNST) is the focus of investigations searching for less-toxic transplantation regimens. We report studies on the kinetics of lymphodepletion and safety of pentostatin (PT) conditioning in alloNST. Patients with hematologic malignancy received mobilized blood from human leukocyte antigen-matched related (n=4) or unrelated (n=8) donors. PT 4 mg/m2 was administered on days -21, -20, and -19 and 200 cGy of total-body irradiation was administered on day -1, followed by cyclosporine A and mycophenolate mofetil. Mononuclear cell adenosine deaminase after PT was inhibited 84%. The absolute CD3+ cells decreased significantly by day -7 (49%) and CD19+ cells declined 92% by day -1. CD4+ cells were depressed more than CD8+ cells. Neutrophils and monocytes were minimally affected by PT. Median posttransplant peripheral blood chimerism on day 70 showed 95% donor leukocytes and 82.5% donor CD3 lymphocytes. PT demonstrated lymphodepleting effects and promising safety, supporting alloNST as early as 7 days after initiation of PT.

Adult↗