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Biomedical subjects

S Raimondi

Publications and source records attributed to S Raimondi.

At least 19 recordsLinked to original sources

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Asian People↗

Meta-analysis of cancer incidence in children born after assisted reproductive technologies.

A meta-analysis was performed on 11 cohort studies of Assisted Reproductive Technologies (ART) and subsequent childhood cancer, published up to February 2005, which reported comparable, nonoverlapping data, and then restricted to eight studies which presented a similar research design. The overall Standardised Incidence Ratio was 1.33 (95% CI 0.62-2.85), and 0.77 (95% CI 0.41-1.42) when the analysis was restricted to eight studies. No evidence of publication bias was observed for the overall analysis. The data are consistent with a lack of increase in risk of childhood cancer, though the amount of data on ART and cancer is still limited; larger multicentric studies as well as a pooled analysis on the available data are warranted.

Child↗

Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation.

Methotrexate (MTX) is one of the most active and widely used agents for the treatment of acute lymphoblastic leukemia (ALL). To elucidate the mechanism for higher accumulation of MTX polyglutamates (MTX-PG) in hyperdiploid ALL and lower accumulation in T-lineage ALL, expression of the reduced folate carrier (RFC) was assessed by reverse transcription-polymerase chain reaction in ALL blasts isolated from newly diagnosed patients. RFC expression exhibited a 60-fold range among 29 children, with significantly higher expression in hyperdiploid B-lineage ALL (median, 11.3) compared with nonhyperdiploid ALL (median, 2.1; P <.0006), but no significant difference between nonhyperdiploid B-lineage and T-lineage ALL. Furthermore, mRNA levels of RFC (mapped by FISH to chromosome 21) were significantly related to chromosome 21 copy number (P =.0013), with the highest expression in hyperdiploid ALL blasts with 4 copies of chromosome 21. To assess the functional significance of gene copy number, MTX-PG accumulation was compared in ALL blasts isolated from 121 patients treated with either low-dose MTX (LDMTX; n = 60) or high-dose MTX (HDMTX; n = 61). After LDMTX, MTX-PG accumulation was highest in hyperdiploid B-lineage ALL with 4 copies of chromosome 21 (P =.011), but MTX-PG accumulation was not significantly related to chromosome 21 copy number after HDMTX (P =.24). These data show higher RFC expression as a mechanism for greater MTX accumulation in hyperdiploid B-lineage ALL and indicate that lineage differences in MTX-PG accumulation are not due to lower RFC expression in T-lineage ALL.

Carrier Proteins↗

Comparison of cytogenetics, Southern blotting, and fluorescence in situ hybridization as methods for detecting MLL gene rearrangements in children with acute leukemia and with 11q23 abnormalities.

Bone marrow samples from 67 children with acute leukemia and with cytogenetic evidence of chromosome 11 band q23 (11q23) abnormalities were characterized by fluorescence in situ hybridization (FISH) and Southern blot analysis to determine whether FISH could reliably detect MLL gene rearrangements in this population. Among the 42 patients with acute lymphoblastic leukemia (ALL), MLL gene rearrangements were detected in cells from 23 patients (54.8%) by both FISH and Southern blot analysis. FISH identified allelic deletions of MLL gene in five of 12 patients (42%) with ALL and with deletion of 11q23. In 22 of 25 children (88%) with AML, FISH detected MLL gene rearrangements, whereas Southern blot analysis identified rearrangements in 24 of 25 patients (96%). For children with acute leukemia and with 11q23 abnormalities, we recommend that FISH be used for the rapid screening of MLL gene rearrangements and that Southern blot analysis be used for the definitive assessment of the MLL gene status.

Acute Disease↗

[Stereotaxic radiotherapy of brain metastases: experiences in Lausanne].

We report the first series of patients treated by stereotactic radiation therapy for brain metastases in Switzerland. From August 1993 to December 1994, 19 patients were treated using a linear accelerator adapted for stereotactic treatment set-up. Most of the patients received combined treatment including external irradiation. The crude overall control rate for brain metastases was 79%. Median survival was 12.2 months. Overall survival at one year was 50 +/- 12%. These data compare reasonably well with the reported median survival of 3-6 months using external cranial irradiation alone. There was no "late toxicity". The data thus indicate that stereotactic radiation therapy combined with external whole brain irradiation appears to increase life expectancy and quality of life in a selected cohort of patients.

Actuarial Analysis↗

All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders.

The involvement of 11q23-balanced translocations in acute leukemia after treatment with drugs that inhibit the function of DNA topoisomerase II (topo II) is being recognized with increasing frequency. We and others have shown that the gene at 11q23 that is involved in all of these treatment-related leukemias is MLL (also called ALL1, Htrx, and HRX). In general, the translocations in these leukemias are the same as those occurring in de novo leukemia [eg, t(9;11), t(11;19), and t(4;11)], with the treatment-related leukemias accounting for no more than 5% to 10% of any particular translocation type. We have cloned the t(11;16)(q23;p13.3) and have shown that it involves MLL and CBP (CREB binding protein). The CBP gene was recently identified as a partner gene in the t(8;16) that occurs in acute myelomonocytic leukemia (AML-M4) de novo and rarely in treatment-related acute myeloid leukemia. We have studied eight t(11;16) patients, all of whom had prior therapy with drugs targetting topo II with fluorescence in situ hybridization (FISH) using a probe for MLL and a cosmid contig covering the CBP gene. Both probes were split in all eight patients and the two derivative (der) chromosomes were each labeled with both probes. Use of an approximately 100-kb PAC located at the breakpoint of chromosome 16 from one patient revealed some variability in the breakpoint because it was on the der(16) in three patients, on the der(11) in another, and split in four others. We assume that the critical fusion gene is 5'MLL/3'CBP. Our series of patients is unusual because three of them presented with a myelodysplastic syndrome (MDS) most similar to chronic myelomonocytic leukemia (CMMoL) and one other had dyserythropoiesis; MDS is rarely seen in 11q23 translocations either de novo or with t-AML. Using FISH and these same probes to analyze the lineage of bone marrow cells from one patient with CMMoL, we showed that all the mature monocytes contained the fusion genes as did some of the granulocytes and erythroblasts; none of the lymphocytes contained the fusion gene. The function of MLL is not well understood, but many domains could target the MLL protein to particular chromatin complexes. CBP is an adapter protein that is involved in regulating transcription. It is also involved in histone acetylation, which is thought to contribute to an increased level of gene expression. The fusion gene could alter the CBP protein such that it is constitutively active; alternatively, it could modify the chromatin-association functions of MLL.

Adolescent↗

Development and validation of a liquid chromatographic method for the determination of related substances in verapamil hydrochloride.

The development of a reversed-phase liquid chromatographic method for the determination of related substances in verapamil hydrochloride is described. The method is based on the use of a simple mobile phase on a specialty base-deactivated reversed-phase column. It enables the resolution of 13 related compounds from the parent drug and from each other. Validation of the method showed it to be reproducible, selective, accurate and linear over the concentration range of analysis with a limit of detection of 0.5 microgram ml-1. The developed method proved to be a real improvement compared with the LC test for chromatographic purity described in the USP monograph for verapamil hydrochloride.

Calcium Channel Blockers↗

Image quality and dose in spiral computed tomography.

Image quality and dose produced by a spiral CT with various pitch values were investigated on the basis of test-object images and measurements of CT dose indexes. No major difference in image quality or dose was observed when comparing sequential and spiral mode acquisition with a pitch of one. Increase in pitch value produces a loss of contrast which leads to a loss of detectability. Nevertheless, in realistic protocols the image quality in the transverse plane remains acceptable up to pitch values of 1.3-1.6.

Artifacts↗

Cobalt-60 treatment of choroidal hemangiomas.

PURPOSE: We investigated the therapeutic possibilities of gamma brachytherapy to improve the final functional results of eyes with choroidal hemangiomas, which are benign vascular tumors that can induce progressive impairment of visual acuity. METHODS: We treated 41 patients with choroidal hemangioma with cobalt-60 applicators. The lesions consisted of 39 circumscribed hemangiomas and two diffuse hemangiomas in patients with Sturge-Weber syndrome. Before treatment, visual acuity in the affected eye was 20/200 in ten patients, 20/200 to 20/50 in 17 patients, 20/40 to 20/25 in 11 patients, and 20/20 in three patients. All patients were symptomatic. The macula was infiltrated by the tumor in 12 eyes (29.3%). There was retinal detachment in 40 eyes (97.6%), cystoid edema in ten eyes (24.4%), subretinal fibrosis in eight eyes (19.5%), and areolar atrophy in two eyes (4.9%). RESULTS: After treatment, the retina was reattached in all eyes, and the tumor progressively transformed into a flat scar. The postirradiation macular lesions that we identified were pigment migrations in the macular region, subretinal fibrosis, and an areolar atrophic scar. We correlated the functional results at two, five, and ten years after treatment with the initial visual acuity, and with pre-existing and posttreatment macular lesions. CONCLUSIONS: Our results suggest that radiotherapy is a valuable therapeutic modality for choroidal hemangiomas, particularly in hemangiomas that involve the macula, and for tumors associated with bullous retinal detachment.

Adolescent↗

Combined radioimmunotherapy and radiotherapy of human colon carcinoma grafted in nude mice.

The effect of combined radioimmunotherapy (RIT) and fractionated external beam radiotherapy (RT) was assessed in two human colon cancer xenografts, Co112 and LS174T in nude mice. These tumors were selected for being resistant to RIT alone, as is usually the case in the clinical situation. Tumor-bearing mice were treated with a combination of five X-ray fractions over 5 days followed by RIT with two doses of 1.5 mCi 131I-labeled anticarcinoembryonic antigen monoclonal antibody F(ab')2. In Co112 and LS174T, RIT alone achieved a regrowth delay similar to that of fractionated RT with total doses of 28 and 26 Gy, respectively. In both tumor types, an additive therapeutic effect, measured as increased regrowth delay or local control, was observed when combining RT of different dose levels with RIT. Normal tissue responses were assessed by monitoring acute peak skin reactions and blood cell count. Bone marrow depression for the combination treatment was similar to that of RIT alone; relative to skin, at equitoxic levels, no mice bearing Co112 tumors were locally controlled with a 32 Gy RT dose alone, while this RT combined with RIT gave a local control of 100%. These studies show a therapeutic benefit when external beam RT is combined with RIT.

Animals↗

Clinical features and treatment outcome for children with CD30+ large-cell non-Hodgkin's lymphoma.

PURPOSE: To determine the frequency of CD30 expression and its relationship to clinical features, immunophenotype, histotype, and outcome in childhood large-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: We reviewed 45 cases of large-cell NHL in children treated at St Jude Children's Research Hospital from 1975 to 1990 for whom there was sufficient tissue to perform immunophenotypic studies. All 45 were screened with a panel of antibodies to detect the presence of CD30 and T-cell and B-cell antigens. Cases were classified according to the National Cancer Institute (NCI) Working Formulation and the Kiel classification system. Clinical features, immunophenotype, pathologic classification, and treatment outcome were compared for CD30+ and CD30- cases. RESULTS: CD30 expression was documented in 18 cases (40%). These 13 boys and five girls had a median age of 13 years at diagnosis. Most (n = 14) had advanced-stage (III and IV) disease. Nodal disease was equally common in CD30+ and CD30- cases, whereas skin involvement was significantly more frequent in CD30+ cases (P = .007). There was no significant association of CD30 expression with histologic subtype according to the NCI Working Formulation, but CD30+ cases were more likely to be anaplastic by the Kiel classification (P < .001). All CD30+ cases had either T-cell or null-cell phenotype, while the majority of CD30- cases were B-cell phenotype (P < .001). Among patients with limited-stage disease, the mean +/- SE estimated 5-year event-free survival (EFS) was 75% +/- 22% for CD30+ cases and 92% +/- 9% for CD30- cases (P = .10); estimates for advanced-stage disease were 57% +/- 17% and 29% +/- 17%, respectively (P = .096). For patients with advanced-stage disease, CD30 expression was associated with a significantly better overall 5-year survival probability (84% +/- 12% v 27% +/- 16%, P = .0016). CONCLUSION: CD30 is frequently expressed in pediatric large-cell NHL and is significantly associated with T-cell or null-cell phenotype, anaplastic morphology, skin involvement, and better overall survival among advanced-stage patients.

Adolescent↗

[Radiation doses delivered to the critical organs during radiological studies of chronic sinusitis. Comparison between TDM and standard radiographies].

Computed tomography (CT) is the gold standard for exact delineation of inflammatory sinus disease, especially before endoscopic surgical treatment. Thermoluminescent dosimetry studies were performed on a Rando humanoid phantom to compare radiation doses used in sinus examinations. Radiation doses were determined for lens, thyroid gland, condylar marrow and brain. Studies included standard sinus views (Waters, Caldwell, Hirtz and lateral), CT scan in axial and coronal planes and in planes determined by the axis of the naso-frontal duct, CT low-dose. Lens received doses of 7.4 mGy, 33.6 mGy, 32.2 mGy, 15.0 mGy, respectively, for standard sinus views, CT scan axial and coronal planes, CT scan in planes determined by the axis of the naso-frontal duct and low-dose CT, thyroid gland received doses of 10.1 mGy, 27.2 mGy, 3.9 mGy and 1.4 mGy respectively, condylar marrow received doses of 2.0 mGy, 32.0 mGy, 20.4 mGy and 7.2 mGy respectively and brain received doses of 2.3 mGy, 14.2 mGy, 6.0 mGy and 2.0 mGy. The radiation doses from CT low-dose are slightly higher than standard sinus views but the health benefits are also higher. Therefore, the authors recommend the use of CT low-dose in paranasal sinus studies.

Bone Marrow↗

Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt.

We have developed a restriction map of the chromosome 21 breakpoint region involved in t(8;21)(q22;q22.3) acute myelogenous leukemia (AML) and have isolated a genomic junction clone containing chromosome 8 and 21 material. Using probes from these regions, rearrangements have been identified in each of nine cases of t(8;21) AML examined. In addition, we have isolated cDNA clones from a t(8;21) AML cDNA library that contain fused sequences from chromosome 8 and 21. The chromosome 8 component, referred to as ETO (for eight twenty-one), is encoded over a large genomic region, as suggested by the analysis of corresponding yeast artificial chromosomes (YACs). The DNA sequence of the chromosome 21 portion of the fusion transcript is derived from the normal AML1 gene. A striking similarity (67% identity over 387 bp, with a corresponding 69% amino acid identity) was detected between AML1 and the Drosophila segmentation gene, runt. The critical consequence of the translocation is the juxtaposition of 5' sequences of AML1 to 3' sequences of ETO, oriented telomere to centromere on the der(8) chromosome.

Amino Acid Sequence↗

S1 nuclease hypersensitive sites in an oligopurine/oligopyrimidine DNA from the t(10;14) breakpoint cluster region.

Recurring chromosomal translocations are frequently seen in cancers, especially in leukemias and lymphomas. The genes affected by these chromosomal translocations appear to play an important role in oncogenesis. The mechanism underlying the formation of chromosomal translocation is a subject under extensive study. In chromosomal translocations involving the Ig and TCR loci, complete heptamer-spacer-nonamer signal motifs are usually present at the break of the Ig and TCR genes, indicating the involvement of V-D-J recombinase(s). On the other hand, in only about 50% of the cases signal motif sequences have been found at the break in the other participating chromosome, suggesting that different mechanisms may be involved in the scission of the corresponding chromosome. Here we report the identification of an oligopurine/oligopyrimidine DNA in the t(10;14) breakpoint cluster region associated with T-cell acute lymphoblastic leukemia. S1 nuclease mapping revealed multiple S1 hypersensitive sites in the oligopurine/oligopyrimidine DNA. These data suggest a role for oligopurine/oligopyrimidine sequences (non-B DNA) in the formation of chromosomal translocation.

Base Sequence↗

A software tool to assist placement of multiple parallel brachytherapy sources using the Brown-Roberts-Wells stereotactic system.

The authors present a simple software written in Turbo Pascal which allows placement of multiple parallel sources for interstitial brachytherapy using the Brown-Roberts-Wells CT stereotactic system. The user can choose any direction in space, independently from the CT plane, and any number of linear sources arranged on one or more hypothetical cylinders of variable radius. The sources can be rotated on the cylinder in order to avoid critical structures. This small program runs on any IBM compatible computer.

Brachytherapy↗