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Biomedical subjects

A Fortin

Publications and source records attributed to A Fortin.

At least 19 recordsLinked to original sources
PubMed2001

Markers of neck failure in oral cavity and oropharyngeal carcinomas treated with radiotherapy.

BACKGROUND: Neck management after radiotherapy remains controversial. It is not clear which patients may benefit from postradiotherapy neck dissection. Biologic markers may be useful in this setting. METHOD: This study includes 81 patients with oral cavity and oropharyngeal carcinomas. The primary tumor had been treated with radical radiotherapy. Immunohistochemical staining to p53, ki-67, NEU, HSP-27, and GST has been performed. RESULTS: There were 50 T1-2 and 31 T3-4 patients, as well as 36 NO and 45 N1-3. A total of 25 nodal failures was observed. With expressed HSP2, 23% of patients had neck failure compared with 51% when HSP-27 was absent (p = .02). With NEU overexpression, nodal control decreased from 72% to 34% (p = .008). In a Cox model, NEU (p = .01) and HSP-27 (p = .05) were associated with neck failure. CONCLUSIONS: HSP-27 and NEU expression may play a role in predicting nodal failure. This should be confirmed in a larger, prospective study.

Biomarkers, Tumor↗
PubMed2001

The impact of skin washing with water and soap during breast irradiation: a randomized study.

BACKGROUND: The effect of washing the irradiated skin during radiotherapy for breast cancer is uncertain. The purpose of this study was to evaluate the impact of washing the breast skin with water and soap during radiotherapy on the intensity of acute skin toxicity. MATERIALS AND METHODS: Ninety-nine patients treated for breast cancer were prospectively randomized prior to receiving radiotherapy to the breast into two groups: (1), no washing was allowed during radiotherapy (49 patients); and (2), washing was allowed with water and soap (50 patients). Acute toxicity was recorded according to the Radiation Therapy Oncology Group (RTOG) acute skin toxicity scale for each patient every week during radiotherapy and 1 month after the end of radiotherapy. Symptoms related to skin toxicity were scored by visual analogue scales at the same time intervals. Other data collected included sociodemographic data, characteristics related to the tumor and previous treatments, radiation technique, necessity for a second simulation due to loss of skin marks and treatment interruptions. RESULTS: In the non-washing group, the following maximum acute toxicity scores were observed: grade 0, 2%; grade 1, 41%; grade 2, 57%; grades 3 and 4, 0%. For the washing group, the scores were: grade 0, 0%; grade 1, 64%; grade 2, 34%; grade 3, 2%; and grade 4, 0%. Moist desquamation was seen in 33% of non-washing patients, but in only 14% of washing patients. The median scores of pain, itching and burning of the treated skin were higher in the non-washing group, although this was not statistically significant. In a multivariate analysis using logistic regression, acute skin toxicity was associated with the patient's weight, concomitant radiochemotherapy and hot spots on dosimetry, and there was a trend toward more acute skin toxicity in the non-washing group. CONCLUSION: Washing the irradiated skin during the course of radiotherapy for breast cancer is not associated with increased skin toxicity and should not be discouraged.

Acute Disease↗
PubMed2000

Overexpression of the 27 KDa heat shock protein is associated with thermoresistance and chemoresistance but not with radioresistance.

PURPOSE: The heat shock protein (hsp27) correlates with thermotolerance and chemoresistance. Our main objective was to assess the response to radiotherapy both in vitro and in vivo in correlation with various concentrations of hsp27. The second objective was to evaluate the relation between hsp27 and glutathione-s-transferase pi (GST pi). METHODS AND MATERIALS: For the in vitro study, thermoresistant cell lines, expressing various amounts of hsp27, were used to assess the role of this protein in radioresistance. To verify the efficiency of hsp27 in these cells lines to confer resistance to cytotoxic agents, these cells were also treated with heat shock and cisplatin. Furthermore, the role of hsp27 expression was studied in vivo by immunochemistry in 98 patients with head and neck squamous cell carcinoma treated by radiotherapy. hsp27 was correlated with local control of the tumor and with clinical and biologic factors potentially able to affect the local control, including p53, ki-67, ploidy, and GST. RESULTS: In vitro, high constitutive levels of expression of hsp27 did not significantly influence the survival curves of transfected cells exposed to radiation as compared to control cells although hsp27 overexpression was confirmed to increased the cellular resistance to heat and to cisplatinum. In vivo, we showed that overexpression of various amounts of hsp27 did not correlate with local control of the tumor. In vivo, hsp27 was only significantly associated with GST pi. Expression of GST pi was associated with poor local (p = 0.01) control and survival (p = 0.08) in a Cox model. CONCLUSIONS: It is concluded that the mechanisms responsible for hsp27-mediated heat and drug resistance are not involved in radioprotection.

Animals↗
PubMed2000

Identification and characterization of naturally occurring variants of the macrophage scavenger receptor (SR-A).

The scavenger receptor (SR) family comprises a group of cell surface proteins functionally defined by their ability to bind chemically modified lipoproteins. In macrophages, the class A Type I and Type II SRs (SR-AI/II) are thought to play a key role in adherence to and phagocytosis of infectious agents. Immunoprecipitation studies show that the rat anti-SR-AI/II monoclonal antibody 2F8 detects the mature, trimeric form of the receptor expressed in peritoneal macrophages from A/J, but not from C57Bl/6J (B6) mice. Subsequent sequencing of cDNA and genomic clones indicates that SR-AI and AII of A/J and B6 mice differ in sequence at nine positions, two in the cytoplasmic domain and seven in the extracellular spacer and alpha-helical coiled coil domains. These sequence polymorphisms are non-conservative and produce distinct receptor molecules that differ by four charged residues and alter recognition of the receptor by the monoclonal 2F8 antibody. The B6 SR-AI/II haplotype appears unique, since most inbred strains analyzed show the A/J-type haplotype. Interestingly, several of the B6 polymorphic variant residues are conserved in human and bovine receptors, suggesting a recent divergence of the A/J haplotype. Initial studies in CHO-derived cells expressing individual receptor isoforms indicate that the A/J and B6 receptors are stable and can mature into oligomers expressed in the membrane fractions of these cells. In these transfectants, no major functional differences were detected between receptors of the two haplotypes with respect to internalization and degradation of (125)I-labeled acetylated LDL. However, since SR-AI/II recognizes a large number of structurally unrelated anionic molecules, the possibility that different haplotypes may affect either binding and release of other ligands, or receptor recycling, cannot be excluded.

Animals↗
PubMed2000

Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice.

Genetic factors play a key role in host response, disease severity, and ultimate outcome of infection with Mycobacterium tuberculosis in humans. In the mouse, the DBA/2J strain is very susceptible to M. tuberculosis H37Rv infection, while the C57Bl/6J strain is resistant. In DBA/2J, a heavier bacterial burden causes a unique phenotype, that includes very severe and rapidly fatal pulmonary disease with extensive exudation of neutrophils and tissue necrosis, as opposed to slower progressive pulmonary disease characterized by the accumulation of epithelioid macrophages with protective immune and inflammatory responses in C57Bl/6J. To identify the genes responsible for differences in host response to M. tuberculosis in these two strains, 95 animals of an informative (C57Bl/6J x DBA/2J) F2 cross were infected intravenously with M. tuberculosis (1 x 10(5) CFU) and duration of survival was used as a quantitative phenotypic measure of susceptibility in a whole genome scan. Quantitative trait locus analysis (QTL) showed that the genetically controlled susceptibility was multigenic. QTL analysis identified two significant linkages on the distal portion of chromosome 1 (Trl-1, LOD, 4.80) and on the proximal portion of chromosome 7 (Trl-3, LOD, 4.66) that each account for approximately 21% of the phenotypic variance. A third suggestive linkage was identified on the proximal portion of chromosome 3 (Trl-2, LOD, 3.93; additional 18% of the variance). At each locus, homozygosity for the parental C57Bl/6J alleles was associated with increased resistance to infection. These novel mouse loci provide the basis for evaluating a possible association of the corresponding syntenic chromosomal regions in humans with susceptibility to tuberculosis.

Animals↗
PubMed2000

Preventing postoperative pain by local anesthetic instillation after laparoscopic gynecologic surgery: a placebo-controlled comparison of bupivacaine and ropivacaine.

UNLABELLED: We tested the hypothesis that local anesthetics instilled at the end of laparoscopic gynecologic procedures are able to prevent postoperative pain at wake-up and during the first 24 h. A total of 180 patients were randomly assigned into three groups to receive an intraperitoneal instillation of 20 mL of either bupivacaine 0.5% (Group B), ropivacaine 0.75% (Group R) or saline (Group S) at the end of surgery. All patients received analgesia with acetaminophen and ketoprofen IV infusions. Pain was assessed by using a 0-10 graded numerical scale (NS) every 5 min in the postanesthesia care unit and IV morphine was administered if NS was >4. Assessment of pain was continued every 4 h on the ward, and subcutaneous morphine was injected if needed to keep the NS score < 4. Postoperative nausea and vomiting (PONV) was rated on a 4-point scale. The morphine consumption at wake-up and over the first 24 h was significantly lower (P < 0.05) in Group B (mean, 0.92 mg at wake-up; 3.08 mg over 24 h) and in Group R (mean, 0.25 mg at wake-up; 0.69 mg over 24 h), than in Group S (mean, 4.18 mg at wake-up; 12.93 mg over 24 h). The morphine-sparing effect of ropivacaine was significantly greater than that of bupivacaine. Both local anesthetics were effective in the prevention of PONV. We concluded that local anesthetics should be instilled in all gynecologic patients at the end of all laparoscopic procedures. IMPLICATIONS: Local anesthetic instillation (ropivacaine rather than bupivacaine) at the end of laparoscopy prevents postoperative pain and dramatically decreases the need for morphine. This technique, compared with placebo, is safe, improves patient comfort, shortens the stay in the postoperative care unit and decreases nursing care in the ward.

Adolescent↗
PubMed2000

Nuclear DNA content, an adjunct to p53 and Ki-67 as a marker of resistance to radiation therapy in oral cavity and pharyngeal squamous cell carcinoma.

Factors of prognosis and radioresistance in oral cavity and pharyngeal squamous cell carcinoma (OCPSCC) are limited. In the present study, the usefulness of tumor DNA content in predicting radioresistance in patients with OCPSCC has been investigated. Radioresistance has been defined as local recurrence or tumor persistence after radiation therapy. DNA-ploidy analysis was performed by static cytometry on smears of cell suspensions obtained from formalin-fixed paraffin-embedded material and stained with Feulgen. DNA-ploidy was correlated with the proliferation rate (Ki-67) and p53 protein accumulation obtained by immunohistochemistry. The follow-up of patients ranged from 8 to 62 months. Radioresistance was more common in non-diploid tumors; 14/28 (50%) non-diploid tumors recurred, whereas only 3 (10.7%) out of 28 diploid tumors had local failure (P=0.0019). Proliferation rate and p53 accumulation, evaluated by immunohistochemistry, also added prognostic information. Twelve out of 14 failures were from non-diploid tumors with a low proliferation rate (Ki-67<20%), whereas none of 20 p53-negative diploid tumors developed recurrences. This study showed that non-diploid tumors responded poorly to radiotherapy. DNA content appeared, therefore, as a significant prognostic marker for the evaluation of OCPSCC in patients receiving radiation therapy. This study also showed that DNA content adds information to p53 accumulation and the proliferation rate (Ki-67) for the purposes of determining patient management.

Adult↗
PubMed1999

Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy.

PURPOSE: The aim of the present study was to evaluate the role of local failure (LF) in the survival of patients treated with lumpectomy and postoperative radiotherapy and to investigate whether LF is not only a marker for distant metastasis (DM) but also a cause. METHODS: Charts of patients treated with breast conservative surgery between 1969 and 1991 were reviewed retrospectively. There were 2,030 patients available for analysis. The median duration of follow-up was 6 years. A Cox regression multivariate analysis was performed using LF as a time-dependent covariate. RESULTS: Local control (LC) was 87% at 10 years. Local failure led to poorer survival at 10 years than local control (55% v 75%, P < .00). In a Cox model, local failure was a powerful predictor of mortality. The relative risk associated with LF was 3.6 for mortality and 5.1 for DM (P < .00). In patients with LF, the rate of DM peaked at 5 to 6 years, whereas it peaked at 2 years for patients with LC. The mean time between surgery and DM was 1,050 days for patients without LF and 1,650 days for patients with LF (P < .00). CONCLUSION: Our results show that local failure is associated with an increase in mortality. The difference in the time distribution of distant metastasis for LF and LC could imply distinct mechanisms of dissemination. Local failure should be considered not only as a marker of occult circulating distant metastases but also as a source for new distant metastases and subsequent mortality.

Actuarial Analysis↗
PubMed1998

Improved high-performance liquid chromatographic assay for the determination of procainamide and its N-acetylated metabolite in plasma: application to a single-dose pharmacokinetic study.

An improved high-performance liquid chromatographic assay for the determination of procainamide and N-acetylprocainamide (NAPA) at concentrations observed up to 32 h after a single oral dose administration of procainamide to human subjects is reported. Following liquid-liquid extraction of plasma samples, procainamide, NAPA, and the internal standard (N-propionylprocainamide) are separated on a reversed-phase C8 column with retention times of 4.0, 6.7, and 13.2 min, respectively. The ultraviolet detection limit (wavelength, 280 nm) of procainamide and NAPA is 2 ng/mL (signal-to-noise ratio, 3:1), and the quantitation limit is 4 ng/mL (signal-to-noise ratio, 5:1). Intra- and interday coefficients of variation are less than 8% in the range of 20-500 ng/mL.

Acecainide↗
PubMed1997

Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer.

PURPOSE: The aim of the present study is to investigate whether combined androgen blockade associated with radiation therapy for localized prostate cancer decreases at 12 and 24 months the rate of positive follow-up biopsies and serum PSA compared to radiation therapy alone. This is the report of an interim analysis. METHODS AND MATERIALS: One hundred and twenty patients with clinical Stage B1-T2a, B2-T2b/T2c, and C-T3/T4, adenocarcinoma of the prostate were entered in a prospective randomized study. After written informed consent, the subjects were randomly allocated between external beam radiation therapy (EBRT) alone (group 1), 3 months of neoadjuvant combination therapy (LHRH-agonist + Flutamide) prior to EBRT (group 2), and a third group receiving combination therapy 3 months before, during, and 6 months after EBRT. There is no significant difference between the three groups concerning age, stage of disease, grade of tumor, and pretreatment PSA levels. Control transrectal ultrasound (TRUS)-guided needle biopsies (one core was taken from the initial cancer site regardless of the presence or absence of TRUS abnormalities) were done 12 and 24 months after the end of EBRT. Serum PSA measurements were done on schedule visits. RESULTS: Ninety-two and 68 patients underwent biopsies at 12 and 24 months, respectively, after the end of radiation therapy. While 62% of control patients at 12 months in Group 1 disclosed residual neoplasm, only 30% and 4% showed residual disease in groups 2 and 3, respectively (p = 0.00005). When looking at 24 months, 65, 28, and 5% showed residual cancer for groups 1, 2, and 3, respectively (p = 0.00001). The PSA measurements indicate also at 12 months a difference between the three groups (p < 0.0001), except at 24 months, the difference between the group 2 and 3 is no longer significant. CONCLUSION: The preliminary analysis of this clinical trial indicates that patients treated with radiation therapy alone show a significantly higher rate of positive biopsies at 12 and 24 months after the end of radiation therapy as compared with those treated with total antiandrogen blockade (TAB) and radiation therapy. When analyzing the median PSA serum levels, we found the same advantage at 12 months, but, at the time of the analysis at 24 months, the PSA levels are not different between groups 2 and 3.

Aged↗
PubMed1997

mdr1 mRNA expression by RT-PCR in patients with primary breast cancer submitted to neoadjuvant therapy.

mdr1 expression by reverse transcription and polymerase chain reaction (RT-PCR) has been compared to P-glycoprotein (Pgp) expression by immunohistochemistry (IHC) and correlated with clinical response to neoadjuvant therapy. RNA has been recovered from glass slide smears of fine-needle aspiration from 57 untreated primary breast cancers prior to neoadjuvant chemotherapy (33 cases), hormone therapy (23 cases), or both (1 case). Furthermore, mdr1 mRNA has been analyzed in 6 cases after 2 months of treatment. The neoadjuvant therapy consisted of 4 cycles of adriamycin and cyclophosphamide or tamoxifen. Of 57 tumor specimens, an interpretable result was obtained in 52 cases, indicating the feasibility of the analysis by RT-PCR with very small tumor specimens. The presence of mdr1 mRNA has been documented in 44/52 (84%) tumor samples with a spectrum of expression levels. The expression of mdr1 mRNA was compared with P-glycoprotein (Pgp) expression by IHC using JSB-1, 4E3, and C494 monoclonal antibodies in 48 of the 52 interpretable tumor samples. 12/48 (25%) expressed Pgp by IHC. All tumors expressing Pgp by IHC were also positive by RT-PCR. The results confirm the higher prevalence of mdr1 mRNA compared to the protein expression. However, mdr1 mRNA expression was found to correlate significantly with resistance to neoadjuvant hormone therapy only while Pgp expression detected by JSB-1 immunostaining only correlated with chemoresistance. The lack of convincing correlation with chemoresistance suggests that mRNA and Pgp may not be directly or solely responsible for clinical response to drugs. Further studies should focus on the post-translational modulation of P-glycoprotein and other mechanisms of drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

The fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes.

The fragile X syndrome results from a transcriptional silencing of the FMR1 gene and the absence of its encoded protein. FMRP is a cytoplasmic RNA-binding protein, whose specific cellular function is still unknown. We present evidence that virtually all detectable cytoplasmic FMRP in mouse NIH 3T3 and human HeLa cells is found strictly in association with mRNA in actively translating polyribosomes. Furthermore, FMRP released from polyribosomes is associated with ribonucleoprotein complexes with sedimentation coefficients of 60-70S and selection on oligo(dT)-cellulose reveals that this association is specific to poly(A)-containing mRNPs. This association with actively translating polyribosomes is not affected by alteration of translational processes induced by serum stimulation and starvation in NIH 3T3 cells, suggesting that FMR1 expression is not cell cycle regulated and that FMRP might have a house-keeping function. FXR2 protein, which is closely related to FMRP, is also detected associated with mRNPs in translating polyribosomes. The results strongly suggest that FMRP might be a mRNA chaperone interacting with mRNP complexes.

3T3 Cells↗
PubMed1997

Role of CYP2D6 in the N-hydroxylation of procainamide.

Sequential oxidations at the arylamine moiety of the procainamide molecule leading to the formation of N-hydroxyprocainamide and its nitroso derivative may be responsible for lupus erythematosus observed in patients treated with the drug. The objective of the present study was to characterize major cytochrome P450 isozyme(s) involved in the N-hydroxylation of procainamide. Firstly, incubations were performed with microsomes from either lymphoblastoid cells or yeast transfected with cDNA encoding for specific human cytochrome P450 isozymes. Experiments performed with these enzyme expression systems indicated that the highest formation rate of N-hydroxyprocainamide was observed in the presence of CYP2D6 enriched microsomes. Additional experiments demonstrated that the formation rate of N-hydroxyprocainamide by CYP2D6 enriched microsomes was decreased from 45 +/- 4% to 93 +/- 1% by quinidine at concentrations ranging from 30 nM to 100 microM (all p < 0.05 vs control) and by approximately 75% by antibodies directed against CYP2D6. Secondly, incubations were performed with microsomes prepared from 15 human liver samples. Using this approach, an excellent correlation was observed between the formation rate of N-hydroxyprocainamide and dextromethorphan O-demethylase activity (CYP2D6; r = 0.9305; p < 0.0001). In contrast, no correlation could be established between N-hydroxyprocainamide formation rate and caffeine N3-demethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), S-mephenytoin N-demethylase (CYP2B6), tolbutamide methlhydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), chlorzoxazone 6-hydroxylase (CYP2E1), dextromethorphan N-demethylase (CYP3A4), testosterone 6 beta-hydroxylase (CYP3A4/5) or lauric acid 12-hydroxylase (CYP4A11) activities. Furthermore, formation rate of N-hydroxyprocainamide was decreased in a concentration-dependent manner by quinidine (300 nM to 100 microM) and by antibodies directed against CYP2D6 but not by furafylline 20 microM (CYP1A2), ketoconazole 1 microM (CYP3A4), sulfaphenazole 10 microM (CYP2C9) or antibodies directed against CYP1A1/1A2, CYP2C, CYP2A6, CYP2E1 or CYP3A4/3A5. In conclusion, the results obtained in the present study demonstrate that CYP2D6 is the major human cytochrome P450 isozyme involved in the formation of the reactive metabolite of procainamide, namely N-hydroxyprocainamide.

Anti-Arrhythmia Agents↗
PubMed1997

Markers of radioresistance in squamous cell carcinomas of the head and neck: a clinicopathologic and immunohistochemical study.

PURPOSE: The lack of accurate criteria to predict the response to radiotherapy for individual patients with squamous cell carcinoma of the head and neck (HN-SCC) remains a major problem. The purpose of this study was to investigate the role of several biologic tumor markers to complement clinical prognostic factors in the assessment of response to radiotherapy in SCCs. PATIENTS AND METHODS: p53, ki-67, c-erb B-2, heat-shock protein-27 (HSP-27), and glutathione S transferase (GSTpi) were evaluated by immunohistochemistry on biopsies from 101 patients treated for head and neck cancer by radical radiotherapy. Expression of each marker was correlated with local control and survival using Kaplan-Meier curves. A Cox regression multivariate analysis was also performed that included all clinical and immunohistochemical variables. RESULTS: Expression of p53 and low cell proliferation allowed identification of patients whose tumors did not respond to radiation. Patients with p53-expressing tumors displayed a relative risk (RR) of 3.78 for not being controlled by radiotherapy compared with patients with p53-negative tumors. For tumors with a high growth fraction (ki-67 > 20%) the RR was 0.25 compared with tumors with a low growth fraction (ki-67 < 20%). When p53 expression and cell proliferation were considered simultaneously in a Cox model, the association with resistance to radiation was significant (P = .000004). The RR for resistance with one (p53 staining or ki-67 < 20%) or two (p53 staining and ki-67 < 20%) unfavorable markers was, respectively, 3.8 and 14.87. CONCLUSION: Patients whose tumor expressed p53 with low growth fraction (ki-67 < 20%) had a strong probability not to respond to radiation therapy. Similarly, absence of p53 expression with a high cell proliferation predicted an excellent outcome after radiotherapy even for patients with advanced disease. Prediction of the outcome of radiotherapy would eventually facilitate the early choice of an adequate treatment.

Adult↗
PubMed1997

Chromosome 11q13 gene amplifications in oral and oropharyngeal carcinomas: no correlation with subclinical lymph node invasion and disease recurrence.

Gene amplifications in the q13 band of chromosome 11 are among the most frequent genetic alterations in head and neck squamous cell carcinomas. Previous studies have suggested that such amplification is a marker of aggressive tumor evolution. Their potential for predicting subclinical lymph node invasion or disease recurrence was investigated in a prospective series of 50 oral and oropharyngeal carcinomas. Cell DNA content was also measured in 32 tumors of this series. Gene amplifications affecting the 11q13 band were detected in 11 of 50 (20%) patients, a relatively low frequency in comparison with data reported previously for other carcinomas of the upper aerodigestive tract, especially hypopharyngeal carcinomas. These gene amplifications were preferentially associated with aneuploidy. Cervical lymph nodes of 26 clinically N0 (Tumor-Node-Metastasis staging) patients were surgically explored. The frequency of 11q13 amplifications was very similar in the presence or in the absence of histological invasion, 3 of 15 (20%) and 2 of 11 (18%), respectively. Thus, 11q13 amplifications do not appear to be a reliable marker for prediction of subclinical lymph-node invasion in oral and oropharyngeal carcinomas. The detection of 11q13 amplifications was also not associated with a higher risk of disease recurrence. These data suggest that not only the prevalence but also the prognostic significance of 11q13 amplifications varies between tumors at different sites in the upper aerodigestive tract.

Adult↗