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Biomedical subjects

B Dubray

Publications and source records attributed to B Dubray.

At least 37 records · Page 2Linked to original sources
PubMed1997

Concomitant chemoradiotherapy followed, where feasible, by surgery for cancer of the esophagus.

PURPOSE: To conduct a multicenter phase II study of a concomitant combination of chemotherapy and radiotherapy followed by surgery, where feasible, in patients with nonmetastatic esophageal tumor, stratified on operability at diagnosis. METHODS: Each cycle consisted of fluorouracil (5FU) 800 mg/m2/d by continuous intravenous (IV) infusion on days 1 to 5, cisplatin (CDDP) 50 mg/m2/d IV bolus on days 1 and 8, hydroxyurea (HU) 1.5 or 2 g/d orally on days 8 to 12 and concomitant radiotherapy 20 Gy in 10 fractions over 12 days. All patients were to receive two cycles on days 1 and 22. If feasible, surgery was performed 3 to 6 weeks after cycle two completion. Otherwise, a third cycle was administered. RESULTS: Eighty-eight patients were included between September 1990 and September 1993. Of the 47 operable patients, 41 (87%) underwent surgery and 38 (81%) had a complete resection. No residual primary tumor was found in the surgical specimen in 17 cases (36%), and only microscopic foci in 13 (28%). Two-year overall and disease-free survival probabilities were 51% (95% confidence interval [CI]; 37 to 65) and 43% (95% CI, 28 to 57), respectively. Among the 41 inoperable patients, 12 (29%) became operable. Seven (17%) had complete resection, two incomplete resection, and three exploratory surgery. Two-year overall and disease-free survival probabilities were 29% (95% CI, 15 to 43) and 27% (95% CI, 13 to 40), respectively. Five deaths occurred during chemoradiotherapy, six postoperatively and four in patients with evidence of cancer. Five late complications (one myelopathy) were observed. CONCLUSION: Despite a high histologic response rate in initially operable patients, overall survival was similar to that observed in other preoperative chemoradiation series because of substantial toxicity.

Aged↗
PubMed1997

[Physiopathology of human superficial radiation-induced fibrosis].

The radiation-induced fibrosis is a late sequela of both therapeutic and accidental irradiations, and has been described in several tissues such as skin and underlying sub-cutaneous tissues, and lung. Based on the newest findings arising from cellular and molecular radiobiology, this review synthesis different aspects of the human superficial radiation-induced fibrosis: clinical and paraclinical observations, radiobiological aspects, gross histological changes, cellular and molecular regulations, and medical management. However, the underlying mechanisms of the superficial radiation-induced fibrosis still remain to be resolved.

Fibrosis↗
PubMed1996

Ionizing radiation effects on the KG1a primitive hematopoietic cell line.

PURPOSE: Better understanding of radiation-induced effects on the hematopoietic system is important in both the context of therapeutic intervention and accidental exposure. However, direct study of these effects on the hematopoietic stem cell pool is hampered by the small number of accessible cells. We, thus, studied radiation-induced effects on the KG1a stem cell line. METHODS AND MATERIALS: We confirmed and extended the immunophenotype of KG1a with monoclonal antibodies, established a radiation survival curve, and quantified mRNAs by Northern blotting 30 min after 1, 2, and 3 Gy of ionizing radiation (IR) and followed for up to 48 h after a 3 Gy dose. Cell cycle status and apoptosis were assessed by fluorescent-activated cell sorter (FACS) analysis, cell morphology, and DNA fragmentation. RESULTS: KG1a was found to be CD34+, CD7+, Thy1 low, CD38 low, lineage negative (neg), C-KITneg and HLA-DRneg, a phenotype consistent with a primitive hematopoietic origin. This immunophenotype was not altered by x-ray irradiation. The D0 value was 1.75 Gy. We showed a time-dependent variation of c-jun mRNA expression with an early and transient dose-dependent induction followed by a second increase at 24 and 48 h: a biphasic dose-dependent variation of bcl-2 expression 30 min after irradiation with a reduction of mRNA level at 1 Gy, and a normalization at higher doses and stable levels of mRNA for c-fos, c-myc, G-CSF, GM-CSF, IL-6, TNF-alpha, TGF-beta, and MIP-1 alpha genes. Cell cycle analysis showed the absence of G1/S phase arrest, a point consistent with the absence of detection of P53 mRNA by Northern blot analysis. The dose-dependent G2/M phase arrest was not followed by significant apoptotic cell death. CONCLUSION: Taken together, this data indicates that radiation-induced cell death of KG1a, a cell line that has a relatively high D0 value, does not seem to be the result of the apoptotic pathway but occurs subsequent to a G2/M phase arrest.

Cell Survival↗
PubMed1996

Anemia is associated with lower local-regional control and survival after radiation therapy for head and neck cancer: a prospective study.

PURPOSE: To evaluate the prognostic value of anemia in squamous cell carcinomas in the head and neck treated with curative radiation therapy alone. MATERIALS AND METHODS: In a prospective study, the hemoglobin level was measured prior to radiation therapy in 217 patients (188 [87%] men and 29 [13%] women) with cancer of the oral cavity (n = 61 [28%]), oropharynx (n = 53 [24%]), hypopharynx (n = 21 [10%]), and larynx (n = 82 [38%]). Anemia, defined as hemoglobin level below 13.5 g/dL in men and below 12.0 g/dL in women, was diagnosed in 58 (31%) of the men and five (17%) of the women. Median follow-up was 29 months (range, 2-63 months). RESULTS: The 2-year actuarial probability of local-regional control was 69% (95% confidence interval, 63%, 76%). Multivariate analysis showed the relative risk of failure of local-regional control to increase for stage T3 and T4 tumors (1.8 [95% confidence interval, 1.1, 3.1]), stage N3 nodes (3.6 [95% confidence interval, 1.8, 7.1]), weight loss (2.2 [95% confidence interval, 1.3, 4.0]), and anemia (1.6 [95% confidence interval, 1.0-2.7]). The relative risk of death increased for stage T3 and T4 tumors (2.5 [95% confidence interval, 1.4, 4.3]), N3 nodes (4.0 [95% confidence interval, 1.0, 7.9]), oral cavity tumors (2.0 [95% confidence interval, 1.2, 3.2]), male sex (4.1 [95% confidence interval, 1.3, 13.1]), weight loss (2.2 [95% confidence interval, 1.3, 3.7]), and anemia (1.7 [95% confidence interval, 1.03, 2.7]). CONCLUSION: Moderate anemia appeared to be an independent prognostic factor in squamous cell carcinoma of the head and neck treated with radiation therapy alone.

Actuarial Analysis↗
PubMed1996

[Gene transfer and radiotherapy].

Recent studies have shown that experimental tumors could be treated more efficiently with ionizing radiation if genetic material was transfered into tumor cells. Several approaches have been reported, and among them, the first one consisted of increasing the apoptotic response to radiation by modulating genes involved in the regulation of the apoptotic pathway. Indeed the modulation of p53 and bcl-2 gene expression has recently been used successfully in several experimental models to increase the apoptotic death after radiation. A second approach consisted of taking advantage of the conditional expression of some genes after exposure to ionizing radiation. Indeed, some genes exhibit a radio-inducible promoter which can be combined to a gene, able to enhance or decrease the biological effect of radiation. The irradiation of such a transgene under the control of a radio-inducible promoter can lead to a second biological effect, concomitant to the irradiation, as reported for the TNF alpha under the control of the EGR (early growth response) promoter. A third approach consisted of enhancing the effect of radiation induced tumor cell death by the expression of a suicide gene in these cells, as suggested recently for the HSV-tk (herpes virus thymidine kinase gene). These preliminary results obtained in experimental models appear to be very promising and might improve the efficacy and specificity of radiation therapy in a not too distant future.

Animals↗
PubMed1996

[Changes of the cutaneous micro-relief in superficial radiation-induced fibrosis: a qualitative study].

Cutaneous radiation-induced fibrosis (RIF) is characterized by a skin retraction or atrophy, toughness to the palpation and often entails functional limitation. Its clinical evaluation remains poorly quantified. The aim of this study was to propose an analytical method to quantify RIF skin surface with the replica technique. In this preliminary study, we report the qualitative and quantitative evaluation of the cutaneous microrelief in 44 healthy controls and in four patients presenting a superficial RIF, 3 to 20 years after radiotherapy for cancer. The microrelief of these RIF presented an abnormal anisotropy with a parallel reorganization of cutaneous valleys in three cases out of four, suggesting a premature radiation-induced ageing of the skin. Each subject being his own control, the relative vertical amplitude of the skin microrelief was +/-15% in control skin. Vertical amplitude was respectively increased by 84% in one inflammatory fibrosis (3 years after RT), decreased by 18% in one evolutive fibrosis (6 years after RT), decreased by 26% in one voluminous stabilized fibrosis (8 years after RT) and decreased by 53% in one atrophic fibrosis (20 years after RT). The present study suggests that the variations of the microrelief parameters could reflect the RIF evolution. This technique requires a validation in a larger series of patients, including patients with telangiectasia.

Adult↗
PubMed1995

Prognostic value of tumor regression during radiotherapy for head and neck cancer: a prospective study.

OBJECTIVE: Prospective evaluation of tumor regression during external irradiation for head and neck squamous cell carcinomas and its association with long-term local control. METHODS AND MATERIALS: Two hundred twenty-eight patients with histologically confirmed squamous cell carcinoma [oral cavity: 59 (26%), oropharynx: 65 (29%), hypopharynx: 37 (16%), larynx: 67 (29%)] were included between January 1986 and December 1990. Curative intent external irradiation delivered 65-70 Gy over a period of 7 weeks (five 2 Gy fractions per week). Tumor regression was evaluated clinically and endoscopically every week. RESULTS: Tumor regression, assessed at 2 weeks, was as follows: no response: 62 (30%), 25% response: 121 (59%); 50% response: 23 (11%). At 5 weeks, 9 (4%) patients showed 0-25% regression, 75 (33%) showed 50% regression, 115 (50%) showed 75% regression, and 29 (13%) showed complete regression. Median follow-up was 79 months (range: 6-96 months). The local control probability was 68% (62-74%) at 2 years, 65% (59-70%) at 5 years. Univariate analysis showed that, at 2 weeks, local control was significantly different between the nonresponders and the patients with 25% or greater response (p < 0.025) and that, at the fifth week, local control was very different between the major responders (75 and 100%) and the minor responders (0-50%) (p < 0.0001). Multivariate analysis (Cox Proportional Hazards Model) showed that the probability of local relapse was significantly and independently increased for minor regression at 5 weeks [Relative risk (RR) of failure was 2.3 (1.4-3.7)], for nonlaryngeal tumors [RR: 2.4 (1.3-4.5)], and for Stage T3-T4 [RR:2.4 (1.4-4)]. Three prognostic groups can, therefore, be proposed: 1) low risk of recurrence when regression > or = 75% and laryngeal tumor or T1-T2 tumors in other sites: 106 (46.5%) patients, 2-year local control probability: 84% (77-92%); 2) high risk of recurrence: regression < or = 50% and T3-T4 nonlaryngeal tumors: 44 (19%) patients, 2-year local control probability: 27% (13-41%); 3) intermediate risk of recurrence: 78 (34.5%) patients, 2-year local control probability: 69% (58-80%). CONCLUSION: The present study suggests that tumor regression during external radiotherapy is an independent predictive factor of local control in head and neck carcinomas.

Carcinoma, Squamous Cell↗
PubMed1995

[Exposure of patients to radiation risk in common medical practice].

Medical radiation includes radiodiagnosis, nuclear medicine, and radiation therapy. This radiation exposure differs from occupational public exposure, since a direct benefit is conferred upon the patient. The theoretical risks include genetic mutations, carcinogenesis and teratogenesis. In radiodiagnosis and nuclear medicine, the absorbed doses are very low, and no hazardous effect has been observed. In radiation therapy however, where high doses are delivered to a small number of patients, radio-induced carcinogenesis is well documented. It is by no means sure that the nuclear risk must be taken into account, and fully justifies the accomplishments and recommendations of the French radiation protection programs. There is no question that the nuclear risk-benefit equation resulting from medical exposure is tipped heavily in favor of benefit.

Humans↗
PubMed1995

[Care of severe accidental irradiation victims].

Two types of "severe accidental irradiation" can be schematically described: high dose localized irradiations and accidental total body overexposure. Actually, these two pathologies may coexist, and may be associated with external or internal radioactive contamination, and with all the "catastrophe medicine" syndromes. For high dose localized irradiation, physicians must manage as well as possible complex surgical procedures which unfortunately cannot always avoid being mutilating. For total body overexposure, haematological problems are at the forefront. In according with various situations, hematological growth factors or even allogeneic bone marrow transplantation will be discussed in specialized haematology (and transplant) units. The optimal management of severe accidental irradiation victims implies a close--and rapidly organized--cooperation between general practitioners, firemen, intensive care units, radiopathologists, specialist surgeons (hand and burns) and haematologists.

Humans↗
PubMed1995

Radiation-induced lung damage after thoracic irradiation for Hodgkin's disease: the role of fractionation.

PURPOSE: to estimate the alpha/beta ratio for damage to human lung after thoracic irradiation for Hodgkin's disease. PATIENTS AND METHODS: The criterion for lung injury was the presence of radiological changes in the vicinity of the mediastinum as assessed on regular follow-up chest X-ray examinations. Patients with supradiaphragmatic stage I-II Hodgkin's disease received mantle field irradiation as part of their treatment between 1964 and 1981 (E.O.R.T.C. protocols H1, H2, and H5). The total mediastinal doses fixed by the protocols were 35-40 Gy. The fractional doses were left to the decision of the physicians in charge: the most frequent regimens were 5 x 1.8, 5 x 2.0, 4 x 2.5 and 3 x 3.3 Gy per week. The data were fit to the linear-quadratic (L.Q.) model using time-to-injury as endpoint. RESULTS: 1048 (97%) of 1082 patients were evaluable. The mean follow-up duration was 8 years. One hundred and ninety-five cases of radiologically-visible lung damage were observed after a median interval of 6 months (range: 0-101). The 3-year actuarial probability of lung damage was 19% (95% confidence limits: 17, 21). Multivariate analysis (Cox model, stratified by protocol) showed an increased risk of damage with dose per fraction (relative risk, R.R. = 2.22 per Gy (1.75, 2.82)), the presence of systemic symptoms (R.R. = 1.53 (1.09, 2.15)), and total mediastinal dose (R.R. = 1.06 per Gy (1.01, 1.12)). Age, sex, histological type, number of involved nodal sites and radiotherapy duration did not significantly modify the risk of lung damage. The L.Q. model parameters were: alpha = 0.031 Gy-1 (0.003, 0.059), beta = 0.010 Gy-2 (0.007, 0.013), alpha/beta = 3.07 Gy (-0.23, 8.46). CONCLUSION: this low alpha/beta ratio is consistent with late effects values from animals and humans, and illustrates the influence of large fraction sizes on the occurrence of late pulmonary complications.

Adolescent↗
PubMed1995

Radiobiological and Clinical Bases for Total Body Irradiation in the Leukemias and Lymphomas.

In spite of the recent introduction of conditioning regimens consisting of chemotherapy alone, therapeutic total body irradiation (TBI) remains a powerful antileukemic and immunosuppressive tool in preparative regimens for bone marrow transplantation. However, the question of the "best" TBI schedule has not been answered. Available radiobiological and clinical data show that (1) the role of fractionation (or dose rate) on leukemia cell killing may vary with the leukemia type. Acute myeloid leukemia cells have been found to be insensitive or only slightly sensitive to fractionation, whereas chronic myeloid leukemia cells appear to be sensitive. Data are still controversial for acute lymphocytic leukemia and the non-Hodgkin's lymphomas; (2) the immunosuppressive effect of TBI is very fractionation sensitive; and (3) most normal tissues at risk are also highly sensitive to fractionation and dose rate. These data permit some cautious adaptations of the TBI schemes to the type of leukemia, use of T-cell-depleted donor marrow, and potential normal tissue toxicity. However, we still lack data concerning the precise intrinsic and fractionation radiosensitivity of the leukemia/lymphoma of a given patient. Recent improvements in leukemia-cell cultures allowing the generation of dose survival curves and the study of in vitro radiation-induced apoptosis (mainly for lymphomas) may soon provide radiation oncologists with the data to allow further refinement and individualization of TBI schedules.

Journal Article↗
PubMed1995

In vivo induction of apoptosis in human lymphocytes by therapeutic fractionated total body irradiation.

Ionizing radiations have been reported as an in vitro apoptosis initiating stimulus in human lymphocytes. As the cytotoxicity of ionizing radiations and chemotherapeutic agents appears to be dependent on the efficacy of cell death induction, the manipulation of apoptosis initiation might be used as a means to supress some pathological process. In the present study the in vivo induction of gamma-ray mediated programmed cell death in humans is reported. The in vivo induction of apoptosis in peripheral blood lymphocytes (PBL) by ionizing radiations was investigated in 33 patients after each of two sessions (2 Gy and 4 Gy) of fractionated total body irradiation (FTBI) as part of their conditioning regimen before bone marrow transplantation. PBL committed to apoptosis were scored before irradiation (S1), 4 h (S2) and 24 h after 2 Gy (S3, 14-17 h after the second 2 Gy fraction). Nuclear morphology and chromatin-DNA were analysed by fluorescence microscopy immediately after blood sample withdrawal (I) and after 24 h in cell culture medium (II). When scored immediately after withdrawal, no circulating PBL with the apoptotic nuclear morphology were observed in S1 and S2 blood samples whereas S3 disclosed 21.9 +/- 11.7% of circulating lymphocytes with an apoptotic nuclear morphology. After 24 h in culture, S1 samples (before irradiation) generally contained less than 20% of apoptotic lymphocytes. A higher percentage of apoptotic cells was noted in some cases in relation with recent chemotherapy and possibly with pathology. After 24 h in culture, S2 and S3 samples contained 51.7 +/- 17.9% and 60.4 +/- 16.4% of apoptotic lymphocytes, respectively. These results confirm that ionizing radiations induce apoptosis in vivo in human lymphocytes and that the commitment to apoptosis can be determined after low doses (2 Gy) of therapeutic whole body irradiation. The results suggest that susceptibility to apoptosis induction by ionizing radiations could be related to previous therapy by cytotoxic drugs and possibly to the type of haematological malignancy.

Adolescent↗
PubMed1995

[Clinical value of the potential doubling time (Tpot) measured by flow cytometry].

The potential doubling time (Tpot) is defined as the time necessary to double the number of proliferating tumor cells in the absence of spontaneous cell loss. Tpot is thought to be a better index of tumor proliferation than clinically observed tumour volume doubling time. The in vivo measurement of Tpot is a possible way to detect fast growing tumours which would be better controlled by accelerated radiotherapy. The published data demonstrate the feasibility and the safety of the technique. Large variations in Tpot values were observed in tumors with similar histology, indicating an accelerated proliferation rate in some tumors. There are technical difficulties related to intra-tumor heterogeneity, sample contamination by normal cells, and inter-laboratory variability, which question the biological interpretation of Tpot. Further studies are ongoing to establish whether the in vivo measurement of Tpot 1) provides information that is independent of the "classical" prognostic factors, and 2) allows the early recognition of the patients likely to benefit from accelerated treatment.

Cell Cycle↗
PubMed1995

Combined chemoradiation for locally advanced nonsmall cell lung cancer.

We report the results of a phase I study investigating the feasibility of concomitant daily doses of Carboplatin (20 to 25 mg/m2/d over 45 or 10 minutes) and accelerated chest irradiation (60 to 64 Gy over 4 weeks, 2 Gy per fraction, using the concomitant boost technique), alone or following three cycles of induction chemotherapy (cisplatin: 25 mg/m2 per day, d1 to d5, 5-Fluorouracil (5-Fu): 600 mg/m2 per day, d1 to d5, and Vinorelbine: 25 mg/m2 per day, d1 and d5, at 4-week intervals) in 15 patients with locally advanced unresectable nonsmall cell lung cancer. All patients received the planned sequence. The dose-limiting toxicity was esophagitis (5/15 WHO grade 4). No toxic deaths were observed. The tumor response rate was high: 6/15 complete responses and 8/15 greater than 50% tumor regressions. The median survival has not been reached after a mean follow-up of 14 months (range: 6, 28). We are now planning a multicenter phase II study, using the following doses: 20 mg/m2 of daily Carboplatin over 10 minutes and 60 Gy of radiotherapy over 4 weeks.

Adult↗
PubMed1994

Single dose versus fractionated total body irradiation before bone marrow transplantation: radiobiological and clinical considerations.

PURPOSE: This present review is intended to evaluate the specific influence of fractionation of total body irradiation on the outcome of a subsequent bone marrow transplantation. METHODS AND MATERIALS: Available experimental and clinical data on the influence of fractionation on leukemia cell killing, immunosuppression, and sparing of normal tissues were analyzed. RESULTS: Review of available data shows: (a) The role of fractionation on leukemia cell killing may vary with the leukemia type. For acute nonlymphoblastic leukemia, a few experimental and several clinical studies show no or little fractionation effect; a 12-13 Gy fractionated scheme could, therefore, be more efficient than a conventional 10 Gy single dose total body irradiation. For chronic myelogenous leukemia, some sensitivity to fractionation is suggested, so that an increase in total or fractional dose may be necessary in fractionated schemes to equate the efficacy of a 10 Gy single dose. For acute lymphoblastic leukemia, a high fractionation sensitivity was observed for some leukemic cell lines in vitro, without undisputable clinical confirmation for the moment. (b) Numerous experimental studies have demonstrated that the immunosuppressive effect of total body irradiation, a major determinant of engraftment, is highly fractionation sensitive. In humans, high rates of graft failures have been reported when T-cell depletion of the graft was associated to fractionated total body irradiation schedules. (c) A large amount of radiobiological and clinical data have demonstrated that late radiation-induced injuries to normal tissues and organs are highly fractionation sensitive. However, in a context of total body irradiation for bone marrow transplantation, the number of other determinants of normal tissue damage makes it difficult to demonstrate a clear-cut advantage of fractionated over single dose scheme, with a possible exception for children. CONCLUSIONS: In 1994, available data suggest that very cautious attempts could be made to adapt total body irradiation schedules to the potential normal tissue toxicity, T-cell depletion, and to the type of leukemia.

Bone Marrow↗
PubMed1994

[Late effects of radiation on normal tissues].

In 1994, late effects of radiotherapy should be limited to an acceptable rate of benign and non-disabling complications. In almost all cases, this goal can be presently reached, owe to recent technological and radiobiological advances. The precise adaptation of irradiated volume, dose, fractionation and total duration of treatment should avoid severe post-radiotherapeutic toxicity. The identification of subgroups of patients with high susceptibility to ionizing radiations should soon allow the radiotherapists to take up the challenge of a both efficient and non-toxic irradiation.

Humans↗
PubMed1994

Male breast carcinoma: a single centre report of clinical parameters.

A total of 68 men (mean age 66.2 years) were treated for a primary carcinoma of the breast at Mount Vernon Hospital between January 1968 and June 1988. The mean duration of the symptoms before diagnosis was 13.3 months. The most common sign of presentation (60% of the patients) was a mass in the breast (mean size 3.9 cm). Thirty-three tumours (48.5%) were fixed to the skin and in nine the skin was ulcerated. Sixty-nine per cent of the patients had a T4 tumour and 51.5% had a palpable axillary node. Thirteen patients (19%) were treated by radiotherapy alone, 46 (67%) by surgery and postoperative radiotherapy, and nine (13.3%) by surgery alone. Sixty patients (88%) were in complete remission after the initial treatment and seven of these (12%) developed a local recurrence. The median follow-up was 54 months. The overall survival was 23% at 10 years and the corrected survival 42% at 10 years. Patients with no nodal disease at presentation had a better survival than those with N1 or N2 disease (55% versus 22% 10 years corrected survival, P < 0.002). The risk of nodal disease was strongly correlated by univariate analysis with the size of the tumour (P = 0.002) and the skin fixation (P = 0.005). The risk of metastatic dissemination was correlated with the nodal clinical involvement (P = 0.02) and the existence of a local recurrence (P = 0.003). In multivariate analysis, T and N stages were significantly associated with an increasing risk of treatment failure (P = 0.01). Forty-seven per cent of the patients with T4 tumours developed metastatic disease. This emphasizes the need for adjuvant systemic treatment for these patients.

Adult↗