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Biomedical subjects

J Bourhis

Publications and source records attributed to J Bourhis.

At least 37 records · Page 2Linked to original sources
PubMed2004

Concomitant radiochemotherapy or accelerated radiotherapy: analysis of two randomized trials of the French Head and Neck Cancer Group (GORTEC).

In the early 1990s, when conventional radiotherapy (RT) was the standard of care in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), two main options were being tested to improve the efficacy and the therapeutic ratio of RT. The first approach evaluated the effect of adding chemotherapy (CT) simultaneously to RT (RT-CT), while the second approach assessed the effect of modified fractionated RT. To answer these two questions, in 1994, the French Group for Head and Neck Oncology Radiotherapy (GORTEC) initiated two randomized trials. A total of 494 patients were entered in these two parallel phase III multicenter trials comparing conventional RT (70 Gy in 35 fractions) either with concomitant RT-CT (226 patients; 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and 5-fluorouracil [5FU]) or with very accelerated RT (268 patients) delivering 64 Gy in 3 weeks. The 5-year overall survival (OS), specific disease-free survival (DFS), and local-regional control rates were improved in favor of simultaneous RT-CT, whereas local-regional control was significantly improved with accelerated RT, along with a marginal effect on OS and DFS. This increased antitumor efficacy was in both cases associated with a marked increase in acute RT-induced toxicity, which was more pronounced with accelerated RT, whereas late effects were marginally increased with the addition of CT and not influenced by accelerated RT. We conclude that both concomitant RT-CT and accelerated RT improved tumor control rates, as compared to conventional RT, along with increased but manageable toxicity. The two regimens are currently being tested in an ongoing randomized study and also being compared to moderately accelerated RT and concomitant CT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Randomized trials of amifostine and radiotherapy: effect on survival?

Amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) is a cytoprotective and radioprotective agent for normal tissues against the deleterious effects of chemotherapeutic agents and/or ionizing radiation. We have compiled a unique database for meta-analysis that aims to address the controversial concept of the tumor protection. The proposed meta-analysis on survival outcome, which is based on individual patient data, will be more useful than literature-based meta-analyses because of the superiority of reliable, longer follow-up patient data. It will be also possible to study the effect(s) of amifostine in different tumor types.

Amifostine↗
PubMed2004

[Larynx preservation: nonsurgical approaches].

The question of larynx preservation is central in the management of patients with a carcinoma of the larynx or hypopharynx, especially to preserve the main functions of the larynx. In early stages (T1-earlyT2) Larynx preservation can generally be obtained with partial surgery or radiotherapy. Some other approaches such as exclusive chemotherapy require further investigations. In locally advanced and infiltrating larynx/hypopharynx carcinomas, (advancedT2-T3), several ways have been used to preserve the larynx including exclusive radiotherapy which can be improved by modified fractionation and acceleration. The efficacy of radiotherapy can be also markedly increased by adding concomitant cisplatin based chemotherapy, as reported recently in a large randomized trial. An alternative approach consisted in using induction chemotherapy (cisplatin-5FU) and followed by a local treatment adapted to the response to chemotherapy. The combined analysis of 3 such randomized trials (GETTEC, Veteran et EORTC) showed that this approach has to be used with caution, and could be safer in good responders to induction chemotherapy. Finally, larynx preservation is generally not proposed in patients with deeply infiltrating tumors and or tumor invading the cartilage or soft tissue in the neck (T4).

Antimetabolites, Antineoplastic↗
PubMed2003

Baseline and treatment-induced chromosomal abnormalities in peripheral blood lymphocytes of Hodgkin's lymphoma patients.

PURPOSE: To study chromosomal abnormalities in 49 patients with Hodgkin's lymphoma (HL), before and after treatment and at several times during a 2-year period. METHODS AND MATERIALS: Simple chromosomal aberrations (CAs) and complex chromosomal rearrangements (CCRs) were counted in peripheral lymphocytes by painting of chromosomes 1, 3, and 4 (fluorescence in situ hybridization). A control population was composed of 20 healthy donors and 69 untreated cancer patients who had undergone various radiologic scans. RESULTS: A greater frequency (p < 10(-4)) of spontaneous cytogenetic abnormalities was observed in untreated HL patients compared with the control populations. CCRs were observed exclusively in the HL population (p < 10(-4)). Chemotherapy was associated with a significant increase in the frequency of CAs (p < 10(-4)), according to the chemotherapy regimen (p = 0.002). Immediately after radiotherapy, a significant increase (p < 10(-4)) was observed in CAs according to the size of the irradiation field. Conversely, the significant increases in the frequency of CCRs observed after treatment did not correlate with the chemotherapy regimens, radiotherapy dose, or size of the irradiation field. The evolution of CAs vs. CCRs over time was also dissociated: during the follow-up of these patients, a significant decrease was observed in the frequency of CAs at 6 months and 1 and 2 years. In contrast, after an initial decrease for up to 6 months after treatment, the frequency of CCRs remained constant for up to 2 years. CONCLUSION: Increased cytogenetic abnormalities were observed in untreated HL patients compared with the control populations. The greater frequency of cytogenetic abnormalities persisted in some patients. The presence of CCRs supports the concept of a unique genetic environment in HL patients that persists in response to potentially noxious treatments.

Adolescent↗
PubMed2003

n-3 polyunsaturated fatty acids decrease mucosal/epidermal reactions and enhance antitumour effect of ionising radiation with inhibition of tumour angiogenesis.

The purpose of this study was to evaluate the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on normal tissue (lip mucosa) and tumour growth when combined with ionising radiation. The oral region (snout) of C57 black mice was irradiated with 16.5 Gy and n-3 PUFAs (100 microl) were injected intravenously for 2 weeks. After exposure to irradiation, the degree and duration of the acute reactions decreased significantly when mice were treated with n-3 PUFAs as compared to the control group. Interestingly, the range of the reactions in the n-3 PUFAs-treated group compared favourably to the group receiving amifostine (27.5 mg/kg i.v.). the effect of n-3 PUFAs was further evaluated in HEP-2 human carcinoma xenograft transplanted in nude mice. An inhibition of tumour growth was observed when mice were treated with n-3 PUFAs alone and this effect was maximal when combined with irradiation. Similar results were obtained using eicosapentaenoic acid. The effect of n-3 PUFAs was associated with inhibition of angiogenesis and tumour proliferation, and significantly decreased expression of cyclooxygenase-2. In conclusion, n-3 PUFAs administration decrease mucosal response, while moderately enhancing the antitumour effect of irradiation. The magnitude of the differential effect suggests that n-3 PUFAs need to be further investigated in the clinic.

Animals↗
PubMed2003

Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma.

Mantle cell lymphomas (MCL) are characterized by their aggressive behavior and poor response to chemotherapy regimens. We report here evidence of increased in vitro radiation sensitivity in two cell lines that we have generated from two MCL patients (UPN1 and UPN2). However, despite their increased radiation sensitivity, UPN2 cells were totally resistant to apoptotic cell death, whereas UPN1 cells underwent massive apoptosis 6 h after irradiation. The frequency of induced chromosomal abnormalities was higher in UPN1 as compared to UPN2. Distinct mechanisms have been found to contribute to this phenotype: a major telomere shortening (UPN1 and UPN2), deletion of one ATM allele and a point mutation in the remaining allele in UPN2, mutation of p53 gene (UPN1 and UPN2) with absence of functional p53 as revealed by functional yeast assays. After irradiation, Ku70 levels in UPN1 increased and decreased in UPN2, whereas in the same conditions, DNA-PKcs protein levels decreased in UPN1 and remained unchanged in UPN2. Thus, irradiation-induced apoptotic cell death can occur despite the nonfunctional status of p53 (UPN1), suggesting activation of a unique pathway in MCL cells for the induction of this event. Overall, our study demonstrates that MCL cells show increased radiation sensitivity, which can be the result of distinct molecular events. These findings could clinically be exploited to increase the dismal response rates of MCL patients to the current chemotherapy regimens.

Antigens, Nuclear↗
PubMed2003

Nasopharyngeal carcinomas: an update.

Among the group of head and neck cancers, nasopharyngeal carcinomas (NPC) represent a distinct entity in terms of their epidemiology, clinical presentation, biological markers, carcinogenic risk factors, prognostic factors, treatment and outcome. Undifferentiated NPC (UCNT), the most frequent histological type, is endemic in certain regions, especially in South East Asia. The disease has also been associated with the presence of the Epstein-Barr Virus (EBV). Although NPC is a radiosensitive and chemosensitive tumour, a substantial number of patients develop local recurrence or distant metastases. For patients with locoregional advanced disease, it is well known that conventional radiotherapy is insufficient in terms of both the local control rates and distant metastases. New techniques of radiation and new combined radiotherapy and chemotherapy modalities have been evaluated in numerous clinical trials in recent years. The purpose of this article is to review the current knowledge in terms of the epidemiology, biology, prognosis, management and outcome of patients with NPC.

Antineoplastic Agents↗
PubMed2002

[Principal therapeutic uses of monoclonal antibodies in oncology].

In the past few years, new agents based on monoclonal antibodies have been developed in Oncology. Indeed in some case tumor cells express antigenic targets at higher levels than normal cells. There are 2 main types of monoclonal antibodies that can be either conjugated to cytotoxic drugs or radio-active compounds or be non-conjugated. Among the last category, some are currently used in the treatment of patients, including 2 monoclonal antibodies targeting receptors with tyrosine kinase activity (HER2: Herceptin (DCI: trastuzumab), EGFr: Erbitux (DCI: cetuximab). A third monoclonal antibody is commonly used in cancer treatment, which targets CD20, a transmembrane marker of B lymphoma (MabThera (DCI: rituximab). Both Herceptin and MabThera have been associated with improved survival in patients with breast carcinoma and lymphoma, respectively. New promising agents are under investigation such anti EGFr in colon and head and neck carcinoma or new compounds such as anti-VEGF. These examples outline the importance of the recent progress in selectively targeting tumor antigen and the potential impact of these approaches in Oncology.

Antibodies, Monoclonal↗
PubMed2002

End points for new agents in induction chemotherapy for locally advanced head and neck cancers.

More than 60% of patients diagnosed with squamous cell carcinoma of the head and neck present at a locally advanced stage. Although multimodality therapy has improved locoregional control, the 5-year survival rate of this population rarely exceeds 30%. In this review, we analyzed the impact of chemotherapy in the management of locally advanced head and neck cancer and we underline the potential benefit of induction chemotherapy. The Meta-Analysis of Chemotherapy in Head and Neck Cancer collaborative group has suggested a survival advantage of 5% at 5 years for platin-5-fluorouracil induction chemotherapy. We have analyzed cofactors that may affect the survival of head and neck patients and propose new end points for assessment of the efficacy of induction chemotherapy. The detrimental effect of second primary tumors on long-term results is stressed and we have suggested the use of overall 2-year survival as a surrogate end point for induction chemotherapy efficacy. Finally, we have examined the impact of new cytotoxic agents and present the promising results of new taxane-based combinations.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Tyrphostin AG 1024 modulates radiosensitivity in human breast cancer cells.

Insulin-like growth factor-1 (IGF-1) plays an important growth-promoting effect by activating the PI3K/Akt signalling pathway, inhibiting apoptotic pathways and mediating mitogenic actions. Tyrphostin AG 1024, one selective inhibitor of IGF-1R, was used to evaluate effects on proliferation, radiosensitivity, and radiation-induced cell apoptosis in a human breast cancer cell line MCF-7. Exposure to Tyrphostin AG 1024 inhibited proliferation and induced apoptosis in a time-dependent manner, and the degree of growth inhibition for IC20 plus irradiation (4 Gy) was up to 50% compared to the control. Examination of Tyrphostin AG 1024 effects on radiation response demonstrated a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis. Western blot analysis indicated that Tyrphostin AG 1024-induced apoptosis was associated with a downregulation of expression of phospho-Akt1, increased expression of Bax, p53 and p21, and a decreased expression of bcl-2 expression, especially when combined with irradiation. To our knowledge, this is the first report showing that an IGF-1 inhibitor was able to markedly increase the response of tumour cells to ionizing radiation. These results suggest that Tyrphostin AG 1024 could be used as a potential therapeutic agent in combination with irradiation.

Adenocarcinoma↗
PubMed2001

Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma.

BACKGROUND: The purpose of this study was to analyze the tolerance and efficacy of full dose reirradiation combined with chemotherapy in patients with head and neck carcinoma (HNC) with a high risk of recurrence after salvage surgery. METHODS: Between 1991 and 1996, 25 patients having a recurrence or a second primary tumor in a previously irradiated area (> 45 grays [Gy]) were entered in this prospective study. All of them received salvage surgery and had a positive surgical margin and/or lymph node involvement with capsular rupture (N+R+). Adjuvant radiochemotherapy was given, delivering 60 Gy per 30 fractions with concomitant hydroxyurea and 5-fluorouracil. The median total cumulative dose of the 2 irradiations was 118 Gy. The median follow-up after the second irradiation was 66 months. RESULTS: During the reirradiation course, Grade 3 and 4 mucositis were observed in 40% and 12%, respectively. Analysis of late effects (> 6 months after reirradiation) showed that 16% of the patients had osteoradionecrosis and 40% had Grade 2-3 cervical fibrosis (Radiation Therapy Oncology Group scoring system). The patterns of failure were as follows: local only (n = 9), lymph node only (n = 2), local and lymph node only (n = 1), and metastatic (n = 4). The 4-year survival rate after reirradiation was 43% (95% confidence interval, 25-62). CONCLUSIONS: Full dose reirradiation combined with chemotherapy after salvage surgery in high risk patients with HNC was feasible with an "acceptable" toxicity and led to a relatively good 5-year survival rate. These results prompted the authors to initiate a multicentric randomized trial that is ongoing (GETTEC-GORTEC 99-01) to evaluate the benefit of adjuvant radiochemotherapy in these types of patients.

Adenocarcinoma↗
PubMed2001

BCR-ABL down-regulates the DNA repair protein DNA-PKcs.

This study demonstrates in both stable and inducible BCR-ABL-expressing hematopoietic cells a down-regulation of the major mammalian DNA repair protein DNA-PKcs by BCR-ABL. Similar results were found in BCR-ABL CD34(+) cells from patients with chronic myelogenous leukemia (CML). DNA-PKcs down-regulation is a proteasome-dependent degradation that requires tyrosine kinase activity and is associated with a marked DNA repair deficiency along with increased sensitivity to ionizing radiation. The conjunction of a major DNA repair deficiency and a resistance to apoptosis, both induced by BCR-ABL, provides a new mechanism to explain how secondary genetic alterations can accumulate in CML, eventually leading to blast crisis. The down-regulation of DNA-PKcs was reversible in CD34(+) CML cells suggesting that this approach might offer a novel and powerful therapeutic strategy in this disease, especially to delay the blast crisis. (Blood. 2001;97:2084-2090)

Acetylcysteine↗
PubMed2001

Individual patient-versus literature-based meta-analysis of survival data: time to event and event rate at a particular time can make a difference, an example based on head and neck cancer.

The objective of this study is to compare the results of an individual patient-based and a literature-based meta-analysis in chemotherapy in head and neck cancer and to identify the sources of difference. For all head and neck cancer randomized controlled clinical trials comparing chemotherapy and loco-regional treatment with loco-regional treatment alone, both the literature data and the individual patient data are retrieved and meta-analyses performed and compared. Only survival data are used as outcome, although both time to death and mortality at specific time points are considered in different analyses. There are substantial differences between the individual patient-based and the literature-based meta-analyses. The most important reason for the differing results is that the individual patient-based meta-analysis is based on a time to event analysis, whereas the literature-based meta-analysis is based on mortality at a specific time point. Mortality can change substantially with follow-up time. The absolute survival differences in the case study, for instance, increase from 2.6% at 2 years to 5.6% at 5 years.

Antineoplastic Agents↗
PubMed2001

[Method of radiotherapy planning for head and neck tumors using simulated CT images and radiographic data, developed at the Gustave Roussy Institute].

The paper deals with the recent improvements introduced in the most usual method applied in the Institut Gustave Roussy radiotherapy department for obtaining the anatomical data of patients treated for head and neck tumors. For each of these patients, five to seven transverses slices and a lateral radiographic film are taken from a Mecaserto simulator-CT. The anatomical representation of the patient sagittal plane is carried out from the digitalisation of the radiographic film on a Vidar Vxr-12 Plus film scanner and integrated into the Dosigray dose calculation programme in order to be used as a support for the laying out of the dose distribution in reference to the treatment. The sagittal anatomical representation obtained from the radiographic film digitalisation is compared with the one resulting from the interpolation between a limited number of irregularly-spaced transverse slices taken on the simulator-CT. The method using the simulator-scanner transverse slices and the radiographic film digitalisation represents an interesting alternative for obtaining an anatomy simulation representative of the patient in hospitals where a scanner is not available full-time for the needs of the radiotherapy process.

Cancer Care Facilities↗
PubMed2001

Antiviral approaches for cancers related to Epstein-Barr virus and human papillomavirus.

Epstein-Barr virus and human papillomaviruses (HPV) are DNA viruses underlying the carcinogenesis of 15-20% of human cancers worldwide. Viral oncoproteins are involved in malignant transformation and maintenance of the malignant phenotype, mainly through interaction between oncoproteins and products of tumour-suppressor genes. The use of vaccines to prevent the occurrence of HPV-related cancers is being investigated. Several approaches have been used to inhibit expression of viral oncoproteins. The first strategy uses antisense oligodeoxynucleotides against viral oncoproteins; downregulation of the oncoproteins can influence tumour cell growth and restore sensitivity to cytotoxic agents. Another approach uses antiviral drugs such as acyclic nucleoside phosphonates; inhibition of virus replication can lead to downregulation of viral oncoproteinsand ultimately reactivate tumour-suppressor-gene pathways. In addition, the combination of acyclic nucleoside phosphonates with conventional cytotoxic agents is more effective than either agent alone. These data provide the basis for a novel anticancer strategy to improve the therapeutic ratio in virus-related cancers, which needs to be further investigated for clinical applications.

Antineoplastic Agents↗
PubMed2001

The olivacine S16020 enhances the antitumor effect of ionizing radiation without increasing radio-induced mucositis.

The combination of a novel topoisomerase II inhibitor, S16020, and ionizing radiation (IR) was investigated with the aim of assessing normal tissue tolerance using a mouse mucosal lip model and antitumor activity in a human carcinoma (HEP2) cell line. No increase of acute mucosal reactions was seen when combining S16020 with IR as compared with IR alone. Using clonogenic cell survival assay, a marked enhancement of HEP2 cell killing was found when S16020 was combined with irradiation. Additional in vivo combination of S16020-IR was able to increase markedly the antitumor efficacy as compared with S16020 or irradiation alone. Interestingly, the radiosensitization effect in vivo was observed at relatively low and nontoxic concentrations of S16020, and no dose-effect relationship was found beyond 30 mg/kg. In conclusion, the combination of IR and S16020 seems promising to enhance antitumor activity without increasing deleterious effect in normal tissues and to provide the basis for a new radio-chemotherapy combination.

Animals↗