Tobacco: deadly in any form or disguise.
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Adolescent↗
Biomedical subjects
David Khayat
Publications and source records attributed to David Khayat.
Cyclooxygenase-2 as a target for anticancer drug development.
The two isoforms cyclooxygenase-1 and -2 catalyze the initial step in the formation of prostaglandins in a variety of pathophysiological processes. More recently their role in carcinogenesis has become more evident. They seem to influence apoptosis, angiogenesis, and invasion, and play a role in the production of carcinogens. Usually, a high level of COX-2 expression is found in cancer cells. However, low COX-2 expression is observed in some cancers like prostate or breast cancer. This phenomenon is quite surprising and should influence on clinical trial designs. Large epidemiological trials studying users and non-users of aspirin have shown that cyclooxygenase (COX) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) could be of benefit against the development and growth of malignancies. Moreover, clinical trials in patients with familial adenomatosis polyposis syndrome have shown too the efficacy of non-selective COX inhibitors and recently also of selective COX-2 inhibitors in the reduction of the number and the size of colorectal polyps. However, a primary chemopreventive effect has not been demonstrated yet. NSAIDs are also supposed to have a preventive and growth inhibitory effect in extra-colonic epithelial malignancies. Several preclinical studies show promising results with combination treatments of either chemotherapy or radiotherapy with COX inhibitors. Preclinical studies with the simultaneous use of inhibitors of the epidermal growth factor receptor and COX-2 inhibitors have shown also promising results. Encouraging results with the first clinical trials combining chemotherapy with COX-2 inhibitors in patients with cancer in the advanced and neoadjuvant setting have recently been reported. However, NSAIDs effects in cancer cells are mediated not only by COX enzymes but also by interactions with downstream effectors of COX-2. Hence, we can state that targeting the COX-2 pathway is a promising strategy in the prevention and treatment of solid tumors. Ongoing trials are expected to answer - at least partly - the remaining questions concerning COX-2 and cancer.
Antineoplastic Agents↗
A new model for cancer research in France.
The new French National Cancer Institute is unique in Europe in that it associates all aspects of cancer care, research and patient advocacy in one single umbrella body. It brings together all sectors of the cancer field in a patient-centred, multidisciplinary approach to the disease. By facilitating national, European and international collaborations, it aims to attack the disease with a strong and united front.
Academies and Institutes↗
An unexpected inverse correlation between soluble epidermal growth factor receptor and interleukin-6 in metastatic malignant melanoma patients.
The exact role of the soluble form of epidermal growth factor receptor (sEGF-R) in melanoma disease remains to be determined. We focused this study on the detection of circulating levels of sEGF-R in metastatic malignant melanoma patients and on the possible relationship between sEGF-R and clinicobiological parameters including circulating interleukin-6 (IL-6) and survival. sEGF-R and IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay in serum from 75 metastatic malignant melanoma patients and 30 healthy controls. In our patients, median sEGF-R level was significantly elevated (P < 0.0001) compared with that of healthy controls (173.4 vs. 91.9 fm/ml). Age or sex was not associated with sEGF-R levels. Regarding tumor burden, in contrary to the detected IL-6 levels, we found that median sEGF-R levels were significantly (P = 0.045) lower in patients with high tumor burden (163 fm/ml) than in those with low tumor burden (193.8 fm/ml). An inverse correlation between IL-6 levels and sEGF-R was observed (r =-0.33; P = 0.040). No relationship between sEGF-R and time to progression or overall survival was observed while circulating IL-6 was found as a predictive factor of survival. Our results showed that sEGF-R level was elevated in metastatic malignant melanoma patients but not related to time to progression or survival and demonstrated an inverse correlation between sEGF-R and IL-6 levels. These findings imply a better understanding of EGF-R and IL-6 cross-talk function in melanoma.
Adult↗
Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies.
The proteasome is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the proteasome inhibitor bortezomib decreases proliferation, induces apoptosis, enhances the activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models in vitro and in vivo. Proteasome inhibition with bortezomib has specifically promoted apoptosis of tumor cells through the stabilization of p53, p21, p27, Bax, and IkappaBalpha, resulting in nuclear factor kappaB inhibition. Bortezomib was the first proteasome inhibitor to enter clinical trials. In two Phase II trials, SUMMIT and CREST, it was found that treatment with bortezomib, alone or in combination with dexamethasone, produced durable responses with meaningful survival benefits in patients with recurrent and/or refractory multiple myeloma. In the APEX Phase III trial, bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma. Clinical trials evaluating the safety and activity of bortezomib alone or in combination regimens with dexamethasone, doxorubicin, melphalan, prednisone, and/or thalidomide in the treatment of patients with newly diagnosed multiple myeloma have shown encouraging results. Preliminary studies suggest that bortezomib may serve as induction therapy before stem cell transplantation. Proteasome inhibition with bortezomib also has shown activity with manageable toxicity in mantle cell and other lymphomas, leukemias, and solid malignancies, including nonsmall cell lung carcinoma. Further studies with bortezomib as monotherapy and in combination regimens in the treatment of solid and hematologic malignancies are warranted.
Antineoplastic Agents↗
Pretreatment serum interleukin-6 concentration as a prognostic factor of overall survival in metastatic malignant melanoma patients treated with biochemotherapy: a retrospective study.
Biological response parameters during biochemotherapy, including chemotherapy with immune modulating agents, have been studied extensively. Of these parameters, interleukin-6 (IL-6) has been implicated in advanced stage disease and tumour recurrence. However, there is limited information available about the significance of IL-6 in metastatic malignant melanoma (MMM). In this study, we evaluated the possible relationship between serum IL-6 level and overall survival. This retrospective study included 125 patients with MMM. Pretreatment serum IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay (ELISA) test. Kaplan-Meier survival curves were constructed and compared using the log-rank test. Cox proportional analysis was performed to assess the predictors of overall survival, which was calculated from the beginning of biochemotherapy until death. In order to establish the possible relationship between IL-6 level and overall survival, patients were divided into two groups according to a cut-off of 5 pg/ml, corresponding to the first quartile obtained by descriptive statistics of the pretreatment IL-6 level in all patients. Thirty-five patients were in the low IL-6 group and 76 patients were in the high IL-6 group. Based on this stratification, overall survival was shown to be affected by IL-6 serum level: it was higher (24.6 months) in the low IL-6 group when compared with the high IL-6 group (9.7 months) (P=0.0006). Furthermore, Cox multivariate analysis including standard melanoma prognostic factors showed that IL-6, as a variable, lactate dehydrogenase (LDH) and tumour burden were significant prognostic factors for overall survival. On the basis of this evidence, the pretreatment serum IL-6 level is a predictive factor of overall survival in MMM.
Adolescent↗
Cancer-related anemia: biological findings, clinical implications and impact on quality of life.
Anemia is a common symptom in cancer patients. The relationship among anemia, cancer progression and clinical outcomes of cancer treatment is complex and much remains to be elucidated. One hypothesis for an etiological link is that anemia contributes to the development of tumor hypoxia, which in turn has been shown to induce proteomic and genomic changes within the tumor cells that ultimately favor malignant progression and treatment resistance. A substantial body of clinical data indicates that anemia can be a significant independent prognostic factor for treatment response and survival in cancer patients treated with chemotherapy or radiotherapy. In addition, studies have shown a correlation between anemia and decline in quality of life (QOL) in cancer patients. Of the many factors that impact cancer patients' QOL, fatigue has emerged as the most prevalent, troubling, under-recognized and under-treated of all symptoms experienced by anemic cancer patients. Systematic correction of anemia with appropriate supportive therapies prior to or during chemotherapy or radiotherapy may enhance patients' QOL.
Anemia, Hypochromic↗
Sequential administration of docetaxel followed by cisplatin-vindesine: a pilot study in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
In this phase II study, the feasibility and efficacy of sequential chemotherapy were tested with agents shown to be active as monotherapy. Patients with chemotherapy-naive, locally advanced or metastatic non-small cell lung cancer were selected for the study. Treatment involved four cycles of docetaxel (100 mg/m(2) on day 1, every 3 weeks) (sequence A), followed by four cycles of cisplatin-vindesine (cisplatin 120 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1, 8, 15, and 22, every 4 weeks) (sequence B). Responding patients received 3 cycles of docetaxel 100 mg/m(2) (day 1, every 3 weeks) as consolidation (sequence C). Thirty-two patients entered the study with thirty being evaluable for efficacy. Four patients showed a partial response and one patient a complete response, resulting in an objective response rate of 16.7 %. The median survival time (intent-to-treat) was 11 months (95 %CI = 8.0-15.4 months) with an estimated 1-year survival rate of 47%. The median time to progression was 17.6 weeks in the evaluable population. Main grade 4 toxicity was neutropenia (21.8 % and 68.2 % of patients in sequence A and B, respectively) while grade 3 peripheral neuropathy was documented in five patients during sequence B. There were no treatment-related deaths. Sequential chemotherapy may show promise for the treatment of advanced non-small cell lung cancer. Given the feasibility of this pilot study, sequential chemotherapy concept should be investigated with newer cisplatin-based regimens using this approach in larger prospective studies.
Adult↗
[Aromatase inhibitors in adjuvant setting in breast cancer].
For more than twenty years, tamoxifen represents the gold standard treatment in adjuvant setting for breast cancer patients. However, the tamoxifen activity remains complex, with its agonist effects, sometimes a poor tolerance and a certain number of patients become refractory to treatment. The aromatase inhibitors, such as progestatifs, were developed to challenge tamoxifen efficacy, along with improved tolerability. The third generation of aromatase inhibitors seems to provide significant gains in efficacy over tamoxifen for postmenopausal patients with hormone receptor positive breast cancer and they have already been approved in patients with metastatic disease. We review, in this article, the rationale for using IA in patients with breast cancer and, across the different clinical trials results already published, their current major role they are playing in adjuvant setting for menopausal hormonal receptor-positive breast cancer patient. One of the main issues using the third generation of IA is their long-term side effects, especially bone turnover and lipid metabolism.
Anastrozole↗
Nuclear localization of apoptosis protease activating factor-1 predicts survival after tumor resection in early-stage non-small cell lung cancer.
The proapoptotic protein apoptosis protein activating factor-1 (Apaf-1), which is normally located in the cytoplasm, can translocate to the nucleus before non-small cell lung carcinoma (NSCLC) cells manifest signs of apoptosis such as mitochondrial damage, caspase activation, or chromatin condensation. This may indicate a stage of imminent apoptosis. Importantly, we found that 24% (15 of 62) of resected stage I NSCLC (T(1)N(0)M(0) or T(2)N(0)M(0)), manifested a marked nuclear localization of Apaf-1 (Apaf-1(Nuc)), as compared with the mostly cytoplasmic localization of Apaf-1 found in the remaining tumors (Apaf-1(Cyt)). After a median follow-up of 6.31 years, the actuarial 5-year overall survival rates were 89% (56-98%) in the Apaf-1(Nuc) group and 54% (36-71%) in the Apaf-1(Cyt) group (P = 0.039). No correlation between the subcellular localization of Apaf-1 and that of p53 and Hsp70 could be established. Thus, the subcellular location of Apaf-1 (but not that of p53 or Hsp70) constitutes an accurate prognostic factor for overall survival in NSCLC.
Adult↗
Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.
BACKGROUND: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. METHODS: We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. RESULTS: The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. CONCLUSIONS: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.
Adenocarcinoma↗
Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design.
As pharmacokinetics represents a bridge between pharmacological concentrations and clinical regimens, the pharmacokinetic exploration of the therapeutic dose range is a major outcome. This study was aimed at assessing pharmacokinetic linearity of i.v. vinorelbine through an open design with intra-patient dose escalation (3 doses/group). Three groups of six patients received either 20-25-30 mg/m2; or 25-30-35 mg/m2; or 30-35-40 mg/m2. The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25-75 years, WHO PS < or =2, normal haematology and biochemistry, life expectancy > or =3 months. The pharmacokinetics was evaluated in both whole blood and plasma over 120 h. Twenty-six patients were recruited and 18 were evaluable for pharmacokinetics. The toxicity consisted in grade < or =3 leucopenia and neutropenia (<20% of courses) and two grade 4 constipation with rapid recovery (2/54 courses). Compared to blood, plasma was demonstrated to underestimate the pharmacokinetic parameters. In blood, the drug total clearance was about 0.6 l/h/kg, with minor contribution of renal clearance, steady state volume of distribution close to 13 l/h/kg, and elimination half-life at about 40 h. A pharmacokinetic linearity was demonstrated up to 40 mg/m2, and even up to 45 mg/m2 when pooling data from another study. A pharmacokinetic-pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.
Adult↗
Oxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients.
This phase I-II trial was designed to assess the effect of irinotecan on oxaliplatin pharmacokinetics and to determine the MDT of both drugs when administered in combination. Treatment was repeated every 2 weeks. Pharmacokinetic studies were performed on cycle 1 and 2 to assess the best sequence and detect any interaction between the two drugs. Thirty-four patients with advanced colorectal cancer were enrolled; 28 of them (82%) had liver involvement. The main toxicities were neutropenia and delayed diarrhea; 5 patients (14%) experienced febrile neutropenia. Dose-limiting toxicity was experienced at levels 1/2/3/4/5 by 4/10, 1/6, 3/6, 3/8, and 3/4 patients, respectively. Fifteen patients responded (2 CR; 13 PR) for an ORR of 44%. No pharmacokinetic interactions between irinotecan and oxaliplatin were detected. The recommended dose for future phase II trials is oxaliplatin 85 mg/m and irinotecan 180 mg/m2 on day 1 combined with 5FU/leucovorin according to the de Gramont regimen at days 2 and 3. Twenty-nine percent of patients underwent secondary hepatectomy with curative intent, and two of them are long-term disease-free survivors. It would appear that the dose and schedule defined by this trial could be proposed as front-line therapy for advanced colorectal carcinoma to establish rapid disease control and to permit patients to proceed to surgery.
Adult↗
Lung cancer in patients with HIV Infection and review of the literature.
BACKGROUND: The improved survival of patients since the use of highly active antiretroviral treatments has lead to the reporting of non-AIDS defining tumors, such as lung cancer. METHODS: Analysis of the records of 22 HIV-infected patients with lung cancer (LC) diagnosed in three hospitals located in the Paris area (France). RESULTS: Twenty-one patients were smokers. The patients (86% male, 14% female) had a median age of 45 yr (range, 33-64 yr). Risk factors for HIV infection were intravenous drug use in 5 patients, homosexual transmission in 10 patients, and heterosexual transmission in 7 patients. At diagnosis of LC, seven patients had previously developed a CDC-defined AIDS manifestation, the median CD4 cell count was 364/mm3 (range 20-854/mm3) and median HIV1 RNA viral load was 3000 copies/mL. The most frequent histological subtype was squamous cell carcinoma (11 cases). A stage III-IV disease was observed in 75% of the patients. Only one patient had a small-cell lung carcinoma. Twenty-one patients received combined specific therapy, of which six patients underwent surgery for the LC. The median overall survival was 7 mo. No opportunistic infections occurred during LC therapy. CONCLUSIONS: LC occurs at a young age in HIV-infected smokers. LC is not associated with severe immunodeficiency. The prognosis is poor because of their initial extensive disease and a poor response to therapy. However, surgery appears to improve outcome in much the same way as in the general population.
Adult↗
[Neoadjuvant endocrine therapy for breast cancer: an overview].
The clinical benefits of endocrine therapy for patients with hormonosensitive breast cancer remains perfectly established. For instance, tamoxifen, the gold standard of the adjuvant treatment, has largely contributed of the effectiveness of such a therapy. The recent development of new endocrine agents (the third-generation aromatase inhibitors, selective estrogen receptors modulators), provides to physicians the opportunity of a more effective and tolerable therapeutic approach, in the metastatic disease setting or likely in adjuvant setting for breast cancer patients. Preoperative therapy has been widely used for the treatment of initially inoperable locally advanced breast cancers with the main objective of breast-conserving surgery. The benefits of neoadjuvant chemotherapy has widely been demonstrated; however, the success of neoadjuvant endocrine therapy is much recent. The clinical and pharmacological data of the main published studies using neoadjuvant hormonotherapy are presented herein this review. Therefore, clinical and histologic assessments of response brings essential informations about the breast cancer hormonal sensitivity, but may also be predictor of the future (adjuvant or metastatic) treatment responsiveness.
Anastrozole↗
Quality trials and quality of life in non-small-cell lung cancer.
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Antineoplastic Protocols↗
Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick).
BACKGROUND: This study addressed the question of whether limited surgery for primary malignant melanoma with a 2-cm margin is as good as a 5-cm margin. An update of a 16-year follow-up is provided. METHODS: Nine European Centers, over a period of 5 years, prospectively randomized 337 patients with melanoma measuring less than 2.1 mm in thickness to undergo a local excision with either a 2-cm or a 5-cm margin. Three hundred twenty-six patients were eligible for statistical analysis. Excluded from the trial were patients older than 70 years; those with melanomas from the toe, nail, or finger; and those with acral-lentiginous melanoma. A separate randomization was performed to independently test an adjuvant treatment with a nonspecific immunostimulant, isoprinosine, compared with observation. The median follow-up time was 192 months (16 years) for the estimation of survival and disease recurrences. RESULTS: There were 22 tumor recurrences in the 2-cm arm and 33 in the 5-cm arm. The median time to disease recurrence was 43 months and 37.6 months, respectively. The 10-year disease-free survival rates were 85% for the group with a 2-cm margin and 83% for the group with a 5-cm margin. There was no difference in the 10-year overall survival rates (87% vs. 86%). Isoprinosine did not demonstrate any activity in this setting. CONCLUSIONS: The authors concluded that for melanoma less than 2.1-mm thick, a margin of excision of 2 cm is sufficient. A larger margin of 5 cm does not appear to have any impact on either the rate or the time to disease recurrence or on survival.
Adult↗
Malignant melanoma.
In the European Community cutaneous melanoma accounts for 1 and 1.8% of cancers occurring in men and women, respectively. The incidence rate is increasing faster than that of any other tumour. Sun exposure, patient's phenotype, family history, and history of a previous melanoma are the major risk factors. The change over a period of months is the main sign of a skin lesion turned into a melanoma. The ABCDE scheme for early detection of melanoma is commonly accepted. A new staging classification will be published in the next AJCC/UICC Cancer Staging System Manual in 2002. The clinical course of melanoma is determined by its dissemination and depends on thickness, ulceration, localisation, gender and histology of the primary tumour. Tumour stage at diagnosis remains the major prognostic factor. Surgery is the standard treatment option for operable local-regional disease. Sentinel node biopsy represents a promising experimental approach in the clinical detection and early treatment of occult lymph node involvement. For metastatic inoperable patients systemic chemotherapy can be attempted, while radiation therapy has to be considered as palliative treatment. No studies concerning frequency of follow-up are currently available, but common procedures may be performed.
Female↗