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A key challenge in the clinical proteomics of cancer is the identification of biomarkers that would enable early detection, diagnosis and monitoring of disease progression to improve long-term survival of patients. Recent advances in proteomic instrumentation and computational methodologies offer a unique chance to rapidly identify these new candidate markers or pattern of markers. The combination of retentate affinity chromatography and mass spectrometry is one of the most interesting new approaches for cancer diagnostics using proteomic profiling. This review presents two technologies in this field, surface-enhanced laser desorption/ionization time-of-flight and Clinprot, and aims to summarize the results of studies obtained with the first of them for the early diagnosis of human cancer. Despite promising results, the use of the proteomic profiling as a diagnostic tool brought some controversies and technical problems, and still requires some efforts to be standardized and validated.

Background: Among advanced non-small cell lung cancer (NSCLC) patients, most will resist or relapse after first-line chemotherapy. As a result, second-line therapy has been a major focus for clinical research., Materials and Methods: A systematic review was carried out from 1996 to February 2005., Results: Second-line chemotherapy provides pre-treated NSCLC patients with a clear survival advantage. Docetaxel 75 mg/m(2) every 3 weeks is the present standard second-line chemotherapy. Despite promising results regarding efficacy and toxicity in phase III studies, a docetaxel weekly schedule could not be recommended. Pemetrexed recently emerged as an alternative with similar efficacy and less toxicity. Although the combination of two drugs was not associated with a survival benefit when compared with single-agent chemotherapy, such regimens induced a dramatic increase in toxicities and therefore mono-chemotherapy remains the standard as second-line therapy. Finally, few new agents were reported with better results than those used previously and clinical research on second-line therapy currently focuses on combinations with targeted therapies., Conclusion: Second-line chemotherapy offers NSCLC patients a small but significant survival improvement. However, this field of clinical research needs further investigations in order to answer certain remaining questions especially concerning targeted therapies.

Little is known regarding malignant thymoma and thymic carcinoma optimal therapy, and a multimodality approach could therefore be proposed in an attempt to improve the survival of patients. We report our experience with 8 cases of malignant thymoma or thymic carcinoma. These patients took part in a multimodality treatment program including neoadjuvant chemotherapy, surgery, and postoperative radiotherapy in our center between December 1995 and June 2001. The induction chemotherapy consisted of 4 courses of the CAP regimen (cyclophosphamide 600 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, and cisplatin 80 mg/m2 day 2), every 3 weeks. Patients underwent surgical resection after complete hematological recovery pending sufficient tumor response with a postchemotherapy resectable status. Adjuvant radiotherapy up to 60 Gy in 30 fractions was attempted postsurgically or after best chemotherapeutic response in nonsurgical patients. Among the 8 patients, 3 had a thymic carcinoma and 5 a malignant thymoma; 5 had a stage IV and 3 a stage III disease (Masaoka). Six patients partially responded to the chemotherapy regimen. Three patients were operated upon, and complete resection was performed in 2 cases. Finally, 4 patients achieved the planned radiotherapy. Four patients are still alive without evidence of tumor activity (23-77 months from the diagnosis) and 1 patient is alive with relapse at 56 months. The low compliance with the program led us to an early discontinuation. The high proportion of thymic carcinoma and advanced disease in our limited series might be an explanation for this unsatisfactory result. Optimal multimodality treatment of epithelial thymic tumor remains to be defined in multicenter trials.

The nasal and bronchial mucosa present similarities and differences. Remodeling is defined as "model again or differently, reconstruct" and is present in the airways of most if not all asthmatic patients. Even though inflammation is similar in allergic rhinitis and asthma, the pathologic extent of nasal remodeling in patients with rhinitis seems to be far less extensive than that in the bronchi of asthmatic patients. Epithelial damage is only minimal, and the reticular basement membrane does not appear to be largely pseudothickened. Moreover, the demonstration of fibrogenic growth factors in the nasal mucosa of patients with allergic rhinitis is lacking because of the paucity of studies. The reasons why remodeling appears to be less extensive in the nasal mucosa than in the bronchial mucosa are still unclear, but 2 hypotheses can be put forward. On one hand, the cytokine production of smooth muscle cells might partly explain differences in remodeling of the 2 sites of the airways. On the other hand, the genes of the embryologic differentiation might persist in the nose and bronchi or might be re-expressed in asthma and rhinitis. Because the nose is of ectodermal origin and the bronchi of endodermal origin, these genes might also govern remodeling patterns. More studies are urgently required to better characterize nasal remodeling in patients with rhinitis. A better understanding of nasal and bronchial remodeling might help to identify new pathways and new therapeutic strategies to reduce long-term remodeling in asthma.

In most of the cases, small cell lung cancer is diagnosed at the extensive disease stage. Regarding the micrometastatic process, it might be considered as a metastatic disease in almost all cases. Therefore, chemotherapy is the cornerstone of small cell lung cancer therapy. Cisplatin and VP-16-based combinations are recommended. Chemotherapy alone remains the only recommended therapy in extensive disease, whereas radiochemotherapy is the treatment of limited disease. Concomitant or alternate modalities are acceptable standards in this latter setting. Prophylactic cranial irradiation is recommended for complete responders with initially limited disease.

This retrospective study aimed at determining the prognostic significance of neuroendocrine markers chromogranin A (CgA), pro-gastrin releasing peptide (ProGRP) and neuron-specific enolase (NSE), together with the cytokeratin 19 marker CYFRA 21-1 in small cell lung cancer (SCLC). A total of 148 histologically proven and previously untreated SCLC patients were included. Among them 118 patients received a cisplatin-etoposide combination or cisplatin-etoposide-cyclophosphamide-4'-epidoxorubicin combination. All tumour markers were tested using immunoradiometric assays except for ProGRP which was tested using an enzyme-linked immunosorbent assay. The thresholds for marker serum titrations were 53 pg/ml, 65, 17, and 3.6 ng/ml for ProGRP, CgA, NSE and CYFRA 21-1 respectively. Univariate analysis showed that patients affected by one of the following characteristics proved to have a significant shorter survival in comparison with the opposite status of each variable: age over 63 years, extensive-stage, serum LDH level higher than 600 U/l, serum NSE level higher than 17 ng/ml, serum CgA level higher than 65 ng/ml and serum CYFRA 21-1 level higher than 3.6 ng/ml. In addition, there was a trend towards a statistical significance for a high serum alkaline phosphatase level and a performance status equal to or worse than two. The following variables were independent determinants of a poor outcome: a poor performance status (hazard ratio [95% confidence interval]: 1.51 [1.02-2.22]), a high CgA level (HR: 1.61 [1.06-2.45]), a high CYFRA 21-1 level (HR: 2.10 [1.40-3.14]) and an age older than 63 years (HR: 1.68 [1.14-2.48]). When the multivariate analysis was restricted to patients receiving a cisplatin-etoposide-based chemotherapy, the same variables were prognostic determinants with nearly similar hazard ratios. In conclusion, aside classical variables such as age and performance status, high serum CYFRA 21-1 and high serum CgA level in SCLC are both prognostic determinants of prognosis, in particular in patients receiving conventional chemotherapy consisting of cisplatin and etoposide-based combinations., (Copyright 2002 Elsevier Science Ireland Ltd.)

Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy-toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. QUALY methods based on time without symptoms and toxicity allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing non-platinum-based doublets with either single-drug chemotherapy or standard cisplatin-based doublets., (Copyright 2002 Elsevier Science Ireland Ltd.)

Introduction: Adenocarcinoma of the pancreas remains one of the most difficult malignancies to treat. Its incidence has steadily increased over the past four decades, and its prognosis is still dismal. AIM To assess tumor control and the palliative benefit of 5-fluorouracil (5-FU), cisplatin (CDDP), and radiotherapy in patients with advanced pancreatic cancer., Methodology: Systemic chemotherapy consisted of 5-FU (600 mg/m ), given as a 22-hour infusion on days 1 to 5, and CDDP (100 mg/m ), given as a 90-minute infusion on day 2. Treatment courses were repeated identically on day 21. Radiotherapy was delivered using megavolt irradiation of 25-MV photons with a two- or four-field isocentric technique., Results: Twenty-seven patients were treated with this radiochemotherapy (RCT). Twenty-one patients (78%) completed initial treatment. The median dose of radiation therapy delivered was 42.5 Gy. At the time of evaluation (1 month after the end of the RCT), no grade 4 (WHO) toxicity was observed; 12 patients had improved or stable body weight; pain was improved for 20 patients, with 11 experiencing no pain; and analgesic consumption decreased for 18 patients, of whom 11 stopped intake. The clinical benefit response was 7/27 (26%). Median survival and time to progression were, respectively, 9 and 4.4 months., Conclusion: This RCT regimen had a good impact on clinical benefit in locally advanced pancreatic carcinoma, without severe side effects.

Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy/toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. Qualy methods based on time without symptoms and toxicity (TWiST) allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing gemcitabine--navelbine or gemcitabine--taxane combinations with either single-drug chemotherapy or standard chemotherapy based on cisplatin. The choice of end-points is discussed.

Gemcitabine is a pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors including bladder, non-small cell lung and pancreatic cancers. Gemcitabine is a potent radiosensitizer of human tumor cells. This review summarizes preclinical studies designed to elucidate the mechanism of action of gemcitabine with ionizing radiation. Phase I-II ongoing trials of combination of radiation therapy and gemcitabine are trying to determine the optimal dose and schedule which could be used in daily clinical activity. The mechanism of radiosensitization is thought to be simultaneously gemcitabine-induced dATP (deoxyadenosine triphosphate) depletion and cell cycle redistribution into the S phase. Although there are no real study which has proven supra-additive combination, the recent acute side effects in several clinical studies oblige physicists to determine with precision the maximum tolerated dose of gemcitabine in association with ionizing radiation. Radiosensitization conditions can be obtained either with a long exposition to a low concentration or a short exposition to a high concentration. Radiation sensitivity begin to be detected four hours after treatment for 48 hours. A dose about 100 mg/m2/week of gemcitabine could be used with radiation therapy according to recent phase I results. This limiting dose is approaching to a radiosensitization context where the effect of one agent is increased by another agent which is inactive or poorly active for the effect under consideration. In this type of regimen, the two modalities do interact with a frequent inhibition of recovery from potentially lethal damage and a probably increase of late side effects of radiation therapy. In contrast, radio-chemotherapy combination is used for a therapeutic advantage when the drug by itself is active against the tumor but does not enhance late side effects of radiation on the critical normal tissues within the irradiated volume. Gemcitabine surely is a strong radiosensitizer even at low doses with future extended combined modality therapeutic indications. The ultimate goal of combined treatments should be an increased therapeutic ratio.