Philippe Lothaire

The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis

The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with meta-analysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using meta-analytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16–1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26–2.02) and in studies using PCR (HR 1.40; 95% CI 1.18–1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86–1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.

Ki-67 expression and patients survival in lung cancer: systematic review of the literature with meta-analysis.

Among new biological markers that could become useful prognostic factors for lung carcinoma, Ki-67 is a nuclear protein involved in cell proliferation regulation. Some studies have suggested an association between Ki-67 and poor survival in lung cancer patients. In order to clarify this point, we have performed a systematic review of the literature, using the methodology already described by our Group, the European Lung Cancer Working Party. In total, 37 studies, including 3983 patients, were found to be eligible. In total, 49% of the patients were considered as having a tumour positive for the expression of Ki-67 according to the authors cutoff. In all, 29 of the studies dealt with non-small-cell lung carcinoma (NSCLC), one with small-cell carcinoma (SCLC), two with carcinoid tumours and five with any histology. In terms of survival results, Ki-67 was a bad prognosis factor for survival in 15 studies while it was not in 22. As there was no statistical difference in quality scores between the significant and nonsignificant studies evaluable for the meta-analysis, we were allowed to aggregate the survival results. The combined hazard ratio for NSCLC, calculated using a random-effects model was 1.56 (95% CI: 1.30–1.87), showing a worse survival when Ki-67 expression is increased. In conclusion, our meta-analysis shows that the expression of Ki-67 is a factor of poor prognosis for survival in NSCLC.

Has Cox-2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results

Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer, especially in adenocarcinoma (ADC). Our aim was to determine the prognostic value of COX-2 on survival in patients with lung cancer. Studies evaluating the survival impact of COX-2 in lung cancer, published until December 2005, were selected. Data for estimation of individual hazard ratios (HR) for survival were extracted from the publications and combined in a pooled HR. Among 14 eligible papers, all dealing with non-small-cell lung cancer, 10 provided results for meta-analysis of survival data (evaluable studies). Cyclooxygenase-2 positivity was associated with reduced survival, improved survival or no statistically significant impact in six, one and seven studies, respectively. Combined HR for the 10 evaluable studies (1236 patients) was 1.39 (95% confidence intervals (CI): 0.97–1.99). In stage I lung cancer (six evaluable studies, 554 patients), it was 1.64 (95% CI: 1.21–2.24). No significant impact was shown in ADC. A slight detrimental effect on survival in patients with lung cancer is associated with COX-2 expression, but the statistical significance is not reached. This effect is statistically significant in stage I, suggesting that COX-2 expression could be useful at early stages to distinguish those with a worse prognosis.

Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer

PURPOSE Optimum management of the N0 neck is unresolved in oral cancer. Sentinel node biopsy (SNB) can reliably detect microscopic lymph node metastasis. The object of this study was to establish whether the technique was both reliable in staging the N0 neck and a safe oncological procedure in patients with early-stage oral squamous cell carcinoma. METHODS An European Organisation for Research and Treatment of Cancer-approved prospective, observational study commenced in 2005. Fourteen European centres recruited 415 patients with radiologically staged T1-T2N0 squamous cell carcinoma. SNB was undertaken with an average of 3.2 nodes removed per patient. Patients were excluded if the sentinel node (SN) could not be identified. A positive SN led to a neck dissection within 3 weeks. Analysis was performed at 3-year follow-up. RESULTS An SN was found in 99.5% of cases. Positive SNs were found in 23% (94 in 415). A false-negative result occurred in 14% (15 in 109) of patients, of whom eight were subsequently rescued by salvage therapy. Recurrence after a positive SNB and subsequent neck dissection occurred in 22 patients, of which 16 (73%) were in the neck and just six patients were rescued. Only minor complications (3%) were reported following SNB. Disease-specific survival was 94%. The sensitivity of SNB was 86% and the negative predictive value 95%. CONCLUSION These data show that SNB is a reliable and safe oncological technique for staging the clinically N0 neck in patients with T1 and T2 oral cancer. EORTC Protocol 24021: Sentinel Node Biopsy in the Management of Oral and Oropharyngeal Squamous Cell Carcinoma.

Association of duoxes with thyroid peroxidase and its regulation in thyrocytes.

CONTEXT Thyroid hormone synthesis requires H(2)O(2) produced by dual oxidases (Duoxes) and thyroperoxidase (TPO). Defects in this system lead to congenital hypothyroidism. H(2)O(2) damage to the thyrocytes may be a cause of cancer. OBJECTIVE The objective of the study was to investigate whether Duox and TPO, the H(2)O(2) producer and consumer, might constitute a complex in the plasma membrane of human thyroid cells, thus maximizing efficiency and minimizing leakage and damage. DESIGN The interaction between Duox and TPO was studied by coimmunoprecipitation and Western blotting of plasma membranes from incubated follicles prepared from freshly resected human thyroid tissue from patients undergoing thyroidectomy, and COS-7 cells transiently transfected with the entire Duoxes or truncated [amino (NH2) or carboxyl (COOH) terminal]. RESULTS The following results were reached: 1) Duox and TPO from membranes are coprecipitated, 2) this association is up-regulated through the Gq-phospholipase C-Ca(2+)-protein kinase C pathway and down-regulated through the Gs-cAMP-protein kinase A pathway, 3) H(2)O(2) increases the association of Duox1 and Duox2 to TPO in cells and in membranes, and 4) truncated NH(2)- or COOH-terminal Duox1 and Duox2 proteins show different binding abilities with TPO. CONCLUSION Coimmunoprecipitations show that Duox and TPO locate closely in the plasma membranes of human thyrocytes, and this association can be modulated by H(2)O(2), optimizing working efficiency and minimizing H(2)O(2) spillage. This association could represent one part of a postulated pluriprotein complex involved in iodination. This suggests that defects in this association could impair thyroid hormone synthesis and lead to thyroid insufficiency and cell damage.

Molecular profiling of head and neck tumors.

Purpose of review Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. Unfortunately, patients with the same diagnostic and prognostic profile can have markedly different clinical outcomes. This most likely results from the fact that the current taxonomy of head and neck squamous cell carcinoma groups molecularly different diseases with distinct clinical phenotypes into classifications based mainly on morphology. A combination of circumstances, including the advent of array-based technology and progress in the human genome initiative, now provides an ideal opportunity to begin performing comprehensive molecular and genetic profiling of head and neck squamous cell carcinoma. This article reviews recently reported studies that have used such approaches. Recent findings Comparison of gene expression profiles between head and neck squamous cell carcinoma and normal tissues showed altered expression levels of genes involved in the control of cell growth and differentiation, angiogenesis, apoptosis, cell cycle, and signaling, most of which have not been previously described in head and neck squamous cell carcinoma. Additionally, they revealed the implication of different signaling and metabolic pathways such wnt and noch, highlighting the potential role of these pathways in oral cancer development. Their results provide new insights into the carcinogenesis of head and neck squamous cell carcinoma as well as a source of potential prognostic and predictive markers and targets for its prevention and therapeutics. Summary Although the sample sizes of these studies were small and their findings therefore require further validation in larger trials, such preliminary results provide important clues to the understanding of the various gene networks implicated in oral carcinogenesis and may contribute to the selection of target genes for possible molecular diagnosis and therapy in the future.

Acrylamide, an in vivo thyroid carcinogenic agent, induces DNA damage in rat thyroid cell lines and primary cultures

Chronic treatment of rats with acrylamide induces various tumors among which thyroid tumors are the most frequent. The aim of the present study was to develop an in vitro model of acrylamide action on thyroid cells to allow the investigation of the mechanism of this tumorigenic action. The first part of the study considered as targets, characteristics of thyroid metabolism, which could explain the thyroid specificity of acrylamide action: the cAMP mitogenic effect and the important H2O2 generation by thyroid cells. However, acrylamide did not modulate H2O2 or cAMP generation in the thyroid cell models studied. No effect on thyroid cell proliferation was observed in the rat thyroid cell line FRTL5. On the other hand, as shown by the comet assay, acrylamide induced DNA damage, as the positive control H2O2 in the PC Cl3 and FRTL5 rat thyroid cell lines, as well as in thyroid cell primary cultures. The absence of effect of acrylamide on H2AX histone phosphorylation suggests that this effect does not reflect the induction of DNA double strand breaks. DNA damage leads to the generation of mutations. It is proposed that such mutations could play a role in the carcinogenic effect of acrylamide. The mechanism of this effect can now be studied in this in vitro model.

Long term results of sentinel lymph node biopsy in early oral squamous cell carcinoma.

The objective of the study was to evaluate the long term results of the sentinel node (SN) biopsy technique in the management of the clinically negative (N0) neck in patients with early oral squamous cell carcinoma (T1–T2). Patients with positive SN underwent neck dissection. A sentinel lymph node (SLN) biopsy was performed on 31 consecutive patients. Six of the 31 patients were upstaged by the results of the SLN biopsy. The SLN biopsy allowed the identification of node metastasis in 100% of the cases with a sensitivity of 100%, specificity of 100%, and negative predictive value of 100%. There was a mean follow-up of 59 months. The neck control rate was 100% in the SLN negative group and two SLN positive patients developed subsequent neck disease (neck control rate of 88%). One SLN patient presented at the follow-up with a second primary tumor, 18 months later treated successfully by chemoradiotherapy. The overall survival rate was 100% in both groups. The promising reported short-term results have been sustained by long term follow-up. Patients with negative SLN achieved an excellent neck control rate. The neck control rate in SN negative patients was superior to that in SLN positive patients, but not statistically different.

Does clinical and radiological response predict complete tumor control in N2–N3 squamous cell head and neck cancer after non-operative management of the neck?

Conclusion: A complete clinical and radiological response observed following chemotherapy and radiotherapy is not predictive of the absence of residual disease. Moreover, salvage neck surgery does not always seem to be an effective strategy. Consequently, early neck dissection should be advised for patients with complete clinical and radiological response (CCRR) after chemoradiotherapy for tumors with N2–N3 disease. Background: We retrospectively reviewed the outcome of 28 patients with N2–N3 disease treated initially with chemotherapy and radiotherapy. Patients and methods: A neck dissection was performed for all patients with residual disease in the neck. Results: A CCRR in the neck was achieved in 25 of 28 patients. The remaining three patients with residual neck mass underwent a salvage neck dissection: the pathological examination confirmed the persistence of tumoral disease. No regional failure was observed in these three patients. In 25 patients considered to have CCRR in the neck, 5 patients (20%) developed regional recurrence. Successful salvage approach was not possible for any of these patients.

Les tumeurs malignes secondaires de la parotide

Les tumeurs malignes secondaires de la parotide sont peu frequentes. Elles proviennent essentiellement de tumeurs malignes cervico-faciales mais peuvent aussi provenir de tumeurs malignes extra-cervico-faciales. Les premieres sont dominees par les epitheliomas cutanes et les melanomes, les secondes par les cancers renaux et bronchiques. La connaissance de la nature primitive ou secondaire d’une tumeur parotidienne est d’une grande importance pour determiner le traitement et influence le pronostic. Methodes La rarete des tumeurs secondaires de la parotide est illustree par cette serie de 23 patients. Les donnees cliniques et pathologiques ont ete systematiquement revues. Les traitements adoptes dans la prise en charge des metastases parotidiennes et les resultats ont ete discutes afin d’optimaliser le choix therapeutique. Resultats Les types histologiques les plus frequemment diagnostiques etaient les epitheliomas epidermoides et les melanomes d’origine cervico-faciale. Elles ont ete decouvertes apres un delai median de 18 mois apres le diagnostic de la tumeur primitive. Aucun patient ne presentait de deficit du nerf facial au moment du diagnostic. Tous les patients ont ete traites par parotidectomie superficielle avec dissection du nerf facial. Dans 14 cas, un curage fonctionnel homolateral a ete realise et, dans six cas, un curage radical homolateral a ete necessaire. Une radiotherapie complementaire a ete faite dans 21 cas. Dans le suivi des patients, 7 patients sont decedes dont 3 d’une recidive cervicale associee a une evolution locale du primitif ; 4 patients presentaient une recidive cervicale et une atteinte metastatique plurifocale. Conclusion Cette etude retrospective confirme le mauvais pronostic des tumeurs secondaires de la parotide, d’autant qu’il s’y associe une atteinte metastatique ganglionnaire. La radiotherapie complementaire ne semble pas modifier, dans cette serie, ce pronostic.