DeltaN TP63 reactivation, epithelial phenotype maintenance, and survival in lung squamous cell carcinoma.

Genes, active during normal development, are frequently reactivated during neoplastic transformation and may be related to progression. One of them, the transcription factor TP63, is crucial for pulmonary epithelial development and a possible target of the recurrent 3q amplifications in lung squamous cell carcinoma (SCC). Here, we explored whether TP63 reactivation could be associated to cancer progression in lung SCC through an epithelial to mesenchymal transition. We studied TP63 amplification and TP63 expression at RNA and protein levels and we analyzed the ΔNTP63/TATP63 ratio that quantifies the proportion of the isoform lacking the transactivation domain/the isoform containing the transactivation domain. We correlated TP63 status to survival and to the expression of epithelial (E-cadherin and plakoglobin) and mesenchymal (N-cadherin, vimentin, TWIST1, and SNAIL) markers. We found that high ΔN/TA TP63 ratio was related to high E-cadherin and plakoglobin mRNA levels (P < 0.05) and that E-cadherin mRNA level was the only marker related to survival. Kaplan-Meier survival curves stratified according to the expression level of E-cadherin showed, as already reported in breast cancer, that patients with low (first quartile) or high (last quartile) E-cadherin expression had a worse survival with respect to patients with intermediate E-cadherin expression. Altogether, our results indicate that a reactivation of ΔNTP63 is linked to the maintenance of epithelial markers and suggest that E-cadherin has a dual role in lung SCC.

PAI-1 and functional blockade of SNAI1 in breast cancer cell migration.

INTRODUCTION: Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasion. The Plasminogen Activation (PA) system, including urokinase plasminogen activator (uPA), its receptor and its inhibitor, plasminogen activator inhibitor type 1(PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non-proteolytic modulation of cell adhesion and migration. Thus, Snail and the PA system are both over-expressed in cancer and influence this process. In this study we aimed to determine if the activity of SNAI1 (a member of the Snail family) is correlated with expression of the PA system components and how this correlation can influence tumoural cell migration. METHODS: We compared the invasive breast cancer cell-line MDA-MB-231 expressing SNAI1 (MDA-mock) with its derived clone expressing a dominant-negative form of SNAI1 (SNAI1-DN). Expression of PA system mRNAs was analysed by cDNA microarrays and real-time quantitative RT-PCR. Wound healing assays were used to determine cell migration. PAI-1 distribution was assessed by immunostaining. RESULTS: We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. After performing an in vitro wound-healing assay, we observed that SNAI1-DN cells migrate more slowly than MDA-mock cells and in a more collective manner. The blockade of SNAI1 activity resulted in the redistribution of PAI-1 in SNAI1-DN cells decorating large lamellipodia, which are commonly found structures in these cells. CONCLUSIONS: In the absence of functional SNAI1, the expression of PAI-1 transcripts is decreased, although the protein is redistributed at the leading edge of migrating cells in a manner comparable with that seen in normal epithelial cells.

Fixed-dose rate gemcitabine in elderly patients with advanced pancreatic cancer: an observational study.

Pancreatic cancer represents one of the most lethal cancers and treatment of advanced disease remains palliative. Age-related physiologic changes can increase chemotherapy's toxicity but the use of gemcitabine in elderly patients has not been properly evaluated. This observational prospective study evaluated patients aged 70 years and over, receiving gemcitabine for an advanced pancreatic carcinoma. Gemcitabine was delivered according to the usual fixed-dose rate schedule (1000mg/(m(2)week) over 100min, every week, 3 weeks over 4). Thirty-nine patients (median age 74) were treated between November 1999 and August 2004. Twenty-three patients (59%) received 100% of the planned dose-intensity. Grade 3-4 toxicities were neutropenia (38% of patients), thrombocytopenia (28%), anemia (18%) and alopecia (18%). Four partial responses (10%) and 13 stabilizations (33%) were observed. Eight patients (20%) experienced clinical benefit. The median progression free and overall survivals were 7 and 10 months, respectively. Gemcitabine can be administered in selected elderly patients.

Aggressive non-Hodgkin's lymphoma: concomitant evaluation of interleukin-2, soluble interleukin-2 receptor, interleukin-4, interleukin-6, interleukin-10 and correlation with outcome.

The purpose of this study was to assess the prognostic value of a large panel of cytokines in aggressive non-Hodgkin's lymphoma (NHL) and to confront it to parameters of the International Prognostic Index (IPI). It investigated the concomitant determination of interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-4 (IL-4), interleukin-6 (IL-6) and interleukin-10 (IL-10) on a uniform population of 116 previously untreated patients. Commercially available enzyme-linked immunoassay kits were used for cytokines measurements. Results were correlated with complete remission (CR), overall survival (OS) and failure free survival (FFS). In univariate analysis, sIL-2R and IL-6 demonstrated prognostic significance for CR (p = 0.016 and p = 0.048), OS (p = 0.0011 and p = 0.0387) and FFS (p = 0.0001 and p = 0.0363), but multi-variate analysis failed to demonstrate an independent prognostic significance. In the intermediate group risk defined by IPI, patients presenting high level of sIL-2R or IL-6 demonstrated lower CR rate and survival than those with low level. In conclusion, sIL-2R and IL-6 serum levels are elevated in high grade NHL and are correlated to CR, OS and FFS, but this study did not support their independent prognostic value. However, sIL-2R and IL-6 measurements may improve risk assignment by IPI and allow a better prognostic evaluation of patients with intermediate prognosis NHL.

[The PAI-1 swing: microenvironment and cancer cell migration]. / Microenvironnement cellulaire, PAI-1 et migration cancéreuse.

Cancer is a complex and dynamic process caused by a cellular dysfunction leading to a whole organ or even organism vital perturbation. To better understand this process, we need to study each one of the levels involved, which allows the scale change, and to integrate this knowledge. A matricellular protein, PAI-1, is able to induce in vitro cell behaviour modifications, morphological changes, and to promote cell migration. PAI-1 influences the mesenchymo-amaeboid transition. This matricellular protein should be considered as a potential 'launcher' of the metastatic process acting at the molecular, cellular, tissular levels and, as a consequence, at the organism's level.

A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective.

OBJECTIVES: Adjuvant chemotherapy with vinorelbine plus cisplatin (VC) improves survival in resected non-small-cell lung cancer (NSCLC), but has negative impact on quality of life (QoL). In advanced NSCLC, gemcitabine plus cisplatin (GC) and docetaxel plus cisplatin (DC) exhibit comparable efficacy, with possibly superior QoL compared to VC. This trial investigated these regimens in the adjuvant setting. METHODS: Patients with Stage IB to III NSCLC were eligible following standardized surgery. Overall, 136 patients were included, with 67 and 69 assigned to the GC and DC arms, respectively. Cisplatin (75 mg/m(2), Day [D] 1) plus gemcitabine (1250 mg/m(2), D1 and D8) or docetaxel (75 mg/m(2) D1) were administered for three cycles. Primary end-point was QoL (EORTC QLQ-C30), with the study designed to detect a 10-point difference between arms. Overall survival, safety and cost were secondary end-points. RESULTS: No between-group imbalance was observed in terms of patient characteristics. At inclusion, global health status (GHS) scores (/100) were 63.5 and 62.7 in GC and DC, respectively (P = 0.8), improving to 64.5 and 65.4 after 3 months (P = 0.8). No significant difference in functional or symptoms scores was observed between the arms except for alopecia. Grade 3/4 haematological and non-haematological toxicities were found in 33.8 and 21.7% (P = 0.11), and 33.8 and 26.1% (P = 0.33) of patients, in GC and DC, respectively. At 2 years, 92.9 and 89.8% of patients remained alive in GC and DC, respectively (P = 0.88). CONCLUSIONS: DC and GC adjuvant chemotherapies for completely resected NSCLC were well tolerated and appear free of major QoL effects, and are therefore representing candidates for comparison with the standard VC regimen.

Progress in the medical treatment of advanced colorectal cancer.

Despite recent progress made in screening, prevention and adjuvant treatment of colorectal cancer, a large proportion of patients with this disease develop local recurrences or distant metastases. The management of these patients requires a multidisciplinary approach. Surgery must be performed whenever possible for metastases confined to the liver or lung. However, in most cases, chemotherapy and supportive care are the only feasible treatments. This review describes the research carried out in this field through randomized trials and meta-analyses aimed at optimizing the efficacy of front-line chemotherapy.

Should all cases of lung cancer be presented at Tumor Board Conferences?

Tumor Board Conferences (TBCs) have been associated with higher adherence of staging and treatment to guidelines. The influence of TBCs on the rate of curative treatments has been established. Patients with lung nodules and tumors of unknown histology should not be presented before surgery, but every patient with malignant histology should be declared to the TBC coordinator and registered at the time of histologic confirmation. This approach allows physicians to deal rapidly with simple cases on a systematic basis, to give more attention to the most complicated situations, and to offer every patient the benefit of a multidisciplinary approach.

Long-term survival with surgery as part of a multimodality approach for N3 lung cancer.

OBJECTIVES: The extension of non-small-cell lung cancer (NSCLC) to supraclavicular (SC) and contralateral (CL) mediastinal lymph nodes is termed N3 and usually forbids surgical resection. However, scarce surgical series have reported encouraging results, and we sought to analyse our experience with this particular subgroup of patients. METHODS: We retrospectively reviewed the charts of 5857 patients undergoing surgery for NSCLC during the last 30 years in two French centres. Eleven patients presenting with pathological-N3 were found, and more closely analysed concerning lymphatic spread, surgical indication and prognosis. RESULTS: N3 consisted of tumoural extension to the SC (n = 5), CL mediastinal (n = 5) or both (SC + CL, n = 1) stations. Patients underwent induction treatment with chemotherapy alone (n = 4), chemoradiotherapy (n = 3) or first-line surgery (n = 4). All patients underwent a complete surgical resection of the tumour associated with ipsilateral systematic mediastinal lymph node dissection. Additional resection of N3 lymph nodes was performed in 8 cases. Adjuvant treatment included chemoradiotherapy (n = 6), chemotherapy alone (n = 1) or radiation therapy alone (n = 1). All 5 patients with SC-N3 presented with ipsilateral disease; 3 of them survived 5 years. Four patients with CL-N3 presented with left-sided tumour and nodal extension to the 4R station, and none of them survived. CONCLUSIONS: Some N3-patients with specific anatomical location may benefit from multimodality treatment including surgery. These results support further prospective studies for selected N3-patients.

Genome wide SNP comparative analysis between EGFR and KRAS mutated NSCLC and characterization of two models of oncogenic cooperation in non-small cell lung carcinoma.

BACKGROUND: Lung cancer with EGFR mutation was shown to be a specific clinical entity. In order to better understand the biology behind this disease we used a genome wide characterization of loss of heterozygosity and amplification by Single Nucleotide Polymorphism (SNP) Array analysis to point out chromosome segments linked to EGFR mutations. To do so, we compared genetic profiles between EGFR mutated adenocarcinomas (ADC) and KRAS mutated ADC from 24 women with localized lung cancer. RESULTS: Patterns of alterations were different between EGFR and KRAS mutated tumors and specific chromosomes alterations were linked to the EGFR mutated group. Indeed chromosome regions 14q21.3 (p = 0.027), 7p21.3-p21.2 (p = 0.032), 7p21.3 (p = 0.042) and 7p21.2-7p15.3 (p = 0.043) were found significantly amplified in EGFR mutated tumors. Within those regions 3 genes are of special interest ITGB8, HDAC9 and TWIST1. Moreover, homozygous deletions at CDKN2A and LOH at RB1 were identified in EGFR mutated tumors. We therefore tested the existence of a link between EGFR mutation, CDKN2A homozygous deletion and cyclin amplification in a larger series of tumors. Indeed, in a series of non-small-cell lung carcinoma (n = 98) we showed that homozygous deletions at CDKN2A were linked to EGFR mutations and absence of smoking whereas cyclin amplifications (CCNE1 and CCND1) were associated to TP53 mutations and smoking habit. CONCLUSION: All together, our results show that genome wide patterns of alteration differ between EGFR and KRAS mutated lung ADC, describe two models of oncogenic cooperation involving either EGFR mutation and CDKN2A deletion or cyclin amplification and TP53 inactivating mutations and identified new chromosome regions at 7p and 14q associated to EGFR mutations in lung cancer.

Retroperitoneal liposarcomas: follow-up analysis of dedifferentiation after clinicopathologic reexamination of 86 liposarcomas and malignant fibrous histiocytomas.

BACKGROUND: Dedifferentiated liposarcoma (DDL) juxtapose components of well-differentiated liposarcoma (WDL) and nonlipogenic sarcoma. Malignant fibrous histiocytoma (MFH) is no longer considered a homogeneous entity, but rather as the common morphologic appearance of various subtypes of sarcomas. The objectives of the current retrospective study were: 1( to analyze the relation between DDLs and tumors previously diagnosed as MFHs; 2) to trace the evolution of liposarcomas, and 3) to assess the consequences of dedifferentiation. METHODS: Between 1974 and 2001, 86 patients with retroperitoneal liposarcoma (61 patients) or MFH (25 patients) underwent surgery at Institut Bergonie in Bordeaux, France. Histologic review was performed and tumors reclassified as WDL or DDL were retained for further clinicohistologic study. Subsequently, initial presentation and all recurrences were analyzed. RESULTS: The 61 liposarcomas consisted of 21 WDLs and 35 DDLs; 17 MFHs were reclassified as DDL. In all, approximately half of the retroperitoneal liposarcomas and MFHs were found to be DDLs. The DDLs presented with a smaller size (20 cm vs.30 cm; P = .05) but a lower rate of complete resection (72% vs.90%; P = .015) and remission (72% vs. 100%; P = .0015). Dedifferentiated recurrence was evidenced in 7 WDLs. Ten DDLs presented with metastatic evolution. DDLs demonstrated a tendency toward lower rates of 5-year overall survival (55% vs. 82%; P = .075). CONCLUSIONS: Most occurrences of retroperitoneal liposarcomas and MFHs are in fact DDLs and dedifferentiated recurrence of WDLs is frequent. Retroperitoneal DDLs present a lower rate of complete remission than WDLs and a risk of metastatic recurrence. Therefore, extensive histologic analysis of WDLs is required to identify an undifferentiated component and avoid misdiagnosis of DDL.