Distribution de la morphologie des tumeurs incidentes dans le canton de Vaud [Morphologic distribution of tumors occuring in the canton of Vaud].

After a short presentation of the methodological aspects of cancer registration and morphological coding, the results concerning cancer of the upper digestive tract, lung, testis and ovary were discussed. Some distributions of the main histological types are analysed by age, sex, site and multiple primaries. Known statistical associations are described between morphology and sex for lung cancer and between morphology and controlateral tumor for ovary.

Lung Cancer That Harbors an HER2 Mutation: Epidemiologic Characteristics and Therapeutic Perspectives.

PURPOSE HER2 mutations are identified in approximately 2%of non-small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC. PATIENTS AND METHODS We retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments. Results HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti-human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate [DCR], 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively. CONCLUSION This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.

A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin κ C as a compatible prognostic marker in human solid tumors.

PURPOSE: Although the central role of the immune system for tumor prognosis is generally accepted, a single robust marker is not yet available. EXPERIMENTAL DESIGN: On the basis of receiver operating characteristic analyses, robust markers were identified from a 60-gene B cell-derived metagene and analyzed in gene expression profiles of 1,810 breast cancer; 1,056 non-small cell lung carcinoma (NSCLC); 513 colorectal; and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin-embedded tissue of 330 breast cancer patients. The cell types were identified with immunohistochemical costaining and confocal fluorescence microscopy. RESULTS: We identified immunoglobulin κ C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis-free survival across different molecular subtypes in node-negative breast cancer (n = 965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n = 845; P < 0.001). In addition, IGKC gene expression was prognostic in NSCLC and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin-embedded tissues of 330 breast cancer patients. Tumor-infiltrating plasma cells were identified as the source of IGKC expression. CONCLUSION: Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anticancer therapy. It could be validated in several independent cohorts and carried out similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.

Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.

The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.

Distribution of free and liposomal doxorubicin after isolated lung perfusion in a sarcoma model.

BACKGROUND: Isolated lung perfusion (ILP) with free and a novel liposomal-encapsulated doxorubicin (Liporubicin, CT Sciences SA, Lausanne, Switzerland) was compared with respect to drug uptake and distribution in rat lungs bearing a sarcomatous tumor. METHODS: A single sarcomatous tumor was generated in the left lung of 39 Fischer rats, followed 10 days later by left-sided ILP (n = 36) with free and equimolar-dosed liposomal doxorubicin at doses of 100 microg (n = 9) and 400 microg (n = 9) for each doxorubicin formulation. In each perfused lung, the drug concentration and distribution were assessed in the tumor and in three areas of normal lung parenchyma by high-performance liquid chromatography (n = 6) and fluorescence microscopy (n = 3). Histologic assessment and immunostaining with von Willebrand factor was performed in 3 animals with untreated tumors. RESULTS: The sarcomatous tumors in controls were well vascularized with fine branching capillaries present throughout the tumors. Isolated lung perfusion resulted in a heterogeneous drug distribution within the perfused lung and a consistently lower drug uptake in tumors than in lung parenchyma for both doxorubicin formulations and both drug doses applied. Isolated lung perfusion with free doxorubicin resulted in a significantly higher drug uptake than Liporubicin in both the tumor and lung tissue for both drug doses applied (p < 0.01). However, the tumor/normal tissue drug ratio was lower for free than for liposomal doxorubicin at a drug dose of 100 microg (0.27 +/- 0.1 vs 0.53 +/- 0.5; p = 0.225) and similar for both doxorubicin formulations at a drug dose of 400 microg (0.67 +/- 0.2 vs 0.54 +/- 0.2; p = 0.335). Both doxorubicin formulations resulted in fluorescence signaling emerging from all tissue compartments of normal lung parenchyma but only in weak and sporadic signaling from the tumors confined to the tumor periphery and vessels situated within the tumor for both drug doses assessed. CONCLUSIONS: Isolated lung perfusion with free and liposomal doxorubicin resulted in a heterogeneous drug distribution within the perfused lung and in a lower drug uptake in tumors than in lung tissue for both doxorubicin formulations and drug doses applied.

High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.

Mechanisms of CYR61 mediated breast cancer metastasis to the lung

CYR61 (Cysteine-rich angiogenic inducer 61) is a matricellular protein that regulates cell proliferation, adhesion, migration and cell survival through interaction with various types of integrin cell adhesion receptors. At tissue level it is implicated in the regulation of embryonic development, wound healing and angiogenesis. CYR61 has also been involved in cancer progression, however its role appears to be diverse and complex depending on the cancer type and stage. Its contribution to metastasis formation is still unclear. Previous findings reported by our laboratory demonstrated that CYR61 cooperates with avßs integrin to promote invasion and metastasis of cancers growing in a pre-irradiated microenvironment. In this work, we used an orthotopic model of breast cancer to show for the first time that silencing of CYR61 in breast cancer cells suppresses lung metastasis formation. Silencing of MDA-MB-231 reduced both local growth and lung metastasis formation of tumor cells implanted in a pre-irradiated mammary fat pad. CYR61 silencing in tumors growing in non-irradiated mammary fat pads did not impact primary tumor growth but decreased lung metastasis formation. The effect of CYR61 on spontaneous lung metastasis formation during natural cancer progression was further examined by using an experimental model of metastasis. Results from these experiments indicate that CYR61 is critically involved in promoting cancer cells entry into lung parenchyma rather than later steps of colonization. In vitro experiments showed that CYR61 promotes tumor cell spreading, migration and transendothelial migration. CYR61 also supported colony formation under anchorage-independent condition and promotes resistance to anoikis through the involvement of ß1 and ß3 integrin. These results indicate that CYR61 promotes lung metastasis of breast cancer by facilitating extravasation into lung parenchyma through enhanced motility, transendothelial migration and resistance to anoikis. - CYR61 (Cysteine-rich angiogenic inducer 61) est une protéine matricellulaire qui régule la prolifération, l'adhérence, la migration et la survie des cellules par son interaction avec différents types de récepteurs d'adhésion cellulaire de la famille des intégrine. Au niveau des tissus, CYR61 est impliquée dans la régulation du développement embryonnaire, de la cicatrisation et de l'angiogenèse. CYR61 a également été impliquée dans le cancer, mais son rôle semble être divers et complexe en fonction du type du cancer et de son stade. Son rôle dans la formation des métastases n'est pas encore clair. Des résultats antérieurs rapportés par notre laboratoire ont montré que CYR61 coopère avec l'intégrine avß5 pour favoriser l'invasion et la métastase de tumeurs se développant dans un micro-environnement pré-irradié. Dans ce travail, nous avons utilisé un modèle orthotopique de cancer du sein pour démontrer pour la première fois que l'extinction (silencing) du gène CYR61 dans le cancer du sein réduit la formation de métastases pulmonaires. L'extinction de CYR61 dans la lignée cellulaire de cancer du sein humain MDA-MB- 231 réduit à la fois la croissance local ainsi que la formation de métastases pulmonaires à partir de cellules implantés dans les coussinets adipeux mammaires pré-irradié. L'extinction de CYR61 dans des tumeurs grandissant dans les coussinets adipeux mammaires non irradiées n'a pas d'incidence sur la croissance tumorale primaire mais réduit la formation des métastases pulmonaires. Par la suite nous avons examiné l'effet de CYR61 sur la formation de métastases pulmonaires en utilisant un modèle expérimental de métastase. Les résultats de ces expériences indiquent que CYR61 est impliquée de manière cruciale dans les étapes précoces de la formation de métastases, plutôt que dans les étapes tardives de colonisation du poumon. Des expériences in vitro ont montré que CYR61 favorise l'étalement, la migration et la transmigration endothéliale des cellules tumorales. CYR61 favorise également la formation de colonies dans des conditions indépendante de l'ancrage et la résistance à l'anoïkis par l'engagement des intégrines ß1 et ß3. Ces résultats indiquent que CYR61 favorise les métastases pulmonaires du cancer du sein en facilitant l'extravasation dans le parenchyme pulmonaire grâce à la stimulation de la motilità, de la migration transmigration endothéliale et de la résistance à l'anoïkis.

Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases.

Lung cancer is characterized by the highest incidence of solid tumor-related brain metastases, which are reported with a growing incidence during the last decade. Prognostic assessment may help to identify subgroups of patients that could benefit from more aggressive therapy of metastatic disease, in particular when central nervous system is involved. The recent sub-classification of non-small cell lung cancer (NSCLC) into molecularly-defined "oncogene-addicted" tumors, the emergence of effective targeted treatments in molecularly defined patient subsets, global improvement of advanced NSCLC survival as well as the availability of refined new radiotherapy techniques are likely to impact on outcomes of patients with brain dissemination. The present review focuses on key evidence and research strategies for systemic treatment of patients with central nervous system involvement in non-small cell lung cancer.

Photodynamic therapy enhances lipodoxorubcin distribution in sarcoma lung metastasis by lowering tumor interstitial fluid pressure in a rodent model

Objective: The management of sarcoma metastasis by systemic chemotherapy is often unsatisfactory. This has paradoxally been attributed to the leakiness of tumor neovessels which induce high intratumor interstitial fluid pressure (IFP) and limit convection forces that are important for drug distribution. In a rodent model, we have recently shown that photodynamic (PDT) pre treatment of lung metastasis could enhance their uptake of chemotherapy. We hypothesized that PDT transiently decreases tumor IFP which enhances convection and promotes drug distribution.Methods: Sarcoma tumors were generated sub-pleurally in the lungs of 12 rats. Animals were randomized at 10 days into i. no pre-treatment (control) and ii. low dose PDT pre-treatment (0・0625 mg/kg Visudyne, 10J/cm2 and 35 mW/cm2) followed by intravenous Liposomal doxorubicin (LiporubicinTM) administration. Using the wick-in-needle technique, we determined tumor and normal tissue IFP before, during and after PDT. In parallel, the uptake of LiporubicinTM was determined by high performance liquid chromatography in tumor and lung tissues.Results: Tumor IFP was significantly higher than normal tissue IFP in all animals. PDT pre-treatment did not affect normal tissue IFP but caused a significant decrease in tumor IFP (mean decrease by 2+/− 1mmHg) which lasted an average of 30 minutes before reaching baseline values. Tumor but not normal lung tissue LiporubicinTM uptake was significantly increased by 67% with PDT pre-treatment when liporubicin was allowed to circulate for one hour.Conclusion: Photodynamic therapy pre-treatment enhances LiporubicinTM uptake in sarcoma lung metastasis by transiently decreasing tumor IFP. These PDT conditions seem to specifically modulate tumor neovessels but not normal lung vessels.

Current state of vaccine therapies in non-small-cell lung cancer.

A large variety of cancer vaccines have undergone extensive testing in early-phase clinical trials. A limited number have also been tested in randomized phase II clinical trials. Encouraging trends toward increased survival in the vaccine arms have been recently observed for 2 vaccine candidates in patients with non-small-cell lung cancer. These have provided the impetus for the initiation of phase III trials in large groups of patients with lung cancer. These vaccines target 2 antigens widely expressed in lung carcinomas: melanoma-associated antigen 3, a cancer testis antigen; and mucin 1, an antigen overexpressed in a largely deglycosylated form in advanced tumors. Therapeutic cancer vaccines aim at inducing strong CD8 and CD4 T-cell responses. The majority of vaccines recently tested in phase I clinical trials show efficacy in terms of induction of specific tumor antigen immunity. However, clinical efficacy remains to be determined but appears limited. Efforts are thus aimed at understanding the basis for this apparent lack of effect on tumors. Two major factors are involved. On one hand, current vaccines are suboptimal. Strong adjuvant agents and appropriate tumor antigens are needed. Moreover, dose, route, and schedule also need optimization. On the other hand, it is now clear that large tumors often present a tolerogenic microenvironment that hampers effective antitumor immunity. The partial understanding of the molecular pathways leading to functional inactivation of T cells at tumor sites has provided new targets for intervention. In this regard, blockade of cytotoxic T-lymphocyte antigen-4 and programmed death-1 with humanized monoclonal antibodies has reached the clinical testing stage. In the future, more potent cancer vaccines will benefit from intense research in antigen discovery and adjuvant agents. Furthermore, it is likely that vaccines need to be combined with compounds that reverse major tolerogenic pathways that are constitutively active at the tumor site. Developing these combined approaches to vaccination in cancer promises new, exciting findings and, at the same time, poses important challenges to academic research institutions and the pharmaceutical industry.

Survival after lung metastasectomy in colorectal cancer patients with previously resected liver metastases

Objective: Resection of hepatic metastases is indicated in selected Stage IV colorectal cancer (CRC) patients. A minority will eventually develop pulmonary metastases and may be candidates for lung surgery. The aim of this study was to assess clinical outcome, and identify parameters predicting survival after pulmonary metastasectomy, in patients who underwent prior resection of hepatic CRC metastases.Methods: We performed a retrospective analysis of 27 consecutive patients (median age 62 [range 33-75] years) who underwent resection of pulmonary metastases from CRC in two institutions from 1996 to 2009. All patients considered in the analysis had previously undergone colorectal and hepatic surgery with curative intent, and were considered cured in both locations (R0).Results: Median follow-up was 32 (range 3-69) months after resection of lung metastases and 65 (range 19-146) months after resection of primary CRC. Eleven (40?7%) patients had their primary tumors located in the rectum, and 12 (44%) patients presented initially with synchronous liver metastases (stage IV). Median disease-free interval between primary colorectal tumor and development of first metastasis was 6 (range 0-50) months. At the time of last follow-up, seven patients only (26%) were alive without evidence of recurrence. Three- and 5-year overall survival rates after lung surgery were 56% and 39%, respectively. Median survival after pulmonary metastasectomy was 46 months. In multivariate analysis, the number of pulmonary lesions was significantly correlated with survival (log-rank test, p = 0?035).Conclusion: Resection of lung metastases from CRC patients is compatible with prolonged (median = 4 years) survival, even when those patients had undergone prior resection of liver metastases. While prolonged, disease-free survival remains the exception, patients presentin

Cancer Cell-Associated MT1-MMP Promotes Blood Vessel Invasion and Distant Metastasis in Triple-Negative Mammary Tumors.

Functional roles for the cancer cell-associated membrane type I matrix metalloproteinase (MT1-MMP) during early steps of the metastatic cascade in primary tumors remain unresolved. In an effort to determine its significance, we determined the in vivo effects of RNAi-mediated downregulation in mammary cancer cells on the migration, blood and lymphatic vessel invasion (LVI), and lymph node and lung metastasis. We also correlated the expression of cancer cell MT1-MMP with blood vessel invasion (BVI) in 102 breast cancer biopsies. MT1-MMP downregulation in cancer cells decreased lung metastasis without affecting primary tumor growth. The inhibition of lung metastasis correlated with reduced cancer cell migration and BVI. Furthermore, cancer cell-expressed MT1-MMP upregulated the expression of MT1-MMP in vascular endothelial cells, but did not affect MT1-MMP expression in lymphatic endothelial cells, LVI, or lymph node metastasis. Of clinical importance, we observed that elevated MT1-MMP expression correlated with BVI in biopsies from triple-negative breast cancers (TNBC), which have a poor prognosis and high incidence of distant metastasis, relative to other breast cancer subtypes. Together, our findings established that MT1-MMP activity in breast tumors is essential for BVI, but not LVI, and that MT1-MMP should be further explored as a predictor and therapeutic target of hematogenous metastasis in TNBC patients. Cancer Res; 71(13); 4527-38. ©2011 AACR.

Malignant metastasizing solitary fibrous tumors of the liver: a report of three cases.

Solitary fibrous tumors are rare neoplasms of mesenchymal origin that have been reported in various other extrathoracic sites, including the liver. We present a case series of three malignant solitary fibrous tumors of the liver, occurring in two women 74 and 80 years old and one 65-year-old man. No clinical features were predictive of malignancy except the large sizes and synchronous presence of lung metastases in two of the three cases. Histological examinations revealed the presence of high pleomorphic cellularity with nuclear atypia, necrosis and high mitotic ratios. All patients died of disease progression.

Present standards and future perspectives in the treatment of metastatic non-small cell lung cancer.

The development of novel effective immunotherapeutic agents and early clinical data hinting at significant activity in non-small cell lung cancer (NSCLC) has introduced yet another player in the field of management of advanced disease. At present, first-line cytotoxic chemotherapy is generally withheld pending results of molecular testing for any actionable genetic alteration that could lead to targeted treatment, and in their absence chemotherapy is prescribed as a default therapy. Phase III trials comparing head-to-head immune checkpoint inhibitors with standard platinum-based doublet chemotherapy are underway. Second-line chemotherapy is likewise being challenged in phase III trials, one of which having recently reported positive results in advanced squamous cell carcinoma. In tumors harboring actionable transforming genetic alterations such as EGFR mutations and ALK rearrangements, second- and third-generation inhibitors allow for multiple lines of targeted treatment beyond initial resistance, postponing the use of cytotoxic chemotherapy to very late lines of therapy. Chemotherapy as a longstanding but still present standard of care capable of prolonging survival, improving quality of life, and relieving symptoms sees its role increasingly restricted to clinical, immunological, and molecular subsets of patients where its activity and efficacy have never been tested prospectively.

Carcinoembryonic antigen (CEA) in non digestive cancerous and normal tissues.

Carcinoembryonic antigen (CEA), immunologically identical to CEA derived from colonic carcinoma, was identified and purified from perchloric acid (PCA) extracts of bronchial and mammary carcinoma. CEA extracted from bronchial and mammary carcinoma was quantitated by single radial immunodiffusion and was found to be in average about 50-75 times less abundant in these tumors than in colonic carcinoma. CEA could also be detected in one normal breast in lactation and at lower concentrations in normal lung (1000-4000 times lower than in colonic carcinoma). The small amounts of CEA present in normal tissues are distinct from the glycoprotein of small mol. wt showing only partial identity with CEA, that we recently identified and extracted in much larger quantities from normal lung and spleen. The demonstration of the presence of CEA in non digestive carcinoma by classical gel precipitation analysis suggests that the CEA detected in the plasma of such patients by radioimmunoassay is also identical to colonic carcinoma CEA. Our comparative study of plasma CEA from bronchial and colonic carcinoma, showing that CEA from both types of patient has the same elution pattern on Sephadex G-200 and gives parallel inhibition curves in the radioimmunoassay, is in favor of this hypothesis. However, it should not be concluded that all positive CEA radioimmunoassay indicate the presence of an antigen identical to colonic carcinoma CEA. A word of warning concerning the interpretation of radioimmunoassay is required by the observation that the addition of mg amounts of PCA extract of normal plasma, cleared of CEA by Sephadex filtration, could interfere in the test and mimic the presence of CEA.