High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis.

AIMS: c-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting. METHODS AND RESULTS: c-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis. CONCLUSIONS: Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.

Clinical utility of a molecular test in adjuvant treatment decision making in women with endocrine-sensitive early stage breast cancer: a retrospective, single center one year experience

Background. Molecular tests for breast cancer (BC) risk assessment are reimbursed by health insurances in Switzerland since the beginning of year 2015. The main current role of these tests is to help oncologists to decide about the usefulness of adjuvant chemotherapy in patients with early stage endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-negative BC. These gene expression signatures aim at predicting the risk of recurrence in this subgroup. One of them (OncotypeDx/OT) also predicts distant metastases rate with or without the addition of cytotoxic chemotherapy to endocrine therapy. The clinical utility of these tests -in addition to existing so-called "clinico-pathological" prognostic and predictive criteria (e.g. stage, grade, biomarkers status)-is still debated. We report a single center one year experience of the use of one molecular test (OT) in clinical decision making. Methods. We extracted from the CHUV Breast Cancer Center data base the total number of BC cases with estrogen-receptor positive (ER+), HER2-negative early breast cancer (node negative (pN0) disease or micrometastases in up to 3 lymph nodes) operated between September 2014 and August 2015. For the cases from this group in which a molecular test had been decided by the tumor board, we collected the clinicopathologic parameters, the initial tumor board decision, and the final adjuvant systemic therapy decision. Results. A molecular test (OT) was done in 12.2% of patients with ER + HER2 negative early BC. The median age was 57.4 years and the median invasive tumor size was 1.7 cm. These patients were classified by ODX testing (Recurrence Score) into low-, intermediate-, and high risk groups, respectively in 27.2%, 63.6% and 9% of cases. Treatment recommendations changed in 18.2%, predominantly from chemotherapyendocrine therapy to endocrine treatment alone. Of 8 patients originally recommended chemotherapy, 25% were recommended endocrine treatment alone after receiving the Recurrence Score result. Conclusions. Though reimbursed by health insurances since January 2015, molecular tests are used moderately in our institution as per the decision of the multidisciplinary tumor board. It's mainly used to obtain a complementary confirmation supporting the decision of no chemotherapy. The OncotypeDx Recurrence Score results were in the intermediate group in 66% of the 9 tested cases but contributed to avoid chemotherapy in 2 patients during the last 12 months.

Overexpression of GPC6 and TMEM132D in Early Stage Ovarian Cancer Correlates with CD8+ T-Lymphocyte Infiltration and Increased Patient Survival.

Infiltration of cytotoxic T-lymphocytes in ovarian cancer is a favorable prognostic factor. Employing a differential expression approach, we have recently identified a number of genes associated with CD8+ T-cell infiltration in early stage ovarian tumors. In the present study, we validated by qPCR the expression of two genes encoding the transmembrane proteins GPC6 and TMEM132D in a cohort of early stage ovarian cancer patients. The expression of both genes correlated positively with the mRNA levels of CD8A, a marker of T-lymphocyte infiltration [Pearson coefficient: 0.427 (p = 0.0067) and 0.861 (p < 0.0001), resp.]. GPC6 and TMEM132D expression was also documented in a variety of ovarian cancer cell lines. Importantly, Kaplan-Meier survival analysis revealed that high mRNA levels of GPC6 and/or TMEM132D correlated significantly with increased overall survival of early stage ovarian cancer patients (p = 0.032). Thus, GPC6 and TMEM132D may serve as predictors of CD8+ T-lymphocyte infiltration and as favorable prognostic markers in early stage ovarian cancer with important consequences for diagnosis, prognosis, and tumor immunobattling.

Three Essays on International Trade and the Labor Market

The thesis is made of three independent chapters interested in the impact of globalization on workers in industrialized countries. The dissertation is especially focused on identifying the causal impact of international trade on workers' mobility, wages, and employment with both a short- and medium-term perspective. The first paper explores the relation between intra-industry trade (IIT) expansion and associated worker flows, taking the latter as an indicator of labor-market adjustment costs. Being the first study to combine theoretical simulations and a novel identification strategy, we find that both theoretical and empirical analyses are consistent with the "smooth adjustment hypothesis", according to which IIT expansion is less disruptive than inter-industry trade expansion. The study therefore lends support to the use of IIT indices as first-pass proxies for the adjustment effects of trade expansion. The second chapter contrasts the impact of increased import competition coming from China and the European Union (EU) on workers in the United Kingdom over a 15-year period. The most salient findings show that increased imports from China had significantly negative effects on workers' earnings, wages and employment. In contrast, larger imports from the EU are associated with positive worker-level outcomes, which is largely explained by the fact that increased imports from the EU were mostly offset by increased same-industry exports to the EU. Besides, we find that increased imports from China exert additional pressure on workers through spillovers to employment and wages in downstream industries. Finally, the last chapter is focused on the impact of exposure to trade and real exchange rate shocks on wages for Swiss manufacturing workers. A particular attention is made to consistently estimate the causal effect in using a two-step gravity-type identification strategy. The study shows that the impact of trade and exchange rate movements is concentrated among high-skilled workers almost exclusively.

Stereotactic body radiation therapy with helical tomotherapy for medical inoperable early-stage primary and second-primary non-small cell lung neoplasm : one-year outcome and toxicity analysis

Le cancer du poumon est la première cause de mortalité associée au cancer dans le monde. Le traitement curatif des tumeurs pulmonaires non-à-petites-cellules (NSCLC) diagnostiquées à un stade précoce se base sur une approche chirurgicale. Cependant, étant donné les comorbidités liées à la consommation de tabac, dont la bronchopneumopathie chronique occupe la première place, l'éligibilité chirurgicale pour ce type de cancer se trouve fréquemment limitée. Dans ce contexte, l'emploi de la radiothérapie stéréotaxique (SBRT) est une alternative valable chez les patients atteints d'un NSCLC primaire de stade précoce, et qui sont considérés inopérables à cause de leurs comorbidités. Depuis peu seulemement, le spectre de la SBRT a été élargi aux patients atteints d'un deuxième NSCLC primaire (SPLC), faisant suite à un premier NSCLC, traité avec un but curatif. Ils concernent donc des patients ayant déjà subits une intervention chirurgicale au préalable et qui présentent une réserve fonctionnelle pulmonaire extrêmement réduite. Le succès croissant de la SBRT résulte soit d'une efficacité thérapeutique comparables à la chirurgie, soit de sa toxicité qui semble limitée. À notre connaissance, seulement une étude a reporté des issues cliniques de patients affectés par des NSCLC primaires traités par SBRT. Cette dernière a utilisé la tomothérapie comme système d'irradiation (T-SBRT), sur un faible échantillon de patients (n = 27). Concernant l'irradiation des patients présentant des SPLC, la littérature disponible est pauvre et aucune publication a décrit l'utilisation de la T-SBRT. Ces éléments innovants ont donc motivé la rédaction d'un travail de thèse concernant les premières données cliniques de l'expérience faite au CHUV. Du point de vue des effets secondaires, si la pneumonie actinique précoce et tardive survenant au niveau du champ d'irradiation est désormais une complication iatrogène bien connue de la SBRT, une seule étude s'est intéressée à ce sujet dans le cadre de la T-SBRT. De plus, une entité bénigne et transitoire de pneumonie ( ?) a été reconnue depuis peu : la pneumonie organisée radio-induite (OP). Celle-ci semble se chevaucher comme un autre effet iatrogène à l'extérieur du champ d'irradiation. Originellement, cette dernière avait été rapportée dans les suites de la radiothérapie pour les cancer du sein. Elle a été décrite comme étant initialement limitée au champ d'irradiation et successivement pouvant s'étendre dynamiquement en dehors de celui-ci. Nous avons donc supposé que des infiltrats de OP peuvent être présents chez des patients asymptomatiques, et que ce dynamisme pourrait être identifié déjà au sein du champ d'irradiation. Notre étude a démontré que le traitement par T-SBRT garde des issues cliniques très encourageantes, aussi bien pour les tumeurs primaires que pour les SPLC. Entre autre, ce traitement semble avoir une toxicité limitée, et l'existence vraisemblable de la OP, déjà au sein du champ d'irradiation, peut aider les radiologues à différencier les infiltrats radio-induits d'une une récidive tumorale.

Recovery Risk and Labor Costs in Public-Private Partnerships : Contractual Choice in the US Water industry

We use an ordered logistic model to empirically examine the factors that explain varying degrees of private involvement in the U.S. water sector through public-private partnerships. Our estimates suggest that a variety of factors help explain greater private participation in this sector. We find that the risk to private participants regarding cost recovery is an important driver of private participation. The relative cost of labor is also a key factor in determining the degree of private involvement in the contract choice. When public wages are high relative to private wages, private participation is viewed as a source of cost savings. We thus find two main drivers of greater private involvement: one encouraging private participation by reducing risk, and another encouraging government to seek out private participation in lowering costs.

Labor Mobility of the Chinese Graduates from British and Spanish Universities: What Happens to the "Talent Migration"?

The scholarship on migration in Europe heavily focuses on the integration of economically vulnerable migrants. In the age of commercialization of education, however, the European Union attracts a rising number of highly skilled non-EU migrants that take up studies across the continent. Despite economic downturn, the EU universities experience a rapid growth in the number of Chinese students, many of whom settle in Europe upon graduation. Surprisingly, although the number of Chinese students in the EU increases, scholars largely ignore the labor paths that these highly skilled migrants take upon graduating from European universities. This study aims to fill this gap by exploring the variation in the Chinese graduates’ labor incorporation patterns and in their spatial mobility. In this project, I also examine macro-level hypotheses predicting that the EU and host states’ labor market institutions, changes in the EU policies on the highly skilled and the outburst of economic crisis matter for the Chinese highly skilled social and spatial mobility. Seizing on surveys, interviews and on the bodies of literature on stratification and social mobility, economic incorporation, social capital and human capital, I look at the Chinese students that graduated from universities in Great Britain and Spain. These states differ in the university tuition fees, migration policies towards the highly skilled workers and in the period of the Chinese students’ influx, thus providing an economically and socially diverse sample. My research will contribute to the literature on the relations between migrants’ social mobility, class and status background and spatial mobility, at the same time adding a transnational level perspective to the study of highly skilled Asian migration.

Prosthetic joint infections : A retrospective study on the timing of reimplantation in a two-stage exchange

Different therapeutic options for prosthetic joint infections exist, but surgery remains the key. With a two-stage exchange procedure, a success rate above 90% can be expected. Currently, there is no consensus regarding the optimal duration between explantation and the reimplantation in a two-stage procedure. The aim of this study was to retrospectively compare treatment outcomes between short-interval and long-interval two-stage exchanges. Patients having a two-stage exchange of a hip or knee prosthetic joint infection at Lausanne University Hospital (Switzerland) between 1999 and 2013 were included. The satisfaction of the patient, the function of the articulation and the eradication of infection, were compared between patients having a short (2 to 4 weeks) versus a long (4 weeks and more) interval during a two-stage procedure. Patient satisfaction was defined as good if the patient did not have pain and bad if the patient had pain. Functional outcome was defined good if the patient had a prosthesis in place and could walk, medium if the prosthesis was in place but the patient could not walk, and bad if the prosthesis was no longer in place. Infection outcome was considered good if there had been no re-infection and bad if there had been a re-infection of the prosthesis 145 patients (100 hips, 45 knees) were identified with a median age of 68 years (range 19-103). The median hospital stay was 58 days (range 10-402). The median follow-up was 12.9 months (range 0.5-152). 28 % and 72 % of the patients had a short-interval and long-interval exchange of the prosthesis, respectively. Patient satisfaction, functional outcome and infection outcome for patients having a short versus a long interval are reported in the Table. The patient satisfaction was higher when a long interval was performed whereas the functional and infection outcomes were higher when a short interval was performed. According to this study a short-interval exchange appears preferable to a long interval, especially in the view of treatment effectiveness and functional outcome.

Final results of the SAKK 16/00 trial: a randomized phase III trial comparing neoadjuvant chemoradiation to chemotherapy alone in stage IIIA/N2 non-small cell lung cancer (NSCLC).

Aim: One standard option in the treatment of stage IIIA/N2 NSCLC is neoadjuvant chemotherapy followed by surgery. We investigated in a randomized trial whether the addition of neoadjuvant radiotherapy would improve the outcome. Here we present the final results of this study. Methods: Patients (pts.) with pathologically proven, resectable stage IIIA/N2 NSCLC, performance status 0-1, and adequate organ function were randomized 1:1 to chemoradiation (CRT) with 3 cycles of neoadjuvant chemotherapy (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3weeks) followed by accelerated concomitant boost radiotherapy (RT) with 44 Gy in 22 fractions in 3 weeks, or neoadjuvant chemotherapy alone (CT), with subsequent surgery for all pts. The primary endpoint was event-free survival (EFS). Results: 232 pts. were randomized in 23 centers, the median follow-up was 53 months. Two thirds were men, median age was 60 years (range 37-76). Histology was squamous cell in 33%, adenocarcinoma in 43%. Response rate to CRT was 61% vs. 44% with CT. 85% of all pts. underwent surgery, 30-day postoperative mortality was 1%. The rate of complete resection was 91% (CRT) vs. 81% (CT) and the pathological complete remission (pCR) rate was 16% vs. 12%. The median EFS was 13.1 months (95% CI 9.9 - 23.5) for the CRT group vs. 11.8 months (95% CI 8.4 - 15.2) in the CT arm (p 0.665). The median overall survival (OS) with CRT was 37.1 months (95% CI 22.6 -50), with CT 26.1 months ( 95% CI 26.1 - 52.1, p 0.938). The local failure rate was 23% in both arms. In the CT arm 12 pts. were given postoperative radiotherapy (PORT) for R1 resection, 6 pts. received PORT in violation of the protocol. Pts. with a pCR, mediastinal downstaging to ypN0/1 and complete resection had a better outcome. Toxicity of chemotherapy was substantial, especially febrile neutropenia was common, whereas RT was well tolerated. Conclusions: This is the first completed phase III trial to evaluate the role of induction chemoradiotherapy and surgery, in comparison to neoadjuvant CT alone followed by surgery. RT was active, it increased response, complete resection and pCR rates. However, this failed to translate into an improvement of local control, EFS or OS. Notably, surgery after induction treatment was safe, including pneumonectomy. The overall survival rates of our neoadjuvant regimen are very encouraging, especially for a multicenter setting. Disclosure: M. Pless: Advisory Board for Sanofi; R. Cathomas: Advisory Board Sanofi D.C. Betticher: Advisory Board Sanofi. All other authors have declared no conflicts of interest.

Posibles beneficios fisiológicos y psicológicos del método madre canguro (MMC) en bebés prematuros y sus madres

Objetivos: La preocupación por la crisis económica que azota España y por lo tanto, a la comunidad autónoma de Navarra, sumado a la evidencia científica de las consecuencias que sufre el bebé al ser separado de su madre tras el nacimiento, siendo más notable por debajo de las 37 semanas de gestación, y al elevado estrés y sufrimiento de los padres cuando su hijo está encerrado en una incubadora, llevó al planteamiento de querer demostrar los posibles beneficios fisiológicos y psicológicos del método madre canguro (MMC) en bebés prematuros y sus madres. Metodología: Será un estudio experimental, longitudinal y prospectivo dirigido a 40 mujeres y a sus bebés prematuros, que den a luz en el hospital Virgen del Camino. El grado de satisfacción se determinará con preguntas extraídas de la escala validada Caring Assement Instrument (CARE- Q) y con otro cuestionario no validado. Los parámetros fisiológicos se medirán con un termómetro de mercurio y una cinta métrica. El programa informático SPSS® vs 21.0. será el elegido para el análisis estadístico. Limitaciones del estudio: La larga duración de la participación de la unidad madre-hijo, la tercera etapa domiciliaria del MMC, las restricciones de la UCIN del hospital Virgen del Camino junto al uso de una escala no validada, podría conllevar a la aparición de obstáculos a la hora, tanto de poder llevar a cabo el proyecto, como de la obtención de sus resultados.