Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

BRAF Alterations as Therapeutic Targets in Non-Small-Cell Lung Cancer.

BACKGROUND: Several subsets of non-small-cell lung cancer (NSCLC) are defined by molecular alterations acting as tumor drivers, some of them being currently therapeutically actionable. The rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway constitutes an attractive potential target, as v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations occur in 2-4% of NSCLC adenocarcinoma. METHODS: Here, we review the latest clinical data on BRAF serine/threonine kinase inhibitors in NSCLC. RESULTS: Treatment of V600E BRAF-mutated NSCLC with BRAF inhibitor monotherapy demonstrated encouraging antitumor activity. Combination of BRAF and MEK inhibitors using dabrafenib and trametinib is under evaluation. Preliminary data suggest superior efficacy compared with BRAF inhibitor monotherapy. CONCLUSION: Targeting BRAF alterations represents a promising new therapeutic approach for a restricted subset of oncogene-addicted NSCLC. Prospect ive trials refining this strategy are ongoing. A next step will probably aim at combining BRAF inhibitors and immunotherapy or alternatively improve a multilevel mitogen-activated protein kinase (MAPK) pathway blockade by combining with ERK inhibitors.

Overcoming limitations of modelling rare species by using ensembles of small models

1. Species distribution models (SDMs) have become a standard tool in ecology and applied conservation biology. Modelling rare and threatened species is particularly important for conservation purposes. However, modelling rare species is difficult because the combination of few occurrences and many predictor variables easily leads to model overfitting. A new strategy using ensembles of small models was recently developed in an attempt to overcome this limitation of rare species modelling and has been tested successfully for only a single species so far. Here, we aim to test the approach more comprehensively on a large number of species including a transferability assessment. 2. For each species numerous small (here bivariate) models were calibrated, evaluated and averaged to an ensemble weighted by AUC scores. These 'ensembles of small models' (ESMs) were compared to standard Species Distribution Models (SDMs) using three commonly used modelling techniques (GLM, GBM, Maxent) and their ensemble prediction. We tested 107 rare and under-sampled plant species of conservation concern in Switzerland. 3. We show that ESMs performed significantly better than standard SDMs. The rarer the species, the more pronounced the effects were. ESMs were also superior to standard SDMs and their ensemble when they were independently evaluated using a transferability assessment. 4. By averaging simple small models to an ensemble, ESMs avoid overfitting without losing explanatory power through reducing the number of predictor variables. They further improve the reliability of species distribution models, especially for rare species, and thus help to overcome limitations of modelling rare species.

Non-small cell lung cancer: the prevalence of oncogenic driver mutations in Switzerland

Background. Predictive molecular marker analyses are standard of care in order to select non-small cell lung cancer (NSCLC) patients for targeted therapies. The aim of this study was to determine the prevalence of targetable oncogenic driver mutations including EGFR, KRAS, BRAF, HER2, ALK and ROS1 in Switzerland. Methods. Eight Swiss pathology institutions provided retrospective and anonymized data on their predictive molecular marker results performed on NSCLC from January 2012 to December 2014. Clinico-pathological data were recorded including age, gender, histological NSCLC-subtype and specimen type (biopsy, conventional cytology and cell block, respectively) used for molecular analyses. The prevalence of oncogenic mutations were calculated and compared between the centres. Results. A total of 4187 NSCLC were included into the study. The median age was 67 years and 55% were male patients. The tumor specimens for molecular analysis were mostly derived from biopsies (69%), 26% were from conventional cytology specimens and only in 5% from cell blocks. The most prevalent gene mutation was KRAS with 30.6% (range: 27.3-33.9%), followed by EGFR, BRAF and HER2 mutations in 12.2% (range: 10.2-13.1%), 3.9% (range: 2.5-5.6%) and 1.1% (range: 0.9-4.0%), respectively, without significant differences between the eight centers. Concomitant EGFR and KRAS mutations were detected in only 3/2027 NSCLC. In contrast the prevalence of ALK (mean 6.5%, range: 2.8-11.7%) and ROS1 (mean 2.4%, range: 1.5-6.2%) rearrangements varied significantly between centers. Conclusions. The Prevalence of EGFR, KRAS, BRAF and HER2 mutations are well in line with data from other West European populations. Concomitant EGFR, KRAS, BRAF or HER2 mutations are exceptional. ALK FISH results vary significantly between the eight centres. Concomitant ALK FISH positive results in NSCLC harbouring other oncogenic driver mutation have only been observed in two smaller centres, highlighting the difficulty in ALK-FISH interpretation.

State of Logistics and Operations Management in Finnish and Swedish Companies – Survey Research Findings

In this research we are examining what is the status of logistics and operations management in Finnish and Swedish companies. Empirical data is based on the web based questionnaire, which was completed in the end of 2007 and early 2008. Our examination consists of roughly 30 answers from largest manufacturing (highest representation in our sample), trade and logistics/distribution companies. Generally it could be argued that these companies operate in complex environment, where number of products, raw materials/components and suppliers is high. However, usually companies rely on small amount of suppliers per raw material/component (highest frequency is 2), and this was especially the case among Swedish companies, and among those companies, which favoured overseas sourcing. Sample consisted of companies which mostly are operating in an international environment, and are quite often multinationals. Our survey findings reveal that companies in general have taken logistics and information technology as part of their strategy process; utilization of performance measures as well as system implementations have followed the strategy decisions. In the transportation mode side we identify that road transports dominate all transport flow classes (inbound, internal and outbound), followed by sea and air. Surprisingly small amount of companies use railways, but in general we could argue that Swedish companies prefer this mode over Finnish counterparts. With respect of operations outsourcing, we found that more traditional areas of logistics outsourcing are driving factors in company's performance measurement priority. In contrary to previous research, our results indicate that the scope of outsourcing is not that wide in logistics/operations management area, and companies are not planning to outsource more in the near future. Some support is found for more international operations and increased outsourcing activity. From the increased time pressure of companies, we find evidence that local as well as overseas customers expect deliveries within days or weeks, but suppliers usually supply within weeks or months. So, basically this leads into considerable inventory holding. Interestingly local and overseas sourcing strategy does not have that great influence on lead time performance of these particular sourcing areas - local strategy is anyway considerably better in responding on market changes due to shorter supply lead times. In the end of our research work we have completed correlation analysis concerning items asked with Likert scale. Our analysis shows that seeing logistics more like a process rather than function, applying time based management, favouring partnerships and measuring logistics within different performance dimensions results on preferred features and performance found in logistics literature.

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.

Operational Reliability Analysis of a Three-Tiered Thin-Client ERP-system in an International Corporate Environment

Internationalization and the following rapid growth have created the need to concentrate the IT systems of many small-to-medium-sized production companies. Enterprise Resource Planning systems are a common solution for such companies. Deployment of these ERP systems consists of many steps, one of which is the implementation of the same shared system at all international subsidiaries. This is also one of the most important steps in the internationalization strategy of the company from the IT point of view. The mechanical process of creating the required connections for the off-shore sites is the easiest and most well-documented step along the way, but the actual value of the system, once operational, is perceived in its operational reliability. The operational reliability of an ERP system is a combination of many factors. These factors vary from hardware- and connectivity-related issues to administrative tasks and communication between decentralized administrative units and sites. To accurately analyze the operational reliability of such system, one must take into consideration the full functionality of the system. This includes not only the mechanical and systematic processes but also the users and their administration. All operational reliability in an international environment relies heavily on hardware and telecommunication adequacy so it is imperative to have resources dimensioned with regard to planned usage. Still with poorly maintained communication/administration schemes no amount of bandwidth or memory will be enough to maintain a productive level of reliability. This thesis work analyzes the implementation of a shared ERP system to an international subsidiary of a Finnish production company. The system is Microsoft Dynamics Ax, currently being introduced to a Slovakian facility, a subsidiary of Peikko Finland Oy. The primary task is to create a feasible base of analysis against which the operational reliability of the system can be evaluated precisely. With a solid analysis the aim is to give recommendations on how future implementations are to be managed.

Implementing Agile Software Development Methods in a Small Organization

Currently there is a vogue for Agile Software Development methods and many software development organizations have already implemented or they are planning to implement agile methods. Objective of this thesis is to define how agile software development methods are implemented in a small organization. Agile methods covered in this thesis are Scrum and XP. From both methods the key practices are analysed and compared to waterfall method. This thesis also defines implementation strategy and actions how agile methods are implemented in a small organization. In practice organization must prepare well and all needed meters are defined before the implementation starts. In this work three different sample projects are introduced where agile methods were implemented. Experiences from these projects were encouraging although sample set of projects were too small to get trustworthy results.

Osakeyhtiölain muutokset pienen osakeyhtiön toiminnassa

Osakeyhtiölain kokonaisuudistus astui voimaan 1.9.2006. Lain tavoitteeksi asetettiin yhtiöiden toimintaedellytysten hallittu lisääminen velkojain- tai vähemmistöosakkaiden suojaa heikentämättä. Erityisesti pienten yhtiöiden asemaan kiinnitettiin huomiota selventämällä lakia ja keventämällä muotomääräyksiä. Tämän tutkimuksen tavoitteena on selvittää, miten uudistukset vaikuttivat pienen osakeyhtiön toimintaan. Tutkimuksessa käydään läpi niitä osakeyhtiölain säädöksiä, jotka vaikuttavat pienyhtiön toimintaan sekä kirjallisuuden pohjalta että case-yhtiöiden avulla. Case-yhtiöinä tutkimuksessa on kaksi pientä osakeyhtiötä. Tutkimusmenetelmä on kvalitatiivinen ja osin deskriptiivinen tutkimus. Tutkimus osoitti, että osakeyhtiölain uudistuksen kokonaisvaikutus pienissä yhtiössä näkyy muotosäännösten kevenemisenä ja tahdonvaltaisuuden lisääntymisenä. Suurin haaste pienille yhtiöille on lain maksukykyisyysvaatimus varojenjakopäätöstä tehtäessä. Se, missä määrin lain suomia mahII dollisuuksia käytäntöjen keventämiseen yhtiöissä otetaan käyttöön, riippuu täysin yhtiön johdon aktiivisuudesta ja muutosvastarinnan voittamisesta.

Privatization, cooperation and costs of solid waste services in small towns

This paper analyzes the cost implications of privatization and cooperation in the provision of solid waste services for a sample of small municipalities. In conducting this empirical analysis, a survey is first designed and administered to municipalities in the Spanish region of Aragon, and then an estimation of the determinants of service costs is undertaken, considering the possible endogeneity of delivery choices. Our findings indicate that cooperation is more effective than privatization in saving costs. Both production forms can enable small municipalities to cut costs by exploiting scale economies. However, the fact that inter-municipal cooperation involves lower transaction costs and is less likely to be affected by competition problems would seem to account for the fact that it is a more effective way of reducing costs.

Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy.

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging.

Toimintolaskentamallin luominen kiinteistönhuoltoon

Toimintolaskennasta on tehty runsaasti tutkimuksia suuriin teollisuusyrityksiin, mutta pienille palveluyrityksille tehtyjä toimintolaskennan julkaistuja tutkimuksia on vähän. Tämän tutkimuksen tavoitteena oli tutkia toimintolaskennan soveltuvuutta pienen kiinteistönhuoltoyrityksen kustannuslaskentaan sekä rakentaa alustava toimintolaskentaan pohjautuva asiakas-kustannusten laskentamalli ja testata luotua mallia työaikaseurannan avulla. Tutkimuksen teoriaosassa on perehdytty toimintolaskennan kehitysvaiheisiin ja nykytilaan sekä kuvattu toimintolaskentaprosessin eteneminen käyttöönoton valmistelusta aina laskentatietojen hyväksikäyttöön saakka. Tutkimuksen empiriaosuus etenee edellä mainittuun teoriaan pohjautuen. Teoria- ja empiriaosuuden perusteella voidaan todeta, että kuukausi ei ole riittävän pitkä aika kattavaan seurantaan kiinteistönhuollon toiminnoista, koska vuodenaikojen vaihtelu aiheuttaa suuria muutoksia tehtäviin toimintoihin. Rakennetun laskentamallin ja toteutetun seurannan tulosten perusteella voidaan siitä huolimatta todeta, että toimintolaskentaan pohjautuva kustannusten laskentamalli tuottaa lisäarvoa kiinteistönhuollon asiakaskustannusten määrittelyssä.