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.

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.

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.

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.

Postmating-prezygotic isolation between two allopatric populations of Drosophila montana: fertilisation success differs under sperm competition

Postmating but prezygotic (PMPZ) interactions are increasingly recognized as a potentially important early-stage barrier in the evolution of reproductive isolation. A recent study described a potential example between populations of the same species: single matings between Drosophila montana populations resulted in differential fertilisation success because of the inability of sperm from one population (Vancouver) to penetrate the eggs of the other population (Colorado). As the natural mating system of D. montana is polyandrous (females remate rapidly), we set up double matings of all possible crosses between the same populations to test whether competitive effects between ejaculates influence this PMPZ isolation. We measured premating isolation in no-choice tests, female fecundity, fertility and egg-to-adult viability after single and double matings as well as second-male paternity success (P-2). Surprisingly, we found no PMPZ reproductive isolation between the two populations under a competitive setting, indicating no difficulty of sperm from Vancouver males to fertilize Colorado eggs after double matings. While there were subtle differences in how P-2 changed over time, suggesting that Vancouver males' sperm are somewhat less competitive in a first-male role within Colorado females, these effects did not translate into differences in overall P-2. Fertilisation success can thus differ dramatically between competitive and noncompetitive conditions, perhaps because the males that mate second produce higher quality ejaculates in response to sperm competition. We suggest that unlike in more divergent species comparisons, where sperm competition typically increases reproductive isolation, ejaculate tailoring can reduce the potential for PMPZ isolation when recently diverged populations interbreed.

Gathering support from rivals: the two rivals case

Two voters must choose between two alternatives. Voters vote in a fixed linear order. If there is not unanimity for any alternative, the procedure is repeated. At every stage, each voter prefers the same alternative to the other, has utilities decreasing with stages, and has an impatience degree representing when it is worth voting for the non-preferred alternative now rather than waiting for the next stage and voting for the preferred alternative. Intuition suggests that the more patient voter will get his preferred alternative. I found that in the unique solution of the sequential voting procedure obtained by backward induction, the first voter get his preferred alternative at the first stage independently from his impatience rate. Keywords: sequential voting, impatience rate, multi-stage voting, unanimity

Некоторые наблюдения по поводу построения компьютерного морфологического анализатора марийского языка. [Problems in writing a two-level model of Mari morphology]

The article describes some concrete problems that were encountered when writing a two-level model of Mari morphology. Mari is an agglutinative Finno-Ugric language spoken in Russia by about 600 000 people. The work was begun in the 1980s on the basis of K. Koskenniemi’s Two-Level Morphology (1983), but in the latest stage R. Beesley’s and L. Karttunen’s Finite State Morphology (2003) was used. Many of the problems described in the article concern the inexplicitness of the rules in Mari grammars and the lack of information about the exact distribution of some suffixes, e.g. enclitics. The Mari grammars usually give complete paradigms for a few unproblematic verb stems, whereas the difficult or unclear forms of certain verbs are only superficially discussed. Another example of phenomena that are poorly described in grammars is the way suffixes with an initial sibilant combine to stems ending in a sibilant. The help of informants and searches from electronic corpora were used to overcome such difficulties in the development of the two-level model of Mari. The variation of the order of plural markers, case suffixes and possessive suffixes is a typical feature of Mari. The morphotactic rules constructed for Mari declensional forms tend to be recursive and their productivity must be limited by some technical device, such as filters. In the present model, certain plural markers were treated like nouns. The positional and functional versatility of the possessive suffixes can be regarded as the most challenging phenomenon in attempts to formalize the Mari morphology. Cyrillic orthography, which was used in the model, also caused problems. For instance, a Cyrillic letter may represent a sequence of two sounds, the first being part of the word stem while the other belongs to a suffix. In some cases, letters for voiced consonants are also generalized to represent voiceless consonants. Such orthographical conventions distance a morphological model based on orthography from the actual (morpho)phonological processes in the language.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia

Performance Improvement of Centrifugal Compressor Stage with Pinched Geometry or Vaned Diffuser

Centrifugal compressors are widely used for example in refrigeration processes, the oil and gas industry, superchargers, and waste water treatment. In this work, five different vaneless diffusers and six different vaned diffusers are investigated numerically. The vaneless diffusers vary only by their diffuser width, so that four of the geometries have pinch implemented to them. Pinch means a decrease in the diffuser width. Four of the vaned diffusers have the same vane turning angle and a different number of vanes, and two have different vane turning angles. The flow solver used to solve the flow fields is Finflo, which is a Navier-Stokes solver. All the cases are modeled with the Chien's k – έ- turbulence model, and selected cases are modeled also with the k – ώ-SST turbulence model. All five vaneless diffusers and three vaned diffusers are investigated also experimentally. For each construction, the compressor operating map is measured according to relevant standards. In addition to this, the flow fields before and after the diffuser are measured with static and total pressure, flow angle and total temperature measurements. When comparing the computational results to the measured results, it is evident that the k – ώ-SST turbulence model predicts the flow fields better. The simulation results indicate that it is possible to improve the efficiency with the pinch, and according to the numerical results, the two best geometries are the ones with most pinch at the shroud. These geometries have approximately 4 percentage points higher efficiency than the unpinched vaneless diffusers. The hub pinch does not seem to have any major benefits. In general, the pinches make the flow fields before and after the diffuser more uniform. The pinch also seems to improve the impeller efficiency. This is down to two reasons. The major reason is that the pinch decreases the size of slow flow and possible backflow region located near the shroud after the impeller. Secondly, the pinches decrease the flow velocity in the tip clearance, leading to a smaller tip leakage flow and therefore slightly better impeller efficiency. Also some of the vaned diffusers improve the efficiency, the increment being 1...3 percentage points, when compared to the vaneless unpinched geometry. The measurement results confirm that the pinch is beneficial to the performance of the compressor. The flow fields are more uniform with the pinched cases, and the slow flow regions are smaller. The peak efficiency is approximately 2 percentage points and the design point efficiency approximately 4 percentage points higher with the pinched geometries than with the un- pinched geometry. According to the measurements, the two best geometries are the ones with the most pinch at the shroud, the case with the pinch only at the shroud being slightly better of the two. The vaned diffusers also have better efficiency than the vaneless unpinched geometries. However, the pinched cases have even better efficiencies. The vaned diffusers narrow the operating range considerably, whilst the pinch has no significant effect on the operating range.

LS-SVM: uma nova ferramenta quimiométrica para regressão multivariada. Comparação de modelos de regressão LS-SVM e PLS na quantificação de adulterantes em leite em pó empregando NIR

Least-squares support vector machines (LS-SVM) were used as an alternative multivariate calibration method for the simultaneous quantification of some common adulterants found in powdered milk samples, using near-infrared spectroscopy. Excellent models were built using LS-SVM for determining R², RMSECV and RMSEP values. LS-SVMs show superior performance for quantifying starch, whey and sucrose in powdered milk samples in relation to PLSR. This study shows that it is possible to determine precisely the amount of one and two common adulterants simultaneously in powdered milk samples using LS-SVM and NIR spectra.

The role of arbuscular mycorrhizal fungi on the early-stage restoration of seasonally dry tropical forest in Chamela, Mexico

It was evaluated the effect of two different sources of local inocula from two contrasting sites (mature forest, pasture) of arbuscular mycorrhizae fungi (AMF) and a non-mycorrhizal control on the plant growth of six woody species differing in functional characteristics (slow-, intermediate- and fast-growth), when introduced in a seasonally tropical dry forest (STDF) converted into abandoned pasture. Six plots (12 X 12m) were set as AMF inoculum source. Six replicates of six different species arranged in a Latin Square design were set in each plot. Plant height, cover area and the number of leaves produced by individual plant was measured monthly during the first growing season in each treatment. Species differed in their ability to benefit from AMF and the largest responsiveness in plant height and leaf production was exhibited by the slow-growing species Swietenia humilis, Hintonia latiflora and Cordia alliodora. At the end of the growing season (November), the plant height of the fast growing species Tabebuia donnel-smithii, Ceiba pentandra and Guazuma ulmifolia were not influenced by AMF. However, inocula of AMF increased leaf production of all plant species regardless the functional characteristics of the species, suggesting a better exploitation of above-ground space and generating a light limited environment under the canopy, which contributed to pasture suppression. Inoculation of seedlings planted in abandoned pasture areas is recommended for ecological restoration due to the high responsiveness of seedling growth in most of species. Use of forest inoculum with its higher diversity of AMF could accelerate the ecological restoration of the above and below-ground comunities.

Effects of water deficit in two phenological stages on production of japanese cucumber cultived in greenhouse

The experiment was performed in the experimental area of the Engineering Department Federal University of Lavras, Minas Gerais State, Brazil. It aimed at identifying the adequate irrigation management of the greenhouse-cultivated Japanese cucumber (Cucumis sativus L.). complete randomized design, with four levels of soil water potential (15; 30; 60 e 120 kPa) at two phenological phases (vegetative and reproductive), and 5 replications. Overall, the results showed decrease of yield according to increase of soil water potentials. During the reproductive stage, Japanese cucumber plants were more sensitive to water deficit, resulting in further decrease in yield compared to applied water deficit during the vegetative stage of the culture.

Impact of irrigation on yield and energy balance of the production of oil and cake of two sunflower varieties

The energy balance for the production of sunflower oil and cake was carried out during the agricultural and industrial stage phase, where it was considered a cold extraction by hydraulic pressing, with the plant location in a rural area with a radius of 30km range. Data on productivity was used in two varieties of sunflower (Helio 358 and Aguará 04) grown in different seasons (2007/2008, 2008/2009), under different irrigation levels. Data showed that irrigation resulted in an increase in productivity of both varieties, and the best response was observed for Aguará 04 variety. Moreover, the increased intensity of irrigation negatively affected the energy balance, reducing the ratio between energy produced and energy used in the production chain. The most significant inputs in the energy intake were fertilizer followed by diesel oil, when irrigation was not used for. When the irrigation technique was used, the most significant inputs, in order of representativeness, were: energy, fertilizer and equipment.

Deficit irrigation in grapevine cv. Syrah during two growing seasons in the brazilian semiarid

Irrigation plays an important role for grape’s yield as well as on its quality for winemaking. Thus, the effects of deficit irrigation strategies on yield and quality of wine grapes cv. Syrah were evaluated in Petrolina, State of Pernambuco, Brazil. Evaluations were carried out throughout the second and third growing seasons, which were from November 2010 to February 2011 (rainy season) and from May to September 2011 (dry season), respectively. Vines were drip irrigated and the experimental design was completely randomized with three treatments and four replications. The treatments were full irrigation (FI), performed according crop evapotranspiration; regulated deficit irrigation (RDI), in which irrigation was interrupted in phenological growth stage of bunch closure, but was occasionally performed according soil water monitoring of the root zone; and deficit irrigation (DI), when irrigation was interrupted from bunch closure to harvesting. Differences on leaf water content among treatments were observed in both growing seasons and RDI and DI treatment plants presented moderate water stress. The number of bunches did not differ among treatments in both growing seasons; however, bunch weight per plant, average bunch weight and soluble solid content were higher in FI treatment during the dry season. Deficit irrigation strategies promoted water saving.

Criteria for prediction of metastatic axillary lymph nodes in early-stage breast cancer

PURPOSE: To estimate the likelihood of axillary lymph node involvement for patients with early-stage breast cancer, based on a variety of clinical and pathological factors. METHODS: A retrospective analysis was done in hospital databases from 1999 to 2007. Two hundred thirty-nine patients were diagnosed with early-stage breast cancer. Predictive factors, such as patient age, tumor size, lymphovascular invasion, histological grade and immunohistochemical subtype were analyzed to identify variables that may be associated with axillary lymph node metastasis. RESULTS: Patients with tumors that are negative for estrogen receptor, progesterone receptor, and HER2 had approximately a 90% lower chance of developing lymph node metastasis than those with luminal A tumors (e.g., ER+ and/or PR+ and HER2-) - Odds Ratio: 0.11; 95% confidence interval: 0.01-0.88; p=0.01. Furthermore, the risk for lymph node metastasis of luminal A tumors seemed to decrease as patient age increased, and it was directly correlated with tumor size. CONCLUSION: The molecular classification of early-stage breast cancer using immunohistochemistry may help predicting the probability of developing axillary lymph node metastasis. Further studies are needed to optimize predictions for nodal involvement, with the aim of aiding the decision-making process for breast cancer treatment.