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.

Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study.

PURPOSE: The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. METHODS: Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. RESULTS: After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. CONCLUSION: The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.

Variation in Current Management of Term and Late-preterm Neonates at Risk for Early-onset Sepsis: An International Survey and Review of Guidelines.

BACKGROUND: Uncertainty about the presence of infection results in unnecessary and prolonged empiric antibiotic treatment of newborns at risk for early-onset sepsis (EOS). This study evaluates the impact of this uncertainty on the diversity in management. METHODS: A web-based survey with questions addressing management of infection risk-adjusted scenarios was performed in Europe, North America, and Australia. Published national guidelines (n = 5) were reviewed and compared with the results of the survey. RESULTS: 439 Clinicians (68% were neonatologists) from 16 countries completed the survey. In the low-risk scenario, 29% would start antibiotic therapy and 26% would not, both groups without laboratory investigations; 45% would start if laboratory markers were abnormal. In the high-risk scenario, 99% would start antibiotic therapy. In the low-risk scenario, 89% would discontinue antibiotic therapy before 72 hours. In the high-risk scenario, 35% would discontinue therapy before 72 hours, 56% would continue therapy for 5-7 days, and 9% for more than 7 days. Laboratory investigations were used in 31% of scenarios for the decision to start, and in 72% for the decision to discontinue antibiotic treatment. National guidelines differ considerably regarding the decision to start in low-risk and regarding the decision to continue therapy in higher risk situations. CONCLUSIONS: There is a broad diversity of clinical practice in management of EOS and a lack of agreement between current guidelines. The results of the survey reflect the diversity of national guidelines. Prospective studies regarding management of neonates at risk of EOS with safety endpoints are needed.

Incidence and Outcome of Group B Streptococcal Sepsis in Infants in Switzerland.

The incidence and outcome of group B streptococcal (GBS) sepsis were assessed prospectively between September 2011 and February 2015 in all tertiary care pediatric hospitals of Switzerland. We describe a low incidence of GBS early-onset sepsis (0.12/1000 livebirths) and a predominance of GBS late-onset sepsis (0.36/1000 livebirths), a pattern that has not been reported in other countries.

DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer.

PURPOSE: Prospective-retrospective assessment of theTOP1gene copy number andTOP1mRNA expression as predictive biomarkers for adjuvant irinotecan in stage II/III colon cancer. EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant colon cancer trial (PETACC3) where patients were randomized to 5-fluorouracil/folinic acid with or without additional irinotecan.TOP1copy number status was analyzed by fluorescencein situhybridization (FISH) using aTOP1/CEN20 dual-probe combination.TOP1mRNA data were available from previous analyses. RESULTS: TOP1FISH and follow-up data were obtained from 534 patients.TOP1gain was identified in 27% using a single-probe enumeration strategy (≥4TOP1signals per cell) and in 31% when defined by aTOP1/CEN20 ratio ≥ 1.5. The effect of additional irinotecan was not dependent onTOP1FISH status.TOP1mRNA data were available from 580 patients with stage III disease. Benefit of irinotecan was restricted to patients characterized byTOP1mRNA expression ≥ third quartile (RFS: HRadjusted, 0.59;P= 0.09; OS: HRadjusted, 0.44;P= 0.03). The treatment byTOP1mRNA interaction was not statistically significant, but in exploratory multivariable fractional polynomial interaction analysis, increasingTOP1mRNA values appeared to be associated with increasing benefit of irinotecan. CONCLUSIONS: In contrast to theTOP1copy number, a trend was demonstrated for a predictive property ofTOP1mRNA expression. On the basis ofTOP1mRNA, it might be possible to identify a subgroup of patients where an irinotecan doublet is a clinically relevant option in the adjuvant setting of colon cancer.Clin Cancer Res; 22(7); 1621-31. ©2015 AACR.

Reduction in the use of diagnostic tests in infants with risk factors for early-onset neonatal sepsis does not delay antibiotic treatment

BACKGROUND: Despite a low positive predictive value, diagnostic tests such as complete blood count (CBC) and C-reactive protein (CRP) are commonly used to evaluate whether infants with risk factors for early-onset neonatal sepsis (EOS) should be treated with antibiotics. STUDY DESIGN: We investigated the impact of imple- menting a protocol aiming at reducing the number of dia- gnostic tests in infants with risk factors for EOS in order to compare the diagnostic performance of repeated clinical examination with CBC and CRP measurement. The primary outcome was the time between birth and the first dose of antibiotics in infants treated for suspected EOS. RESULTS: Among the 11,503 infants born at 35 weeks during the study period, 222 were treated with antibiotics for suspected EOS. The proportion of infants receiving an- tibiotics for suspected EOS was 2.1% and 1.7% before and after the change of protocol (p = 0.09). Reduction of dia- gnostic tests was associated with earlier antibiotic treat- ment in infants treated for suspected EOS (hazard ratio 1.58; 95% confidence interval [CI] 1.20-2.07; p <0.001), and in infants with neonatal infection (hazard ratio 2.20; 95% CI 1.19-4.06; p = 0.01). There was no difference in the duration of hospital stay nor in the proportion of infants requiring respiratory or cardiovascular support before and after the change of protocol. CONCLUSION: Reduction of diagnostic tests such as CBC and CRP does not delay initiation of antibiotic treat- ment in infants with suspected EOS. The importance of clinical examination in infants with risk factors for EOS should be emphasised.

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

DC Boost Stage in Photovoltaic Systems

The performance of Grid connected Photovoltaic System working with DCBoost stage is investigated. The DC-Boost Converter topology is deduced from three phase half controlled bridge and controlled by Sliding Mode Control. Due to the fact that Grid connected Photovoltaic System includes Solar cells as a DC source and inverter for grid connection, those are under the scope of this research as well. The advantages of using MPPT are analyzed. The system is simulated in Matlab-Simulink™ environment.

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.

¿Sepsis en LES?. Anticoagulante lúpico. Cuatro casos clínicos pediátricos

En el lupus eritematoso diseminado no son infrecuentes los trastornos de la coagulación, con hemorragias, que incluso en ocasiones pueden ser la primera manifestación; si además se añade fiebre puede malinterpretarse como un cuadro infeccioso, sabre todo si se acompaña de la presencia de anticoagulante lúpico (inmunoglobulina presente en el l0-25% de los casos, con afinidad por los fosfolípidos cargados negativamente, que impide que el proceso de coagulación in vitro se desarrolle normalmente), ya que se asemejará a una sepsis con coagulopatía. Los cuatro casas reseñados son ejemplos de esta situación. Una minuciosa anamnesis y examen clínico, la correcta interpretación de los exámenes complementarios junto con la sospecha diagnóstica son básicos en la orientación de estos pacientes.

Final chlorine dioxide stage at near-neutral pH for bleaching eucalypt pulp

It is well known that pH is an important parameter for controlling the eucalyptus pulp bleaching when using the final chlorine dioxide stage, since it affects the effectiveness of the process. Recommendations found in the literature for operating are in the 3.5 to 4.0 range. However, in this paper it was shown that final chlorine dioxide has better performance, with significant brightness gain while also preserving pulp quality, when it is operated at near neutral pH. This result can be explained by the generation of sodium bicarbonate in situ upon adding carbon dioxide at this stage.

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.

Immunohistochemical evaluation for P53 and VEGF (Vascular Endothelial Growth Factor) is not prognostic for long term survival in end stage esophageal adenocarcinoma

OBJECTIVES: To correlate the expression of p53 protein and VEGF with the prognosis of patients submitted to curative resection to treat esophageal adenocarcinoma. METHODS: Forty-six patients with esophageal adenocarcinoma, submitted to curative resection, were studied. The expressions of p53 protein and VEGF were assessed by immunohistochemistry in 52.2% and 47.8% of tumors, respectively. RESULTS: P53 protein and VEGF expressions coincided in 26% of the cases, and no correlation between these expressions was observed. None of the clinicopathological factors showed a significant correlation with p53 protein or VEGF expressions. There was no significant association between p53 protein and VEGF expressions and long-term survival. CONCLUSION: The expression of p53 protein and VEGF did not correlate with prognosis in esophageal adenocarcinoma patients submitted to curative resection.

Temporary abdominal closure with zipper-mesh device for management of intra-abdominal sepsis

OBJECTIVE: to present our experience with scheduled reoperations in 15 patients with intra-abdominal sepsis. METHODS: we have applied a more effective technique consisting of temporary abdominal closure with a nylon mesh sheet containing a zipper. We performed reoperations in the operating room under general anesthesia at an average interval of 84 hours. The revision consisted of debridement of necrotic material and vigorous lavage of the involved peritoneal area. The mean age of patients was 38.7 years (range, 15 to 72 years); 11 patients were male, and four were female. RESULTS: forty percent of infections were due to necrotizing pancreatitis. Sixty percent were due to perforation of the intestinal viscus secondary to inflammation, vascular occlusion or trauma. We performed a total of 48 reoperations, an average of 3.2 surgeries per patient. The mesh-zipper device was left in place for an average of 13 days. An intestinal ostomy was present adjacent to the zipper in four patients and did not present a problem for patient management. Mortality was 26.6%. No fistulas resulted from this technique. When intra-abdominal disease was under control, the mesh-zipper device was removed, and the fascia was closed in all patients. In three patients, the wound was closed primarily, and in 12 it was allowed to close by secondary intent. Two patients developed hernia; one was incisional and one was in the drain incision. CONCLUSION: the planned reoperation for manual lavage and debridement of the abdomen through a nylon mesh-zipper combination was rapid, simple, and well-tolerated. It permitted effective management of severe septic peritonitis, easy wound care and primary closure of the abdominal wall.

Total esophagogastrectomy in the neoplasms of the esophagus and esofagogastric junction: when must be indicated?

Objective: to analyse the indications and results of the total esophagogastrectomy in cancers of the distal esophagus and esophagogastric junction. Methods: twenty patients with adenocarcinomas were operated with a mean age of 55 ± 9.9 years (31-70 years), and 14 cases were male (60%). Indications were 18 tumors of the distal esophagus and esophagogastric junction (90%) and two with invasion of gastric fundus (10%) in patients with previous gastrectomy. Preoperative colonoscopy to exclude colonic diseases was performed in ten cases. Results: the surgical technique consisted of median laparotomy and left cervicotomy, followed by transhiatal esophagectomy associated with D2 lymphadenectomy. The reconstructions were performed with eight esophagocoloduodenoplasty and the others were Roux-en-Y esophagocolojejunoplasty to prevent the alkaline reflux. Three cases were stage I / II, while 15 cases (85%) were stages III / IV, reflecting late diagnosis of these tumors. The operative mortality was 5 patients (25%): a mediastinitis secondary to necrosis of the transposed colon, abdominal cellulitis secondary to wound infection, severe pneumonia, an irreversible shock and sepsis associated with colojejunal fistula. Four patients died in the first year after surgery: 3 (15%) were due to tumor recurrence and 1 (5%) secondary to bronchopneumonia. The 5-year survival was 15%. Conclusion: the total esophagogastrectomy associated with esophagocoloplasty has high morbidity and mortality, requiring precise indication, and properly selected patients benefit from the surgery, with the risk-benefit acceptable, contributing to increased survival and improved quality of life