A multicenter study to validate the reproducibility of MSI testing with a panel of 5 quasimonomorphic mononucleotide repeats.

Microsatellite instability (MSI) testing in clinics is becoming increasingly widespread; therefore, there is an urgent need for methodology standardization and the availability of quality control. This study is aimed to assess the interlaboratory reproducibility of MSI testing in archive samples by using a panel of 5 recently introduced, mononucleotide repeats (MNR). The quality control involved 8 European institutions. Participants were supplied with DNA extracted from 15 archive colon carcinoma samples and from the corresponding normal tissues. Every group was asked to assess the MSI status of the samples by using the BAT25, BAT26, NR21, NR24, and NR27 mononucleotide markers. Four institutions repeated the analysis using the NCI reference panel to confirm the results obtained with the MNR markers. The overall concordance among institutions for MSI analyses at single locus level was 97.7% when using the MNR panel and 95.0% with the NCI one. The laboratories obtained a full agreement in scoring the MSI status of each patient sample, both using the mononucleotide and the NCI marker sets. With the NCI marker set, however, concordance was lowered to 85.7% when considering the MSI-Low phenotype. Concordance between the 2 panels in scoring the MSI status of each sample was complete if no discrimination was made between MSI-Stable and MSI-L, whereas it dropped to 76.7% if MSI-L was considered. In conclusion, the use of the MNR panel seems to be a robust approach that yields a very high level of reproducibility. The results obtained with the 5 MNR are diagnostically consistent with those obtained by the use of the NCI markers, except for the MSI-Low phenotype.

Neonatal Minimally Invasive Surgery for Congenital Diaphragmatic Hernias: a multicenter study using thoracoscopy or laparoscopy.

BACKGROUND: Minimally invasive surgery (MIS) for late-presenting congenital diaphragmatic hernia (CDH) has been described previously, but few neonatal cases of CDH have been reported. This study aimed to report the multicenter experience of these rare cases and to compare the laparoscopic and thoracoscopic approaches. METHODS: Using MIS procedures, 30 patients (16 boys and 14 girls) from nine centers underwent surgery for CDH within the first month of life, 26 before day 5. Only one patient had associated malformations. There were 10 preterm patients (32-36 weeks of gestational age). Their weight at birth ranged from 1,800 to 3,800 g, with three patients weighing less than 2,600 g. Of the 30 patients, 18 were intubated at birth. RESULTS: The MIS procedures were performed in 18 cases by a thoracoscopic approach and in 12 cases by a laparoscopic approach. No severe complication was observed. For 20 patients, reduction of the intrathoracic contents was achieved easily with 15 thoracoscopies and 5 laparoscopies. In six cases, the reduction was difficult, proving to be impossible for the four remaining patients: one treated with thoracoscopy and three with laparoscopy. The reasons for the inability to reduce the thoracic contents were difficulty of liver mobilization (1 left CDH and 2 right CDH) and the presence of a dilated stomach in the thorax. Reductions were easier for cases of wide diaphragmatic defects using thoracoscopy. There were 10 conversions (5 laparoscopies and 5 thoracoscopies). The reported reasons for conversion were inability to reduce (n = 4), need for a patch (n = 5), lack of adequate vision (n = 4), narrow working space (n = 1), associated bowel malrotation (n = 1), and an anesthetic problem (n = 1). Five defects were too large for direct closure and had to be closed with a patch. Four required conversion, with one performed through video-assisted thoracic surgery. The recurrences were detected after two primer thoracoscopic closures, one of which was managed by successful reoperation using thoracoscopy. CONCLUSIONS: In the neonatal period, CDH can be safely closed using MIS procedures. The overall success rate in this study was 67%. The indication for MIS is not related to weeks of gestational age, to weight at birth (if >2,600 g), or to the extent of the immediate neonatal care. Patients with no associated anomaly who are hemodynamically stabilized can benefit from MIS procedures. Reduction of the herniated organs is easier using thoracoscopy. Right CDH, liver lobe herniation, and the need for a patch closure are the most frequent reasons for conversion.

Mechanical ventilation and clinical practice heterogeneity in intensive care units: a multicenter case-vignette study.

BACKGROUND: Observational studies on mechanical ventilation (MV) show practice variations across ICUs. We sought to determine, with a case-vignette study, the heterogeneity of processes of care in ICUs focusing on mechanical ventilation procedures, and whether organizational patterns or physician characteristics influence practice variations. METHODS: We conducted a cross-sectional multicenter study using the case-vignette methodology. Descriptive analyses were calculated for each organizational pattern and respondent characteristics. An Index of Qualitative Variation (IQV, from 0, no heterogeneity, to a maximum of 1) was calculated. RESULTS: Forty ICUs from France (N = 33) and Switzerland (N = 7) participated; 396 physicians answered our case-vignettes. There was major heterogeneity of management processes related to MV within and across centers (mean IQV per center 0.51, SD 0.09). We observed the lowest variability (mean IQV per question < 0.4) for questions related to intubation procedure, ventilation of acute respiratory distress syndrome and the use of the semirecumbent position. We observed a high variability (mean IQV per question > 0.6) for questions related to management of endotracheal tube or suctioning, management of sedation and analgesia, and respect of autonomy. Heterogeneity was independent of respondent characteristics and of the presence of written procedures. There was a correlation between the processes associated with the highest variability (mean IQV per question > 0.6) and the annual volume of ICU admission (r = 0.32 (0.01 to 0.58)) and MV (r = 0.38 (0.07 to 0.63)). Within ICUs there was a large heterogeneity regarding knowledge of a local written procedure. CONCLUSIONS: Large clinical practice variations were found among ICUs. High volume centers were more likely to have heterogeneous practices. The presence of a local written procedure or respondent characteristics did not influence practice variation.

Validation of diagnosis criteria for acquired sensory neuronopathy. a francophone multicenter study

Recently published criteria using clinical (ataxia or asymmetrical distribution at onset or full development, and sensory loss not restricted to the lower limbs) and electrophysiological items (less than two abnormal lower limb motor nerves and at least an abolished SAP or three SAP below 30% of lower limit of normal in the upper limbs) were sensitive and specific for the diagnosis of sensory neuronopathy (SNN) (Camdessanche et al., Brain, 2009). However, these criteria need to be validated on a large multicenter population. For this, a database collecting cases from fifteen Reference Centers for Neuromuscular diseases in France and Switzerland is currently developed. So far, data from 120 patients with clinically pure sensory neuropathy have been collected. Cases were classified independently from the evaluated criteria as SNN (53), non-SNN (46) or suspected SNN (21) according to the expert's diagnosis. Using the criteria, SNN was possible in 83% (44/53), 23.9% (11/46) and 71.4% (15/21) of cases, respectively. In the non-SSN group, half of the patients with a diagnosis of possible SSN had an ataxic form of inflammatory demyelinating neuropathy. In the SNN group, half of those not retained as possible SNN had CANOMAD, paraneoplasia, or B12 deficiency. In a second step, after application of the items necessary to reach the level of probable SNN (no biological or electrophysiological abnormalities excluding SNN; presence of onconeural antibody, cisplatin treatment, Sj ¨ ogren's syndrome or spinal cord MRI high signal in the posterior column), a final diagnosis of possible or probable SNN was obtained in, respectively, 90.6% (48/53), 8.8% (4/45), and 71.4% (15/21) of patients in the three groups. Among the 5 patients with a final non-SNN but initial SNN diagnosis, 3 had motor conduction abnormalities (one with CANOMAD) and among the 4 patients with a final SNN but initial non-SSN diagnosis, one had anti-Hu antibody and one was discussed as a possible ataxic CIDP. These preliminary results confirm the sensitivity and specificity of the proposed criteria for the diagnosis of SNN.

Santé et styles de vie des adolescents âgés de 16 à 20 ans en Suisse (2002). SMASH 2002 : Swiss multicenter adolescent survey on health 2002

Le présent rapport décrit les grandes tendances qui se dégagent des résultats de l'Enquête SMASH 2002 et propose quelques hypothèses pour éclairer la compréhension et les enjeux de la situation actuelle ainsi que des pistes de réflexion pour l'avenir. Cette étude repose sur deux approches complémentaires de la santé: l'une donne la primauté aux aspects sociologiques des conduites de santé ("lifestyle"); l'autre, de nature épidémiologique, met l'accent sur la prévalence des comportements et procède à des analyses dans divers sous-groupes ou dans le temps. L'étude SMASH 2002 fournit une photographie de la situation des adolescents et de leur état de santé : besoins et comportements de santé, facteurs associés et évaluation des grands changements intervenus depuis une dizaine d'années. Ces données doivent permettre de réfléchir à une planification optimale des services de soins et des programmes de prévention et de promotion de la santé en faveur des adolescents. [extraits du résumé des auteurs]

The AO comprehensive classification of pediatric long-bone fractures: a web-based multicenter agreement study.

The first AO comprehensive pediatric long-bone fracture classification system has been proposed following a structured path of development and validation with experienced pediatric surgeons. A Web-based multicenter agreement study involving 70 surgeons in 15 clinics and 5 countries was conducted to assess the reliability and accuracy of this classification when used by a wide range of surgeons with various levels of experience. Training was provided at each clinic before the session. Using the Internet, participants could log in at any time and classify 275 supracondylar, radius, and tibia fractures at their own pace. The fracture diagnosis was made following the hierarchy of the classification system using both clinical terminology and codes. kappa coefficients for the single-surgeon diagnosis of epiphyseal, metaphyseal, or diaphyseal fracture type were 0.66, 0.80, and 0.91, respectively. Median accuracy estimates for each bone and type were all greater than 80%. Depending on their experience and specialization, surgeons greatly varied in their ability to classify fractures. Pediatric training and at least 2 years of experience were associated with significant improvement in reliability and accuracy. Kappa coefficients for diagnosis of specific child patterns were 0.51, 0.63, and 0.48 for epiphyseal, metaphyseal, and diaphyseal fractures, respectively. Identified reasons for coding discrepancies were related to different understandings of terminology and definitions, as well as poor quality radiographic images. Results supported some minor adjustments in the coding of fracture type and child patterns. This classification system received wide acceptance and support among the surgeons involved. As long as appropriate training could be performed, the system classification was reliable, especially among surgeons with a minimum of 2 years of clinical experience. We encourage broad-based consultation between surgeons' international societies and the use of this classification system in the context of clinical practice as well as prospectively for clinical studies.

Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.

PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

Predicting Bacteremia in Children With Cancer and Fever in Chemotherapy-induced Neutropenia: Results of the Prospective Multicenter SPOG 2003 FN Study.

STUDY AIM:: To develop a score predicting the risk of bacteremia in cancer patients with fever and neutropenia (FN), and to evaluate its performance. METHODS:: Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of bacteremia was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. RESULTS:: Bacteremia was reported in 67 (16%) of 423 FN episodes. In 34 episodes (8%), bacteremia became known only after reassessment after 8 to 24 hours of inpatient management. Predicting bacteremia at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The reassessment score predicting future bacteremia in 390 episodes without known bacteremia used the following 4 variables: hemoglobin ≥90 g/L at presentation (weight 3), platelet count <50 G/L (3), shaking chills (5), and other need for inpatient treatment or observation according to the treating physician (3). Applying a threshold ≥3, the score-simplified into a low-risk checklist-predicted bacteremia with 100% sensitivity, with 54 episodes (13%) classified as low-risk, and a specificity of 15%. CONCLUSIONS:: This reassessment score, simplified into a low-risk checklist of 4 routinely accessible characteristics, identifies pediatric patients with FN at risk for bacteremia. It has the potential to contribute to the reduction of use of antimicrobials in, and to shorten the length of hospital stays of pediatric patients with cancer and FN.

Myocardial infarct size and mortality depend on the time of day-a large multicenter study.

BACKGROUND: Different studies have shown circadian variation of ischemic burden among patients with ST-Elevation Myocardial Infarction (STEMI), but with controversial results. The aim of this study was to analyze circadian variation of myocardial infarction size and in-hospital mortality in a large multicenter registry. METHODS: This retrospective, registry-based study was based on data from AMIS Plus, a large multicenter Swiss registry of patients who suffered myocardial infarction between 1999 and 2013. Peak creatine kinase (CK) was used as a proxy measure for myocardial infarction size. Associations between peak CK, in-hospital mortality, and the time of day at symptom onset were modelled using polynomial-harmonic regression methods. RESULTS: 6,223 STEMI patients were admitted to 82 acute-care hospitals in Switzerland and treated with primary angioplasty within six hours of symptom onset. Only the 24-hour harmonic was significantly associated with peak CK (p = 0.0001). The maximum average peak CK value (2,315 U/L) was for patients with symptom onset at 23:00, whereas the minimum average (2,017 U/L) was for onset at 11:00. The amplitude of variation was 298 U/L. In addition, no correlation was observed between ischemic time and circadian peak CK variation. Of the 6,223 patients, 223 (3.58%) died during index hospitalization. Remarkably, only the 24-hour harmonic was significantly associated with in-hospital mortality. The risk of death from STEMI was highest for patients with symptom onset at 00:00 and lowest for those with onset at 12:00. DISCUSSION: As a part of this first large study of STEMI patients treated with primary angioplasty in Swiss hospitals, investigations confirmed a circadian pattern to both peak CK and in-hospital mortality which were independent of total ischemic time. Accordingly, this study proposes that symptom onset time be incorporated as a prognosis factor in patients with myocardial infarction.

Early Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study

Purpose/Objective(s): Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas, and 4-5% of all extranodal lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with stage I and II PBL.Materials/Methods: Between 1987 and 2008, 116 consecutive patients with PBL treated in 13 RCNinstitutions were included in this study. Inclusion criteriawere: age.17 yrs, PBLin stage I and II, andminimum6months follow-up. The median agewas 51 yrs (range: 17-93).Diagnosticwork-up included plain boneXray (74%of patients), scintigraphy (62%), CT-scan (65%),MRI (58%), PET (18%), and bone-marrow biopsy (84%).All patients had biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). The histopathological type was predominantly diffuse large B-cell lymphoma (78%) and follicular lymphoma (6%), according to theWHOclassification. One hundred patients had a high-grade, 7 intermediate and 9 low-gradeNHL. Ninety-three patients had anAnn-Arbor stage I, and 23 had a stage II. Seventy-seven patients underwent chemoradiotherapy (CXRT), 12 radiotherapy (RT) alone, 10 chemotherapy alone (CXT), 9 surgery followed by CXRT, 5 surgery followed by CXT, and 2 surgery followed by RT. One patient died before treatment.Median RT dosewas 40Gy (range: 4-60).Themedian number ofCXTcycleswas 6 (range, : 2-8).Median follow-upwas 41months (range: 6-242).Results: Following treatment, the overall response rate was 91% (CR 74%, PR 17%). Local recurrence was observed in 12 (10%) patients, and systemic recurrence in 17 (15%) patients. Causes of death included disease progression in 16, unrelated disease in 6, CXT-related toxicity in 1, and secondary cancer in 2 patients. The 5-yr overall survival (OS), disease-free survival (DFS), lymphoma- specific survival (LSS), and local control (LC) were 76%, 69%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for survival were: age\50 years (p = 0.008), IPI score #1 (p = 0.009), complete response (p\0.001), CXT (p = 0.008), number of CXT cycles $6 (p = 0.007), and RT dose . 40 Gy (p = 0.005). In multivariate analysis age, RT dose, complete response, and absence of B symptoms were independent factors influencing the outcome. There were 3 patients developing grade 3 or more (CTCAE.V3.0) toxicities.Conclusions: This large multicenter study, confirms the relatively good prognosis of early stage PBL, treated with combined CXRT. Local control was excellent, and systemic failure occurred infrequently. A sufficient dose of RT (. 40 Gy) and completeCXT regime (. 6 cycles) were associated with a better outcome. Combined modality appears to be the treatment of choice.Author Disclosure: L. Cai, None; M.C. Stauder, None; Y.J. Zhang, None; P. Poortmans, None; Y.X. Li, None; N. Constantinou, None; J. Thariat, None; S. Kadish, None; M. Ozsahin, None; R.O. Mirimanoff, None.

Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.

Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study.

PURPOSE To develop a score predicting the risk of adverse events (AEs) in pediatric patients with cancer who experience fever and neutropenia (FN) and to evaluate its performance. PATIENTS AND METHODS Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of future AEs (ie, serious medical complication, microbiologically defined infection, radiologically confirmed pneumonia) was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results An AE was reported in 122 (29%) of 423 FN episodes. In 57 episodes (13%), the first AE was known only after reassessment after 8 to 24 hours of inpatient management. Predicting AE at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The score predicting future AE in 358 episodes without known AE at reassessment used the following four variables: preceding chemotherapy more intensive than acute lymphoblastic leukemia maintenance (weight = 4), hemoglobin > or = 90 g/L (weight = 5), leukocyte count less than 0.3 G/L (weight = 3), and platelet count less than 50 G/L (weight = 3). A score (sum of weights) > or = 9 predicted future AEs. The cross-validated performance of this score exceeded the performance of published risk prediction rules. At an overall sensitivity of 92%, 35% of the episodes were classified as low risk, with a specificity of 45% and a negative predictive value of 93%. CONCLUSION This score, based on four routinely accessible characteristics, accurately identifies pediatric patients with cancer with FN at risk for AEs after reassessment.

Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study.

BACKGROUND: The quality of colon cleansing is a major determinant of quality of colonoscopy. To our knowledge, the impact of bowel preparation on the quality of colonoscopy has not been assessed prospectively in a large multicenter study. Therefore, this study assessed the factors that determine colon-cleansing quality and the impact of cleansing quality on the technical performance and diagnostic yield of colonoscopy. METHODS: Twenty-one centers from 11 countries participated in this prospective observational study. Colon-cleansing quality was assessed on a 5-point scale and was categorized on 3 levels. The clinical indication for colonoscopy, diagnoses, and technical parameters related to colonoscopy were recorded. RESULTS: A total of 5832 patients were included in the study (48.7% men, mean age 57.6 [15.9] years). Cleansing quality was lower in elderly patients and in patients in the hospital. Procedures in poorly prepared patients were longer, more difficult, and more often incomplete. The detection of polyps of any size depended on cleansing quality: odds ratio (OR) 1.73: 95% confidence interval (CI)[1.28, 2.36] for intermediate-quality compared with low-quality preparation; and OR 1.46: 95% CI[1.11, 1.93] for high-quality compared with low-quality preparation. For polyps >10 mm in size, corresponding ORs were 1.0 for low-quality cleansing, OR 1.83: 95% CI[1.11, 3.05] for intermediate-quality cleansing, and OR 1.72: 95% CI[1.11, 2.67] for high-quality cleansing. Cancers were not detected less frequently in the case of poor preparation. CONCLUSIONS: Cleansing quality critically determines quality, difficulty, speed, and completeness of colonoscopy, and is lower in hospitalized patients and patients with higher levels of comorbid conditions. The proportion of patients who undergo polypectomy increases with higher cleansing quality, whereas colon cancer detection does not seem to critically depend on the quality of bowel preparation.