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Background: In Norway, we have offered testing of PMS2 since 2006, and have a large national cohort of carriers. The aim of this study was to describe all PMS2 variants identified, and to describe frequency, spectrum and penetrance of cancers in carriers of class 4/5 variants., Methods: All detected PMS2 variants were collected from the diagnostic laboratories and reclassified according to ACMG criteria and gene specific guidelines. Data on variant, gender, cancer diagnosis, age at diagnosis, and age at last known follow-up was collected on all carriers of class 4/5 variants from electronic patient records. The Kaplan-Meier algorithm was used to calculate cumulative risk of any cancer, colorectal cancer and endometrial cancer., Results: In total, 220 different PMS2 variants were detected. Twenty nine class 4/5 variants were identified in 482 carriers. The most common pathogenic variant was the founder mutation c.989-1G > T, detected in 204 patients from 58 families. Eighty seven out of 482 (18.0%) had been diagnosed with colorectal cancer, 10 of these (11.8%) before 40 years. Cumulative risk at 70 years in our cohort was 34.7% for colorectal cancer and 26.1% for endometrial cancer., Conclusions: After 15 years of genetic testing, 29 different class 4/5 variants have been detected in Norway. Almost half of Norwegian PMS2 carriers have the founder variant 989-1G > T. Penetrance of colorectal cancer in our cohort was moderate but variable, as 11.5% of those diagnosed were younger than 40 years., (© 2024. The Author(s).)

Background: Pathogenic germline variants in the mismatch repair (MMR) genes are associated with an increased risk of prostate cancer (PCa). Since 2010 we have recommended MMR carriers annual PSA testing from the age of 40. Prospective studies of the outcome of long-term PSA screening are lacking. This study aimed to investigate the incidence and characteristics of PCa in Norwegian MMR carriers attending annual PSA screening (PSA threshold >3.0 ng/mL) to evaluate whether our recommendations should be continued., Methods: This is a prospective observational study of 225 male MMR carriers who were recommended annual PSA screening by the Section of Inherited Cancer, Oslo University Hospital from 2010 and onwards. Incidence and tumor characteristics (age, PSA at diagnosis, Gleason score, TNM score) were described. IHC and MSI-analyses were done on available tumors. Standardized incidence ratio (SIR) was calculated based on data from the Cancer Registry of Norway., Results: Twenty-two of 225 (9.8%) had been diagnosed with PCa, including 10/69 (14.5%) MSH2 carriers and 8/61 (13.1%) MSH6 carriers. Ten of 20 (50%) tumors had Gleason score ≥4 + 3 on biopsy and 6/11 (54.5%) had a pathological T3a/b stage. Eight of 17 (47.1%) tumors showed abnormal staining on IHC and 3/13 (23.1%) were MSI-high. SIR was 9.54 (95% CI 5.98-14.45) for all MMR genes, 13.0 (95% CI 6.23-23.9) for MSH2 and 13.74 for MSH6 (95% CI 5.93-27.08)., Conclusions: Our results indicate that the MMR genes, and especially MSH2 and MSH6, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of MSH2 and MSH6 carriers. Studies are needed to provide optimal recommendations for PSA-threshold and to evaluate whether MLH1 and PMS2 carriers should not be recommended screening., (© 2024 The Authors. The Prostate published by Wiley Periodicals LLC.)

Importance: Targeted analgosedation is a challenge in critically ill children, and this challenge becomes even more significant with drug shortages., Observations: Published guidelines inform the provision of analgosedation in critically ill children. This review provides insights into general approaches using these guidelines during drug shortages in Pediatric Intensive Care Units as well as strategies to optimize both pharmacological and non-pharmacological approaches in these situations., Conclusions and Relevance: Considering that drug shortages are a recurrent worldwide problem, this review may guide managing these drugs in critically ill children in situations of scarcity, such as in pandemics or disasters., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Castro, Rodríguez-Rubio, Magalhães-Barbosa, Prata-Barbosa, Holbrook, Kamat and Stormorken.)

Background and Objective: Improved survival has shifted research focus toward understanding alternate PICU outcomes, including neurocognitive and functional changes. Bronchiolitis is a common PICU diagnosis, but its neuro-functional outcomes have not been adequately described in contemporary literature. The objective of the study is to describe the epidemiology and associated clinical characteristics of acute neuro-functional morbidity (ANFM) in critical bronchiolitis., Methods: Patients <2 years old admitted with bronchiolitis between 2014 and 2016 were identified. Demographics, medical history, length of stay (LOS), and need for intubation were collected. Children with a history of neurologic illness or illness associated with neurologic sequelae were termed "high risk"; others were termed "low risk." ANFM was defined both at PICU and hospital discharge as the presence of swallowing difficulty, nasogastric tube feeds, hypotonia, or lethargy. Variables were compared by using χ2 and Wilcoxon rank tests., Results: Among 417 children, 16.7% had ANFM, predominantly swallow difficulties (95.7%). Children with ANFM had lower weight (5.9 [4.4-8.2] vs 7.7 [5.5-9.7] kg, P = .001), longer LOS (6.6 [2.5-13.3] vs 1.9 [0.9-3.5] days, P < .001), intubation (51.4% vs 6.1%, P < .001) and high-risk status (37.1% vs 8.4%, P < .001). Among 362 low risk subjects, ANFM was identified in 44 (12%). In a multivariate logistic regression model, high-risk status, intubation, and ICU LOS were associated with ANFM. ANFM persisted to hospital discharge in 46% of cases., Conclusions: One out of 6 patients with critical bronchiolitis had documentation consistent with ANFM at PICU discharge. Risk factors included previous neurologic conditions, longer LOS, and intubation. Many were low-risk and/or did not require intubation, indicating a risk for neuro-functional morbidities despite moderate acuity., (Copyright © 2022 by the American Academy of Pediatrics.)

Rationale: A guideline that both evaluates current practice and provides recommendations to address sedation, pain, and delirium management with regard for neuromuscular blockade and withdrawal is not currently available., Objective: To develop comprehensive clinical practice guidelines for critically ill infants and children, with specific attention to seven domains of care including pain, sedation/agitation, iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment, and early mobility., Design: The Society of Critical Care Medicine Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility Guideline Taskforce was comprised of 29 national experts who collaborated from 2009 to 2021 via teleconference and/or e-mail at least monthly for planning, literature review, and guideline development, revision, and approval. The full taskforce gathered annually in-person during the Society of Critical Care Medicine Congress for progress reports and further strategizing with the final face-to-face meeting occurring in February 2020. Throughout this process, the Society of Critical Care Medicine standard operating procedures Manual for Guidelines development was adhered to., Methods: Taskforce content experts separated into subgroups addressing pain/analgesia, sedation, tolerance/iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment (family presence and sleep hygiene), and early mobility. Subgroups created descriptive and actionable Population, Intervention, Comparison, and Outcome questions. An experienced medical information specialist developed search strategies to identify relevant literature between January 1990 and January 2020. Subgroups reviewed literature, determined quality of evidence, and formulated recommendations classified as "strong" with "we recommend" or "conditional" with "we suggest." Good practice statements were used when indirect evidence supported benefit with no or minimal risk. Evidence gaps were noted. Initial recommendations were reviewed by each subgroup and revised as deemed necessary prior to being disseminated for voting by the full taskforce. Individuals who had an overt or potential conflict of interest abstained from relevant votes. Expert opinion alone was not used in substitution for a lack of evidence., Results: The Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility taskforce issued 44 recommendations (14 strong and 30 conditional) and five good practice statements., Conclusions: The current guidelines represent a comprehensive list of practical clinical recommendations for the assessment, prevention, and management of key aspects for the comprehensive critical care of infants and children. Main areas of focus included 1) need for the routine monitoring of pain, agitation, withdrawal, and delirium using validated tools, 2) enhanced use of protocolized sedation and analgesia, and 3) recognition of the importance of nonpharmacologic interventions for enhancing patient comfort and comprehensive care provision., Competing Interests: Drs. Smith and Berkenbosch were responsible for the adjudication of any conflicts of interest for this guideline. The following relevant disclosures were provided for consideration. Dr. Srinivasan authored “Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children,” World Journal of Clinical Pediatrics (May 2017). Dr. Almgren authored “Pharmacological Strategies for Decreasing Opioid Therapy and Management of Side Effects From Chronic Use”, Children (2018) and “Multidisciplinary Pain Management for Pediatric Patients with Acute and Chronic Pain: A Foundational Treatment Approach When Prescribing Opioids,” Children (2019). Dr. Grant was a lead author for the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) Study Investigators (2016) and for “Dexmedetomidine Use in Critically-Ill Children with Acute Respiratory Failure,” Pediatric Critical Care Medicine. Dr. deAlmeida was a contributing author on “Delirium in Critically Ill Children: An International Point Prevalence Study,” Critical Care Medicine (2017). Dr. Simone is a lead author for “Analgesia, Sedation, Paralytics, and Opioid Syndrome (2021); Pediatric Acute Care. A Guide for Interprofessional Practice, second Edition (2019); Delirium and Pharmacologic Treatment in Critically Ill Children: A Retrospective Matched Cohort Study,” Journal of Pediatric Pharmacologic and Therapeutics (2017). “Implementation of an ICU Bundle: An Interprofessional Quality Improvement Project to Enhance Delirium Management and Monitor Delirium Prevalence in a Single PICU,” Pediatric Critical Care Medicine (2017). Dr. Su was a lead author for “Pharmacokinetics of Dexmedetomidine in Infants and Children After Orthotopic Liver Transplantation,” Anesthesia Analog (2018). Dr. Traube was a lead author on “Detection and Management of Delirium in the Neonatal Unit: A Case Series,” Pediatrics (2016); “Prospective Study to Establish the German version of the CAPD for the Assessment of Delirium in Children Undergoing Intensive Care” (German), Monatsschrift Kinderheilkunde (2016); “Cost Associated With Pediatric Delirium in the ICU,” Critical Care Medicine (2016); “Validity of the Richmond Agitation-Sedation Scale (RASS) in Critically Ill Children,” Journal of Intensive Care (2016); “Sedation, Analgesia, and Paralysis During Mechanical Ventilation of Premature Infants,”(2017), “Patterns of Postoperative Delirium in Children,” Pediatric Critical Care Medicine (2017); “Delirium in Children After Cardiac Bypass Surgery,” Pediatric Critical Care Medicine (2017); “Delirium in Critically Ill Children: An International Point Prevalence Study,”Critical Care Medicine (2017); “Delirium and Mortality in Critically Ill Children: Epidemiology and Outcomes of Pediatric Delirium,” Critical Care Medicine (2017); “Iatrogenic Withdrawal Syndrome or Undiagnosed Delirium?,” Critical Care Medicine (2017); “‘The Times They Are A-Changin’: Universal Delirium Screening in Pediatric Critical Care,” Pediatric Critical Care Medicine (2017); “Quality Improvement Initiative to Reduce Pediatric Intensive Care Unit Noise Pollution With the Use of a Pediatric Delirium Bundle,” Journal of Intensive Care Medicine (2017); “Delirium in Pediatric Critical Care,” Pediatric Clinics of North America (2017); “Delirium in the Pediatric Cardiac Extracorporeal Membrane Oxygenation Patient Population: A Case Series,” Pediatric Critical Care Medicine (2017); “Delirium in Hospitalized Children with Cancer: Incidence and Associated Risk Factors,” The Journal of Pediatrics (2017); “Provider Beliefs Regarding Early Mobilization in the Pediatric Intensive Care Unit,” Journal of Pediatric Nursing (2018); “Identify Delirium, Then Investigate for Underlying Etiology,” Pediatric Critical Care Medicine (2018); “Consensus Report by PALISI and PBMTC Joint Working Committees, Supportive Care Guidelines for Management of VOD in Children and Adolescents; Part 3: Focus on Cardio-Respiratory Dysfunction, Infections, Liver Dysfunction and Delirium,” Biology of Blood and Marrow Transplantation (2018); “Delirium is a Common and Early Finding in Patients in the Pediatric Cardiac Intensive Care Unit,” The Journal of Pediatrics (2018); “Delirium Upon Presentation to the Pediatric Emergency Department: A Case Series,” Pediatric Emergency Care (2018); “Benzodiazepines and Development of Delirium in Critically Ill Children: Estimating the Causal Effect,” Critical Care Medicine (2018); “Association Between Transfusion of RBCs and Subsequent Development of Delirium in Critically Ill Children,” Pediatric Critical Care Medicine (2018); “All Delirium May Not Be Created Equal: Consideration of Differential Effects of Delirium Based Upon Underlying Etiology,” Pediatric Critical Care Medicine (2018); “Risk Factors for the Development of Postoperative Delirium in Pediatric Intensive Care Patients,” Pediatric Critical Care Medicine (2018); “Management Guidelines For Paediatric Patients Receiving Chimeric Antigen Receptor T Cell Therapy,” Nature Reviews Clinical Oncology (2019); and “A Systematic Approach to Family Engagement: Feasibility Pilot of a Pediatric Delirium Management And Prevention Toolkit,” Palliative and Supportive Care (2019). Stacey Williams was lead author for “The Preschool Confusion Assessment Method for the ICU: Valid and Reliable Delirium Monitoring for Critically Ill Infants and Children,” Critical Care Medicine(2016). The remaining authors have disclosed that they do not have any potential conflicts of interest. Taskforce content experts separated into subgroups addressing pain/analgesia, sedation, tolerance/iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment (family presence and sleep hygiene), and early mobility. Subgroups created descriptive and actionable Population, Intervention, Comparison, and Outcome questions. An experienced medical information specialist developed search strategies to identify relevant literature between January 1990 and January 2020. Subgroups reviewed literature, determined quality of evidence, and formulated recommendations classified as “strong” with “we recommend” or “conditional” with “we suggest.” Good practice statements were used when indirect evidence supported benefit with no or minimal risk. Evidence gaps were noted. Initial recommendations were reviewed by each subgroup and revised as deemed necessary prior to being disseminated for voting by the full taskforce. Individuals who had an overt or potential conflict of interest abstained from relevant votes. Expert opinion alone was not used in substitution for a lack of evidence., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants., Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual., Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0)., Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings., Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer., Competing Interests: Declaration of interests HL holds patents on intact PSA assays and is named on a patent for a statistical method to detect prostate cancer licensed to Arctic Partners and commercialised by OPKO Health, and has stock in Arctic Partners and OPKO Health and receives royalties from sales of the 4Kscore test. RAE has received speaker honoraria from Genitourinary-American Society of Clinical Oncology, The University of Chicago, European Society for Medical Oncology (paid by Bayer and Ipsen), and The Royal Marsden NHS Foundation Trust (with support from Janssen), and is a member of the AstraZeneca UK Limited Prostate Dx Advisory Panel external expert committee. No organisation had any role in the decision to publish or in the writing of the manuscript. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Pediatric subspecialists routinely provide procedural sedation outside the operating room. No large study has reported trends in outpatient pediatric procedural sedation. Our purpose in this study was to identify significant trends in outpatient procedural sedation using the Pediatric Sedation Research Consortium., Methods: Prospectively collected data from 2007 to 2018 were used for trending procedural sedation. Patient characteristics, medications, type of providers, serious adverse events, and interventions were reported. The Cochran-Armitage test for trend was used to explore the association between the year and a given characteristic., Results: A total of 432 842 sedation encounters were identified and divided into 3 4-year epochs (2007-2011, 2011-2014, and 2014-2018). There was a significant decrease in infants <3 months of age receiving procedural sedation (odds ratio = 0.97; 95% confidence interval, 0.96-0.98). A large increase was noticed in pediatric hospitalists providing procedural sedation (0.6%-9.5%; P < .001); there was a decreasing trend in sedation by other providers who were not in emergency medicine, critical care, or anesthesiology (13.9%-3.9%; P < .001). There was an increasing trend in the use of dexmedetomidine (6.3%-9.3%; P < .001) and a decreasing trend in the use of chloral hydrate (6.3%-0.01%; P < .001) and pentobarbital (7.3%-0.5%; P < .001). Serious adverse events showed a nonsignificant increase overall (1.35%-1.75%)., Conclusions: We report an increase in pediatric hospitalists providing sedation and a significant decrease in the use of chloral hydrate and pentobarbital by providers. Further studies are required to see if sedation services decrease costs and optimize resource use., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Introduction Effective debriefing during simulation-based training (SBT) is critical to promote learning outcomes. Despite debriefing's central role in learning and various published debriefing methods and techniques, little is known about faculty development structure for debriefing training among novice facilitators. Continuing medical education courses often use simulation-based methods but provide minimal training in debriefing techniques to novice facilitators. We describe the development, implementation, and evaluation of a structured debriefing training workshop for novice facilitators. Methods Designed and conducted by simulation debriefing experts, a debriefing workshop was provided to novice facilitators serving as faculty during the simulation-based Sedation Provider Course (PC) at the 2018 Society of Pediatric Sedation conference. Emphasizing evidence-based key elements of effective debriefing, the workshop was divided into three components: 1) an introductory 30 minute didactic, 2) 75 minutes role modeling of simulated effective and ineffective debriefing 3) 120 minutes repetitive deliberate practice sessions with summative and formative feedback. Effective transfer of learned debriefing skills was assessed during facilitators' PC debriefing using the Objective Structured Assessment of Debriefing (OSAD) tool, facilitators' self-efficacy, and PC student learners' evaluation of facilitator debriefings during the PC. Results Sixteen facilitators participated in the 4-h workshop and the next day served as PC faculty. The median OSAD score was 31 (13-40) for all facilitators. OSAD components with lowest and highest performance were "Establishing Learning Environment" with a median score of 1 (1-5) and "Engagement of Learners," with a median score of 4.75 (2.5-5). Facilitators' self- assessment in debriefing significantly improved on the 5-point Likert scale pre- and post-workshop, respectively. PC student learners' evaluations revealed high degrees of satisfaction with debriefing quality. Conclusions A proposed model integrating full-length debriefing and repetitive practice paired with summative and formative feedback provides a feasible and effective approach for debriefing training of novice facilitators for simulation-based educational courses., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Abulebda et al.)

Objectives: No guidelines are available regarding initiation of enteral nutrition in children with bronchiolitis on high-flow nasal cannula (HFNC) support. We hypothesized that the incidence of feeding-related adverse events (AEs) would not be associated with HFNC support., Methods: This retrospective study included children ≤24 months old with bronchiolitis receiving HFNC in a PICU from September 2013 through April 2014. Data included demographics, respiratory support during feeding, and feeding-related AEs. Feeding-related AEs were extracted from nursing documentation and defined as respiratory distress or emesis. Feed route and maximum HFNC delivery were recorded in 8-hour shifts (6 am-2 pm, 2 pm-10 pm, and 10 pm-6 am)., Results: 70 children were included, with a median age of 5 (interquartile range [IQR] 2-10) months. HFNC delivery at feed initiation varied widely, and AEs related to feeding occurred rarely. Children were fed in 501 of 794 (63%) of nursing shifts, with AEs documented in only 29 of 501 (5.8%) of those shifts. The incidence of AEs at varying levels of respiratory support did not differ ( P = .092). Children in the "early feeding" (fed within first 2 shifts) group ( n = 22) had a shorter PICU length of stay (2.2 days [IQR 1.4-3.9] vs 3.2 [IQR 2.5-5.3], P = .006) and shorter duration of HFNC use (26.0 hours [IQR 15.8-57.0] vs 53.5 [IQR 37.0-84.8], P = .002), compared with children in the "late feeding" group ( n = 48)., Conclusions: In this small, single-institution patient cohort, feeding-related AEs were rare and not related to the delivered level of respiratory support., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Background: Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions., Methods: All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm., Results: Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers., Conclusions: The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males.

We report prospectively observed risk for breast cancer in breast cancer kindreds without a demonstrable BRCA1/2 mutation. According to family history, the optimal available member(s) of each breast cancer kindred attending our clinic was tested for BRCA mutations. Women in families without a demonstrable BRCA mutation were subjected to annual mammography. BRCA mutations were demonstrated in 496/2,118 (23 %) breast cancer kindreds. In families without a demonstrable BRCA mutation, a total of 3,161 healthy women aged 25-59 years were prospectively followed for 24,808 observation years. Sixty-four cancers were observed, compared to 34.0 expected (p < 0.01), arriving at a 7.9 % cumulative risk at age 60 compared to 4.0 % in the population [relative risk (RR) = 2.0]. Women with one mother or sister affected ≤50 years and with no other close relatives with breast cancer did not have increased risk (0 cancers observed and 0.6 expected at age 40, 11 cancers observed and 7.9 expected at age 60, p > 0.05). Excluding these, cumulative risk at 60 years was 8.8 % (RR = 2.2). The highest cumulative risk at 60 years was 11.4 %, found in families with two cases ≤55 years (RR = 2.8). In breast cancer kindreds without a demonstrable BRCA mutation, the risk for breast cancer in female first degree relatives was about twice the risk in the general population. Women with one early affected relative only did not have increased risk for early onset breast cancer, while those with more than one young affected relative had close to three times population risk.

The aim of this study was to evaluate the outcome of risk-reducing mastectomy in BRCA1/2 mutation carriers with and without breast cancer. Uptake, methods of operation and reconstruction, complications, patient satisfaction and histopathological findings were registered at all five departments of genetics in Norway. Data from 267 affected and unaffected BRCA1/2 mutation carriers were analyzed, including a study-specific questionnaire returned by 178 mutation carriers. There was a steady increase in the uptake of risk-reducing mastectomies during the study period. Complications were observed in 106/266 (39.7%) women. Patient satisfaction was high. The majority of women expressed great relief after risk-reducing mastectomy and would have chosen the same option again., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

We report the 5- and 10-year survival rate of women diagnosed with breast cancer in the context of an annual MRI-based surveillance program. In 2001, as part of a national initiative, women in Norway with a BRCA1 mutation were offered annual screening with breast MRI in addition to mammography. 802 women with a BRCA1 mutation were screened one or more times and followed for a mean of 4.2 years. As of December 2011, 68 of 802 women in the screening program were diagnosed with DCIS or invasive breast cancer (8.5 %), including eight prevalent, 50 incident screen-detected and eight interval cancers. Two latent cancers were detected at prophylactic mastectomy. Sixty-three of the cancers were invasive and five were in situ. The mean tumour size was 1.4 cm (range 0.2-4.5 cm), and 85 % of the patients were node-negative. Ten of the 68 patients died of cancer in the follow-up period. The 5-year breast cancer-specific survival for women with cancer was 75 % (95 % CI 56-86 %) and the 10-year survival was 69 % (95 % CI: 48-83 %). The 5-year survival for women with Stage 1 breast cancer was 82 % compared to 98 % in the population. The 5- and 10-year survival of women with a BRCA1-associated breast cancer detected in a national MRI-based screening program in BRCA1 mutation carriers Norway was less than anticipated. The benefit of annual MRI surveillance on reducing breast cancer mortality in BRCA1 mutation carriers remains to be proven.

Background: No standardized educational curriculum exists for pediatric sedation practitioners. We sought to describe the curriculum and implementation of a pediatric sedation provider course and assess learner satisfaction with the course curriculum., Description: The course content was determined by formulating a needs assessment using published sedation guidelines, reports of sedation related adverse events, and a survey of sedation practitioners. Students provided feedback regarding satisfaction with the course immediately following the course and 6 months later., Evaluation: The course consisted of 5 didactic lectures, 1 small-group session, 6 simulation scenarios, a course syllabus, and a written examination. The course was conducted over 1 day at 3 different locations. Sixty-nine students completed the course and were uniformly satisfied with the course curriculum., Conclusions: A standardized pediatric sedation provider course was developed for sedation practitioners and consisted of a series of lectures and simulation scenarios. Overall satisfaction with the course was positive.

Background: Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases., Objective: To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation., Methods: Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria., Results: Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations., Conclusion: Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.

Endometrial cancer is frequent in MMR-mutation carriers. Estimates of annual incidence rates have, however, been based on retrospective studies. The purpose of our study was to prospectively assess the incidence rates of endometrial cancer in women either having a mutation in one of the four MMR genes MLH1, MSH2, MSH6 or PMS2 (Mut+) or belonging to families meeting the revised Amsterdam criteria in which no MMR mutation was detected (Ams+). Eight out of 80 Mut+ (10%) contracted invasive endometrial cancer compared to 1/171 (0.6%) of the Ams+ (P = 0.0006). The annual incidence rate after first control was 2.5% in Mut+ and 0.2% in Ams+. Two of the 8 Mut+ women (25%) had synchronous gynaecological tumours. The numbers included did not allow for firm conclusions, but the results are in keeping with the notion that the inherited colon-endometrial cancer syndrome may be restricted to carriers of MMR mutations.

Background: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.

Norwegian health care for persons at risk for inherited colorectal cancer is regulated by national legislation on the use of predictive genetic testing and conforms with the international guidelines. This paper from the Norwegian Group on Inherited Cancer, is a consensus between all medical genetic institutions in Norway who handle hereditary colorectal cancer. The recommendations take locally available technology and health care resources into account and are realistic with regard to what can be done within the structure of the Norwegian health service. It gives an update of known genetic syndromes, including colorectal cancer, and indications for remitting patients to genetic examinations. The medical health care is detailed for each genetic group and includes prophylactic surgery and follow-up aimed at early diagnosis and treatment according to international standards. Genetic examinations include a thorough family history verified by medical files for all affected relatives, and comprehensive genetic testing for known syndromes in question. For hereditary colon cancer syndrome (HNPCC), the approach is to screen one tumour in a family member who is an obligate carrier with immunohistochemistry for lack of mismatch gene products, and --if found--proceed to full mutation analysis of the corresponding gene. The clinical geneticists are responsible for coordinating health services to those in need. They also have an obligation to collaborate to present the empirical results of the interventions made.

Recently, carriers of biallelic mutations in the base excision repair gene MUTYH, have been demonstrated to have a predisposition for multiple adenomas and colorectal cancer. Still, many questions remain unanswered concerning MUTYH. We have addressed the following: Do biallelic MUTYH mutation carriers invariably demonstrate FAP, and may MUTYH be a gene causing HNPCC, HNPCC-like or dominantly inherited late onset colorectal cancer? We examined affecteds from our total series of HNPCC, HNPCC-like and dominantly inherited late onset colorectal cancer kindreds not demonstrated to have any MMR mutations. Bloodsamples from 96 patients were subjected to sequencing of exon 7 and exon 13 in the MUTYH gene. Two heterozygotes and one homozygote for the European founder mutations were found. The homozygous carrier did not meet criteria for FAP/AFAP. We conclude that MUTYH, when mutated, causes a rare recessively inherited disorder including colorectal- and duodenal cancers. It is not verified that heterozygous carriers of MUTYH mutations have an increased risk of cancer, and they do not explain the occurrence of familial colorectal cancer in the population.

Background: Although quality of life (QoL) and mental distress in women belonging to familial cancer families have been studied, little is known on these matters in women with absence of demonstrated mutations. The aim of this study was to examine QoL and cancer-related distress in such women., Methods: About 330 women at risk for familial cancers in the absence of demonstrated mutations were invited to the study. About 239 women (72%) (risk group) completed the Short Form 12 (SF-12) and the Impact of Event Scale (IES). The SF-12-findings were compared to the age-adjusted findings from the general female population (controls)., Results: The risk group had significantly better physical QoL than controls, while no significant difference was found for mental QoL. Within the risk group the type of familial cancer did not make a significant difference in QoL, but to have a father with cancer or a deceased parent, was associated with increased risk of being a case with low QoL. Mental QoL showed moderate correlation with cancer-related distress., Conclusions: Women belonging to familial cancer families in the absence of demonstrated mutations had at least as good QoL as controls in spite of living with a permanent cancer-related threat.

This is a case of a 3-week-old male who presented to the emergency department with intermittent apnea and cyanosis. While in the emergency department, he had respiratory compromise with stress and required intubation. Further evaluation confirmed the diagnosis of a thyroglossal duct cyst. Congenital lesions causing extrinsic airway compression should be considered in all neonates with apnea, cyanosis, and respiratory compromise. Knowledge of pediatric airway anatomy and physiology is important in all cases where obstructive apnea is suspected.

Aim: To examine psychological distress in women at risk of familial breast-ovarian cancer (FBOC) or hereditary non-polyposis colorectal cancer (HNPCC) with absence of demonstrated mutations in the family (unknown mutation)., Materials and Methods: Two-hundred and fifty three consecutive women at risk of FBOC and 77 at risk of HNPCC and with no present or past history of cancer. They were aware of their risk and had received genetic counseling. Comparisons were made between these two groups, normal controls, and women who were identified to be BRCA1 mutation carriers. The questionnaires Beck Hopelessness Scale (BHS), General Health Questionnaire (GHQ-28), Hospital Anxiety and Depression Scale (HADS) and Impact of Event Scale (IES) were employed to assess psychological distress., Results: No significant differences concerning psychological distress were observed between women with FBOC and women with HNPCC. Compared to mutation carriers for BRCA1, the level of anxiety and depression was significantly higher in the FBOC group with absence of demonstrated mutation. Compared to normal controls, the level of anxiety was higher, while the level of depression was lower in the groups with unknown mutation., Conclusions: Women in the absence of demonstrated mutations have higher anxiety and depression levels than women with known mutation-carrier status. Access to genetic testing may be of psychologically benefit to women at risk for FBOC or HNPCC.

Background & Aims: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers., Methods: Mutation analysis was performed in 20 families with a germline mutation in MSH6. We compared the cancer risks between MSH6 and MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors., Results: A total of 146 MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in MSH6 than in MLH1 or MSH2 mutation carriers (P = 0.002). In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in MSH6 mutation carriers, but the difference was not significant (P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in MSH6., Conclusions: We recommend starting colonoscopic surveillance in female MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for MSH6 mutation analysis.

Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations., Patients and Methods: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives., Results: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant., Conclusion: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.

Background and Aims: Hereditary non-polyposis colorectal cancer (HNPCC) may be caused by mutations in the mismatch repair (MMR) genes MLH1, MSH2 or MSH6. Family history (Amsterdam criteria) has traditionally been used to select patients for mutation testing. It has been demonstrated that germline mutations in the MMR genes are associated with lack of the corresponding gene product as assessed with immunohistochemistry (IHC) in tumour specimens. The aim of the study was to assess the value of the Amsterdam criteria II and IHC in predicting germline mutations., Methods: Fifty-six families that were previously tested for MLH1, MSH2 and MSH6 mutations were selected for this study. All pedigrees were extended and verified and the families were scored according to the original (I) and the revised Amsterdam criteria (II). The probabilities for MLH1 and MSH2 mutations were calculated by logistic regression. In addition, all available tumour material from indexed family members was examined by IHC for the presence of the three gene products., Results: Three out of seven (39%) families where the mutation could be identified complied with the Amsterdam criteria I, while all seven (100%) met the Amsterdam criteria II. All families carrying a MLH1 or MSH2 mutation had > 15% calculated probability of finding a mutation. Tumours from all seven mutation carriers lacked the immunohistochemical expression of the corresponding MMR gene., Conclusion: The results indicate that the Amsterdam criteria II in combination with immunohistochemistry of the mismatch repair proteins in tumours may be a cost-effective approach to select families for mutation analysis.

Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes., (Copyright 2000 John Wiley & Sons, Ltd.)

About 13% of all colorectal cancer may be dominantly inherited. This amounts to about 300 new cases a year in Norway. Colorectal cancer can be cured by early diagnosis and treatment. Coloscopy with polypectomy may prevent infiltrating cancer. Affected families should be offered genetic evaluation, and family members subjected to regular colonoscopy. The genetic bases of five colorectal cancer syndromes, accounting for most cases of hereditary early onset colorectal cancer, have now been determined. These are familial adenomatous polyposis, colon-endometrial cancer (hereditary non-polyposis colon cancer), Cowden's syndrome, Peutz-Jegher's syndrome and juvenile polyposis. These account for at most 3% of all colorectal cancers. In this group, predictive genetic testing may be employed in families with known mutation. Demonstration of mutation carriers by predictive testing must be based on health service available to the persons at risk. With regard to prophylactic measures, experimental and epidemiological data suggest a preventive effect of aspirin and resistant starch. Empirical information on the effect of intervention is insufficient; multicentre studies are needed.

To assess the impact of ATLS education on early trauma management, charts of patients with an ISS of 14 or greater were reviewed for a 1 year period before and after ATLS training of emergency room trauma care providers. There were 50 patients in the before ATLS group, with a mean age of 41.6 years and an ISS of 29.8, and 71 patients in the after ATLS group, with a mean age of 40.6 years and an ISS of 30.6. Of those parameters evaluated as measures of early assessment, only rectal examination was found to be performed significantly more frequently after ATLS training. The mortality rates of 26 percent before ATLS and 20 percent after ATLS were not significantly different. In evaluating assessment and management parameters in the patients who died, no airway management errors were found in the after ATLS group; however, there were more missed injuries in this group. We have concluded that ATLS instruction failed to produce a quantifiable improvement in patient assessment or outcome. Further studies directed at assessing the retention rate for ATLS education and determining the impact on clinical performance are needed.