Tolerability of sublingual versus vestibular allergy immunotherapy tablet administration: A randomized pilot study.

BACKGROUND: Local application site reactions are common with sublingual allergy immunotherapy (AIT)-tablets for the treatment of allergic rhinitis/conjunctivitis (AR/C) and occasionally lead to treatment discontinuation. Because of the lower mast cell density in the vestibular mucosa than the sublingual area, vestibular AIT-tablet administration may result in fewer adverse events (AEs). This pilot study evaluated the tolerability of the vestibular administration route of AIT-tablets compared with the sublingual route in adult subjects with AR/C. METHODS: Adults (n = 164) aged 18-65 years with AR/C treated with daily birch pollen, grass pollen, ragweed pollen or house dust mite AIT in tablet form were randomized 1:1 to vestibular or sublingual administration for 28 days, followed by 28 days of sublingual administration only. The primary endpoint was the severity (mild, moderate, severe) of local treatment-related adverse events (TRAEs) during the first 28 days of treatment. RESULTS: During the first 28 days, the percentage of subjects in the vestibular and sublingual groups reporting mild TRAEs were 55.6% versus 50.6%, respectively; moderate TRAEs were 27.2% versus 30.1%; and severe TRAEs were 12.3% versus 6.0% (p = .16). In the vestibular group, 95.1% of the subjects experienced at least one TRAE during the first period versus 81.9% in the sublingual group (p = .01) and discontinuation rates due to AEs were higher (12.3% vs. 3.6%). CONCLUSION: The frequencies of subjects experiencing severe TRAEs, at least one TRAE, and discontinuations due to AEs at the initiation of AIT-tablets were numerically higher with vestibular administration than sublingual administration. Sublingual administration should remain the standard of care for subjects treated with AIT-tablets for AR/C.

Outcomes of vulnerable elderly patients undergoing elective major surgery: a prospective cohort study.

PURPOSE: Identifying patients at risk of postoperative complications and trying to prevent these complications are the essence of preoperative evaluation. While not overtly frail or disabled, vulnerable patients with mild frailty may be missed by routine assessments and may still have a worse postoperative course. METHODS: We performed a prospective cohort study evaluating vulnerability in older patients undergoing elective surgery. Vulnerability was assessed using the Clinical Frailty Scale. Our primary outcome was postoperative hospital length of stay (LOS) and our secondary outcome was non-home hospital discharge. We performed multivariable analyses to assess the association between vulnerability and our primary and secondary outcome. RESULTS: Between 1 January 2017 and 1 January 2018, 271 older patients with a median [interquartile range (IQR)] age of 72 [69-76] yr underwent frailty assessment prior to surgery. Eighty-eight (32.5%) of the cohort were classified as vulnerable. The median [IQR] duration of hospital LOS was 4 [2-7] days for vulnerable patients, 4 [2-6] days for robust patients, and 7 [3-10] days for frail patients. After adjusting for confounders, hospital LOS was not longer for vulnerable patients than for robust patients, but was associated with a higher rate of non-home discharge (odds ratio, 3.7; 95% confidence interval, 1.1 to 12.9; P = 0.04). CONCLUSIONS: Vulnerability was not associated with a longer hospital LOS but with higher risk of non-home discharge. Vulnerable patients might benefit from early identification and advanced planning with earlier transfer to rehabilitation centres.

RéSUMé: OBJECTIF: L'identification des patients à risque de complications postopératoires et la prévention de ces complications constituent le fondement de l'évaluation préopératoire. Sans être ouvertement fragiles ou handicapés, les patients vulnérables avec une fragilité légère pourraient passer entre les mailles des évaluations de routine et tout de même souffrir d'un parcours postopératoire plus difficile. MéTHODE: Nous avons réalisé une étude de cohorte prospective évaluant la vulnérabilité des patients âgés subissant une chirurgie élective. La vulnérabilité a été évaluée à l'aide de l'Échelle Clinical Frailty Scale. Notre critère d'évaluation principal était la durée de séjour hospitalier postopératoire; notre critère d'évaluation secondaire était le congé de l'hôpital sans retour au foyer. Nous avons réalisé des analyses multivariées afin d'évaluer l'association entre la vulnérabilité et nos critères d'évaluation principal et secondaire. RéSULTATS: Entre le 1er janvier 2017 et le 1er janvier 2018, 271 patients d'un âge médian [écart interquartile (ÉIQ)] de 72 [69­76] ans ont passé une évaluation de fragilité avant leur chirurgie. Quatre-vingt-huit personnes (32,5 %) de la cohorte ont été catégorisées comme vulnérables. La durée médiane [ÉIQ] de séjour hospitalier était de 4 [2­7] jours pour les patients vulnérables, 4 [2­6] pour les patients robustes, et 7 [3­10] pour les patients fragiles. Après l'ajustement pour tenir compte des facteurs confondants, la durée de séjour hospitalier n'était pas plus longue pour les patients vulnérables que pour les patients robustes, mais était associée à un taux plus élevé de congé sans retour au foyer (rapport de cotes, 3,7; intervalle de confiance 95 %, 1,1 à 12,9; P = 0,04). CONCLUSION: La vulnérabilité n'a pas été associée à une durée de séjour hospitalier plus longue mais à un risque plus élevé de congé sans retour au foyer. Les patients vulnérables pourraient bénéficier d'une identification précoce et d'une planification avancée avec un transfert plus rapide vers les centres de réadaptation.

A case report of Muir-Torre syndrome in a woman with breast cancer and MSI-Low skin squamous cell carcinoma.

BACKGROUND: The tumor spectrum in the Lynch syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch syndrome spectrum. Hence, the real link between Lynch syndrome, or Muir-Torre syndrome, and these tumors remains difficult to assess. CASE PRESENTATION: We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma. CONCLUSION: Squamous cell carcinomas have been described in Lynch syndrome and Muir-Torre syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch syndrome and squamous cell carcinoma.

Somatic MMR gene mutations as a cause for MSI-H sebaceous neoplasms in Muir-Torre syndrome-like patients.

Sebaceous neoplasms are a major clinical feature of Muir-Torre syndrome (MTS) associated with visceral malignancies, especially colorectal and endometrial tumors. The diagnosis of MTS relies largely on the microsatellite instability (MSI) phenotype in tumors, suggesting germline mutations in DNA mismatch repair (MMR) genes responsible for the inherited disease. We hypothesized that in some MSI-H sebaceous tumors, acquired rather than inherited mutations in MMR genes could be involved. Using next-generation sequencing, we screened MMR gene mutations in 18 MSI-H sebaceous tumors. We found mutations in 17 samples (94%). Indeed, 12/17 (71%) were shown to carry acquired somatic mutations and among 12 samples, seven were shown to be associated with additional somatic alterations like loss of heterozygosity or multiple mutations, suggesting somatic second hits. Our findings strongly suggest that somatic MMR deficiency is responsible for a proportion of MSI-H sebaceous tumors.

Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice.

BACKGROUND: The alkylating agents (ALKYs) streptozotocin, dacarbazine, and temozolomide currently are the main drugs used in systemic chemotherapy for neuroendocrine tumors (NETs). The promising activity shown by gemcitabine and oxaliplatin (GEMOX) in previous studies prompted this study 1) to confirm the use of GEMOX in a larger population of NET patients, 2) to compare its efficacy with that of ALKYs, and 3) to explore whether the O(6) -methylguanine-DNA methyltransferase (MGMT) status could help in selecting the chemotherapy regimen. METHODS: One hundred four patients with metastatic NETs (37 pancreatic NETs, 33 gastrointestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin) were treated with GEMOX between 2004 and 2014. Among these patients, 63 also received ALKYs. MGMT promoter gene methylation was assessed via pyrosequencing in 42 patients. RESULTS: Patients received a median of 6 courses of GEMOX. Twenty-four (23%) had an objective response (OR). The median progression-free survival (PFS) and overall survival were 7.8 and 31.6 months, respectively. In the 63 patients treated with both ALKYs and GEMOX, the ORs (22% and 22%) and the PFSs (7.5 and 7.3 months) were similar. The response was concordant in 53% of the patients. Promoter gene methylation of MGMT was associated with better outcomes with ALKYs (P = .03 for OR and P = .04 for PFS) but not GEMOX. CONCLUSIONS: GEMOX is effective against NETs; its activity is comparable to that of ALKYs, and it is not influenced by the MGMT status. Our data suggest that GEMOX might be preferred for patients with unmethylated MGMT tumors. Cancer 2015;121:3435-43. © 2015 American Cancer Society.

[Cerebellar gangliocytoma in an 11-year-old child]. / Gangliocytome du cervelet chez un enfant de 11ans.

Cerebellar gangliocytoma can correspond to Lhermitte-Duclos disease, a benign hamartomatous malformation encountered in young adults. It can also be a part of gangliogliomas/gangliocytomas family, which usually encompasses temporal pediatric neoplasms associated with longstanding seizures. We report a case of a young 11-year-old patient who presented with a gangliocytoma of the cerebellum revealed by neurologic manifestations (headache, dyspraxia, equilibrium and gait disturbances). Diagnosis was made on surgical material. Tumour was characterized by dysplastic mature ganglion cells, perivascular lymphocytic infiltrates and no glial neoplastic component. By immunohistochemistry, ganglion cells expressed neurofilaments, MAP2 protein, synaptophysin, chromogranin A and S100 protein. BRAF V600E mutation was absent. Clinical characteristics, radiology, histopathology of the two main diagnoses are discussed.

Comparison of pregnancy outcomes after bariatric surgery by sleeve gastrectomy versus gastric bypass.

Objective: Bariatric surgery has an impact on subsequent pregnancies, in particular an association between gastric bypass and small for gestational age. Knowledge is lacking on whether sleeve gastrectomy is associated with more favorable pregnancy outcomes. This study aimed to compare the impact of sleeve gastrectomy and Roux-en-Y gastric bypass on the incidence of small for gestational age (SGA), and of adverse pregnancy outcomes. Study design: We conducted a retrospective study in a single reference center, including all patients with a history of sleeve or bypass who delivered between 2004 and 2021 after their first pregnancy following bariatric surgery. We compared the incidence of SGA, intrauterine growth retardation, preterm delivery and adverse maternal outcomes between patients who had sleeve versus bypass. Results: Of 244 patients, 145 had a sleeve and 99 had a bypass. The proportion of SGA < 10th percentile did not differ between the two groups (38/145 (26.2 %) vs 22/99 (22.22 %), respectively, p = 0.48). Preterm birth < 37 WG was lower in the sleeve group (5/145 (3.45%) vs 12/99 (12.12 %) in the bypass group (p = 0.01), as well as NICU hospitalizations (3 (2.07%) vs 12/99 (12.12%), p < 0.01). There was no difference regarding adverse maternal outcomes such as gestational diabetes and hypertensive complications. The proportion of SGA was not lower in patients with bypass when adjusting for other risk factors (BMI, smoking, geographic origin, diabetes and hypertension) (aOR 0.70; 95%CI 0.01 - 2.85). Conclusion: sleeve was associated with an incidence of SGA which was as high as after bypass, however the incidence of preterm birth was lower.

Annealing 1,2,4-triazine to iridium(III) complexes induces luminogenic behaviour in bioorthogonal reactions with strained alkynes.

A phenanthroline-type ligand containing an annealed 1,2,4-triazine ring was used to prepare novel Ir(III) complexes 3 and 4. The complexes are non-luminescent but show luminogenic behaviour following the inverse electron demand Diels-Alder (IEDDA) reaction with bicyclononyne (BCN) derivatives. It was observed that the complexes react with BCN-C10 faster than the corresponding free ligands. The magnitude of this accelerating metal-coordination effect, however, is less profound than in previously reported Ir(III) complexes of 1,2,4-triazines, in which the triazine was directly coordinated to the Ir(III) metal centre. Nevertheless, luminogenic behaviour opens prospects for the use of such complexes in bioimaging applications, which was demonstrated by developing a convenient methodology using the "chemistry on the complex" concept for labelling antibodies with luminescent Ir(III) complexes. The bioorthogonal reactivity of complex 4 was demonstrated by metabolically labelling live cells with BCN groups, followed by a luminogenic IEDDA reaction with the triazine iridium complex.

An inventory of Canadian pregnancy and birth cohort studies: research in progress.

BACKGROUND: A web-based inventory was developed as a voluntary registry of Canadian pregnancy and birth cohort studies, with the objective to foster collaboration and sharing of research tools among cohort study groups as a means to enrich research in maternal and child health across Canada. DESCRIPTION: Information on existing birth cohort studies conducted in Canada exclusively or as part of broader international initiatives was accessed by searching the literature in PubMed and PsychInfo databases. Additional studies were identified by enquiring about the research activities of researchers at Canadian universities or working in affiliated hospitals or research centres or institutes. Of the fifty-eight birth cohort studies initially identified, forty-six were incorporated into the inventory if they were of a retrospective and/or prospective longitudinal design and with a minimum of two phases of data collection, with the first period having occurred before, during, or shortly after pregnancy and had an initial study sample size of a minimum of 200 participants.Information collected from each study was organized into four main categories: basic information, data source and period of collection, exposures, and outcome measures and was coded and entered into an Excel spreadsheet. The information incorporated into the Excel spreadsheet was double checked, completed when necessary, and verified for completeness and accuracy by contacting the principal investigator or research coordinator. All data collected were then uploaded onto the website of the Institute of Human Development Child and Youth Health of the Canadian Institutes of Health Research. Subsequently, the database was updated and developed as an online searchable inventory on the website of the Maternal, Infant, Child and Youth Research Network. CONCLUSIONS: This inventory is unique, as it represents detailed information assembled for the first time on a large number of Canadian birth cohort studies. Such information provides a valuable resource for investigators in the planning stages of cohort studies and identifying current research gaps.

Intensity-dependent constitutional MLH1 promoter methylation leads to early onset of colorectal cancer by affecting both alleles.

Constitutional epimutation is one of the causes for MLH1 gene inactivation associated with hereditary non-polyposis colon cancer (HNPCC) syndrome. Here we investigate MLH1 promoter hypermethylation in 110 sporadic early-onset colorectal cancer patients. Variable levels of hypermethylation were detected in 55 patients (50%). Importantly a reduced MLH1 gene expression was found in patients with high-level methylation, with the association of microsatellite instability (MSI) in their tumor cells. Such high-level methylation accounts for 7.4% of all patients included in this study. Furthermore, we found that in one case constitutional methylation affected both alleles, indicating a post-zygotic methylation dysregulation. Our findings suggest that constitutional epimutation is a mechanism underlying early-onset colorectal cancer, although it is involved in only a small proportion of patients, who require appropriate surveillance. Our findings provide further insight into the role of aberrant constitutional methylation in colon carcinogenesis and raise the question of whether prevalent low-level methylation constitutes a potential risk factor for cancer development.

Practitioners' views on the effects of the "For caring supervised visitation in child welfare" training.

BACKGROUND: In youth protection, the supervision of visits between children and their parent(s) with whom they no longer live is a complex clinical practice. The "For Caring Supervised Visitation in Child Welfare" training was designed to equip workers on the subject. The training was developed in Quebec (Canada), based on a co-construction approach (clinical and scientific) of knowledge and a rigorous pedagogical engineering methodology. OBJECTIVES: This article presents the results of a research study that sought to explore the perceived impact of the training, from the worker's perspective. PARTICIPANTS AND SETTINGS: Semi-directed interviews were conducted with 20 workers who had completed the training. METHOD: A thematic analysis of the full content of the interviews was carried out (Braun & Clarke, 2006). RESULTS: This project has produced initial exploratory findings that the training has made it possible to develop a more rigorous analysis of the need for supervision, better planning of visits, greater uniformity of practices among workers and adoption of practices that promote parental engagement. According to workers, these effects of the training are influenced by factors such as time devoted solely to training in the schedule, a workload adapted to the practice to be put in place and sufficient support from managers and organization. CONCLUSIONS: These results suggest that training improves practices in the context of supervised visits. To maximize these benefits, it is suggested that workers benefit from ongoing clinical support and adequate practice conditions.

Foster family assessment: The assessor's perspective - A qualitative study.

Children in foster care are more likely to exhibit emotional, behavioral, social, and developmental problems. Accordingly, foster families should provide them with a safe family environment that promotes their development. Therefore, to ensure that foster families adequately meet children's needs, it is crucial for youth protection services to properly assess prospective foster family applicants. However, the specific assessment methods are understudied. This study aims to capture the experiences of caseworkers and the challenges they face in assessing and selecting potential foster caregivers, as well as their needs for support to perform the assessments. Focus groups were held in child protection services agencies in the province of Québec (Canada). Three group interviews with a total of 15 caseworkers were transcribed and subjected to content analysis using NVivo 11. The caseworkers identified nine most important dimensions for assessing prospective foster families, notably motivation and engagement. Differences in the assessment process between caseworkers were observed, particularly for the type of foster family assessed. The caseworkers reported certain common needs for assessment training, primarily in interview techniques and the handling of multicultural issues. They also complained of lack of time allocated for clinical support during assessments. The results call for collaborative efforts between researchers and practitioners to provide appropriate training and tools to support the assessment process.

Human rights in countries of origin and the mental health of migrants to Canada.

This study explores the effect of human rights violations in countries of origin on migrants' mental health, using archival data on human rights violations from 1970-2011, merged to a representative probability sample of 2412 adults living in a large Canadian metropolitan area. The context of exit is defined at the country level, as opposed to self-reported individual experiences of trauma. While most studies start from a question about direct exposure to human rights violations, they may miss the effect of the national-level social context - threat, instability, disruption of lives, and uncertainty - on mental health. Findings indicate that high levels of human rights violations in countries of origin have long-term effects on migrants' mental health. The impact of human rights violations is substantially explained by the combined effect of stressors both before and after migration, suggesting a cumulative process of stress proliferation following this context of exit.

MLH1 promoter hypermethylation: are you absolutely sure about the absence of MLH1 germline mutation? About a new case.

Lynch syndrome accounts for 3-5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Somatic hypermethylation of the MLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors located in the rectosigmoid and in the ileocecal angle. Both tumors were microsatellites instability-high (MSI-H) and showed a loss of MLH1 and PMS2 protein expression, but only one had MLH1 promoter hypermethylation. Constitutional analysis of mismatch repair genes could not be performed from a blood sample, because of the early death of the patient. However, tumoral tissue analyses revealed in both tumors a pathogenic variant in the MLH1 gene. Further analysis of the surrounding tumor-free tissue also showed the presence of this alteration of the MHL1 gene. Finally, the same pathogenic variant was present constitutionally in one of the siblings of the patient, confirming its hereditary nature. This new case of concomitant presence of MLH1 promoter hypermethylation and MLH1 germline mutation demonstrates that the presence of MLH1 promoter hypermethylation should not rule out the diagnosis of Lynch Syndrome.

Evaluation of p16/Ki-67 Dual Staining Compared with HPV Genotyping in Anal Cytology with Diagnosis of ASC-US for Detection of High-Grade Anal Intraepithelial Lesions.

INTRODUCTION: Human Papillomavirus (HPV) infection is the main risk factor for anogenital cancer. The objective of this study was to compare p16/Ki-67 dual staining to HPV genotyping in anal cytology samples with an atypical squamous cell of undetermined significance (ASC-US) for the identification of high-grade squamous intraepithelial lesion (HSIL). METHODS: Anal cytology samples with an ASC-US result (n = 111) were collected from patients of a university hospital (Lyon, France) from 2014 to 2015. Cases with remaining squamous cells (n = 82) were stained using p16/Ki-67 dual staining (CINtec-Plus kit) and analyzed for HPV screening (CLART2-PCR kit) using a composite endpoint of biopsy and cytology results on follow-up specimens. RESULTS: Detection of HSIL on follow-up specimens (5/22 biopsies; 1/29 cytology samples) was obtained in two out of six cases with p16/Ki-17 versus. five out of six with HPV genotyping alone. Sensitivity and specificity to detect HSIL for p16/Ki-67 was 33% (95% confidence interval [CI] [4; 77]) and 49% (95%CI [34; 64]) versus. 83% (95%CI [36; 99.6]) and 13% (95%CI [5; 27]) for HPV genotyping. CONCLUSION: Herein, HPV genotyping was more sensitive but less specific than p16/Ki-67 staining for the detection of subsequent HSIL in ASC-US anal cytology. A larger study is required to evaluate the combination of these biomarkers for triage.

Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.

Since the first report by our group in 1999, more than 20 unrelated biallelic mutations in DNA mismatch repair genes (MMR) have been identified. In the present report, we describe two novel cases: one carrying compound heterozygous mutations in the MSH6 gene; and the other, compound heterozygous mutations in the PMS2 gene. Interestingly, the inactivation of one PMS2 allele was likely caused by gene conversion. Although gene conversion has been suggested to be a mutation mechanism underlying PMS2 inactivation, this is the first report of its involvement in a pathogenic mutation. The clinical features of biallelic mutation carriers were similar to other previously described patients, with the presence of café-au-lait spots (CALS), early onset of brain tumors, and colorectal neoplasia. Our data provide further evidence of the existence, although rare, of a distinct recessively inherited syndrome on the basis of MMR constitutional inactivation. The identification of this syndrome should be useful for genetic counseling, especially in families with atypical hereditary nonpolyposis colon cancer (HNPCC) associated with childhood cancers, and for the clinical surveillance of these mutation carriers.

Characteristics of H3 K27M-mutant gliomas in adults.

BACKGROUND: Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults. The aim of this study was to describe the characteristics of H3 K27M-mutant gliomas in adults. METHODS: We analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type). RESULTS: The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3). CONCLUSION: In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis.

Type 1 serrated polyposis represents a predominantly female disease with a high prevalence of dysplastic serrated adenomas, without germline mutation in MUTYH, APC, and PTEN genes.

AIM: The aim of this article is to clarify the epidemiologic, clinical, endoscopic, biological and genetic characteristics of type 1 serrated polyposis patients. PATIENTS AND METHODS: Consecutive patients responding to the WHO definition of type 1 serrated polyposis in one reference center for polyposis patients accepted genetic counseling. Detailed data on previous endoscopies, histology, and life habits were recorded, after informed consent, germline analysis of MUTYH, APC, and PTEN germline mutations. Molecular biology was tested on available fixed tissue from different lesion types. RESULTS: We included 29 patients (mean age 53.5 years, 21 women (72.4%)), four with a personal history of colorectal cancer (CRC), with a mean of 11.6 SSAs, with associated hyperplastic polyps in 93.1% and adenomas in 82.8%. SSAs showed no dysplasia in 46.9% of lesions (three of 29 patients), LGD in 51.9% (22/29 patients), and HGD in 1.2% (four of 29 patients). Dysplasia was more frequent in proximal SSAs and in women. Colectomy 15 patients (51.7%), upper digestive neoplasms: eight patients (27.5%); smokers: 24 patients (82.8%); family history of CRC: 16 patients (55.2%). Biology: MSI-H phenotype in one SSA, V600E BRAF mutation in 95% of SSAs; MGMT hypermethylation in three of 17 SSAs. No germline mutation was detected in MYH, APC or PTEN genes. CONCLUSION: Type 1 serrated polyposis corresponds to a majority of women, with a high prevalence of smokers, a high prevalence of dysplastic serrated adenomas, particularly in females, without identified germline mutation in targeted predisposing genes.

Impact of a large deletion in the neuraminidase protein identified in a laninamivir-selected influenza A/Brisbane/10/2007 (H3N2) variant on viral fitness in vitro and in ferrets.

Viral fitness of a laninamivir-selected influenza A/Brisbane/10/2007-like (H3N2) isolate (LRVp9) containing a 237-amino acid neuraminidase deletion and a P194L hemagglutinin mutation was evaluated in vitro and in ferrets. LRVp9 and the wild-type (WT) virus showed comparable replication kinetics in MDCK-ST6GalI cells. Cultured virus was recovered between days 2 and 5 post-infection in nasal washes (NW) from the 4 WT-infected ferrets whereas no virus was recovered from the LRVp9-infected animals. There was a ≥1 log reduction in viral RNA copies/µl of NW for LRVp9 compared to WT at most time points. The large neuraminidase deletion compromises viral infectivity in vivo.