Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases

AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer(CRC) predisposing genes in early-onset or familial CRC cases.METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with nonpolyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 firstdegree relative diagnosed with CRC at ≤ 55 years of age.Genomic DNA from blood was enriched for exome sequences using the Sure Select Human All Exon Kit, version 2(Agilent Technologies) and sequencing was performed on an Illumina Hi Seq 2000 platform.Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes.RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing.In 6 of the 21 families(29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1(5 patients), MSH2(1 patient), and MUTYH(biallelic, 1 patient), five of which were reported as pathogenic.Inthe remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations.One previously unreported variant identified in a conserved region of EIF2AK4(p.Glu738_Asp739insA rgA rg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy(33.3% vs 7%, P 0.001).CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.     

Rational and clinical development of the anti-MAdCAM monoclonal antibody for the treatment of IBD

Introduction: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in gut-associated lymphoid tissue is upregulated in patients with inflammatory bowel disease (IBD). Blocking adhesion molecules and thereby inhibiting migration of lymphocytes into sites of inflammation in the gut is an attractive new treatment target in drug development for IBD.

Areas covered: This review discusses the preclinical and clinical experience on SHP647 (previously called PF-00547659 and PF-00547,659), a fully human IgG2K monoclonal antibody that binds to MAdCAM-1 to selectively reduce lymphocyte homing to the intestinal tract.

Expert opinion: Blocking endothelial adhesion molecule MAdCAM?1 could represent an attractive target for the treatment of IBD. In the next years, the results from the phase III studies as well as data to support therapeutic drug monitoring based on drug levels to guide and optimize individual therapy will become available. Furthermore, much effort is put in the development of clinical prediction models to predict which drug is optimal for an individual patient.

Trial registration: ClinicalTrials.gov identifier: NCT03259334.

Trial registration: ClinicalTrials.gov identifier: NCT03259308.

Trial registration: ClinicalTrials.gov identifier: NCT03559517.

Trial registration: ClinicalTrials.gov identifier: NCT03566823.

Trial registration: ClinicalTrials.gov identifier: NCT01298492.     

Influence of oral contraceptive pills on phenotype expression in women with polycystic ovary syndrome

Polycystic ovarian syndrome (PCOS) is characterized by a heterogeneous phenotype including chronic anovulation, hyperandrogenism and polycystic ovaries. The use of oral contraceptive pills (OCP) alters features characteristic for the syndrome. In the present study, PCOS features were compared between women using or not using OCP at the time of the study. One hundred and one women diagnosed with normogonadotrophic anovulatory infertility were included. A total of 81 (80%) women were diagnosed with PCOS (revised 2003 criteria). From these women, a total of 54 did not use OCP, whereas 27 women did. Corrected for age, women taking OCP had increased serum concentrations of sex hormone-binding globulin (P < 0.001). Serum concentrations of testosterone (P = 0.04) and androstenedione (P = 0.01) were decreased. These differences resulted in a decreased free androgen index for women currently taking OCP compared with women without (P < 0.001). The mean ovarian volume/ovary and the mean follicle number/ovary were not different. Use of OCP influences phenotype expression (the observable trait) of individual women known to suffer from PCOS by reducing hyperandrogenism. Despite taking OCP, women still fulfilled the revised 2003 criteria for the syndrome, as PCO morphology was still present. Hence, OCP use does not appreciably affect the PCOS phenotype.     

Responsiveness of functional health status measures frequently used in stroke research

Purpose. To compare the responsiveness of several functional health status measures frequently used in stroke research, namely the Barthel Index (BI), Functional Independence Measure (FIM), Frenchay Activities Index (FAI) and Stroke-Adapted Sickness Impact Profile 30 (SA-SIP 30).

Method. Patients with a first-ever supratentorial stroke admitted for inpatient rehabilitation were included. Complete datasets for 163 patients were available for analysis. Floor/ceiling effects and responsiveness, quantified by effect sizes, were studied for the periods between rehabilitation admission and six months post stroke (subacute phase) and between six and 12 months post stroke (chronic phase).

Results. Effect sizes in the subacute phase were similar and were classified as large for the BI, FIM total and FIM motor score. The FIM cognitive score showed a considerable ceiling effect and had the smallest effect size in the subacute phase. In the chronic phase, the FAI and SA-SIP 30 detected the most changes and had moderate effect sizes.

Conclusions. BI, FIM total and FIM motor score, FAI and SA-SIP 30 were responsive measures. We recommend the use of the BI in the subacute phase and the use of the FAI and SA-SIP 30 in the chronic phase, especially for the stroke rehabilitation population.     

Social participation and psychosocial outcomes of young adults with chronic physical conditions: Comparing recipients and non-recipients of disability benefits

Background

Little is known about any differences between young people with chronic physical conditions who do and do not apply for disability benefits in young adulthood for providing insights for future policy and rehabilitation care.

Effects of a functional therapy program on motor abilities of children with cerebral palsy.

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether the motor abilities of children with spastic cerebral palsy who were receiving functional physical therapy (physical therapy with an emphasis on practicing functional activities) improved more than the motor abilities of children in a reference group whose physical therapy was based on the principle of normalization of the quality of movement. SUBJECTS: The subjects were 55 children with mild or moderate cerebral palsy aged 2 to 7 years (median=55 months). METHODS: A randomized block design was used to assign the children to the 2 groups. After a pretest, the physical therapists for the functional physical therapy group received training in the systematic application of functional physical therapy. There were 3 follow-up assessments: 6, 12, and 18 months after the pretest. Both basic gross motor abilities and motor abilities in daily situations were studied, using the Gross Motor Function Measure (GMFM) and the self-care and mobility domains of the Pediatric Evaluation of Disability Inventory (PEDI), respectively. RESULTS: Both groups had improved GMFM and PEDI scores after treatment. No time x group interactions were found on the GMFM. For the PEDI, time x group interactions were found for the functional skills and caregiver assistance scales in both the self-care and mobility domains. DISCUSSION AND CONCLUSION: The groups' improvements in basic gross motor abilities, as measured by the GMFM in a standardized environment, did not differ. When examining functional skills in daily situations, as measured by the PEDI, children in the functional physical therapy group improved more than children in the reference group.     

Validation of the Dutch Giving Youth a Voice Questionnaire (GYV-20): a measure of the client-centredness of rehabilitation services from an adolescent perspective

PURPOSE. The objective was to validate the Dutch translation of the Canadian Giving Youth a Voice Questionnaire (GYV-20) for use in paediatric rehabilitation settings in The Netherlands. The GYV-20 consists of 20 items (assessing four domains) and was designed to evaluate the client-centredness of rehabilitation services from an adolescent perspective. METHOD. The construct validity, concurrent validity, and reliability of the Dutch GYV-20 were determined. Participants were 116 youngsters aged 11 - 21 years (Mean = 15.9; SD = 2.1) recruited through six paediatric rehabilitation settings in The Netherlands. RESULTS. Correlations between the GYV-20 scale scores were positive (r = 0.69 - 0.78). The GYV-20 showed adequate internal consistency, with Cronbach's alpha ranging from 0.76 - 0.81. The ICCs of test-retest reliability ranged from 0.82 - 0.92, which demonstrated good stability of the GYV-20. Dutch adolescents judged the GYV-20 as a valuable and useful tool to evaluate rehabilitation services in The Netherlands. CONCLUSIONS. The Dutch GYV-20 showed sufficient evidence of construct validity and good reliabilities. The Dutch GYV-20 offers users a useful measurement option for various research and clinical purposes.     

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

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Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance

Hereditary diffuse gastric cancer (HDGC) is a relatively rare disorder, with a mutated CDH1 gene as the only known cause. Carriers of a germline mutation in CDH1 have a lifetime risk of >80% of developing diffuse gastric cancer. As periodic gastric surveillance is of limited value in detecting early stages of HDGC, prophylactic gastrectomy is advised for this patient group. Little is known about other types of familial gastric cancer. The Dutch working group on hereditary gastric cancer has formulated guidelines for various aspects of medical management for families and individuals at high risk of developing gastric cancer, including criteria for referral, classification, diagnostics, and periodic gastric surveillance. These guidelines are not limited to HDGC and are therefore partially complementary to the guidelines on hereditary diffuse gastric cancer of the international gastric cancer linkage consortium (IGCLC 2010). In order to optimize the care and increase the knowledge on hereditary gastric cancer it is important to centralize medical care for these patients. National and international collaboration is warranted to improve the quality of research by increasing the size of study cohorts.