Higher Adalimumab Concentration is Associated with Complete Fistula Healing in Patients with Perianal Fistulizing Crohn's Disease.

Perianal fistulas can develop in around 30% of patients with Crohn's disease (CD) and are associated with impaired quality of life and worse outcomes including increased rates of hospitalizations and surgeries.1 The cornerstone of pharmacologic treatment for perianal fistulizing CD is anti-tumor necrosis factor therapy, mainly infliximab and adalimumab (ADM).2 Therapeutic drug monitoring (TDM) can be used to identify potential pharmacokinetic and pharmacodynamic issues and avoid or manage unwanted outcomes, such as primary nonresponse and secondary loss of response.3 There are several exposure-response relationship data demonstrating a positive correlation between serum infliximab concentrations and favorable objective therapeutic outcomes in patients with perianal fistulizing CD.4 Nevertheless, there are only limited data, which is mostly from small retrospective studies regarding the association of ADM concentration and outcomes in patients with perianal fistulizing CD.4-8 Furthermore, the optimal ADM concentration for fistula healing still remains to be elucidated. This is clinically important because drug concentration cutoffs are used in reactive and proactive TDM algorithms to define therapeutic drug concentrations. This study investigates the association of maintenance ADM concentrations with complete fistula healing (CFH) and identifies an optimal ADM concentration threshold for CFH.

The race that never slows: Otolaryngology - Head and Neck Surgery residency applicant parameters over time.

Background: There has been an increasing number of Canadian medical graduates who have gone unmatched in the residency selection process. Medical students have been engaging in extracurricular activities outside the formal curriculum which may help to distinguish themselves from their peers in the selection process. To understand how competitiveness in residency selection shapes applicant demographic characteristics and behaviours, this study set out to explore the demographic characteristics and prevalence of reported extra-curricular activities by applicants to Canadian Otolaryngology - Head & Neck Surgery (OTL-HNS) residency across time. Methods: A retrospective, descriptive study reviewed specific sections of the curriculum vitae (CV) of applicants to OTL-HNS programs in Canada. These sections were self-reported, and included research productivity, involvement in volunteer and leadership activities, membership in associations, and honours or awards granted. Data was quantified and analyzed descriptively. Results: Between 2013 to 2017, a total of 267 applicants reported a median of 12.6 research publications, 9.6 volunteer activities, six leadership activities, six association memberships and 9.8 honours/awards. Applicants were younger over time, with proportions of applicants over 30 years old decreasing from 56% in 2013 to 9% in 2017. Conclusion: Applicants to Canadian OTL-HNS residency programs are reporting consistently high numbers of extracurricular activities and were of increasingly younger ages. Medical students are investing significant time and energy to pursue these activities which are above and beyond the formal curriculum, possibly contributing to decreased diversity in applicants for competitive residencies, increasing the likelihood of misrepresentation in residency applications, and likely contributing to medical student burnout.

Contexte: De plus en plus de diplômés en médecine canadiens demeurent non jumelés à l'issue du processus de sélection des résidents. Certains font des activités hors programme afin de se distinguer de leurs pairs dans le processus de sélection. Pour comprendre comment la compétition dans la sélection de résidents influence les caractéristiques démographiques et les comportements des candidats, cette étude visait à explorer l'évolution des caractéristiques démographiques et la prévalence d'activités hors programme déclarées par les candidats à la résidence en oto-rhino-laryngologie ­ chirurgie cervico-faciale (ORL-CCF) à travers le temps. Méthodes: Dans le cadre d'une étude rétrospective et descriptive, nous avons parcouru des sections pertinentes du curriculum vitae (CV) des candidats aux programmes d'oto-rhino-laryngologie et chirurgie cervico-faciale au Canada. Ces sections étaient auto-déclarées et comprenaient les activités de recherche, la participation à des activités de bénévolat et de leadership, l'appartenance à des associations et les prix et distinctions obtenus. Les données ont été quantifiées et analysées de manière descriptive. Résultats: Entre 2013 et 2017, un total de 267 candidats ont déclaré une médiane de 12,6 publications de recherche, 9,6 activités de bénévolat, 6 activités de leadership, 6 adhésions à des associations et 9,8 prix et distinctions. Au fil du temps, on observe que les candidats sont de plus en plus jeunes ; ainsi, la proportion de candidats âgés de 30 ans et plus a diminué de 56 % en 2013 à 9 % en 2017. Conclusion: Les candidats aux programmes de résidence en ORL-CCF au Canada déclarent d'une année à l'autre un nombre élevé d'activités hors programme et sont de plus en plus jeunes. Les étudiants en médecine investissent beaucoup de temps et d'énergie dans ces activités qui vont au-delà du programme d'études officiel. Cela pourrait nuire à la diversité des candidats aux programmes de résidence fortement contingentés, augmenter la probabilité de fausses déclarations dans les demandes de résidence et probablement contribuer à l'épuisement professionnel des étudiants en médecine.

Portrait of DNA methylated genes predictive of poor prognosis in head and neck cancer and the implication for targeted therapy.

In addition to chronic infection with human papilloma virus (HPV) and exposure to environmental carcinogens, genetic and epigenetic factors act as major risk factors for head and neck cancer (HNC) development and progression. Here, we conducted a systematic review in order to assess whether DNA hypermethylated genes are predictive of high risk of developing HNC and/or impact on survival and outcomes in non-HPV/non-tobacco/non-alcohol associated HNC. We identified 85 studies covering 32,187 subjects where the relationship between DNA methylation, risk factors and survival outcomes were addressed. Changes in DNA hypermethylation were identified for 120 genes. Interactome analysis revealed enrichment in complex regulatory pathways that coordinate cell cycle progression (CCNA1, SFN, ATM, GADD45A, CDK2NA, TP53, RB1 and RASSF1). However, not all these genes showed significant statistical association with alcohol consumption, tobacco and/or HPV infection in the multivariate analysis. Genes with the most robust HNC risk association included TIMP3, DCC, DAPK, CDH1, CCNA1, MGMT, P16, MINT31, CD44, RARß. From these candidates, we further validated CD44 at translational level in an independent cohort of 100 patients with tongue cancer followed-up beyond 10 years. CD44 expression was associated with high-risk of tumor recurrence and metastasis (P = 0.01) in HPV-cases. In summary, genes regulated by methylation play a modulatory function in HNC susceptibility and it represent a critical therapeutic target to manage patients with advanced disease.

Molecular testing for cytologically suspicious and malignant (Bethesda V and VI) thyroid nodules to optimize the extent of surgical intervention: a retrospective chart review.

BACKGROUND: Molecular testing has been used for cytologically indeterminate thyroid nodules (Bethesda III and IV), where the risk of malignancy is 10-40%. However, to date, the role of molecular testing in cytologically suspicious or positive for malignancy (Bethesda V and VI) thyroid nodules has been controversial. The aim of this study was to determine whether patients who had molecular testing in Bethesda V and VI thyroid nodules had the optimal extent of surgery performed more often than patients who did not have molecular testing performed. METHODS: A retrospective chart review of 122 cases was performed: 101 patients from the McGill University teaching hospitals and 21 patients from the Hillel Yaffe Medical center, Technion University. Patients included in the study were those with Bethesda V or VI thyroid nodules who underwent molecular testing (ThyGenext® or ThyroseqV3®) (McGill n = 72, Hillel Yaffe n = 14). Patients with Bethesda V or VI thyroid nodules who did not undergo molecular testing were used as controls (McGill n = 29, Hillel Yaffe n = 7). Each case was reviewed in order to determine whether the patient had optimal surgery. This was defined as total thyroidectomy in the presence of either a positive lymph node, extrathyroidal extension, or an aggressive pathological variant of papillary thyroid carcinoma (tall cell, hobnail, columnar cell, diffuse sclerosing, and solid/trabecular) documented on the final pathology report. In all other cases, a lobectomy/hemi/subtotal thyroidectomy was considered as optimal surgery. Chi-squared testing was performed to compare groups. RESULTS: When molecular testing was done, 91.86% (79/86) of surgeries in the molecular testing group were optimal, compared to 61.11% (22/36) in the control group. At McGill University teaching hospitals and at Hillel Yaffe, 91.67% (66/72) and 92.86% (13/14) of surgeries in the intervention group were considered as optimal, respectively. This compares to 58.62% (17/29) at McGill and 71.43% (5/7) at Hillel Yaffe when molecular testing was not performed (p = .001, p = .186). CONCLUSIONS: In this study, molecular testing in Bethesda V and VI thyroid tumors significantly improved the likelihood of optimal surgery. Therefore, molecular testing may have an important role in optimizing surgical procedures performed in the setting of Bethesda V and VI thyroid nodules. Prospective studies with larger sample sizes are required to further investigate this finding.

Co-Overexpression of TWIST1-CSF1 Is a Common Event in Metastatic Oral Cancer and Drives Biologically Aggressive Phenotype.

Invasive oral squamous cell carcinoma (OSCC) is often ulcerated and heavily infiltrated by pro-inflammatory cells. We conducted a genome-wide profiling of tissues from OSCC patients (early versus advanced stages) with 10 years follow-up. Co-amplification and co-overexpression of TWIST1, a transcriptional activator of epithelial-mesenchymal-transition (EMT), and colony-stimulating factor-1 (CSF1), a major chemotactic agent for tumor-associated macrophages (TAMs), were observed in metastatic OSCC cases. The overexpression of these markers strongly predicted poor patient survival (log-rank test, p = 0.0035 and p = 0.0219). Protein analysis confirmed the enhanced expression of TWIST1 and CSF1 in metastatic tissues. In preclinical models using OSCC cell lines, macrophages, and an in vivo matrigel plug assay, we demonstrated that TWIST1 gene overexpression induces the activation of CSF1 while TWIST1 gene silencing down-regulates CSF1 preventing OSCC invasion. Furthermore, excessive macrophage activation and polarization was observed in co-culture system involving OSCC cells overexpressing TWIST1. In summary, this study provides insight into the cooperation between TWIST1 transcription factor and CSF1 to promote OSCC invasiveness and opens up the potential therapeutic utility of currently developed antibodies and small molecules targeting cancer-associated macrophages.