Non-oral manifestations in adults with a clinical and molecularly confirmed diagnosis of periodontal Ehlers-Danlos syndrome.

Introduction: Periodontal Ehlers-Danlos Syndrome (pEDS) is a rare autosomal dominant type of EDS characterised by severe early-onset periodontitis, lack of attached gingiva, pretibial plaques, joint hypermobility and skin hyperextensibility as per the 2017 International EDS Classification. In 2016, deleterious pathogenic heterozygous variants were identified in C1R and C1S, which encode components of the complement system. Materials and Methods: Individuals with a clinical suspicion of pEDS were clinically and molecularly assessed through the National EDS Service in London and Sheffield and in genetic services in Austria, Sweden and Australia. Transmission electron microscopy and fibroblast studies were performed in a small subset of patients. Results: A total of 21 adults from 12 families were clinically and molecularly diagnosed with pEDS, with C1R variants in all families. The age at molecular diagnosis ranged from 21-73 years (mean 45 years), male: female ratio 5:16. Features of easy bruising (90%), pretibial plaques (81%), skin fragility (71%), joint hypermobility (24%) and vocal changes (38%) were identified as well as leukodystrophy in 89% of those imaged. Discussion: This cohort highlights the clinical features of pEDS in adults and contributes several important additional clinical features as well as novel deleterious variants to current knowledge. Hypothetical pathogenic mechanisms which may help to progress understanding and management of pEDS are also discussed.

Developing a digitally innovative ethics and professionalism curriculum for neonatal-perinatal medicine fellows: a 3-year multicenter pilot study.

OBJECTIVES: The purpose of this study was to develop and regionally pilot a digitally innovative curriculum in ethics and professionalism in neonatology and study the effects on trainee knowledge and confidence. STUDY DESIGN: We developed 13 modules in ethics for neonatology fellows and piloted them at three academic institutions utilizing a flipped-classroom approach. Baseline surveys in ethics knowledge and confidence in approaching ethical dilemmas were compared with repeat surveys after curriculum completion. Pre- and post-tests were also administered for all 13 modules. RESULTS: Forty-four of 49 eligible fellows participated (90% response rate). Pre/post comparisons demonstrated significant improvements in overall knowledge and in 8/13 modules, as well as improvement in overall confidence and individually when navigating 16/22 ethical dilemmas. CONCLUSIONS: After completing this curriculum, participants' knowledge scores and reported confidence in approaching ethical challenges significantly improved. Future steps include assessing the effects of this innovative curriculum via an ongoing international pilot.

Transcriptomic analysis of hepatocellular carcinoma reveals molecular features of disease progression and tumor immune biology.

Hepatocellular carcinoma (HCC) develops in the context of chronic inflammatory liver disease and has an extremely poor prognosis. An immunosuppressive tumor microenvironment may contribute to therapeutic failure in metastatic HCC. Here, we identified unique molecular signatures pertaining to HCC disease progression and tumor immunity by analyzing genome-wide RNA-Seq data derived from HCC patient tumors and non-tumor cirrhotic tissues. Unsupervised clustering of gene expression data revealed a gradual suppression of local tumor immunity that coincided with disease progression, indicating an increasingly immunosuppressive tumor environment during HCC disease advancement. IHC examination of the spatial distribution of CD8+ T cells in tumors revealed distinct intra- and peri-tumoral subsets. Differential gene expression analysis revealed an 85-gene signature that was significantly upregulated in the peri-tumoral CD8+ T cell-excluded tumors. Notably, this signature was highly enriched with components of underlying extracellular matrix, fibrosis, and epithelial-mesenchymal transition (EMT). Further analysis condensed this signature to a core set of 23 genes that are associated with CD8+ T cell localization, and were prospectively validated in an independent cohort of HCC specimens. These findings suggest a potential association between elevated fibrosis, possibly modulated by TGF-ß, PDGFR, SHH or Notch pathway, and the T cell-excluded immune phenotype. Indeed, targeting fibrosis using a TGF-ß neutralizing antibody in the STAM™ model of murine HCC, we found that ameliorating the fibrotic environment could facilitate redistribution of CD8+ lymphocytes into tumors. Our results provide a strong rationale for utilizing immunotherapies in HCC earlier during treatment, potentially in combination with anti-fibrotic therapies.

Global Curriculum in Research Literacy for the Surgical Oncologist.

BACKGROUND: The ability to provide optimal care to cancer patients depends on awareness of current evidence-based practices emanating from research or involvement in research where circumstances permit. The significant global variations in cancer-related research activity and its correlation to cancer-specific outcomes may have an influence on the care provided to cancer patients and their outcomes. The aim of this project is to develop a global curriculum in research literacy for the surgical oncologist. MATERIALS AND METHODS: The leadership of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in research literacy for the Surgical Oncologist. RESULTS: A global curriculum in research literacy is developed to incorporate the required domains considered to be essential to interpret the published research or become involved in research activity where circumstances permit. The purpose of this curriculum is to promote research literacy for the surgical oncologist, wherever they are based. It does not mandate direct research participation which may not be feasible due to restrictions within the local health-care delivery environment, socio-economic priorities and the educational environment of the individual institution where they work. CONCLUSIONS: A global curriculum in research literacy is proposed which may promote research literacy or encourage involvement in research activity where circumstances permit. It is hoped that this will enhance cancer-related research activity, promote awareness of optimal evidence-based practices and improve outcomes for cancer patients globally.

Global curriculum in research literacy for the surgical oncologist.

BACKGROUND: The ability to provide optimal care to cancer patients depends on awareness of current evidence-based practices emanating from research or involvement in research where circumstances permit. The significant global variations in cancer-related research activity and its correlation to cancer-specific outcomes may have an influence on the care provided to cancer patients and their outcomes. The aim of this project is to develop a global curriculum in research literacy for the surgical oncologist. MATERIALS AND METHODS: The leadership of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in research literacy for the Surgical Oncologist. RESULTS: A global curriculum in research literacy is developed to incorporate the required domains considered to be essential to interpret the published research or become involved in research activity where circumstances permit. The purpose of this curriculum is to promote research literacy for the surgical oncologist, wherever they are based. It does not mandate direct research participation which may not be feasible due to restrictions within the local health-care delivery environment, socio-economic priorities and the educational environment of the individual institution where they work. CONCLUSIONS: A global curriculum in research literacy is proposed which may promote research literacy or encourage involvement in research activity where circumstances permit. It is hoped that this will enhance cancer-related research activity, promote awareness of optimal evidence-based practices and improve outcomes for cancer patients globally.

Global curriculum in surgical oncology.

BACKGROUND: The significant global variations in surgical oncology training paradigms can have a detrimental effect on tackling the rising global cancer burden. While some variations in training are essential to account for the differences in types of cancer and biology, the fundamental principles of providing care to a cancer patient remain the same. The development of a global curriculum in surgical oncology with incorporated essential standards could be very useful in building an adequately trained surgical oncology workforce, which in turn could help in tackling the rising global cancer burden. MATERIALS AND METHODS: The leaders of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in surgical oncology. RESULTS: A global curriculum in surgical oncology was developed to incorporate the required domains considered to be essential in training a surgical oncologist. The curriculum was constructed in a modular fashion to permit flexibility to suit the needs of the different regions of the world. Similarly, recognizing the various sociocultural, financial and cultural influences across the world, the proposed curriculum is aspirational and not mandatory in intent. CONCLUSIONS: A global curriculum was developed which may be considered as a foundational scaffolding for training surgical oncologists worldwide. It is envisioned that this initial global curriculum will provide a flexible and modular scaffolding that can be tailored by individual countries or regions to train surgical oncologists in a way that is appropriate for practice in their local environment.

Practices and education surrounding anticipated periviable deliveries among neonatal-perinatal medicine and maternal-fetal medicine fellowship programs.

OBJECTIVES: To explore national practices of periviable decision-making and care, and to determine and compare trainee education in this domain, within neonatal-perinatal medicine (NPP) and maternal-fetal medicine (MFMP) fellowship programs. STUDY DESIGN: A 75-item survey was sent to NPP and MFMP program directors in the United States. RESULTS: In all, 79 of 168 surveys were completed (47%). MFMPs reported offering active interventions for bigger or more mature fetuses (versus NPPs). Variability exists in estimated frequency of simultaneous antenatal counseling by both specialties (range 0 to 90%) and of inter-specialty communication before consultation (range 5 to 100%). One-quarter of MFMPs reported no fellow education regarding periviable deliveries, versus 2% of NPPs (P=0.002); 40% of MFMPs teach fellows about periviable ethics, versus 63% of NPPs (P=0.05). NPPs more frequently utilize role modeling (P=0.01) and simulation (P=0.01) as learning methods. CONCLUSION: NPPs and MFMPs report different, often asynchronous, practices and fellow education regarding antenatal counseling and resuscitation at periviability.

Variations in training of surgical oncologists: Proposal for a global curriculum.

BACKGROUND: The global cancer burden is predicted to rise significantly over the next few decades. While there are several barriers to providing optimal cancer care on the global stage, some are related to the absence of an adequately trained workforce. This could be attributed in part to the significant global variations in the training of surgical oncology professionals. There are currently no published data mapping the training pathways for surgical oncologists for all countries in the world. The aims of this descriptive article are to report on the training paradigms in surgical oncology for all countries in the world, and to correlate the influence of economic standing on these training paradigms. MATERIALS AND METHODS: The training paradigms for all countries in the world were analyzed and categorized on the basis of the six World Health Organization geographic regions and economic standing stratified by the Human Development Index. RESULTS: Data on the training paradigms were obtained for 174 countries from a total of 211 (82%). We noted extremely significant and concerning variations in the length, availability and structure of training paradigms depending on the geographic region and economic standing. CONCLUSIONS: The results of our study demonstrated significant global variations in the training paradigms of surgical oncologists. These variations call for a global curriculum which has been developed by the Society of Surgical Oncology and the European Society of Surgical Oncology. It is hoped that this curriculum will serve a role in streamlining education to tackle the rising global cancer burden.

Variations in Training of Surgical Oncologists: Proposal for a Global Curriculum.

BACKGROUND: The global cancer burden is predicted to rise significantly over the next few decades. While there are several barriers to providing optimal cancer care on the global stage, some are related to the absence of an adequately trained workforce. This could be attributed in part to the significant global variations in the training of surgical oncology professionals. There are currently no published data mapping the training pathways for surgical oncologists for all countries in the world. The aims of this descriptive article are to report on the training paradigms in surgical oncology for all countries in the world, and to correlate the influence of economic standing on these training paradigms. MATERIALS AND METHODS: The training paradigms for all countries in the world were analyzed and categorized on the basis of the six World Health Organization geographic regions and economic standing stratified by the Human Development Index. RESULTS: Data on the training paradigms were obtained for 174 countries from a total of 211 (82 %). We noted extremely significant and concerning variations in the length, availability and structure of training paradigms depending on the geographic region and economic standing. CONCLUSIONS: The results of our study demonstrated significant global variations in the training paradigms of surgical oncologists. These variations call for a global curriculum which has been developed by the Society of Surgical Oncology and the European Society of Surgical Oncology. It is hoped that this curriculum will serve a role in streamlining education to tackle the rising global cancer burden. © 2016 Society of Surgical Oncology and the European Society of Surgical Oncology. Published by SpringerNature. All rights reserved.

Global Curriculum in Surgical Oncology.

BACKGROUND: The significant global variations in surgical oncology training paradigms can have a detrimental effect on tackling the rising global cancer burden. While some variations in training are essential to account for the differences in types of cancer and biology, the fundamental principles of providing care to a cancer patient remain the same. The development of a global curriculum in surgical oncology with incorporated essential standards could be very useful in building an adequately trained surgical oncology workforce, which in turn could help in tackling the rising global cancer burden. MATERIALS AND METHODS: The leaders of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in surgical oncology. RESULTS: A global curriculum in surgical oncology was developed to incorporate the required domains considered to be essential in training a surgical oncologist. The curriculum was constructed in a modular fashion to permit flexibility to suit the needs of the different regions of the world. Similarly, recognizing the various sociocultural, financial and cultural influences across the world, the proposed curriculum is aspirational and not mandatory in intent. CONCLUSIONS: A global curriculum was developed which may be considered as a foundational scaffolding for training surgical oncologists worldwide. It is envisioned that this initial global curriculum will provide a flexible and modular scaffolding that can be tailored by individual countries or regions to train surgical oncologists in a way that is appropriate for practice in their local environment. © 2016 Society of Surgical Oncology and the European Society of Surgical Oncology. Published by SpringerNature. All rights reserved.

Ethics and professionalism education during neonatal-perinatal fellowship training in the United States.

OBJECTIVE: The objectives of this study were to determine the perceived adequacy of ethics and professionalism education for neonatal-perinatal fellows in the United States, and to measure confidence of fellows and recent graduates when navigating ethical issues. STUDY DESIGN: Neonatal-Perinatal Fellowship Directors, fellows and recent graduates were surveyed regarding the quality and type of such education during training, and perceived confidence of fellows/graduates in confronting ethical dilemmas. RESULT: Forty-six of 97 Directors (47%) and 82 of 444 fellows/graduates (18%) completed the surveys. Over 97% of respondents agreed that ethics training is 'important/very important'. Only 63% of Directors and 37% of fellows/graduates rated ethics education as 'excellent/very good' (P=0.004). While 96% of Directors reported teaching of ethics, only 70% of fellows/graduates reported such teaching (P<0.001). Teaching methods and their perceived effectiveness varied widely. CONCLUSION: Training in ethics and professionalism for fellows is important, yet currently insufficient; a more standardized curriculum may be beneficial to ensure that trainees achieve competency.

Stress-caused anergy of leukocytes towards Staphylococcal enterotoxin B and exposure transcriptome signatures.

Leucocytes from soldiers exposed to battlefield-like stress (RASP: Rangers Assessment and Selection Program) were exposed in vitro to Staphylococcal enterotoxin B (SEB). We assayed SEB-induced regulation of gene expression, both in the presence and absence of severe stress, to generate two sets of gene profiles. One set of transcripts and microRNAs were specific to post-RASP SEB exposure, and another set were signatures of SEB exposure common to both the pre- and post-RASP leucocytes. Pathways and upstream regulatory analyses indicated that the post-RASP SEB-signature transcripts were manifestation of the anergic state of post-RASP leucocytes. These were further verified using expression-based predictions of cellular processes and literature searches. Specificity of the second set of transcripts to SEB exposure was verified using machine-learning algorithms on our and four other (Gene Expression Omnibus) data sets. Cell adhesion, coagulation, hypoxia and vascular endothelial growth factor-mediated vascular leakage were SEB-specific pathways even under the background of severe stress. Hsa-miR-155-3p was the top SEB exposure predictor in our data set, and C-X-C motif chemokine ligand 9 was SEB specific in all the analyzed data sets. The SEB-signature transcripts (which also showed distinct expression signatures from Yersinia pestis and dengue virus) may serve as potential biomarkers of SEB exposure even under the background of stress.

Familial clustering of systemic lupus erythematosus in the cayman islands.

OBJECTIVE: To describe the unusual clustering of systemic lupus erythematosus (SLE) in a family from the Cayman Islands. METHOD: An observational retrospective study of SLE was done following an index case of mixed connective tissue disease in a 51-year old West Indian woman of African descent. Her two daughters of the same father, who is of Cayman Islands origin, were also diagnosed with SLE. A family tree was subsequently drawn up to 1890 to identify other cases in the same family. RESULTS: There were 13 cases identified and all occurred between the 6th and the 8th generation. A family tree linked all cases to a man from the Cayman Islands who died in 1890. The nine cases with full medical records showed eight females and one male (8:1). The mean age at diagnosis was 29 years; polyarthritis occured in all nine patients (100%), kidney involvement in 6/9 (66.6%), skin rash in 6/9 (66.6%), pleuritis and pericarditis in 6/9 (66.6%) and anaemia in 6/9 (66.6%). The autoantibodies were mainly ANA in all patients (100%) and anti-dsDNA in 8/9 (88.8%). CONCLUSION: The unusual extensive familial clustering in this study represents the first to be described in a West Indian population where SLE is most prevalent and may suggest a genetic predisposition.

Development of patient-specific molecular imaging phantoms using a 3D printer.

PURPOSE: The aim of the study was to investigate rapid prototyping technology for the production of patient-specific, cost-effective liquid fillable phantoms directly from patient CT data. METHODS: Liver, spleen, and kidney volumes were segmented from patient CT data. Each organ was converted to a shell and filling holes and leg supports were added using computer aided design software and prepared for printing. Additional fixtures were added to the liver to allow lesion inserts to be fixed within the structure. Phantoms were printed from an ultraviolet curable photopolymer using polyjet technology on an Objet EDEN 500V 3D printer. RESULTS: The final print material is a clear solid acrylic plastic which is watertight, rigid, and sufficiently durable to withstand multiple assembly and scanning protocols. Initial scans of the phantoms have been performed with Tc-99m SPECT and F-18 PET/CT. CONCLUSIONS: The organ geometry showed good correspondence with anatomical references. The methodology developed can be generally applied to other anatomical or geometrical phantoms for molecular imaging.

Prevalence of human papillomavirus among oesophageal squamous cell carcinoma cases: systematic review and meta-analysis.

BACKGROUND: Oncogenic human papillomavirus (HPV) has been hypothesised as a risk factor for oesophageal squamous cell carcinoma (OSCC), but aetiological research has been limited by the varying methodology used for establishing HPV prevalence. The aims of this systematic review and meta-analysis were to estimate the prevalence of HPV DNA detected in OSCC tumours and the influence of study characteristics. METHODS: Study-level estimates of overall and type-specific HPV prevalence were meta-analysed to obtain random-effects summary estimates. RESULTS: This analysis included 124 studies with a total of 13 832 OSCC cases. The average HPV prevalence (95% confidence interval) among OSCC cases was 0.277 (0.234, 0.320) by polymerase chain reaction; 0.243 (0.159, 0.326) by in situ hybridisation; 0.304 (0.185, 0.423) by immunohistochemistry; 0.322 (0.154, 0.490) by L1 serology; and 0.176 (0.061, 0.292) by Southern/slot/dot blot. The highest HPV prevalence was found in Africa and Asia, notably among Chinese studies from provinces with high OSCC incidence rates. CONCLUSIONS: Future research should focus on quantifying HPV in OSCC cases using strict quality control measures, as well as determining the association between HPV and OSCC incidence by conducting large, population-based case-control studies. Such studies will provide a richer understanding of the role of HPV in OSCC aetiology.

Tumour biomechanical response to the vascular disrupting agent ZD6126 in vivo assessed by magnetic resonance elastography.

BACKGROUND: Magnetic resonance elastography (MRE) is an emerging imaging technique that affords non-invasive quantitative assessment and visualization of tissue mechanical properties in vivo. METHODS: In this study, MRE was used to quantify (kPa) the absolute value of the complex shear modulus |G*|, elasticity Gd and viscosity Gl of SW620 human colorectal cancer xenografts before and 24 h after treatment with either 200 mg kg(-1) of the vascular disrupting agent ZD6126 (N-acetylcolchinol-O-phosphate) or vehicle control, and the data were compared with changes in water diffusivity measured by diffusion-weighted magnetic resonance imaging. RESULTS: A heterogeneous distribution of |G*|, Gd and Gl was observed pre-treatment with an intertumoral coefficient of variation of 13% for |G*|. There were no significant changes in the vehicle-treated cohort. In contrast, ZD6126 induced a significant decrease in the tumour-averaged |G*| (P<0.01), Gd (P<0.01) and Gl (P<0.05), and this was associated with histologically confirmed central necrosis. This reduction in tumour viscoelasticity occurred at a time when no significant change in tumour apparent diffusion coefficient (ADC) was observed. CONCLUSIONS: These data demonstrate that MRE can provide early imaging biomarkers for treatment-induced tumour necrosis.

A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop.

Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC.