Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.

PURPOSE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.

Boric acid and Molybdenum trioxide synergistically stimulate osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells.

INTRODUCTION: Metals and their metal ions have been shown to exhibit certain biological functions that make them attractive for use in biomaterials, for example in bone tissue engineering (BTE) applications. Recent data shows that Molybdenum (Mo) is a potent inducer of osteogenic differentiation in human bone marrow-derived mesenchymal stromal cells (BMSCs). On the other hand, while boron (B) has been shown to enhance vascularization in BTE applications, its impact on osteogenic differentiation is volatile: while improved osteogenic differentiation has been described, other data show that B might slow down osteogenic differentiation or reduce the calcification of the extracellular matrix (ECM) when applied in higher doses. Still, the combination of pro-osteogenic Mo and pro-angiogenic B is certainly attractive in the context of biomaterials intended for the use in BTE. METHODS: Therefore, the combined effect of molybdenum trioxide and boric acid at different ratios was investigated in this study to evaluate the effects on the viability, proliferation, osteogenic differentiation, ECM production and maturation of BMSCs. RESULTS: Mo ions proved to be stronger osteoinductive compared to B, in fact, while some osteogenic differentiation markers were downregulated in the presence of B, the presence of Mo provided compensation. The combined application of B and Mo indicated a combination of individual effects, partially even enhancing the expected combined performance of the single stimulations. CONCLUSIONS: The combination of B and Mo might be beneficial for BTE applications since the limited osteogenic properties of B can be compensated by Mo. Furthermore, since B is known to be pro-angiogenic, the combination of both substances may synergistically lead to improved vascularization and bone regeneration. Future studies should assess the angiogenic performance of this combination in greater detail.

Catheter Directed Thrombectomy and Other Deep Venous Interventions in Cancer Patients.

Treating cancer patients with deep venous thrombosis/venous thromboembolism (DVT/VTE) can be challenging as patients are frequently unable to receive the standard therapy of anticoagulation due to the increased risk of bleeding complications seen in this population. Similarly, the hesitation of interventionalists to use thrombolytic agents due to bleeding risks limits percutaneous intervention options as well. Further, outcome data and guidelines do not exist for oncologic patients and often treatment is tailored to patient-specific factors after multidisciplinary discussion. This article reviews specific factors to consider when planning percutaneous treatment of cancer patients with DVT/VTE, focusing on the iliocaval system.

Predictors for Nonhome Patient Discharge following Lower Extremity Arterial Interventions.

PURPOSE: To identify the variables associated with patient discharge disposition to optimize postprocedural care and discharge planning following lower extremity arterial interventions for peripheral artery disease (PAD). MATERIALS AND METHODS: The 2014-2017 American College of Surgeons National Surgical Quality Improvement Program database was queried using current procedural terminology codes for endovascular infrainguinal interventions for PAD. The main outcome variable of interest was nonhome discharge. Covariates included patient sociodemographic variables, age quartile (upper quartile, ≥77 years), comorbidities (diabetes, renal disease, bleeding disorder, congestive heart failure [CHF], and chronic obstructive pulmonary disease), presence of an open wound before a procedure, type of procedure, operative time, symptom severity, American Society of Anesthesiologists class, and baseline functional status. Univariate analysis and multivariate logistic regression were performed on Stata/SE 15.1. RESULTS: A total of 3,190 patients met the inclusion criteria, of whom 664 (20.8%) had nonhome discharge. Multivariate regression revealed that age (odds ratio [OR], 1.9 for the upper age quartile [>77 years]; 95% confidence interval [CI], 1.46-2.50), operative time (OR, 1.2 per increase in quartile; 95% CI, 1.09-1.30), preoperative wound (OR, 1.5; 95% CI, 1.24-1.90), renal failure (OR, 1.7; 95% CI, 1.30-2.14), CHF (OR, 2.2; 95% CI, 1.51-3.24), symptom severity (OR, 1.7; 95% CI, 1.46-1.98), and independent functional status (OR, 0.74; 95% CI, 0.59-0.92; P = .007) were associated with nonhome discharge. All P values were ≤.001 unless otherwise stated. CONCLUSIONS: Prolonged procedural time, the presence of preprocedural wound and patient comorbidities, symptomatology, and baseline functional status may be used to identify patients who will require a nonhome discharge and early discharge planning.

STING regulates BCR signaling in normal and malignant B cells.

STING is an endoplasmic reticulum (ER)-resident protein critical for sensing cytoplasmic DNA and promoting the production of type I interferons; however, the role of STING in B cell receptor (BCR) signaling remains unclear. We generated STING V154M knock-in mice and showed that B cells carrying constitutively activated STING specifically degraded membrane-bound IgM, Igα, and Igß via SEL1L/HRD1-mediated ER-associated degradation (ERAD). B cells with activated STING were thus less capable of responding to BCR activation by phosphorylating Igα and Syk than those without activated STING. When immunized with T-independent antigens, STING V154M mice produced significantly fewer antigen-specific plasma cells and antibodies than immunized wild-type (WT) mice. We further generated B cell-specific STINGKO mice and showed that STINGKO B cells indeed responded to activation by transducing stronger BCR signals than their STING-proficient counterparts. When B cell-specific STINGKO mice were T-independently immunized, they produced significantly more antigen-specific plasma cells and antibodies than immunized STINGWT mice. Since both human and mouse IGHV-unmutated malignant chronic lymphocytic leukemia (CLL) cells downregulated the expression of STING, we explored whether STING downregulation could contribute to the well-established robust BCR signaling phenotype in malignant CLL cells. We generated a STING-deficient CLL mouse model and showed that STING-deficient CLL cells were indeed more responsive to BCR activation than their STING-proficient counterparts. These results revealed a novel B cell-intrinsic role of STING in negatively regulating BCR signaling in both normal and malignant B cells.

Development of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy.

The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against cancer cells is highly variable. To design better therapeutic strategies for B-cell cancer, we systematically compared the ability of these compounds to inhibit the RNase activity of IRE-1 in vitro and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency.

Rose-trellis periosteal release in oral mucosal advancement flaps in pigs.

The aims of this study were to find out whether scoring in a rose-trellis pattern improved the stretch of mucoperiosteal flaps more than conventional scoring in the horizontal plane, and to consider its application in the closure of oroantral communications. Sixteen sections of cadaveric porcine buccal mucoperiosteum were removed from the molar region of the maxilla and mandible. A three-sided flap was raised in the subperiosteal plane, excised, and pinned to a cork board with the periosteal side facing upwards. Eight samples were scored in the horizontal plane (control) using lines perpendicular to the line of simulated advancement, and eight in a rose-trellis or criss-cross pattern. Scoring using a rose-trellis pattern yielded a mean increase in stretch of 24.3% (p=0.0003) when compared with the conventional method. Buccal advancement flaps are widely used to close oroantral communications, and scoring of the mucoperiosteum facilitates the stretching of the tissue over the defect. To be successful, defects should be fully closed to prevent contamination, and closure should be tension-free. In this study, scoring in a rose-trellis pattern increased the stretch of the tissue sample more than scoring in the horizontal plane. The rose-trellis technique therefore could aid the effective closure of oroantral communications.

Review of the Intercollegiate Surgical Curriculum Programme for oral and maxillofacial surgery aesthetics: are we underselling ourselves?

Aesthetic facial surgery is considered to be within the remit of the maxillofacial surgeon but this is not reflected currently in the trainees' curriculum. In contrast, the plastic surgery curriculum demands detailed training in facial aesthetics. In this paper we have compared the UK OMFS, plastics, and otolaryngology curricula, and used the feedback of trainees to suggest a new aesthetics curriculum. Our method was based on the first three steps of Kern's 1998 six-step model of curricula development: identification of problems, assessment of need, and goals or objectives. The cosmetic certification criterion of the Royal College of Surgeons was used as a baseline for comparison. There was huge variation in the detail and specification of the three specialties' curricula: plastics covered 11/11 of the assessed procedures, while OMFS and otolaryngology covered 7/11 And 4/11, respectively. A total of 45 trainees provided feedback and there was an overall consensus that more training in aesthetics would be beneficial, though accessibility to resources would be an issue. With input from the BAOMS aesthetics lead, our ambitious curriculum increases the number of logbooks to reflect our expertise in the head and neck. It also broadens the span of training over all years of specialist training and, most importantly, relaxes the criteria for transferrable skills. Embracing aesthetics as part of the core curriculum will be beneficial for the future of OMFS, and will produce more rounded surgeons at the end of training. Even the most optimistic observers cannot ignore the financial and logistical setbacks that will have to be faced to achieve this, but we hope that this paper will stimulate a discussion.

Unicondylar knee arthroplasty using cobalt-chromium implants in patients with self-reported cutaneous metal hypersensitivity.

AIMS: The treatment of patients with allergies to metal in total joint arthroplasty is an ongoing debate. Possibilities include the use of hypoallergenic prostheses, as well as the use of standard cobalt-chromium (CoCr) alloy. This non-designer study was performed to evaluate the clinical outcome and survival rates of unicondylar knee arthroplasty (UKA) using a standard CoCr alloy in patients reporting signs of a hypersensitivity to metal. PATIENTS AND METHODS: A consecutive series of patients suitable for UKA were screened for symptoms of metal hypersensitivity by use of a questionnaire. A total of 82 patients out of 1737 patients suitable for medial UKA reporting cutaneous metal hypersensitivity to cobalt, chromium, or nickel were included into this study and prospectively evaluated to determine the functional outcome, possible signs of hypersensitivity, and short-term survivorship at a minimum follow-up of 1.5 years. RESULTS: At a mean follow-up of three years (1.5 to 5.7), no local or systemic symptoms of hypersensitivity to metal were observed. One patient underwent revision surgery to a bicondylar prosthesis due to a tibial periprosthetic fracture resulting in a survival rate of 98.8% (95% confidence interval (CI) 91.7 to 99.8; number at risk, 28) at three years with the endpoint of revision for any reason and a survival rate of 97.6% (95% CI 90.6 to 99.3; number at risk, 29) for the endpoint of all reoperations. Clinical outcome was good to excellent with a mean Oxford Knee Score of 42.5 (sd 2.5; 37 to 48). CONCLUSION: This study is the first demonstrating clinical results and survival analysis of UKA using a CoCr alloy in patients with a history of metal hypersensitivity. Functional outcome and survivorship are on a high-level equivalent to those reported for UKA in patients without a history of metal hypersensitivity. No serious local or systemic symptoms of metal hypersensitivity could be detected, and no revision surgery was performed due to an adverse reaction to metal ions.

Endobronchial forceps-assisted complex retrieval of inferior vena cava filters.

OBJECTIVE: The objective of this study was to assess the safety, feasibility, and effectiveness of endobronchial forceps-assisted retrieval of inferior vena cava (IVC) filters when standard retrieval techniques fail. METHODS: An Institutional Review Board-approved single-center retrospective review during a 6-year period identified 60 consecutive patients (23 men and 37 women; mean age, 49.3 years; range, 19-77 years) in whom rigid endobronchial forceps were required for IVC filter retrieval after standard techniques failed. Factors affecting retrieval success, including an embedded or tilted filter, overall dwell time, filter fracture, and caval penetration, were recorded, as were success rates, procedural details, and complications. RESULTS: Mean dwell time between filter placement and removal was 565 days (range, 15-7366 days). Various IVC filters were encountered: 33 Option (Argon Medical, Frisco, Tex), 8 Celect (Cook Medical, Bloomington, Ind), 9 Günther Tulip (Cook Medical), 4 G2 and 3 Eclipse (Bard, Murray Hill, NJ), 2 OptEase (Cordis, Bridgewater, NJ), and 1 Simon Nitinol (Bard). Imaging before retrieval showed grade 1 (3/60), grade 2 (44/60), and grade 3 (13/60) filter interaction with IVC wall. The degree of secondary tilt as assessed on images acquired before attempted retrieval was <10 degrees (n = 22; 36.7%), 10 to 20 degrees (n = 26; 43.3%), and >20 degrees (n = 12; 20%), with an average tilt of 13.8 degrees (range, 0-48.9 degrees). Of the 60 filters, 58 were retrieved successfully (96.7%). Two of these required a second attempt (one because of migration into the right atrium and the other because of extreme discomfort of the patient requiring subsequent general anesthesia). Five of 60 procedures were forceps-assisted loop snare retrievals in which the forceps were used to dissect the embedded hook free from surrounding hyperplastic caval venous endothelium. Mean fluoroscopy retrieval time was 33.2 minutes (range, 10-76.9 minutes). Intraprocedural inconsequential filter fracture was observed in 10 patients. There were four complications: one retroperitoneal hemorrhage, one IVC dissection flap, and two filter fractures with subsequent migration of filter components to the right side of the heart and to the right pulmonary artery. The first two complications required hospital admission and conservative management; in the last two, the fractured and migrated filter limbs were retrieved successfully using a snare device. CONCLUSIONS: Rigid endobronchial forceps can be safely and reliably used to remove embedded, fractured, or tilted retrievable IVC filters from patients in whom standard retrieval techniques are unsuccessful. There is a high success rate and minimal complications. We propose that the degree of filter tilt, caval penetration, and filter fracture are predictive of the need for the use of forceps as a first-line retrieval technique.

Human papillomavirus (HPV) and its vaccine: awareness and opinions of clinical dental students in a UK dental school.

Introduction: Dental clinicians are in a position to educate their patients on the subject of HPV as part of a primary healthcare multidisciplinary team and to detect HPV-related disease. Attention needs to be paid to dental undergraduate teaching on the topic. This study aims to ascertain awareness and opinions of our dental undergraduate students about HPV, its relation to oral health and its vaccine. Method: A questionnaire was distributed to undergraduate dental students in clinical years 3, 4 and 5 of the BDS programme at Bristol Dental School. Results: Dental students demonstrated an understanding of HPV and oropharyngeal cancer and expressed that they felt dentists should play a role in health promotion in relation to oropharyngeal cancers. They also wished for more teaching on the subject and suggested topic areas that they wished to know more about. Conclusion: New teaching strategies on the topic of HPV should be considered for inclusion into undergraduate dental programmes and encompass both knowledge and communication skills training to prepare future dentists for their role in confronting this preventable disease.

Complications of endovascular aneurysm repair of the thoracic and abdominal aorta: evaluation and management.

In recent decades, endovascular aneurysm repair or endovascular aortic repair (EVAR) has become an acceptable alternative to open surgery for the treatment of thoracic and abdominal aortic aneurysms and other aortic pathologies such as the acute aortic syndromes (e.g., penetrating aortic ulcer, intramural hematoma, dissection). Available data suggest that endovascular repair is associated with lower perioperative 30-day all-cause mortality as well as a significant reduction in perioperative morbidity when compared to open surgery. Additionally, EVAR leads to decreased blood loss, eliminates the need for cross-clamping the aorta and has shorter recovery periods than traditional surgery. It is currently the preferred mode of treatment of thoracic and abdominal aortic aneurysms in a subset of patients who meet certain anatomic criteria conducive to endovascular repair. The main disadvantage of EVAR procedures is the high rate of post-procedural complications that often require secondary re-intervention. As a result, most authorities recommend lifelong imaging surveillance following repair. Available surveillance modalities include conventional radiography, computed tomography, magnetic resonance angiography, ultrasonography, nuclear imaging and conventional angiography, with computed tomography currently considered to be the gold standard for surveillance by most experts. Following endovascular abdominal aortic aneurysm (AAA) repair, the rate of complications is estimated to range between 16% and 30%. The complication rate is higher following thoracic EVAR (TEVAR) and is estimated to be as high as 38%. Common complications include both those related to the endograft device and systemic complications. Device-related complications include endoleaks, endograft migration or collapse, kinking and/or stenosis of an endograft limb and graft infection. Post-procedural systemic complications include end-organ ischemia, cerebrovascular and cardiovascular events and post-implantation syndrome. Secondary re-interventions are required in approximately 19% to 24% of cases following endovascular abdominal and thoracic aortic aneurysm repair respectively. Typically, most secondary reinterventions involve the use of percutaneous techniques such as placement of cuff extension devices, additional endograft components or stents, enhancement of endograft fixation, treatment of certain endoleaks using various embolization techniques and embolic agents and thrombolysis of occluded endograft components. Less commonly, surgical conversion and/or open surgical modification are required. In this article, we provide an overview of the most common complications that may occur following endovascular repair of thoracic and AAAs. We also summarize the current surveillance recommendations for detecting and evaluating these complications and discuss various current secondary re-intervention approaches that may typically be employed for treatment.

Mid-term results of lateral unicondylar mobile bearing knee arthroplasty: a multicentre study of 363 cases.

AIMS: The aim of this independent multicentre study was to assess the mid-term results of mobile bearing unicondylar knee arthroplasty (UKA) for isolated lateral osteoarthritis of the knee joint. PATIENTS AND METHODS: We retrospectively evaluated 363 consecutive, lateral UKAs (346 patients) performed using the Oxford domed lateral prosthesis undertaken in three high-volume knee arthroplasty centres between 2006 and 2014. Mean age of the patients at surgery was 65 years (36 to 88) with a mean final follow-up of 37 months (12 to 93) RESULTS: A total of 36 (10.5%) patients underwent revision surgery, giving a survival rate of 90.1% at three years (95% confidence intervals (CI) 86.1 to 93.1; number at risk: 155) and 85.0% at five years (95% CI 77.9 to 89.9; number at risk: 43). Dislocation of the mobile bearing occurred in 18 patients (5.6%) at three years (95% CI 1.0 to 16.4; number at risk: 154) and in 20 patients (8.5%) at five years (95% CI 1.0 to 27.0; number at risk: 42). There were no significant differences in the dislocation rate between the participating centres or the surgeons. We were not able to identify an effect of each surgeon's learning curve on the dislocation rate of the mobile bearing. The clinical outcome in patients without revision surgery at final follow-up was good to excellent, with a mean Oxford knee score of 40.3 (95% CI 39.4 to 41.2), a mean Tegner activity score of 3.2 (95% CI 3.1 to 3.3) and a mean University of California, Los Angeles score of 5.7 (95% CI 5.5 to 5.9). CONCLUSION: Our data, which consists of a high number of patients treated with mobile bearing UKA in the lateral compartment, indicates a high revision rate of 15% at five years with dislocation of the mobile bearing being the main reason for implant failure. Despite the good functional and clinical results and the high patient satisfaction in our study group, we therefore discontinued using mobile-bearing lateral UKA in favour of a fixed-bearing component. Cite this article: Bone Joint J 2018;100-B:42-9.

Aortic Elongation and Stanford B Dissection: The Tübingen Aortic Pathoanatomy (TAIPAN) Project.

OBJECTIVE/BACKGROUND: Aortic elongation has not yet been considered as a potential risk factor for Stanford type B dissection (TBD). The role of both aortic elongation and dilatation in patients with TBD was evaluated. METHODS: The aortic morphology of a healthy control group (n = 236) and patients with TBD (n = 96) was retrospectively examined using three dimensional computed tomography imaging. Curved multiplanar reformats were used to examine aortic diameters at defined landmarks and aortic segment lengths. RESULTS: Diameters at all landmarks were significantly larger in the TBD group. The greatest diameter difference (56%) was measured in dissected descending aortas (p < .001). The segment with the most considerable difference between the study groups with regard to elongation was the non-dissected aortic arch of patients with TBD (36%; p < .001). Elongation in the aortic arch was accompanied by a diameter increase of 21% (p < .001). In receiver-operating curve analysis, the area under the curve was .85 for the diameter and .86 for the length of the aortic arch. CONCLUSIONS: In addition to dilatation, aortic arch elongation is associated with the development of TBD. The diameter and length of the non-dissected aortic arch may be predictive for TBD and may possibly be used for risk assessment in the future. This study provides the basis for further prospective evaluation of these parameters.