Dynamics of Fibril Collagen Remodeling by Tumor Cells: A Model of Tumor-Associated Collagen Signatures.

Many solid tumors are characterized by a dense extracellular matrix (ECM) composed of various ECM fibril proteins. These proteins provide structural support and a biological context for the residing cells. The reciprocal interactions between growing and migrating tumor cells and the surrounding stroma result in dynamic changes in the ECM architecture and its properties. With the use of advanced imaging techniques, several specific patterns in the collagen surrounding the breast tumor have been identified in both tumor murine models and clinical histology images. These tumor-associated collagen signatures (TACS) include loosely organized fibrils far from the tumor and fibrils aligned either parallel or perpendicular to tumor colonies. They are correlated with tumor behavior, such as benign growth or invasive migration. However, it is not fully understood how one specific fibril pattern can be dynamically remodeled to form another alignment. Here, we present a novel multi-cellular lattice-free (MultiCell-LF) agent-based model of ECM that, in contrast to static histology images, can simulate dynamic changes between TACSs. This model allowed us to identify the rules of cell-ECM physical interplay and feedback that guided the emergence and transition among various TACSs.

Implementing routine use of self-removed ureteric stents on extraction strings: prospective patient-reported outcome measures and complications.

PURPOSE: Ureteric stents placed after ureteroscopy typically require cystoscopy for removal. Stent extraction strings allow the option of patient self-removal. This facilitates shorter stent dwell time, and cost-savings. Concerns regarding safety and limited evidence regarding patient acceptability are speculated reasons for infrequent clinical use of extraction strings. This study investigates our recent experience using routine self-removal of stents on extraction strings to provide evidence to address these concerns. METHODS: In February 2020, our hospital adopted a policy for self-removal of stents on extraction strings to be routine following ureteroscopy. This was influenced by motivation to improve service capacity for diagnostic flexible cystoscopy, hospital avoidance during the pandemic, perceived improvement for the patient experience, and cost-saving. Prospective clinical and patient-reported outcome data were collected and evaluated. RESULTS: There were 168 patients who had stents on extraction strings. Mean stent dwell time was 5.2 ± 1.8 days. Primary ureteroscopy was performed in 40.5%, and 59.5% had procedures using an access sheath. Self-removal at home was successful for 79% of patients. Stent dislodgement rate was 3.0% (5/168) and retained stents due to string detachment occurred in 1.8% (3/168). Almost all indicated they "would remove the stent on string again" (90%, 128/142) and the majority reported stent removal as "very easy" (61%, 87/142). Cost modelling estimates a total saving of AUD $148,869 per annum for routine use of extraction strings at our hospital. CONCLUSION: Our experience reflects that stent extraction strings may be used routinely with acceptable low complication rates, favourable patient experiences and associated cost savings.

Experience of the 'Ear Glove' in children with microtia.

INTRODUCTION: Microtia is a congenital condition which can be found in isolation or as part of a syndrome. The key factors to consider when treating a child with microtia are hearing, speech and language development, cosmesis, and the psychological impact on the patient as well as the family. As children age and become more self-aware, the anxiety about transition from primary to secondary school can often be a trigger for carers and child to want a cosmetic solution at a younger age. Any form of cosmetic surgery ideally requires a child with an understanding of what is involved, as well as sufficient growth and anatomy to provide soft tissue resources for surgery. An additional issue for some children with microtia is the concern about adding to their already 'different' appearance by using a bone conduction solution/hearing implant. We present the outcomes of a novel non-surgical prosthesis 'Ear Glove' offered to pediatric patients with microtia. METHODS: Children with microtia are seen in the multidisciplinary outpatient clinic and reviewed by the team which includes an Otolaryngologist, Audiologist, Plastic surgeon and Maxillofacial prosthetist. When discussing cosmesis, all reconstruction options are explored. These include a 'no treatment' option, both adhesive and implant-retained prosthetic ears, and autologous and/or MedporⓇ ear reconstruction (age appropriate). All children who chose to undergo the adhesive non-surgical prosthetic option 'Ear Glove' for microtia were identified by our prosthetic department (n = 9), and their outcomes reviewed. RESULTS: Nine children have been fitted with the 'Ear Glove', with all 9 achieving excellent symmetry and aesthetics. Seven patients continue to successfully use their prostheses either daily or for special occasions. Two of these patients also decided to undergo bone anchored hearing implant surgery. One patient opted to change his treatment plans and chose 'no treatment' after feeling he preferred his 'little' ears. Finally, one patient reported the daily use of adhesive to be a deterrent. No skin reactions to the adhesive were reported in any patient. CONCLUSIONS: The 'Ear Glove' is increasingly being used by microtia patients in our department to good effect. This non-surgical alternative allows young patients to appreciate the cosmetic results of the surgical options before committing to an invasive procedure.

Proton export upregulates aerobic glycolysis.

INTRODUCTION: Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect." It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. RESULTS: To test this hypothesis, we stably transfected lowly glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton-exporting systems: either PMA1 (plasma membrane ATPase 1, a yeast H+-ATPase) or CA-IX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher-grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. CONCLUSIONS: Therefore, cancer cells which increase export of H+ equivalents subsequently increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards an upregulation of aerobic glycolysis, a Warburg phenotype. Overall, we have shown that the traditional understanding of cancer cells favoring glycolysis and the subsequent extracellular acidification is not always linear. Cells which can, independent of metabolism, acidify through proton exporter activity can sufficiently drive their metabolism towards glycolysis providing an important fitness advantage for survival.

Systematic Review of Medpor Versus Autologous Ear Reconstruction.

ABSTRACT: Ear reconstruction is 1 of the most technically challenging sub-specialties of craniofacial and reconstructive plastic surgery. The reconstructive ear must not only fulfil the requirement of being aesthetically pleasing but must also have good vascularity with a low complication rate. Several ear reconstructive techniques have been developed such as the autologous ear reconstruction technique using costal cartilage and ear reconstruction with high-density porous polyethylene or Medpor (Porex Surgical, Inc, College Park, GA). Autologous ear reconstructive techniques have advantages of durability and low infection rates however are associated with poorer aesthetic outcomes such as poor projection of the ear. Medpor has advantages of a more consistent three-dimensional definition without the need to harvest costochondral cartilage and create a donor site. However, due to its alloplastic material properties, Medpor has historically been reported as having a higher rate of extrusion and infection. This is the first systematic review to compare the outcomes of both techniques. The 6 studies that were reviewed were analyzed against 3 evaluative criteria: aesthetic outcome, complication rate, and convenience of intervention. This is so a comprehensive, evidence-based decision can be made by the surgeon and patient when ear reconstruction is required. The results showed heterogeneity in data and a lack of detailed descriptions of the assessment for aesthetic outcomes and convenience, hence were inconclusive. The results however showed that there were more complications with Medpor framework with 15% of total cases resulting in either extrusion or infection compared to 2% of autologous ear reconstruction framework.

Quadrant Excision of Benign Lesions: A Prospective Outcome Study of Pediatric Patients.

ABSTRACT: Serial excision is a commonly used technique for the excision of large lesions. The procedure in children is challenging due to different skin quality and unpredictable scar patterns compared to adults. Quadrant excision is a modification of serial excision. The authors report quadrant excisions in 3 pediatric cases with facial congenital melanocytic naevi in aesthetically challenging areas. Based on our results we recommend the use of this technique in similar cases.

Objective Scoring of Information Websites for Vascular Anomalies.

ABSTRACT: One of the challenging aspects of caring for patients with vascular anomalies has been the use of inconsistent terminologies which has resulted in inconsistencies with treatment, miscommunication between clinicians, and subsequently patient misinformation and confusion. In this study, we objectively assessed the quality of online information on vascular anomalies. Our results emphasize the crucial role of vascular anomaly services in the communication and provision of patient information.

Empowerment of Parents of Children With Cleft Lip and Palate by Objective Scoring of Patient Information Websites.

BACKGROUND: Whether a new diagnosis or for ongoing care, the Internet is now an established and massively frequented resource for parents and patients with cleft lip and/or palate. The purpose of this study was to assess the correlation between the first 50 ranked websites for cleft lip and palate via the Google search engine versus those ranked with an objective patient information scoring tool. METHODS: The first 50 websites ranked by Google were recorded for the search items "Cleft Lip," "Cleft Palate" and "Cleft Lip and Palate." Quality assessment was performed using the DISCERN score, an objective and validated patient information website scoring tool. The Google rank was compared to the DISCERN rank to assess for correlation. The top five websites for each search item were then ranked by blinded cleft health professionals for quality. RESULTS: Based on Google ranking, 36% of websites were the same across the search terms used. The DISCERN ranking scores demonstrated no evidence of positive or negative correlation when compared to Google ranking. In the top 10 DISCERN ranked websites for each search item, 4 websites appear in the top 10 Google rankings. CONCLUSION: This is the first study that demonstrates that high-quality information on cleft lip and palate is available on the Internet. However, this may be difficult and confusing for parents and patients to access due to the ranking system used by internet search engines. Cleft healthcare professionals should be aware of these problems when recommending websites to families and patients.

Secukinumab as a potential trigger of inflammatory bowel disease in ankylosing spondylitis or psoriatic arthritis patients.

OBJECTIVE: Real-world secukinumab gastrointestinal-related adverse events (GIRAE) data during treatment for AS and PsA are lacking. We aimed to obtain this through baseline evaluation of pre-existing IBD rates and predictors of GIRAE. METHODS: Patient electronic and paper records commencing secukinumab from 10 UK hospitals between 2016 and 2019 were reviewed. GIRAE after initiation were defined as: definite [objective evidence of IBD (biopsy proven), clear temporal association, resolution of symptoms on drug withdrawal, no alternative explanation felt more likely], probable (as per definite, but without biopsy confirmation) or possible (gastrointestinal symptoms not fulfilling definite or probable criteria). RESULTS: Data for all 306 patients started on secukinumab were analysed: 124 (40.5%) AS and 182 (59.5%) PsA. Twenty-four of 306 (7.8%) experienced GIRAE after starting secukinumab. Amongst patients who developed GIRAE, four (1.3%) had definite, seven (2.3%) probable and 13 (4.2%) possible IBD. All definite cases were patients with AS and stopped secukinumab; two had pre-existing IBD and two (0.7%) were de novo cases of which one required surgical intervention. Seven patients (2.3%) had pre-existing diagnoses of IBD prior to initiation, of which five patients experienced GIRAE. CONCLUSION: Absolute rates of new IBD in patients starting secukinumab are low. The majority of patients developing new GIRAE did not develop objective evidence of IBD or stop therapy. For patients with pre-existing IBD and AS the risk of GIRAE is much higher, and prescribing alternatives should be considered.

An international study to develop the EAR-Q patient-reported outcome measure for children and young adults with ear conditions.

BACKGROUND: There is currently a lack of patient-reported outcome measures for ear reconstruction. We developed the EAR-Q to measure ear appearance and post-operative adverse effects from the patient perspective. METHODS: Field-test data were collected from children and young adults in eight countries between 13 May 2016 and 12 December 2019. Rasch measurement theory (RMT) analysis was used to refine the scales and to examine their psychometric properties. RESULTS: Participants had microtia (n = 607), prominent ears (n = 145) or another ear condition (n = 111), and provided 960 assessments for the Appearance scale (e.g., size, shape, photos), and 137 assessments for the Adverse Effects scale (e.g., itchy, painful, numb). RMT analysis led to the reduction of each scale to 10-items. Data fit the Rasch model for the Appearance (X2(80) = 90.9, p = 0.19) and Adverse Effects (X2(20) = 24.5, p = 0.22) scales. All items in each scale had ordered thresholds and good item fit. There was no evidence of differential item function for the Appearance scale by age, gender, language, or type of ear condition. Reliability was high for the Appearance scale, with person separation index (PSI) and Cronbach alpha values with and without extremes ≥0.92. Reliability for the Adverse Effects scale was adequate (i.e., PSI and Cronbach alpha values ≥0.71). Higher scores (liked appearance more) correlated with higher scores (better) on Psychological, Social and School scales. INTERPRETATION: The EAR-Q can be used in those 8-29 years of age to understand the patient perspective in clinical practice and research, and in addition, can be used to benchmark outcomes for ear reconstruction internationally.

A Single Surgeon's Experience of Starting a New Ear Reconstruction Service in the UK.

ABSTRACT: Autologous ear reconstruction is known as one of the most difficult types of reconstruction to perform in plastic surgery. Very rarely is a trainee exposed to the level of complexity and variety of cases they will treat as a sole care provider in a tertiary care setting. This is because the learning curve is steep and those few surgeons that already perform ear reconstruction are limited in what technical experience they can offer trainees due to the plethora of factors competing against the surgeon. These include patient expectations, level of experience, length of anesthetic and accountability for results and complications. For this reason, once a plastic surgeon is nominated to provide autologous ear reconstruction, they face the daunting prospect of not only performing what is a very complex surgery with a very steep learning curve but also the judgment of their patients and colleagues. This paper charts the endeavors of the senior author to provide a service over the last 5 years. It will hopefully provide insight and context on setting up a service, dealing with complications, patient and peer expectations, and finally acknowledgment from both alike as experience is gained and excellence is reached.

Versatility of Pedicled Perforator-Based V-Y Advancement Flaps for Reconstruction of the Upper Limb: A Case Series and Review of the Literature.

INTRODUCTION: The aim of any reconstruction is to provide a robust and cosmetically pleasing result that does not significantly alter function. We describe our experience of using the V-Y principle in advancement flaps designed around a distinct perforator to reconstruct soft tissue defects of the upper limb. The shortcomings of fasciocutaneous and fascial flaps requiring skin grafting can be eliminated. METHODS: This was a 10-year retrospective review of patients who had V-Y flaps based on a distinct perforator for defects of the shoulder, axilla, arm, elbow, forearm, wrist, and hand. Defects of the digits and thumb were excluded. RESULTS: There were 59 flaps in 52 patients with an average age of 44 years (18-72 years). Skin malignancy was the most common primary etiology. The average defect size was 35 cm (9-80 cm). There were no total flap failures; however, there were 4 partial losses, which healed by secondary intention. Seven flaps had to be explored for the hematoma evacuation. CONCLUSIONS: The use of V-Y flaps based on distinct perforators in the upper limb retains limb aesthetics, allows early mobility and is a safe and reliable technique.

Epstein-Barr virus associated CNS lymphoproliferative disorder after long-term immunosuppression.

The incidence of Epstein-Barr virus (EBV)associated lymphoproliferative disorders has increased with greater use of immunomodulatory therapies. We present a woman who developed subacute cognitive decline and unilateral weakness while taking long-term mycophenolate mofetil for granulomatosis with polyangiitis; her postmortem brain histopathology confirmed an EBV-driven lymphoproliferative disorder. Clinicians must have a high index of suspicion for EBV-driven lymphoma in people taking long-term immunosuppression who develop new neurological problems. We review the role of mycophenolate mofetil in EBV-driven lymphoproliferative disorders, and discuss checking EBV status in all patients starting immunosuppression and in older people already taking immunosuppression.

Propranolol for Surgeons in the Treatment of Infantile Hemangiomas.

INTRODUCTION: Beta-blocker (Propanolol or Timolol maleate) treatment of infantile hemangiomas (IH) is a safe and effective treatment in the outpatient setting. The authors report a single surgeon's initial experience with setting up an outpatient service of beta-blocker treatment for head and neck IH at a tertiary children's hospital. METHODS: A prospective study of children with head and neck IHs commenced in January 2015 with the end point being December 2018. Each child started either oral propranolol (2 mg/kg/day) or topical Timolol 0.5%. RESULTS: Thirty-eight patients commenced a beta-blocker during the study duration. The mean age at time of starting therapy was 9 months (range 3 weeks to 116 months). Four patients were older than 12 months at commencement. The mean duration of treatment was 9 months. The response to treatment was excellent or complete in 29% (n = 11), good in 50% (n = 18) and mild in 10% (n = 4). The non response rate was 10% (n = 4). No major adverse effects occurred but 29% (n = 11) experienced minor side effects. CONCLUSION: Low dose propranolol and topical Timolol is been safe and easy to use for surgeons who may not be regular prescribers or unfamiliar with treating children with IHs with beta-blocker therapy. In patient monitoring is unnecessary and parents can be taught easily to recognise side effects. Treating children from the start builds a trusting relationship with the family before the child requesting cosmetic revision of the fibro-fatty remnant.

The Influence of Epigenetic Factors in Four Pairs of Twins With Non-Syndromic Craniosynostosis.

The aims of this retrospective case series were to investigate whether twins born with craniosynostosis mirrored each other regarding operative surgery performed, age of undertaking surgery; outcomes in speech, language, and developmental milestones and what environmental factors were present for each set of twins.Case selection was based on clinical and radiographical evidence of craniosynostosis amongst twin sets. The twin sets included were those with craniosynostosis who had different sutures affected or those with the same suture affected but with a varying degree of severity.The presence of the following factors may have played an influential role in the clinical presentation of the twins; these were as follows: a maternal history of smoking, breech presentation, and genetic mutations. It was notable that the overall outcomes for the twins in this study were similar.These cases highlight the multifactorial nature in the development of craniosynostosis and how this influenced the phenotypic presentation of the twins.

A Biographical Journey Through the History of Ear Reconstruction.

This historical literature review of ear reconstruction differs from much of the published literature in that it focuses on the biographies of the innovators and evangelists of ear reconstruction rather than specific techniques. A biographical account of ear reconstruction demonstrates the importance of surgeons as artists, scientists, technicians, politicians, and most importantly carers of this special and fascinating group of patients who benefit from this technically challenging form of reconstruction.

Single Suture Synostosis and Isolated Cleft Palate in Non-Apert Syndrome Patients.

INTRODUCTION: Single suture craniosynostosis (SSC) and isolated cleft palate (ICP) in non-Apert syndrome patients rarely occur together. Management includes airway optimization, timing surgery appropriately, and assessing both cranial vault aesthetics and speech outcomes. The aim of this study was to compare treatment pathways and outcomes in patients with both conditions to standard treatment for these conditions in isolation. METHODS: Patient hospital medical records were retrospectively reviewed for demographic data, timing of surgery, aesthetic outcome (using the Whitaker grading system for head shape), and speech outcome (from speech therapy records of general development and speech assessment). RESULTS: Six patients with SSC and ICP were identified over an 18-year period. Cranial surgery was performed between 4 and 16 months and cleft surgery between 6 and 34 months of age in all cases. Documentation of cleft surgery and genetic testing was not available for 1 patient. One patient with hemi-palatal absence had an obturator inserted at 34 months. Two patients were found to have Fragile X and Emanuel syndrome, respectively.No increased perioperative airway risk was highlighted in any case. Four cases were designated Whitaker grade 1, 1 case was designated grade 2, and 1 case was not graded as no cranial surgery was performed. Half of the patients had general and speech developmental delay, while the other half demonstrated no signs of developmental delay. DISCUSSION/CONCLUSION: Examination of 6 patients with SSC and ICP suggests the presence of both conditions does not adversely impact management or outcome for each condition, or increase perioperative risk.

Bioinformatics Associated With Conjoined Twin Separation.

The separation of conjoined twins is a rare event in the medical field and presents many unique challenges to overcome. With the complexities of today's interconnected healthcare technology and electronic medical record, there are many intricate details that need significant attention to guarantee proper care and accurate record keeping for conjoined twins. Items that require attention are how to digitally represent the twins-as 1 patient or 2, how to incorporate the physiological monitors into the medical record, and how to ensure the proper amount of infrastructure, equipment, and space. With careful planning and consideration, technology can be used as an aid in separating conjoined twins at any institution.

Accessory Auricles: Systematic Review of Definition, Associated Conditions, and Recommendations for Clinical Practice.

Accessory auricles are rare congenital abnormalities embryologically derived from the first branchial arch. Presentation may be variable with locations grouped into anatomical zones based on the frequency of location found in the literature. This study reviewed the papers between 1981 and 2017. Findings included an association with syndromes including Goldenhar, VACTERL, Treacher-Collins, Townes-Brocks, and Wolf-Hirschhorn. Based on histological and embryological evidence, the term "accessory auricle" is best used as an umbrella term to define this difference. Finally, indications are provided for imaging and laboratory investigations to guide the physician treating patients with accessory auricles.

Tissue Engineering Strategies for Auricular Reconstruction.

Simulating natural characteristics and aesthetics in reconstructed ears has provided a complex 3-dimensional puzzle for those treating patients with microtia. Costochondral grafts remain the gold standard for autologous reconstruction. However, other options such as Medpor and prosthetics are indicated depending on patient circumstances and personal choice. Research into tissue engineering offers an alternative method to a traditional surgical approach that may reduce donor-site morbidity. However, tissue engineering for microtia reconstruction brings new challenges such as cell sourcing, promotion of chondrogenesis, scaffold vascularization, and prevention of scaffold contraction. Advancements in 3D printing, nanofiber utilization, stem cell technologies, and decellularization techniques have played significant roles in overcoming these challenges. These recent advancements and reports of a successful clinical-scale study in an immunocompetent animal suggest a promising outlook for future clinical application of tissue engineering for auricular reconstruction.