Differential cytokine expression in direct and indirect co-culture of islets and mesenchymal stromal cells.

BACKGROUND: Transplantation of allogenic Langerhans islets (ISL) has been employed as an alternative to pancreas transplantation to provide endogenous supply of insulin and treat hypoglycemia unawareness in type 1 diabetes. Nevertheless, the process of islets isolation exposes the islets to hypoxia and other aggressive conditions that results in the recover of less than half of the islets present in the pancreas. Several studies demonstrated that co-culturing islets with mesenchymal stromal cells (MSC) before implantation enhances islets survival and function and this effect is mediated by cytokines. However, it remains unclear if the profile of cytokines secreted by MSC in co-culture with islets changes upon the type of co-culture: direct and indirect. MATERIALS AND METHODS: In 3 series of experiments with human islets of 3 different donors, we compared the levels of a panel of cytokines measured in the supernatant of ISL cultured alone, Wharton Jelly MSC (WJMSC) cultured alone, direct co-culture of ISL-WJMSC and indirect co-culture using a permeable transwell membrane to separate ISL and WJMSC. RESULTS: Comparing the profile of cytokines secreted by islets alone with islets in direct co- culture with WJMSC, we found higher expression of IL1b, IL17, IFγ, IL4, IL10, IL13, Granulocyte-macrophage colony-stimulating factor (GMCSF) and Leptin, in the supernatant of the co-cultures. In contrast, when comparing islets cultured alone with islets in indirect co-culture with MSC, we found no significant differences in the levels of cytokines we analyzed. CONCLUSION: Direct contact between human WJMSC and pancreatic islets is required for elevated expression of a range of immune cytokines, including both those considered inflammatory, and anti-inflammatory.

Abdominal Wall Transplantation: Skin as a Sentinel Marker for Rejection.

Abdominal wall transplantation (AWTX) has revolutionized difficult abdominal closure after intestinal transplantation (ITX). More important, the skin of the transplanted abdominal wall (AW) may serve as an immunological tool for differential diagnosis of bowel dysfunction after transplant. Between August 2008 and October 2014, 29 small bowel transplantations were performed in 28 patients (16 male, 12 female; aged 41 ± 13 years). Two groups were identified: the solid organ transplant (SOT) group (n = 15; 12 ITX and 3 modified multivisceral transplantation [MMVTX]) and the SOT-AWTX group (n = 14; 12 ITX and 2 MMVTX), with the latter including one ITX-AWTX retransplantation. Two doses of alemtuzumab were used for induction (30 mg, 6 and 24 h after reperfusion), and tacrolimus (trough levels 8-12 ng/mL) was used for maintenance immunosuppression. Patient survival was similar in both groups (67% vs. 61%); however, the SOT-AWTX group showed faster posttransplant recovery, better intestinal graft survival (79% vs. 60%), a lower intestinal rejection rate (7% vs. 27%) and a lower rate of misdiagnoses in which viral infection was mistaken and treated as rejection (14% vs. 33%). The skin component of the AW may serve as an immune modulator and sentinel marker for immunological activity in the host. This can be a vital tool for timely prevention of intestinal graft rejection and, more important, avoidance of overimmunosuppression in cases of bowel dysfunction not related to graft rejection.

Inter- and intrarater reliability of osteoarthritis classification at the trapeziometacarpal joint.

PURPOSE: To assess the reliability of the Eaton and Glickel classification for base of thumb osteoarthritis. METHODS: The interrater and intrarater reliability of this classification were assessed by comparing ratings from 6 raters using quadratic weighted kappa scores. RESULTS: Median inter-rater reliability ranged from kappa of .53 to .54; intrarater reliability ranged from kappa of .60 to .82. Using unweighted kappa interrater reliability was "slightly" reliable, and intrarater reliability was "fairly" reliable. Overall, the value of the intraclass correlation for all 6 raters was .56. CONCLUSIONS: This radiological classification does not describe all stages of carpometacarpal joint osteoarthritis accurately enough to permit reliable and consistent communication between clinicians. Therefore we believe it should be used with an understanding of its limitations when communicating disease severity between clinicians or as a tool to assist in clinical decision making.

Remote revascularization of abdominal wall transplants using the forearm.

Primary abdominal wall closure following small bowel transplantation is frequently impossible due to contraction of the abdominal domain. Although abdominal wall transplantation was reported 10 years ago this, technique has not been widely adopted, partly due to its complexity, but largely because of concerns that storing the abdominal allograft until the end of a prolonged intestinal transplant procedure would cause severe ischemia-reperfusion injury. We report six cases of combined small bowel and abdominal wall transplantation where the ischemic time was minimized by remotely revascularizing the abdominal wall on the forearm vessels, synchronous to the intestinal procedure. When the visceral transplant was complete, the abdominal wall was removed from the forearm and revascularized on the abdomen (n = 4), or used to close the abdomen while still vascularized on the forearm (n = 2). Primary abdominal wall closure was achieved in all. Mean cold ischemia was 305 min (300-330 min), and revascularization on the arm was 50 min (30-60 min). Three patients had proven abdominal wall rejection, all treated successfully. Immediate revascularization of the abdominal wall allograft substantially reduces cold ischemia without imposing constraints on the intestinal transplant. Reducing storage time may also have benefits with respect to ischemia-reperfusion-related graft immunogenicity.

A single center experience of abdominal wall graft rejection after combined intestinal and abdominal wall transplantation.

We report our outcomes following combined intestinal and abdominal wall transplantation, focusing on the presentation and treatment of acute rejection of the abdominal wall vascularized composite allograft (VCA). Retrospective analysis of all patients with combined intestinal/VCA transplantation was undertaken. Graft abnormalities were documented photographically and biopsies taken, with histological classification of rejection according to Banff 2007 guidelines. We have performed five combined intestinal and abdominal wall transplants to date. Two patients developed erythematous, maculopapular to papular eruptions confined to the VCA, histologically confirmed as grade II/III rejection, yet with normal bowel on endoscopy. Both patients' rashes resolved within 72 h of increasing immunosuppressive treatment. One patient later developed a recurrence of the rash, confirmed as skin rejection, but did not immediately seek medical attention. Treatment was therefore delayed, and mild intestinal rejection developed. We describe the rash associated with VCA rejection, and propose that while the skin of an abdominal wall VCA may reject independently of the intestinal allograft, delay in treatment of rejection episodes may result in rejection of the intestinal graft.

Randomized controlled trial of fibrin sealant to reduce postoperative drainage following elective lymph node dissection.

BACKGROUND: Excessive postoperative drainage following groin and axillary lymphadenectomy may be associated with a prolonged hospital stay and an increased complication rate. The use of fibrin sealant before wound closure may reduce postoperative wound drainage. METHODS: Consecutive patients undergoing elective groin or axillary lymphadenectomy were randomized to standard wound closure or to having fibrin sealant sprayed on to the wound bed before closure. Postoperative wound drainage, duration of drainage and complications were recorded, as were locoregional recurrence, distant metastasis and mortality. RESULTS: A total of 74 patients requiring 38 groin and 36 axillary dissections were randomized. The median postoperative wound drainage volume for the groin dissection cohort was 762 (range 25-3255) ml in the control group and 892 (265-2895) ml in the treatment group (P = 0·704). Drainage volumes in the axillary cohort were 590 (230-9605) and 565 (30-1835) ml in the control and treatment groups respectively (P = 0·217). There was no difference in the duration of drainage or postoperative complication rate between the treatment groups in both the axillary and groin cohorts. Local recurrence, distant metastasis and mortality rates did not differ between the treatment groups. CONCLUSION: There was no advantage in using fibrin sealant during elective lymphadenectomy in terms of reducing drainage output or postoperative complication rate.

Safety of major reconstructive surgery during the peak of the COVID-19 pandemic in the United Kingdom and Ireland - multicentre national cohort study.

BACKGROUND: The safety of surgery during and after the coronavirus disease-2019 (COVID-19) pandemic is paramount. Early reports of excessive perioperative mortality in COVID-positive patients promoted the widespread avoidance of operations. However, cancelling or delaying operations for cancer, trauma, or functional restitution has resulted in increased morbidity and mortality. METHODS: A national multicentre cohort study of all major reconstructive operations carried out over a 12-week period of the 'COVID-19 surge' in the United Kingdom and Ireland was performed. Primary outcome was 30-day mortality and secondary outcome measures were major complications (Clavien-Dindo grade ≥3) and COVID-19 status of patients and healthcare professionals before and after surgery. RESULTS: A total of 418 patients underwent major reconstructive surgery with a mean operating time of 7.5 hours and 12 days' inpatient stay. Cancer (59.8%) and trauma (29.4%) were the most common indications. COVID-19 infection was present in 4.5% of patients. The 30-day post-operative mortality was 0.2%, reflecting the death of one patient who was COVID-negative. Overall complication rate was 20.8%. COVID status did not correlate with major or minor complications. Eight healthcare professionals developed post-operative COVID-19 infection, seven of which occurred within the first three weeks. CONCLUSIONS: Major reconstructive operations performed during the COVID-19 crisis have been mostly urgent cases involving all surgical specialties. This cohort is a surrogate for all major operations across all surgical specialties. Patient safety and surgical outcomes have been the same as in the pre-COVID era. With adequate precautions, major reconstructive surgery is safe for patients and staff. This study helps counsel patients of COVID-19 risks in the perioperative period.

Genetic screening of 202 individuals with congenital limb malformations and requiring reconstructive surgery.

BACKGROUND: Congenital limb malformations (CLMs) are common and present to a variety of specialties, notably plastic and orthopaedic surgeons, and clinical geneticists. The authors aimed to characterise causative mutations in an unselected cohort of patients with CLMs requiring reconstructive surgery. METHODS: 202 patients presenting with CLM were recruited. The authors obtained G-banded karyotypes and screened EN1, GLI3, HAND2, HOXD13, ROR2, SALL1, SALL4, ZRS of SHH, SPRY4, TBX5, TWIST1 and WNT7A for point mutations using denaturing high performance liquid chromatography (DHPLC) and direct sequencing. Multiplex ligation dependent probe amplification (MLPA) kits were developed and used to measure copy number in GLI3, HOXD13, ROR2, SALL1, SALL4, TBX5 and the ZRS of SHH. RESULTS: Within the cohort, causative genetic alterations were identified in 23 patients (11%): mutations in GLI3 (n = 5), HOXD13 (n = 5), the ZRS of SHH (n = 4), and chromosome abnormalities (n = 4) were the most common lesions found. Clinical features that predicted the discovery of a genetic cause included a bilateral malformation, positive family history, and having increasing numbers of limbs affected (all p<0.01). Additionally, specific patterns of malformation predicted mutations in specific genes. CONCLUSIONS: Based on higher mutation prevalence the authors propose that GLI3, HOXD13 and the ZRS of SHH should be prioritised for introduction into molecular genetic testing programmes for CLM. The authors have developed simple criteria that can refine the selection of patients by surgeons for referral to clinical geneticists. The cohort also represents an excellent resource to test for mutations in novel candidate genes.

The coracoid process is supplied by a direct branch of the 2nd part of the axillary artery permitting use of the coracoid as a vascularised bone flap, and improving it's viability in Latarjet or Bristow procedures.

BACKGROUND: A comprehensive understanding of the anatomy of the vascular supply of the coracoid is needed to ensure that the coracoid remains vascularised in order to optimize bone union during any coracoid transfer procedures. It is the purpose of this study to present an anatomical overview of the blood supply of the coracoid process, describing a previously unidentified vessel that arises directly from the axillary artery and nourishes the coracoid process, permitting the coracoid to be used as a free bone flap. METHODS: An anatomical study examining the blood supply to the coracoid process of the scapula was performed in 14 shoulders from 7 fresh frozen (unembalmed) adult cadavers. In addition, the vascular supply to the coracoid was studied in 22 shoulders in patients during operations around the anterior shoulder. RESULTS: In all the cadaveric shoulders studied there was a single consistent direct branch of the second part of the axillary artery that supplied the distal 2-3 cm of the coracoid process with a corresponding vein. The mean pedicle length for the artery was 4.46 cm (range 3.1-5.6 cm). This artery originated from the axillary artery from the antero-lateral position in 6, lateral position in 3 and posterolateral position in 5 shoulders. The mean pedicle length for the vein was 5.8 cm (range 4.5-7.8 cm). The vein joined directly to the axillary vein in 3 shoulders and via another tributary (parallel to the axillary vein) in 9 shoulders. The diameter of the artery and vein averaged 1-1.5 mm. The clinical study confirmed the findings of the cadaveric study. CONCLUSION: Our anatomical cadaveric and clinical studies demonstrate the presence of a previously unidentified direct arterial branch from the second part of the axillary artery supplying the anterior 2-3 cm of the coracoid process of the scapula. This consistent vessel and accompanying vein should be preserved for any surgical procedure that involves transfer of the coracoid process, such as the Laterjet and Bristow procedures for shoulder dislocation and can be used for free transfer of the coracoid where a small vascularised bone flap may be required.

Management and outcome of acral soft-tissue sarcomas.

AIMS: The aim of this study was to evaluate the surgical management and outcome of patients with an acral soft-tissue sarcoma of the hand or foot. PATIENTS AND METHODS: We identified 63 patients with an acral soft-tissue sarcoma who presented to our tertiary referral sarcoma service between 2000 and 2016. There were 35 men and 28 women with a mean age of 49 years (sd 21). Of the 63 sarcomas, 27 were in the hands and 36 in the feet. The commonest subtypes were epithelioid sarcoma in the hand (n = 8) and synovial sarcoma in the foot (n = 11). RESULTS: In 41 patients (65%), the tumour measured less than 5 cm in its largest dimension (median size 3 cm (2 to 6)); 27 patients (43%) were diagnosed after inadvertent excision prior to their referral to the specialist sarcoma unit. After biopsy and staging, primary surgical intervention at the sarcoma unit was excision and limb salvage in 43 (68%), partial (digit or ray) amputation in 14 (22%), and more proximal amputation in six (10%). At final follow up, local recurrence had been treated by one partial amputation and six amputations, resulting in a partial amputation rate of 24% and a proximal amputation rate of 19%. The five-year survival rate was 82%. Patients who underwent inadvertent excision showed no statistically significant difference in survival or local recurrence, but were more likely to undergo amputation (p = 0.008). Large tumour size (> 5 cm) was associated with lower survival (p = 0.04) and a higher risk of local recurrence (p = 0.009;). CONCLUSION: Most acral soft-tissue sarcomas measure less than 5 cm at presentation, indicating that while size can be a useful prognostic factor, it should not be used as a diagnostic threshold for referral. Increased tumour size is associated with a higher rate of local recurrence and reduced survival. Sarcoma excision with limb preservation does not result in an increased risk of local recurrence. Cite this article: Bone Joint J 2018;100-B:1518-23.

Could Sentinel Skin Transplants Have Some Utility in Solid Organ Transplantation?

Accurate diagnosis of allograft rejection can be hazardous and challenging. A strategy that has emerged from experience with vascularized composite allografts (VCAs) is the use of sentinel skin transplants (SSTs)-portions of donor skin transplanted synchronously to an allograft. Work in nonhuman animal models and experience with VCAs suggest concordance between rejection occurring in the primary allograft and the SST, and that appearance of rejection in the SST may precede rejection in the primary allograft, permitting early therapeutic intervention that may improve outcomes with lower rates of chronic rejection. The encouraging findings reported in VCA transplantation raise the possibility that SST may also be useful in solid organ transplantation. Some evidence is provided by experience with abdominal wall transplantation in some intestinal and multivisceral transplant recipients. Results from those reports raise the possibility that rejection may manifest in the skin component before emergence in the intestinal allograft, providing a "lead time" during which treatment of rejection of the abdominal wall could prevent the emergence of intestinal rejection. It is plausible that these findings may be extrapolated to other solid organ allografts, especially those for which obtaining an accurate diagnosis of acute rejection can be hazardous and challenging, such as the lung or pancreas. However, more data are required to support widespread adoption of this technique.

Modified liver-free multivisceral transplantation for a metastatic small bowel neuroendocrine tumor: a case report.

Neuroendocrine tumors originating from the small bowel frequently metastasize to the lymph nodes and/or liver. Although surgical extirpation of the primary tumor and locoregional metastases epitomizes the management of patients with such tumors, this is not always possible with conventional surgical techniques. Nonresectable, slow-growing tumors involving the mesenteric root represent a generally accepted indication for deceased donor intestinal and multivisceral transplantation. Furthermore, vascularized sentinel forearm flaps offer opportunities for monitoring graft rejection and tailoring immunosuppression regimens. Here, we report the first documented case of modified liver-free multivisceral transplantation preceded by neoadjuvant 177-lutetium peptide receptor radionuclide therapy in a patient with a small bowel neuroendocrine tumor and extensive lymph node metastases in the mesenterium. At a follow-up of 21 months the patient is biochemically and radiologically disease-free.

The vascularised fibular graft for limb salvage after bone tumour surgery: a multicentre study.

Vascularised fibular grafts (VFGs ) are a valuable surgical technique in limb salvage after resection of a tumour. The primary objective of this multicentre study was to assess the risk factors for failure and complications for using a VFG after resection of a tumour. The study involved 74 consecutive patients (45 men and 29 women with mean age of 23 years (1 to 64) from four tertiary centres for orthopaedic oncology who underwent reconstruction using a VFG after resection of a tumour between 1996 and 2011. There were 52 primary and 22 secondary reconstructions. The mean follow-up was 77 months (10 to 195). In all, 69 patients (93%) had successful limb salvage; all of these united and 65 (88%) showed hypertrophy of the graft. The mean time to union differed between those involving the upper (28 weeks; 12 to 96) and lower limbs (44 weeks; 12 to 250). Fracture occurred in 11 (15%), and nonunion in 14 (19%) patients. In 35 patients (47%) at least one complication arose, with a greater proportion in lower limb reconstructions, non-bridging osteosynthesis, and in children. These complications resulted in revision surgery in 26 patients (35%). VFG is a successful and durable technique for reconstruction of a defect in bone after resection of a tumour, but is accompanied by a significant risk of complications, that often require revision surgery. Union was not markedly influenced by the need for chemo- or radiotherapy, but should not be expected during chemotherapy. Therefore, restricted weight-bearing within this period is advocated.

One in 13 'original' articles in the Journal of Bone and Joint Surgery are duplicate or fragmented publications.

Duplicate publication in orthopaedic journals may further an author's academic career but this is at the cost of both scientific integrity and knowledge. Multiple publications of the same work increase the workload of editorial boards, misguide the reader and affect the process of meta-analysis. We found that of 343 'original' articles published in the Journal of Bone and Joint Surgery in 1999, 26 (7.6%) had some degree of redundancy. The prevalence of duplicate publications in the orthopaedic literature appears to be less than that in other surgical specialties but it is still a matter of concern. It is the author's responsibility to notify the editor of any duality when submitting a paper for publication.

Skin closure after acute shortening.

Z-plasty is used to lengthen scars and wounds. We describe the use of a modified technique to shorten wounds in ten consecutive patients undergoing acute shortening of a limb as part of an Ilizarov procedure. The modified technique gave good exposure, easy closure of the wound and fewer problems with healing than standard incisions.

Management of full thickness burns to lactating breasts.

A 19-year-old female sustained 8 per cent full thickness petrol flame burns to the neck, chest, breasts, upper abdomen and portions of the right upper limb. The patient had been breast-feeding until the time of the injury. Following assessment of the risks of potential complications such as engorgement, hyperprolactinaemia, mastitis, milk fistulae, glandular loss, scarring and nipple distortion, surgical tangential excision was delayed until bromocriptine produced cessation of lactation and breast involution occurred. This case report demonstrates that consideration of the potential problems in burns to the lactating breasts and prophylactic management can lead to successful healing and probable restoration of function.

Direct measurement of cutaneous pressures generated by pressure garments.

Pressure garments are the mainstay of burn scar management despite limited scientific evidence. This study demonstrates a simple method of directly measuring the cutaneous pressures generated by a pressure garment. The results show pressure garments generate an increase in subdermal pressures in the range 9-90 mmHg depending on the anatomical site. Garments over soft sites generate pressures ranging from 9 to 33 mmHg. Over bony prominences the pressures range from 47 to 90 mmHg. This method is believed to be more representative of the pressures generated than the interpositional techniques that measure garment-skin interface pressure, as it avoids garment distortion, the interference effect of the measurement device (size, conformation, area) and directly measures subdermal pressures. The method should be useful for larger research projects on pressure therapy and also for clinical management of pressure garments in the treatment of hypertrophic scar.

Anatomical variations in pressures generated by pressure garments.

Pressure therapy is the predominant means for prophylaxis and treatment of hypertrophic scar. Despite this, there is little scientific evidence to support its use. This study examines the pressures generated by pressure garments in four subjects at 36 different anatomical sites chosen to represent the varying body geometry. Direct subdermal pressures were measured by an established method, though novel for this application. Pressure garments create a mean increase in subdermal pressures of 22.2 mmHg (range -10 to 102 mmHg). A significant objective difference exists in pressures generated at different anatomical sites. These differences correlate to local tissue compliance and to known areas of good clinical response and inversely correlate to the radius of anatomic curvature. The data suggest that pressures around 15 mmHg are required to effect a positive scar response and that close experienced monitoring of garments be performed.

Early use of pressure masks to avoid facial contracture during the pregrafting phase.

This article introduces the concept of early application of pressure therapy as a form of splinting in the pregrafting phase. It is based on the principles of (1) the use of pressure therapy to reduce contraction and hypertrophic scar formation and (2) the knowledge that most wound contraction occurs within the initial few weeks of healing. This idea has most application in facial burns, where wound contraction can be disfiguring and functionally disabling, and in situations where unavoidable delay in debridement and grafting may be present. The idea is illustrated with a case report.

Hildreth's test is a reliable clinical sign for the diagnosis of glomus tumours.

Hildreth's test is a clinical test for the diagnosis of glomus tumours. It is positive if there is a reduction in pain and tenderness on exsanguination and ischaemia of the affected part. This study assessed Hildreth's test, and found 92% sensitivity and 91% specificity with a positive predictive value of 92% and a negative predictive value of 91%.