Implementing a Robotic Hepatopancreatobiliary Program for New Faculty: Safety, Feasibility and Lessons Learned.

Background: Robotic surgery is increasingly utilized in hepatopancreatobiliary (HPB) surgery, but the learning curve is a substantial obstacle hindering implementation. Comprehensive robotic training can help to surmount this obstacle; however, despite the expansion of robotic training into residency and fellowship programs, limited data is available about how this translates into successful incorporation in faculty practice. Methods: All operations performed during the first three years of practice of a complex general surgical oncology-trained surgical oncologist at a tertiary care academic institution were retrospectively reviewed. The surgeon underwent comprehensive robotic training during residency and fellowship. Results: 137 HPB operations were performed during the initial three years of practice. Over 80% were performed robotically each year across a spectrum of HPB procedures with a 6% conversion rate. Median operative time, the optimal metric for operative proficiency and evaluation for a learning curve, was similar throughout the study period for each major operation and below several reported optimized operative times. Major complications were similar across the experience and comparable to published series. Conclusion: Comprehensive robotic training in residency and fellowship as well as a dedicated, well-trained operative team allows for early attainment of optimized outcomes in a new HPB robotic practice.

Training and Evaluation of Residents to Ensure Competent Physician Metrics to Recognize Struggling Residents.

Assessing competency across domains of knowledge, skills, and behavior is critical to ensure that graduating orthopaedic residents possess the requisite skills and attributes to enter independent orthopaedic practice. Of the domains, knowledge is most easily assessed. In addition to the AAOS Orthopaedic In-Training Examination®, which provides a yearly gauge of residents' orthopaedic knowledge relative to their peers, there are several online platforms such as Orthobullets, the American Academy of Orthopaedic Surgeons ResStudy program, and the Journal of Bone and Joint Surgery Clinical Classroom that offer online learning resources and question banks. Clinical skills are best assessed through a combination of observation tools, including live or video assessments, 360° evaluations, and objective structured clinical examinations. Surgical skills can be evaluated in two domains: live surgical cases or simulations. The American Board of Orthopaedic Surgery is attempting to standardize live surgical evaluations through the use of the O-P tool. Although most available models feature only arthroscopic procedures, surgical simulators provide for opportunity to objectively evaluate resident performance. Behavior and professionalism has traditionally been the most challenging domain to assess. The American Board of Orthopaedic Surgery's Behavior Assessment Tool has demonstrated success in pilot testing and is being introduced as the standard for measuring behavior and professionalism in orthopaedic training. Although no single assessment tool can accurately gauge a resident's overall performance, a combination of readily available tools should be used to assess competence across domains.

Substantial Loss of Skeletal Muscle Mass Occurs After Femoral Fragility Fracture.

BACKGROUND: Femoral fragility fractures in older adults can result in devastating loss of physical function and independence. Skeletal muscle atrophy likely contributes to disability. The purpose of this study was to characterize the change in skeletal muscle mass, investigate the relationship with malnutrition and physical function, and identify risk factors for skeletal muscle loss. METHODS: Adults ≥65 years of age who were treated with operative fixation of an isolated femoral fragility fracture were enrolled in this multicenter, prospective observational study. Skeletal muscle mass was assessed within 72 hours of admission using multifrequency bioelectrical impedance analysis, which was repeated at 6 weeks, 3 months, and 6 months. Sarcopenia was defined by sex-specific cutoffs for the appendicular skeletal muscle mass index. The Mini Nutritional Assessment was used to measure nutritional status at the time of injury. Physical function was measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function domain. Linear mixed models were used to evaluate changes in skeletal muscle mass and PROMIS Physical Function scores over time and to evaluate factors associated with skeletal muscle mass changes. RESULTS: Ninety participants (74% female) with a mean age of 77.6 ± 9.0 years were enrolled. At the time of injury, 30 (33%) were sarcopenic and 44 (49%) were at risk for malnutrition or had malnutrition. Older age was associated with lower skeletal muscle mass (age of ≥75 versus <75 years: least squares mean [and standard error], -3.3 ± 1.6 kg; p = 0.042). From the time of injury to 6 weeks, participants lost an average of 2.4 kg (9%) of skeletal muscle mass (95% confidence interval [CI] = ‒3.0 to ‒1.8 kg; p < 0.001). This early loss did not recover by 6 months (1.8 kg persistent loss compared with baseline [95% CI = ‒2.5 to ‒1.1 kg]; p < 0.001). Participants with normal nutritional status lost more skeletal muscle mass from baseline to 6 weeks after injury compared with those with malnutrition (1.3 kg more loss [standard error, 0.6 kg]; p = 0.036). A 1-kg decrease in skeletal muscle mass was associated with an 8-point decrease in the PROMIS Physical Function (model parameter estimate, 0.12 [standard error, 0.04]; p = 0.002). CONCLUSIONS: We found that older adults with femoral fragility fractures lost substantial skeletal muscle mass and physical function. Participants with adequate baseline nutrition actually lost more muscle mass than those who were malnourished, indicating that future investigations of interventions to prevent muscle loss should focus on older adults regardless of nutritional status. LEVEL OF EVIDENCE: Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Comparisons of Procedures Performed in Training vs in Early Practice by Orthopaedic Trauma Surgeons.

INTRODUCTION: The Orthopaedic Trauma Association (OTA) has maintained an accreditation process of orthopaedic trauma fellowships with various requirements including an annually reviewed list of qualifying trauma cases in the form of American Medical Association Current Procedural Terminology (CPT) codes. The correlation between these established and monitored CPTs and the actual practices of orthopaedic trauma surgeons has not been studied. METHODS: American Board of Orthopaedic Surgery part II case logs (trauma subspecialty) (2012 to 2018) were compared with OTA fellowship case logs (2015 to 2019). Case logs from 447 surgeons and 166 trauma fellowship programs were compared. Four CPT code categories were defined: complex trauma (OTA required CPT codes, excluding Accreditation Council for Graduate Medical Education [ACGME] orthopaedic residency requirements), general trauma (ACGME residency required trauma codes), general orthopaedics (nontrauma ACGME residency requirements), and others (codes not included in residency or trauma fellowship requirements). RESULTS: OTA fellows performed a higher median percentage of complex trauma compared with American Board of Orthopaedic Surgery candidates (34% vs. 21%, P < 0.001): Both cohorts performed a similar percentage of general trauma (23%). OTA fellows performed more general orthopaedics (40% vs. 1%, P < 0.001). Several OTA required codes were performed infrequently (0 to 3 during board collection) by most surgeons, and several procedures are being performed that are not included in current CPT code requirements. DISCUSSION: Early-career traumatologists are performing orthopaedic trauma procedures they were trained on during residency and fellowship, with varying complexity. Trauma fellows perform a higher percentage of complex trauma compared with early-career trauma surgeons. Continued surveillance is necessary such that educational improvements can be made to maximize the quality of trauma fellowship education. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Robotic modified Strong procedure for superior mesenteric artery syndrome.

Key Clinical Message: The robotic modified Strong procedure is a safe and effective approach for surgical management of superior mesenteric artery syndrome in properly selected patients. Abstract: Superior mesenteric artery syndrome is a rare syndrome of small bowel obstruction resulting from vascular compression of the duodenum. Here we present our modification of a robotic Strong procedure for the surgical management of SMA syndrome. This procedure is a safe and effective approach for management in properly selected patients.

The Evolution, Current State and Clinical Benefits of Far Cortical Fracture Fixation.

Treatment of distal femur fractures have reported high fracture healing complications in several studies. The development of far cortical locking (FCL) technology results in improved fracture healing outcomes. There are biomechanical and animal studies demonstrating that the locked plating incorporating FCL screws provides a more flexible form of fixation compared to traditional locking plates (LP). Clinical studies have shown that the commercially available Zimmer Motionloc system with FCL screws provide good results in distal femur fractures and periporsthetic distal femur fractures. FCL constructs may help resolve fracture healing problems in the future. However, there is not enough available clinical evidence to conclusively indicate whether clinical healing rates are improved with FCL screw constructs compared to traditional LP's. Therefore, further prospective study designs are needed to compare FCL to LP constructs and to investigate the role of interfragmentary motion on callus formation. Level of Evidence: V.

Posttraumatic osteoarthritis: from basic science to clinical implications.

Posttraumatic osteoarthritis (PTOA) is a subset of osteoarthritis that occurs after joint injury and is associated with degradation of articular cartilage and subchondral bone. As compared with primary osteoarthritis, PTOA occurs in a time window initiated by a traumatic event resulting in damage to layers of joint structure and alterations in joint shape. As techniques in open reduction and internal fixation continue to mature, our success in preventing posttraumatic osteoarthritis has not kept pace. Advances in research in the subchondral bone, inflammatory response, and joint mechanics continue to open our understanding of this posttraumatic process. In addition, there are possibilities emerging as biological agents to therapeutically alter the progression of PTOA.

Core protocol for the adaptive Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO).

BACKGROUND: The need for coronavirus 2019 (COVID-19) vaccination in different age groups and populations is a subject of great uncertainty and an ongoing global debate. Critical knowledge gaps regarding COVID-19 vaccination include the duration of protection offered by different priming and booster vaccination regimens in different populations, including homologous or heterologous schedules; how vaccination impacts key elements of the immune system; how this is modified by prior or subsequent exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and future variants; and how immune responses correlate with protection against infection and disease, including antibodies and effector and T cell central memory. METHODS: The Platform Trial In COVID-19 priming and BOOsting (PICOBOO) is a multi-site, multi-arm, Bayesian, adaptive, randomised controlled platform trial. PICOBOO will expeditiously generate and translate high-quality evidence of the immunogenicity, reactogenicity and cross-protection of different COVID-19 priming and booster vaccination strategies against SARS-CoV-2 and its variants/subvariants, specific to the Australian context. While the platform is designed to be vaccine agnostic, participants will be randomised to one of three vaccines at trial commencement, including Pfizer's Comirnaty, Moderna's Spikevax or Novavax's Nuvaxovid COVID-19 vaccine. The protocol structure specifying PICOBOO is modular and hierarchical. Here, we describe the Core Protocol, which outlines the trial processes applicable to all study participants included in the platform trial. DISCUSSION: PICOBOO is the first adaptive platform trial evaluating different COVID-19 priming and booster vaccination strategies in Australia, and one of the few established internationally, that is designed to generate high-quality evidence to inform immunisation practice and policy. The modular, hierarchical protocol structure is intended to standardise outcomes, endpoints, data collection and other study processes for nested substudies included in the trial platform and to minimise duplication. It is anticipated that this flexible trial structure will enable investigators to respond with agility to new research questions as they arise, such as the utility of new vaccines (such as bivalent, or SARS-CoV-2 variant-specific vaccines) as they become available for use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12622000238774. Registered on 10 February 2022.

The Effect of Lumpectomy and Cavity Shave Margin Status on Recurrence and Survival in Breast-Conserving Surgery.

BACKGROUND/OBJECTIVE: Cavity shave margins (CSMs) decrease rate of positive margins and need for re-excision. Recurrence data following breast-conserving surgery (BCS) are not always available in large cancer registries. We sought to define our recurrence and survival data in BCS with routine excision of CSMs. METHODS: A single institution, 10-year retrospective review of breast cancer patients who underwent BCS with routine CSMs was conducted. Cavity shave margin technique was standard. Cox proportional hazard analyses and the Kaplan-Meier method were used to estimate recurrence and survival. RESULTS: Breast-conserving surgery with CSM was performed in 839 patients. Re-excision rate to achieve negative margins was 8.5%. Fifty-two patients (75%) underwent margin re-excision vs 18 patients (25%) underwent salvage mastectomy. Positive margin rate stratified by tumor histology was highest for invasive lobular carcinoma followed by mixed invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS), followed by pure DCIS and lowest for IDC. Length of follow-up was (4.7 ± 2.6, years). Overall recurrence rate (locoregional and systemic) was 4.3%: highest in patients with negative lumpectomy margin but positive CSM (L-S+ = 15%) followed by positive lumpectomy and CSMs (L+S+ = 14%), followed by patients with positive lumpectomy margin but negative CSMs (L+S- = 13%) and lowest for negative lumpectomy and CSM (L-S- = 5%), (P = .0008). There was no difference in 5-year breast cancer-specific survival between the 4 subgroups: 96% for L-S-, 86.7% L-S+, 94.7% L+S+ and 90% L+S- (P = .094). CONCLUSIONS: Recurrence following BCS with CSMs can be stratified based on both lumpectomy and cavity shave margin positivity. Routine excision of CSMs allows identification of these patient subsets.

Syndesmosis Malposition Assessed on Weight-Bearing CT Is Common After Operative Fixation of Intra-articular Distal Tibia Plafond Fracture.

OBJECTIVES: To evaluate reliability of measurement techniques for syndesmosis position after operative fixation of distal tibia plafond fracture on weight-bearing computed tomography (WBCT), identify risk factors for syndesmosis malposition, and determine if syndesmosis malposition is associated with higher pain and lower physical function. DESIGN: Prospective cohort study. SETTING: Three Level 1 trauma centers. PARTICIPANTS: Twenty-six subjects who underwent open reduction and internal fixation of distal tibia plafond fractures with bilateral ankle WBCT 1 year or greater after injury were included in the study. INTERVENTION: Operative fixation of distal tibia plafond fracture. MAIN OUTCOME MEASUREMENT: Fibula position in the tibia incisura, injury characteristics, and patient-reported outcomes were the main outcome measurements. RESULTS: Interrater reliability for syndesmosis position measurements were excellent for the Phisitkul technique on both injured and healthy ankles (intraclass correlation coefficients [ICCs]: 0.93-0.98). The Nault technique demonstrated moderate-to-excellent interrater reliability (ICCs: 0.67-0.98), apart from the angle of rotation measurement (ICCs: 0.18-0.67). Sixteen of 26 subjects (62%) had syndesmosis malposition defined as >2 mm difference comparing the tibial-fibular relationship in injured and uninjured ankles using these 2 methods. Patients with syndesmosis malposition reported lower Foot and Ankle Ability Measure: Activities of Daily Living scores; other recorded patient-reported outcomes were not significantly different. CONCLUSIONS: Measurement techniques for syndesmosis position on WBCT were reliable after operative fixation of distal tibia plafond fracture. Syndesmosis malposition is common after these injuries and predicted impaired physical function. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Case report: Surgical resection of a retro-hepatic leiomyosarcoma involving atrial reconstruction, cardiopulmonary bypass, ex vivo tumor resection, and liver re-implantation.

Introduction: Leiomyosarcomas (LMS) involving the inferior vena cava (IVC) is a clinically rare entity, accounting for approximately 0.5% of all adult sarcomas. Case presentation: A 67-year-old male presented to the emergency department with mild back and lower abdominal pain. During the workup, a computed tomography scan without contrast showed an area of decreased attenuation within the liver adjacent to the intrahepatic IVC. Magnetic resonance imaging confirmed the involvement of the retro-hepatic IVC; biopsy confirmed the diagnosis of LMS. Given the location of the involvement of the retro-hepatic IVC, liver explantation was deemed necessary for adequate tumor resection. The superior extension of the tumor toward the heart necessitated Cardio-Pulmonary (CPB). The patient successfully underwent a complex surgical procedure involving liver explantation with ex vivo back-table resection of the retro-hepatic LMS, replacement of the retro-hepatic vena cava with a ringed Gore-Tex graft, liver re-implantation, and hepatic vein-atrial reconstruction under cardiopulmonary bypass. There were no intraoperative or post-op complications. Discussion: The role of vascular reconstruction of the IVC varies depending on the level and extent of the tumor, with options ranging from primary repair, ligation, or reconstruction dictated. Surgical resection with negative margins remains the treatment of choice due to the lack of efficacy of adjuvant therapies. Importantly, liver explantation offers a chance for complete surgical resection and reconstruction. Similarly, the complex nature of the tumor necessitated a pioneering approach involving direct hepato-atrial venous anastomosis. Conclusion: To the best of our knowledge, this is the first reported case in which the hepatic veins were anastomosed directly to the right atrium while also replacing the native vena cava with a separate graft.

Summary Report of the Arthritis Foundation and the American Orthopaedic Foot & Ankle Society's Symposium on Targets for Osteoarthritis Research: Part 1: Epidemiology, Pathophysiology, and Current Imaging Approaches.

This first of a 2-part series of articles recounts the key points presented in a collaborative symposium sponsored jointly by the Arthritis Foundation and the American Orthopaedic Foot & Ankle Society with the intent to survey the state of scientific knowledge related to incidence, diagnosis, pathologic mechanisms, and injection treatment options for osteoarthritis (OA) of the foot and ankle. A meeting was held virtually on December 3, 2021. A group of experts were invited to present brief synopses of the current state of knowledge and research in this area. Part 1 overviews areas of epidemiology and pathophysiology, current approaches in imaging, diagnostic and therapeutic injections, and genetics. Opportunities for future research are discussed. The OA scientific community, including funding agencies, academia, industry, and regulatory agencies, must recognize the needs of patients that suffer from arthritis of foot and ankle. The foot and ankle contain a myriad of interrelated joints and tissues that together provide a critical functionality. When this functionality is compromised by OA, significant disability results, yet the foot and ankle are generally understudied by the research community. Level of Evidence: Level V - Review Article/Expert Opinion.

Summary Report of the Arthritis Foundation and the American Orthopaedic Foot & Ankle Society's Symposium on Targets for Osteoarthritis Research: Part 2: Treatment Options.

This second of a 2-part series of articles recounts the key points presented in a collaborative symposium sponsored jointly by the Arthritis Foundation and the American Orthopaedic Foot & Ankle Society with the intent to survey current treatment options for osteoarthritis (OA) of the foot and ankle. A meeting was held virtually on December 10, 2021. A group of experts were invited to present brief synopses of the current state of knowledge and research in this area. Topics were chosen by meeting organizers, who then identified and invited the expert speakers. Part 2 overviews the current treatment options, including orthotics, non-joint destructive procedures, as well as arthroscopies and arthroplasties in ankles and feet. Opportunities for future research are also discussed, such as developments in surgical options for ankle and the first metatarsophalangeal joint. The OA scientific community, including funding agencies, academia, industry, and regulatory agencies, must recognize the importance to patients of addressing the foot and ankle with improved basic, translational, and clinical research. Level of Evidence: Level V, review article/expert opinion.

Corrigendum: Gut bacteria regulate the pathogenesis of Huntington's disease in Drosophila model.

[This corrects the article DOI: 10.3389/fnins.2022.902205.].

Gut Bacteria Regulate the Pathogenesis of Huntington's Disease in Drosophila Model.

Changes in the composition of gut microbiota are implicated in the pathogenesis of several neurodegenerative disorders. Here, we investigated whether gut bacteria affect the progression of Huntington's disease (HD) in transgenic Drosophila melanogaster (fruit fly) models expressing full-length or N-terminal fragments of human mutant huntingtin (HTT) protein. We find that elimination of commensal gut bacteria by antibiotics reduces the aggregation of amyloidogenic N-terminal fragments of HTT and delays the development of motor defects. Conversely, colonization of HD flies with Escherichia coli (E. coli), a known pathobiont of human gut with links to neurodegeneration and other morbidities, accelerates HTT aggregation, aggravates immobility, and shortens lifespan. Similar to antibiotics, treatment of HD flies with small compounds such as luteolin, a flavone, or crocin a beta-carotenoid, ameliorates disease phenotypes, and promotes survival. Crocin prevents colonization of E. coli in the gut and alters the levels of commensal bacteria, which may be linked to its protective effects. The opposing effects of E. coli and crocin on HTT aggregation, motor defects, and survival in transgenic Drosophila models support the involvement of gut-brain networks in the pathogenesis of HD.

American Board of Orthopaedic Surgery's Initiatives Toward Competency-Based Education.

The American Board of Orthopaedic Surgery (ABOS) is the national organization charged with defining education standards for graduate medical education in orthopaedic surgery. The purpose of this article is to describe initiatives taken by the ABOS to develop assessments of competency of residents to document their progress toward the independent practice of orthopaedic surgery and provide feedback for improved performance during training. These initiatives are called the ABOS Knowledge, Skills, and Behavior Program. Web-based assessment tools have been developed and validated to measure competence. These assessments guide resident progress through residency education and better define the competency level by the end of training. The background and rationale for these initiatives and how they serve as steps toward competency-based education in orthopaedic residency education in the United States will be reviewed with a vision of a hybrid of time and competency-based orthopaedic residency education that will remain 5 years in length, with residents assessed using standardized tools.

Conditionally Essential Amino Acid Supplementation Reduces Postoperative Complications and Muscle Wasting After Fracture Fixation: A Randomized Controlled Trial.

BACKGROUND: Postoperative complications and substantial loss of physical function are common after musculoskeletal trauma. We conducted a prospective randomized controlled trial to assess the impact of conditionally essential amino acid (CEAA) supplementation on complications and skeletal muscle mass in adults after operative fixation of acute fractures. METHODS: Adults who sustained pelvic and extremity fractures that were indicated for operative fixation at a level-I trauma center were enrolled. The subjects were stratified based on injury characteristics (open fractures and/or polytrauma, fragility fractures, isolated injuries) and randomized to standard nutrition (control group) or oral CEAA supplementation twice daily for 2 weeks. Body composition (fat-free mass [FFM]) was measured at baseline and at 6 and 12 weeks postoperatively. Complications were prospectively collected. An intention-to-treat analysis was performed. The relative risk (RR) of complications for the control group relative to the CEAA group was determined, and linear mixed-effects models were used to model the relationship between CEAA supplementation and changes in FFM. RESULTS: Four hundred subjects (control group: 200; CEAA group: 200) were enrolled. The CEAA group had significantly lower overall complications than the control group (30.5% vs. 43.8%; adjusted RR = 0.71; 95% confidence interval [CI] = 0.55 to 0.92; p = 0.008). The FFM decreased significantly at 6 weeks in the control subjects (-0.9 kg, p = 0.0205), whereas the FFM was maintained at 6 weeks in the CEAA subjects (-0.33 kg, p = 0.3606). This difference in FFM was not seen at subsequent time points. CONCLUSIONS: Our results indicate that CEAA supplementation has a protective effect against common complications and early skeletal muscle wasting after operative fixation of extremity and pelvic fractures. Given the potential benefits of this inexpensive, low-risk intervention, multicenter prospective studies in focused trauma populations are warranted. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.