Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig.

Genetic modification of porcine donors, combined with optimized immunosuppression, has been shown to improve outcomes of experimental xenotransplant. However, little is known about outcomes in sensitized recipients, a population that could potentially benefit the most from the clinical implementation of xenotransplantation. Here, five highly allosensitized rhesus macaques received a porcine kidney from GGTA1 (α1,3-galactosyltransferase) knockout pigs expressing the human CD55 transgene (1KO.1TG) and were maintained on an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen. These recipients developed de novo xenoreactive antibodies and experienced xenograft rejection with evidence of thrombotic microangiopathy and antibody-mediated rejection (AMR). In comparison, three highly allosensitized rhesus macaques receiving a kidney from GGTA1, CMAH (cytidine monophospho-N-acetylneuraminic acid hydroxylase), and b4GNT2/b4GALNT2 (ß-1,4-N-acetyl-galactosaminyltransferase 2) knockout pigs expressing seven human transgenes including human CD46, CD55, CD47, THBD (thrombomodulin), PROCR (protein C receptor), TNFAIP3 (tumor necrosis factor-α-induced protein 3), and HMOX1 (heme oxygenase 1) (3KO.7TG) experienced significantly prolonged graft survival and reduced AMR, associated with dampened post-transplant humoral responses, early monocyte and neutrophil activation, and T cell repopulation. After withdrawal of all immunosuppression, recipients who received kidneys from 3KO.7TG pigs rejected the xenografts via AMR. These data suggest that allosensitized recipients may be suitable candidates for xenografts from genetically modified porcine donors and could benefit from an optimized immunosuppression regimen designed to target the post-transplant humoral response, thereby avoiding AMR.

Downstaging strategies for unresectable hepatocellular carcinoma.

A significant number of patients with hepatocellular carcinoma (HCC) are usually diagnosed in advanced stages, that leads to inability to achieve cure. Palliative options are focusing on downstaging a locally advanced disease. It is well-supported in the literature that patients with HCC who undergo successful conversion therapy followed by curative-intent surgery may achieve a significant survival benefit compared to those who receive chemotherapy alone or those who are successfully downstaged with conversion therapy but not treated with surgery. Hepatic artery infusion chemotherapy can be a potential downstaging strategy, since recent studies have demonstrated excellent outcomes in patients with colorectal liver metastatic disease as well as primary liver malignancies.

Clinical Prediction Models for Prognosis of Colorectal Liver Metastases: A Comprehensive Review of Regression-Based and Machine Learning Models.

Colorectal liver metastasis (CRLM) is a disease entity that warrants special attention due to its high frequency and potential curability. Identification of "high-risk" patients is increasingly popular for risk stratification and personalization of the management pathway. Traditional regression-based methods have been used to derive prediction models for these patients, and lately, focus has shifted to artificial intelligence-based models, with employment of variable supervised and unsupervised techniques. Multiple endpoints, like overall survival (OS), disease-free survival (DFS) and development or recurrence of postoperative complications have all been used as outcomes in these studies. This review provides an extensive overview of available clinical prediction models focusing on the prognosis of CRLM and highlights the different predictor types incorporated in each model. An overview of the modelling strategies and the outcomes chosen is provided. Specific patient and treatment characteristics included in the models are discussed in detail. Model development and validation methods are presented and critically appraised, and model performance is assessed within a proposed framework.

Elective Appendectomy Following Antibiotics for Appendicitis.

This Viewpoint considers which may be the better long-term approach to appendicitis­interval elective appendectomy or nonsurgical treatment with antibiotics.

Regorafenib combined with a PD-1 inhibitor in the second-line setting for unresectable hepatocellular carcinoma in real-world practice.

Background: Most advanced hepatocellular carcinoma (HCC) cases administered molecular targeted agents and/or anti-programmed cell death-1 (PD-1) inhibitors have no response or develop resistance. Moreover, second-line therapies still cannot provide beneficial clinical outcomes. A pilot study assessing combined regorafenib and PD-1 inhibitor as second-line treatment of advanced HCC reported promising effectiveness. Methods: The current single-center, retrospective, real-world study was carried out between January 2019 and July 2021. Advanced HCC cases were administered second-line regorafenib combined with a PD-1 inhibitor or regorafenib alone were assessed. Progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were determined. Results: Totally 46 HCC cases were analyzed, most of whom underwent previous systemic treatment comprising targeted therapy and immunotherapy. Tumor response was evaluated in 25 and 21 individuals in the regorafenib + PD-1 inhibitor and regorafenib monotherapy groups, respectively: ORRs were 21.7% and 8.7%, and DCRs were 47.8% and 32.6%, respectively. Median PFS was markedly longer in the regorafenib plus PD-1 inhibitor group (11.5 months) compared with the regorafenib monotherapy group (5.1 months, P=0.049). Conclusions: This study suggested regorafenib and a PD-1 inhibitor in combination may provide significant clinical benefits in HCC cases showing progression following first-line treatment. Further analysis in real-world studies with large cohorts is warranted to confirm these findings.

Endovascular Treatment of a Multi-visceral Aortic Conduit Blowout With Parallel Stent Grafts and Coils.

Multi-visceral transplantation (MVT) is a complex surgical procedure involving the transplantation of multiple abdominal organs as a single unit, typically used as bailout treatment of patients with devastating abdominal pathologies. Due to the complexity of the procedure, major and even life-threatening complications can happen. Vascular complications, including anastomotic breakdowns or pseudoaneurysms due to infections, can be universally lethal. Open surgical repair is often not an option due to the hostile operative field. We report a case of endovascular salvage of multi-visceral aortic conduit blowout utilizing parallel stent grafts and coils without sacrifice of the transplanted viscera. This combination can successfully control bleeding and maintain graft perfusion in this rare but devastating complication.

Idiopathic Megaduodenum in a Teenager: A Case Report.

Megaduodenum is a rare clinical syndrome characterized by significant duodenal dilation, elongation, and hypertrophy. Given its rarity and nonspecific clinical manifestations, megaduodenum may be misdiagnosed, leading to delays in surgical care and increased morbidity. We describe a case of idiopathic megaduodenum in a teenage Caucasian female, who presented with a five-year history of halitosis, recurrent belching, bloating, nausea and vomiting, and postprandial epigastric abdominal pain. She was diagnosed with megaduodenum by dramatic findings on contrast radiography. She developed a duodenal volvulus necessitating emergency exploratory laparotomy, during which a duodenal plication and a side-to-side duodenojejunostomy were performed. Exploratory laparotomy and histopathological analysis were unrevealing of any definitive abnormalities to explain her megaduodenum. Postoperatively, she developed two early small bowel obstructions, both from subsequent adhesions requiring repeat laparotomy with adhesiolysis. She has subsequently recovered without incident. Diagnosis and accurate classification of megaduodenum requires surgical exploration with a full-thickness biopsy and subsequent histopathologic analysis to rule out obstructive or functional disorders of the duodenum. Treatment of megaduodenum depends on the underlying cause and degree of duodenal distention. It is crucial that clinicians are knowledgeable of the various surgical options, their indications, and the potential postoperative complications that may arise.

Banff 2022 Vascularized Composite Allotransplantation Meeting Report: Diagnostic criteria for vascular changes.

As more data become available, the Banff 2007 working classification of skin-containing vascularized composite allograft (VCA) pathology is expected to evolve and develop. This report represents the Banff VCA Working Group's consensus on the first revision of the 2007 scoring system. Prior to the 2022 Banff-CanXadian Society of Transplantation Joint Meeting, 83 clinicians and/or researchers were invited to a virtual meeting to discuss whether the 2007 Banff VCA system called for a revision. Unanimously, it was determined that the vascular changes were to be included in the first revision. Subsequently, 2 international online surveys, each followed by virtual discussions, were launched. The goals were (1) to identify which changes define severe rejection, (2) to grade their importance in the evaluation of severe rejection, and (3) to identify emerging criteria to diagnose rejection. A final hybrid (in-person and virtual) discussion at the Banff/Canadian Society of Transplantation Joint Meeting finalized the terminology, the definition, a scoring system, and a reporting system of the vascular changes. This proposal represents an international consensus on this topic and establishes the first revision of the Banff 2007 working classification of skin-containing vascularized composite allograft pathology.

Management of Colorectal Cancer Liver Metastases.

Ivey et al [...].

Surgical Management of Intrahepatic Cholangiocarcinoma: Quo Vadis.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy related to very high mortality rates [...].

Desensitization and belatacept-based maintenance therapy in pregnancy-sensitized monkeys receiving a kidney transplant.

Among sensitized patients awaiting a transplant, females are disproportionately represented, partly because of pregnancy-induced sensitization. Using female NHPs sensitized by pregnancy alone, we examined the efficacy of costimulation blockade and proteasome inhibition for desensitization. Three animals received no desensitization (control), and seven animals received weekly carfilzomib (27 mg/m2) and belatacept (20 mg/kg) before kidney transplantation. All animals received renal allografts from crossmatch-positive/maximally MHC-mismatched donors. Controls and three desensitized animals received tacrolimus-based immunosuppression. Four desensitized animals received additional belatacept with tacrolimus-based immunosuppression. Multiparous females had less circulating donor-specific antibody when compared to skin-sensitized males before transplantation. While females receiving desensitization showed only a marginal survival benefit over control females (MST = 11 days versus 63 days), additional belatacept to posttransplant maintenance significantly prolonged graft survival (MST > 164 days) and suppressed posttransplant DSA and circulating follicular helper T-like cells. This combination of therapies demonstrates great potential to reduce antibody-mediated rejection in sensitized recipients.

Immune Phenotype and Postoperative Complications After Elective Surgery.

OBJECTIVES: To characterize and quantify accumulating immunologic alterations, pre and postoperatively in patients undergoing elective surgical procedures. BACKGROUND: Elective surgery is an anticipatable, controlled human injury. Although the human response to injury is generally stereotyped, individual variability exists. This makes surgical outcomes less predictable, even after standardized procedures, and may provoke complications in patients unable to compensate for their injury. One potential source of variation is found in immune cell maturation, with phenotypic changes dependent on an individual's unique, lifelong response to environmental antigens. METHODS: We enrolled 248 patients in a prospective trial facilitating comprehensive biospecimen and clinical data collection in patients scheduled to undergo elective surgery. Peripheral blood was collected preoperatively, and immediately on return to the postanesthesia care unit. Postoperative complications that occurred within 30 days after surgery were captured. RESULTS: As this was an elective surgical cohort, outcomes were generally favorable. With a median follow-up of 6 months, the overall survival at 30 days was 100%. However, 20.5% of the cohort experienced a postoperative complication (infection, readmission, or system dysfunction). We identified substantial heterogeneity of immune senescence and terminal differentiation phenotypes in surgical patients. More importantly, phenotypes indicating increased T-cell maturation and senescence were associated with postoperative complications and were evident preoperatively. CONCLUSIONS: The baseline immune repertoire may define an immune signature of resilience to surgical injury and help predict risk for surgical complications.

A random forest model using flow cytometry data identifies pulmonary infection after thoracic injury.

BACKGROUND: Thoracic injury can cause impairment of lung function leading to respiratory complications such as pneumonia (PNA). There is increasing evidence that central memory T cells of the adaptive immune system play a key role in pulmonary immunity. We sought to explore whether assessment of cell phenotypes using flow cytometry (FCM) could be used to identify pulmonary infection after thoracic trauma. METHODS: We prospectively studied trauma patients with thoracic injuries who survived >48 hours at a Level 1 trauma center from 2014 to 2020. Clinical and FCM data from serum samples collected within 24 hours of admission were considered as potential variables. Random forest and logistic regression models were developed to estimate the risk of hospital-acquired and ventilator-associated PNA. Variables were selected using backwards elimination, and models were internally validated with leave-one-out. RESULTS: Seventy patients with thoracic injuries were included (median age, 35 years [interquartile range (IQR), 25.25-51 years]; 62.9% [44 of 70] male, 61.4% [42 of 70] blunt trauma). The most common injuries included rib fractures (52 of 70 [74.3%]) and pulmonary contusions (26 of 70 [37%]). The incidence of PNA was 14 of 70 (20%). Median Injury Severity Score was similar for patients with and without PNA (30.5 [IQR, 22.6-39.3] vs. 26.5 [IQR, 21.6-33.3]). The final random forest model selected three variables (Acute Physiology and Chronic Health Evaluation score, highest pulse rate in first 24 hours, and frequency of CD4 + central memory cells) that identified PNA with an area under the curve of 0.93, sensitivity of 0.91, and specificity of 0.88. A logistic regression with the same features had an area under the curve of 0.86, sensitivity of 0.76, and specificity of 0.85. CONCLUSION: Clinical and FCM data have diagnostic utility in the early identification of patients at risk of nosocomial PNA following thoracic injury. Signs of physiologic stress and lower frequency of central memory cells appear to be associated with higher rates of PNA after thoracic trauma. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level IV.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Systematic review and meta-analysis of open versus laparoscopy-assisted versus pure laparoscopic versus robotic living donor hepatectomy.

The value of minimally invasive approaches for living donor hepatectomy remains unclear. Our aim was to compare the donor outcomes after open versus laparoscopy-assisted versus pure laparoscopic versus robotic living donor hepatectomy (OLDH vs. LALDH vs. PLLDH vs. RLDH). A systematic literature review of the MEDLINE, Cochrane Library, Embase, and Scopus databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (up to December 8, 2021). Random-effects meta-analyses were performed separately for minor and major living donor hepatectomy. The risk of bias in nonrandomized studies was assessed using the Newcastle-Ottawa Scale. A total of 31 studies were included. There was no difference in donor outcomes after OLDH versus LALDH for major hepatectomy. However, PLLDH was associated with decreased estimated blood loss, length of stay (LOS), and overall complications versus OLDH for minor and major hepatectomy, but also with increased operative time for major hepatectomy. PLLDH was associated with decreased LOS versus LALDH for major hepatectomy. RLDH was associated with decreased LOS but with increased operative time versus OLDH for major hepatectomy. The scarcity of studies comparing RLDH versus LALDH/PLLDH did not allow us to meta-analyze donor outcomes for that comparison. There seems to be a marginal benefit in estimated blood loss and/or LOS in favor of PLLDH and RLDH. The complexity of these procedures limits them to transplant centers with high volume and experience. Future studies should investigate self-reported donor experience and the associated economic costs of these approaches.

Management and outcomes of mixed adenoneuroendocrine carcinoma of the ampulla of Vater: A systematic review and pooled analysis of 56 patients.

BACKGROUND: Tumors of mixed neuroendocrine and nonneuroendocrine histology are classified as collision, combined, or amphicrine and can occur in most organs, including the hepato-pancreato-biliary tract. Given the rarity of mixed adenoneuroendocrine carcinoma (MANEC) of the ampulla of Vater, the patient characteristics, management, and outcomes remain unclear. We sought to systematically review the worldwide literature on ampullary MANECs. METHODS: Eligible studies were identified through a systematic search of the MEDLINE (via PubMed), Scopus, and Cochrane Library databases (end-of-search-date: January 5th, 2022), according to the PRISMA 2020 statement. RESULTS: A total of 39 studies reporting on 56 patients with ampullary MANEC were included. The median age was 63.0 (interquartile range [IQR]: 51.0-69.0) years and 55.6% were male (n = 25/45). Most had combined tumors (64.4%; n = 29/45), followed by collision (24.4%; n = 11/45), and amphicrine tumors (11.1%; n = 5/45). More than half had lymph node metastasis (56.8%; n = 25/44), yet only 7.9% had distant metastasis (n = 3/38). Tumor resection (i.e., mostly pancreaticoduodenectomy) was performed in 96.3% (n = 52/54), followed by adjuvant chemotherapy in 61.8% (n = 21/34). Nearly half experienced disease recurrence (47.2%; n = 17/36) over a median follow-up of 12.0 (IQR: 3.0-16.0) months, and 42.1% (n = 16/38) died over a median follow-up of 12.0 (IQR: 4.0-18.0) months. The most common cause of death was disease progression/recurrence in 81.3% (n = 13/16). CONCLUSION: Early diagnosis and management of ampullary MANEC is challenging yet crucial to improve outcomes since many patients are diagnosed at an advanced disease stage and have unfavorable outcomes. Multicenter granular data are warranted to further understand and improve outcomes in these patients.

Leadership Training in Medicine-12 Years of Experience From the Feagin Leadership Program.

INTRODUCTION: Increasingly, physicians find themselves in demanding leadership positions. However, leadership education for medical trainees remains lacking with most physicians reporting that they are ill-equipped to tackle the challenges of leadership. Here, we set out to describe the Feagin Leadership Program (FLP) and assess its reception and impact on trainees over the past 12 years. MATERIALS AND METHODS: During the 1-year FLP, selected scholars from Duke University, Wake Forest University, and the University of North Carolina participate in five leadership sessions, individual coaching, a leadership forum, and a multidisciplinary team-based capstone project. A 28-question survey with six optional free-response questions was distributed to the Feagin Alumni Network, and descriptive statistics were assessed. RESULTS: Since its founding, 212 scholars have graduated from the FLP and 117 (55%) alumni have gone on to surgical specialties. A survey was distributed among all Feagin alumni. A total of 56 (26%) surveys were completed. Forty-three percent (n = 24) had held at least one leadership position since completing the FLP. When asked about the impact of their experience, 96% (n = 54) said that the program encouraged them to pursue a position of leadership within their field, 95% (n = 53) stated that it prepared them for such a position, and 93% (n = 52) stated that the program positively influenced their decision to be involved with current or future positions of leadership. CONCLUSIONS: Over the last 12 years, the FLP has demonstrated a high perceived impact on personal growth, leadership proficiency, and the decision to pursue leadership positions in medicine. The current dearth of leadership education for surgical trainees can best be addressed with models such as the FLP, with adoption benefiting medical trainees, the medical community, and patients they serve.