Thyroid Hormone Levels Correlate With the Maturation of Implanted Pancreatic Endoderm Cells in Patients With Type 1 Diabetes.

BACKGROUND: Macroencapsulated pancreatic endoderm cells (PECs) can reverse diabetes in rodents and preclinical studies revealed that thyroid hormones in vitro and in vivo bias PECs to differentiate into insulin-producing cells. In an ongoing clinical trial, PECs implanted in macroencapsulation devices into patients with type 1 diabetes were safe but yielded heterogeneous outcomes. Though most patients developed meal responsive C-peptide, levels were heterogeneous and explanted grafts had variable numbers of surviving cells with variable distribution of endocrine cells. METHODS: We measured circulating triiodothyronine and thyroxine levels in all patients treated at 1 of the 7 sites of the ongoing clinical trial and determined if thyroid hormone levels were associated with the C-peptide or glucagon levels and cell fate of implanted PECs. RESULTS: Both triiodothyronine and thyroxine levels were significantly associated with the proportion of cells that adopted an insulin-producing fate with a mature phenotype. Thyroid hormone levels were inversely correlated to circulating glucagon levels after implantation, suggesting that thyroid hormones lead PECs to favor an insulin-producing fate over a glucagon-producing fate. In mice, hyperthyroidism led to more rapid maturation of PECs into insulin-producing cells similar in phenotype to PECs in euthyroid mice. CONCLUSION: These data highlight the relevance of thyroid hormones in the context of PEC therapy in patients with type 1 diabetes and suggest that a thyroid hormone adjuvant therapy may optimize cell outcomes in some PEC recipients.

Outcomes of liver transplant recipients with high MELD scores: an experience from a Canadian centre.

BACKGROUND: The frequency with which patients with high Model for End-Stage Liver Disease (MELD) scores undergo liver transplantation has been increasing. Canadian literature regarding the outcomes of liver transplantation in recipients with high MELD scores is limited. The primary objective of this study was to assess patient and graft survival among recipients with high (> 35) and low (≤ 35) MELD scores. Secondary objectives were to potentially identify independent predictors of graft failure and patient mortality. METHODS: We conducted a retrospective chart review of patients undergoing liver transplantation at a single Canadian centre from 2012 to 2017. RESULTS: A total of 332 patients were included in the study: 280 patients had a MELD score of 35 or lower, and 52 had a MELD score above 35. Patients with high MELD scores had higher rates of pretransplant acute kidney injury and dialysis (p < 0.001), admission to the intensive care unit (ICU) or intubation (p < 0.001), intraoperative blood product transfusions (p < 0.001) and post-transplantation acute kidney injury and dialysis (p < 0.001), as well as longer ICU (p < 0.001) and hospital stays (p = 0.002). One- and 3-year patient survival in recipients with MELD scores of 35 or lower was 93.1% and 84.9% versus 85.0% and 80.0% in recipients with MELD scores above 35 (p = 0.37). One- and 3-year graft survival in recipients with MELD scores of 35 or lower was 91.7% and 90.9% versus 77.2% and 72.8% in recipients with MELD scores above 35 (p < 0.001). Prior liver transplant was an independent predictor of patient mortality, and no independent predictors of graft failure were identified. When MELD was replaced with D-MELD (donor age × recipient MELD), it predicted graft failure but not patient survival. CONCLUSION: No difference in patient mortality was found between MELD groups. Graft survival was significantly lower in recipients with MELD scores above 35. D-MELD may potentially be used as an adjunct in determining risk of graft failure in recipients with high MELD scores.

Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes.

An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1high T cells, and IL17A+CD4+ T cells. Explanted grafts contained cells with a mature ß cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.

Successful Liver Transplantation in a Patient With Acute COVID-19 Infection and Acute Liver Failure: A Case Report.

Current liver transplantation societies recommend recipients with active coronavirus disease 2019 (COVID-19) be deferred from transplantation for at least 2 wks, have symptom resolution and at least 1 negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test.1 This approach does not address patients who require urgent transplantation and will otherwise die from liver failure. We report a successful orthotopic liver transplant (OLT) in a patient with active COVID-19 infection. This is only the second to be reported worldwide and the first in Canada.

The role of intraperitoneal chemotherapy in the surgical management of pancreatic ductal adenocarcinoma: a systematic review.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis, particularly for patients with metastatic disease. Treatment for oligometastatic presentation has been reported in recent literature, but the role of intraperitoneal chemotherapy for patients with peritoneal metastases (PM) remains unclear. We performed a systematic literature search of the PubMed, Cochrane and Embase databases in order to identify clinical trials and case-series reporting on the safety and efficacy of intraperitoneal chemotherapy in patients with PDAC-derived PM. Eight publications reporting on 85 patients were identified, using three different therapeutic strategies. First, 37 patients received cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for PDAC with PM. Grade 3 and 4 complications occurred in 37.8% of patients, without perioperative mortality. Median disease-free survival and overall survival (OS) rates varied from 4 to 36 months and 4 to 62 months, respectively. Secondly, 40 patients with resectable PDAC without PM received prophylactic HIPEC following pancreatic resection, with postoperative morbidity and mortality rates of 30% and 5%, and 5-year OS rates of 23-24%. Finally, eight patients with PDAC-derived peritoneal disease were converted to resectable disease after receiving neoadjuvant intraperitoneal chemotherapy and operated on with curative intent, achieving a median OS of 27.8 months. In conclusion, CRS with HIPEC for PDAC-derived PM appears to be safe, conferring the same postoperative morbidity and mortality as reported on non-pancreatic malignancies. In highly selected patients, it could be considered for short-term disease control. However, long-term survival remains poor. The addition of prophylactic HIPEC for resectable PDAC cannot be recommended.

Pancreatic Gastrinoma, Gastrointestinal Stromal Tumor (GIST), Pheochromocytoma, and Hürthle Cell Neoplasm in a Patient with Neurofibromatosis Type 1: A Case Report and Literature Review.

BACKGROUND Neurofibromatosis type 1 (NF1) is a multi-tumor syndrome in which affected patients develop malignancies that are rare in the overall population, such as tumors of neural or endocrine origin. CASE REPORT A 67-year-old woman with a clinical diagnosis of NF1 presented with abdominal pain and pneumoperitoneum. She underwent small-bowel resections for a perforated jejunal lesion and a second lesion in the ileum; pathology showed a neurofibroma at the site of the perforation and a 1-cm low-grade GIST, respectively. Additional staging with cross-sectional imaging identified a 3.7-cm pancreatic head mass and a 1.7-cm left adrenal mass; biochemical studies revealed elevated serum gastrin and urinary free metanephrines and catecholamines consistent with pheochromocytoma. Initial surgical management was a left posterior retroperitoneoscopic adrenalectomy. Postoperatively, gallium-68-DOTATOC PET/CT showed uptake in the pancreatic head and a 28-mm left thyroid nodule. Months later, she had an open pancreaticoduodenectomy. Pathology showed pheochromocytoma and a low-grade (G1) gastrinoma involving 2/8 peripancreatic lymph nodes (pT3pN1M0), respectively. Fine-needle aspiration biopsy of the thyroid nodule showed features consistent with a Hürthle cell neoplasm. Genetic testing identified a pathogenic mutation in NF1 and no mutations in BRCA1/2, CDC72, MEN1, or PALB2. The patient continues surveillance, with no evidence of recurrent disease. CONCLUSIONS We report the fifth case of gastrinoma associated with NF1 and the first to arise from the pancreas. This case of a pancreatic neuroendocrine tumor was associated with multiple additional neoplasms. Neuroendocrine tumors found in NF1 should raise suspicion of other malignancies.

Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening.

BACKGROUND: Recent guidelines recommend consideration of germline testing for all newly diagnosed pancreatic ductal adenocarcinoma (PDAC). The primary aim of this study was to determine the burden of hereditary cancer susceptibility in PDAC. A secondary aim was to compare genetic testing uptake rates across different modes of genetic counselling. PATIENTS AND METHODS: All patients diagnosed with PDAC in the province of British Columbia, Canada referred to a population-based hereditary cancer program were eligible for multi-gene panel testing, irrespective of cancer family history. Any healthcare provider or patients themselves could refer. RESULTS: A total of 305 patients with PDAC were referred between July 2016 and January 2019. Two hundred thirty-five patients attended a consultation and 177 completed index germline genetic testing. 25/177 (14.1%) of unrelated patients had a pathogenic variant (PV); 19/25 PV were in known PDAC susceptibility genes with cancer screening or risk-reduction implications. PDAC was significantly associated with PV in ATM (OR, 7.73; 95% CI, 3.10 to 19.33, P = 6.14E-05) when comparing age and gender and ethnicity-matched controls tested on the same platform. The overall uptake rate for index testing was 59.2% and was significantly higher with 1-on-1 consultations and group consultations compared to telehealth consultations (88.9% vs 82.9% vs 61.8%, P < .001). CONCLUSION: In a prospective clinic-based cohort of patients with PDAC referred for testing irrespective of family history, germline PV were detected in 14.1%. PV in ATM accounted for half of all PVs and were significantly associated with PDAC. These findings support recent guidelines and will guide future service planning in this population.

The role of multiorgan procurement for abdominal transplant in general surgery resident education.

BACKGROUND: To assess the impact of participation of multiorgan procurement (MP) by general surgery (GS) residents on surgical knowledge and skills, a prospective cohort study of GS residents during transplant surgery rotation was performed. METHODS: Before and after participation in MPs, assessment of knowledge was performed by written pre and post tests and surgical skills by modified Objective Structured Assessment of Technical Skill (OSATS) score. Thirty-nine residents performed 84 MPs. RESULTS: Significant improvement was noted in the written test scores (63.3% vs 76.7%; P < 0.001). Better surgical score was associated with female gender (15.4 vs 13.3, P = <0.01), prior MP experience (16.2 vs 13.7, P = 0.03), and senior level resident (15.1 vs 13.0, P = 0.03). Supraceliac aortic dissection (P = 0.0017) and instrument handling (P = 0.041) improved with more MP operations. CONCLUSIONS: Participation in MP improves residents' knowledge of abdominal anatomy and surgical technique.

Significance of measured intraoperative portal vein flows after thrombendvenectomy in deceased donor liver transplantations with portal vein thrombosis.

Adequate portal vein (PV) flow in liver transplantation is essential for a good outcome, and it may be compromised in patients with portal vein thrombosis (PVT). This study evaluated the impact of intraoperatively measured PV flow after PV thrombendvenectomy on outcomes after deceased donor liver transplantation (DDLT). The study included 77 patients over a 16-year period who underwent PV thrombendvenectomy with complete flow data. Patients were classified into 2 groups: high PV flow (>1300 mL/minute; n = 55) and low PV flow (≤1300 mL/minute; n = 22). Postoperative complications and graft survival were analyzed according to the PV flow. The 2 groups were similar in demographic characteristics. Low PV flow was associated with higher cumulative rates of biliary strictures (P = 0.02) and lower 1-, 2-, and 5-year graft survival (89%, 85%, and 68% versus 64%, 55%, and 38%, respectively; P = 0.002). There was no difference in the incidence of postoperative PVT between the groups (1.8% versus 9.1%; P = 0.19). No biliary leaks or hepatic artery thromboses were reported in either group. By multivariate analyses, age >60 years (hazard ratio [HR], 3.04, 95% confidence interval [CI], 1.36-6.82; P = 0.007) and low portal flow (HR, 2.31; 95% CI, 1.15-4.65; P = 0.02) were associated with worse survival. In conclusion, PV flow <1300 mL/minute after PV thrombendvenectomy for PVT during DDLT was associated with higher rates of biliary strictures and worse graft survival. Consideration should be given to identifying reasons for low flow and performing maneuvers to increase PV flow when intraoperative PV flows are <1300 mL/minute. Liver Transplantation 23 1032-1039 2017 AASLD.

Low Measured Hepatic Artery Flow Increases Rate of Biliary Strictures in Deceased Donor Liver Transplantation: An Age-Dependent Phenomenon.

BACKGROUND: This study was conducted to determine effect of lower measured hepatic arterial (HA) flow (<400 mL/min) on biliary complications and graft survival after deceased donor liver transplantation. Hepatic artery is the main blood supply to bile duct and lack of adequate HA flow is thought to be a risk factor for biliary complications. METHODS: A retrospective review of 1300 patients who underwent deceased donor liver transplantation was performed. Patients with arterial complications were excluded to eliminate potential contribution to biliary complications from HA thrombosis. Patients were divided into low (<400 mL/min; N = 201) and high (≥400 mL/min; N = 1099) HA flow groups. Incidence of biliary complications and graft survival were analyzed. RESULTS: HA flows less than 400 mL/min were associated with increased rate of biliary strictures in younger donors (<50 years old), and in patients with duct-to-duct anastomoses (P = 0.028). Lower HA flows were associated with decreased graft survival (P = 0.013). Donor older than 50 years was associated with increased rate of biliary strictures (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.14-2.45; P = 0.0085) and graft failure (HR, 1.68; 95% CI, 1.35-2.1; P <0.0001) on multivariate analyses. HA flow less than 400 mL/min was associated with biliary strictures (HR, 1.53; 95% CI, 1.04-2.24; P = 0.0297) on univariate analysis only. CONCLUSIONS: HA flow less than 400 mL/min was associated with higher rate of biliary strictures in younger donors with duct-to-duct reconstruction and lower graft survival. A consideration should be given to increase the intraoperative HA flow to prevent biliary strictures in such patients.

Living donor liver transplantation in the USA.

Living donor liver transplant (LDLT) accounts for a small volume of the transplants in the USA. Due to the current liver allocation system based on the model for end-stage liver disease (MELD), LDLT has a unique role in providing life-saving transplantation for patients with low MELD scores and significant complications from portal hypertension, as well as select patients with hepatocellular carcinoma (HCC). Donor safety is paramount and has been a topic of much discussion in the transplant community as well as the general media. The donor risk appears to be low overall, with a favorable long-term quality of life. The latest trend has been a gradual shift from right-lobe grafts to left-lobe grafts to reduce donor risk, provided that the left lobe can provide adequate liver volume for the recipient.

Prevention and treatment of liver allograft antibody-mediated rejection and the role of the 'two-hit hypothesis'.

PURPOSE OF REVIEW: The review outlines the diagnosis, prevention strategies, and possible treatment options for acute and chronic antibody-mediated rejection (AMR). RECENT FINDINGS: Although rare, severe acute AMR (aAMR) usually occurs in patients with high mean fluorescence intensity despite serial dilutions or high-titer preformed class I donor-specific alloantibodies (DSA). The diagnosis is suspected when allograft dysfunction occurs with DSA, diffuse C4d staining, and a microvascular injury, and may be aided by the aAMR score. However, the incidence of and treatment approach to combined T-cell-mediated rejection (TCMR) with DSA present and some but not all features of AMR is yet to be determined. Chronic liver allograft AMR is characterized by low-grade chronic inflammation and progressive fibrosis with DSA, the chronic AMR (cAMR) score may facilitate diagnosis. The 'two-hit' hypothesis, whereby a coexistent insult upregulates human leukocyte antigen class II target antigens on the microvascular endothelium, may explain why suboptimal donors with lower sensitization levels might suffer from acute AMR and those with chronic complications (e.g., recurrent original disease) might be more susceptible to chronic AMR. Although treatment algorithms are needed, prevention is preferable and at a minimum includes transfusion minimization, and medication adherence. SUMMARY: Severe acute AMR is rare but diagnosable, and there is need to determine the incidence of and optimal therapy for less severe combined AMR and TCMR. Chronic AMR is likely more common and of significant relevance to long-term allograft survival improvement. The two-hit hypothesis may help to explain the rarity of both findings and shed insight onto future prevention and treatment strategies.

Inferior vena cava reconstruction for leiomyosarcoma of Zone I-III requiring complete hepatectomy and bilateral nephrectomy with autotransplantation.

The inferior vena cava (IVC) is the most common site of leiomyosarcomas arising from a vascular origin. Leiomyosarcomas of the IVC are categorized by anatomical location. Zone I refers to the infrarenal portion of the IVC, Zone II from the hepatic veins to the renal veins, and Zone III from the right atrium to the hepatic veins. This is a rare presentation of a Zone I-III leiomyosarcoma. Fifty-two-years-old female with a medical history significant only for HTN was admitted to the hospital with bilateral lower extremity edema and dyspnea. Two-dimensional echo demonstrated a right atrial thrombus, extending into the IVC. On subsequent CT and MRI, a 15 cm mass was noted that began in the right atrium and extended into the IVC, with continuation below the renal veins to above the level of the confluence of the common iliac veins. The patient underwent a complete resection of the mass, replacement of the IVC with Dacron graft, total hepatectomy and bilateral nephrectomy, with liver and kidney autotransplantation. Pathology was consistent with a high grade spindle cell sarcoma of vena cava origin. Patient was readmitted approximately 4 weeks postoperatively to begin adjuvant chemotherapy. This case represents a zone I-III IVC leiomyosarcoma treated with surgical R0 resection. This included a hepatectomy, bilateral nephrectomy, and hepatic and left renal autotransplantation. These complex tumors should be treated with surgical resection, and require a multidisciplinary approach.

Long-term follow-up of biliary complications after adult right-lobe living donor liver transplantation.

INTRODUCTION: Long-term biliary complications after living donor liver transplantation (LDLT) are not well described in the literature. This study was undertaken to determine the long-term impact of biliary complications after adult right-lobe LDLT. METHODS: This retrospective review analyzed an 11-yr experience of 344 consecutive right-lobe LDLTs with at least two yr of follow-up. RESULTS: Biliary leaks occurred in 50 patients (14.5%), and strictures occurred in 67 patients (19.5%). Cumulative biliary complication rates at 1, 2, 5, and 10 yr were 29%, 32%, 36%, and 37%, respectively. Most early biliary leaks were treated with surgical drainage (N = 29, 62%). Most biliary strictures were treated first with endoscopic retrograde cholangiography (42%). There was no association between biliary strictures and the number of ducts (hazard ratio [HR] 1.017 [0.65-1.592], p = 0.94), but freedom from biliary stricture was associated with a more recent era (2006-2010) (HR 0.457 [0.247-0.845], p = 0.01). Long-term graft survival did not differ between those who had or did not have biliary complications (66% vs. 67% at 10 yr). CONCLUSIONS: Biliary strictures are common after LDLT but may decline with a center's experience. With careful follow-up, they can be successfully treated, with excellent long-term graft survival rates.

Improved long-term outcomes after resection of pancreatic adenocarcinoma: a comparison between two time periods.

BACKGROUND: Despite reduced perioperative mortality and routine use of adjuvant therapy following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), improvement in long-term outcome has been difficult to ascertain. This study compares outcomes in patients undergoing resection for PDAC within a single, high-volume academic institution over two sequential time periods. METHODS: Retrospective review of patients with resected PDAC, in two cohorts: period 1 (P1), 1991-2000; and period 2 (P2), 2001-2010. Univariate and multivariate analyses using the Cox proportional hazards model were performed to determine prognostic factors associated with long-term survival. Survival was evaluated using Kaplan-Meier analyses. RESULTS: A total of 179 pancreatectomies were performed during P1 and 310 during P2. Perioperative mortality was 6.7 % (12/179) in P1 and 1.6 % (5/310) in P2 (p = 0.003). P2 had a greater number of lymph nodes resected (17 [0-50] vs. 7 [0-31]; p < 0.001), and a higher lymph node positivity rate (69 % [215/310] vs. 58 % [104/179]; p = 0.021) compared with P1. The adjuvant therapy rate was 30 % (53/179) in P1 and 63 % (195/310) in P2 (p < 0.001). By multivariate analysis, node and margin status, tumor grade, adjuvant therapy, and time period of resection were independently associated with overall survival (OS) for both time periods. Median OS was 16 months (95 % confidence interval [CI] 14-20) in P1 and 27 months (95 % CI 24-30) in P2 (p < 0.001). CONCLUSIONS: Factors associated with improved long-term survival remain comparable over time. Short- and long-term survival for patients with resected PDAC has improved over time due to decreased perioperative mortality and increased use of adjuvant therapy, although the proportion of 5-year survivors remains small.