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Background: With the advent of peptide receptor radionuclide therapy, the timing and sequence of surgery in the treatment of metastatic gastroenteropancreatic neuroendocrine tumors merits further study. We hypothesized that surgery before peptide receptor radionuclide therapy might enhance its effectiveness in patients with metastatic gastroenteropancreatic neuroendocrine tumors., Methods: Eighty-nine patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors treated with 177 Lutetium-dotatate peptide receptor radionuclide therapy between 2018 and 2023 were included. Fifty-six patients underwent surgery (primary tumor resection and/or liver debulking) before peptide receptor radionuclide therapy and 33 patients did not. Primary outcome was progression-free survival according to Response Evaluation Criteria in Solid Tumors. Pretreatment dotatate positron emission tomography/computed tomography was used to calculate tumor volumes., Results: The surgery and no-surgery groups were well-matched. Median progression-free survival after peptide receptor radionuclide therapy was 15.6 months (interquartile range, 9.1-22.7 months) in the no-surgery group compared with 26.1 months (interquartile range, 12.7-38.1 months) in the surgery group (P = .04). On subgroup analysis, median progression-free survival was 18.1 months (interquartile range, 11.9-38.4 months) in patients who underwent primary tumor resection only compared with 26.2 months (interquartile range, 14.0-38.1 months) in patients who underwent liver debulking (P = .04). Tumor volume was lowest in patients who underwent liver debulking (median 146.07 mL 3 ) compared with no surgery (median 626.42 mL 3 ) (P = .001). On univariable analysis, a tumor volume <138.8 mL 3 was associated with longer progression-free survival (hazard ratio, 2.03; 95% confidence interval, 0.95-4.34, P = .05), with a median progression-free survival of 38.1 months (interquartile range, 16.9-41.3 months) compared with 17.8 months (interquartile range, 10.8-28.7 months)., Conclusion: Surgery may enhance the effectiveness of 177 Lutetium-dotatate in the treatment of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors. This positive effect may be the result of a lower tumor volume in patients after surgery. Our findings fortify the concept of using surgical debulking to improve systemic therapies such as peptide receptor radionuclide therapy., Competing Interests: Conflicts of Interest/Disclosure The authors have no potential conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Across surgery, marginalized individuals experience worse postoperative outcomes. These disparities stem from the interplay between multiple factors., Methods: We introduced a novel framework to assess the role of barriers to access and bias in surgical complications (the uChicago Health Inequity Classification System, CHI-CS) in the setting of morbidity and mortality conference and assessed impact through pre and post implementation surveys., Results: Access and bias were related to surgical complications in 14 ​% of cases. 97 ​% reported enhanced M&M presentations with the grading system, and 47 ​% reported a change in decision-making or practice style. Although post-implementation response rate was low, there were improvements in self-reported confidence and comfort in recognizing and discussing these issues., Conclusions: Implementation of the CHI-CS framework to discuss bias and access to care positively impacted the way providers view, discuss, and process health inequities., Competing Interests: Declaration of competing interest I declare that the manuscript is original, has not been published before, and is not currently being considered for publication elsewhere and will not be sent to another journal until a decision is made concerning publication by The American Journal of Surgery. The authors have no relevant financial disclosures or conflict of interests. All authors have seen and approved the final version of this manuscript as well as fulfill the COPE (Committee on Publication Ethics) requirements for authorship., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hepatic inflammatory myofibroblastic tumours (HIMTs) are rare and poorly described in the literature. Most publications are single patient case reports and lack detailed reporting on characteristics, management, and outcomes. This systematic review aimed to assess the demography, clinical presentation, typical imaging features, histopathology, treatment, and outcomes of patients presenting with HIMTs., Methods: A systematic literature search was performed in MEDLINE (PubMed), EMBASE (Scopus), JSTOR, Cochrane CENTRAL (Cochrane Library), and the databases included in the Web of Science for studies published between 1940 and 2023 on HIMTs, including its reported synonyms. Case series or cohort studies that reported on the management and outcomes of at least four patients with histologically confirmed HIMTs were included in the analysis., Results: After screening 4553 publications, 22 articles including a total of 440 patients with confirmed HIMTs were eligible for inclusion. The average age was 53.4 years (range 42.0-65.0) with a male to female ratio of 1.7:1. Abdominal pain, discomfort, fever, and loss of weight were the most common presenting symptoms. Surgical resection is the standard of care for HIMTs and is associated with low mortality of 3.4% and low disease recurrence., Conclusion: HIMT is a disease more often affecting middle-aged males. The lesions are typically solitary with low recurrence after treatment. The relative roles of surgical versus medical treatment remain unclear. Differences in clinical presentation, histopathology, and treatment of HIMTs compared to inflammatory myofibroblastic tumour (IMT) at extrahepatic sites could challenge the current view of IMT as a single pathological entity., (Copyright© Authors.)

Background: Reported outcomes after surgical debulking in patients with advanced neuroendocrine tumor liver metastases (NETLM) are sparse., Methods: NETLM patients that underwent surgical debulking from 2019 to 2021 were reviewed. Trends in perioperative liver function, complications, symptom response, and progression-free survival were examined., Results: 1069 liver lesions were debulked from 53 patients using a combination of parenchymal-sparing resections (PSR) and ultrasound-guided microwave ablations (MWA). Post-operative transaminitis and thrombocytopenia were common, and severity correlated with increasing number of lesions. Laboratory markers for synthetic liver function did not differ according to the number of lesions debulked. 13% of patients sustained a Clavien-Dindo grade 3 or 4 complication which was not associated with the number of lesions targeted. All patients with preoperative symptoms had improvement after surgery. Median time to progression was 10.9 months., Conclusions: PSR with MWA for large numbers of NETLM is safe and effective for symptom control and does not affect synthetic liver function., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts nor competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The aim of this review was to review the ethical and multidisciplinary clinical challenges facing trauma surgeons when resuscitating patients presenting with penetrating brain injury (PBI) and multicavitary trauma., Background: While there is a significant gap in the literature on managing PBI in patients presenting with multisystem trauma, recent data demonstrate that resuscitation and prognostic features for such patients remains poorly described, with trauma guidelines out of date in this field., Methods: We reviewed a combination of recent multidisciplinary evidence-informed guidelines for PBI and coupled this with expert opinion from trauma, neurosurgery, neurocritical care, pediatric and transplant surgery, surgical ethics and importantly our community partners., Results: Traditional prognostic signs utilized in traumatic brain injury may not be applicable to PBI with a multidisciplinary team approach suggested on a case-by-case basis. Even with no role for neurosurgical intervention, neurocritical care, and neurointerventional support may be warranted, in parallel to multicavitary operative intervention. Special considerations should be afforded for pediatric PBI. Ethical considerations center on providing the patient with the best chance of survival. Consideration of organ donation should be considered as part of the continuum of patient, proxy and family-centric support and care. Community input is crucial in guiding decision making or protocol establishment on an institutional level., Conclusions: Support of the patient after multicavitary PBI can be complex and is best addressed in a multidisciplinary fashion with extensive community involvement., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Normothermic machine perfusion (NMP) allows viability assessment and potential resuscitation of donor livers prior to transplantation. The immunological effect of NMP on liver allografts is undetermined, with potential implications on allograft function, rejection outcomes and overall survival. In this study we define the changes in immune profile of human livers during NMP., Methods: Six human livers were placed on a NMP device. Tissue and perfusate samples were obtained during cold storage prior to perfusion and at 1, 3, and 6 hours of perfusion. Flow cytometry, immunohistochemistry, and bead-based immunoassays were used to measure leukocyte composition and cytokines in the perfusate and within the liver tissue. Mean values between baseline and time points were compared by Student's t-test., Results: Within circulating perfusate, significantly increased frequencies of CD4 T cells, B cells and eosinophils were detectable by 1 hour of NMP and continued to increase at 6 hours of perfusion. On the other hand, NK cell frequency significantly decreased by 1 hour of NMP and remained decreased for the duration of perfusion. Within the liver tissue there was significantly increased B cell frequency but decreased neutrophils detectable at 6 hours of NMP. A transient decrease in intermediate monocyte frequency was detectable in liver tissue during the middle of the perfusion run. Overall, no significant differences were detectable in tissue resident T regulatory cells during NMP. Significantly increased levels of pro-inflammatory and anti-inflammatory cytokines were seen following initiation of NMP that continued to rise throughout duration of perfusion., Conclusions: Time-dependent dynamic changes are seen in individual leukocyte cell-types within both perfusate and tissue compartments of donor livers during NMP. This suggests a potential role of NMP in altering the immunogenicity of donor livers prior to transplant. These data also provide insights for future work to recondition the intrinsic immune profile of donor livers during NMP prior to transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Edobor, Lysandrou, Mirle, Sadek, Johnston, Piech, Rose, Hart, Amundsen, Jendrisak, Millis, Donington, Madariaga, Barth, di Sabato, Shanmugarajah and Fung.)

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.

Background: The COVID-19 has grown into a global pandemic. This study investigated the public psychosocial and behavioral responses through different time periods of the pandemic, and assessed whether these changes are different in age, gender, and region. Methods: A three-phase survey was conducted through the DaDui Social Q&A Software for COVID-19. A total of 13,214 effective responses of COVID-19 were collected. Statistical analysis was performed based on their basic information and psychosocial responses. Results: The degree of attention, understanding, and cooperation with preventive and control measures of the disease increased and then decreased. The panic level gradually increased with the epidemic process. The degree of satisfaction with management measures and of confidence in defeating COVID-19 increased throughout the survey. Compared with residents in other areas, respondents from the COVID-19 epicenter (Wuhan) reported a higher degree of self-protection during the outbreak and a significantly lower degree of satisfaction with respect to government prevention and control measures during all phases. Shortages of medical supplies and low testing capacity were reported as the biggest shortcoming in the prevention and control strategies during COVID-19, and an abundance of disorderly and inaccurate information from different sources was the primary cause of panic. Conclusions and Relevance: Major public health events elicit psychosocial and behavioral changes that reflect the different phases of the biologic curve. Sufficient medical supplies and improved organization and accurate information during epidemics may reduce panic and improve compliance with requested changes in behavior. We need to recognize this natural phenomenon and our public policy preparedness should attempt to move the social/psychological curve to the left in order to minimize and flatten the biologic curve., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Xian, Hu, Millis, Zhao, Lu, Sang, Zhong, Zhang, Yin and Mao.)

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The rapid spread of COVID-19 underscores the need for new treatments. Here we report that cannabidiol (CBD), a compound produced by the cannabis plant, inhibits SARS-CoV-2 infection. CBD and its metabolite, 7-OH-CBD, but not congeneric cannabinoids, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after cellular infection, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD induces interferon expression and up-regulates its antiviral signaling pathway. A cohort of human patients previously taking CBD had significantly lower SARS-CoV-2 infection incidence of up to an order of magnitude relative to matched pairs or the general population. This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection.

A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin ( N = 8) or placebo ( N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years ( P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group ( n = 7) than in the placebo ( n = 3) group ( P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT ( P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov.

We present a patient with intractable and debilitating pain secondary to chronic pancreatitis who was effectively treated with total pancreatectomy with islet autotransplantation (TPIAT). Islets engrafted into his liver significantly contributed to improved blood glucose control and quality of life. Subsequently, the patient developed alcohol related acute liver failure and en bloc liver and pancreas transplantation was performed to replace the failing liver with engrafted islets. Pancreas transplantation was required to resolve his life-threatening severe hypoglycemic episodes. Herein, we detail an innovative and multidisciplinary management of this complex medical problem., Competing Interests: Disclosure The authors declare no conflict of interest.

SmartFlare™ RNA Detection Probes from Millipore is a novel technology to detect RNA in live cells based on the use of 12 nm gold nanoparticles coated with nucleotides. We proved that SmartFlares™ are internalized by human primary lymphocytes. However, fluorescence signals from target RNA detection can only be observed in the presence of Fetal Bovine Serum (FBS) in the medium, whereas it is not detectable without FBS or when medium is supplemented with human albumin. Image analysis of fluorescence generated from SmartFlare™ Uptake Control (gives constant signal regardless of contact with RNA) and RNA Specific Probes revealed further differences. In the presence of FBS, the fluorescence signal for both reagents was diffused within the cells, whereas in the absence of FBS, it was detected as single spots within the cells only when the Uptake Control was used. It is possible that FBS components are necessary for SmartFlare™ Probes to be released from cellular compartments into the cytoplasm where they can get into contact with target RNA. The exact mechanism of this phenomena should be further determined. However, for the first time, we present here that FBS in the cell culture medium is essential for RNA detection by SmartFlare™ technology in human lymphocytes., Competing Interests: Compliance with Ethical Standards: Conflict of Interest: The authors declare that they have no conflict of interest.

Background: Migration of the left hepatic lobe into the potential space following right lobe resection can result in torsion and hepatic venous outflow obstruction with compromised venous return from the IVC. If untreated, significant morbidity and mortality can develop., Case Presentation: We report a case of a 29-year-old female with Lynch syndrome who underwent right lobe resection for a metastatic hepatic tumor. There was subsequent migration of the liver remnant, torsion of the IVC, and impaired hepatic outflow, successfully treated with thrombectomy and stenting., Conclusion: Following right hepatectomy, hepatic venous outflow obstruction should be consdered in the setting of hepatorenal failure and hemodynamic instability. Endovascular stenting is a viable treatment option.

We investigated six indices based on a single fasting blood sample for evaluation of the beta-cell function after total pancreatectomy with islet autotransplantation (TP-IAT). The Secretory Unit of Islet Transplant Objects (SUITO), transplant estimated function (TEF), homeostasis model assessment (HOMA-2B%), C-peptide/glucose ratio (CP/G), C-peptide/glucose creatinine ratio (CP/GCr) and BETA-2 score were compared against a 90-min serum glucose level, weighted mean C-peptide in mixed meal tolerance test (MMTT), beta score and the Igls score adjusted for islet function in the setting of IAT. We analyzed values from 32 MMTTs in 15 patients after TP-IAT with a follow-up of up to 3 years. Four (27%) individuals had discontinued insulin completely prior to day 75, while 6 out of 12 patients (50%) did not require insulin support at 1-year follow-up with HbA1c 6.0% (5.5-6.8). BETA-2 was the most consistent among indices strongly correlating with all reference measures of beta-cell function (r = 0.62-0.68). In addition, it identified insulin independence (cut-off = 16.2) and optimal/good versus marginal islet function in the Igls score well, with AUROC of 0.85 and 0.96, respectively. Based on a single fasting blood sample, BETA-2 score has the most reliable discriminant value for the assessment of graft function in patients undergoing TP-IAT., (© 2018 Steunstichting ESOT.)

The selection of optimal pancreas donors is one of the key factors in determining the ultimate outcome of clinical islet isolation. North American Islet Donor Score (NAIDS) allows for estimating the chance of the success of islet isolation. It was developed based on the data from over 1000 donors from 11 islet isolation centers and validated in the University of Alberta, Edmonton, on the cohort from the most active islet transplant center. Now we aimed to also validate it in our much less active program. Areas under the receiver operating characteristic curves (AUROCs) and logistic regression analyses were obtained to test if NAIDS would better predict successful islet isolation (defined as post-purification islet yield >400,000 islet equivalents (IEQ)) than previously described Edmonton islet donor score (IDS) and our modified version of IDS. We analyzed the donor scores with reference to 82 of our islet isolation outcomes. The success rate increased proportionally as NAIDS increased, from 0% success in NAIDS < 50 points to 40% success in NAIDS ≥ 80 points. AUROCs were 0.67 (95% confidence interval (CI) 0.55-0.79) for NAIDS, 0.58 (95% CI 0.44-0.71) for modified IDS, and 0.51 (95% CI 0.37-0.65) for IDS and did not differ significantly. However, based on logistic regression analyses, NAIDS was the only statistically significant predictor of successful isolation (p = 0.01). The main advantage of NAIDS is an enhanced ability to discriminate poor-quality donors than previously used scoring systems at University of Chicago, with 0% chance for success when NAIDS was <50 as compared with 40% success rate for IDS <50. NAIDS was found to be the most useful available tool for donor pancreas selection in clinical and research practice in our center, allowing for identification and rejection of poor-quality donors, saving time and resources.

Body mass index (BMI) is widely used to define obesity. In studies of pancreatic beta-cell/islet mass, BMI is also a common standard for matching control subjects in comparative studies along with age and sex, based on the existing dogma of their significant positive correlation reported in the literature. We aimed to test the feasibility of BMI and BSA to assess obesity and predict beta-cell/islet mass. We used National Health and Nutrition Examination Survey (NHANES) data that provided dual-energy Xray absorptiometry (DXA)-measured fat mass (percent body fat; %BF), BMI, and BSA for adult subjects (20-75y; 4,879 males and 4,953 females). We then analyzed 152 cases of islet isolation performed at our center for correlation between islet yields and various donor anthropometric indices. From NHANES, over 50% of male subjects and 60% of female subjects with BMI:20.1-28.1 were obese as defined by %BF, indicating a poor correlation between BMI and %BF. BSA was also a poor indicator of %BF, as broad overlap was observed in different BSA ranges. Additionally, BMI and BSA ranges markedly varied between sex and race/ethnicity groups. From islet isolation, BMI and BSA accounted for only a small proportion of variance in islet equivalent (IEQ; r 2  = 0.09 and 0.11, respectively). BMI and obesity were strongly correlated in cases of high BMI subjects. However, the critical populations were non-obese subjects with BMI ranging from 20.1-28.1, in which a substantial proportion of individuals may carry excess body fat. Correlations between BMI, BSA, pancreas weight and beta-cell/islet mass were low.

Hepatocellular carcinoma (HCC) is the sixth-most common cancer and the third leading cause of cancer-related death in the world. However, 40-70% patients eventually suffer from postoperative recurrence within 5 years. HCC recurrence after surgery severely affects prognosis of the patients. Nevertheless, there is an opportunity to improve patients' prognosis if doctors and researchers can recognize the importance of a standardized perioperative management and study it in clinical and pre-clinical settings. Hence, based on our own experience and published studies from other researchers, we develop this consensus regarding multidisciplinary management of locally recurrent and metastatic hepatocellular carcinoma after resection. This consensus consists of the entire course of recurrent hepatocellular carcinoma (RHCC) management, including prediction of recurrence, prevention, diagnosis, treatment and surveillance of RHCC. Consensus recommendations are presented with grades of evidences (Ia, Ib, IIa, IIb, III and IV), and strength of recommendations (A, B, C, D and E). We also develop a decision-making path for RHCC treatment, which can intuitively demonstrate the management for RHCC. It is hoped that we may make some effort to standardize the management of RHCC and ultimately understand how to improve outcomes., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Six single fasting blood sample-based indices-Secretory Unit of Islet Transplant Objects (SUITO), Transplant Estimated Function (TEF), Homeostasis Model Assessment (HOMA)2-B%, C-peptide/glucose ratio (CP/G), C-peptide/glucose creatinine ratio (CP/GCr), and BETA-2 score-were compared against commonly used 90-minute mixed meal tolerance test (MMTT) serum glucose and beta score to assess which of them best recognizes the state of acceptable blood glucose control without insulin supplementation after islet allotransplantation (ITx). We also tested whether the indices could identify the success of ITx based on the Igls classification of beta cell graft function. We analyzed values from 47 MMTT tests in 4 patients with up to 140 months follow-up and from 54 MMTT tests in 13 patients with up to 42 months follow-up. SUITO, CP/G, HOMA2-B%, and BETA-2 correlated well with the 90-minute glucose of the MMTT and beta-score (r 0.54-0.76), whereas CP/GCr showed a modest performance (r 0.41-0.52) while TEF showed little correlation. BETA-2 and SUITO were the best identifiers and predictors of the need for insulin support, glucose intolerance, and ITx success (P < .001), while HOMA2-B% and TEF were unreliable. Single fasting blood sample SUITO and BETA-2 scores are very practical alternative tools that allow for frequent assessments of graft function., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Congenital membranous occlusion of the inferior vena cava (IVC) in pediatric liver recipients may present with outflow occlusion and if unrecognized, result in graft loss. Prompt evaluation of outflow obstruction in the setting of unexplained inflow compromise is paramount. We report a case of successful IVC reconstruction in a patient with recurrent hepatic artery thrombosis (HAT). A 2-year-old child with history of two liver transplantations developed fevers, ascites, and abdominal tenderness one month after her second liver transplant. Hepatic duplex revealed decreased flow in the hepatic artery and IVC venogram revealed patent hepatic veins with occlusion of the suprahepatic IVC. We performed reconstruction of her suprahepatic IVC to intrapericardial IVC using an end-to-side technique after complete mobilization of the liver. Recovery was uneventful and the patient has been doing well for the last 5 years., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The first clinical trials with adoptive Treg therapy have shown safety and potential efficacy. Feasibility of such therapy could be improved if cells are cryopreserved and stored until optimal timing for infusion. Herein, we report the evaluation of two cell-banking strategies for Treg therapy: 1) cryopreservation of CD4 + cells for subsequent Treg isolation/expansion and 2) cryopreservation of ex-vivo expanded Tregs (CD4 + CD25 hi CD127 lo/- cells). First, we checked how cryopreservation affects cell viability and Treg markers expression. Then, we performed Treg isolation/expansion with the final products release testing. We observed substantial decrease in cell number recovery after thawing and overnight culture. This observation might be explained by the high percentage of necrotic and apoptotic cells found just after thawing. Furthermore, we noticed fluctuations in percentage of CD4 + CD25 hi CD127 - and CD4 + FoxP3 + cells obtained from cryopreserved CD4 + as well as Treg cells. However, after re-stimulation Tregs expanded well, presented a stable phenotype and fulfilled the release criteria at the end of expansions. Cryopreservation of CD4 + cells for subsequent Treg isolation/expansion and cryopreservation of expanded Tregs with re-stimulation and expansion after thawing, are promising solutions to overcome detrimental effects of cryopreservation. Both of these cell-banking strategies for Treg therapy can be applied when designing new clinical trials., Competing Interests: CONFLICTS OF INTEREST The authors do not have any conflicts of interest to declare.

Objective: The aim of this study was to assess short-term and long-term results of the pancreatic islet transplantation using the Edmonton protocol at the University of Chicago., Materials and Methods: Nine patients underwent pancreatic islet cell transplantation using the Edmonton Protocol; they were followed up for 10 years after initial islet transplant with up to 3 separate islet infusions. They were given induction treatment using an IL-2R antibody and their maintenance immunosuppression regimen consisted of sirolimus and tacrolimus., Results: Nine patients received a total of 18 islet infusions. Five patients dropped out in the early phase of the study. Greater than 50% drop-out and noncompliance rate resulted from both poor islet function and recurrent side effects of immunosuppression. The remaining 4 (44%) patients stayed insulin free with intervals for at least over 5 years (cumulative time) after the first transplant. Each of them received 3 infusions, on average 445 000 islet equivalent per transplant. Immunosuppression regimen required multiple adjustments in all patients due to recurrent side effects. In the long-term follow up, kidney function remained stable, and diabetic retinopathy and polyneuropathy did not progress in any of the patients. Patients' panel reactive antibodies remained zero and anti-glutamic acid decarboxylase 65 antibody did not rise after the transplant. Results of metabolic tests including hemoglobin A1c, arginine stimulation, and mixed meal tolerance test were correlated with clinical islet function., Conclusions: Pancreatic islet transplantation initiated according to Edmonton protocol offered durable long-term insulin-free glycemic control in only highly selected brittle diabetics providing stable control of diabetic neuropathy and retinopathy and without increased sensitization or impaired renal function. Immunosuppression adjustments and close follow-up were critical for patient retention and ultimate success., Competing Interests: The authors declare no conflicts of interest.

Selection of an optimal donor pancreas is the first key task for successful islet isolation. We conducted a retrospective multicenter study in 11 centers in North America to develop an islet donor scoring system using donor variables. The data set consisting of 1,056 deceased donors was used for development of a scoring system to predict islet isolation success (defined as postpurification islet yield >400,000 islet equivalents). With the aid of univariate logistic regression analyses, we developed the North American Islet Donor Score (NAIDS) ranging from 0 to 100 points. The c index in the development cohort was 0.73 (95% confidence interval 0.70-0.76). The success rate increased proportionally as the NAIDS increased, from 6.8% success in the NAIDS < 50 points to 53.7% success in the NAIDS ≥ 80 points. We further validated the NAIDS using a separate set of data consisting of 179 islet isolations. A comparable outcome of the NAIDS was observed in the validation cohort. The NAIDS may be a useful tool for donor pancreas selection in clinical practice. Apart from its utility in clinical decision making, the NAIDS may also be used in a research setting as a standardized measurement of pancreas quality.

Previous studies describing the symptomatic onset of type 1 diabetes (T1D) and rate of beta-cell loss (C-peptide) support the notion that childhood onset T1D exhibits more severe beta-cell depletion compared to adult onset T1D. To test this notion, we performed whole pancreas analyses in two T1D cases, one of childhood onset (7-year old, onset at 1.5-year) along with an adult onset case (43-year old with onset at 27-year). Both cases were matched for age and gender with control subjects. Striking regional differences in beta-cell loss were observed in both T1D cases, with severity of loss in the order of tail > body > head regions. In contrast, pancreatic alpha- and delta-cell mass was similar in controls and T1D patients. In the childhood onset T1D case, no intra-islet beta-cells were detected while in the adult onset case, beta-cell containing islets were found, exclusively in the head region. In the latter case, considerable numbers of small cellular clusters negative for three major endocrine hormones were observed, in islets with or without beta-cells. Ultrastructural analysis suggests these cells correspond to degenerating beta-cells, with empty granular membranes and abnormal morphology of nuclei with intranuclear pseudo-inclusions, adjacent to healthy alpha- and delta-cells. These results support a hypothesis that during T1D development in childhood, beta-cells are more susceptible to autoimmune destruction or immune attack is more severe, while beta-cell death in the adult onset T1D may be more protracted and incomplete. In addition, T1D may be associated with the formation of "empty" beta-cells, an interesting population of cells that may represent a key facet to the disorder's pathogenesis.

The aim of the study was to assess the rate of insulin independence in patients after total pancreatectomy (TP) and islet autotransplantation in our center. TP followed by islet autotransplantation was performed in 10 patients. Severe unrelenting pain associated with chronic pancreatitis was the major indication for surgery. Islets were isolated using the modified Ricordi method and infused through the portal vein. Exogenous insulin therapy was implemented for at least two months posttransplant to support islet engraftment and was subsequently weaned off, if possible. Median follow-up was 26 months (range, 2 to 60 months). Median islet yield was 158,860 islet equivalents (IEQ) (range, 40,203 to 330,472 IEQ) with an average islet yield of 2,478 IEQ/g (range, 685 to 6,002 IEQ/g) of processed pancreas. One patient developed transient partial portal vein thrombosis, which resolved without sequela. Five (50%) patients are currently off insulin with excellent glucose control and HbA1c below 6. Patients who achieved and maintained insulin independence were transplanted with significantly more islets (median, 202,291 IEQ; range, 145,000 to 330,474 IEQ) than patients who required insulin support (64,348 IEQ; range, 40,203 to 260,476 IEQ; P < 0.05). Patient body mass index and time of chronic pancreatitis prior transplant procedure did not correlate with the outcome. The remaining five patients, who require insulin support, had present C-peptide in blood and experience good glucose control without incidence of severe hypoglycemic episodes. Islet autotransplantation efficiently preserved beta cell function in selected patients with chronic pancreatitis and the outcome correlated with transplanted islet mass.

Organ donation and transplant systems have unique characteristics based on the local culture and socioeconomic context. China's transplant and organ donation systems developed without regulatory oversight until 2006 when regulation and policy were developed and then implemented over the next several years. Most recently, the pilot project of establishing a voluntary citizen-based deceased donor program was established. The pilot program addressed the legal, financial, and cultural barriers to organ donation in China. The pilot program has evolved into a national program. Significantly, it established a uniquely Chinese donor classification system. The Chinese donor classification system recognizes donation after brain death (category I), donation after circulatory death (category II), and donation after brain death followed by circulatory death (category III). Through August 2014, the system has identified 2326 donors and provided 6416 organs that have been allocated though a transparent organ allocation system. The estimated number of donors in 2014 is 1147. As China's attitudes toward organ donation have matured and evolved and as China, as a nation, is taking its place on the world stage, it is recognizing that its past practice of using organs from executed prisoners is not sustainable. It is time to recognize that the efforts to regulate transplantation and provide voluntary citizen-based deceased organ donation have been successful and that China should use this system to provide organs for all transplants in every province and hospital in China. At the national organ transplant congress on October 30, 2014, the Chairman of the China's national organ donation and transplantation committee, Jeifu Huang required all hospitals to stop using organs from executed prisoners immediately and the civilian organ donation will be sole source for organ transplant in China starting January 2015., (© 2015 American Association for the Study of Liver Diseases.)

Morphogenesis, spontaneous formation of organism structure, is essential for life. In the pancreas, endocrine α, β, and δ cells are clustered to form islets of Langerhans, the critical micro-organ for glucose homeostasis. The spatial organization of endocrine cells in islets looks different between species. Based on the three-dimensional positions of individual cells in islets, we computationally inferred the relative attractions between cell types, and found that the attractions between homotypic cells were slightly, but significantly, stronger than the attractions between heterotypic cells commonly in mouse, pig, and human islets. The difference between α-β cell attraction and β-β cell attraction was minimal in human islets, maximizing the plasticity of islet structures. Our result suggests that although the cellular composition and attractions of pancreatic endocrine cells are quantitatively different between species, the physical mechanism of islet morphogenesis may be evolutionarily conserved.

Background: We showed that T regulatory (Treg) cells can be attached to the surface of pancreatic islets providing local immunoprotection. Further optimization of the method can improve coating efficiency, which may prolong graft survival. In this study, we compared the effectiveness of two different molecules used for binding of the Tregs to the surface of pancreatic islets. Our aim was to increase the number of Treg cells attached to islets without compromising islets viability and function., Methods: The cell surface of human Treg cells and pancreatic islets was modified using biotin-polyethylene glycol-N-hydroxylsuccinimide (biotin-PEG-NHS) or biotin-PEG-succinimidyl valeric acid ester (biotin-PEG-SVA). Then, islets were incubated with streptavidin as islet/Treg cells binding molecule. Treg cells were stained with CellTracker CM-DiL dye and visualized using a Laser Scanning Confocal Microscope. The number of Treg cells attached per islets surface area was analyzed by Imaris software. The effect of coating on islet functionality was determined using the glucose-stimulated insulin response (GSIR) assay., Results: The coating procedure with biotin-PEG-SVA allowed for attaching 40% more Treg cells per 1 μm(2) of islet surface. Although viability was comparable, function of the islets after coating using the biotin-PEG-SVA molecule was better preserved than with NHS molecule. GSIR was 62% higher for islets coated with biotin-PEG-SVA compared to biotin-PEG-NHS., Conclusion: Coating of islets with Treg cells using biotin-PEG-SVA improves effectiveness with better preservation of the islet function. Improvement of the method of coating pancreatic islets with Treg cells could further facilitate the effectiveness of this novel immunoprotective approach and translation into clinical settings., (Copyright © 2014 Elsevier Inc. All rights reserved.)

To maximize the islet isolation yield for successful islet transplantation, the key task has been to identify an ideal pancreas donor. Since implementation of the islet donor score in donor selection, we have consistently obtained higher islet yields and transplantation rates. In this study, we tested whether assessing donor height as an independent variable in combination with the donor score could improve the pancreas donor selection. Donor and islet isolation information (n = 22) were collected and studied between 2011 and 2012. Pearson correlation analysis was used in statistical analysis. Donor height as an independent variable was significantly correlated to the weight of the pancreas, pre-Islet Equivalents (pre-IEQ), post-IEQ, and IDS (P < .05). When donor with height of 179 cm ± 3 was selected in combination with IDS > 80, the clinical islet transplantation rate reached 80%., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: We are reporting first successful intrahepatic autologous islet transplantation after total pancreatectomy in a patient with chronic pancreatitis and primary sclerosing cholangitis., Methods: Total pancreatectomy and subsequent islet autotransplantation were performed in a 16-year-old boy with intractable pain due to chronic pancreatitis in the setting of ulcerative colitis and primary sclerosing cholangitis (PSC). Liver biopsy revealed PSC with focal bridging fibrosis. The pancreas was surgically removed and digested, and islets were isolated, highly purified, and infused intraportally., Results: Over 18-month follow-up, the patient did not show progression of chronic liver disease or signs of portal hypertension. Magnetic resonance cholangiopancreatography revealed no new changes, and liver biopsy did not show progression of the periportal fibrosis. Pain medication was weaned over 12 months at which time glycemic control was excellent without exogenous insulin supplementation. HbgA1c was 5.9. Fifteen months after the procedure, stimulation with a mixed meal led to a fourfold increase of serum C-peptide and an eightfold increase of insulin level., Conclusion: Pancreatic autologous islets can be successfully transplanted into a liver affected by PSC without compromising hepatic or graft function. Durability of the procedure may be limited in the future by the natural course of the liver injury caused by PSC.

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The large size of the human pancreas challenges unbiased quantitative analyses that require a practical stereological approach. While many histological studies of the pancreas in the past lacked regional information, we have shown marked heterogeneity within an individual, where islet distribution/density is relatively low in the head and gradually increases through the body toward the tail region by>2-fold. Studies focusing on the tail region may be prone to overestimation of β-cell/islet mass when normalizing measured values per person by using pancreas weight or volume. In this article, beyond technical issues, we discuss the pathophysiological importance of studying the head region of the human pancreas regarding its unique characteristics in early development, and the anatomical disposition that may lead to a preferential loss of β-cells in patients with type 2 diabetes and the development of pancreatic cancer.

T regulatory cells (Tregs) play a critical role in the immunologic tolerance to the graft in transplantation. Thus, due to their immunosuppressive capability, ex vivo expanded Tregs may be used as a cellular therapy and an attractive novel strategy to control chronic rejection and eliminate need for lifelong pharmacological immunosuppression. Since Treg therapy is still in its infancy, initially Tregs still need to be applied in combination with pharmacological agents to prevent rejection. Fortunately, some of the medications have been shown to enhance the function and number of Tregs. In the clinic, different immunosuppressive regimens are used for individual patients for different types of organ transplantation. In this review, we present the most commonly used pharmacological agents for immunosuppression and discuss how they affect the Treg population. It is extremely difficult to dissect the effect of single agent on Tregs population in clinical settings since usually the combination of several medications is applied at the same time for graft protection. Nevertheless, experimental and clinical data indicate that thymoglobulin as immunosuppressive induction and mTOR inhibitors as immunosuppressive maintenance agents have the most beneficial effect on Treg population in the blood. Among supplemental agents promoting Tregs, anti-TNFα preparations have been in clinical use (in autoimmune diseases) for many years, so they are optimal candidates for testing in transplant settings in combination with Treg based cellular therapy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A recently discovered population of lymphocytes, called T regulatory cells (Tregs), is characterized by expression of transcription factor Forkhead box P3 (FoxP3). These cells have been successfully used as therapeutic treatments and prophylaxis for graft-versus-host disease (GVHD) and diabetes and might become an attractive alternative to traditional immunotherapy. Here we evaluated how the type of culture medium and the type of serum can influence yield and quality of Tregs after in vitro expansion. We compared Treg fold of expansion and their phenotypical characteristics including expression of FoxP3, CD25, CD127, CD62L and CD45RA in three commercially available culture media (RPMI 1640 (Cellgro; Manassas VA, USA), SCGM (Cellgenix; Freiburg, Germany), and X-VIVO 20 (Lonza; Walkersville, MD, USA)) with addition of human serum (HS, 10%) or fetal bovine serum (FBS, 10%). Among the tested media, X-VIVO 20 supplemented with HS produced the highest yield after 17days of in vitro expansion (a median of 86-fold expansion, range 30-1365) and highest level of FoxP3 expression (a median of 66.8% of positive cells, range 56-84.8%) in CD4(+) CD25(hi)CD127(lo/neg) FACS sorted polyclonal Tregs. There was no difference in Tregs yield whether HS or FBS serum was used. In conclusion, the yield of the ex vivo expanded Tregs is related to the type of media applied. Supplementation of the culture with FBS or human serum is equally beneficial., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Promising results of initial studies applying ex-vivo expanded regulatory T cell (Treg) as a clinical intervention have increased interest in this type of the cellular therapy and several new clinical trials involving Tregs are currently on the way. Methods of isolation and expansion of Tregs have been studied and optimized to the extent that such therapy is feasible, and allows obtaining sufficient numbers of Tregs in the laboratory following Good Manufacturing Practice (GMP) guidelines. Nevertheless, Treg therapy could even more rapidly evolve if Tregs could be efficiently cryopreserved and stored for future infusion or expansions rather than utilization of only freshly isolated and expanded cells as it is preferred now. Currently, our knowledge regarding the impact of cryopreservation on Treg recovery, viability, and functionality is still limited. Based on experience with cryopreserved peripheral blood mononuclear cells (PBMCs), cryopreservation may have a detrimental effect on Tregs, can decrease Treg viability, cause abnormal cytokine secretion, and compromise expression of surface markers essential for proper Treg function and processing. Therefore, optimal strategies and conditions for Treg cryopreservation in conjunction with cell culture, expansion, and processing for clinical application still need to be investigated and defined., (Copyright © 2013 Elsevier B.V. All rights reserved.)

While regional heterogeneity in islet distribution has been well studied in rodents, less is known about human pancreatic histology. To fill gaps in our understanding, regional differences in the adult human pancreas were quantitatively analyzed including the pathogenesis of type 2 diabetes (T2D). Cadaveric pancreas specimens were collected from the head, body and tail regions of each donor, including subjects with no history of diabetes or pancreatic diseases (n = 23) as well as patients with T2D (n = 12). The study further included individuals from whom islets were isolated (n = 7) to study islet yield and function in a clinical setting of islet transplantation. The whole pancreatic sections were examined using an innovative large-scale image capture and unbiased detailed quantitative analyses of the characteristics of islets from each individual (architecture, size, shape and distribution). Islet distribution/density is similar between the head and body regions, but is >2-fold higher in the tail region. In contrast to rodents, islet cellular composition and architecture were similar throughout the pancreas and there was no difference in glucose-stimulated insulin secretion in islets isolated from different regions of the pancreas. Further studies revealed preferential loss of large islets in the head region in patients with T2D. The present study has demonstrated distinct characteristics of the human pancreas, which should provide a baseline for the future studies integrating existing research in the field and helping to advance bi-directional research between humans and preclinical models.