Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed a protocol for neoadjuvant therapy and LT for patients with locally advanced, unresectable iCCA in 2010. Patients undergoing LT were required to demonstrate disease stability for 6 months on neoadjuvant therapy with no extrahepatic disease. During the study period, 32 patients were listed for LT and 18 patients underwent LT. For transplanted patients, the median number of iCCA tumors was 2, and the median cumulative tumor diameter was 10.4 cm. Patients receiving LT had an overall survival at 1-, 3-, and 5-years of 100%, 71%, and 57%. Recurrences occurred in seven patients and were treated with systemic therapy and resection. The study population had a higher than expected proportion of patients with genetic alterations in fibroblast growth factor receptor (FGFR) and DNA damage repair pathways. These data support LT as a treatment for highly selected patients with locally advanced, unresectable iCCA. Further studies to identify criteria for LT in iCCA and factors predicting survival are warranted.

Pre-transplant T-cell Clonality: An Observational Study of a Biomarker for Prediction of Sepsis in Liver Transplant Recipients.

OBJECTIVE: This study investigated the ability of pre-transplant T-cell clonality to predict sepsis after liver transplant (LT). SUMMARY BACKGROUND DATA: Sepsis is a leading cause of death in LT recipients. Currently, no biomarkers predict sepsis before clinical symptom manifestation. METHODS: Between December 2013 and March 2018, our institution performed 478 LTs. After exclusions (eg, patients with marginal donor livers, autoimmune disorders, nonabdominal multi-organ, and liver retransplantations), 180 consecutive LT were enrolled. T-cell characterization was assessed within 48 hours before LT (immunoSEQ Assay, Adaptive Biotechnologies, Seattle, WA). Sepsis-2 and Sepsis-3 cases, defined by presence of acute infection plus ≥2 SIRS criteria, or clinical documentation of sepsis, were identified by chart review. Receiver-operating characteristic analyses determined optimal T-cell repertoire clonality for predicting post-LT sepsis. Kaplan-Meier and Cox proportional hazard modeling assessed outcome-associated prognostic variables. RESULTS: Patients with baseline T-cell repertoire clonality ≥0.072 were 3.82 (1.25, 11.40; P = 0.02), and 2.40 (1.00, 5.75; P = 0.049) times more likely to develop sepsis 3 and 12 months post-LT, respectively, when compared to recipients with lower (<0.072) clonality. T-cell repertoire clonality was the only predictor of sepsis 3 months post-LT in multivariate analysis (C-Statistic, 0.75). Adequate treatment resulted in equivalent survival rates between both groups: (93.4% vs 96.2%, respectively, P = 0.41) at 12 months post-LT. CONCLUSIONS: T-cell repertoire clonality is a novel biomarker predictor of sepsis before development of clinical symptoms. Early sepsis monitoring and management may reduce post-LT mortality. These findings have implications for developing sepsis-prevention protocols in transplantation and potentially other populations.

Donation after circulatory death liver transplantation: An in-depth analysis and propensity score-matched comparison.

BACKGROUND: Careful donor-recipient matching and reduced ischemia times have improved outcomes following donation after circulatory death (DCD) liver transplantation (LT). This study examines a single-center experience with DCD LT including high-acuity and hospitalized recipients. METHODS: DCD LT outcomes were compared to a propensity score-matched (PSM) donation after brain death (DBD) LT cohort (1:4); 32 DCD LT patients and 128 PSM DBD LT patients transplanted from 2008 to 2018 were included. Analyses included Kaplan-Meier estimates and Cox proportional hazards models examining patient and graft survival. RESULTS: Median MELD score in the DCD LT cohort was 22, with median MELD of 27 for DCD LT recipients with decompensated cirrhosis. No difference in mortality or graft loss was found (p < .05) between DCD LT and PSM DBD LT at 3 years post-transplant, nor was DCD an independent risk factor for patient or graft survival. Post-LT severe acute kidney injury was similar in both groups. Ischemic-type biliary lesions (ITBL) occurred in 6.3% (n = 2) of DCD LT recipients, resulting in 1 graft loss and 1 death. CONCLUSION: This study supports that DCD LT outcomes can be similar to DBD LT, with a low rate of ITBL, in a cohort including high-acuity recipients. Strict donor selection criteria, ischemia time minimization, and avoiding futile donor/recipient combinations are essential considerations.

Successful Kidney Transplantation Is Associated With Weight Gain From Truncal Obesity and Insulin Resistance.

OBJECTIVE: The objective of this study is to compare changes in body composition, lifestyle factors, and metabolic responses occurring in living kidney transplant recipient patients after transplantation. DESIGN AND METHODS: The study was a single-site, prospective, observational study. To identify metabolic responses during the initial years after transplantation, we obtained state-of-the-art, high-resolution measurements of body composition from a 4-compartment model using dual-energy X-ray absorptiometry, air displacement plethysmography, and total body potassium and nitrogen counters. We also assessed dietary recalls and actigraphy before transplantation and 3- and 12-month after transplantation. The study was conducted at a quaternary care hospital outpatient transplant center and a United States Department of Agriculture Agricultural Research Service center. Thirty-one adults receiving a living donor kidney allograft were studied. The main outcome measures were change in body composition at 3 months and 1 year after transplantation, and this was correlated with the occurrence of insulin resistance. RESULTS: In patients receiving a successful kidney transplant from living donors treated with standard immunosuppression, significant increases in body weight were detected at 3 and 12 months after transplantation (2.2 kg, P = .03 and 6.6 kg, P < .0001, respectively). Weight gain was principally due to adipose tissue accumulation in the truncal region. There was no increase in muscle mass or fluid accumulation. Weight gain was not associated with changes in resting energy expenditure or physical activity. Notably, increases in visceral and subcutaneous adipose tissue were positively correlated with insulin resistance. CONCLUSION: Successful transplantation was associated with increased insulin resistance and weight gain without increases in muscle or fluid. This metabolic pattern suggests potential interventions that could prevent or mitigate the consequences of adipose tissue accumulation in transplant recipients.

Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient's quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

Precision Nutrition Model Predicts Glucose Control of Overweight Females Following the Consumption of Potatoes High in Resistant Starch.

Individual glycemic responses following dietary intake result from complex physiological processes, and can be influenced by physical properties of foods, such as increased resistant starch (RS) from starch retrogradation. Predictive equations are needed to provide personalized dietary recommendations to reduce chronic disease development. Therefore, a precision nutrition model predicting the postprandial glucose response (PPGR) in overweight women following the consumption of potatoes was formulated. Thirty overweight women participated in this randomized crossover trial. Participants consumed 250 g of hot (9.2 g RS) or cold (13.7 g RS) potatoes on two separate occasions. Baseline characteristics included demographics, 10-day dietary records, body composition, and the relative abundance (RA) and α-diversity of gut microbiota. Elastic net regression using 5-fold cross-validation predicted PPGR after potato intake. Most participants (70%) had a favorable PPGR to the cold potato. The model explained 32.2% of the variance in PPGR with the equation: 547.65 × (0 [if cold, high-RS potato], ×1, if hot, low-RS potato]) + (BMI [kg/m2] × 40.66)-(insoluble fiber [g] × 49.35) + (Bacteroides [RA] × 8.69)-(Faecalibacterium [RA] × 73.49)-(Parabacteroides [RA] × 42.08) + (α-diversity × 110.87) + 292.52. This model improves the understanding of baseline characteristics that explain interpersonal variation in PPGR following potato intake and offers a tool to optimize dietary recommendations for a commonly consumed food.

Transarterial Chemoembolization (TACE) Plus Sorafenib Compared to TACE Alone in Transplant Recipients with Hepatocellular Carcinoma: An Institution Experience.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. Transarterial chemoembolization has shown survival benefits in patients with early to intermediate-stage HCC, becoming the standard of care and recommended treatment modality by most clinical practice guidelines. The most recent trials of the TACE plus sorafenib combined therapy in patients with unresectable HCC have yielded inconsistent outcomes. The purpose of this study was to compare the outcomes of HCC patients treated with the TACE sorafenib combination as opposed to TACE monotherapy. METHODS: This retrospective study included all patients with unresectable HCC who underwent liver transplantation and were treated by either TACE alone or TACE plus sorafenib between July 2008-December 2019. Demographic and clinical data as well as HCC recurrence post-liver transplant (LT) were reported as frequencies and proportions for categorical variables and as the median and interquartile range (IQR) or mean. Chi-square or Fisher's exact tests were performed for categorical variables and the Kruskal-Wallis test or unpaired test was performed for continuous variables. Kaplan-Meier curves present overall patient survival and HCC-free survival. RESULTS: A total of 128 patients received LT, with a median (IQR) age of 61.4 (57.0, 66.3) years; most were males (77%). Within the TACE-only group, 79 (77%) patients met the Milan criteria and 24 (23%) were beyond the Milan criteria, while the TACE plus sorafenib group had a higher proportion of patients beyond the Milan criteria: 16 (64%) vs. 9 (36%); p = 0.01. The five-year disease-free survival (DFS) between the treatment groups approached significance, with 100% DFS in the TACE plus sorafenib group vs. 67.2% in the TACE-alone group, p = 0.07. Five-year patient survival was 77.8% in the TACE plus sorafenib group compared to 61.5% in the TACE-alone group (p = 0.51). However, in patients who met the beyond Milan criteria, those who received TACE alone had a lower average amount of (percent) tumor necrosis on explant pathology (43.8% ± 32%) compared to patients who received TACE plus sorafenib (69.6% ± 32.8%, p = 0.03). CONCLUSION: This study identified that using TACE plus sorafenib is generally well-tolerated and demonstrated improved overall survival compared to TACE only in transplant recipients with unresectable HCC. A multi-center and prospective randomized controlled trial is needed to substantiate these findings.

An imageomics and multi-network based deep learning model for risk assessment of liver transplantation for hepatocellular cancer.

INTRODUCTION: Liver transplantation (LT) is an effective treatment for hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Patients with small HCC (<5 cm) are given priority over others for transplantation due to clinical allocation policies based on tumor size. Attempting to shift from the prevalent paradigm that successful transplantation and longer disease-free survival can only be achieved in patients with small HCC to expanding the transplantation option to patients with HCC of the highest tumor burden (>5 cm), we developed a convergent artificial intelligence (AI) model that combines transient clinical data with quantitative histologic and radiomic features for more objective risk assessment of liver transplantation for HCC patients. METHODS: Patients who received a LT for HCC between 2008-2019 were eligible for inclusion in the analysis. All patients with post-LT recurrence were included, and those without recurrence were randomly selected for inclusion in the deep learning model. Pre- and post-transplant magnetic resonance imaging (MRI) scans and reports were compressed using CapsNet networks and natural language processing, respectively, as input for a multiple feature radial basis function network. We applied a histological image analysis algorithm to detect pathologic areas of interest from explant tissue of patients who recurred. The multilayer perceptron was designed as a feed-forward, supervised neural network topology, with the final assessment of recurrence risk. We used area under the curve (AUC) and F-1 score to assess the predictability of different network combinations. RESULTS: A total of 109 patients were included (87 in the training group, 22 in the testing group), of which 20 were positive for cancer recurrence. Seven models (AUC; F-1 score) were generated, including clinical features only (0.55; 0.52), magnetic resonance imaging (MRI) only (0.64; 0.61), pathological images only (0.64; 0.61), MRI plus pathology (0.68; 0.65), MRI plus clinical (0.78, 0.75), pathology plus clinical (0.77; 0.73), and a combination of clinical, MRI, and pathology features (0.87; 0.84). The final combined model showed 80 % recall and 89 % precision. The total accuracy of the implemented model was 82 %. CONCLUSION: We validated that the deep learning model combining clinical features and multi-scale histopathologic and radiomic image features can be used to discover risk factors for recurrence beyond tumor size and biomarker analysis. Such a predictive, convergent AI model has the potential to alter the LT allocation system for HCC patients and expand the transplantation treatment option to patients with HCC of the highest tumor burden.

Transplant Oncology: An Evolving Field in Cancer Care.

Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The application of oncology, transplant medicine, and surgery to improve patients' survival and quality of life is the core of transplant oncology. Hepatobiliary malignancies have been treated by liver transplantation (LT) with significant improved outcome. In addition, as the liver is the most common site of metastasis for colorectal cancer (CRC), patients with CRC who have stable unresectable liver metastases are good candidates for LT, and initial studies have shown improved survival compared to palliative systemic therapy. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years in a stepwise manner; however, they have only been shown to improve patient survival in the setting of limited systemic therapy options. This review illustrates the concept and history of transplant oncology as an evolving field for the management of hepatocellular carcinoma, intrahepatic biliary cancer, and liver-only metastasis of non-hepatobiliary carcinoma. The utility of immunotherapy in the transplant setting is discussed as well as the feasibility of using circulating tumor DNA for surveillance post-transplantation.

Healthy Eating Index of Living Donor Renal Transplantation Recipients During the First Year Posttransplant.

BACKGROUND: The aim of this study was to examine the relationship between diet quality and weight gain in kidney transplant recipients from pretransplant baseline through posttransplant at 3 months and 1 year. METHODS: Data from a prospective, observational cohort study of kidney transplant patients (n = 26) were analyzed. Participants were adult (aged 18-65 years), living donor kidney transplant recipients who were participating in a prospective body composition study. Body weight, body mass index, dietary intake, and Healthy Eating Index scores were used to assess changes in weight, nutrient intake, and diet quality. FINDINGS: At the time of kidney transplantation, 42% (n = 11) were obese and 27% (n = 7) were overweight. Weight significantly increased from transplantation to 12 months (mean [SD]: 83 [18] kg and 90 [18] kg, respectively; mean change 8.4%, P = .002). At 12 months posttransplant, dietary fat intake significantly increased (P = .033). Body weight was strongly correlated with total dietary fat intake (r = 0.56, P = .003). The Healthy Eating Index total scores at baseline and 1-year posttransplant were not significantly different (45.75 [14.99] and 42.59 [12.70]). Likewise, component scores did not change from pretransplant to posttransplant. DISCUSSION: Diet quality of transplant recipients was poor both before and after transplantation. Using the Healthy Eating Index confirmed that improvements in food intake are needed. Further research is warranted to identify dietary recommendations for the prevention of excessive weight gain and the potential adverse health complications following kidney transplantation.

Chilled Potatoes Decrease Postprandial Glucose, Insulin, and Glucose-dependent Insulinotropic Peptide Compared to Boiled Potatoes in Females with Elevated Fasting Glucose and Insulin.

Resistant starch (RS) has been shown to improve postprandial glycemia and insulin sensitivity in adults with metabolic syndrome. RS is found naturally in potatoes, where the amount varies based on cooking method and serving temperature. Thirty females with a mean BMI of 32.8 ± 3.7 kg/m2, fasting glucose of 110.5 mg/dL, and insulin of 10.3 µIU/L, completed this randomized, crossover study. A quantity of 250 g of boiled (low RS) and baked then chilled (high RS) russet potatoes were consumed on two separate occasions. Glycemic (glucose and insulin) and incretin response, subjective satiety, and dietary intake were measured. Results showed that the chilled potato elicited significant reductions at 15 and 30 min in glucose (4.8% and 9.2%), insulin (25.8% and 22.6%), and glucose-dependent insulinotropic peptide (GIP) (41.1% and 37.6%), respectively. The area under the curve for insulin and GIP were significantly lower after the chilled potato, but no differences were seen in glucose, glucagon-like peptide-1, and peptide YY, or overall subjective satiety. A higher carbohydrate and glycemic index but lower fat diet was consumed 48-hours following the chilled potato than the boiled potato. This study demonstrates that consuming chilled potatoes higher in RS can positively impact the glycemic response in females with elevated fasting glucose and insulin.

Nutrition Trends in Kidney Transplant Recipients: the Importance of Dietary Monitoring and Need for Evidence-Based Recommendations.

Many physiological properties of the renal system influence nutrient metabolism, elimination, and homeostasis. Kidney failure poses significant challenges to maintaining adequate nutrition, most of which transplantation ameliorates. Comprehensive recommendations for managing nutritional derangements for patients with chronic kidney disease and end stage renal disease exist; however, there are only sparse guidelines for post-transplant malnutrition and adverse outcomes. Not only are guidelines limited, but little is known about dietary trends of post-kidney transplant recipients. This review describes guidelines for prevalent metabolic and nutritional complications post-kidney transplantation and also evaluates changes in caloric intake and diet composition after transplantation. This topic is important because nutrition influences allograft function and a number of cardiovascular risk factors including blood pressure, dyslipidemia, weight, and diabetes. In addition, many dietary recommendations and modifiable lifestyle changes should be tailored for specific complications of transplant patients, namely immunosuppression side effects, dietary restrictions, and electrolyte imbalances.

A randomised crossover trial of patient controlled intranasal fentanyl and oral morphine for procedural wound care in adult patients with burns.

This study sought to compare the analgesic efficacy and safety of patient controlled intra-nasal (PCIN) fentanyl with oral morphine for procedural wound care in burns patients. A randomised double-blind placebo controlled, two period, two-treatment crossover trial was conducted within the Burns Unit of a major teaching hospital in Perth, Western Australia. Patients requiring identical wound care procedures on two consecutive mornings (and not prescribed intravenous analgesia) were randomised to receive either PCIN fentanyl with oral placebo or oral morphine with intranasal placebo on 1 day, followed by the alternate active drug on the following day. Twenty-six patients (22 males), aged between 18 and 69 years (35.5 +/- 12.4 years), with total body surface burns (TBSA) range 1-25% (6.9 +/- 4.5), indicated their level of pain on a 10 point (0-10) numeric scale at various time periods before, during and after the procedure. A mean total dose of 1.48 +/- 0.57 microg/kg of PCIN fentanyl and 0.35 +/- 0.12 mg/kg of oral morphine was administered. No statistically significant difference was found between the pain scores recorded for patients during the procedure with PCIN fentanyl compared to that with oral morphine (mean difference = -0.75, 95% CI = -1.97 to 0.47, P = 0.22). Two patients experienced hypotension during the procedure--both had received active oral morphine. No patients experienced respiratory depression or a significant drop in oxygen saturation. There were four episodes (in three patients) where 'rescue analgesia' for severe pain was required--two episodes involving oral morphine and two involving PCIN fentanyl. It was concluded that PCIN fentanyl is similar in efficacy and safety to oral morphine for relief of procedural wound care pain in burns patients.

Developing clinical quality indicators for a Bi-National Burn Registry.

BACKGROUND: Clinical quality indicators are routinely used to benchmark and drive improvements in healthcare. There is a dearth of standardised clinical quality indicators established for management of burns that allow quality of care to be monitored and benchmarked across Australia and New Zealand. METHOD: Using published quality indicator development processes and clinician experience, the Bi-National Burn Registry (Bi-NBR) working party developed quality indicators for burn care to be included as routine data items in the Bi-NBR. RESULTS: Twenty indicators covering structure, process and outcome measures were identified. Preliminary testing resulted in further revision to the quality indicators to increase validity, reliability and improve data quality. The quality indicators are routinely collected in the Bi-NBR and reported quarterly. CONCLUSION: This is the first published account of the development and testing of standardised Bi-National clinical quality indicators for burns. The Bi-NBR quality indicators project remains a work in progress and it is hoped that further refinement of the indicators, in conjunction with international collaborators will assist in driving improvements in burn care.

Core outcomes for adult burn survivors: a clinical overview.

Burn trauma ranges from the minor burn to the devastating injury, which can impact on all aspects of a person's life including aesthetic appearance, relationships with others and psychological, social and physical functioning. Measurement of outcome in burns patients is therefore complex and multi-faceted. The increasing numbers of major burn survivors implies that understanding health outcomes in these patients has assumed high priority. This paper sets out a conceptual framework for unifying outcome measurement, which may be useful to all members of the multidisciplinary team who are contemplating outcome assessment in their burn patients. It outlines seven core domains of assessment which are (i) skin; (ii) neuromuscular function; (iii) sensory and pain; (iv) psychological function; (v) physical role function; (vi) community participation; and (vii) perceived quality of life. Within each domain, we present a brief clinical review of the most commonly administered measurement tools that have been, or potentially could be, used to assess aspects of these core domains. Where possible, the psychometric properties and clinical utility of these tools are presented. A concise discussion of key methodological issues which should be addressed in this assessment process is then provided, together with suggestions for future research.

Nanocrystalline silver dressings in wound management: a review.

This paper describes the properties of nanocrystalline silver products (Acticoat) and their applications and examines available evidence supporting their use in wound management. Acticoat utilizes nanotechnology to release nanocrystalline silver crystals. Acticoat releases 30 times less silver cations than silversulfadiazine cream or 0.5% silver nitrate solution but more of the silver released (by Acticoat). Silver-impregnated slow-release dressings release minute concentrations of silver which are quickly bound up by the chloride in the wound exudate. While extrapolations from in vitro and animal studies are cautious, evidence from these studies suggests Acticoat is: effective against most common strains of wound pathogens; can be used as a protective covering over skin grafts; has a broader antibiotic spectrum activity; and is toxic to keratinocytes and fibroblasts. Animal studies suggest a role for nanocrystalline silver in altering wound inflammatory events and facilitation of the early phase of wound healing. Quality human clinical trials into nanocrystalline silver are few. However, evidence suggests using Acticoat in wound management is cost effective, reduces wound infection, decreases the frequency of dressing changes and pain levels, decreases matrix metalloproteinase activity, wound exudate and bioburden levels, and promotes wound healing in chronic wounds. Although there is no in vivo evidence to suggest nanocrystalline silver is toxic to human keratinocytes and fibroblasts, there is in vitro evidence to suggest so; thus these dressings should be used cautiously over epithelializing and proliferating wounds. Future clinical research, preferably randomized controlled trials into nanocrystalline silver technology, may provide clinicians a better understanding of its applications in wound management.