Utilization of Immunotherapy as a Neoadjuvant Therapy for Liver Transplant Recipients with Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is widely recognized as the predominant type of primary liver malignancy. Orthotopic liver transplantation (OLT) has emerged as a highly effective treatment option for unresectable HCC. Immunotherapies as neoadjuvant options are now being actively investigated in the transplant oncology era to enhance outcomes in patients with HCC. Here, we report our experience with patients with HCC who had received Immune Checkpoint Inhibitors (ICPI) prior to curative OLT. Methods: This was a retrospective cohort that included patients with HCC who received ICPI prior to OLT at a single institution from January 2019 to August 2023. Graft rejection was assessed and reported along with the type of ICPI, malignancy treated, and the timing of ICPI in association with OLT. Results: During this cohort period, six patients with HCC underwent OLT after neoadjuvant ICPI. All patients were male with a median age of 61 (interquartile range: 59-64) years at OLT. Etiology associated with HCC was viral (N = 4) or Non-alcoholic steatohepatitis, NASH (N = 2). Tumor focality was multifocal (N = 4) and unifocal (N = 2). Lymphovascular invasion was identified in four patients. No perineural invasion was identified in any of the patients. All patients received ICPI including atezolizumab/bevacizumab (N = 4), nivolumab/ipilimumab (N = 1), and nivolumab as monotherapy (N = 1). All patients received either single or combined liver-directed/locoregional therapy, including transarterial chemoembolization (TACE), Yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and radiofrequency ablation (RFA). The median washout period was 5 months. All patients responded to ICPI and achieved a safe and successful OLT. All patients received tacrolimus plus mycophenolate as immunosuppressant (IS) therapy post-OLT and one patient received prednisone as additional IS. No patient had clinical evidence of rejection. Conclusions: This cohort emphasizes the success of tumor downstaging by ICPI for OLT when employed as the neoadjuvant therapy strategy. In addition, this study illustrated the importance of timing for the administration of ICPI before OLT. Given the lack of conclusive evidence in this therapeutic area, we believe that our study lays the groundwork for prospective trials to further examine the impact of ICPI prior to OLT.

The reverse Trendelenburg position in proximal ureteral stone management: A systematic review and meta-analysis.

INTRODUCTION: Ureteroscopy lithotripsy (URSL) presents a therapeutic option for patients with proximal ureteral calculi warranting active removal. This systematic review and meta-analysis aimed to assess the efficacy of the reverse Trendelenburg (RT) position during this procedure. MATERIALS: A comprehensive literature search was conducted across PubMed, Embase, and Cochrane databases to identify randomized controlled trials and observational studies comparing RT versus standard positioning (STD) in patients undergoing URSL for proximal ureteral stones. Heterogeneity was measured with the Cochran's Q test, I2 statistics, and prediction intervals (PI). A DerSimonian and Laird random-effects model was utilized for all outcomes. RESULTS: Four studies encompassing 505 patients undergoing URSL were analyzed. Among the studied participants, 293 (58%) underwent RT positioning. Overall, RT was associated with a lower average incidence of stone retropulsion (RR 0.42; 95% CI 0.27-0.65; I2=48%; PI 0.08-2.10) and a higher mean stone-free rate (RR 1.33; 95% CI 1.18-1.49; I2=0%). However, no significant difference between groups was found in the mean rate of overall complications (RR 0.76; 95% CI 0.40-1.43; I2=51%; PI 0.00-520.22) and operative time (MD -0.65; 95% CI -9.58-8.27; I2=94%; PI -111.95-110.65). In those with proximal ureteral stones undergoing RT positioning at only the 20° angle, there was a reduction in stone retropulsion without any measured heterogeneity (RR 0.35; 95% CI 0.23-0.52; I2=0%). CONCLUSION: These findings suggest that RT positioning is effective in improving outcomes for patients with proximal ureteral stones undergoing URSL, and its use should be considered during the procedure.

Preoperative α1-Blockers Impact on Outcomes of Patients Undergoing Ureteroscopy with Ureteral Access Sheaths: A Systematic Review and Meta-Analysis.

Introduction: The use of a ureteral access sheath (UAS) during ureteroscopy (URS) has been associated with the risk for ureteral injuries. Preoperative administration of α1-blockers presents a potential mitigator of such lesions by inducing ureteral relaxation, which may also contribute to improving other surgical outcomes. Methods: A comprehensive literature search was conducted across MEDLINE, Embase, and Cochrane databases for studies comparing preoperative α1-blockers administration vs its non-use in adult patients without pre-stenting undergoing URS. Binary outcomes were evaluated using risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was measured with the Cochran's Q test, I2 statistics, and prediction intervals (PIs). A DerSimonian and Laird random-effects model was utilized for all outcomes. Results: Eleven studies encompassing 1074 patients undergoing URS were included, of whom 522 (48.60%) received α1-blockers before the procedure. Preoperative α1-blockers were associated with a reduction in significant ureteral injuries (RR 0.30; 95% CI 0.17-0.53; I2 = 6%; PI 0.10-0.88) and an increase in mean successful UAS insertion (OR 2.14; 95% CI 1.08-4.23; I2 = 23%; PI 0.51-8.93). In patients undergoing exclusively ureteroscopy lithotripsy (URSL), the medications also reduced total complications (RR 0.62; 95% CI 0.46-0.84; I2 = 0%) and complications graded Clavien-Dindo III or higher (RR 0.16; 95% CI 0.04-0.69; I2 = 0%), but no significant difference between groups was found in the stone-free rate (RR 1.10; 95% CI 0.86-1.40; I2 = 91%; PI 0.47-2.59). Conclusion: Preoperative α1-blockers were linked to a decrease in significant ureteral injuries with UAS use and fewer complications during URSL procedures. However, their impact on the successful insertion of a UAS remains uncertain. Consideration of administering preoperative α1-blockers in non-stented adult patients undergoing URS with UAS is advisable.

Training Robust T1-Weighted Magnetic Resonance Imaging Liver Segmentation Models Using Ensembles of Datasets with Different Contrast Protocols and Liver Disease Etiologies.

Image segmentation of the liver is an important step in several treatments for liver cancer. However, manual segmentation at a large scale is not practical, leading to increasing reliance on deep learning models to automatically segment the liver. This manuscript develops a deep learning model to segment the liver on T1w MR images. We sought to determine the best architecture by training, validating, and testing three different deep learning architectures using a total of 819 T1w MR images gathered from six different datasets, both publicly and internally available. Our experiments compared each architecture's testing performance when trained on data from the same dataset via 5-fold cross validation to its testing performance when trained on all other datasets. Models trained using nnUNet achieved mean Dice-Sorensen similarity coefficients > 90% when tested on each of the six datasets individually. The performance of these models suggests that an nnUNet liver segmentation model trained on a large and diverse collection of T1w MR images would be robust to potential changes in contrast protocol and disease etiology.

Single-center Outcomes After Liver Transplantation With SARS-CoV-2-Positive Donors: An Argument for Increased Utilization.

Background: The COVID-19 pandemic has led to an increase in SARS-CoV-2-test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19-positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19-positive donors at a single center are presented here. Methods: A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19-positive (n = 29 total; 25 index, 4 redo) and COVID-19-negative (n = 472 total; 454 index, 18 redo) deceased donor liver grafts were compared. Results: COVID-19-positive donors were significantly younger (P = 0.04) and had lower kidney donor profile indices (P = 0.04) than COVID-19-negative donors. Recipients of COVID-19-positive donor grafts were older (P = 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; P = 0.89). There were 3 deaths among recipients of liver grafts from COVID-19-positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants. Conclusions: The utilization of liver grafts from COVID-19-positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19-positive donors may be used safely to expand the deceased donor pool.

Effect of a Hispanic outreach program on referral and liver transplantation volume at a single center.

BACKGROUND: Although Hispanic patients have high rates of end-stage liver disease and liver cancer, for which liver transplantation (LT) offers the best long-term outcomes, they are less likely to receive LT. Studies of end-stage renal disease patients and kidney transplant candidates have shown that targeted, culturally relevant interventions can increase the likelihood of Hispanic patients receiving kidney transplant. However, similar interventions remain largely unstudied in potential LT candidates. METHODS: Referrals to a single center in Texas with a large Hispanic patient population were compared before (01/2018-12/2019) and after (7/2021-6/2023) the implementation of a targeted outreach program. Patient progress toward LT, reasons for ineligibility, and differences in insurance were examined between the two eras. RESULTS: A greater proportion of Hispanic patients were referred for LT after the implementation of the outreach program (23.2% vs 26.2%, p = 0.004). Comparing the pre-outreach era to the post-outreach era, more Hispanic patients achieved waitlisting status (61 vs 78, respectively) and received a LT (971 vs 82, respectively). However, the proportion of Hispanic patients undergoing LT dropped from 30.2% to 20.3%. In the post-outreach era, half of the Hispanic patients were unable to get LT for financial reasons (112, 50.5%). CONCLUSIONS: A targeted outreach program for Hispanic patients with end-stage liver disease effectively increased the total number of Hispanic LT referrals and recipients. However, many of the patients who were referred were ineligible for LT, most frequently for financial reasons. These results highlight the need for additional research into the most effective ways to ameliorate financial barriers to LT in this high-need community.

Bloodstream infections after solid organ transplantation: clinical epidemiology and antimicrobial resistance (2016-21).

Background: Solid organ transplant (SOT) recipients are at risk of bloodstream infections (BSIs) with MDR organisms (MDROs). Objectives: To describe the epidemiology of BSI in the year after several types of SOT, as well as the prevalence of MDRO infections in this population. Methods: We conducted a single-centre, retrospective study of kidney, liver, heart, and multi-organ transplantation patients. We examined BSIs ≤1 year from SOT and classified MDRO phenotypes for Staphylococcus aureus, enterococci, Enterobacterales, Pseudomonas aeruginosa and Candida spp. We compared BSI characteristics between SOT types and determined risk factors for 90 day mortality. Results: We included 2293 patients [1251 (54.6%) kidney, 663 (28.9%) liver, 219 (9.6%) heart and 160 (7.0%) multi-organ transplant]. Overall, 8.5% of patients developed a BSI. BSIs were most common after multi-organ (23.1%) and liver (11.3%) transplantation (P < 0.001). Among 196 patients with BSI, 323 unique isolates were recovered, 147 (45.5%) of which were MDROs. MDROs were most common after liver transplant (53.4%). The most frequent MDROs were VRE (69.8% of enterococci) and ESBL-producing and carbapenem-resistant Enterobacterales (29.2% and 27.2% of Enterobacterales, respectively). Mortality after BSI was 9.7%; VRE was independently associated with mortality (adjusted OR 6.0, 95% CI 1.7-21.3). Conclusions: BSI incidence after SOT was 8.5%, with a high proportion of MDROs (45.5%), especially after liver transplantation. These data, in conjunction with local antimicrobial resistance patterns and prescribing practices, may help guide empirical antimicrobial selection and stewardship practices after SOT.

Proceedings of the 28th Annual Congress of the International Liver Transplantation Society.

The 2023 Joint International Congress of the International Liver Transplantation Society (ILTS), the European Liver and Intestine Transplant Association (ELITA), and the Liver Intensive Care Group of Europe (LICAGE) held in Rotterdam, the Netherlands, marked a significant recovery milestone for the liver transplant community after COVID-19. With 1159 participants and a surge in abstract submissions, the event focused on "Liver Disorders and Transplantation: Innovations and Evolving Indications." This conference report provides a comprehensive overview of the key themes discussed during the event, encompassing Hepatology, Anesthesia and Critical Care, Acute Liver Failure, Infectious Disease, Immunosuppression, Pediatric Liver Transplantation, Living Donor Liver Transplantation, Transplant Oncology, Surgical Approaches, and Machine Perfusion. The congress provided a platform for extensive discussions on a wide range of topics, reflecting the continuous advancements and collaborative efforts within the liver transplant community.

Pushing the limits of treatment for hepatocellular carcinoma.

PURPOSE OF REVIEW: We review existing and newer strategies for treatment and surveillance of hepatocellular carcinoma (HCC) both pre and postliver transplantation. SUMMARY: HCC is rising in incidence and patients are often diagnosed at later stages. Consequently, there is a need for treatment strategies which include collaboration of multiple specialties. Combinations of locoregional, systemic, and surgical therapies are yielding better postliver transplantation (post-LT) outcomes for patients with HCC than previously seen. Tumor biology (tumor size, number, location, serum markers, response to therapy) can help identify patients who are at high risk for HCC recurrence posttransplantation and may expand transplant eligibility for some patients.

Transplant Oncology: An Emerging Discipline of Cancer Treatment.

Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The applications of oncology, transplant medicine, and surgery are the core of transplant oncology to improve patients' survival and quality of life. The main concept of transplant oncology is to radically cure cancer by removing the diseased organ and replacing it with a healthy one, aiming to improve the survival outcomes and quality of life of cancer patients. Subsequently, it seeks to expand the treatment options and research for hepatobiliary malignancies, which have seen significantly improved survival outcomes after the implementation of liver transplantation (LT). In the case of colorectal cancer (CRC) in the transplant setting, where the liver is the most common site of metastasis of patients who are considered to have unresectable disease, initial studies have shown improved survival for LT treatment compared to palliative therapy interventions. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years beyond Milan criteria in a stepwise manner. However, the outcome improvements and overall patient survival are limited to the specifics of the setting and systematic intervention options. This review aims to illustrate the representative concepts and history of transplant oncology as an emerging discipline for the management of hepatobiliary malignancies, in addition to other emerging concepts, such as the uses of immunotherapy in a peri-transplant setting as well as the use of circulating tumor DNA (ctDNA) for surveillance post-transplantation.

Evidence to Date: Clinical Utility of Tremelimumab in the Treatment of Unresectable Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide and is associated with significant health care costs and burden. Management of HCC is guided based on the Barcelona Clinic Liver Cancer (BCLC) system and includes liver transplantation, surgical resection, and liver-directed and systemic therapies. In recent years, there have been significant advancements in understanding the immunogenicity of HCC and this has led to approval of different targeted agents as well as immunotherapy for advanced HCC. Tremelimumab is a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) blocking antibody and has recently been approved in combination with durvalumab (a programmed death-ligand 1 [PDL1] inhibitor) as first-line therapy for advanced (Barcelona Clinic Liver Cancer Stage C) HCC. In this article, we review the different available systemic therapies for advanced HCC with special focus on the clinical utility of tremelimumab for the treatment of unresectable HCC.

Prevalence of Steatotic Liver Disease (MASLD, MetALD, and ALD) in the United States: NHANES 2017-2020.

Following the Delphi consensus process, the term steatotic liver disease (SLD) was introduced to replace fatty liver disease, while the term metabolic dysfunction-associated steatotic liver disease (MASLD) emerged as the successor to the term nonalcoholic fatty liver disease (NAFLD).1 This revised nomenclature aims to enhance precision and mitigate negative connotations and potential stigmatization, while refining comprehension and disease categorization. Concurrently, a novel category was introduced to capture individuals whose alcohol consumption exceeded the previously defined thresholds of NAFLD but remained unclassified within the existing system. This category, termed MetALD, now delineates a spectrum of conditions and is defined as a daily intake of 20 to 50 g of alcohol (or weekly 140-350 g) for females and 30 to 60 g daily for males (or weekly 210-420 g).1 Within the MetALD spectrum, some individuals might predominantly exhibit MASLD characteristics, whereas others might be more inclined toward alcoholic liver disease (ALD).1 In the present study, we used a US nationally representative data set to calculate the prevalence of SLD and its subcategories in the United States.

Management of Established Small-for-size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS-iLDLT-LTSI Consensus Conference.

Small-for-size syndrome (SFSS) following living donor liver transplantation is a complication that can lead to devastating outcomes such as prolonged poor graft function and possibly graft loss. Because of the concern about the syndrome, some transplants of mismatched grafts may not be performed. Portal hyperperfusion of a small graft and hyperdynamic splanchnic circulation are recognized as main pathogenic factors for the syndrome. Management of established SFSS is guided by the severity of the presentation with the initial focus on pharmacological therapy to modulate portal flow and provide supportive care to the patient with the goal of facilitating graft regeneration and recovery. When medical management fails or condition progresses with impending dysfunction or even liver failure, interventional radiology (IR) and/or surgical interventions to reduce portal overperfusion should be considered. Although most patients have good outcomes with medical, IR, and/or surgical management that allow graft regeneration, the risk of graft loss increases dramatically in the setting of bilirubin >10 mg/dL and INR>1.6 on postoperative day 7 or isolated bilirubin >20 mg/dL on postoperative day 14. Retransplantation should be considered based on the overall clinical situation and the above postoperative laboratory parameters. The following recommendations focus on medical and IR/surgical management of SFSS as well as considerations and timing of retransplantation when other therapies fail.

Antisynthetase Syndrome With Predominant Pulmonary Involvement: A Case Report.

Antisynthetase syndrome (ASyS) is an autoimmune disease characterized by the presence of aminoacyl-transfer RNA synthetase antibodies. Its clinical presentation is variable and may include interstitial lung disease (ILD), myositis, arthritis, fever, Raynaud's phenomenon, and "mechanic's hands." ILD is more prevalent in this entity when compared to other idiopathic inflammatory myopathies and imparts greater severity to the condition. Here, we report the case of a 42-year-old female patient who sought care for severe ILD and persistent fever. Her diagnosis was made only after the detection of anti-Jo1 autoantibodies. Treatment was refractory to both prednisone monotherapy and cyclophosphamide pulse therapy, requiring the introduction of rituximab. A high degree of clinical suspicion is required to allow early diagnosis of ASyS in patients with pulmonary involvement in the absence of accompanying muscle weakness or other clinical symptoms.

Polyarteritis Nodosa Associated With Hepatitis C Virus Infection.

Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis that affects medium-sized arteries. The association of hepatitis B virus (HBV)and HIV with PAN is well documented. Although there are documented cases of PAN in patients with hepatitis C virus (HCV) infection, the connection between PAN and HCV is not well established. We report a case of PAN in a patient with HCV infection who failed treatment with interferon.

Physical fitness level and the risk of severe COVID-19: A systematic review.

To verify systematically the association between the status of physical fitness and the risk of severe Coronavirus disease 2019 (COVID-19). This systematic review is in accordance with the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) statement and the eligibility criteria followed the Population, Intervention, Comparison, Outcomes and Study (PICOS) recommendation. PubMed, Embase, SciELO and Cochrane electronic databases were searched. All studies that explored the relationship between the pattern of physical fitness and COVID-19 adverse outcomes (hospitalization, intensive care unit admission, intubation, or mortality), were selected. The quality of the studies was assessed by the specific scale of the Newcastle-Ottawa Scale. A total of seven observational studies were identified in this systematic review; 13 â€‹468 patients were included in one case-control study, two cohort studies, and four cross-sectional studies. All studies reported an inverse association between high physical fitness and severe COVID-19 (hospitalization, intensive care admission, or mortality). Only some studies reported comorbidities, especially obesity and cardiovascular disorders, but the results remained unchanged after controlling for comorbidities. The quality of the seven studies included was moderate according to the Newcastle-Ottawa Quality Assessment Scale. The methodological heterogeneity of the studies included did not allow a meta-analysis of the findings. In conclusion, higher physical fitness levels were associated with lower risk of hospitalization, intensive care admissions, and mortality rates among patients with COVID-19.

Naming and shaming as a strategy for enforcing the Paris Agreement: The role of political institutions and public concern.

Enforcement is a challenge for effective international cooperation. In human rights and environmental law, along with many other domains of international cooperation, "naming and shaming" is often used as an enforcement mechanism in the absence of stronger alternatives. Naming and shaming hinges on the ability to identify countries whose efforts are inadequate and effectively shame them toward better behavior. Research on this approach has struggled to identify factors that explain when it influences state behavior in ways that lead to more cooperation. Via survey of a large (N = 910) novel sample of experienced diplomats involved in the design of the Paris Agreement, we find support for the proposition that naming and shaming is most accepted and effective in influencing the behavior of countries that have high-quality political institutions, strong internal concern about climate change, and ambitious and credible international climate commitments. Naming and shaming appears less effective in other countries, so further enforcement mechanisms will be needed for truly global cooperation. We also find that the climate diplomacy experts favor a process of naming and shaming that relies on official intergovernmental actors, in contrast with studies suggesting that NGOs, media, and other private actors are more effective at naming and shaming. We suggest that these tensions-the inability for naming and shaming to work effectively within the countries least motivated for climate action and the preference for namers and shamers that seem least likely to be effective-will become central policy debates around making cooperation on climate change more enforceable.

Combined Hepatocellular Neuroendocrine Carcinoma: A Rare Tumor.

Neuroendocrine tumors originate from neuroendocrine cells primarily located in the gastrointestinal tract. These tumors often metastasize to the liver. Primary hepatic neuroendocrine carcinomas are uncommon, and combined hepatocellular neuroendocrine carcinomas are exceedingly rare. There is a lack of data on the management of these rare tumors. Most cases have very poor prognosis secondary to aggressive behavior of the neuroendocrine tumor component. It is important for clinicians to be aware of this rare carcinoma to allow for early diagnosis and optimize potential treatment options.

Pancreatic tuberculosis in a liver transplant recipient: a case report.

The pancreatic form of tuberculosis (TB) is rare and its diagnosis is challenging, since it manifests itself with non-specific symptoms and non-pathognomonic radiological findings, mimicking a neoplasia of the pancreas. Here, we report the case of a patient who had previously undergone liver transplantation and sought care for abdominal pain, weight loss, anorexia, hematochezia and postprandial fullness. Following an exploratory laparotomy and nucleic acid amplification testing on a pancreatic sample that had been collected, the patient was diagnosed with pancreatic TB. The patient received anti-tubercular pharmacological therapy and required percutaneous biliary drainage. Awareness of the possibility of a pancreatic TB diagnosis is important for clinicians. This attention should be even greater in patients who have undergone transplants, who are immunodeficient or who are from endemic areas.