Cholangiocarcinoma: The Current Status of Surgical Options including Liver Transplantation.

Cholangiocarcinoma (CCA) poses a substantial threat as it ranks as the second most prevalent primary liver tumor. The documented annual rise in intrahepatic CCA (iCCA) incidence in the United States is concerning, indicating its growing impact. Moreover, the five-year survival rate after tumor resection is only 25%, given that tumor recurrence is the leading cause of death in 53-79% of patients. Pre-operative assessments for iCCA focus on pinpointing tumor location, biliary tract involvement, vascular encasements, and metastasis detection. Numerous studies have revealed that portal vein embolization (PVE) is linked to enhanced survival rates, improved liver synthetic functions, and decreased overall mortality. The challenge in achieving clear resection margins contributes to the notable recurrence rate of iCCA, affecting approximately two-thirds of cases within one year, and results in a median survival of less than 12 months for recurrent cases. Nearly 50% of patients initially considered eligible for surgical resection in iCCA cases are ultimately deemed ineligible during surgical exploration. Therefore, staging laparoscopy has been proposed to reduce unnecessary laparotomy. Eligibility for orthotopic liver transplantation (OLT) requires certain criteria to be granted. OLT offers survival advantages for early-detected unresectable iCCA; it can be combined with other treatments, such as radiofrequency ablation and transarterial chemoembolization, in specific cases. We aim to comprehensively describe the surgical strategies available for treating CCA, including the preoperative measures and interventions, alongside the current options regarding liver resection and OLT.

Twelve-Year Progression of Osteochondral Lesions of the Talus Observed Using Magnetic Resonance Imaging.

Osteochondral lesions of the talus are common injuries that are most often the result of trauma. The natural progression of osteochondral lesions is not well understood. It is still unclear which lesions eventually lead to joint degeneration and osteoarthritic changes and if the treatment method affects the progression. The existing literature surrounding this topic is sparse, with inconsistent findings. The presented images are taken from a 72-year-old man with bilateral osteochondral lesions of the talus. To our knowledge, this is the first published series of images illustrating the natural progression of a patient with bilateral osteochondral lesions of the talus over a 12-year time period.

Comparative analysis of short-term efficacy between robot-assisted retrograde drilling and arthroscopic microfracture for osteochondral lesions of the talus.

Objective: To investigate the short-term clinical efficacy of robot-assisted retrograde drilling and arthroscopic microfracture for osteochondral lesions of the talus (OCLT). Methods: This study was divided into two groups: experimental group: robot-assisted retrograde drilling group; control group: arthroscopic microfracture group. A total of 6 OCLT patients who were treated with robot navigation-assisted retrograde drilling and 10 OCLT patients who were treated with arthroscopic microfracture between October 2020 and October 2021 were retrospectively analyzed. There were 11 males and five females, with a mean age of 36 years. The patients were followed up for 6-12 months to compare the changes in the OCLT lesion area by magnetic resonance imaging (MRI), visual analogue scale/score (VAS) and American Orthopedic Foot and Ankle Society score (AOFAS) before and after surgery. Results: All 16 patients were followed up for an average of 8 months, and no complications such as joint infection, nerve injury, or active bleeding occurred during the follow-up period. Only one patient suffered discomfort involving transient postoperative pain in the operative area, but did not experience long-term numbness or chronic pain. Postoperative MRI revealed that none of the patients had severe signs of osteonecrosis, osteolysis or cystic changes of the talus, with lesion areas smaller than those before surgery. The difference was statistically significant (P < 0.01). The patients in the experimental group showed a more significant improvement in the last 3 months than in the first 3 months of the follow-up period. At the last follow-up, the VAS score was 3 points in the experimental group and 2.2 points in the control group, and the AOFAS score was 88.6 points in the experimental group and 88 points in the control group, all of which were significantly higher than those before operation, and the differences were statistically significant, but there was no statistically significant difference between the groups. Conclusion: Both robot navigation-assisted retrograde drilling and arthroscopic microfracture for bone marrow stimulation (BMS) to treat OCLT in all patients obtained satisfactory effects in the short term. In addition, the follow-up revealed that with excellent efficacy and few complications, robot navigation-assisted retrograde drilling was safe and minimally invasive, and greatly reduced operative time. Consequently, robot navigation-assisted retrograde drilling for BMS was a safe and effective procedure for the treatment of OCLT.

A Case of Metastatic Melanoma Post Orthotopic Liver Transplantation.

With the rising prevalence of organ transplantation, clinicians must be aware of the many potential complications that may arise. One such complication is post-transplantation melanoma. Herein, we present a case of advanced metastatic melanoma following orthotopic liver transplantation (OLT).  This is a 54-year-old cirrhotic male who underwent OLT that was complicated by metastatic melanoma. Despite adherence to yearly screening guidelines and timely radiation and immunotherapy, the disease course was rapidly progressive and fatal. This case aims to highlight the risk of post-transplantation melanoma and the potential need for screening modifications to identify melanoma earlier in its development.  The association between organ transplantation and melanoma is well-reported, but the underlying risks and mechanisms remain incompletely understood. One potential risk factor is post-transplant immunosuppressive therapy, which may result in fatally aggressive melanoma. Understanding the potential mortality risks in transplant patients, modifications to peri-transplant screening guidelines, and immunosuppressive therapy may be lifesaving.

Osteochondral Injuries of the Talus.

Osteochondral lesions of the talus are a common sequelae of trauma and are often associated with ankle sprains and ankle fractures. Because the surface of the talus is composed primarily of hyaline cartilage, the regenerative capacity of these injuries is limited. Therefore, several open and arthroscopic techniques have been described to treat osteochondral injuries of the talus and underlying bone marrow lesions. Throughout this review, these treatment options are discussed along with their indications and currently reported outcomes. A commentary on the authors' preferences among these techniques is also provided.

Osteochondral Lesion of the Talus: Quality of Life, Lesion Site, and Lesion Size.

Osteochondral lesions of the talus (OLTs) are the lesions that affect the articular cartilage and the subchondral bone of the talus. Symptoms develop between 6 and 12 months after the index trauma and are associated with degradation of quality of life. Two-thirds of the lesions (73%) are located on the medial part of the talus, 28% of the lesions are posteromedial, and 31% of the lesions are centromedial. Currently, OLT of up to 100 mm2 can behave in a more indolent condition, and above that area, the defect tends to transmit more shearing forces to adjacent cartilage and is more symptomatic.

Deformity Correction: Do Osteochondral Lesion of the Talus and Tibia Change After Realignment Surgery?

Malalignment of the lower limb, distal tibia, foot, and hindfoot can all contribute to altered biomechanics in the ankle joint, resulting in increased focal pressure. The development of some osteochondral lesions of the ankle joint may share a similar pathophysiology, where eccentric loading to the talus or tibia within the ankle joint can lead to cartilage injury or adaptive changes. While the association between malalignment and the development of osteochondral lesions of the ankle joint may seem intuitive, the impact of realignment procedures on these lesions and patient symptoms remains a relatively underexplored topic in the literature. A comprehensive understanding of the potential role of realignment surgery in managing osteochondral lesions of the talus and tibia is crucial for advancing our knowledge of this challenging pathologic condition.

Fresh Osteochondral Allograft for Large Talar Osteochondral Lesions.

Osteochondral lesions of the talus are being recognized as an increasingly common injury. Large osteochondral lesions have significant biomechanical consequences and often require resurfacing with both boney and cartilaginous graft. The current treatment options include osteochondral autograft transfer, mosaicplasty, autologous chondrocyte implantation, or osteochondral allograft transplantation. Allograft procedures have the advantage of no donor site morbidity and ability to match the defect line to line. Careful transportation, storage, and handling of the allograft are critical to success. The failure of nonoperative management, failure of arthroscopic treatment, or large defects are an indication for resurfacing.

Regeneration: AT-AMIC Technique: Limits and Indication.

Osteochondral lesion of the talus (OLT) is a commune cause of chronic ankle pain. Symptomatic lesions require surgical treatment. Currently, lesions with diameter less than 107.4 mm2 are treated with bone marrow stimulating technique with notable success rate. However, more extensive lesions show less predictable surgical results. Autologous matrix-induced chondrogenesis has proven to provide satisfactory medium and long-term results on OLTs. In the current review, we describe an all-arthroscopic technique and the Milan-Tel Aviv lesion assessment protocol.

Fixation of Osteochondral Lesions of the Talus: Indications, Techniques, Outcomes, and Pearls from the Amsterdam Perspective.

The treatment of osteochondral lesions of the talus (OLT) remains a topic of debate as no superior treatment has yet been identified. The current consensus is that it is crucial to incorporate lesion and patient characteristics into the treatment algorithm. One such lesion type is the OLT with a fragment, which may benefit from in situ fixation. Fixation preserves the native hyaline cartilage and offers a direct stabilization of the fragment with high-quality subchondral bone repair. This current concepts review describes the evidence-based clinical work-up, indications, surgical techniques, outcomes, and clinical pearls for fixation techniques of OLT from the Amsterdam perspective.

Osteochondral Lesions of the Talus: Etiology, Clinical Presentation, Treatment Options, and Outcomes.

This article reviews the etiology, clinical presentation, classification schemes, and treatment options for osteochondral lesions of the talus. These lesions typically occur after a traumatic injury and are best diagnosed on MRI. Asymptomatic lesions and incidentally found lesions are best treated conservatively; however, acute displaced osteochondral fragments may require surgical treatment. Lesion characteristics may dictate surgical technique. Outcomes following surgical treatment may be impacted by patient age, BMI, and lesion characteristics.

Improvement in Clinical and Radiographic Outcomes After Isolated Realignment Surgery in Patients With Large Cystic Osteochondral Lesion of the Talar Shoulder and Concurrent Malalignment.

Background: Malalignment has been suggested as a predisposing factor for the development of osteochondral lesions of the talus (OLTs). Purpose: To evaluate the clinical and radiographic outcomes of realignment surgery in patients with a large cystic OLT of the talar shoulder and concurrent malalignment of the foot and ankle. Study Design: Case series; Level of evidence, 4. Methods: The authors reviewed consecutive patients with large cystic OLTs (diameter, >10 mm) of the talar shoulder and concurrent malalignment of the foot and ankle who underwent realignment surgery between September 2013 and April 2021. The type of realignment procedure was determined based on patient symptoms and findings on plain radiographs and weightbearing computed tomography. Clinical improvement was assessed using pre- and postoperative Foot Function Index (FFI) scores and the visual analog scale (VAS) for pain. The OLT location was categorized according to Raikin zone, and the OLT area and volume were measured and compared pre- and postoperatively. The comparative analysis was performed using the Wilcoxon signed-rank test. Results: In total, 27 ankles in 27 patients (mean age, 34.4 ± 11.9 years) were included in the analysis. There were 25 patients with a medial lesion (zone 4 [n = 19], zone 7 [n = 5], and zone 1 [n = 1]), and 2 patients with a lateral lesion (zone 6). Despite OLT location, patients' symptoms varied; 15 (55.6%) patients reported both medial- and lateral-sided pain, 10 (37%) reported lateral-sided pain, and 2 (7%) reported medial-sided pain. Supramalleolar osteotomy was performed in 18 patients, while foot and hindfoot correction without supramalleolar osteotomy was performed in 9 patients. Postoperatively, both the median FFI (from 44.4 [interquartile range (IQR), 35.7-52.2] to 9.1 [IQR, 5.2-13.9]) and median VAS pain score (from 6 [IQR, 5-6] to 1 [IQR, 1-2]) improved significantly (P < .0001 for both), and the median lesion size (from 25.8 mm2 [IQR, 19.3-45.2 mm2] to 13.8 mm2 [IQR, 6.8-26.5 mm2]) and median volume (from 2226.8 mm3 [IQR, 1311-3104 mm3] to 1326.5 mm3 [IQR, 714-2100 mm3]) decreased significantly (P < .0001 for both). During the mean follow-up of 4.1 ± 2.1 years, no subsequent surgery for OLT was necessary. Conclusion: The results suggest that realignment procedures can improve the symptoms and radiographic profile of OLTs in patients with large cystic OLTs of the talar shoulder and malalignment of the foot and ankle.

The NLRP3 inhibitor, OLT1177 attenuates brain injury in experimental intracerebral hemorrhage.

BACKGROUND AND PURPOSE: It has been reported activation of NLRP3 inflammasome after intracerebral hemorrhage (ICH) ictus exacerbates neuroinflammation and brain injury. We hypothesized that inhibition of NLRP3 by OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could reduce brain edema and attenuate brain injury in experimental ICH. METHODS: ICH was induced by injection of autologous blood into basal ganglia in mice models. Sixty-three C57Bl/6 male mice were randomly grouped into the sham, vehicle, OLT1177 (Dapansutrile, 200 mg/kg intraperitoneally) and treated for consecutive three days, starting from 1 h after ICH surgery. Behavioral test, brain edema, brain water content, blood-brain barrier integrity and vascular permeability, cell apoptosis, and NLRP3 and its downstream protein levels were measured. RESULTS: OLT1177 significantly reduced cerebral edema after ICH and contributed to the attenuation of neurological deficits. OLT1177 could preserve blood-brain barrier integrity and lessen vascular leakage. In addition, OLT1177 preserved microglia morphological shift and significantly inhibited the activation of caspase-1 and release of IL-1ß. We also found that OLT1177 can protect against neuronal loss in the affected hemisphere. CONCLUSIONS: OLT1177 (dapansutrile) could significantly attenuate the brain edema after ICH and effectively alleviate the neurological deficit. This result suggests that the novel NLRP3 inhibitor, OLT1177, might serve as a promising candidate for the treatment of ICH.

Large variation in postoperative rehabilitation protocols following operative treatment of osteochondral lesions of the talus: A systematic review and meta-analysis on >200 studies.

PURPOSE: A treatment-specific rehabilitation protocol and well-defined return-to-play criteria guide clinical decision-making on return to normal function, activity, sports and performance after surgical treatment for osteochondral lesion of the talus (OLT). The optimal rehabilitation protocols in the current literature remain unclear. The purpose of this study was to explore the existing literature on rehabilitation protocols from the early postoperative phase to return to sport onwards after different types of surgical treatment of OLTs. METHODS: PubMed, Embase, CDSR, DARE and Central were searched systematically from inception to February 2023 according to the PRISMA 2020 guidelines. All clinical studies with a description of postoperative rehabilitation criteria after surgical treatment of OLTs were included. The primary outcome of this study is the extent of reportage for each rehabilitation parameter expressed in percentage. The secondary outcome is the reported median time for each parameter in rehabilitation protocols for all different treatment modalities (type of surgery). The median time, expressed as number of weeks, for each parameter was compared between different types of surgery. RESULTS: A total of 227 articles were included reporting on 255 different rehabilitation protocols from seven different types of surgery. Weight-bearing instructions were reported in 84%-100% and the use of a cast or walker was prescribed in 27%-100%. Range of motion exercises were described in 54%-100% whereas physical therapy was advised in 21%-67% of the protocols. Any advice on return to sport was described in 0%-67% protocols. A nonparametric analysis of variance showed significant differences between the different surgical treatment modalities for the following parameters between the treatment groups: time to full weight-bearing (p < 0.0003) and return to high impact level of sports (p < 0.0003). Subjective or objective criteria for progression during rehabilitation were reported in only 24% of the studies. CONCLUSION: An in-depth exploration of the current literature showed substantial variation in postoperative rehabilitation guidelines with an associated underreporting of the most important rehabilitation parameters in postoperative protocols after surgical treatment of OLTs. Furthermore, nearly all rehabilitation protocols were constructed according to a time-based approach. Only one out of four reported either objective or subjective criteria. LEVEL OF EVIDENCE: Level IV, systematic review.

The role of an integrated referral program for patients with liver disease: A network between hub and spoke centers.

INTRODUCTION: Access to Liver transplantation (LT) can be affected by several barriers, resulting in delayed referral and increased risk of mortality due to complications of the underlying liver disease. AIM: To assess the clinical characteristics and outcomes of patients with acute or chronic liver disease referred using an integrated referral program. MATERIALS AND METHODS: An integrated referral program was developed in 1 October 2017 based on email addresses and a 24/7 telephone availability. All consecutive adult patients with liver disease referred for the first time using this referral program were prospectively collected until 1 October 2021. Characteristics and outcomes of inpatients were compared with a historical cohort of patients referred without using the integrated referral program (1 October 2015-1 October 2017). Patients were further divided according to pre- and post-Covid-19 pandemic. RESULTS: Two hundred eighty-one referred patients were considered. End stage liver disease was the most common underlying condition (79.3%), 50.5% of patients were referred as inpatients and 74.7% were referred for LT evaluation. When inpatient referrals (n = 142) were compared with the historical cohort (n = 86), a significant increase in acute liver injury due to drugs/herbals and supplements was seen (p = 0.01) as well as an increase in End stage liver disease due to alcohol-related liver disease and NASH, although not statistically significant. A significant increase in referrals for evaluation for Trans-jugular intrahepatic portosystemic shunt placement was seen over time (5.6% vs. 1%; p = 0.01) as well as for LT evaluation (84.5% vs. 81%; p = 0.01). Transplant-free survival was similar between the study and control groups (p = 0.3). The Covid-19 pandemic did not affect trends of referrals and patient survival. CONCLUSIONS: The development of an integrated referral program for patients with liver disease can represent the first step to standardize already existing referral networks between hub and spoke centers. Future studies should focus on the timing of referral according to different etiologies to optimize treatment options and outcomes.

Interrogating direct NLRP3 engagement and functional inflammasome inhibition using cellular assays.

As a key regulator of the innate immune system, the NLRP3 inflammasome responds to a variety of environmental insults through activation of caspase-1 and release of the proinflammatory cytokines IL-1ß and IL-18. Aberrant NLRP3 inflammasome function is implicated in numerous inflammatory diseases, spurring drug discovery efforts at NLRP3 as a therapeutic target. A diverse array of small molecules is undergoing preclinical/clinical evaluation with a reported mode of action involving direct modulation of the NLRP3 pathway. However, for a subset of these ligands the functional link between live-cell target engagement and pathway inhibition has yet to be fully established. Herein we present a cohort of mechanistic assays to both query direct NLRP3 engagement in cells, and functionally interrogate different nodes of NLRP3 pathway activity. This system enabled the stratification of potency for five confirmed NLRP3 inhibitors, and identification of two reported NLRP3 inhibitors that failed to demonstrate direct pathway antagonism.

Open lift-drill-fill-fix for medial osteochondral lesions of the talus: surgical technique.

OBJECTIVE: Osteochondral lesions of the talus (OLT) with a fragment on the talar dome that fail conservative treatment and need surgical treatment can benefit from in situ fixation of the OLT. Advantages of fixation include the preservation of native cartilage, a high quality subchondral bone repair, and the restoration of the joint congruency by immediate fragment stabilization. To improve the chance of successful stabilization, adequate lesion exposure is critical, especially in difficult to reach lesions located on the posteromedial talar dome. In this study we describe the open Lift, Drill, Fill, Fix (LDFF) technique for medial osteochondral lesions of the talus with an osteochondral fragment. As such, the lesion can be seen as an intra-articular non-union that requires debridement, bone-grafting, stabilization, and compression. The LDFF procedure combines these needs with access through a medial distal tibial osteotomy. INDICATIONS: Symptomatic osteochondral lesion of the talus with a fragment (≥ 10 mm diameter and ≥ 3 mm thick as per computed tomography [CT] scan) situated on the medial talar dome which failed 3-6 months conservative treatment. CONTRAINDICATIONS: Systemic disease, including active bacterial arthritis, hemophilic or other diffuse arthropathies, rheumatoid arthritis of the ankle joint, and malignancies. Neuropathic disease. End-stage ankle osteoarthritis or Kellgren and Lawrence score 3 or 4 [3]. Ipsilateral medial malleolus fracture less than 6 months prior. Relative contra-indication: posttraumatic stiffness with range of motion (ROM) < 5°. Children with open physis: do not perform an osteotomy as stabilization of the osteotomy may lead to early closure of the physis, potentially resulting in symptomatic varus angulation of the distal tibia. In these cases only arthrotomy can be considered. SURGICAL TECHNIQUE: The OLT is approached through a medial distal tibial osteotomy, for which the screws are predrilled and the osteotomy is made with an oscillating saw and finished with a chisel in order to avoid thermal damage. Hereafter, the joint is inspected and the osteochondral fragment is identified. The cartilage is partially incised at the borders and the fragment is then lifted as a hood of a motor vehicle (lift). The subchondral bone is debrided and thereafter drilled to allow thorough bone marrow stimulation (drill) and filled with autologous cancellous bone graft from either the iliac crest or the distal tibia (fill). The fragment is then fixated (fix) in anatomical position, preferably with two screws to allow additional rotational stability. Finally, the osteotomy is reduced and fixated with two screws. POSTOPERATIVE MANAGEMENT: Casting includes 5 weeks of short leg cast non-weightbearing and 5 weeks of short leg cast with weightbearing as tolerated. At 10-week follow-up, a CT scan is made to confirm fragment and osteotomy healing, and patients start personalized rehabilitation under the guidance of a physical therapist.

Limited evidence in support of bone marrow aspirate concentrate as an additive to the bone marrow stimulation for osteochondral lesions of the talus: a systematic review and meta-analysis.

PURPOSE: Bone marrow aspirate concentrate can be used as an additive to surgical treatment of osteochondral lesions of the talus. This systematic literature review aims to study the effect of the additional use of bone marrow aspirate concentrate on top of a surgical treatment for osteochondral lesions of the talus on clinical outcomes compared to surgical treatment alone. METHODS: An online literature search was conducted using PubMed (Medline), Embase (Ovid), and the Cochrane library for all studies comparing a surgical intervention with bone marrow aspirate concentrate, with a surgical intervention without bone marrow aspirate concentrate. The methodological quality was rated according to the methodological index for non-randomised studies checklist. The primary outcome measure were clinical outcomes. Secondary outcome measures consisted of revision rate, complication rate, radiographic outcome measures and histological analyses. Subgroups were created based on type of surgical intervention used in the studies. If multiple articles were included in a subgroup, a linear random-effects model was used to compare the bone marrow aspirate concentrate-augmented group with the control group. RESULTS: Out of 1006 studies found, eight studies with a total of 718 patients were included. The methodological quality, assessed according to the methodological index for non-randomised studies checklist, was weak. A significantly better functional outcome measures (p < 0.05) was found in the subgroup treated with bone marrow stimulation + bone marrow aspirate concentrate compared to the group treated with bone marrow stimulation alone, based on three non-blinded studies. No significant differences regarding clinical outcomes were found in the subgroups comparing matrix-induced autologous chondrocyte implantation with matrix-induced bone marrow aspirate concentrate, osteochondral autologous transplantation alone with osteochondral autologous transplantation + bone marrow aspirate concentrate and autologous matrix-induced chondrogenesis plus peripheral blood concentrate vs. matrix-associated stem cell transplantation bone marrow aspirate concentrate. CONCLUSION: There is insufficient evidence to support a positive effect on clinical outcomes of bone marrow aspirate concentrate as an additive to surgical treatment of osteochondral lesions of the talus. However, based on the safety reports and initial results, sufficiently powered, patient- and researcher-blinded, prospective randomised controlled trials are justified and recommended. Until then, we advise not to implement a therapy (addition of bone marrow aspirate concentrate) without clinical evidence that justifies the additional costs involved. LEVEL OF EVIDENCE: Level III.

Elevated Liver Fibrosis Progression in Isolated PSC Patients and Increased Malignancy Risk in a PSC-IBD Cohort: A Retrospective Study.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (CU), and rarely with Crohn's disease (CD). Various long-term analyses show different rates of cancer and the need for orthotopic liver transplantation (OLT) in patients with isolated PSC and with concomitant IBD, respectively. However, data on the detailed course of PSC with or without IBD are limited. We aimed to analyze the clinical disease course of PSC patients without IBD compared to PSC patients with UC and CD, respectively. A retrospective data analysis of patients with isolated PSC (n = 41) and of patients with concomitant IBD (n = 115) was performed. In detail, PSC disease characteristics including occurrence of dominant stenoses, liver cirrhosis, OLT and malignancy, as well as the temporal course of PSC activity and disease progression, were analyzed. A multivariable Cox regression model and a Fine-Gray competing risk model were further used for the independent risk factor analysis of cirrhosis development and OLT. Patients with isolated PSC were significantly older at first diagnosis than patients with PSC-IBD (39 vs. 28 years, p = 0.02). A detailed analysis of the course of PSC revealed a faster PSC progression after initial diagnosis in isolated PSC patients compared to PSC-IBD including significantly earlier diagnosis of dominant stenoses (29 vs. 74 months, p = 0.021) and faster progression to liver cirrhosis (38 vs. 103 months, p = 0.027). Patients with isolated PSC have a higher risk of developing cirrhosis than patients with PSC-IBD (Gray's test p = 0.03). OLT was more frequently performed in male patients with isolated PSC compared to males with coincident IBD (48% (n = 13) vs. 33% (n = 25), p = 0.003). Colorectal carcinoma was significantly more often diagnosed in patients with PSC-IBD than in isolated PSC (8.7% vs. 0%, p = 0.042). Patients with isolated PSC seem to have a different clinical course of disease than PSC patients with concomitant IBD characterized by a more pro-fibrotic disease course with earlier onset of liver cirrhosis and dominant stenosis but with less malignancy. These data may be interpreted as either a more progressive disease course of isolated PSC or a later diagnosis of the disease at an advanced disease stage. The different clinical courses of PSC and the underlying mechanisms of the gut-liver axis need further attention.

A narrative review and expert recommendations on the assessment of the clinical manifestations, follow-up, and management of post-OLT patients with ATTRv amyloidosis.

Orthotopic liver transplantation (OLT) was the first treatment able to modify the natural course of hereditary transthyretin (ATTRv) amyloidosis, which is a rare and fatal disorder caused by the accumulation of misfolded transthyretin (TTR) variants in different organs and tissues and which leads to a progressive and multisystem dysfunction. Because the liver is the main source of TTR, OLT dramatically reduces the production of the pathogenic TTR variant, which should prevent amyloid formation and halt disease progression. However, amyloidosis progression may occur after OLT due to wild-type TTR deposition, especially in the nerves and heart. In this review, we discuss the disease features influencing OLT outcomes and the clinical manifestations of ATTRv amyloidosis progression post-OLT to improve our understanding of disease worsening after OLT and optimize the follow-up and clinical management of these patients. By conducting a literature review on the PubMed database, we identified patient characteristics that have been associated with worse post-OLT outcomes, including late-onset V50M and non-V50M variants, age >40 years, long disease duration, advanced neuropathy and autonomic dysfunction, and malnutrition. Regarding post-OLT mortality, deaths occurring within the first year after OLT were mainly associated with fatal graft complications and infectious diseases, whereas cardiovascular-related deaths usually occurred later. Considering the diverse clinical manifestations of ATTRv amyloidosis progression post-OLT, including worsening neuropathy and/or cardiomyopathy, autonomic dysfunction, and oculoleptomeningeal involvement, we present advice on the most relevant tests for assessing disease progression post-OLT. Finally, we discuss the use of new therapies based on TTR stabilizers and TTR mRNA silencers for the treatment of ATTRv amyloidosis patients post-OLT.