Routine end-ischemic hypothermic machine perfusion in liver transplantation from donors after brain death: results of two-year follow-up of a randomized controlled trial.

BACKGROUND: Data on routine hypothermic machine perfusion of livers procured from donors after brain death (DBD) are scarce, and the benefits of the method have only been demonstrated in extended criteria grafts. The aim of this study was to assess if end-ischemic dual hypothermic oxygenated machine perfusion (dHOPE) is superior to static cold storage (SCS) in preservation of livers procured from DBD donors with respect to long-term outcomes. Existing data on short-term outcomes favours dHOPE in patients receiving high-risk grafts. METHODS: This prospective randomized controlled trial included 104 recipients of DBD livers randomly assigned to static cold storage arm (78 patients) and dHOPE arm (26 patients). Endpoints of interest were occurrence of biliary complications (biliary fistula, anastomotic, and nonanastomotic strictures) and overall patient (OS) and graft survival (GS) during two-year follow-up. RESULTS: A total of 36 patients developed biliary complications (at least one event) - 6 events in dHOPE arm and 30 in SCS arm. There was no significant difference in biliary complications between groups (23.7% vs. 43.4% [P=0.11]). No differences were found significant with respect to anastomotic (19.9% vs. 33.7% [P=0.20]) and non-anastomotic strictures (0% vs. 11.1% [P=0.10]) as well as biliary fistulas (11.7% vs. 12.2% [P=0.93]). Survival analysis did not show significantly different result in the study population - OS: 92.3% in dHOPE and 83.9% in SCS (P=0.35), and GS: 92.3% and 81.4% (P=0.23), respectively. However, significant difference in GS was noted in recipients of high-risk grafts - 100% in dHOPE and 73.1% in SCS, respectively (P=0.038). CONCLUSIONS: The long-term outcome data suggest that the routine use of dHOPE may be beneficial for recipients of high-risk grafts from DBD donors. The present study does not provide any evidence for benefits of dHOPE in low-risk grafts.

Routine End-ischemic Hypothermic Oxygenated Machine Perfusion in Liver Transplantation From Donors After Brain Death: A Randomized Controlled Trial.

OBJECTIVE: To assess whether end-ischemic hypothermic oxygenated machine perfusion (HOPE) is superior to static cold storage (SCS) in preserving livers procured from donors after brain death (DBD). BACKGROUND: There is increasing evidence of the benefits of HOPE in liver transplantation, but predominantly in the setting of high-risk donors. METHODS: In this randomized clinical trial, livers procured from DBDs were randomly assigned to either end-ischemic dual HOPE for at least 2 hours or SCS (1:3 allocation ratio). The Model for Early Allograft Function (MEAF) was the primary outcome measure. The secondary outcome measure was 90-day morbidity (ClinicalTrials. gov, NCT04812054). RESULTS: Of the 104 liver transplantations included in the study, 26 were assigned to HOPE and 78 to SCS. Mean MEAF was 4.94 and 5.49 in the HOPE and SCS groups ( P =0.24), respectively, with the corresponding rates of MEAF >8 of 3.8% (1/26) and 15.4% (12/78; P =0.18). Median Comprehensive Complication Index was 20.9 after transplantations with HOPE and 21.8 after transplantations with SCS ( P =0.19). Transaminase activity, bilirubin concentration, and international normalized ratio were similar in both groups. In the case of donor risk index >1.70, HOPE was associated with significantly lower mean MEAF (4.92 vs 6.31; P =0.037) and lower median Comprehensive Complication Index (4.35 vs 22.6; P =0.050). No significant differences between HOPE and SCS were observed for lower donor risk index values. CONCLUSION: Routine use of HOPE in DBD liver transplantations does not seem justified as the clinical benefits are limited to high-risk donors.

Sarcoid-like Lung Disease as a Reaction to Silica from Exposure to Bentonite Cat Litter Complicated by End-Stage Renal Failure-A Case Report.

A 44-year-old woman was admitted to hospital with end-stage renal failure, productive cough, and decreased exercise tolerance. She had owned nine cats, which resulted in long-term exposure (18 years) to silica-containing bentonite cat litter. High-resolution computed tomography of the chest showed micronodular lesions in the lungs, and mild mediastinal lymphadenopathy. A lung biopsy revealed multinucleated giant cells, some of which had birefringent material and Schaumann bodies. X-ray photoelectron spectroscopy revealed the presence of silicon in the lung biopsy specimen, as well as in the patient's cat litter. The pulmonary condition was suggestive of sarcoid-like lung disease, rather than silicosis, sarcoidosis, or hypersensitivity pneumonitis, according to the clinicopathological findings. Renal failure appeared to be a result of chronic hypercalcemia due to extrarenal calcitriol overproduction in activated alveolar macrophages. Ultimately, the patient was diagnosed with sarcoid-like lung disease complicated by end-stage renal failure from exposure to bentonite cat litter. Therapy with steroids, in addition to elimination of the bentonite cat litter exposure, resulted in a significant improvement in the health condition. At a follow-up visit after 4 months, an almost complete resolution of the lung lesions and a significant improvement in renal function were observed.

Liver Transplantation for Unresectable Calcifying Nested Stromal Epithelial Tumor: Case Report With a 1-Year Follow-Up and Review of Literature.

Introduction: Calcifying nested stromal epithelial tumor (CNSET) is an extremely rare diagnosis among patients treated for primary hepatic neoplasms. There are only 45 cases reported worldwide. Histopathological characteristics are well-demarcated nests of spindle and epithelioid cells in a dense desmoplastic stroma with variable calcification and ossification. It is mostly diagnosed in children and young females. Treatment strategies implemented for the management of CNSET include radiofrequency ablation, transarterial chemoembolization, surgical resection, adjuvant and neoadjuvant chemotherapy, and liver transplantation. Given the small number of available cases, there are still no established standards of treatment for this neoplasm. Case Presentation: A 28-year-old female diagnosed with CNSET presented mild abdominal pain, with normal laboratory values. The tumor was initially deemed unresectable, therefore, the patient was disqualified from liver resection. Further deterioration of the patient's clinical condition and local tumor progression led to qualification for liver transplantation. The patient underwent liver transplantation 1 year following initial diagnosis and a 12 months recurrence-free period was observed. During the course of treatment, she did not receive systemic chemotherapy, radiotherapy, or loco-regional treatment. Conclusion: Multiple strategies have been implemented for the treatment of CNSET, with liver resection providing the best outcomes. Transarterial chemoembolization, radiofrequency ablation, and radiotherapy are reported to be insufficient in the management of this tumor. Various chemotherapy regimens turned out to be ineffective as well. There have been only eight reported cases of patients undergoing liver transplantation for CNSET, with tumor recurrence in two cases. CNSET appears to be a neoplasm with low malignancy potential, although an aggressive progression has subsequently been reported. Further investigation is still required in this field.

MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis.

The clinical picture of autoimmune hepatitis (AIH) varies markedly between patients, potentially due to genetic modifiers. The aim of this study was to evaluate genetic variants previously associated with fatty liver as potential modulators of the AIH phenotype. The study cohort comprised 313 non-transplanted adults with AIH. In all patients, the MARC1 (rs2642438), HSD17B13 (rs72613567), PNPLA3 (rs738409), TM6SF2 (rs58542926), and MBOAT7 (rs641738) variants were genotyped using TaqMan assays. Mitochondrial damage markers in serum were analyzed in relation to the MARC1 variant. Carriers of the protective MARC1 allele had lower ALT and AST (both P < 0.05). In patients treated for AIH for ≥ 6 months, MARC1 correlated with reduced AST, ALP, GGT (all P ≤ 0.01), and lower APRI (P = 0.02). Patients carrying the protective MARC1 genotype had higher total antioxidant activity (P < 0.01) and catalase levels (P = 0.02) in serum. The PNPLA3 risk variant was associated with higher MELD (P = 0.02) in treated patients, whereas MBOAT7 increased the odds for liver cancer (OR = 3.71). None of the variants modulated the risk of death or transplantation. In conclusion, the MARC1 polymorphism has protective effects in AIH. Genotyping of MARC1, PNPLA3, and MBOAT7 polymorphisms might help to stratify patients with AIH.

Spontaneous rupture of a mucinous cystic neoplasm of the liver resulting in a huge biloma in a pregnant woman: A case report.

BACKGROUND: Mucinous cystic neoplasm of the liver (MCN-L) and intraductal papillary neoplasm of the bile duct (IPN-B) are two different types of mucin-producing bile duct tumour that may complicate the course of pregnancy. To the best of our knowledge, we describe herein the first case of MCN-L with spontaneous rupture during pregnancy necessitating complex surgical treatment. CASE SUMMARY: A 24-year-old woman was initially admitted to another hospital in October 2018 with signs of jaundice (serum bilirubin level 12 mg/dL) and upper abdominal pain radiating to the left shoulder. Initial magnetic resonance imaging (MRI) of the abdominal cavity revealed a multilocular cystic tumour of the liver hilum (37 mm × 40 mm in diameter) located between segments 3 and 4 of the left liver lobe. Six weeks later (December 2018), the patient was found to be 12 wk pregnant and was referred to our institution for further diagnostics and treatment. At admission, a soft, palpable, and tender mass in the left upper abdomen was found. It was determined via MRI (with no intravenous contrast in view of the first-trimester pregnancy) to be a large collection of fluid (19 cm × 17 cm × 10 cm) located close to the liver hilum and below the left liver lobe. The patient did not undergo any diagnostic or therapeutic procedures nor did they have any abdominal trauma in the preceding weeks. The fluid collection proved to be of biliary origin following percutaneous drainage. Therefore, we concluded this was a spontaneous rupture of an MCN-L with the formation of a biloma. The MRI study also revealed the previously found cystic tumour of the liver hilum communicating with the left hepatic duct, which, together with left hepatic duct dilatation, suggested the diagnosis of IPN-B. The follow-up MRI with intravenous gadolinium contrast performed in the second trimester of pregnancy (week 14) showed, in turn, some features of MCN-L, including enhancement of the internal septations within the cystic liver mass. A precise preoperative differential diagnosis between IPN-B and MCN-L was therefore not possible. The patient was submitted to surgery in the second trimester of pregnancy (week 18). Surgery included a cholecystectomy, left hepatectomy, and concomitant resection of the extrahepatic bile ducts followed by anastomosis of the right hepatic duct with the Roux limb of the jejunum. The post-operative period was uneventful and the patient was discharged 8 days after surgery. The histopathological examination of the resected specimen revealed a final diagnosis of MCN-L with low-grade dysplasia and epithelium surrounded by ovarian-type stromal tissue. The patient delivered a healthy baby girl and both remain well at present, after 2 years of follow-up since surgery. CONCLUSION: The differential diagnosis and management of MCN-L and IPN-B may be very challenging, particularly in the setting of pregnancy. When indications for surgery are obvious, the final diagnosis is based on histopathological examination, with ovarian-type stroma being pathognomonic for MCN-L. We believe that the growth of this subepithelial stroma secondary to the high levels of sex hormones produced during pregnancy might have been the main causative factor leading to the tumour rupture with the formation of a biloma in our patient.

Chronic Fatigue Persists in a Significant Proportion of Female Patients After Transplantation for Primary Sclerosing Cholangitis.

Chronic fatigue and an impairment of general health-related quality of life (HRQoL) are frequently reported by patients with primary sclerosing cholangitis (PSC). Studies on patients with primary biliary cholangitis (PBC) suggest that, unlike pruritus, fatigue may not be ameliorated by liver transplantation (LT). However, there are few data regarding the assessment of fatigue before and after transplantation in PSC. To investigate the effect of LT on fatigue and HRQoL in patients with PSC, 81 patients with PSC (median age 33 years; 69% men) were prospectively enrolled in this study. The PBC-40 and Short Form 36 (SF-36) questionnaires were used for assessment before and twice after LT. A total of 26 patients who received a transplant for PBC were included as controls. The potential impact of the clinical and laboratory parameters was evaluated by univariate and multivariate analyses. Although in addition to other well-being indexes the median fatigue score improved after LT (P < 0.001), a detailed analysis demonstrated that fatigue persists in one-third of patients. A significant fatigue reduction was seen in men (P < 0.001) but not women (P = 0.25). Posttransplant fatigue did not depend on concomitant inflammatory bowel disease, laboratory indexes of cholestasis, or disease recurrence. In the multivariate regression model, female sex was the only independent covariate associated with persistent fatigue. In terms of other measures of HRQoL, LT caused a substantial improvement in the majority of SF-36 and PBC-40 domains. Recurrent PSC and unemployment negatively affected the well-being of patients. Patients who received a transplant for PSC had significantly better HRQoL than those patients with PBC. LT improves various measures of HRQoL, but it does not ameliorate fatigue in female patients with PSC.

Measurement of liver and spleen stiffness as complementary methods for assessment of liver fibrosis in autoimmune hepatitis.

BACKGROUND AND AIMS: Liver stiffness measurements (LSM), commonly performed by transient elastography (TE) or two-dimensional shear wave elastography (2D-SWE), are used to quantify liver fibrosis. Active hepatitis, a hallmark of autoimmune hepatitis (AIH), could bias LSM. This bias might be overcome by measurement spleen 2D-SWE. Here, we compare liver and spleen 2D-SWE to TE and liver biopsy (LB) in prospectively recruited patients with AIH. METHODS: We analysed liver and spleen 2D-SWE in relation to liver TE in 90 patients treated ≥ 6 months for AIH. Liver and spleen 2D-SWE were also compared to LB in 63 individuals with AIH. Finally, we evaluated these tools in 220 patients with AIH and during 18 months follow-up. RESULTS: Liver 2D-SWE correlated with surrogate markers of active hepatitis (ALT and IgG, both P < .001) but there was no link between spleen 2D-SWE and ALT. Liver 2D-SWE, but not spleen 2D-SWE, was associated with histopathological inflammatory score (P < .01). When compared to LB, the optimal cut-offs for detecting cirrhosis by liver and spleen 2D-SWE were 16.1 kPa (AUROC 0.93) and 29.8 kPa (AUROC 0.95), respectively. In patients with active hepatitis the combined diagnostic approach including liver and spleen 2D-SWE had significantly better AUROC for detecting cirrhosis than liver 2D-SWE alone. CONCLUSIONS: Liver and spleen 2D-SWE are reliable complementary methods for the diagnosis of advanced fibrosis in AIH. Spleen 2D-SWE seems to be less biased by inflammation and could facilitate fibrosis assessment in therapy-naïve patients or in the presence of active hepatitis.

Evaluation of liver fibrosis in patients with Wilson's disease.

OBJECTIVES: Staging of fibrosis in chronic liver disease is important for prognosis and treatment planning. Liver biopsy is the gold standard in fibrosis assessment; however, new methods for fibrosis and stiffness measurement exist which have not been evaluated in patients with Wilson's disease. To evaluate the accuracy of collagen proportionate area (CPA), transient elastography and shear wave elastography (SWE) in the assessment of liver fibrosis in adult patients with Wilson's disease. METHODS: In this retrospective study of 60 patients with Wilson's disease, results of percutaneous cutting liver biopsy assessed using the Ishak fibrosis score and CPA were compared with liver stiffness measured with transient elastography and SWE. RESULTS: CPA correlated with the Ishak score (r = 0.45; P = 0.001) and transient elastography results correlated with SWE measurements (r = 0.80; P = 0.0001). In contrast, transient elastography or SWE did not significantly correlate with the Ishak score or CPA. CONCLUSION: Collagen content assessment may be useful for estimation of liver fibrosis in patients with Wilson's disease. However, single time-point elastographic liver stiffness measurements have a limited diagnostic value in Wilson's disease.

Spinal Cord Ischemia Because of Microvascular Thrombosis in a Patient with Necrotizing Pancreatitis. Case Report and Literature Review.

BACKGROUND Central nervous system ischemia in acute pancreatitis is rare with only a handful of cases reported in the literature. We report a case of spinal cord ischemia due to microvascular thrombosis complicating acute on chronic pancreatitis. CASE REPORT A 37-year-old male was transferred to a university hospital intensive care unit with a diagnosis of acute onset chronic pancreatitis, paraplegia, and multi-organ failure. Laboratory studies showed elevated serum amylase activity and leukocytosis. The patient deteriorated quickly and anemia with thrombocytopenia and coagulation abnormalities developed. Computed tomography showed large pancreatic pseudocyst and ischemic lesions in abdominal organs. Symptoms of paraplegia preceded by the bilateral paresis were noted 7 days from the onset of his disease and magnetic resonance imaging showed ischemia involving the central part of the medullary cone resulting from microvascular thrombosis. The patient underwent endoscopic retrograde cholangiopancreatography and repeated surgery with a number of complications but 2 months later was discharged to rehabilitation center due to persistent neurologic deficit. CONCLUSIONS Patients with severe pancreatitis and multiorgan failure requiring intensive care should undergo routine neurological examination to identify and treat deficits early.

Surgical treatment of extra-appendiceal colorectal neuroendocrine tumors.

BACKGROUND: Extra-appendiceal colorectal neuroendocrine tumors are rare neoplasms with a variable biological behavior. MATERIALS AND METHODS: The study group consisted of 15 patients with an extra-appendiceal colorectal neuroendocrine tumor who underwent surgical resection (M/F=3:12, mean age=62.9 years). Lower-grade neuroendocrine tumors and neuroendocrine carcinomas were recognized in 5 and 10 patients, respectively. Data were evaluated retrospectively with regard to clinical and pathologic characteristics and outcomes. RESULTS: The median age of the patients with lower-grade NETs was significantly lower than that in patients with NECs (53 yr vs. 68 yr, p=0.03). NETs G1-G2 were significantly smaller than neuroendocrine carcinomas (4.0 cm vs. 6.4 cm, p=0.02). There were no differences between lower-grade NETs and NECs with regard to tumor location, rate of nodal involvement and distant metastases. All the patients underwent open segmental resection of the colon or rectum. Complete resection was achieved in 3 of 5 patients from the lower-grade NET group, and in 5 of 10 patients in the NEC group. Overall survival was significantly better for lower-grade NETs tumors (p=0.005). The median survival was 4.8 months in the NEC group. The median survival in the lower-grade NET group was not achieved after a median follow-up of 69 months. Three-year overall survival was 100% for lower-grade NETs, and only 27% for NECs. CONCLUSION: Lower-grade neuroendocrine tumors seem to exhibit comparable potential for dissemination as neuroendocrine carcinomas, but prognostic implications of metastases are distinct.

[IgG4-related disease - a case report]. / Choroba IgG4-zalezna ­ opis przypadku.

Immunoglobulin G4-related disease (IgG4-RD) is a comparatively new condition that may involve more than one organ. The lack of characteristic, pathognomonic clinical symptoms may delay the diagnosis of this disease. The diagnosis is based upon clinical manifestation, elevated serum levels of IgG4 and histopathologic examination with immunohistochemical staining to reveal infiltration of IgG4-positive plasma cells. The first line treatment is oral glucocorticoids. A CASE REPORT: 38-year-old woman with Hashimoto disease, chronic sinusitis and chronic hepatitis of unknown etiology was admitted to the Department of Endocrinology because of moderate eyelids swelling accompanied by redness for 3 years. Graves' orbitopathy and systemic vasculitis were suspected, however both were excluded (negative antibodies results: anty-TSHR, ANCA, ANA). Serologic investigation of Sjögren's syndrome was also negative. In Magnetic Resonance Imaging (MRI) of orbits there were described bilateral mild extension of lateral rectus muscles, normal signal of adipose tissue and bilateral lacrimal glands enlargement. Moreover, increased IgG4 serum levels were detected. The material derived from perinasal sinuses surgery was analyzed in histopathology examination with immunohistochemical staining, which revealed characteristic features of chronic inflammatory process and increased numbers of IgG4 - positive plasma cells (>50 in a large field of view). The diagnosis of IgG4-RD was established. Because of non-effective oral methylprednisolone therapy in the past, the patient was referred to Clinic of Rheumatology for further treatment. After the therapy with methylprednisolone and azathioprine there were observed the significant reduction of symptoms. CONCLUSIONS: Because of lack of characteristic symptoms of IgG4- RD, it should be always considered in differential diagnosis of chronic inflammatory diseases of various organs.

Clinicopathological and immunohistochemical analysis of epithelial-lined (true) cysts of the adrenal gland with proposal of a new histogenetic categorization.

Epithelial- lined (true) cysts are rare lesions and until now the only information we had about their histogenesis was based on the analysis of a few cases. We retrospectively reviewed 8 cases of cysts with a true epithelial lining (confirmed immunohistochemically). The pathological findings and immunohistochemical analysis of the epithelial linings allowed for categorization of the cysts into 3 groups. Five cysts had pure mesothelial lining, which was flattened to cuboidal, and demonstrated a positive reaction for mesothelial markers (eg. calretinin, WT1), and a negative reaction for EpCAM, EMA, PAX8 and ER. Two cysts had cuboidal to flattened lining, the cells of which were diffusely or focally positive for mesothelial markers, for some epithelial markers (eg. EpCAM and EMA) and despite a lack of müllerian-type epithelium demonstrated a positive reaction for PAX8 and focally for ER. A cyst derived from adreno-hepatic fusion (AHF)-related intra-adrenal bile ductules was diagnosed in a right adrenal gland which was directly adherent to the liver, microscopically features of AHF were visible with intermingling of adrenal and liver parenchymal cells. The immunoreactivity pattern was similar among the preserved cells of the cyst-lining, the intra-adrenal bile ductules and the normal bile ductules in the adjoining liver parenchyma. On the basis of this case series from a single institution (8 presented now and 1 reported before) we propose a new histogenetic categorization of adrenal epithelial cysts into: 1. pure mesothelial cysts (the most common type), 2. mesothelial cysts with incomplete or complete müllerian metaplasia 3. AHF-related cysts.

Adrenal cyst with both Müllerian and mesothelial differentiation- a clinicopathological and immunohistochemical study with implications for histogenesis.

True epithelial-lined cysts are rare forms of adrenal cystic lesions, the pathogenesis of which is still not fully understood. In this report we present a case of an adrenal cyst diagnosed incidentally on imaging in a 31-year-old, previously healthy, obese woman. Due to non-specific hormonal disorders and enlargement of the lesion, a right-sided laparoscopic adrenalectomy was performed. The cyst was lined predominantly by ciliated cuboidal-to-columnar, Müllerian-type epithelium, and focally by flat-to-cuboidal, mesothelium-like lining. Immunohistochemistry demonstrated a strong positive reaction in the cells of both types of lining for CKAE1+E3, CK19, CK7 and WT1, and both had a negative reaction for CK20, CD34, Melan-A, SF1, TTF1, SMA and CDX2. The cells of the ciliated cuboidal-to-columnar epithelium were strongly positive for PAX8, ER, Ep-CAM and EMA, focally positive for PR, and were negative for calretinin, whereas the cells of the flat-to-cuboidal lining were positive for calretinin and podoplanin and showed only a weak positive response in individual cells for PAX8, EMA and Ep-CAM, but were negative for ER and PR. This is the first reported case of an adrenal ciliated epithelial cyst with Müllerian differentiation (confirmed immunohistochemically) in the English literature. The differences in morphology and immunophenotype of the two types of lining (epithelial Müllerian phenotype versus mesothelial phenotype), suggest that some adrenal epithelial cysts probably form due to metaplasia of mesothelium-derived lining. A similar mechanism may also be involved in the pathogenesis of at least some of the so-called Müllerian cysts (or inclusions) in other locations.