Surgical margin clearance and extended chemotherapy defines survival for synchronous oligometastatic liver lesions of the ductal adenocarcinoma of the pancreas.

BACKGROUND: The role of surgery for circumscribed synchronous hepatic lesions of the pancreatic ductal adenocarcinoma (PDAC) remains controversial. Thus, the aim of our study was to compare survival outcome (OS) after surgery of patients with hepatic metastases (M1surg) to patients with only localized disease. METHODS: Correlation analysis of clinicopathological data and OS after resection of M1surg patients and patients with localized PDACs (M0) was performed. Patients were included for survival analysis only if a complete staging including perineural, venous and lymphatic invasion was available. RESULTS: Out of the study collective, 35 patients received extended surgery (M1surg), whereas 131 patients received standardized surgery for localized disease (M0). Length of hospitalization and mortality was similar in both groups. FOLFIRNOX as an adjuvant treatment regime was administered in ~ 23 and ~ 8% of M1surg and M0 patients, respectively. In subgroup analysis of R0 resected patients and in multivariate analysis of the total cohort, there was no difference in overall survival between both groups. Only the resection status (R1 vs R0) and venous invasion (V1) were identified as independent prognostic factors. Site of recurrence in R0 resected M1surg patients and in M0 patients were homogenously distributed. CONCLUSION: This is the first study demonstrating a survival benefit after extended surgery for synchronously hepatic-metastasized PDACs. We found no difference in survival outcome of metastasized patients when compared to patients with localized disease. FOLFIRINOX as an adjuvant treatment regime for resected M1surg presumably is worthwhile. Larger multicenter studies are still needed to validate our results.

Mesopancreatic excision for pancreatic ductal adenocarcinoma improves local disease control and survival.

BACKGROUND: Survival in ductal adenocarcinoma of the pancreatic head (hPDAC) is poor. After implementation of the circumferential resection margin (CRM) into standard histopathological evaluation, the margin negative resection rate has drastically dropped. However, the impact of surgical radicality on survival and the influence of malignant infiltration of the mesopancreatic fat remains unclear. At our institution, a standardized dissection of the mesopancreatic lamina and peri-pancreatic vessels are obligatory components of radical pancreatoduodenectomy. The aim of our study was to histopathologically analyze mesopancreatic tumor infiltration and the influence of CRM-evaluated resection margin on relapse-free and overall survival. METHOD: Clinicopathological and survival parameters of 264 consecutive patients who underwent surgery for hPDAC were evaluated. RESULTS: The rate of R0 resection R0(CRM-) was 48.5%, after the implementation of CRM. Mesopancreatic fat infiltration was evident in 78.4% of all consecutively treated patients. Patients with mesopancreatic fat infiltration were prone to lymphatic metastases (N1 and N2) and had a higher rate of positive resection margin (R1/R0(CRM+)). In multivariate analysis, only R0 resection was shown to be an independent prognostic parameter. Local recurrence was diagnosed in only 21.1% and was significantly lower in patients with R0(CRM-) resected hPDACs (10.9%, p < 0.001). CONCLUSION: Mesopancreatic excision is justified, since mesopancreatic fat invasion was evident in the majority of our patients. It is associated with a significantly improved local tumor control as well as longer relapse-free and overall survival.

Site of relapse of ductal adenocarcinoma of the pancreas affects survival after multimodal therapy.

BACKGROUND: Ductal adenocarcinoma of the pancreas (PDAC) remains one of the most lethal malignancies. To date, no guidelines exists for isolated resectable metachronous disease. It is still unknown, which patients may benefit from relapse surgery. The aim of our study was to compare disease free survival (DFS) and post relapse survival (PRS) in patients with isolated local recurrence, metachronous hepatic or pulmonary metastases. METHODS: Patients with isolated resectable local recurrence, metachronous hepatic or pulmonary metastases were included for survival analyses. PRS of surgically treated patients (local (n = 11), hepatic (n = 6) and pulmonary metastases (n = 9)) was compared to conservatively treated patients (local (n = 17), hepatic (n = 37) and pulmonary metastases (n = 8)). RESULTS: Resected PDAC patients suffering from isolated metachronous hepatic metastases initially had a higher T-stage and venous invasion (V1) compared to the other patients. DFS in the metachronous pulmonary metastases group was longer compared to DFS of the hepatic metastases and local recurrence groups. Surgical resection significantly improved PRS in patients with local recurrence and pulmonary metastases, when compared to patients receiving chemotherapy alone. Very-long term survivors (> 5 years) were detected following secondary resection of local recurrence and 45% of these patients were still alive at the end of our study period. CONCLUSION: Although DFS in PDAC patients suffering from isolated local recurrence was dismal and comparable to that of patients with isolated hepatic metastases, very-long term survivors were present only in this group. These results indicate that a surgical approach for isolated local recurrence, if anatomically possible, should be considered.

Cholestasis After Pediatric Liver Transplantation-Recurrence of a Progressive Familial Intrahepatic Cholestasis Phenotype as a Rare Differential Diagnosis: A Case Report.

INTRODUCTION: Nonobstructive cholestasis after pediatric liver transplantation is a common diagnostic and therapeutic dilemma. We describe a girl with neonatal cholestasis because of progressive familial intrahepatic cholestasis 2 (PFIC-2) and presence of a homozygous splice site mutation in the ABCB11 gene. Liver transplantation was performed because of end-stage liver disease at the age of 6. Cholestasis with normal gamma-glutamyl transferase (GGT) developed 8 years after liver transplantation. A liver biopsy showed canalicular cholestasis and giant cell hepatitis without evidence of rejection, mimicking PFIC-2. Immunofluorescence staining of normal human liver sections with patient's serum revealed reactivity toward a canalicular epitope, which could be identified as bile salt export pump (BSEP) using BSEP-yellow fluorescent protein (YFP) transfected cells. Our patient developed a recurrence of a PFIC-2 phenotype due to production of antibodies against BSEP (alloimmune BSEP disease [AIBD]). Intensification of immunosuppressive therapy as well as antibody treatment with plasmapheresis and Rituximab were initiated, leading to stabilization of the clinical condition and depletion of anti-BSEP antibodies in serum. However, after 1 year liver transplantation was necessary again because of end-stage liver insufficiency. Afterward, immunomodulatory treatment consisted of tacrolimus, mycophenolate mofetil, prednisone, immunoadsorption, and high-dose immunoglobulin therapy (1 g/kg/d). CONCLUSION: Cholestasis after liver transplantation may indicate an AIBD with a PFIC-2 phenotype. Besides enhancement of immunosuppressive therapy, an antibody depletion with plasmapheresis, immunoadsorption, immunoglobulins, and B-cell depletion represents a therapeutic option.

Intrahepatic cholestasis of pregnancy (ICP): case report and review of the literature.

Intrahepatic cholestasis of pregnancy (ICP) represents the most common pregnancy-related liver disease in women. Women frequently present in the third trimester with pruritus and elevated serum bile acid and/or alanine transaminase levels. Clinical symptoms quickly resolve after delivery; however, recurrence in subsequent pregnancies has to be expected. Intrahepatic cholestasis of pregnancy is associated with increased perinatal complications, such as premature delivery, meconium staining of the amniotic fluid, respiratory distress, low Apgar scores, and even stillbirth. The risk for the fetus is significantly increased with maternal serum bile acid levels above 40 µmol/L, which characterize severe ICP. An important factor for ICP development is a rise of gestational hormones leading to cholestasis in genetically predisposed women. Variants in the bile salt export pump (BSEP) and the multidrug resistance protein 3 (MDR3) are most often identified in ICP. Here, we give an overview of the current literature on ICP and present the case of a woman with recurrent severe ICP. A common BSEP polymorphism as well as a rare MDR3 mutation may underlie the development of ICP in our patient. She had a premature delivery with meconium staining of the amniotic fluid. The neonate showed signs of respiratory distress with a low Apgar score. This case emphasizes that women with severe ICP have an increased risk for perinatal complications. Furthermore, severe ICP was associated with a MDR3 mutation, which has already been described in adult patients with liver cirrhosis. Thus, ICP may unmask an underlying MDR3 defect, which may predispose to development of hepatobiliary diseases such as gallstone disease, liver fibrosis/cirrhosis, as well as hepatobiliary malignancies. Therefore, genetic testing should be considered in women with severe as well as early onset ICP. Furthermore, regular follow-up should be discussed for women with genetic variants.

Genetic variants in adult liver diseases.

In the last decades, understanding of genetic variants contributing to liver disease development has considerably improved through novel genotyping techniques. Genetic variants of single genes are known to be decisive for the development of monogenetic liver diseases of varying severity. Identification of genetic variants is an important part of the diagnostic process, e. g. the majority of patients with high iron [Fe] (HFE)-associated hemochromatosis carry the homozygous mutation p.C282Y. Detection of mutations in genes encoding hepatobiliary transport proteins like familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance protein 3 (MDR3) is the basis to differentiate various forms of intrahepatic cholestasis. Moreover, genetic variants in a variety of genes are known to act as disease modifiers and represent risk factors for disease progression and the development of cirrhosis or even hepatocellular carcinoma. Success of drug treatment or appearance of severe side effects can also be influenced by specific genetic variants. All these aspects underscore the increasing importance of genetic variants, which in the future may help to identify patients at risk for disease progression or help to guide treatment decisions. In the present overview, specific frequent genetic variants are summarized that play roles in monogenetic liver diseases, forms of intrahepatic cholestasis, gallstone development, fatty liver disease, drug-induced liver injury, and liver disease progression as well as hepatocellular carcinoma development.

Effect of maternal cholestasis on TGR5 expression in human and rat placenta at term.

BACKGROUND & AIMS: TGR5 (Gpbar-1) is a plasma membrane-bound bile acid receptor expressed in several tissues, including liver, intestine and brain. High levels of TGR5 mRNA have been detected in human and rodent placenta, however, localization of the TGR5 protein has not been studied in this tissue. We aimed at characterizing TGR5 expression in placental tissue and investigated the effect of bile acids and progesterone metabolites, which accumulate during intrahepatic cholestasis of pregnancy (ICP), on receptor expression and localization. METHODS: TGR5 mRNA levels and cell-specific localization were determined by quantitative PCR and immunofluorescence, respectively. RESULTS: In human term placentas, TGR5 was mainly localized in fetal macrophages and to a lower extent in trophoblasts. In placentas from ICP patients and pregnant rats with obstructive cholestasis a marked down-regulation of TGR5 mRNA expression was observed. However, the cell-specific distribution of the TGR5 protein was unaffected. Besides bile acids, progesterone and its metabolites (5α-pregnan-3α-ol-20-one/5α-pregnan-3ß-ol-20-one), which increase in serum during ICP, were able to dose-dependently activate TGR5. In addition, progesterone metabolites but not their sulfated derivatives nor taurolithocholic acid, significantly down-regulated TGR5 mRNA and protein expression in isolated human macrophages and a macrophage-derived cell line. CONCLUSION: Since fetal macrophages and trophoblast cells are exposed to changes in the flux of compounds across the placental barrier, the expression of TGR5 in these cells together with its sensitivity to bile acids and progesterone metabolites regarding receptor activity and mRNA expression suggest that TGR5 may play a role in the effect of maternal cholestasis on the placenta.

Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome.

The Dubin-Johnson syndrome is an inherited disorder characterized by conjugated hyperbilirubinemia. The deficient hepatobiliary transport of anionic conjugates is caused by the absence of a functional multidrug-resistance protein 2 (MRP2, symbol ABCC2) from the apical (canalicular) membrane of hepatocytes. Mechanisms underlying this deficiency may include rapid degradation of mutated MRP2 messenger RNA (mRNA) or impaired MRP2 protein maturation and trafficking. We investigated the consequences of the mutation MRP2Delta(R,M), which leads to the loss of 2 amino acids from the second ATP-binding domain of MRP2. The MRP2Delta(R,M) mutation is associated with the absence of the MRP2 glycoprotein from the apical membrane of hepatocytes. Transfection of mutated MRP2 complementary DNA (cDNA) led to an MRP2Delta(R,M) protein that was only core glycosylated, sensitive to endoglycosidase H digestion, and located in the endoplasmic reticulum (ER) of transfected HEK293 and HepG2 cells. This indicated that deletion of Arg1392 and Met1393 leads to impaired maturation and trafficking of the protein from the ER to the Golgi complex. Inhibition of proteasome function resulted in a paranuclear accumulation of the MRP2Delta(R,M) protein, suggesting that proteasomes are involved in the degradation of the mutant protein. This is the first mutation in Dubin-Johnson syndrome shown to cause deficient MRP2 maturation and impaired sorting of this glycoprotein to the apical membrane.