Liver resection and transplantation for intrahepatic cholangiocarcinoma

The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing worldwide. Although several advances have been made in the past decades to better understand this complex malignancy and to develop new treatment strategies, the prognosis of iCCA remains dismal. Liver resection (LR) is the mainstay of treatment but only a minority of patients are amenable to surgery. In most cases, patients with iCCA will require a major hepatectomy for complete resection of the tumour. This may be contraindicated or increase the surgical burden in patients with chronic liver disease and small remnant liver volume. Lymphadenectomy with a minimal harvest of 6 lymph nodes is considered adequate, as microscopic nodal metastases have been shown in more than 40% of patients. Current 5-year overall survival following LR is in the range of 25%\u201340%. For locally advanced disease not amenable to upfront LR, neoadjuvant locoregional therapies may be used with the aim of converting these patients to resectability or even to transplantation in well-selected cases. Recent studies have shown that liver transplantation (LT) might be a treatment option for patients with unresectable very-early iCCA (i.e. 642 cm), with survival outcomes comparable to those of hepatocellular carcinoma. In patients with unresectable, advanced tumours, confined to the liver who achieve sustained response to neoadjuvant treatment, LT may be considered an option within prospective protocols. The role of adjuvant therapies in iCCA is still under debate. Herein, we review the recent advances in the surgical treatment of iCCA and examine its correlation with locoregional therapies, adjuvant and neo-adjuvant strategies

Functional abdominal complaints occurred frequently in living liver donors after donation

Background. Donor outcome after living donor liver transplantation has not been examined extensively with regard to postoperative abdominal complaints. We wanted to examine the extent and type of abdominal complaints after removal of a part of the liver and gallbladder in living donors as well as potential similarities with known disorders. Methods. Twelve patients of mixed ethnicity, nine men, aged 18-45 years, and three women, aged 32-46 years, were enrolled in the study during a 3-year period and followed up at 6 and 12 months. Patients filled out questionnaires pertaining to functional abdominal complaints (FAC) using a recognized questionnaire, Rome II, as well as specific abdominal pain symptoms known from gallstone disease. Results. FAC occurred in 11 patients at 6 months and nine patients at 12 months while abdominal pain occurred in seven and six patients, respectively. Three patients had FAC but no abdominal pain while two patients had no complaints at 12 months. Irritable bowel syndrome (IBS) was found in the majority of patients. Conclusions. FAC and pain seemed to indicate a general postoperative disorder, of a psychosomatic character, and not connected with removal of part of the liver and gallbladder in particular. However, the occurrence of IBS and FD should merit attention, as they are known to impair quality of life.Fil: Søndenaa, Karl. University of Bergen; NoruegaFil: Gondolesi, Gabriel Eduardo. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Roayaie, Sasan. No especifíca;Fil: Goldman, Jody S.. No especifíca;Fil: Hausken, Trygve. University of Bergen; NoruegaFil: Schwartz, Myron E.. No especifíca

Prognostic Significance of Lymph Node Metastases in Small Intestinal Neuroendocrine Tumors

Background/Aims: Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the LN ratio (number of positive LNs/number of total LNs examined, LNR):0.2-0.5, and \u3e0.5. We used the Kaplan-Meier method and Cox models to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status. Results: We identified 2,984 surgically resected patients with stage IIIb (N1, M0) SI-NETs with detailed LN data. More than half of the NETs were located in the ileum. A higher LNR was significantly associated with worse NET cancer-specific survival (p \u3c 0.0001). Ten-year NET-specific survival was 85, 77, and 74% for patients in the0.2-0.5, and \u3e0.5 LNR groups, respectively. In stratified analyses, higher LNR groups had worse survival only in early tumor (T1, T2) disease (p \u3c 0.0001). Conclusions: The extent of LN involvement provides independent prognostic information on patients with LN-positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about the use of adjuvant therapy. (C) 2015 S. Karger AG, Base

Differential Protein Expression in Small Intestinal Neuroendocrine Tumors and Liver Metastases

OBJECTIVE: Small intestinal neuroendocrine tumors (SI-NETs) are often detected after they have become metastatic. Using a novel protein array, we identified pathways important in SI-NET metastasis development in surgically resected patients. METHODS: Paired primary tumors and liver metastases from 25 patients undergoing surgical resection for metastatic SI-NETs were harvested. Extracted proteins were separated by sodium dodecyl sulfate gel and multiplex immunoblots were performed with 136 antibodies. Significant Analysis of Microarray was used to select for differentially expressed proteins. A tissue microarray was constructed from 27 archived specimens and stained by immunohistochemistry. RESULTS: Comparing primary SI-NETs with matched normal small-bowel mucosa, 9 proteins were upregulated and cyclin E was downregulated. The SI-NET liver metastases demonstrated upregulation of P-ERK and p27 but downregulation of CDK2 and CDC25B. When comparing primary SI-NET with their paired liver metastases, cyclin E demonstrated a significant upregulation in the liver metastasis. Tissue microarray demonstrated higher p38 expression and lower Cdc 25b expression in SI-NETs versus liver metastases and confirmed higher expression of p27 in liver metastases versus normal liver. CONCLUSIONS: Few studies have compared protein expression in paired primary and metastatic SI-NETs. Our findings reveal changes in a limited number of proteins, suggesting that these may be targets for therapy

Ammonium-Acetate Is Sensed by Gustatory and Olfactory Neurons in Caenorhabditis elegans

Background: Caenorhabditis elegans chemosensation has been successfully studied using behavioral assays that treat detection of volatile and water soluble chemicals as separate senses, analogous to smell and taste. However, considerable ambiguity has been associated with the attractive properties of the compound ammonium-acetate (NH 4Ac). NH 4Ac has been used in behavioral assays both as a chemosensory neutral compound and as an attractant. Methodology/Main Findings: Here we show that over a range of concentrations NH4Ac can be detected both as a water soluble attractant and as an odorant, and that ammonia and acetic acid individually act as olfactory attractants. We use genetic analysis to show that NaCl and NH4Ac sensation are mediated by separate pathways and that ammonium sensation depends on the cyclic nucleotide gated ion channel TAX-2/TAX-4, but acetate sensation does not. Furthermore we show that sodium-acetate (NaAc) and ammonium-chloride (NH4Cl) are not detected as Na + and Cl 2 specific stimuli, respectively. Conclusions/Significance: These findings clarify the behavioral response of C. elegans to NH4Ac. The results should have an impact on the design and interpretation of chemosensory experiments studying detection and adaptation to soluble compounds in the nematode Caenorhabditis elegans

Liver Transplantation for Hepatocellular Carcinoma

Background: Orthotopic liver transplantation (OLT) is the best available option for early hepatocellular carcinoma (HCC), although its application is limited by stringent selection criteria, costs, and deceased donor graft shortage, particularly in Asia, where living donor liver transplant (LDLT) has been developed. Methods: This article reviews the present standards for patient selection represented by size-and-number criteria with particular references to Milan Criteria and novel prediction models based on results achieved in patients exceeding those limits, with consideration of the expanded indication represented by the UCSF Criteria. Results: The expected outcomes after deceased donor liver transplant (DDLT) or LDLT are favorable if predetermined selection criteria are applied. However, selection bias, difference in waiting time, and ischemia-regeneration injuries of the graft among DDLT vs LDLT may influence long-term results. In the article, the differences between East and West in first-line treatments for HCC (resection vs transplantation), indications, and ethics for the donor, are summarized as well as possible novel predictors of tumor biology (especially DNA mutation and fractional allelic loss, FAI) to be considered for better outcome prediction. Conclusions: Liver transplantation remains the most promising product of modern surgery and represents a cornerstone in the management of patients with HCC. © 2007 The Author(s)

Predictor for Histological Microvascular Invasion of Hepatocellular Carcinoma: A Lesson from 229 Consecutive Cases of Curative Liver Resection.

BACKGROUND: Microscopic vascular invasion is an important risk factor for recurrent hepatocellular carcinoma (HCC), even after curative liver resection or orthotopic liver transplantation. To predict microscopic portal venous invasion, the following two questions were examined retrospectively: Is it possible to detect microvascular invasion preoperatively? What are the characteristics of a group of early HCC recurrences even with no microvascular invasion? METHODS: Study 1 included 229 patients with HCC who underwent curative liver resection between 1991 and 2008; 127 had HCC without microscopic portal venous invasion, and 52 had HCC with microscopic portal venous invasion (MPVI). These two distinct groups were analyzed with regard to various clinicopathologic factors. Subsequently, we specifically investigated if HCCs 5 cm, the macroscopic appearance of HCC, and high levels of preoperative des-gamma-carboxyprothrombin are significant prognostic factors in identifying microvascular invasion of HCC. The strongest predictor of early recurrence (within 2 years) was the serum alpha-fetoprotein level in patients without clear microvascular invasion. CONCLUSIONS: Tumor size, macroscopic appearance, and high tumor marker levels are important elements in identifying the group of patients with a low HCC recurrence rate after curative liver resection

Temperature- and Touch-Sensitive Neurons Couple CNG and TRPV Channel Activities to Control Heat Avoidance in Caenorhabditis elegans

Background: Any organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding,35uC and also senses changes in its environmental temperature in the range between 15 and 25uC. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches. Methodology/Principal Findings: We show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicinsensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons. Conclusions/Significance: Our results identify distinct thermal responses mediated by a single neuron, but also show tha