Nagorney, David M.

291 Background: Cholangiocarcinoma (CCA) is a rare malignancy with poor survival. The only curative therapy is resection and the role of adjuvant therapy is not well defined. Despite the unproven benefit, adjuvant therapy is used in resected CCA. The aim of this study is to analyze our institution’s outcomes for peri-operative treatment of resected intrahepatic and extrahepatic CCA. Methods: We retrospectively analyzed 145 intrahepatic (iCCA) and 109 extrahepatic (eCCA) CCA patients who underwent resection at the Mayo Clinic, Rochester. The majority of treated patients received adjuvant chemotherapy; however neo-adjuvant and radiation were also included. Results: In stage 1-2 iCCA patients, the HR indicated worse outcomes for time to recurrence and death. For stage 3-4 or node positive disease, outcomes were not significantly different. Those with node unknown/negative disease had significantly worse time to recurrence but not OS. There was a significant difference in stage and treatment modality between these groups (see table). Among eCCA, for any stage and node positive disease, outcomes were not different. In the node unknown/negative group, neither time to recurrence nor OS differed significantly. In controlling for different features in multi-variable analyses, no significant differences were observed (see table). Conclusions: This retrospective study does not show a significant difference in recurrence free or OS for treated patients. The apparent lack of benefit most likely reflects selection bias among treatment groups. Prospective, randomized trials are needed to make sound recommendations in adjuvant treatment for CCA. [Table: see text] [Table: see text]

PURPOSE: The current American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) fails to stratify patients adequately with respect to prognosis. PATIENTS AND METHODS: The ability of the currently proposed tumor (T) categories to effectively stratify the survival of 557 patients who underwent complete resection for HCC at four centers was examined. Independent predictors of survival were combined into a new staging system. RESULTS: Using the current AJCC T classification, patients with T1 and T2 tumors had similar 5-year survivals (P = .6). In addition, the survival of patients with multiple bilobar tumors (T4) matched that of T3 patients (P = .5). Independent predictors of death were major vascular invasion (P < .001), microvascular invasion (P = .001), severe fibrosis/cirrhosis of the host liver (P = .001), multiple tumors (P = .007), and tumor size greater than 5 cm (P = .01). Based on our results, a simplified stratification is proposed: (a) patients with a single tumor and no microvascular invasion, (b) patients with a single tumor and microvascular invasion or multiple tumors, none more than 5 cm, and (c) patients with either multiple tumors, any more than 5 cm, or tumor with major vascular invasion (P < .001). Severe fibrosis/cirrhosis had a negative impact on survival within all categories. The survival of patients with lymph node involvement matched that of patients with major vascular invasion (P = .3). CONCLUSION: The current AJCC staging system for HCC is unnecessarily complex. We propose a simplified model of stratification that is based on vascular invasion, tumor number, and tumor size and incorporates the effect of fibrosis on survival.

Although short‐term risks of living donor hepatectomy have been well defined, little is known about the longterm impact. We aimed to perform a systematic follow‐up to screen for unanticipated health consequences of liver donation. All donors who were more than 1 year from donation were invited for a systematic evaluation including physical and laboratory assessment, quality of life questionnaire, and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP). Those unable to return were offered the questionnaire and laboratory assessment at home. Out of our total of 97 donors, 45 returned for a full assessment and 23 completed labs and survey locally (total n = 68; 70%) after a median of 5.5 years (1.5‐10.9 years) after donation. The only laboratory abnormality was a significant decrease in platelet count (median 198 ×109/L versus 224 ×109/L before donation; P < 0.001), whereas 93% of patients were still above normal limits. No late biliary strictures or other structural abnormalities were found on MRI/MRCP. Liver regeneration was complete. Spleen volume did significantly increase (median 278 cm3 versus 230 cm3 before donation; P < 0.001) without resulting in lowered platelets (P = 0.73). The most common complaints were persistent incisional numbness and changed bowel habits. Seven donors (11%) reported problems obtaining insurance. The vast majority (97%) would have donated again. In conclusion, longterm outcome following liver donation appears satisfactory. None of our donors have developed occult biliary strictures, failure of regeneration, abnormal liver function, or other important health consequences after a median of 5.5 years from surgery. These findings can be used when counseling potential donors in the future. Liver Transplantation 22 934–942 2016 AASLD

Hypophosphatemia has been described in patients undergoing right hepatectomy for liver cancer and in living donors for liver transplantation who also received total parenteral nutrition. At the study centre, significant hypophosphatemia (0.36 mmol/L or less) requiring intravenous replacement was seen in two of the first nine living donors for adult-to-adult liver transplantation. To determine the frequency of hypophosphatemia in living donors, the authors obtained phosphate levels on stored serum samples from postoperative days 0, 1, 3 and 7 in all nine patients, none of whom were on total parenteral nutrition. Within the first week, hypophosphatemia developed in 55.6% of patients and phosphate levels returned to normal by day 7 in all nine patients. One patient had normal phosphate levels during the first week, but had profound hypophosphatemia (0.32 mmol/L) on day 14 when he presented with a Staphylococcus aureus infection of a bile collection and significant hypoxemia. The extent of hepatectomy and the rate of liver regeneration, estimated by baseline and postoperative day 7 volumetric computed tomography scans, did not correlate with the development of hypophosphatemia. In conclusion, hypophosphatemia is common in living donors undergoing right hepatectomy and may be associated with complications. All living donors should be monitored for the development of hypophosphatemia during the first two postoperative weeks.

Abstract Previous work by us and others reported decreased expression of miR-199a-3p in hepatocellular carcinoma (HCC) tissues compared to adjacent benign tissue. We report here a significant reduction of miR-199a-3p expression in 7 HCC cell lines (Huh7, HepG2, SNU182, PLC/PRF/5, Hep3B, SNU423 and SNU449) compared to primary hepatocytes. To determine if miR-199a-3p has a tumor suppressive role, miR-199a-3p mimetic was transfected into the 7 HCC cell lines. miR-199a-3p mimetic reduced cell proliferation by approximately 60% compared to control oligonucleotide in only two cell lines (SNU449 and SNU423); the proliferation of the other 5 treated cell lines was similar to control oligonucleotide. A miR-199a-3p mimetic formulated with chemical modifications to enhance stability while preserving processing reduced cell proliferation in SNU449 and SNU423 to the same extent as the commercially available miR-199a-3p mimetic. Furthermore, only the duplex miR-199a-3p mimetic, and not the guide strand alone, was effective at reducing cell viability. Since a CD44 variant was essential for c-Met signaling (Orian-Rousseau, et al., Genes Dev. 2002) and c-Met is a known miR-199a-3p target, we hypothesized that miR-199a-3p may also target CD44. Indeed, miRNA target algorithms predict miR-199a-3p to be a putative target of CD44. Immunoblotting confirmed that only the HCC lines that were sensitive to the effects of miR-199a-3p mimetic (SNU449 and SNU423) were CD44+. Direct targeting of CD44 by miR-199a-3p was confirmed using luciferase reporter assays and immunoblotting. Transfection of miR-199a-3p into SNU449 cells reduced in vitro invasion and sensitized the cells to doxorubicin; both effects were enhanced when hyaluronic acid was added to the cell cultures. An inverse correlation between the expression of miR-199a-3p and CD44 protein was noted in primary HCC tissue specimens. The anti-proliferative and anti-invasive properties of miR-199a-3p mimetic on CD44+ HCC may be a useful targeted therapy for CD44+ HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1183. doi:10.1158/1538-7445.AM2011-1183

Abstract Background Outcomes for patients with hepatocellular carcinoma (HCC) without cirrhosis and factors associated with disease progression remain unclear. The goals of this single-institution study were to define the outcomes for such patients, and to determine factors associated with survival and disease progression. Methods This was a retrospective review of consecutive patients with HCC without cirrhosis who underwent hepatic resection between 1985 and 2003. Survival was estimated by the Kaplan–Meier method and risk factors were identified by Cox proportional hazards models. Results A total of 143 patients were enrolled, of whom 29·4 per cent had identifiable risk factors for chronic liver disease. Major resection (at least three segments) was undertaken in 63·6 per cent of patients. The operative mortality rate was 3·5 per cent. Median disease-free survival was 2·4 years. Multivariable analysis revealed presence of multiple tumours as the only independent predictor of tumour recurrence. Median overall survival was 3·3 years. Factors independently associated with decreased overall survival were multiple tumours, high histological grade, perioperative transfusion, male sex and age at least 66 years. Conclusion Patients with HCC but without cirrhosis have acceptable outcomes after resection. Specific risk factors for the development of HCC in these patients have yet to be defined.