Management of Gallstones and Acute Cholecystitis in Patients with Liver Cirrhosis: What Should We Consider When Performing Surgery?

Acute cholecystitis and several gallbladder stone-related conditions, such as impacted common bile duct stones, cholangitis, and biliary pancreatitis, are common medical conditions in daily practice. An early cholecystectomy or drainage procedure with delayed cholecystectomy is the current standard of treatment based on published clinical guidelines. Cirrhosis is not only a condition of chronically impaired hepatic function but also has systemic effects in patients. In cirrhotic individuals, several predisposing factors, including changes in the bile acid composition, increased nucleation of bile, and decreased motility of the gallbladder, contribute to the formation of biliary stones and the possibility of symptomatic cholelithiasis, which is an indication for surgical treatment. In addition to these predisposing factors for cholelithiasis, systemic effects and local anatomic consequences related to cirrhosis lead to anesthesiologic risks and perioperative complications in cirrhotic patients. Therefore, the treatment of the aforementioned biliary conditions in cirrhotic patients has become a challenging issue. In this review, we focus on cholecystectomy for cirrhotic patients and summarize the surgical indications, risk stratification, surgical procedures, and surgical outcomes specific to cirrhotic patients with symptomatic cholelithiasis.

Characterization of intrahepatic cholangiocarcinoma after curative resection: outcome, prognostic factor, and recurrence.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a relatively rare subtype of cholangiocarcinoma. The study herein gathered experience of surgical treatment for ICC, and aimed to analyze the prognosis of patients who had received curative-intent liver resection. METHODS: A total of 216 patients who had undergone curative-intent liver resection for ICC between January 1977 and December 2014 was retrospectively reviewed. RESULTS: Overall, the rates of 5-years recurrence-free survival (RFS) and overall survival (OS) were 26.1 and 33.9% respectively. Based on multivariate analysis, four independent adverse prognostic factors including morphology patterns, maximum tumor size > 5 cm, pathological lymph node involvement, and vascular invasion were identified as affecting RFS after curative-intent liver resection for ICC. Among patients with cholangiocarcinoma recurrence, only 27 (16.9%) were able to receive surgical resection for recurrent cholangiocarcinoma that had a significantly better outcome than the remaining patients. CONCLUSION: Despite curative resection, the general outcome of patients with ICC is still unsatisfactory because of a high incidence of cholangiocarcinoma recurrence after operation. Tumor factors associated with cholangiocarcinoma remain crucial for the prognosis of patients with ICC after curative liver resection. Moreover, aggressive attitude toward repeat resection for the postoperative recurrent cholangiocarcinoma could provide a favorable outcome for patients.

Stapleless laparoscopic left lateral sectionectomy for hepatocellular carcinoma: reappraisal of the Louisville statement by a young liver surgeon.

BACKGROUND: Laparoscopic liver resection has been regarded as the standard treatment for liver tumors located at the left lateral liver sector. However, few studies have reported the results of laparoscopic left lateral sectionectomy (LLS) for HCC, not to mention the feasibility of this emerging technique for the less experienced liver surgeons. The current study would reappraise the Louisville statement by examining the outcome of LLS performed by a young liver surgeon. METHODS: We retrospectively reviewed two separate groups of patients who underwent open or laparoscopic left lateral sectionectomies at Chung Gung Memorial Hospital, Linkou. All laparoscopic hepatectomies were performed by the index young surgeon following a stepwise stapleless LLS. The surgical results and oncological outcomes of laparoscopic vs. open hepatectomies (LH and OH, respectively) with the surgical indication of HCC at left lateral liver sector were further compared and analyzed. RESULTS: 18 of 29 patients in the laparoscopic group and 75 patients in the conventional open group had primary HCC. The demographic data was essentially the same for the two groups. Statistical analysis revealed that the LH group had smaller tumor size, higher blood transfusion requirement, longer duration of inflow control and parenchymal transection, and longer operation time. However, no significant difference was observed in terms of complication rate, mortality rate, and hospital stay between the two groups. After adjusting for tumor size, LH and OH showed no statistical difference in the amount of blood transfusion, operation time and patient survival. CONCLUSIONS: This study demonstrated that stapleless LLS is a safe and feasible procedure for less experienced liver surgeons to resect HCC located at the left lateral liver sector. This stepwise stapleless LSS can not only achieve surgical results comparable to OH but also can provide a platform for liver surgeons to apply laparoscopic technique before conducting more complicated liver resections.

Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos).

Although the diagnostic and severity grading criteria on the 2013 Tokyo Guidelines (TG13) are used worldwide as the primary standard for management of acute cholangitis (AC), they need to be validated through implementation and assessment in actual clinical practice. Here, we conduct a systematic review of the literature to validate the TG13 diagnostic and severity grading criteria for AC and propose TG18 criteria. While there is little evidence evaluating the TG13 criteria, they were validated through a large-scale case series study in Japan and Taiwan. Analyzing big data from this study confirmed that the diagnostic rate of AC based on the TG13 diagnostic criteria was higher than that based on the TG07 criteria, and that 30-day mortality in patients with a higher severity based on the TG13 severity grading criteria was significantly higher. Furthermore, a comparison of patients treated with early or urgent biliary drainage versus patients not treated this way showed no difference in 30-day mortality among patients with Grade I or Grade III AC, but significantly lower 30-day mortality in patients with Grade II AC who were treated with early or urgent biliary drainage. This suggests that the TG13 severity grading criteria can be used to identify Grade II patients whose prognoses may be improved through biliary drainage. The TG13 severity grading criteria may therefore be useful as an indicator for biliary drainage as well as a predictive factor when assessing the patient's prognosis. The TG13 diagnostic and severity grading criteria for AC can provide results quickly, are minimally invasive for the patients, and are inexpensive. We recommend that the TG13 criteria be adopted in the TG18 guidelines and used as standard practice in the clinical setting. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos).

The Tokyo Guidelines 2013 (TG13) for acute cholangitis and cholecystitis were globally disseminated and various clinical studies about the management of acute cholecystitis were reported by many researchers and clinicians from all over the world. The 1st edition of the Tokyo Guidelines 2007 (TG07) was revised in 2013. According to that revision, the TG13 diagnostic criteria of acute cholecystitis provided better specificity and higher diagnostic accuracy. Thorough our literature search about diagnostic criteria for acute cholecystitis, new and strong evidence that had been released from 2013 to 2017 was not found with serious and important issues about using TG13 diagnostic criteria of acute cholecystitis. On the other hand, the TG13 severity grading for acute cholecystitis has been validated in numerous studies. As a result of these reviews, the TG13 severity grading for acute cholecystitis was significantly associated with parameters including 30-day overall mortality, length of hospital stay, conversion rates to open surgery, and medical costs. In terms of severity assessment, breakthrough and intensive literature for revising severity grading was not reported. Consequently, TG13 diagnostic criteria and severity grading were judged from numerous validation studies as useful indicators in clinical practice and adopted as TG18/TG13 diagnostic criteria and severity grading of acute cholecystitis without any modification. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis.

We propose a new flowchart for the treatment of acute cholecystitis (AC) in the Tokyo Guidelines 2018 (TG18). Grade III AC was not indicated for straightforward laparoscopic cholecystectomy (Lap-C). Following analysis of subsequent clinical investigations and drawing on Big Data in particular, TG18 proposes that some Grade III AC can be treated by Lap-C when performed at advanced centers with specialized surgeons experienced in this procedure and for patients that satisfy certain strict criteria. For Grade I, TG18 recommends early Lap-C if the patients meet the criteria of Charlson comorbidity index (CCI) ≤5 and American Society of Anesthesiologists physical status classification (ASA-PS) ≤2. For Grade II AC, if patients meet the criteria of CCI ≤5 and ASA-PS ≤2, TG18 recommends early Lap-C performed by experienced surgeons; and if not, after medical treatment and/or gallbladder drainage, Lap-C would be indicated. TG18 proposes that Lap-C is indicated in Grade III patients with strict criteria. These are that the patients have favorable organ system failure, and negative predictive factors, who meet the criteria of CCI ≤3 and ASA-PS ≤2 and who are being treated at an advanced center (where experienced surgeons practice). If the patient is not considered suitable for early surgery, TG18 recommends early/urgent biliary drainage followed by delayed Lap-C once the patient's overall condition has improved. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

RAM score is an effective predictor for early mortality and recurrence after hepatectomy for hepatocellular carcinoma.

BACKGROUND: Liver resection had been regarded as a standard treatment for primary hepatocellular carcinoma (HCC). However, early mortality and recurrence after surgery were still of major concern. RAM (Risk Assessment for early Mortality) scoring system is a newly developed tool for assessing early mortality after hepatectomy for HCC. In this study, we compared RAM scoring system with ALBI and MELD scores for their capability of predicting short-term outcome. METHODS: We retrospectively reviewed patients with hepatocellular carcinoma who were treated with hepatectomy at Chang Gung Memorial Hospital between 1986 and 2015. Their clinical characteristics and perioperative variables were collected. We applied RAM, albumin-bilirubin (ALBI), and model for end-stage liver disease (MELD) scoring systems to predict early mortality and early recurrence in HCC patients after surgery. We investigated the discriminative power of each scoring system by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). RESULTS: A total of 1935 patients (78% male) who underwent liver resection for HCC were included in this study. The median follow-up period was 41.9 months. One hundred and forty-nine patients (7.7%) died within 6 months after hepatectomy (early mortality). All the three scoring systems were effective predictor for early mortality, with higher score indicating higher risk of early mortality (AUC of RAM = 0.723, p < 0.001; AUC of ALBI = 0.682, p < 0.001; AUC of MELD = 0.590, p = 0.002). Cox regression multivariate analysis demonstrated that the RAM class was the most significant independent predictor of early mortality after surgery, while MELD grade failed to discriminatively predict early mortality. In addition to early mortality, the RAM score was also predictive of early recurrence in HCC after surgery. CONCLUSIONS: This study demonstrated that RAM score is an effective and user-friendly bedside scoring system to predict early mortality and early recurrence after hepatectomy for HCC. In addition, the predictive capability of RAM score is superior to ALBI and MELD scores. Further study is warranted to validate our findings.

Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis.

BACKGROUND: The international practice guidelines for patients with acute cholangitis and cholecystitis were released in 2007 (TG07) and revised in 2013 (TG13). This study investigated updated epidemiology and outcomes among patients with acute cholangitis on a larger scale for the first time. METHODS: This is an international multi-center retrospective observational study in Japan and Taiwan. All consecutive patients older than 18 years of age and given a clinical diagnosis of acute cholangitis by clinicians between 1 January 2011 and 31 December 2012 were enrolled. Those who met the diagnostic criteria of acute cholangitis by TG13 were statistically analyzed. RESULTS: A total of 7,294 patients were enrolled and 6,433 patients met the TG13 diagnostic criteria. The severity distribution was Grade I (37.5%), Grade II (36.2%), and Grade III (26.2%). The 30-day all-cause mortality was 2.4%, 4.7%, and 8.4% in Grade I, II, III severity, respectively (P < 0.001). The incidence of liver abscess and endocarditis as complications of acute cholangitis was 2.0% and 0.26%, respectively. CONCLUSIONS: This is the first large scale study to investigate patients with acute cholangitis. This study provides the basis to define the best practices to manage patients with acute cholangitis in future studies.

Optimal treatment strategy for acute cholecystitis based on predictive factors: Japan-Taiwan multicenter cohort study.

BACKGROUND: Although early laparoscopic cholecystectomy is widely performed for acute cholecystitis, the optimal timing of a cholecystectomy in clinically ill patients remains controversial. This study aims to determine the best practice for the patients presenting with acute cholecystitis focused on disease severity and comorbidities. METHODS: An international multicentric retrospective observational study was conducted over a 2-year period. Patients were divided into four groups: Group A: primary cholecystectomy; Group B: cholecystectomy after gallbladder drainage; Group C: gallbladder drainage alone; and Group D: medical treatment alone. RESULTS: The subjects of analyses were 5,329 patients. There were statistically significant differences in mortality rates between patients with Charlson comorbidity index (CCI) scores below and above 6 (P < 0.001). The shortest operative time was observed in Group A patients who underwent surgery 0-3 days after admission (P < 0.01). Multiple regression analysis revealed CCI and low body mass index <20 as predictive factors of 30-day mortality in Grade I+II patients. Also, jaundice, neurological dysfunction, and respiratory dysfunction were predictive factors of 30-day mortality in Grade III patients. In Grade III patients without predictive factors, there were no difference in mortality between Group A and Group B (0% vs. 0%), whereas Group A patients had higher mortality rates than that of Group B patients (9.3% vs. 0.0%) in cases with at least one predictive factor. CONCLUSION: Even patients with Grade III severity, primary cholecystectomy can be performed safely if they have no predictive factors of mortality. Gallbladder drainage may have a therapeutic role in subgroups with higher CCI or higher disease severity.

Clinical application and verification of the TG13 diagnostic and severity grading criteria for acute cholangitis: an international multicenter observational study.

BACKGROUND: The Tokyo Guidelines 2007 (TG07) first presented the diagnostic and severity grading criteria for acute cholangitis. Subsequently updated in 2013, the Tokyo Guidelines (TG13) have been widely adopted throughout the world as global standard guidelines. We set out to verify the efficacy of these TG13 criteria in an international multicenter study. METHODS: We reviewed 6,063 patients who were clinically diagnosed with acute cholangitis in Japan and Taiwan over a 2-year period. The TG13 diagnostic and severity grading criteria were retrospectively applied, and 30-day mortality was investigated. RESULTS: A diagnosis of acute cholangitis was made in 5,454 (90.0%) patients on the basis of the TG13 criteria, and in 4,815 (79.4%) patients on the basis of the TG07 criteria. The 30-day mortality rates of patients with Grade III, Grade II, and Grade I were 5.1%, 2.6%, and 1.2%, respectively, and increased significantly along with disease severity. The mortality rate in the 1,272 Grade II cases where urgent or early biliary drainage was performed was 2.0% (n = 25), which was significantly lower than that of 3.7% (n = 28) in the other 748 cases. CONCLUSION: By using the TG13 diagnostic and severity grading criteria, more patients with possible acute cholangitis can be diagnosed, and patients whose prognosis can potentially be improved by early biliary drainage can be identified. The TG13 criteria are appropriate and useful for clinical practice.

Validation of TG13 severity grading in acute cholecystitis: Japan-Taiwan collaborative study for acute cholecystitis.

BACKGROUND: The collaborative multicenter retrospective study of acute cholecystitis (AC) was performed in Japan and Taiwan. The aim for this study was evaluation of the clinical value of TG13 severity grading for AC. METHOD: The study was designed as an international multicenter retrospective study of AC from 2011 to 2013. Based on the data, we investigated the TG13 severity grading by analyzing the correlations between grade and prognosis, surgical procedures, histopathology, and organ dysfunction and prognosis. RESULTS: An investigation revealed that 30-day overall mortality rate was 1.1% for Grade I, 0.8% for Grade II, 5.4% for Grade III. The mortality rate for Grade III was significantly higher than lower grades (P < 0.001). The greater the number of organ dysfunction, the higher the mortality rate (P < 0.001). However, the mortality rate varied depending on the number of organ dysfunction (3.1-25%). With respect to the surgical procedures, laparoscopic cholecystectomy was performed for Grade I patients (P < 0.001), and the higher the grade, the more likely open surgery would be selected (P < 0.001). CONCLUSION: TG13 severity grading criteria for AC are providing great benefits in actual clinical settings. From this study, the position of each severity grade was obviously confirmed.

Percutaneous and endoscopic gallbladder drainage for acute cholecystitis: international multicenter comparative study using propensity score-matched analysis.

BACKGROUND: Tokyo Guideline 2013 (TG13) proposed three drainage techniques for the treatment of acute cholecystitis. We evaluated the clinical efficacy and adverse events between percutaneous transhepatic intervention (PTGBI) including percutaneous transhepatic gallbladder drainage (PTGBD) and percutaneous transhepatic gallbladder aspiration (PTGBA) and endoscopic transpapillary gallbladder drainage (EGBD). METHODS: A cohort study was performed using propensity score matching to reduce treatment selection bias. This involved the analysis of collected data for 1,764 patients who underwent PTGBI and EGBD. RESULTS: Propensity score matching extracted 330 pairs of patients. The difference in the clinical success rate within 3 days between PTGBI and EGBD were 62.5% and 69.8%, respectively (P = 0.085). The differences in the suboptimal clinical success rates within 7 days between PTGBI and EGBD were 87.6% and 89.2% (P = 0.579). The differences in the complication rate between PTGBI and EGBD were 4.8% and 8.2% (P = 0.083). The differences in the complication rate among PTGBD, PTGBA and EGBD were 5.6%, 1.6% and 8.2% (P = 0.11). Median required days of PTGBD (3.0 days) was significantly longer than those of PTGBA and EGBD (1.5 and 2.0 days, respectively) (P = 0.001). CONCLUSION: The current study showed the PTGBI showed similar clinical efficacy compared with EGBD without significant discrepancy of complication rate for the treatment of acute cholecystitis.

Risk factors for early mortality after hepatectomy for hepatocellular carcinoma.

Despite advances in surgical technique and medical care, liver resection for hepatocellular carcinoma (HCC) remains a high-risk major operation. The present study evaluated the risk factors for early mortality after hepatectomy.We retrospectively reviewed records of patients undergoing liver resection for HCC between 1983 and 2015. A point score (Risk Assessment for early Mortality (RAM) score) for hepatectomy was developed based on multivariate analyses.Three hundred eighty-three patients (11.3%) expired within 6 months after the operation. Logistic regression analyses identified that operative duration >270 minutes and blood loss >800 cc were significant predictors of major surgical complications (P = 0.013 and 0.002, respectively). On the other hand, diabetes mellitus, albumin ≤3.5 g/dL, α-fetoprotein (AFP) >200 ng/mL, major surgical procedure, blood loss >800 cc, and major surgical complications were independent risk factors for early mortality after hepatectomy (P = 0.019, <0.001, <0.001, 0.006, 0.018, and <0.001, respectively). Risk Assessment for early Mortality score (RAM score) identified 3 subgroups of patients with distinct 6-month mortality rate, with Class III (score 10) having highest risk of early mortality.Our study demonstrated that meticulous surgical techniques to minimize blood loss and avoid prolonged operative time may help decrease the occurrence of major surgical complications. In addition to major surgical complications, diabetes mellitus, hypoalbuminemia, high AFP, massive blood loss, and major surgical procedure are also associated with early mortality after liver resection. Further study is warranted to validate the utility of RAM score as a bedside scoring system to predict postoperative outcome.

The Hepatitis Viral Status in Patients With Hepatocellular Carcinoma: a Study of 3843 Patients From Taiwan Liver Cancer Network.

Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research.

Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.

BACKGROUND: Intrahepatic biliary mucinous cystic neoplasms are rare hepatic tumors and account for less than 5% of intrahepatic cystic lesions. Accurate preoperative diagnosis is difficult and the outcome differs among various treatment modalities.The aim of this study is to investigate the clinico-radiological characteristics of intrahepatic biliary mucinous cystic neoplasms and to establish eligible diagnostic and treatment suggestions. METHODS: Nineteen patients with intrahepatic biliary cystadenomas and two patients with biliary cystadenocarcinomas were retrospectively reviewed. Their clinico-radiological variables and survival outcome were analyzed. RESULTS: Of the 19 patients with biliary cystadenoma, 16 (84.2 %) were female. 11 (57.9 %) patients had symptoms before operation with the most common presenting symptom being abdominal pain. Among the patients with available data, serum and cystic fluid CA 19-9 levels were invariably elevated and the CA 19-9 level in the cystic fluid was significantly higher than that in the serum. Loculations (84.2 %) and septations (63.2 %) were the most common radiologic findings. For treatment, 11 (57.9 %) patients received radical resection by either enucleation or hepatic resection, while the remaining 8 (42.1 %) patients underwent only fenestration of liver cysts. Radical resection provided a significantly better clinical outcome than fenestration in terms of tumor recurrence (p = 0.018). The only two male patients with biliary cystadenocarcinoma received radical hepatic resection and achieved a disease-free survival of 16.5 months and 33 months, respectively. CONCLUSION: Intrahepatic biliary mucinous cystic neoplasms are rare and preoperative diagnosis is difficult. Internal septations and loculations on radiologic examinations should raise some suspicion of this diagnosis. Complete tumor excision is the standard treatment that may provide patients with better long term results after the operation.

Gastric cancer patients with end-stage renal disease who underwent radical gastrectomy.

BACKGROUND: Radical gastrectomy (RG) with lymph node (LN) dissection is a standard procedure for gastric cancer (GC). Patients with end-stage renal disease (ESRD) usually have high risk for any operative procedure. However, information for ESRD on RG for GC is limited. PATIENTS AND METHODS: A total of 2,021 GC patients who underwent RG with LN dissection were retrospectively reviewed. Among them, 26 patients had ESRD. The clinicopathological features and surgical outcomes were compared between GC with ESRD (ESRD-GC group) and GC without ESRD (GC group). RESULTS: ESRD-GC patients could be independently differentiated from GC patients by lower hemoglobin, negative lymph node (LN) involvement and higher postoperative complications. The overall survival rate of ESRD-GC group seemed better than that of GC group patients. Lesser depth of tumor invasion, LN metastasis and lymphatic invasion and early-staged tumor contributed to favorable prognosis of ESRD-GC group of patients. CONCLUSION: RG might be beneficial for GC-ESRD patients especially for early-stage disease; however, RG for GC patients with ESRD should be more cautiously performed, otherwise the benefit might be compromised by higher postoperative complications and even mortality.

WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer.

WNT1 inducible signaling pathway protein 1 (WISP1) plays a key role in many cellular functions in a highly tissue-specific manner; however the role of WISP1 in breast cancer is still poorly understood. Here, we demonstrate that WISP1 acts as an oncogene in human breast cancer. We demonstrated that human breast cancer tissues had higher WISP1 mRNA expression than normal breast tissues and that treatment of recombinant WISP1 enhanced breast cancer cell proliferation. Further, ectopic expression of WISP1 increased the growth of breast cancer cells in vitro and in vivo. WISP1 transfection also induced epithelial-mesenchymal-transition (EMT) in MCF-7 cells, leading to higher migration and invasion. During this EMT-inducing process, E-cadherin was repressed and N-cadherin, snail, and ß-catenin were upregulated. Filamentous actin (F-actin) remodeling and polarization were also observed after WISP1 transfection into MCF-7 cells. Moreover, forced overexpression of WISP1 blocked the expression of NDRG1, a breast cancer tumor suppressor gene. Our study provides novel evidence that WISP1-modulated NDRG1 gene expression is dependent on a DNA fragment (-128 to +46) located within the human NDRG1 promoter. Thus, we concluded that WISP1 is a human breast cancer oncogene and is a potential therapeutic target.

Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma.

BACKGROUND: Several unfavorable prognostic factors have been proposed for peripheral cholangiocarcinoma (PCC) in patients undergoing hepatectomy, including gross type of tumor, vascular invasion, lymph node metastasis, a high carbohydrate antigen 19-9 level, and a positive resection margin. However, the clinical effect of a positive surgical margin on the survival of patients with PCC after hepatectomy still needs to be clarified due to conflicting results. METHODS: A total of 224 PCC patients who underwent hepatic resection with curative intent between 1977 and 2007 were retrospectively reviewed. Eighty-nine patients had a positive resection margin, with 62 having a microscopically positive margin and 27 a grossly positive margin (R2). The clinicopathological features, outcomes, and recurrence pattern were compared with patients with curative hepatectomy. RESULTS: PCC patients with hepatolithiasis, periductal infiltrative or periductal infiltrative mixed with mass-forming growth, higher T stage, and more advanced stage tended to have higher positive resection margin rates after hepatectomy. PCC patients who underwent curative hepatectomy had a significantly higher survival rate than did those with a positive surgical margin. When PCC patients underwent hepatectomy with a positive resection margin, the histological grade of the tumor, nodal positivity, and chemotherapy significantly affected overall survival. Locoregional recurrence was the most common pattern of recurrence. CONCLUSION: A positive resection margin had an unfavorable effect on overall survival in PCC patients undergoing hepatectomy. In these patients, the prognosis was determined by the biology of the tumor, including differentiation and nodal positivity, and chemotherapy increased overall survival.

Change and predictors of symptom distress in breast cancer patients following the first 4 months after diagnosis.

BACKGROUND/PURPOSE: Breast cancer patients may encounter a wide range of physical and psychosocial distress symptoms during diagnosis, while awaiting treatment, and during treatment. This study of newly diagnosed breast cancer patients explores: (1) changes in symptom distress over 4 months; and (2) factors predicting changes in symptom distress. METHODS: A prospective longitudinal design was used to collect data from breast cancer patients in northern Taiwan. A set of questionnaires was used to measure anxiety, symptom distress, social support, and demographic and treatment-related characteristics. Repeated measures analysis of variance (RM-ANOVA) with least significant difference (LSD) was used to examine differences in symptom distress, state anxiety, and social-support levels across four time-points. Generalized estimating equation (GEE) is used to determine predictors for the change in symptom distress. RESULTS: Participants showed mild overall symptom distress during treatment that increased from cancer diagnosis to treatment phases, with a peak at 4 months after diagnosis. Insomnia was the most commonly identified distressful symptom over time. Changes in overall symptom distress were significantly predicted by state anxiety, health professional support, and time since cancer diagnosis. CONCLUSION: Change in symptom distress following the first 4 months after diagnosis was predicted by state anxiety, health professional support, and time. Patients should receive social support and be trained in problem-solving skills to relieve distressful symptoms from diagnosis through treatment.

Chemopreventive and chemotherapeutic effect of dietary supplementation of vitamin D on cholangiocarcinoma in a Chemical-Induced animal model.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D, a pro-hormone, is getting popular due to its hormone-like functions after converted to its active form, 1α,25(OH)2D3. Here, we show that dietary supplementation with 6 IU/g of vitamin D greatly suppressed ICC initiation and progression without apparent toxicity in a chemically induced rat model. Microarray analysis of rat ICC tissues showed vitamin D supplementation modulated the expressions of several unique genes, including lipocalin 2 (Lcn2), confirmed by RT-qPCR and immunohistochemical (IHC) staining. Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC. As human ICC SNU1079 cells were treated by 1α,25(OH)2D3, LCN2 expression and cell proliferation were attenuated. The downregulation of LCN2 expression was blunted when vitamin D receptor (VDR) was knocked down, implicating that the in vivo Lcn2 downregulation is a direct consequence of vitamin D supplementation Our results support the prevailing concept that vitamin D status is negatively associated with cancer incidence and mortality and suggest LCN2 may be a potential target against ICC. Further studies of application of vitamin D or its analog against ICC are warranted.