Is the remnant pancreas still working over a year after surgery in patients undergoing pancreaticoduodenectomy with reconstruction by pancreaticogastrostomy?

BACKGROUND: Pancreaticogastrostomy (PG) has been widely used as an alternative to pancreatojejunostomy (PJ) in patients undergoing pancreaticoduodenectomy (PD), but its long-term exocrine function remains unclear. The present study aimed to measure the secretion of pancreatic α-amylase (p-AMY) into the gastric cavity in patients who underwent PG reconstruction after PD over 1 year after surgery and to evaluate the relationship between gastric p-AMY level and clinically available indirect tests. METHODS: Clinical records of 39 patients who underwent PG reconstruction after PD were reviewed. Pancreatic exocrine function was evaluated over 1 year after surgery using the following methods: 1) Measurement of p-AMY level in gastric fluids (gastric p-AMY level) during routine gastrointestinal endoscopy, 2) Qualitative faecal fat determination by Sudan III staining on faeces and 3) Pancreatic function diagnostic (PFD) test using oral administration of N-benzoyl-l-tyrosyl-p-aminobenzoic acid. RESULTS: Gastric p-AMY level was detectable in 31 of 39 patients (79%), and 12 patients (30.8%) had steatorrhea over a year after surgery. Patients with steatorrhea had significantly lower gastric p-AMY level, larger diameter of remnant main pancreatic duct (MPD) and larger pancreatic duct to parenchymal thickness ratio than those without steatorrhea (84 IU/L vs 7979 IU/L, respectively; P < 0.001, 5.3 mm vs 3.2 mm, respectively; P = 0.001, and 0.38 vs 0.23, respectively; P = 0.007). Receiver operating characteristic analysis showed that the cut-off value of the diameter of the remnant MPD to predict steatorrhea was 3.5 mm (sensitivity, 92.3%; specificity, 70.4%). PFD test was not associated with any clinical data. CONCLUSIONS: Pancreatic enzyme was detected in 79% of patients having PG reconstruction. Diameter of remnant MPD >3.5 mm and pancreatic parenchymal atrophy may be surrogate markers of postoperative exocrine insufficiency following PD.

A Prospective, Randomized Phase II Study of Adjuvant Gemcitabine Versus S-1 After Major Hepatectomy for Biliary Tract Cancer (KHBO 1208): Kansai Hepato-Biliary Oncology Group.

OBJECTIVE: To evaluate each arm independently and compare adjuvant gemcitabine (GEM) and S-1 chemotherapy after major hepatectomy (hemihepatectomy or trisectionectomy) for biliary tract cancer (BTC). BACKGROUND: Standardized adjuvant therapy is not performed after major hepatectomy for BTC, and we determined the recommended dose in the former study (KHBO1003). METHODS: We performed a multicenter, randomized phase II study. The primary measure was 1-year recurrence-free survival (RFS); the secondary measures were other RFS, overall survival (OS), and others. The following 6-month adjuvant chemotherapy was administered within 12 weeks of R0/1: GEM (1000 mg/m) every 2 weeks; or S-1 (80 mg/m/d) for 28 days every 6 weeks. Thirty-five patients were assigned to each arm (alpha error, 10%; beta error, 20%). RESULTS: No patients were excluded for the per-protocol analysis. There were no statistically significant differences in the patient characteristics of the 2 arms. The 1-year RFS and 1-year OS rates of the GEM arm were 51.4% and 80.0%, respectively, whereas those of the S-1 group were 62.9% and 97.1%. The comparison of the 2 arms revealed that 2-year RFS rate, 1 and 2-year OS rates, and OS curve of the S-1 arm were superior to GEM. With regard to OS, the hazard ratio of the S-1 group was 0.477 (90% confidence interval 0.245-0.927). CONCLUSION: The comparison of the survival of the 2 groups revealed that adjuvant S-1 therapy may be superior to adjuvant GEM therapy after major hepatectomy for BTC.

Double Purse-String Telescoped Pancreaticogastro stomy using an Atraumatic Self-retaining Ring Retractor in a Subtotal Stomach-Preserving Pancreaticoduodenectomy.

BACKGROUND: Pancreatoenteric anastomotic failure is the main cause of pancreatic fistula after pancreaticoduodenectomy (PD). Double purse-string telescoped pancreaticogastrostomy, reported by Addeo et al., is an easy and safe procedure.1 The aim of this article was to introduce our technique of pancreaticogastrostomy using an atraumatic self-retaining ring retractor (Alexis Wound Retractor) in a patient undergoing subtotal stomach-preserving PD (SSPPD). PATIENT AND METHODS: An 82-year-old woman presented with pancreatic cancer located in the uncinate process of pancreas. She underwent SSPPD with resection of the superior mesenteric vein (SMV) and double purse-string telescoped pancreaticogastrostomy using an Alexis wound retractor. RESULTS: The pancreas was transected on the portal vein and the remnant pancreas was separated from the splenic vein and artery. After extirpation of specimens and reconstruction of the SMV, two seromuscular purse-string sutures were placed on the posterior wall of the upper stomach. The anterior wall of the upper stomach was incised and opened using an Alexis wound retractor. The remnant pancreas was inserted into the gastric cavity through the posterior wall of the stomach and sutured circumferentially with running stitches to fix on the gastric muco-muscular layer. After closure of the anterior wall of the stomach, purse-string sutures were tightened and pancreaticogastrostomy was completed. The patient's postoperative course was uneventful and a computed tomography imaging study revealed no fluid collection around the pancreaticogastrostomy. This patient was discharged on the 14th postoperative day. CONCLUSIONS: Use of an Alexis wound retractor makes it easier to perform a double purse-string telescoped pancreaticogastrostomy by a self-expanding property to allow a wide operative view.

Response Evaluation Criteria in Cancer of the Liver (RECICL) (2015 Revised version).

The Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). Therefore, establishment of response evaluation criteria solely devoted to HCC is needed urgently in clinical practice as well as in clinical trials of HCC treatment, such as molecular-targeted therapies, which cause necrosis of the tumor. The Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2015 by the Liver Cancer Study Group of Japan based on the 2009 version of RECICL, which was commonly used in Japan. Major revised points of the RECICL 2015 is to define the target lesions of two lesions per organ or three lesions per liver, up to a maximum of five lesions. The second revised point is that setting the timing at which the overall treatment response has been changed. The third point is that the definition of treatment effect 1 has been changed to more than 50% tumor enlargement, excluding the area of necrosis after treatment. Overall evaluation of treatment response has been amended to make it possible to evaluate the overall response including extrahepatic lesions by systemic therapy, which is similar to RECIST or modified RECIST. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit HCC treatment response evaluation in the setting of daily clinical practice and clinical trials, not only in Japan, but also internationally.

Comparative outcomes of elderly and non-elderly patients receiving first-line palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND AND AIM: Few studies have reported the efficacy and safety of palliative chemotherapy in elderly patients with advanced biliary tract cancer. We aimed to investigate the clinical outcomes of palliative chemotherapy for advanced biliary tract cancer in elderly patients. METHODS: We retrospectively evaluated 403 consecutive patients who received palliative chemotherapy between April 2006 and March 2009 for pathologically confirmed unresectable or recurrent biliary tract cancer. Clinical outcomes of the elderly group (≥ 75 years old; n = 94) were compared with those of the non-elderly group (< 75 years old; n = 309). RESULTS: Except for the extent of disease, patient baseline characteristics were well balanced between both groups. The median overall survival was 10.4 months in the elderly group and 11.5 months in the non-elderly group (hazard ratio, 1.14; 95% confidence interval, 0.89-1.45; P = 0.31). Although the frequency of adverse events between both groups was similar, interstitial pneumonitis was significantly more frequent in the elderly group than in the non-elderly group (4.3% vs 0%, P < 0.01). CONCLUSIONS: In advanced biliary tract cancer, overall survival of elderly patients receiving palliative chemotherapy is comparable with that of non-elderly patients. To our knowledge, this is one of the largest studies that have reported the clinical outcomes of elderly patients following palliative chemotherapy.

Liver parenchymal sparing surgery for locally advanced gallbladder cancer with extracapsular lymph node invasion.

A complete R0 resection is the standard treatment in patients with gallbladder cancer and the only potentially definitive curative therapy. Major hepatectomy, including right or extended right hepatectomy with extrahepatic bile duct resection, would be an option in patients with locally advanced gallbladder cancer, while morbidity and mortality rate are still high. Herein, we report a case of a locally advanced gallbladder cancer invading the right hepatic artery (RHA), common hepatic duct, and transverse colon. This patient was successfully treated with parenchymal sparing surgery without major hepatectomy and achieved R0 resection by means of extended cholecystectomy combined with resection of the transverse colon, extrahepatic bile duct, and RHA. Intrahepatic arterial flow was preserved without reconstruction of the RHA, and the postoperative course was favorable. Liver parenchymal sparing surgery might be an alternative procedure in patients with gallbladder cancer, to minimize the risk of severe morbidity, if R0 resection is possible.

Characteristic patterns of altered DNA methylation predict emergence of human hepatocellular carcinoma.

UNLABELLED: We aimed to identify the specific subset of tumor suppressor genes (TSGs) that are methylation-silenced during the earliest steps of hepatocarcinogenesis, and to further evaluate whether these genes can serve as predictive biomarkers of hepatocellular carcinoma (HCC) emergence. A total of 482 liver tissues including 177 pairs of HCCs and matched nontumor livers and 128 liver biopsies from chronic hepatitis C (CHC) patients were analyzed for quantitative methylation analysis in 24 TSG promoters and three MINT loci. The tumors were classified as early, less-progressed, and highly progressed HCCs using histology and radiological approaches. A subset of TSGs that harbored distinctly high levels of methylation in early HCCs were selected. Based on the methylation profiles of these genes, Kaplan-Meier analyses were performed to determine time-to-HCC occurrence in CHC patients. Subsequently, multivariate analysis was performed using age, gender, fibrosis stage, and number of methylated TSGs as covariates. Among TSGs analyzed, a subset of eight TSGs (HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC, RUNX3, and PRDM2) demonstrated a distinct cluster by hierarchical clustering and receiver operating characteristic analyses. This subset of TSGs showed significantly higher methylation levels in the early HCCs (P < 0.0001). In the CHC patients, methylation frequencies in these TSGs were associated with shorter time-to-HCC occurrence (P < 0.0001), and number of methylated genes was an independent risk factor for HCC (hazard ratio = 5.21, 95% confidence interval = 2.25-11.76, P = 0.0002). CONCLUSION: Epigenetic inactivation of a subset of TSGs plays a critical role in the earliest steps of hepatocarcinogenesis. Furthermore, epigenetic inactivation of these genes in CHC provides a prognostic value for determining the risk for developing HCC later in life.

The prognostic value of vascular endothelial growth factor in hepatocellular carcinoma for predicting metastasis after curative resection.

OBJECTIVES: Hepatocellular carcinoma (HCC) frequently recurs even after curative resection. The purpose of this study was to identify factors predictive for postoperative recurrence of HCC in patients who underwent curative resection using immunohistochemistry. METHODS: Expression of vascular endothelial growth factor (VEGF), E-cadherin and cyclin D1 in HCC tissue were analyzed for 133 HCC patients who underwent curative resection of tumors using immunohistochemical analysis. Relationships of expressions and disease-free survival of HCC were evaluated using univariate and multivariate analyses. RESULTS: The average period of follow-up of the patients was 6.7 years. Multivariate analyses revealed that only strong expression of VEGF in HCC tissue was significantly associated with metastatic recurrence (p < 0.001, hazard ratio, HR, 3.32). CONCLUSIONS: Evaluating VEGF in HCC tissue after surgical resection has predictive value for metastatic HCC recurrence. The ability to risk stratify should improve the treatment strategies after hepatectomy.

Expression of E-cadherin and vascular endothelial growth factor in noncancerous liver is associated with recurrence of hepatocellular carcinoma after curative resection.

OBJECTIVES: Hepatocellular carcinoma (HCC) frequently recurs even after curative resection. The purpose of this study was to examine how background liver affects postoperative recurrence of HCC that underwent curative resection using expression of cancer-related molecules in the adjacent noncancerous liver of HCC patients. METHODS: We examined expression of E-cadherin and vascular endothelial growth factor in noncancerous liver tissues of 133 HCC patients who underwent curative resection of tumors using immunohistochemical analysis. Associations between expressions of these molecules and disease-free survival of HCC were analyzed using the Kaplan-Meier method. RESULTS: The average period of follow-up of the patients was 6.7 years. Multivariate analyses revealed that low platelet count and negative expression of E-cadherin in adjacent noncancerous liver were significantly associated with metastatic recurrence [p = 0.017, hazard ratio (HR) = 1.31 for low platelet count, and p = 0.009, HR = 1.43 for negative expression of E-cadherin, respectively]. CONCLUSIONS: Expression levels of E-cadherin in adjacent noncancerous liver after surgical resection was associated with metastatic HCC recurrence later on. Analysis of E-cadherin expression should provide important information for predicting recurrence after curative resection of HCC.

Parenchyma-sparing anatomical liver resection based on Hjortsjo's concept: a venous-drainage-guided approach to identify the ventral segment fissure.

PURPOSE: Anatomical liver resection is usually based on Couinaud's anatomical concept. In contrast, Hjortsjo's concept, which divides the right anterior section of the liver into ventral and dorsal segments by the vertical plane named the ventral segment fissure (VSF), has been rarely utilized for liver resection. Identification of the VSF is the most difficult step in liver resection based on Hjortsjo's concept. This study aimed to detail liver resection based on Hjortsjo's concept and report surgical outcomes of this procedure. METHODS: We reviewed the records of 166 consecutive patients who underwent liver resection between September 2009 and June 2012 at Kyoto Medical Center and identified seven liver resections in which Hjortsjo's concept was utilized. These patients consisted of four men and three women aged 55-79 years. Four patients had hepatocellular carcinoma and cirrhosis and three patients had metachronous colorectal liver metastasis. RESULTS: Liver resection along the VSF consisted of two extended left medial sectionectomies, three extended right posterior sectionectomies, and one Sg 7+8-dorsal resection by a venous-drainage-guided approach and one Sg 8-dorsal resection by a Glissonian approach. In all patients, the VSF was successfully identified as a congested or ischemic border on the liver surface. Mortality and major morbidity were nil. No patients underwent blood transfusion. After a median follow-up of 15 months, there were no deaths or local recurrence. CONCLUSIONS: Anatomical liver resection based on Hjortsjo's concept is feasible and advantageous over conventional liver resection because it preserves more parenchyma. The venous-drainage-guided approach is an effective method for identifying the VSF.

Gender differences in the livers of patients with hepatocellular carcinoma and chronic hepatitis C infection.

OBJECTIVES: A unique causative aspect of hepatocellular carcinoma (HCC) is a gender difference in its incidence. To determine the specific factors that contribute to a male predominance, we analyzed the clinicopathological factors, and genetic and epigenetic alterations of HCCs in male and female patients. METHODS: We retrospectively analyzed three cohorts of patients: the first cohort consisted of 547 patients identified with the first event of HCC, the second cohort included 176 HCC patients, and the third 127 patients with chronic hepatitis C (CHC). RESULTS: Male patients were found to have HCC more frequently than female patients in cases of non-cirrhotic liver (p = 0.0030 by the χ(2) test), especially in hepatitis C-positive cases. However, there were no gender-specific differences in the genetic and epigenetic alterations of cancer-related genes. Deposition of iron was more severe in male CHC patients than in female patients. CONCLUSIONS: Male patients with CHC develop HCC more frequently when they have a non-cirrhotic liver than do female patients. This gender difference could be, at least partially, attributed to a different degree of iron deposition, which contributes to the development of HCC in the absence of liver cirrhosis in men with CHC.

Laparoscopic resection for sigmoid and rectosigmoid colon cancer performed by trainees: impact on short-term outcomes and selection of suitable patients.

PURPOSE: This study aimed (1) to evaluate the impact of clinical factors, particularly operation by trainees, on the short-term outcomes of laparoscopic resection for sigmoid and rectosigmoid cancer, and (2) to determine patients suitable for operation by trainees. METHODS: From a prospectively maintained single-institution database, we identified 133 patients who underwent laparoscopic resection for sigmoid or rectosigmoid cancer between 2007 and 2010. Gender, age, body mass index (BMI), previous abdominal surgery, tumor location, tumor size, tumor stage, extent of lymph node dissection, and primary surgeon were evaluated using univariate and multivariate analyses to determine the predictive significance of these variables on surgical outcomes including operative time, blood loss, complication, postoperative stay, and retrieved lymph nodes. RESULTS: Multivariate analysis showed that location of the tumor in the rectosigmoid (p < 0.001), higher BMI (p < 0.001), operation by trainees (p < 0.001), male gender (p = 0.002), and greater tumor depth (p = 0.011) were independently predictive of longer operative time. Larger tumor size (p = 0.025) and higher BMI (p = 0.040) were independently predictive of greater blood loss. Larger tumor size was also related to longer postoperative stay (p = 0.001) and a greater number of retrieved lymph nodes (p = 0.001). CONCLUSIONS: This study identified operation by trainees as an independent risk factor for longer operative time but with no negative impact on any of the other outcomes. Female patients with a low BMI, sigmoid cancer, shallow tumor depth, and/or small tumor are suitable for operation by trainees.

[Oral capecitabine as postoperative adjuvant chemotherapy in stage III colon cancer patients].

Capecitabine(Xeloda®)has been a global standard drug for the treatment of colon cancer since large randomized controlled trials demonstrated its efficacy and safety in treating patients suffering from the disease. Few studies have been conducted to assess the effects of oral capecitabine treatment on Japanese patients. Therefore, we conducted this study to evaluate oral capecitabine as postoperative adjuvant chemotherapy in 50 patients who underwent surgery for stage III colon cancer at our department. Patients received an 8 courses treatment with capecitabine during the study, and the incidence of adverse events, treatment completion rate, and treatment compliance were assessed. Adverse events were reported in a total of 46 patients(92%). The most common adverse event was hand foot syndrome(HFS), reported in 39 patients(78%), whereas bone-marrow toxicity and diarrhea were reported in as few as 2(4%)and 3(6%)patients, respectively. Both these events were mild in severity, and no patients required hospitalization, nor were they associated with treatment-related deaths. The median treatment duration was 8 courses ranging from 3 to 8 courses, and the 8 courses treatment completion rate was 96%. The relative dose intensity, which was used as a treatment compliance index, is expressed as the actual dose taken by the patient divided by the dose planned at baseline. The median and mean of the relative dose intensity were 100%(ranging from 37% to 100%)and 93%, respectively. The results of this study showed that the safety profile of oral capecitabine therapy was generally favorable, with a lower incidence and lesser severity of life-threatening bone-marrow toxicity and diarrhea, although the treatment is still associated with frequent HFS. This is the great advantage of capecitabine when it is used as postoperative adjuvant chemotherapy for gastrointestinal cancer. Indeed, a satisfactory treatment completion rate was achieved in this study while maintaining a sufficient dose and treating HFS, by reducing the dose, interrupting treatment, or providing appropriate corrective measures.

Evaluation of factors affecting the difficulty of laparoscopic anterior resection for rectal cancer: "narrow pelvis" is not a contraindication.

BACKGROUND: This study aims to evaluate the clinical and anatomical factors, particularly pelvic dimensions that influence the difficulty of performing laparoscopic anterior resection for rectal cancer. METHODS: We studied 50 consecutive patients who underwent laparoscopic anterior resection with double-stapling technique (DST) anastomosis for rectal cancer between January 2006 and February 2010. Staging was performed by computed tomography. Five pelvic dimensions (anteroposterior and transverse diameters of pelvic inlet and outlet, and pelvic depth) were measured using three-dimensional volume-rendering images. We also examined a number of other clinical characteristics, including gender, history of laparotomy, body mass index (BMI), operator, tumor location, tumor depth, nodal involvement, and tumor diameter. Univariate and multivariate analyses were performed to determine the predictive significance of these variables on surgical difficulty based on operative time and intraoperative blood loss. RESULTS: Males had significantly shorter pelvic inlets and outlets and significantly greater pelvic depth than females. However, gender did not significantly affect surgical outcomes, although males did tend to experience greater blood loss. Maximum tumor diameter (p=0.014), BMI (p=0.001), operator (p<0.001), and tumor location (p=0.009) were independent predictors of operative time, which, in turn, was related to intraoperative blood loss (p<0.001). CONCLUSIONS: Maximum tumor diameter, BMI, operator experience, and tumor location can be used to predict the operative time required to complete laparoscopic anterior resection with DST anastomosis for rectal cancer, with no correlations between pelvic dimensions and operative time. The difficulty of the procedure was not related to patients' pelvic dimensions, which led us to conclude that "narrow pelvis" is not a contraindication for this surgery. Based on these results, we suggest that laparoscopic anterior resection should be performed by experienced surgeons in patients with large tumors, high BMI, and/or extraperitoneal rectal cancer.

Mesh shrinkage is the potential pathogenesis of chronic somatic pain following transabdominal preperitoneal repair: Report of two cases.

Although mesh-related pain, termed "somatic pain," is a well-known pain syndrome following Lichtenstein repair, few reports are available on somatic pain following transabdominal preperitoneal repair (TAPP) and its pathogenesis remains unclear. We report on two patients with refractory somatic chronic pain following TAPP. In the present two cases, both mesh fixation with rigid permanent metal tackers and mesh shrinkage resulting in contractile forces on the groin musculature could be considered as potential mechanisms in the etiology of chronic somatic pain following TAPP. The lessons learned from these two cases are: (a) mesh shrinkage resulting in contractile forces on the groin musculature could be considered as potential mechanisms in the etiology of chronic somatic pain following TAPP; (b) partial mesh removal would be an effective alternative to total mesh removal in those patients for remedial surgery.

Combination of lymphocyte count and albumin concentration as a new prognostic biomarker for rectal cancer.

Although numerous studies have highlighted the prognostic values of various inflammation-related markers, clinical significance remains to be elucidated. The prognostic values of inflammation-related biomarkers for rectal cancer were investigated in this study. A total of 448 patients with stage II/III rectal cancer undergoing curative resection were enrolled from the discovery cohort (n = 240) and validation cohort (n = 208). We comprehensively compared the prognostic values of 11 inflammation-related markers-derived from neutrophil, lymphocyte, platelet, monocyte, albumin, and C-reactive protein for overall survival (OS) and recurrence-free survival (RFS). Among 11 inflammation-related markers, only "lymphocyte × albumin (LA)" was significantly associated with both OS and RFS in the discovery cohort (P = 0.007 and 0.015, respectively). Multivariate analysis indicated that low LA was significantly associated with poor OS (hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.09-4.58, P = 0.025), and poor RFS (HR 1.61, 95% CI 1.01-2.80, P = 0.048). Furthermore, using the discovery cohort, we confirmed that low LA was significantly associated with poor OS (HR 2.89, 95% CI 1.42-6.00, P = 0.002), and poor RFS (HR 1.79, 95% CI 1.04-2.95, P = 0.034). LA can be a novel prognostic biomarker for stage II/III rectal cancer.

In vitro hepatic maturation of human embryonic stem cells by using a mesenchymal cell line derived from murine fetal livers.

Hepatocytes derived from human embryonic stem cells (hESCs) are an attractive cell source for regenerative medicine. We previously reported the differentiation of hESCs into alpha-fetoprotein (AFP)-producing endodermal cells by using extracellular matrix and growth factors. We also reported the establishment of the MLSgt20 cell line, which was derived from mesenchymal cells residing in murine fetal livers and accelerated the hepatic maturation of both murine hepatic progenitor cells and murine ESCs. In this study, hESC-derived AFP-producing cells were isolated by using a flow cytometer and co-cultured with MLSgt20 cells. The co-cultured hESC-derived AFP-producing cells had the immunocytological characteristics of hepatocytes, expressed mature hepatocyte markers (as indicated by reverse transcription and the polymerase chain reaction), and displayed higher hepatocyte functions including ammonia removal, cytochrome P450 3A4/7 activity, and the ability to produce and store glycogen. However, the MLSgt20 cells did not directly cause undifferentiated hESCs to mature into hepatocyte-like cells. The co-culture method was thus successfully shown to induce the differentiation of hESC-derived endodermal cells into functional hepatocyte-like cells.

Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma.

UNLABELLED: Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TbetaRI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, TbetaRI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. CONCLUSION: Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.

FDG PET as a prognostic predictor in the early post-therapeutic evaluation for unresectable hepatocellular carcinoma.

PURPOSE: To elucidate the prognostic role of post-therapeutic (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET), we conducted a retrospective cohort study analysing the clinical factors that affect overall survival after non-operative therapy for unresectable hepatocellular carcinoma (HCC). METHODS: Sixty-seven cases with unresectable HCC who received non-operative therapy (transcatheter arterial chemoembolization: n = 24, transcatheter arterial infusion chemotherapy: n = 31, radiofrequency ablation: n = 5 or systemic chemotherapy: n = 7) and had received FDG PET for the evaluation of the therapeutic effect within 1 month after the end of the therapy were evaluated. Overall survival rate was evaluated using the univariate and multivariate analyses of relevant clinical and laboratory parameters before and after therapy, including visual PET analysis and quantitative analysis using maximum standardized uptake value (SUV). RESULTS: Visual PET diagnosis of post-therapeutic lesions was a good predictor of overall survival of unresectable HCC patients. The low FDG group showed significantly longer survival (average: 608 days) than that (average: 328 days) of the high FDG group (p < 0.0001). Multivariate analysis showed four significant prognostic factors for the survival: post-therapeutic alpha-fetoprotein (alphaFP) level (=400 ng/ml, p = 0.004), post-therapeutic visual PET diagnosis (p = 0.006), post-therapeutic clinical stage (UICC stage IV, p = 0.04) and post-therapeutic Milan criteria (p = 0.03), while pre-therapeutic clinical factors, SUV by post-therapeutic FDG PET (5.0 or more) or others did not show significance. CONCLUSION: The present study suggests that post-therapeutic PET performed within 1 month after non-operative therapy can be a good predictor of overall survival in unresectable HCC patients, while pre-therapeutic evaluation including PET, tumour markers and clinical staging may not be useful.

Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis.

OBJECTIVE: Although iodized oil transarterial chemoembolization (TACE) has been found to have survival benefit in the care of patients with unresectable hepatocellular carcinoma, iodized oil infusion chemotherapy without embolization has not been clearly found inferior to or equal to TACE. The purpose of this study was to determine whether one of these therapies is superior to the other or the two are equal in survival benefit and whether embolization with gelatin sponge particles is indispensable to prolonging survival. SUBJECTS AND METHODS: A prospective nonrandomized observational cohort study was conducted over 8 years. Among 11,030 patients with unresectable hepatocellular carcinoma, 8,507 underwent TACE, and 2,523 underwent transarterial infusion therapy with an emulsion of iodized oil and an anticancer agent as initial treatment. Patients with extrahepatic metastasis or any previous treatment were excluded. The primary end point was all-cause mortality. To minimize selection bias, propensity score analysis was used to compare the two groups. RESULTS: During the follow-up period, 5,044 patients (46%) died. In the analysis of all patients, TACE was associated with a significantly higher survival rate than infusion therapy without embolization (hazard ratio, 0.60; 95% CI, 0.56-0.64; p = 0.0001). The propensity score analysis showed that the hazard ratio for death in the TACE group (n = 1,699 patients) compared with the group who underwent infusion therapy without embolization (n = 1,699) was 0.70 (95% CI, 0.63-0.76; p = 0.0001). The median survival time of the TACE group was 2.74 years, and the 1-, 3-, and 5-year survival rates were 81%, 46%, and 25%. The corresponding values for the group who underwent transarterial infusion therapy without embolization were 1.98 years and 71%, 33%, and 16%. CONCLUSION: Propensity score analysis showed that in the treatment of patients with unresectable hepatocellular carcinoma, TACE was associated with significantly better overall survival rates than was transarterial infusion therapy without embolization. TACE can be recommended as initial treatment of these patients.