Yukihiro Iso

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%‐3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico‐pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real‐time polymerase chain reaction–based copy number assay revealed that FGF3/FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico‐pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4‐amplified and three FGFR2‐amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3. Conclusion: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies. (HEPATOLOGY 2013)

Incarceration of a large cell neuroendocrine carcinoma arising from the proximal stomach with an organoaxial gastric volvulus through an esophageal hiatal hernia: report of a case.

An 86-year-old woman was admitted to the hospital to undergo an examination for tarry stools. Laboratory tests showed hypoproteinemia and renal dysfunction. Upper gastrointestinal endoscopy demonstrated a type 5 tumor located in the upper body of the stomach. An upper gastrointestinal series and computed tomography revealed an organoaxial gastric volvulus and the dislocation of the proximal stomach through an esophageal hiatal hernia. The preoperative diagnosis was the incarceration of a gastric carcinoma arising from the proximal stomach with an organoaxial gastric volvulus through an esophageal hiatal hernia. A total gastrectomy and hernia repair were performed. A microscopic examination of the surgical specimen revealed a gastric large cell neuroendocrine carcinoma (GLCNEC). The patient was discharged 22 days after the surgery. Although the prognosis of GLCNEC is significantly worse than that of a conventional adenocarcinoma, the patient was doing well without recurrence at 15 months after surgery. The details of this case are reported with some bibliographical comments.

Aspartate aminotransferase-to-platelet ratio index is associated with liver cirrhosis in patients undergoing surgery for hepatocellular carcinoma.

BACKGROUND Among various preoperative evaluations of liver function, accurate assessment of liver cirrhosis (LC) is especially important in patients undergoing surgery for hepatocellular carcinoma (HCC). OBJECTIVE To explore the most significant laboratory parameter associated with LC in patients undergoing surgery for HCC. METHODS From among 588 HCC patients in our collected database who underwent liver surgery, 371 for whom sufficient laboratory data were evaluable, including direct serum fibrosis markers such as hyaluronic acid and type 3 procollagen peptide (P-3-P), were enrolled. Receiver operating characteristic (ROC) curve analysis was used to define the ideal cutoff values of laboratory parameters, and the area under the ROC curve for LC was measured. Univariate and multivariate analyses were performed to clarify the laboratory parameter most significantly associated with LC. RESULTS Multivariate analysis of 13 laboratory parameters that had been selected by univariate analysis showed that the aspartate aminotransferase-to-platelet ratio index (APRI) (≤ 0.8/>0.8) (odds ratio, 2.687; 95% confidence interval 1.215-5.940; P = 0.015) was associated with LC, along with the aspartate aminotransferase to alanine aminotransferase ratio, the indocyanine green retention ratio at 15 min (ICG R15), and the level of hyaluronic acid. Among these four parameters associated with LC, ROC curve analysis revealed that APRI (0.757) had the largest area under the ROC (aspartate aminotransferase to alanine aminotransferase 0.505, ICG R15 0.714, and hyaluronic acid 0.743). CONCLUSIONS APRI is closely associated with LC in patients undergoing surgery for HCC.

When hepatic-side ductal margin is positive in N+ cases, additional resection of the bile duct is not necessary to render the negative hepatic-side ductal margin during surgery for extrahepatic distal bile duct carcinoma

Background The current standard treatment for extrahepatic distal bile duct carcinoma (EDBDC) is surgical resection, as no effective alternative treatment exists. In this study, we investigated the treatment strategies and outcomes for 90 cases of EDBDC at our department. Material/Methods Between April 2000 and March 2013, 90 pancreatoduodenectomies (PDs) were performed for EDBDC. The mean patient age was 69.1±9.8 years, and there were 59 males and 31 females. Extended lymph adenectomy including lymph nodes around the common hepatic artery and celiac axis was performed in all patients. The mean operation time was 537.1±153.8 min and the mean operative blood loss was 814.0±494.0 ml. There were no operation-related deaths. The overall 1-, 3-, and 5-year survival rates were 90.0%, 51.2%, and 45.0%, respectively. Results Lymph node metastasis was present in 28 patients (N+; 31.1%), and it was absent in 62 (N−; 68.9%). The 5-year survival rate was 20.0% for N+ patients and 52.4% for N− patients, which is significantly higher (P=0.03). Nine cases (10.0%) showed hepatic-side ductal margin (HM) positivity for carcinoma. The 5-year survival rate was 18.7% for HM-positive patients and 48.3% for HM-negative patients, which is significantly higher (P=0.005). In multivariate analysis, N+ was the strongest adverse prognostic factor. Subclass analysis of 62 cases (excluding 28 N+ cases) revealed 7 patients with positive HMs (11.3%) and 55 patients with negative HMs (88.7%). The 5-year survival rate was 47.6% for HM-positive patients and 49.8% for HM-negative patients (P=0.73). Thirty-five cases (38.9%) recurred: there were 19 cases of local recurrence (21.1%), 11 cases of liver metastasis (12.2%), 4 cases of distant recurrence (4.4%), and 1 case of para-aortic lymph node metastasis (1.1%). Conclusions In conclusion, when HM is positive in N+ cases, additional resection of the bile duct is not necessary to render the HM negative for carcinoma.

Successful Right Hemihepatectomy for a Patient with Right-Sided Round Ligament

Right-sided round ligament (RSRL) is a rare congenital anomaly that is strongly associated with a number of intrahepatic vascular anomalies. Here, we report a 77-year-old male case of hepatolithiasis associated with RSRL for which resection was performed using right hemi-hepatectomy (RHH). Intraoperative ultrasonography revealed that the portal branch of segment 4 ramified from the right anterior portal branch, and the patient was diagnosed as having RSRL. To decide the resection line, the portal branch of segment 4 was punctured and stained with indigo carmine under ultrasonographic guidance, clearly demonstrating the demarcation line between the right and left hemiliver. RHH was then carried out successfully without injuring the portal branch of segment 4.

Mini-Laparotomy for Superior Mesenteric Artery Aneurysm Due to Takayasu's Arteritis

Superior mesenteric artery aneurysm (SMAA) is reported to be the third-most common type of visceral aneurysm (VA), accounting for 5% of all VAs. The etiology of SMAA is commonly thought to be infection, and it usually exists in the proximal part of the superior mesenteric artery, which is suitable for endovascular treatment. We herein report an extremely rare case of the distal part of SMAA caused by Takayasus arteritis (TA), which was successfully resected using a mini-laparotomy method without impairing the intestinal blood supply. A 51-year-old woman was admitted to our hospital with sustained fever and lower back pain. Physical examination showed that she had a discrepancies in blood pressure between both arms. Contrast-enhanced whole-body computed tomography showed stenosis of the thoracic aorta and an aneurysm located in the distal part of the superior mesenteric artery. The diameter of the aneurysm was 4.5 cm. The aneurysm was resected via 4-cm mini-laparotomy, and the vascularity of the intestine was successfully preserved. The postoperative course was uneventful, and the patient was diagnosed as having TA based on both clinical and pathologic findings. Additional corticosteroid therapy was started to treat the arteritis, and at 3-month follow-up she was without critical incidents. Mini-laparotomy is a safe and less-invasive approach to treat SMAA, especially when the lesion is located in the distal part of the artery.

Pancreatic Juice Leakage Is a Risk Factor for Deep Mycosis After Pancreatic Surgery

PurposeDeep mycosis (DM) is an opportunistic infection that can be fatal in immunocompromised hosts. Pancreatic surgery is associated with a high degree of stress and patients who undergo pancreatic surgery are considered to be immunocompromised. This study retrospectively evaluated whether DM affects the clinical course after pancreatic surgery.MethodsBetween January 2005 and April 2007, 67 patients underwent pancreatic surgery. There were 42 males (62.7%) and 25 females (37.3%) with a mean age of 66.7 years. Their diagnoses consisted of cancer of the papilla of Vater (n = 9), pancreatic head cancer (n = 20), pancreatic tail cancer (n = 3), bile duct cancer (n = 17), duodenal cancer (n = 3), and others (n = 15). Surgical procedures included pancreatoduodenectomies (PD; n = 52), hepato-pancreatoduodenectomies (HPD; n = 4), distal pancreatectomies (DP; n = 7), total pancreatectomies (TP; n = 2), and the modified Puestow procedure (m-Pp; n = 2). Patients who were positive for any of CAND-TEC (C-T), β-d-glucan (β-d), or culture for mycosis were classified into group 1 (G1; n = 12) and those who were negative for all these examinations were classified into group 2 (G2; n = 55). The preoperative, perioperative, and postoperative data were compared between G1 and G2. An antifungal drug (Micafungin; 75 mg per day) was given to G1 patients.ResultsThe preoperative data included the neutrophil and lymphocyte counts, total protein, blood urea nitrogen, and amylase, and there were no significant differences in these parameters between the two groups. However, the incidences of diabetes mellitus and total bilirubin at maximum in G1 and G2 were 41.7% and 7.3% (P = 0.04), 4.6 ± 1.5 and 1.4 ± 0.9 (P = 0.007), respectively. The mean operation time in G1 and G2 was 548.5 ± 138.1 and 510.0 ± 133.7 min (P = 0.39) and intraoperative blood loss was 762.2 ± 369.5 and 782.5 ± 599.1 ml (P = 0.88), respectively. The postoperative complications included pneumonia (G1: G2 = 7: 20; P = 0.14), pleural effusion (7: 24; P = 0.27) and ascites (10: 33; P = 0.11), with no significant intergroup differences. However, the respective durations of pancreatic juice leakage in G1 and G2 were 12 and 12, respectively, with a statistically significant difference (P < 0.01). All the G1 patients were treated with the antifungal drug for 7.8 days. Postoperative hospital stays in G1 and G2 were 47.3 days and 38.7 days, respectively (P = 0.15) and the survival rates at 19 months after surgery were 46.7% and 79.4%, respectively (P = 0.04).ConclusionsDeep mycosis was observed in patients with pancreatic juice leakage, thus contributing to a poor outcome. Therefore, an early diagnosis of DM and the initiation of antifungal treatment are necessary for the improving prognosis.

Tumor DNA-dependent protein kinase catalytic subunit expression is associated with hepatitis B surface antigen status and tumor progression in patients with hepatocellular carcinoma

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which plays an important role in the DNA damage response, has been reported to be associated with tumor progression in various carcinomas. However, the clinical significance of DNA-PKcs in hepatocellular carcinoma (HCC) patients remains unclear. In the present study, we determined the tumor expression of DNA-PKcs in 104 resected HCC specimens by immunohistochemistry. The DNA-PKcs expression was scored as follows; 0, negative staining; 1, staining of nuclei at the tumor edge; 2, staining of the nuclei deep within the tumor and/or the tumor cytoplasm. The relationships between tumor expression of DNA-PKcs and the clinical characteristics and patient outcomes were investigated. Among the 104 HCCs, the distribution of staining for DNA-PKcs was as follows: 32 tumors were assigned a score of 0, 27 tumors were assigned a score of 1, and 45 tumors were assigned a score of 2. Statistical analyses revealed that tumor DNA-PKcs expression was significantly associated with the HBs antigen (HBsAg) status, presence/absence of portal vein invasion, size of the largest tumor nodule (<3.0 cm/>3.0, cm), and the serum alpha-fetoprotein level. Significant differences in the overall survival and recurrence-free survival were observed between patients showing (staining score 1 or 2) and not showing (staining score 0) tumor DNA-PKcs expression (P = 0.049 and P = 0.045, respectively). Our results suggest that tumor expression of DNA-PKcs is associated with tumor progression, HBsAg status and the postoperative outcomes in patients with HCC.

Hepatic myomatous angiomyolipoma diagnosedpreoperatively from specific imaging features: A case report

Highlights • An extremely rare case report of hepatic myomatous angiomyolipoma.• Including specific imaging features to diagnose with hepatic angiomyolipoma.• There is a significant interesting imaging findings of hepatic myomatous angiomyolipoma.• Previous reports only revealed the pathological findings and a few imaging findings, however we show two specific features of imaging with rare pathological findings.

Living donor liver transplantation in a highly allo-sensitized recipient: confusing influence of rituximab on the lymphocytotoxicity crossmatch test; a case report

Objective: We report a successful living donor liver transplantation (LDLT) from donor (husband) to highly allo-sensitized recipient (wife) against donor-adopting sufficient preoperative preparatio...