Akishige Kanazawa

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)

Acute respiratory failure caused by an incarcerated right-sided adult bochdalek hernia: report of a case.

Abstract.We herein report the case of a 63-year-old woman with a right-sided Bochdalek hernia. She was admitted to our hospital as an emergency patient with dyspnea and abdominal pain. A blood gas analysis showed hypoxia. A chest X-ray and computed tomography revealed a remarkable right diaphragm elevation caused by a herniation of the colon and right kidney. Under a thoracolaparotomy, a herniation of the strangulated colon and right kidney was recognized in the site of the foramen of Bochdalek, and a direct closure of the hernia opening was thus performed after repairing the location of the colon and right kidney. A right-sided Bochdalek hernia in adults is a rare clinical entity and there have been fewer than ten such cases so far reported in the world literature. This case highlights the need for a prompt diagnosis and appropriate surgical intervention.

Hepatocellular carcinoma arising from nonalcoholic steatohepatitis: report of two cases.

Sporadic cases of hepatocellular carcinoma (HCC) originating from nonalcoholic steatohepatitis (NASH) have recently been reported. Thus, we investigated the prevalence of NASH in patients with HCC. A review of the clinical records of 481 patients who underwent liver resection for HCC in our department between January 1991 and December 2003 revealed only two (0.4%) patients with HCC associated with NASH. Both of these patients had noninsulin-dependent diabetes mellitus, and neither had a history of alcohol consumption or blood transfusion. All serologic markers for hepatitis B and C viruses were negative. Histological examination of the noncancerous hepatic tissue revealed NASH with moderate hepatic fibrosis in one patient and cirrhosis in the other. Thus, clinical follow-up and screening for HCC should be done for patients with hepatic fibrosis caused by NASH, even though this form of hepatitis is an uncommon cause of HCC.

Asymptomatic Thrombosis as a Late Complication of a Retrohepatic Vena Caval Graft Performed for Primary Leiomyosarcoma of the Inferior Vena Cava: Report of a Case

Abstract.A 63-year-old woman successfully underwent a graft replacement of the retrohepatic inferior vena cava with a ringed polytetrafluoroethylene graft for primary leiomyosarcoma of the inferior vena cava (IVC). Although anticoagulant had been administered, a thrombus was found in the IVC just cranial of the downstream anastomosis 67 months after the operation. The patient remained free of symptoms, and she had no evidence of any tumor recurrence. She underwent a complete resection with a prosthetic reconstruction for leiomyosarcoma of the IVC and has since been able to enjoy a reasonably long-term survival. The occurrence of thrombosis must be kept in mind in the long-term follow-up of such cases.

Gastric malignant schwannoma presenting with upper gastrointestinal bleeding: a case report

IntroductionWe report a case of gastric malignant schwannoma presenting with gastrointestinal bleeding.Case presentationA 70-year-old Japanese man presented with gastrointestinal bleeding to our hospital. Gastrointestinal endoscopy revealed a protruding lesion in the gastric body. Hematoxylin and eosin staining of biopsy specimens from this lesion revealed sheets of spindle cells. Immunohistochemistry revealed that these cells were positive for S-100 protein and negative for c-Kit and smooth muscle actin. Because mitosis was diffusely visible, this tumor was diagnosed as a gastric malignant schwannoma. Distal gastrectomy with lymph node dissection was performed and the patients postoperative course was uneventful. However, five months after the surgery, he died from multiple liver metastases.ConclusionCases of gastric malignant schwannoma have rarely been reported. The efficacy of surgical resection and postoperative prognosis continues to remain unclear and should be investigated further.

Relationship of the Microvascular Type to the Tumor Size, Arterialization and Dedifferentiation of Human Hepatocellular Carcinoma

Unlike normal liver with the sinusoids, hepatocellular carcinomas (HCCs) possess capillaries. Whether these capillaries derive from the sinusoids remains unclear in human HCCs. This study aimed to examine sinusoidal capillarization in human HCCs and its relationship to the tumor size, arterialization and dedifferentiation. Thirty‐eight HCCs with a diameter of 10–140 mm were pathologically and angiographically examined. By electron microscopy, the microvasculature of tumors was classified into sinusoidal, intermediate and capillary types, which were all negative, partially positive and all positive, respectively, for four parameters, i.e., endothelial defenestration, continuous basement membrane, lack of Kupffer cells, and lack of lipid‐containing hepatic stellate cells. Well‐, moderately and poorly differentiated HCCs displayed sinusoidal/intermediate/capillary types, intermediate/capillary types and only capillary type, respectively, suggesting the transition from the sinusoids to capillaries in well‐differentiated (and probably moderately differentiated) HCCs. Furthermore, well‐differentiated HCCs with a diameter of less than 30 mm often received preferential portal venous blood, while moderately and poorly differentiated ones were all supplied with arterial blood, indicating a relationship between dedifferentiation and arterialization. In contrast, the microvascular type displayed no significant relationship with tumor size or arterialization in well‐differentiated HCCs. The present study has demonstrated that sinusoidal capillarization occurs in human well‐differentiated HCCs and seems to be related to dedifferentiation of parenchymal tumor cells, but not to tumor size or arterialization.

Clinicopathologic features and outcome after liver resection for hepatocellular carcinoma in patients with concurrent versus previous chronic hepatitis B.

PurposeWe compared the clinicopathologic features affecting outcome after surgery for hepatocellular carcinoma (HCC) between patients with concurrent and previous chronic hepatitis B.MethodsGroup A consisted of 58 patients with concurrent chronic hepatitis B, defined by seropositivity for the hepatitis B surface antigen (HBsAg), and group B consisted of 18 patients whose HCC was detected after disappearance of the HBsAg. We assessed the influence of various characteristics on outcome.ResultsThe mean age and percentage of patients suffering from alcohol abuse or diabetes mellitus were significantly greater in group B than in group A, whereas histologic hepatitis activity, hepatic fibrosis, and alanine aminotransferase activity were significantly lower in group B than in group A. The tumor-free survival rates were similar between the two groups, but the risk factors of recurrence differed. In group A, relative youth, high aspartate aminotransferase activity, low platelet count, multiple tumors, large tumor size, portal invasion, cirrhosis, nonanatomic resection, and positive surgical margin were risk factors. In group B, large tumor size and poor differentiation were risk factors.ConclusionHepatitis B status, tumor factors, and the type of operation affected cancer recurrence after surgery for HCC in patients with concurrent chronic HBV, as opposed to only tumor factors in patients with previous chronic hepatitis B.

Resection of needle-tract implantation after percutaneous puncture for hepatocellular carcinoma

To the Editor: From 1996 to 2002, percutaneous puncture guided by ultrasonography (PPGU) for hepatic nodular lesions, to provide an exact diagnosis or for performing any treatment, was performed 1101 times for 480 patients at our institute. Although histologic examinations were not done for all the patients, most patients were suspected of having hepatocellular carcinoma (HCC) before PPGU was done. Subsequently, 5 patients (1%) presented with seeding, and they had complete resections. Their clinical details are shown in Table 1. All 5 patients were Japanese; 4 patients were diagnosed with cirrhosis. The primary indication for PPGU was diagnostic. Findings of enhanced computed tomography or ultrasonography prior to PPGU were strongly suspicious for HCC in all patients. The mean diameter of the target nodules for PPGU was 2.3cm. The average interval from PPGU to the diagnosis of seeding was 39 months. We selected a minimally invasive operative method for complete resection of every lesion. Enucleation was performed in three patients. The tumor diameters were 2, 1, and 2.2 cm, and the tumors were moderately differentiated. In the remaining two patients, en-bloc resection with the parietal thoracic wall was performed. The tumor diameters were 3 and 2.4cm; one was poorly differentiated and one, moderately differentiated. All patients were treated without complications. One patient died in an accident, but the other patients are alive 2 to 81 months after resection, without local recurrence (Table 2). Needle-tract implantation after PPGU is a major complication of this procedure, with an incidence of 0.003% to 2%.1,2 At our facility, the incidence was 1%. During the past two decades, we have performed about 700 hepatic resections for HCC at our department.3 No patients similar to the above five were seen in the 1980s. Therefore, we believe that seeding of HCC is likely to increase as the use of PPGU becomes more common. Imaging tests prior to PPGU suggested the diagnosis of HCC in all five patients. Thus, to avoid this complication, PPGU should not be performed when the nodule is strongly suspected of being HCC by imaging tests. Some radiologists emphasize that PPGU is generally contraindicated.4,5 Whenever biopsy of a small hepatic nodule is necessary, ablation or coagulation should also be done for both the lesion and the needle tract. When a large-caliber biopsy needle is used, such procedures can be performed immediately after biopsy. Even when a definite diagnosis has not been made, it is better to err on the side of caution, and treat the hepatic lesion if HCC is strongly suspected. Because ablation or coagulation therapy of hepatic nodular lesions is safe, with little risk, the use of these procedures may be better than taking the risk of needletract implantation. Because seeding may present long after PPGU and even after coagulation of the needle tract,6 attention to the needle tract must be paid during follow-up.1 Needle-tract implantation should be ruled out when tumor markers increase and hepatic disease is well controlled. Some authors have reported that seeding does not affect prognosis. Our patients did well after treatment of the local disease. Moreover, because resection can be performed safely, when seeding, unfortunately, is detected, surgical resection should be done.6,7

Treatment with STI571, a tyrosine kinase inhibitor, for gastrointestinal stromal tumor with peritoneal dissemination and multiple liver metastases

Background. Gastrointestinal stromal tumors (GISTs) are usually refractory to standard chemotherapeutic agents. We successfully treated a patient with a tyrosine kinase inhibitor (STI571) for GIST with peritoneal dissemination and liver metastases. Methods. In a 32-year-old man presenting with abdominal pain from diffuse peritonitis, a GIST and associated perforated small intestine were resected. Multiple liver metastases were present. After therapies with microwave coagulation, ethanol injection, and local and systemic antineoplastic drugs (fluorouracil, cisplatin, tegafur-uracil, and tegafur) failed, investigational treatment with a tyrosine kinase inhibitor was initiated (STI571, 300 mg, p.o. daily). Results. Anorexia and abdominal fullness resolved within a few days. At 24 days after initiation, positron emission tomography showed a remarkable decrease in the abdominal uptake of [18F] fluorodeoxyglucose. Adverse effects of STI571, including mild alopecia and anemia, were minimal. Conclusions. The tyrosine kinase inhibitor STI571 may be effective against GISTs.

Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment

The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response (CR, N=6) or non-CR (N=39) to sorafenib were collected and were examined for FGF-FGFR gene alterations using next generation sequencing and copy number assay. FGFR mutations were detected in 5 of 45 (11.1%) cases. There was no significant association between FGFR mutation status and the response to sorafenib. We detected no increase in the FGF3/FGF4 copy number in CR cases. An FGF19 copy number gain was detected more frequently among CR cases (2/6, 33.3%) than among non-CR cases (2/39, 5.1%) (P = 0.024, Chi-squared test). In conclusion, a copy number gain for FGF19 may be a predictor of a response to sorafenib, in addition to FGF3/FGF4 amplification.