Fifteen-year survival of a hepatocellular carcinoma extending into the right atrium treated by surgical resection with the heart-first approach under cardiopulmonary bypass: a case report and review of the literature.

Hepatocellular carcinoma with tumor thrombus in the inferior vena cava extending into the right atrium is rare and associated with poor prognosis in most cases. Although liver resection with thrombectomy is the only curative treatment, there is no consensus on the therapeutic options for managing these rare cases. The patient was a 67-year-old man with hepatocellular carcinoma with tumor thrombus in the right atrium. In February 2003, cavo-atrial thrombectomy was first performed using cardiopulmonary bypass with heparinization and cardiac arrest. After thrombectomy, right hepatectomy was performed. The total operative time was 10 h 48 min. Moreover, the total blood loss was 7267 mL. The patient recovered uneventfully except for right pleural effusion. He was cancer-free for approximately 9 years. A new lesion in the remnant liver was detected in March 2012. He underwent transcatheter arterial chemoembolization, followed by sequential administration of sorafenib and sunitinib. Radiation therapy was also administered. Eventually, the patient expired 6 years after recurrence. Cavo-atrial thrombectomy under cardiopulmonary bypass prior to hepatectomy for hepatocellular carcinoma with tumor thrombus in the right atrium could be performed safely. Aggressive surgery with the heart-first approach and multidisciplinary treatments even after recurrence led to long-term survival.

Malignant solitary fibrous tumor of the pancreas: a case report.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare tumors, mostly derived from connective tissue mesenchymal cells that arise from the pleura. There are very few reports of primary pancreatic SFT. Preoperative diagnosis is difficult owing to the lack of distinctive radiological findings. We report a case of pancreatic SFT with particularly rare malignant findings. CASE PRESENTATION: A 60-year-old man was referred to the hospital because of a right upper quadrant mass and abnormal liver function test results. Contrast-enhanced computed tomography (CT) showed a well-defined enhanced tumor measuring approximately 8 cm in the pancreatic head. Magnetic resonance imaging (MRI) showed T1WI hypointensity, T2WI hyperintensity, and DWI hyperintensity. The main pancreatic duct and common bile duct were dilated owing to obstruction by the tumor. The following tumor markers were mildly elevated: carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), SPan-1, and DUPAN-2. The histological diagnosis obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was negative for pancreatic ductal carcinoma, malignant lymphoma and neuroendocrine tumor, suggesting the possibility of mesenchymal tumor, but the diagnosis was not confirmed. The patient was judged suitable for surgery and underwent subtotal stomach-preserving pancreatoduodenectomy with D2 lymph node dissection. On histopathological examination of the resected specimen, infiltrating spindle-shaped cells had proliferated, containing numerous mitotic figures, with necrotic findings inside the tumor. Immunostaining was positive for cluster of differentiation-34 (CD34), B cell CLL/lymphoma-2 (Bcl-2), and signal transducer and activator of transcription (STAT6). On the basis of these findings, a diagnosis of malignant pancreatic SFT was made. The patient remains free of recurrent disease after 12 months of follow-up without adjuvant therapy and he is being carefully followed up as an outpatient. CONCLUSIONS: We experienced a case of malignant pancreatic head SFT. Immunohistochemical staining of the extracted specimens was useful for diagnosis.

Chromogenic in situ hybridization (CISH) to detect HER2 gene amplification in breast and gastric cancer: comparison with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).

The chromogenic in situ hybridization (CISH) assay, designed to detect the amplification of the HER2 gene in formalin-fixed, paraffin-embedded (FFPE) breast cancer (BC) and gastric cancer (GC) tissue specimens, was evaluated in 125 FFPE BC cases and 198 FFPE GC cases for which the HER2 status had been predetermined using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). In the 125 BC cases and the 198 gastric cases, we found a very good concordance (98.4% and 99.0%, respectively) between CISH and FISH. In particular, we evaluated the polysomy cases, as these cases often have ambiguous treatment options in clinical practice. The polysomy of chromosome 17 was defined as the presence of three or more CEP17 signals in at least 10% of the tumor cells. In the 50 BC cases and 54 GC cases displaying chromosome 17 polysomy, the concordance between FISH and CISH was 98.0% and 98.1%, respectively. These results indicate that CISH could provide an accurate and practical alternative to FISH for the clinical diagnosis of HER2 gene amplification in FFPE BC and FFPE GC samples.

Metachronous double cancer after curative resection for pancreatic adenocarcinoma: report of four cases.

We experienced four cases of metachronous double cancer after curative resection for pancreatic adenocarcinoma without the background of intraductal papillary mucinous neoplasm. Case 1, a 67-year-old Japanese female developed tongue cancer 53 months after a pylorus-preserving Whipple resection for pancreatic head adenocarcinoma. Case 2, a 66-year-old female developed multiple breast cancers 52 months after a pylorus-preserving pancreaticoduodenectomy for pancreatic head adenocarcinoma. Case 3, a 59-year-old male developed an adenocarcinoma in the remnant pancreatic head 63 months after a distal pancreatectomy for pancreatic body cancer. Case 4, a 68-year-old male developed lung cancer 92 months after a Whipple procedure for pancreatic head adenocarcinoma. Gemcitabine was administered to three patients as adjuvant chemotherapy at an average administrated dose of 38,199 mg per body surface area. Since primary pancreatic ductal adenocarcinoma is aggressive and always associated with a devastating outcome, metachronous double cancer is scarcely seen. All four cases received curative-intent surgery for each metachronous cancer and were alive for at least 20 months.

[A case of locally advanced sigmoid colon cancer invading the bladder and seminal vesicle effectively treated with preoperative mFOLFOX6].

A 77-year-old male was admitted to our hospital complaining of dyschezia. Computed tomography (CT) and colonoscopy (CF) revealed a huge sigmoid colon cancer invading the bladder and seminal vesicle. Chemotherapy with mFOLFOX6 was initiated preoperatively, and the tumor shrunk markedly after seven courses of treatment. Pelvic exenteration with negative margins was carried out. The patient is still alive and disease-free 16 months after surgery. It was suggested that mFOLFOX6 may be useful for advanced colon cancer invading other organs when used as neoadjuvant chemotherapy.

Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population.

Germline point or small frameshift mutations of the CDH1 (E-cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1-bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation-dependent probe amplification (MLPA) and RT-PCR analyses, we also found a large genomic deletion (c.164-?_387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell-cell adhesion was detected in CHO-K1 cells expressing Ile405fsX12- and Gly55fsX38-type CDH1 compared with cells expressing wild-type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC.

Genetic susceptibility to lung cancer.

Lung cancer is a highly environmental disease, but cancer researchers have long been interested in investigating genetic susceptibility to lung cancer. This paper is a historical review and provides updated perspectives on lung cancer susceptibility research. The recent introduction of easier genotyping methods and the availability of an almost complete human genome database facilitated the association study to thousands of cases and controls for millions of genetic markers. Discoveries in the field of behavior genetics, that is, the genetic aspects of smoking behavior and nicotine addiction, unexpectedly indicated that polymorphisms in the human central nervous system play an important role in eventually leading to lung cancer. These findings were achieved by using comprehensive approaches, such as a genome, transcriptome, or proteome approach, and the studies were often conducted without a hypothesis. Another-omics approach, the "adductome" or "exposome" approach to how life style information can be integrated into the framework of genetic association studies, has recently emerged. These new paradigms will influence the area of lung cancer risk evaluation in genome cohort studies.

Metachronous multiple adenocarcinomas of the pancreas.

We report a rare case of metachronous multiple adenocarcinoma of the pancreas. A 59-year-old Japanese man visited our institute for a routine workup as a hepatitis C virus carrier, resulting in detection of a 3-cm tumor in the pancreatic body by screening echogram. Results from several imaging modalities were consistent with pancreatic carcinoma. Distal pancreatectomy along with dissection of partial gastrectomy, transverse colectomy, and lymph node dissection were performed in November 2003. Histological examination confirmed a pancreatic ductal adenocarcinoma with a clear surgical margin and negative lymph node metastases. Gemcitabine was administered for 5 years, then suspended because no recurrent signs were found. The patient returned to our hospital in March 2009, with obstructive jaundice along with a 2-cm tumor in the head of the remnant pancreas. The condition of the patient was carefully investigated and extra-pancreatic metastatic lesions were not found; a pancreaticoduodenectomy was then carried out. Histological examination revealed a diagnosis of pancreatic adenocarcinoma arising from the remnant pancreas gland.

Absence of germline mono-allelic promoter hypermethylation of the CDH1 gene in gastric cancer patients.

BACKGROUND: Germline mono-allelic promoter hypermethylation of the MLH1 or MSH2 gene in families with hereditary nonpolyposis colorectal cancer has recently been reported. The purpose of this study was to evaluate if germline promoter hypermethylation of the tumor suppressor gene CDH1 (E-cadherin) might cause predisposition to gastric cancer. METHODS: We prepared two groups of samples, a group of blood samples from 22 patients with familial gastric cancer or early-onset gastric cancer selected from among 39 patients, and a group of non-cancerous gastric tissue samples from 18 patients with sporadic gastric cancer showing loss of CDH1 expression selected from among 159 patients. We then investigated the allele-specific methylation status of the CDH1 promoter by bisulfite sequencing of multiple clones. RESULTS: Although there was a difference between the methylation level of the two alleles in some samples, there was no mono-allelic promoter hypermethylation in any of the samples. CONCLUSION: These results suggest that germline mono-allelic hypermethylation of the CDH1 promoter is not a major predisposing factor for gastric cancer.

Macroscopic and histological findings in the healing process of inhalation injury.

Although many investigators reported the diagnostic and therapeutic value of bronchoscopy in the early stage of inhalation injury, few findings in the late stage of inhalation injury have been reported. We investigated histopathological changes of in trachea and bronchi after inhalation injury. Five survivors with inhalation injury underwent bronchoscopic examinations combined with biopsies from the early stage to the late stage. Although the bronchotracheal membranes improved to near normal under the bronchoscopic findings in the late or recovery stage, invasion of inflammatory cells and the capillary dilatation in the subepithelial region were still remarkable histologically. Goblet cells also increased on the surface of mucous membranes. In cases of the inhalation injury with severe burn, pulmonary edema, bronchial edema and secretions tended to be prolonged. Results suggested that continuous secretions in the respiratory tracts sometimes cause airway obstruction. Bronchoscopic and histologic findings in the healing process of inhalation injury predict long-term pulmonary functional outcome. Moreover, the aggressive pulmonary toilet seemed to be effective in removing foreign particles and accumulated secretions which also cause the inflammatory response and the obstruction in inhalation injury.

Chronic gastric anisakiasis presenting as pneumoperitoneum.

Typically, the diagnosis of gastric anisakiasis is made at endoscopy with the identification of anisakis larvae. We report a case of gastric anisakiasis presenting as pneumoperitoneum. A 70-year-old Japanese woman was admitted to our hospital with abdominal fullness and pain. Plain chest X-ray in the upright position showed the presence of free gas below the diaphragm. A tentative diagnosis of perforation peritonitis was made and an emergency laparotomy was performed. At laparotomy, a 4 cm, circumscribed red mass was noted on the anterior wall of the upper body of the stomach near the lesser curvature and a partial gastrectomy was carried out. The histological diagnosis showed a foreign body, assumed to be a part of anisakis larvae, seen in the centre of the granuloma. On the serosal aspect, there was histological evidence of peritonitis with fibrin and neutrophils. In addition, an antianisakis larvae immunoglobulin G antibody test was positive. Chronic gastric anisakiasis was suspected because of the presence of eosinophilic granuloma in the resected area and denatured anisakis larvae. Thus, we interpret this case as gastric perforation acutely based on chronic gastric anisakiasis.

CD7/CD19 double-positive T-cell acute lymphoblastic leukemia.

We report a rare case of T-cell acute lymphoblastic leukemia (T-ALL) with an aberrant phenotype. A 52-year-old man was admitted to our hospital because of lymph node (LN) swelling in the bilateral neck. A computed tomographic scan showed LN swelling in the mediastinum and a right pleural effusion. The tumor cells in the neck LN showed positivity for cytoplasmic CD3, CD7, CD19, and CD79a, whereas the tumor cells in the bone marrow (BM) showed positivity for CD10 and CD13 in addition to the former 4 antigens. The chromosomes in the BM were normal. Neither T-cell receptor gamma nor immunoglobulin heavy chain rearrangement was detected in the neck LN. We diagnosed this case as T-ALL with an aberrant phenotype and started the standard chemotherapy for ALL. The response was so effective that complete remission (CR) was easily attained. The patient is now under maintenance therapy in the first CR without hematopoietic cell transplantation.

Chromosomal numerical abnormality profiles of gastrointestinal stromal tumors.

BACKGROUND: Biological variations in and the heterogeneity of gastrointestinal stromal tumors (GISTs) are well known, but chromosomal numerical abnormality (CNA) has not been fully examined especially in this context. The aim of this study is to test CNA as a possible biological predictor of biological behavior of GISTs. METHOD: We applied microwave-assisted FISH protocol to pathological archives of GIST tumors displaying different clinical features to characterize the CNA profile of these tumors. A panel of 18 centromere enumeration probes (CEP) and 24 bacterial artificial chromosome (BAC) or P1-derived artificial chromosome (PAC) probes containing genes like Aurora kinases (AURKs) and other candidate genes involved in human carcinogenesis were used. CNA profiles, histopathological risk categorization and Ki-67 labeling indexes of 23 primary and/or metastatic GIST tumors of 12 subjects (both primary and metastatic in 7 subjects) were compared between primary GIST with and without metastases, and between metastatic and primary portions in 7 individuals. RESULTS: CNA in the primary sites was more extensive in the GISTs with recurrence and metastasis than in those without, especially as to the loss of chromosome 20 and genomic imbalance of AURKA-containing BAC probe on 20q in the cases with metastasis. The consistent loss of one allele of chromosome 14q was also noted. Interestingly, both primary and metastatic tumors in identical individuals had similar CNA profiles. CONCLUSION: The extent of CNA differed between GISTS with and without recurrence or metastasis; thus, FISH analysis of specimens from the primary sites may predict the biological behavior of this tumor.

Simultaneous imaging of membrane antigen and the corresponding chromosomal locus in pathology archives.

A new procedure for the simultaneous staining of membranous antigens, such as tyrosine kinase-type cell surface receptor HER2 (c-erbB2), and the corresponding chromosome (chromosome 17 for c-erbB2) in the same cell for use in examining pathology archives is presented. A multistep procedure involving microwave-assisted fluorescence in situ hybridization and immunofluorescence yielded cell images having c-erbB2 on the membrane and genomic signals from the chromosome 17 centromere and the c-erbB2 locus. Furthermore, a combination of microwave-assisted chromogenic in situ hybridization and immunohistochemistry found colorized signals from both chromosome 17 centromere in the nuclei and c-erbB2 on the membranes of individual cells. Quantitative image analysis further confirmed the presence of a significantly stronger c-erbB2 immunoreactivity on cells containing three or more signals from chromosome 17 than from those with less than three signals. It was possible to extend the constellation of cell surface markers and corresponding chromosomes or locus-specific makers to several other genes including CDH1. In this case, the disappearances of CDH1 expression, a CDH1 locus signal, and a centromere enumeration probe (CEP) 16 signal were simultaneously demonstrated in the less-adhesive tumor cells. Thus, it is believed that this procedure might pave the way for exploiting pathology archives for the genotype-phenotype analysis of individual cells.

Positron emission tomography with 18F-fluoro-2-deoxyglucose for the detection of recurrent ovarian cancer.

BACKGROUND: Recurrent ovarian cancer is refractory and resistant to treatment in most patients, and no effective treatment for it has been established. Starting a treatment when tumors still consist of micro foci may contribute to improvement of prognosis. Therefore, the early diagnosis of relapse is important. METHODS: Among patients with epithelial ovarian cancer in whom initial treatment achieved remission between April 1998 and December 2003, those patients in whom the cancer-related antigen (CA)125 level was increased during the subsequent follow-up period, or those who showed abnormal computed tomography (CT)/magnetic resonance imaging (MRI) findings despite normal CA125 levels, were examined by 18F-fluoro-2-deoxyglucose - positron emission tomography (FDG-PET). We compared the rates of accurate diagnosis of recurrence achieved using CT/MRI, CA125, and FDG-PET in patients with a definitive diagnosis of relapse. RESULTS: We investigated 29 patients with epithelial ovarian cancer. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of FDG-PET were 84.6% (22/26), 100% (3/3), 100% (22/22), 42.9% (3/7), and 86.2% (25/29), respectively. These values were higher than the corresponding values obtained using CT/MRI or CA125 levels. CONCLUSION: FDG-PET may be very useful for identifying sites of recurrent ovarian cancer, although this procedure had a low NPV because of the high rate of false-negative findings for micro or cystic lesions.

CD5+ diffuse large B-cell lymphoma with c-myc/IgH rearrangement presenting as primary effusion lymphoma.

We report an instructive case of diffuse large B-cell lymphoma presenting as acute heart failure. A 69-year-old human immunodeficiency virus-negative man was admitted to our hospital for general fatigue. A computed tomographic scan of the chest and abdomen showed pericardial effusion, but there was no evidence of tumor masses, lymph node enlargement, or hepatosplenomegaly. During the chemotherapy, increased lactate dehydrogenase and pleural effusion appeared. The tumor cells in the effusion showed positivity for CD5, CD19, CD20, kappa chain, and Bcl-2 and negativity for CD10 and CD23. The chromosomes showed t(8;14)(q24;q32) with c-myc/immunoglobulin (Ig)H rearrangement, and the MIB-1 index was not high (60%). Neither human herpes virus 8 nor Epstein-Barr virus DNA was detected in the cells by polymerase chain reaction. The response to chemotherapy was very poor, and the patient died 4 months after the diagnosis. A spectrum of the symptoms of CD5+ lymphoma encompasses pericardial effusion and also can accompany c-myc/IgH rearrangement.

Cystic hamartoma of the renal pelvis.

Cystic hamartoma of the renal pelvis is a rare benign tumor in the same category as mixed epithelial and stromal tumors. We present a 33-year-old woman with a solid and cystic intrarenal tumor extending into the renal pelvis. She underwent radical nephrectomy and ureterectomy under the diagnosis of renal tumor or renal pelvic tumor. Histopathologically, the tumor was composed of a biphasic proliferation of epithelial and mesenchymal elements. We believe the present case is best classified as a cystic hamartoma of the renal pelvis in the category of mixed epithelial and stromal tumors because of the coexistence of hamartomatous lesions, such as the proliferation of adipose cells and well to poorly differentiated fibromuscular lesions.

A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus.

The MYH gene encodes a DNA glycosylase involved in the excision repair of adenines paired with 8-hydroxyguanines, a major component of oxidative DNA damage, and bi-allelic germline MYH mutations have been reported to predispose individuals to multiple colorectal adenomas and carcinoma. To determine whether the MYH gene is involved in gastric carcinogenesis, we examined blood specimens from 20 Japanese familial gastric cancer (GC) patients for MYH mutations by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis followed by direct sequencing. Bi-allelic germline MYH mutations were not found in any of the specimens, but in addition to four known variants, a novel splice-site variant, IVS10-2A > G (c.892-2A > G), was found in two patients as its heterozygote. Reverse transcription-PCR analysis revealed that the IVS10-2A > G variant caused the production of an aberrant mRNA transcript encoding a truncated MYH protein. Immunofluorescence analysis showed that the wild-type MYH protein, but not the variant-type, is localized in the nucleus. We then searched for the IVS10-2A > G variant in 128 digestive tract cancer patients by PCR with confronting two-pair primers, and eight cancers from six patients with the IVS10-2A/G genotype were identified. However, no other germline MYH mutations or inactivation of the remaining wild-type allele was detected. We next tested the presumed correlation of the IVS10-2G allele with GC risk in a case-control study of 148 GC cases and 292 controls, but no significant difference in the distribution of the IVS10-2A > G variant was found between the cases and controls. Interestingly, the homozygote for the IVS10-2G allele was found in one GC case, but not in any controls. These results suggested that the ability to repair 8-hydroxyguanine in nuclear DNA may differ among Japanese individuals due to the splicing abnormality based on the MYH IVS10-2A > G variant, and that the bi-allelic IVS10-2A > G variation may be responsible for the occurrence of GC.