A case of cisplatin-refractory advanced pure seminoma showing complete remission after treatment with high-dose carboplatin plus etoposide as fourth-line salvage chemotherapy.

We report the case of a patient who achieved complete remission (CR) of cisplatin-refractory metastatic pure seminoma after treatment with high-dose carboplatin and etoposide (CE) with peripheral blood stem cell transplantation as fourth-line chemotherapy. A 38-year-old man was diagnosed with advanced pure seminoma (pT3N3M1aS3). In the international germ cell consensus classification, his prognosis was classified as intermediate. He was treated with high-dose CE as fourth-line chemotherapy after treatment with BEP, VeIP, and TIN. After two cycles of high-dose CE, the concentrations of T-HCG and other tumor markers showed normal levels. A CT scan and PET-CT showed that the lymph node swelling had disappeared and there was no uptake. The CR has continued for 27 months after the treatment. High-dose CE might be less toxic and have a better prognostic outcome than other treatments as salvage chemotherapy for patients with cisplatin-refractory advanced testicular cancer.

[A case of primary testicular diffuse large B-cell lymphoma with a p53 gene point mutation].

A 52-year-old man with bilateral swelling in the scrotum was referred to the department of urology in our hospital in January 2013. Pathological examination of the scrotum revealed diffuse large B-cell lymphoma(DLBCL). Immunohistochemical staining revealed p53 overexpression, and polymerase chain reaction-single strand conformation polymorphism(PCRSSCP) revealed a point mutation in exon 7 of the p53 gene. Rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone(R-CHOP)therapy and intrathecal prophylaxis were initiated. After three courses of R-CHOP therapy, high-dose cytarabine was administered, followed by peripheral blood stem cell harvesting. Busulfan, etoposide, and Ara-C(BEA)therapy was then administered, followed by autologous peripheral blood stem cell transplantation(auto- PBSCT). Primary testicular lymphoma(PTL)is a rare, clinically aggressive form of extranodal lymphoma, and there is a high incidence rate of relapse in the central nervous system(CNS). The vast majority of cases are histologically DLBCL. The p53 mutation is an independent marker of poor prognosis in patients with DLBCL treated with R-CHOP therapy. Our patient has been disease free for 17 months after auto-PBSCT with high-dose chemotherapy, which results in a greater level of penetration into the CNS.

Anti-erythropoietin receptor antibody-associated pure red cell aplasia accompanied by Coombs-negative autoimmune hemolytic anemia in a patient with T cell/histiocyte-rich large B cell lymphoma.

A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal α/ß and γ/δ T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.

Ocular toxicity of benzalkonium chloride homologs compared with their mixtures.

This study was performed to assess the in vivo ocular toxicity of benzalkonium chloride (BAK) homologs compared with commercially available BAK (BAK mixture) and to assess the ocular toxicity of BAK homolog after repeated ocular application. Rabbit eyes were examined by ophthalmology and scanning electron microscopy (SEM) after 10 applications of BAK homologs with C12 (C12-BAK) and C14 (C14-BAK) alkyl chain lengths and a BAK mixture at concentrations of 0.001% (w/v), 0.003% (w/v), 0.005% (w/v), 0.01% (w/v) and 0.03% (w/v). The ocular toxicity of C12-BAK to rabbit eyes was examined by ophthalmology and histopathology after repeated ocular application for 39 weeks. In addition, the antimicrobial activities of C12-BAK and C14-BAK against A. niger, S. aureus and P. aeruginosa were assessed. Ocular toxicity of C12-BAK was less than those of the BAK mixture and C14-BAK. No ocular toxicity was noted after ocular application of 0.01% C12-BAK to rabbits for 39 weeks. C12-BAK showed antimicrobial activities at a concentration of 0.003%. These results suggest that the use of C12-BAK to replace BAK mixture as a preservative in ophthalmic solutions should be considered in order to reduce the incidence of the corneal epithelial cell injury induced clinically by BAK.

Three cases of collagenous fibroma with rim enhancement on postcontrast T1-weighted images with fat suppression.

Collagenous fibroma, also known as desmoplastic fibroblastoma, is a benign fibrous soft tissue tumor showing gradual growth, commonly without aggressive local infiltration. Today, preoperative radiological diagnosis is important to avoid over-treatment and unnecessary extensive procedures, but is difficult because diagnostic imaging findings for collagenous fibroma have not been established. We report MR imaging findings of three collagenous fibromas in correlation with their histopathology. The characteristic rim enhancement on post-contrast T1-weighted images with fat suppression was present in all three cases, and we consider this to represent the difference in vascularity between the outer capsule-like fibrous tissue and the inside of the tumor.

Chondromyxoid fibroma of the rib with prominent exophytic configuration.

Chondromyxoid fibroma (CMF) of the rib is exceedingly unusual and few detailed image findings have been reported. Plain radiograph, computed tomography (CT), and magnetic resonance (MR) imaging findings and pathological aspects of a case of CMF of the right 2nd rib in a 15-year-old woman are reported, which was difficult to diagnose preoperatively. Though it is challenging to diagnose CMF preoperatively, it is important to be aware that CMF can exhibit atypical prominent exophytic features in unexpected locations such as the ribs.

Suppressive effect of sulindac on branch duct-intraductal papillary mucinous neoplasms.

BACKGROUND: When considering surgery for branch duct-intraductal papillary mucinous neoplasms (BD-IPMNs) with suspected malignancy, it should be recognized that these lesions are frequently multifocal and are usually found in elderly patients with potential comorbidities that could affect the outcome of surgery. Clinical trials of chemoprevention have been conducted for a wide variety of malignancies. METHODS: Twenty-two BD-IPMN patients participated in the trial at our institution from June 2004 to January 2007. Ten of the 22 patients who rejected surgical therapy although their lesions or clinical symptoms met the criteria for surgical resection of the International Association of Pancreatology guidelines were assigned to the treatment group. Sulindac (150 mg twice daily) and omeprazole (20 mg once daily) were administered to these patients for 18 months. The remaining 12 patients comprised the control group. Branch duct diameter and mural nodule heights were monitored by either magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) and by endoscopic ultrasonography (EUS). RESULTS: Both branch duct diameter and mural nodule height of BD-IPMNs in the treatment group were significantly reduced, while those in the control group were unchanged. Immunohistochemical staining for cyclooxygenase-1 and -2 was negative in hyperplasia, adenoma and carcinoma portions of resected pancreatic specimens but was clearly positive for glutathione-S-transferase pi (GST-pi), suggesting that GST-pi is a putative target molecule for sulindac. CONCLUSIONS: Although a larger scale randomized controlled study is needed in future, the present results suggest the promise of chemoprevention of carcinoma derived from BD-IPMNs by sulindac.

Differential diagnosis of benign or malignant intraductal papillary mucinous neoplasm of the pancreas by multidetector row helical computed tomography: evaluation of predictive factors by logistic regression analysis.

OBJECTIVE: The purpose of this study is to evaluate predictive factors for discriminating benign from malignant intraductal mucin-producing neoplasm (IPMN) of the pancreas on multidetector row computed tomography (MDCT). MATERIALS AND METHODS: Fifty-three patients with IPMN underwent MDCT, and the imaging and pathological findings were evaluated. In patients with branch duct-type tumors, sex and age of the patient, location, shape, size and multiplicity of the cystic lesion, presence of mural nodule, and maximum diameter of main pancreatic duct (MPD) dilatation were evaluated by logistic regression analysis. RESULTS: Tumors were classified as main duct-type (n = 7) and branch duct-type (n = 46). Among main duct-type tumors, all 7 lesions were diagnosed as malignant. Among 46 lesions of branch-type IPMN, 8 lesions were malignant, and 38 lesions were benign. On adjusted logistic regression analysis, combination factor of main duct dilatation and mural nodule or large cystic size had statistical significance for the risk of malignancy in branch duct-type IPMN. CONCLUSIONS: Main duct-type IPMN is highly suggestive for malignancy. Combination factors of main ductal dilation and mural nodule, and main ductal dilation, and large cystic tumor size are thought to be predictive factors for malignant branch-type IPMN.

[Superior mesenteric and portal vein thrombosis in a polycythemia vera patient with JAK2 mutation].

A 47-year-old woman was admitted to our hospital in December 1994 with polycythemia. The patient's red blood cell volume was 33 ml/kg and bone marrow cytology was able to rule out other myeloproliferative diseases such as chronic myelogenous leukemia, essential thrombocytosis and myelofibrosis. The patient was diagnosed as having polycythemia vera. She had undergone only phlebotomy until 1999 when the thrombocytosis appeared, subsequent to which she was treated with oral hydroxyurea. However, in March 2006, she developed upper abdominal pain and was admitted to our hospital on March 14th, 2006. Computed tomography scan revealed thromboses in the portal and superior mesenteric veins. Anticoagulation therapy delivered intravenously via the superior mesenteric vein dramatically improved her symptoms and liver function. She is currently on anticoagulation therapy in our outpatient clinic.

Human herpesvirus-6 hepatitis associated with cyclosporine-A encephalitis after bone marrow transplantation for chronic myeloid leukemia.

A 31-year-old man referred to our hospital for treatment of his chronic myeloid leukemia (CML) in the first chronic phase by bone marrow transplantation. We pretreated him with cyclophosphamide and total body irradiation and bone marrow transplantation (BMT) was carried out. On day 31, the engraftment was confirmed and on day 52, acute graft versus host disease (GVHD) was observed. On day 189, he lost consciousness due to cyclosporine A-induced leukoencephalopathy and 375 mg cyclosporine A was changed to 100 mg prednisolone. On day 199, liver dysfunction (AST 410 IU/L, ALT 557 IU/L, gammaGTP 385 IU/L, ALP 363 IU/L, D-Bil 0.3 mg/dl) developed and a liver biopsy was performed. PCR analysis of DNA from the liver biopsy specimen was positive for HHV-6 and immunostaining using anti-HHV-6 and anti-HHV-6b antibodies showed positive staining in the cytosol of hepatocytes. No other viruses were found to induce hepatitis. From these results, he was diagnosed as having HHV-6 hepatitis and it was successfully treated with gancyclovir (GCV) administration.

Radiation dose to patients and radiologists during transcatheter arterial embolization: comparison of a digital flat-panel system and conventional unit.

OBJECTIVE: The objective of our study was to evaluate the exposure doses to patients and radiologists during transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) using a new angiographic unit with a digital flat-panel system. SUBJECTS AND METHODS: Doses were assessed for 24 procedures: 12 using a new unit with a digital flat-panel system and 12 using a conventional unit. Doses to patients' skin were evaluated with thermoluminescent dosimeters behind the left, middle, and right portions of the liver. The doses to the radiologists were measured by an electronic personal dosimeter placed on the chest outside a lead protector. The maximal skin doses to the patients and the dose equivalents, Hp(0.07), to the radiologists were compared between the two procedure groups with each angiographic unit. RESULTS: For procedures with the new unit, the mean maximal skin dose to the patients was 284 +/- 127 (SD) mGy (range, 130-467 mGy), and Hp(0.07) to the radiologists was 62.8 +/- 17.4 muSv. For procedures with the conventional unit, the maximal skin dose to the patients was 1,068 +/- 439 mGy (range, 510-1,882 mGy), and Hp(0.07) to the radiologists was 68.4 +/- 25.7 muSv. The maximal skin dose to the patients was significantly lower with the new unit than with the conventional unit (p < 0.0005). There was no significant difference in the Hp(0.07) to the radiologists between the two procedure groups. CONCLUSION: The new digital flat-panel system for angiographic imaging can reduce the radiation dose to patients' skin during TAE for HCC as compared with the conventional system.

Augmentation of antitumor effects of p53 gene therapy by combination with HDAC inhibitor.

We have previously shown that the HDAC inhibitors (HDACI) activate the p53 molecule through acetylation of 320 and 373 lysine residues, upregulate PIG3 and NOXA and induce apoptosis in cancer cells expressing wild and pseudo-wild type p53 genes (Terui T, et al. Cancer Res 2003; 63:8948-54). It has also been reported that expression of the Coxsackie adenovirus receptor and subsequent transfection efficiency of the adenovirus in cancer cells were enhanced by HDACI treatment. In this study, we extended these observations to explore the combination effect of adenoviral vector carrying wild type p53 (Ad-p53) gene therapy with a HDACI, sodium butyrate (SB), on xenografted human gastric cancer cells (KATO-III) and hepatocellular carcinoma cells (HuH7) in nude mice. We first confirmed an increased expression of Coxsackie adenovirus receptors with an associated increment of transgene (X-gal) expression by SB treatment in KATO-III cells. We then injected Ad-p53 into subcutaneous tumors of KATO-III and HuH7 combined with intraperitoneal administration of SB and found a significantly higher growth suppressive effect than single treatments of each. Even a complete regression of tumors was observed in three of five mice treated with this combination while with single treatment no tumor regression was observed. Tumors treated with the combination showed higher numbers of TUNEL positive cells than those treated with a single modality. Moreover, necrotic changes were more evident in tumors treated with the combination than separately, a compatible finding to the observation that vascularity revealed by CD34 staining was poorer in tumors treated with the combination than those treated with p53 gene or SB alone. This was further supported by the finding that BAI-1 (brain specific angiogenesis inhibitor-1), an inhibitor of vascularization, was induced by SB treatment in KATO-III and HuH7 cells transfected with Ad-p53. Thus SB was shown to be an efficient potentiator of p53 gene therapy for cancer.

Localization of islet-cell hyperplasia: value of pre- and intraoperative arterial stimulation and venous sampling.

Arterial stimulation and venous sampling was effective in the localization of Beta-cell hyperplasia of the pancreas in the islets of Langerhans in an 84-year-old woman. The patient presented with repeated episodes of unconsciousness and hypoglycemia. She was first suspected of having insulinoma, but diagnostic imaging failed to reveal any tumors. Arterial stimulation and venous sampling (ASVS) and percutaneous transhepatic portal venous sampling (PTPS) were performed to localize the tumor. By ASVS, increases in immuno reactive insulin (IRI) were noted in renal vein blood samples (because a splenorenal shunt was present) after splenic arterial stimulation and venous sampling, and PTPS revealed a stepup in IRI from splenic venous blood samples. Preoperative diagnosis suggested Beta-cell hyperplasia in the pancreas tail. Intraoperative ultrasound failed to find a tumor. Intraoperative ASVS showed the site of increase IRI as the pancreas tail, so distal pancreatectomy and splenectomy were performed. However, hypoglycemia was observed constantly after this operation. Relaparotomy, causing additional resection, was conducted to confirm the precise location and to remove the residual Beta-cell hyperplasia of the pancreas. At the second resection, the existing part of Beta-cell hyperplasia was confirmed through intraoperative ASVS, and additional resection of the pancreas body and neck was performed. At this time, complete removal of the residual Beta-cell hyperplasia was confirmed through ASVS. The hypoglycemia and impaired consciousness disappeared after the operation, and the patient's blood sugar level was maintained at a normal level. Pathological findings revealed islets of Langerhans hyperplasia extending to 1 cm in the pancreas tail region. We conclude that pre- and intraoperative ASVS is a useful test for Beta-cell hyperplasia, which is difficult to diagnose through ordinary imaging techniques.

A case of Gardner syndrome with a mutation at codon 1556 of APC: a suggested case of genotype-phenotype correlation in dental abnormality.

A 25-year-old man with suspected Gardner syndrome was introduced to our hospital by a dentist who, during examination of the patient, had found dental dysplasias and multiple osteomas of the jaw. Radiographs, endoscopy and biopsies revealed adenomatous polyposis of the colon. Genetic analysis of peripheral lymphocytes revealed a one-base deletion at codon 1556 in exon 15 of APC, which caused a frame shift and a premature stop at codon 1564. The pedigree analysis demonstrated five patients in his family who presented with dental abnormality and osteomas in addition to adenomatous polyposis of the colon. Although the relationship between the location of APC mutations and dental abnormalities remains controversial, this case supports the hypothesis that a mutation at around codon 1556 of APC is closely associated with dental abnormality and osteomas.

Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors.

Two controversial issues regarding p53 are whether it is involved in apoptosis induction of tumor cells by a histone deacetylase (HDAC) inhibitor and, given that p53 is indeed involved, which genes of acetylated p53 targets are responsible for giving rise to apoptotic death. We, in the present study, first confirmed that some substantial extent of apoptotic cell death was seen when p53-deficient cells (KATO-III) were transfected with wild-type p53 and treated with sodium butyrate (SB) or trichostatin A. By Western blotting, using specific antibodies, we then demonstrated that residues 320, 373, and 382 lysines of p53 were acetylated in KATO-III cells transfected with wild-type p53 (KATO-III/p53) treated with a HDAC inhibitor. However, as revealed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining, only those KATO-III cells transfected with K320R p53 or K373R p53 became insensitive to the HDAC inhibitor, suggesting that these two residues of p53 may be essential for HDAC inhibitor-induced apoptosis, whereas others such as K382R p53 may not. Furthermore, reverse transcription-PCR demonstrated that among various p53-related proapoptotic genes, expression of PIG3 and NOXA were clearly enhanced by SB treatment in KATO-III/p53 cells but not in KATO-III/K320R or KATO-III/K373R cells. Finally, we revealed that apoptosis could be evoked by SB even in cells where p53 mutations occur at residues other than 320 lysine or 373 lysine (TMK-1 and HSC-39 cells) and that this apoptosis was significantly, although not totally, suppressed by the anti-p53 antisense. It was, therefore, concluded that acetylation of the p53 molecule at residues 320 and 373, giving rise to up-regulation of PIG3 and NOXA, is one of the mechanisms for induction of apoptosis by HDAC inhibitors in cancer cells.

Aortic and hepatic enhancement and tumor-to-liver contrast: analysis of the effect of different concentrations of contrast material at multi-detector row helical CT.

PURPOSE: To investigate the effect of different iodine concentrations of contrast material on aortic and hepatic enhancement and the detectability of hypervascular hepatocellular carcinoma (HCC) with multi-detector row computed tomography (CT) and a uniphasic contrast material injection technique. MATERIALS AND METHODS: Two hundred one patients with known or who were suspected of having HCC underwent multi-detector row CT; 58 patients with hypervascular HCC were identified. First-, second-, and third-phase scanning was started with the aortic arrival times plus 15 seconds, plus 30 seconds, and plus 105 seconds, respectively. All patients were assigned randomly into two groups. Patients in groups A and B received iopamidol with an iodine concentration of 300 mg/mL and 370 mg/mL, respectively, with the same total iodine load per patient per body weight. The liver and aorta enhancement and tumor-to-liver contrast (TLC) were measured. Depiction of hepatic arteries was evaluated visually by two radiologists. RESULTS: During the first phase, aortic enhancement was significantly (P <.01) higher in group B, with no significant difference in hepatic enhancement between the two groups. During the second phase, aortic enhancement was significantly (P <.01) higher in group A, with no significant difference in hepatic enhancement. The TLC was significantly (P <.01) higher in group B during the first phase, but there was no significant difference between the two groups during the second phase. There was no significant difference in any parameters between the two groups during the third phase. Depiction of the hepatic arteries in group B was significantly (P <.05) superior to that in group A. CONCLUSION: In the arterial phase, administration of a higher concentration of contrast material is effective for a significantly higher TLC.

Effect of superparamagnetic iron oxide-enhanced MRI of the liver with hepatocellular carcinoma and hyperplastic nodule.

PURPOSE: To evaluate the possibility of superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) of the liver in predicting the histologic grade of hepatocellular carcinoma (HCC) and differentiating HCC from benign hyperplastic nodule (HPN). MATERIALS AND METHODS: Thirty patients with 31 histologically proved HCC and HPN underwent MRI (1.5 Tesla). HCCs were graded into well-differentiated HCC (HCCw; n = 10) and moderately to poorly differentiated HCC (HCCmp; n = 15). HPN was categorized into dysplastic nodule (DN; n = 1) and focal nodular hyperplasia (FNH; n = 6). T2-weighted fast spin echo images were obtained before and after administration of SPIO. Signal-to-noise ratios (SNR) of the lesion and surrounding liver parenchyma and contrast-to-noise ratios (CNR) were calculated pre- and postcontrast study. Relative enhancement ratios (RER), also known as signal intensity reduction ratios of the lesions, were also calculated. RESULTS: HCCw, HCCmp, DN, and FNH decreased in SNR after injection of SPIO. RER of HCCw was 19.5 +/- 13.3%, that of HCCmp was 6.8 +/- 5.8%, DN was 44.0%, and FNH was 42.9 +/- 4.8%. Significant statistical differences were seen between HCCw and HCCmp and HCC and HPN in RER. HCCw, HCCmp, and DN increased in CNR, and FNH decreased in CNR, but no lesion showed a statistically significant difference in CNR. CONCLUSION: SPIO-enhanced MR images may help to predict the histologic grade of HCC and distinguish HCC from HPN.

Multidetector row helical CT of the pancreas: value of three-dimensional images, two-dimensional reformations, and contrast-enhanced multiphasic imaging.

Multidetector row helical computed tomography (MD-CT) scanning is performed for the evaluation of pancreatic tumors. Three-phase contrast study is performed using 2.5-mm collimation, and the images are reconstructed at 1.25-mm intervals. CT angiography and pancreatic duct images using two- or three-dimensional techniques are reconstructed from the volumetric data. MD-CT can perform multiphasic scanning rapidly with an optimal temporal window. CT angiography obtained with MD-CT can delineate peripancreatic vasculature with high spatial resolution and sufficient vascular enhancement. Pancreatic duct images can provide important information in assessing pancreatic disease. MD-CT has the potential to improve detection and preoperative assessment of pancreatic tumors.