Successful treatment of metastatic bladder pleomorphic giant cell carcinoma with pembrolizumab.

INTRODUCTION: Bladder pleomorphic giant cell carcinoma is a rare and aggressive malignancy with a poor prognosis. There are no reports of immune checkpoint inhibitors for bladder pleomorphic giant cell carcinoma to date. CASE PRESENTATION: A 72-year-old man presented with gross hematuria due to multiple bladder cancers. Despite transurethral bladder resection and intravesical injection of Bacillus Calmette-Guérin, bladder cancer recurred. Nineteen months later, he underwent total cystectomy. Pathological examination revealed bladder giant cell carcinoma. Twenty-eight months later, pembrolizumab was administered due to para-aortic lymph node metastasis. Forty-four months later, the lymph node metastasis disappeared, and pembrolizumab administration was terminated. Fifty-eight months later, the patient has remained in remission at the time of writing. CONCLUSION: Immune checkpoint inhibitors manifest a therapeutic potential in bladder pleomorphic giant cell carcinoma.

[A case of huge advanced rectal cancer resected successfully after chemotherapy with mFOLFOX6].

The patient, a 75-year-old woman, who was referred to our hospital in April 2010 because of diarrhea and lower abdominal pain. Abdominal CT scan revealed a large tumor, over 8 cm in diameter within the pelvis, and colonoscopy detected rectal cancer. There was no obvious distant metastasis, although invasion to the uterus and regional lymph node metastasis was suspected. After admission, she had been suffering from tumor-accompanying symptoms such as fever, melena, and abdominal pain. Although loop sigmoid colostomy was performed, symptoms were unimproved, and the tumor had grown to 11 cm in diameter. Therefore, chemotherapy(mFOLFOX6)was started. After two courses of chemotherapy, the tumor-accompanying symptoms improved. Six courses of chemotherapy were administered, and subsequent examination revealed shrinkage of the tumor(effect judgment PR). Thirteen days after final chemotherapy, the tumor was successfully resected. Pathological diagnosis of the surgical specimen was tub2, pSI(sigmoid colon), pN0, and Stage II. The surgical margin was completely free of cancer(R0), and the histological effect of chemotherapy was judged as Grade 1b. The patient had received adjuvant chemotherapy with UFT+LV for half a year after discharge. She has been free from any sign of recurrence for 11 months. This case suggests that appropriate preoperative chemotherapy is useful for locally advanced rectal cancer.

[Successful reintroduction of mesylate imatinib after pneumonitis in two patients with gastrointestinal stromal tumor (GIST)].

We report 2 cases of successful reintroduction of mesylate imatinib for gastrointestinal stromal tumor (GIST) after drug-induced pneumonitis. Both of them were women in the fifth decade who had been medicated by mesylate imatinib about for 5 months previously, and had been given a diagnosis of imatinib mesylate-induced pneumonitis. After only cessation of that drug, symptoms and shadows on chest X-ray film improved. However, we had to reintroduce the drug because of the growth of primary tumor, so we gave half the previous dose of imatinib mesylate, with low dose prednisone. There has been no recurrence of drug related pneumonitis and effective control of the primary tumor was obtained. The evidence acquired from our cases suggests that it may be possible to reintroduce imatinib mesylate carefully by adjusting the dose with low dose prednisone in a GIST patient, without causing recurrence of drug-induced pneumonitis.

Induction of Parkinson disease-related proteins in motor neurons after transient spinal cord ischemia in rabbits.

The mechanism of spinal cord injury has been thought to be related to the vulnerability of spinal motor neuron cells against ischemia. However, the mechanisms of such vulnerability are not fully understood. We investigated a possible mechanism of neuronal death by immunohistochemical analysis for DJ-1, PINK1, and alpha-Synuclein. We used a 15-min rabbit spinal cord ischemia model, with use of a balloon catheter. Western blot analysis for DJ-1, PINK1, and alpha-Synuclein; temporal profiles of DJ-1, PINK1, and alpha-Synuclein immunoreactivity; and double-label fluorescence immunocytochemical studies were performed. Western blot analysis revealed scarce immunoreactivity for DJ-1, PINK1, and alpha-Synuclein in the sham-operated spinal cords. However, they became apparent at 8 h after transient ischemia, which returned to the baseline level at 1 day. Double-label fluorescence immunocytochemical study revealed that both DJ-1 and PINK1, and DJ-1 and alpha-Synuclein were positive at 8 h of reperfusion in the same motor neurons, which eventually die. The induction of DJ-1 and PINK1 proteins in the motor neurons at the early stage of reperfusion may indicate oxidative stress, and the induction of alpha-Synuclein may be implicated in the programmed cell death change after transient spinal cord ischemia.

Optimal region-of-interest settings for tissue characterization based on ultrasonic elasticity imaging.

Pathologic changes in arterial walls significantly influence their mechanical properties. We have developed a correlation-based method, the phased tracking method, for measurement of the regional elasticity of the arterial wall. Using this method, elasticity distributions of lipids, blood clots, fibrous tissue and calcified tissue were measured by in-vitro experiments of excised arteries (mean +/- SD: lipids, 89 +/- 47 kPa; blood clots, 131 +/- 56 kPa; fibrous tissue, 1022 +/- 1040 kPa; calcified tissue, 2267 +/- 1228 kPa). It was found that arterial tissues can be classified into soft tissues (lipids and blood clots) and hard tissues (fibrous tissue and calcified tissue) on the basis of their elasticity. However, there are large overlaps between elasticity distributions of lipids and blood clots and those of fibrous tissue and calcified tissue. Thus, it was difficult to differentiate lipids from blood clots and fibrous tissue from calcified tissue by setting a threshold for a single elasticity value. Therefore, we previously proposed a tissue classification method using the elasticity distribution in each small region. In this method, the elasticity distribution of each small region of interest (ROI) (not a single pixel) in an elasticity image is used to classify lipids, blood clots, fibrous tissue and calcified tissue by calculating the likelihood function for each tissue. In the present study, the optimum size of the ROI and threshold T(o) for the likelihood function were investigated to improve the tissue classification. The ratio of correctly classified pixels to the total number of classified pixels was 29.8% when the size of a small region was 75 microm x 300 microm (a single pixel). The ratio of correctly classified pixels became 35.1% when the size of a small region was 1,500 microm x 1,500 microm (100 pixels). Moreover, a region with an extremely low likelihood with respect to all tissue components was defined as an unclassified region by setting threshold T(o) for the likelihood function to 0.21. The tissue classification of the arterial wall was improved using the elasticity distribution of a small region whose size was larger than the spatial resolution (800 microm x 600 microm) of ultrasound. In this study, the arteries used in construction of the elasticity databases were classified into each tissue using the constructed elasticity databases. Other arteries, which are not used for constructing the elasticity databases, should be classified in future work to thoroughly show the effectiveness of the proposed method.

[Ultrasonic measurement of arterial wall for quantitative diagnosis of atherosclerosis--elasticity imaging of arterial wall and atherosclerotic plaque].

To provide useful information for the diagnosis of atherosclerosis in addition to the imaging of morphology using B-mode ultrasonography, we have developed a method, namely, the phased-tracking method, to measure the small change in the thickness of the arterial wall due to the heartbeat. This change in thickness corresponds to strain due to the change in internal pressure, and the elasticity of the arterial wall is obtained by the simultaneous measurement of the change in thickness and pulse pressure. Furthermore, an elasticity image can be classified into tissue components using the reference data obtained by in vitro experiments because the elastic properties are different among the tissue components in the arterial wall. We have measured the elasticity distributions of lipids, blood clots, fibrous tissue, and calcified tissue in vitro. From these results, it was found that arterial tissues can be classified into soft tissues (lipids, blood clots) and hard tissues (fibrous tissue, calcified tissue) on the basis of their elasticity. However, it is difficult to differentiate lipids from blood clots and fibrous tissue from calcified tissue because the elasticity distributions of these components overlap each other. To overcome this problem, we proposed a tissue classification method in which, the elasticity distribution of each small region of interest (not a single pixel) in an elasticity image was used in the classification of lipids, blood clots, fibrous tissue, and calcified tissue, respectively. Tissue classification results obtained by this method showed good agreement with the pathological image of the corresponding section.

Predictive value of N-acetylglucosaminyltransferase-V for superficial bladder cancer recurrence.

PURPOSE: GnT-V is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine on asparagine (N)-linked oligosaccharides of cell proteins. GnT-V expression has been closely related to malignant potentials in colon cancer, brain cancer and hepatocellular carcinoma. We determined whether GnT-V expression is predictive of superficial bladder cancer recurrence. MATERIALS AND METHODS: The cohort comprised 60 consecutive patients with first time superficial bladder cancer treated with transurethral resection. None of the patients received prophylactic intravesical therapy until recurrence. Paraffin embedded tumor specimens were immunohistochemically examined by the avidin-biotin peroxidase method using monoclonal antibody against GnT-V. Kaplan-Meier survival curves were generated to determine disease-free survival. Univariate and multivariate analyses were done to compare GnT-V expression to other clinical and pathological variables. RESULTS: GnT-V expression correlated inversely with tumor grade and stage. The positive incidence of GnT-V in G1 to G3 tumors was 7 of 9 (78%), 21 of 43 (49%) and 3 of 8 (38%), respectively. GnT-V was positive in 26 of 44 cases of pTa (60%) and in 5 of 16 of pT1 (31%) disease. The 31 patients with positive GnT-V expression had significantly higher disease-free survival than the 29 with negative GnT-V expression (log rank test p = 0.0034). Multivariate analysis revealed that patient age, pT, grade and negative GnT-V expression were independent predictors of recurrence (p = 0.015, 0.001, 0.019 and 0.011, respectively). CONCLUSIONS: Immunohistochemical detection of GnT-V is an independent predictor of superficial bladder cancer recurrence.

Electrophysiological and histopathological characteristics of progressive atrioventricular block accompanied by familial dilated cardiomyopathy caused by a novel mutation of lamin A/C gene.

UNLABELLED: Conduction defect caused by lamin A/C gene mutation. INTRODUCTION: Mutations of lamin A/C gene (LMNA) cause dilated cardiomyopathy (DCM) with atrioventricular (AV) conduction defect, although the electrophysiological and histological profiles are not fully understood. METHODS AND RESULTS: We analyzed a large Japanese family (21 affected and 203 unaffected members) of DCM with AV block. The responsible LMNA mutation of IVS3-10A>G was novel and caused an aberrant splicing. The first clinical manifestation was low-grade AV block or atrial fibrillation (AF), which developed in affected members aged >or=30 years. We observed that the AV block progressed to third-degree within several years. The electrophysiological study of the four affected members revealed an impairment of intra-AV nodal conduction. Because of advanced AV block, pacemakers were implanted in 14 out of 21 affected members at the mean age of 44 years. Three affected members died suddenly and two affected members died of heart failure and/or ventricular tachycardia (VT) even after the pacemaker implantation. Postmortem examination showed conspicuous fibrofatty degeneration of the AV node. Endomyocardial biopsies showed remarkably deformed nuclei and substantial glycogen deposits in the subsarcolemma. CONCLUSION: The clinical phenotype in this family was characterized by (1) the first manifestation of the prolonged PQ interval or AF in adolescence, (2) progressive intra-AV nodal block to the third degree in several years, and (3) progressive heart failure after pacemaker implantation. Histological study revealed preferential degeneration at the AV node area and novel cellular damages in the working myocardium.

[Imaging of elasticity distribution in arterial wall by transcutaneous ultrasound and electronic staining].

Knowledge of the physical properties of atherosclerotic plaque is essential when evaluating its vulnerability in a clinical setting. Such knowledge, however, is still difficult to obtain with the various approaches developed to date. This paper describes a novel noninvasive method (phased tracking method) for measuring minute change in thickness of each of the multiple layers of the arterial wall during one cardiac cycle. Such minute change in thickness less than 100 microns of the arterial wall cannot be measured by conventional ultrasound B-mode or M-mode images. A method for evaluation of the regional elastic modulus in the circumference direction, E theta, from the resultant change in wall thickness is also described. This method was applied to in vivo experiments in subjects with hyperlipemia and normal subjects. The spatial distribution of the regional elastic moduli, E theta, was evaluated for the carotid atherosclerotic plaques. By comparing the pathological findings with the distribution of elasticity, average elasticity of lipid and that of a mixture of smooth muscle and collagen fiber could be determined. Based on these reference parameters, each point was statistically categorized as lipid, mixture, or other. Thus, the plaque was electronically stained using transcutaneous ultrasound. By applying this method to the common carotid arteries, the presence of thin collagen fiber was clarified along the arterial axis for normal subjects, while soft inclusion of lipid was found for every plaque in subjects with hyperlipidemia. This novel method offers potential as a diagnostic technique for detection of plaque vulnerability with high spatial resolution.

Elasticity imaging of atheroma with transcutaneous ultrasound: preliminary study.

BACKGROUND: Knowledge of the physical properties of atherosclerotic plaque is essential when evaluating its vulnerability in a clinical setting. Such knowledge, however, is still difficult to obtain with the various approaches developed to date. METHODS AND RESULTS: This article describes a noninvasive method for evaluating the regional elasticity (the elastic modulus in the circumferential direction) of tissue surrounding atherosclerotic plaque in which a novel phased tracking method is applied to measure minute changes in thickness of each of the multiple layers of the arterial wall during one heartbeat. By comparing the pathological findings with the distribution of elasticity, average elasticity of lipid and that of a mixture of smooth muscle and collagen fiber can be determined. On the basis of these reference parameters, each point is statistically categorized as lipid, mixture, or other. Thus, the plaque is electronically stained using transcutaneous ultrasound. By applying the method to the common carotid arteries, the presence of thin collagen fiber was clarified along the arterial axis for normal subjects, whereas soft inclusion of lipid was found for every plaque in subjects with hyperlipidemia. CONCLUSIONS: This novel method offers potential as a diagnostic technique for detection of plaque vulnerability with high spatial resolution.

Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction?

OBJECTIVE: Based on currently available clinical evidence, we should use high-dose angiotensin converting enzyme inhibitor (ACE-I) for patients with acute myocardial infarction (MI), initiating it at incremental doses to avoid excessive hypotension. Recent animal studies with acute MI models failed to demonstrate the superiority of the combination therapy of ACE-I and angiotensin receptor blocker (ARB) to high-dose ACE-I treatment with comparable blood pressure reductions, which however might be attributed to the initiation of the targeted doses from the beginning. The aim of this study was to compare the effect of increasing the dose of ACE-I with that of adding ARB following a relatively low dose of ACE-I on the survival and left ventricular (LV) remodeling after MI. METHODS: Rats underwent left coronary artery ligation and were treated with either ACE-I temocapril (5 mg/kg/day) or vehicle for 2 weeks, which was initiated 3 days after the surgery. The rats treated with temocapril were further randomly assigned to receive either high-dose temocapril (10 mg/kg/day) or combination therapy (temocapril 5 mg/kg/day+olmesartan 2.5 mg/kg/day), which was continued for another 6 weeks. RESULTS: Both treatments similarly reduced the blood pressure, improved survival and ameliorated LV enlargement. In contrast, several parameters of LV function were significantly ameliorated only by the high-dose ACE-I but not by the combination therapy. CONCLUSIONS: After the initiation of a relatively low dose of ACE-I in acute MI, increasing the dose of ACE-I or adding ARB may equally improve survival and LV remodeling in the setting of an equal hypotensive effect. Further study with a longer treatment protocol is required to determine whether the several favorable effects on LV function elicited only by the high-dose ACE-I treatment provide further beneficial effects on survival and LV remodeling compared with the combination therapy.

Epithelial-myoepithelial carcinoma of the parotid gland.

We report a rare case of epithelial-myoepithelial carcinoma (EMC) of the parotid gland. A 70-year-old man presented with a 4-months-history of right-sided subauricular swelling. Computed tomographic scans revealed a well-defined mass with cystic lesion, measuring about 40 mm in diameter, in the right parotid gland. Because the tumor occupied superficial lobe, he underwent superficial parotidectomy with preservation of the facial nerve. On the basis of the histological and immunohistochemical findings, the tumor was diagnosed as EMC. His post-operative course was uneventful, and he is currently free from disease 6 months after surgery. Diagnosis, clinical behavior and treatment of EMC are reviewed from perusal of the literature.

Prevalence of drug-resistance-associated mutations in antiretroviral drug-naive Zambians infected with subtype C HIV-1.

The ability of HIV-1 to evolve resistance to antiretroviral drugs leads to treatment failure. By nucleotide sequencing of HIV-1 subtype B isolates, amino acids responsible for drug resistance have been identified. Less information is available, however, on the extent and distribution of these amino acids in HIV-1 nonsubtype B viruses circulating mainly in developing countries. More HIV-infected patients in the developing world are now using antiretroviral drugs, and hence there is a need to monitor drug resistance mutations in HIV-1 non-subtype B viruses. This study examines the prevalence of drug resistance mutations in 28 antiretroviral drug-naive HIV-1-infected Zambians. HIV-1 proviral DNA was extracted from peripheral blood mononuclear cells. The region encompassing gag p17 to env C2-V3-C3 was amplified by the polymerase chain reaction followed by direct sequencing. Sequence analyses for drug resistance-associated mutations in th e protease and reverse transcriptase genes, and HIV-1 subtyping, were done. Overall, 92.8% of the generated sequences were HIV-1 subtype C. The generated sequences revealed only secondary associated, but no primary, drug-resistance mutations The most frequent secondary mutations in the protease and RT genes were, respectively, I93L(91.7%), L89M (79.2%), M3611V (79%, 4.2%), and R211K (70.8%), S48T (62.5%). The atypical residues M41N (3.6%) and D67A (3.6%) were detected in the RT gene. This study reveals many naturally occurring polymorphisms in HIV-1 subtype C isolates from antiretroviral drug-naive individuals. Such polymorphisms could lead to rapid treatment failure and development of drug-resistant HIV-1 mutants in individuals undergoing antiretroviral therapy.

A case of solitary fibrous tumor of the parotid gland: review of the literatures.

We report a rare case of solitary fibrous tumor of the parotid gland. A 47-year-old woman presented with a 3-year-history of left-sided subauricular swelling. Computed tomographic scans and magnetic resonance images revealed a well-defined and dumbbell-shaped mass, measuring about 30 mm in its greatest dimension, in the left parotid gland. Because the tumor occupied both superficial and deep lobes of the gland, she underwent total parotidectomy with preservation of the facial nerve. The microscopic finding showed short-spindle and ovoid cells arranged in a haphazard pattern with interspersed thin collagen fibrils. Immunohistochemically, the tumor cells were strongly positive for CD34, bcl-2 and vimentin, whereas stains for S-100, cytokeratin, smooth muscle actin, collagen type IV and CD117 (KIT) were negative. On the basis of these findings, the tumor was diagnosed as solitary fibrous tumor. Her post-operative course was uneventful, and she is currently free from disease 14 months after surgery. Diagnosis, clinical behavior and treatment of solitary fibrous tumor are reviewed from perusal of the literature.

Anaplastic ganglioglioma with sarcomatous component: an immunohistochemical study and molecular analysis of p53 tumor suppressor gene.

The present case report describes a case of ganglioglioma with a distinct sarcomatous component in the left temporal lobe of a 59-year-old Japanese man. Neoplastic neuroglial tissue contained both benign and anaplastic glial components with a MIB-1 labeling index of 0.1% and 12.0%, respectively. Sarcomatous tissue adjacent to the anaplastic glial tissue was dominated by pleomorphic fibroblastic cells with a MIB-1 labeling index of 10.8%. They were immunoreactive for smooth muscle actin, type IV collagen, and alpha 1 antitrypsin, but not for desmin and CD34. Interestingly, some of the sarcomatous cells were double-positive for smooth muscle actin and GFAP. The p53 protein had accumulated in the anaplastic astrocytes and sarcomatous cells, but direct DNA sequencing of PCR products failed to detect any mutation in the p53 gene (from exon 4 to exon 10).

Effect of angiotensin converting enzyme inhibition on myocardial phosphoinositide metabolism visualised with 1-[1-11C]-butyryl-2-palmitoyl-rac-glycerol in myocardial infarction in the rat.

We recently reported that myocardial phosphoinositide (PI) metabolism can be visualised by 1-[1-11C]-butyryl-2-palmitoyl-rac-glycerol (11C-DAG) in rats with myocardial infarction (MI). Angiotensin II, the receptors for which are expressed predominantly in infarcted areas with active fibrogenesis rather than in non-infarcted regions, is involved in the upstream signalling systems of PI metabolism and plays an important role in the process of left ventricular (LV) remodelling after MI. We therefore hypothesised that the distribution of 11C-DAG after MI may be affected by the inhibition of angiotensin converting enzyme, which is one of the most important factors in the development of LV remodelling after MI. Rats were injected with 11C-DAG after 3 or 10 weeks of treatment with captopril or no treatment following coronary artery ligation, and quantitative autoradiography was performed. Cells occupying the infarcted region were identified by immunohistochemistry. Compared with untreated rats, treatment with captopril for 3 weeks after MI elicited a reduction in the 11C-DAG uptake in the infarcted region (P<0.05) but not in the non-infarcted region, and was associated with a 22% decrease in the heart weight/body weight ratio. The thallium-201 distribution in the infarcted area was similarly low in the rats with and rats without the 3-week captopril treatment after MI. Abundant macrophages and myofibroblasts occupied the infarcted area in both rats with and rats without the captopril treatment for 3 weeks after MI. The 11C-DAG radioactivity in the infarcted region in the untreated rats was lower 10 weeks after MI than 3 weeks after MI (P<0.01). This finding was in agreement with the results of immunohistochemistry demonstrating that the number and size of macrophages and myofibroblasts were remarkably reduced in rats 10 weeks after MI compared with 3 weeks after MI. Captopril treatment for 10 weeks after MI did not decrease the 11C-DAG radioactivity in the infarcted area further. These data suggest that 11C-DAG is useful for visually detecting regions with activated PI metabolism after MI, and that captopril reduces PI metabolism in the infarcted region in the relatively early phase of MI, which might contribute to the attenuation of ventricular remodelling.

A case of angioglioma composed of astrocytoma with a papillary growth pattern: immunohistochemical and ultrastructural studies.

We report a case of a large cystic astrocytoma associated with arteriovenous malformation in the right cerebral hemisphere of a 16-year-old boy. Neuroimaging showed large abnormal vessels with flow voids and arteriovenous shunt around the cystic lesion. Histologically, the cyst wall was formed by abnormal vasculature and clusters of glial cells forming a papillary growth pattern. The abnormal vasculature consisted of dilated vein-like vessels and medium-sized arteries with incomplete media, and was diagnosed as an arteriovenous malformation. Immunohistochemically, glial fibrillary acidic protein (GFAP) decorated both the perikaryon and the processes of the glial tumor cells. They were negative for epithelial membrane antigen (EMA), cytokeratin, and S-100 protein. Ultrastructurally, the tumor cells were rich in intermediate filaments, and neither cilia, microvilli, nor ependymal rosettes were verified. Based on these morphological features and the low MIB-1 labeling index of 0.8%, the glial tumor was diagnosed as astrocytoma, Grade II, according to the World Health Organization (WHO) tumor classification. An association of glioma with various types of vascular anomalies has been designated as angioglioma. A unique feature of the present case, however, is a papillary growth pattern, which is not listed in the current WHO classification of brain tumors. The recognition of the occurrence of such cases would be important in differential diagnosis of papillary ependymoma and choroid plexus papilloma.