Search

Background and aims We developed a deep learning (DL) model for automated atherosclerotic plaque categorization using optical frequency domain imaging (OFDI) and performed quantitative and visual evaluations. Methods A total of 1103 histological cross-sections from 45 autopsy hearts were examined to compare the ex vivo OFDI scans. The images were segmented and annotated considering four histological categories: pathological intimal thickening (PIT), fibrous cap atheroma (FA), fibrocalcific plaque (FC), and healed erosion/rupture (HER). The DL model was developed based on pyramid scene parsing network (PSPNet). Given an input image, a convolutional neural network (ResNet50) was used as an encoder to generate feature maps of the last convolutional layer. Results For the quantitative evaluation, the mean F-score and IoU values, which are used to evaluate how close the predicted results are to the ground truth, were used. The validation and test dataset had F-score and IoU values of 0.63, 0.49, and 0.66, 0.52, respectively. For the section-level diagnostic accuracy, the areas under the receiver-operating characteristic curve produced by the DL model for FC, PIT, FA, and HER were 0.91, 0.85, 0.86, and 0.86, respectively, and were comparable to those of an expert observer. Conclusions DL semantic segmentation of coronary plaques in OFDI images was used as a tool to automatically categorize atherosclerotic plaques using histological findings as the gold standard. The proposed method can support interventional cardiologists in understanding histological properties of plaques.

Toxoplasmic encephalitis (TE) and post-transplant lymphoproliferative disorder of the central nervous system (CNS-PTLD) are major complications after allogeneic hematopoietic stem cell transplant (allo-SCT); both are fatal without timely diagnosis and disease-specific treatment. Differential diagnosis of TE and CNS-PTLD can be challenging because brain biopsy, a gold standard for diagnosis, is sometimes not possible, owing to poor patient condition after allo-SCT. Here, we describe a case of isolated CNS-PTLD arising during the therapeutic course of TE. A 51-year-old man was admitted with mental abnormalities and fever on Day 106 after allo-SCT to treat myelodysplastic syndrome. Magnetic resonance imaging (MRI) revealed multiple nodular and ring-enhanced lesions in the brain, and the result of polymerase chain reaction (PCR) for Toxoplasma gondii in cerebrospinal fluid was positive; therefore, he was diagnosed with TE. Anti-Toxoplasma therapy led to clinical improvement, and the result of subsequent PCR was negative. However, he developed left-sided hemiplegia on Day 306. Head MRI revealed a new lesion and a growing lesion, presenting as ring-enhanced nodules. Brain biopsy was performed, and a pathologic diagnosis of Epstein-Barr virus-associated CNS-PTLD was made. There was no evidence of TE. He was treated successfully by reducing immunosuppressants, followed by rituximab administration and a donor lymphocyte infusion, resulting in complete remission. While T.gondii-specific PCR has great value for diagnosis of TE, CNS-PTLD can be diagnosed only by brain biopsy; hence, brain biopsy may be warranted in cases of suspected PTLD.

Cancer-associated fibroblasts (CAFs) are an important constituent of the cancer stroma. In intrahepatic cholangiocarcinoma (ICC), the features of CAFs at the primary site and in the metastatic lymph nodes (Met-LNs) and their origin have been unclear. In the present study, we characterized CAFs at the primary site (n = 42) and in the Met-LNs (n = 10) of human ICC by immunohistochemistry using potential molecular markers of CAFs, portal fibroblasts (PFs), hepatic stellate cells (HSCs), and bone marrow-derived fibrocytes (BMDFs). At the primary site, the stroma was strongly positive for α-smooth muscle actin (α-SMA; marker for CAFs), platelet-derived growth factor receptor-β (PDGFR-β) (common marker for HSCs and PFs), fibulin-2, and thymus cell antigen-1 (Thy-1; PF marker), whereas immunoreactivity for fascin (HSC marker) was scarce. Most of the α-SMA-positive cells were found to express PDGFR-β, Thy-1, and fibulin-2 by double immunostaining. A small population of BMDF marker-positive (α-SMA+CD45+CD34+) cells was found by triple immunostaining. In the micro-Met-LNs, α-SMA-positive cells were absent in cancer aggregates of the LN sinus, whereas they were present in the invasion area of cancer cells from the LN sinus to the LN parenchyma. In the macro-Met-LNs, there were abundant α-SMA-positive cells that were also positive for PDGFR-β and Thy-1 but negative for fibulin-2 and fascin. Thus, regarding the expression of molecular markers, CAFs at the primary site of ICC are similar to PFs and different from those of HSCs or CAFs in the Met-LNs. CAFs at the primary sites and in the Met-LN are thought to be derived from PFs/BMDFs and resident cells of LNs, respectively.

We experienced a 58-year-old Japanese female complaining of bleedings at defecation for about one year. Endoscopy revealed an Ip submucosal tumor (SMT) at the rectum. Continuous bleedings at defecation and no evidence malignancy in a biopsy specimen led to a polypectomy. The specimen showed SMT with erosion, while the macroscopic cross-section implied a lipomatous mesenchymal tumor. Under the probable diagnosis of liposarcoma, especially myxoid liposarcoma, fusion-gene analyses were performed. The detection of type 1 FUS-DDIT3 fusion gene led to a definite diagnosis of rectal myxoid liposarcoma. For further treatment, a super low anterior resection was performed, revealing neither residual tumors nor lymph node metastases. The patient is now alive and free of disease for 5 years. To our knowledge of the literature, this is the first case of a rectal myxoid liposarcoma. Keywords: Rectum, Myxoid liposarcoma, Submucosal tumor

Objective Changes in brain tissue can be detected sensitively using PRESTO (principles of echo-shifting with a train of observations) magnetic resonance imaging (MRI). The aim of this study was to evaluate the correlation between the proliferative ability of astrocytoma and intratumoral spotty signal voids seen as hypo-intense dots on PRESTO MRI. Patients and Methods Fifty-seven astrocytic tumors, comprising 14 astrocytomas, 12 anaplastic astrocytomas, and 31 glioblastomas, were included in this retrospective study. The tumors were classified independently by blinded radiologists according to the number of spotty signal voids detected on PRESTO-MRI as follows: spot-free (grade 0), less than 3 spots (grade 1), or more than 3 spots or a large spot (grade 2). Results Thirteen patients (92.9%) with astrocytoma were classified as PRESTO grade 0 and 1 patient (7.1%) was classified as grade 1. Seven patients (58.3%) with anaplastic astrocytoma were classified as PRESTO grade 0, 1 (8.3%) as grade 1, and 4 as grade 2 (33.3%). Three patients (9.7%) with glioblastoma were classified as grade 0, 6 (19.4%) as grade 1, and 22 (70.9%) as grade 2. There was a strong correlation between PRESTO tumor grade and the mean MIB-1 index. Conclusions These results indicate that a grading system based on the number of spotty signal voids detected on PRESTO images would be useful for the diagnosis of astrocytic tumors and predicting their proliferative ability.

Optical coherence tomography (OCT), a catheter-based imaging modality for the visualization of coronary arteries, is widely used during percutaneous coronary intervention to improve the understanding of the anatomy of coronary artery stenosis and to elucidate the mechanisms of atherosclerosis. In this review, we provide a short description of the histopathological validations of OCT for visualizing atherosclerotic plaques and vascular healing response after drug-eluting stent (DES) implantation. Because OCT measures the intensity of light returning from within a tissue, tissue having a higher heterogeneity of optical index of refraction, such as microcalcification deposition and foam cell accumulation on the luminal surface, may exhibit stronger optical scattering that appears as a thin-cap fibroatheroma image. Furthermore, even if OCT shows exposed uncovered stent struts, some of the struts could be re-endothelialized. In our ex vivo histopathological experience, re-endothelialization at the surface of stent struts was confirmed by histopathological analysis, although OCT images showed exposed uncovered struts after DES implantation. Therefore, careful interpretation is required to assess tissue morphology and stent strut coverage by OCT.

We experienced a case of primary malignancy in giant cell tumor of bone (GCTB), arising in the right femur and harboring H3F3A mutation. A 27-year-old Japanese male without any prior disease history complained of pain in his right hip joint and right lower limb. Radiological images revealed an osteolytic and multicystic lesion existing mainly at the proximal epiphysis of the right femur. Preoperative clinical diagnosis was GCTB, although irregular marginal sclerosis was an atypical radiographic finding for conventional GCTBs. Biopsy sample from the lesion revealed the coexistence of typical GCTB and undifferentiated high-grade round cell sarcoma. Despite of the wide local resection of the tumor with preoperative and postoperative chemotherapy, the patient died of multiple distant metastases of the tumor 9 months after the surgery. Since heterozygous H3F3A c. 103G>T (p. Gly34Trp) mutation was detected not only in the biopsy sample from the primary site with typical GCTB and high-grade sarcoma components but also in the resected material from the metastatic site with only pure high-grade sarcoma component, the tumor was considered originally derived from conventional GCTB and acquire malignant transformation to high-grade sarcoma. Thus, this is an extremely rare case of primary malignancy in GCTB and the first case report of primary malignancy in GCTB proved the presence of H3F3A mutation even in the sarcoma component.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue malignant neoplasm with a deceptively benign histological appearance and a potential for late recurrence and metastasis. LGFMS cases with significant ossification are extremely rare. To our knowledge, only three cases of LGFMS with bone formation which is detected as apparent calcification by radiological examinations and proven by histopathology have been reported. Here, we report the fourth such case. A 39-year-old female presented with a 10-year history of a painless tumor in her right buttock. Computed tomography images showed multiple foci of intratumoral calcification. A needle biopsy specimen of the tumor revealed a spindle cell neoplasm with hyalinizing/collagenous stroma and ossification. The tumor cells were immunohistochemically positive for MUC4 and the molecular analysis of the tumor detected FUS-CREB3L2 fusion. Pathological diagnosis of LGFMS was made. Total resection of the tumor with wide margins was performed, and histology of the resected sample showed multiple foci of intratumoral ossification.

Background The clinical benefit of second-generation drug-eluting stents (2nd DES) has been established, compared to first-generation drug-eluting stents (1st DES). However, pathological response after 2nd DES implantation remains unclear, particularly in the Japanese population. Methods Using specimens obtained by autopsy, we compared the histology between 2nd DES (41 sections) and 1st DES (38 sections) lesions within 1 year after stent implantation to evaluate early tissue reaction in Japanese patients. Stent segments were fixed with 10% buffered formalin and embedded in plastic, followed by hematoxylin–eosin and Masson's trichrome staining. Ratio of covered stent struts was calculated, and the area of fibrin deposition was morphometrically evaluated. The degree of inflammation around struts was examined semi-quantitatively (score 0–3). Results The ratio of covered struts and mean fibrin area of 2nd DES were 0.69 ± 0.05 and 658.0 ± 173.4 μm 2 . Those of 1st DES were 0.44 ± 0.12 and 3107.5 ± 1405.9 μm 2 . In the 2nd DES, there was significantly less fibrin deposition and a higher covered struts ratio. The inflammation score was significantly lower in 2nd DESs compared to 1st DESs (1.02 ± 0.16 vs. 1.19 ± 0.54, p Conclusions Histopathological analysis showed advanced healing process in 2nd DES compared with 1st DES lesions. These results are consistent with clinical beneficial outcome of 2nd DES implantation.

We experienced a case of malignant orbital tumor in a 72-year-old Japanese man. He noticed protrusion of his left eye, and received resection of the left orbital tumor. The tumor contained several different components such as high-grade invasive ductal carcinoma, low-grade/minimally invasive adenocarcinoma and pleomorphic adenoma. Pathological diagnosis of high-grade invasive ductal carcinoma ex pleomorphic adenoma of the left lacrimal gland was made. He had undergone surgical removal of the left lacrimal gland tumor at the other hospital 19 years before, and the surgical specimen revealed that most part of the tumor was pleomorphic adenoma but low-grade/minimally invasive adenocarcinoma was included as a minor component (low-grade/minimally invasive adenocarcinoma ex pleomorphic adenoma). Thus, we could observe the natural course of low-grade/minimally invasive adenocarcinoma ex pleomorphic adenoma which transformed into high-grade invasive ductal carcinoma ex pleomorphic adenoma. Lacrimal gland ductal carcinoma is an extremely rare tumor, and only 25 cases have been reported before in English literature. Moreover, our case is the 5th case of lacrimal gland ductal carcinoma ex pleomorphic adenoma. Keywords: Lacrimal gland, Carcinoma ex pleomorphic adenoma, Androgen receptor, HER2

We experienced a diagnostically challenging case of Carney complex (CNC). A 24-year-old woman had a past history of surgical removal of multiple cutaneous tumors in the childhood. She was followed as a patient of neurofibromatosis type 1 (NF1) and referred to our hospital for further treatment after she grew up to adulthood. At our hospital, several cutaneous tumors were excised, and the pathological diagnosis was myxoma arising from not deep soft tissue but cutis (so-called cutaneous myxoma). Despite previous clinical diagnosis of NF1, because of the probability of CNC, detailed systemic examination was undertaken including radiological and endocrinological tests. Imaging techniques showed multiple lumps in both breasts, a mass in left atrium and nodular lesions in adrenal glands. Serum ACTH level was markedly suppressed. Surgically resected specimens revealed breast myxomas, cardiac myxoma and primary pigmented nodular adrenocortical disease (PPNAD). These findings met the diagnostic criteria for CNC. Genetic analysis revealed known non-sense mutation of PRKAR1A c.124C>T (p.R42X) (ClinVar ID 41382). Her 50-year-old mother was also shown to have cardiac myxomas, radiological finding of breast myxomatosis and the same PRKAR1A mutation as her daughter. In the present case, the accurate diagnosis of CNC was difficult not only because CNC is a rare disease but also because skin pigmentation was not obvious. Since cardiac myxoma might result in poor or fatal outcome, early and accurate diagnosis of CNC and subsequent systemic investigation including heart are important. Although pediatric cutaneous myxomas are rare, multiple cutaneous myxomas might suggest the possibility of CNC. In such cases, systemic investigation should be done for the accurate diagnosis. Keywords: Carney complex, Cutaneous myxoma, PPNAD, PRKAR1A mutation

We experienced a 38-year-old Japanese male with t(10;19) CIC-DUX4 -positive undifferentiated small round cell sarcoma in the deep abdominal wall. Three months before his first visit to our hospital, he noticed a mass in his right abdominal wall. Computed tomography on admission revealed a solid abdominal tumor 70×53mm in size and multiple small tumors in both lungs. The biopsy of the abdominal tumor revealed undifferentiated small round cell sarcoma, suggestive of Ewing sarcoma. Under the clinical diagnosis of Ewing-like sarcoma of the abdominal wall with multiple lung metastases, several cycles of ICE (ifosfamide, carboplatin and etoposide) therapy were performed. After the chemotherapy, the lung metastases disappeared, while the primary lesion rapidly grew. Additional VDC (vincristine, doxorubicin and cyclophosphamide) therapy was carried out without apparent effect. Although the surgical removal of the primary lesion was done, peritoneal dissemination and a huge metastatic liver tumor appeared thereafter. The patient died of disease progression two months after the surgery. The total clinical course was approximately one year, showing that the tumor was extremely aggressive. The tumor cells of the surgical specimen were positive for CD99, WT1, calretinin, INI1, ERG and Fli1 by immunohistochemistry. Fusion gene analyses using the frozen surgical material revealed negativity for EWSR1-Fli1, EWSR1-ERG and t(4;19) CIC-DUX4 fusions, but positivity for t(10;19) CIC-DUX4 fusion. Thus, we made a final pathological diagnosis of t(10;19) CIC-DUX4-positive undifferentiated small round cell sarcoma. To our knowledge, this is the 13th case of t(10;19) CIC-DUX4 undifferentiated small round cell sarcoma with precise clinicopathological information. Especially in our case, two types of t(10;19) CIC-DUX4 fusion transcripts were observed, both of which are in-frame and novel.

This study was conducted to evaluate changes in liver stiffness, volume, and function before and after occlusion of spontaneous portosystemic shunt.Twenty-four patients (13 men and 11 women) with a mean age of 68.2 years±10.1 (SD) (age range, 49-82 years) underwent percutaneous occlusion of spontaneous portosystemic shunt because of gastric varices (n=17) or hepatic encephalopathy (n=7) from March 2011 to June 2013. The liver fibrosis index indicating liver stiffness was calculated by using ultrasound elastography before and after shunt occlusion. Liver volume and liver profile were also evaluated.Spontaneous portosystemic shunt occlusion was uneventfully performed in all patients. The mean liver fibrosis index was significantly decreased from 2.7±1.0 before shunt occlusion to 2.0±0.9 (P0.001) at 1 month, 2.2±1.0 at 3 months (P=0.004), and 1.6±0.7 at 6 months (P=0.001) afterwards. A significant increase in the liver volume was observed from 1035.3±340.1mL before shunt occlusion to 1116.8±298.4mL (P=0.006) at 1 month and 1174.2±354.1mL (P0.001) at 3 months afterwards. Significant improvement in the Child-Pugh score was also found at 1 month (6.2±1.4, P0.001), 3 months (6.5±1.1, P=0.022), and 6 months (6.0±0.9, P=0.004) after shunt occlusion as compared with that (7.2±1.9) before.The liver stiffness decreases along with an increase in liver volume and improvement in liver function after spontaneous portosystemic shunt occlusion.

Ovarian Sertoli cell tumors (SCTs) are rare sex cord tumors (Oliva et al., 2005). The standard treatment for high-grade SCTs is surgery followed by platinum-based chemotherapy. Although platinum-based chemotherapy is also an option for recurrent SCTs (Sigismondi et al., 2012), there is no established chemotherapy regimen for platinum-resistant recurrent SCTs. The effectiveness of pazopanib in treating epithelial ovarian cancer has recently been reported (du Bois et al., 2014; Pignata et al., 2015). In the case described herein, pazopanib was used to treat the platinum-resistant recurrence of a high-grade Sertoli cell tumor, and the response was evaluated by 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)-computed tomography (CT). Written informed consent to reporting the case was obtained from the patient.

Background: Chronic inflammation promotes aging and carcinogenesis in colorectal mucosa, particularly in ulcerative colitis (UC); providing a rationale for the development of these molecular alterations as useful biomarkers for diagnosis and risk prediction of UC-associated colorectal cancer (UC-CRC) and sporadic colorectal cancer (S-CRC). Methods: We performed array-based methylation analyses using tissues from 76 patients with S-CRC (vs. normal mucosa) and UC-CRC (vs. UC). In the evaluation phase, 945 colorectal specimens from 352 patients with S-CRC, 31 with UC-CRC, and 57 with UC, were analyzed for methylation levels of identified genes by quantitative pyrosequencing. In the validation phase, 199 non-cancerous rectal mucosa specimens from 20 patients with S-CRC, 61 with UC-CRC, 90 with UC, and 28 healthy volunteers were examined. Findings: Comprehensive analysis identified OPLAH as a hypermethylated CpG site in S-CRC and UC-CRC patients. In the evaluation phase, OPLAH methylation (met-OPLAH) differentiated S-CRC tissue from normal mucosa (area under the receiver operating characteristic curve (AUC):0.95, sensitivity:0.89, specificity:0.95), and met-OPLAH levels in normal mucosa were positively correlated with age. However, met-OPLAH was specifically hypermethylated in UC-CRC tissues and differentiated UC-CRC from UC mucosa (AUC:0.95, sensitivity:0.88, specificity:0.94). Levels of met-OPLAH were significantly higher in rectal tissues vs. proximal mucosa, and were associated with age and disease duration in rectal mucosa. In non-cancerous rectal mucosa, met-OPLAH could discriminate UC patients with or without UC-CRC (AUC:0.84, sensitivity:0.83, specificity:0.72). We further developed ∆met-OPLAH, which could distinguish S-CRC from UC-CRC (P=0.0002, AUC:0.81, sensitivity:0.92, specificity:0.65). Interpretation: Assessment of met-OPLAH can be used for screening of UC-CRC using non-cancerous rectal mucosa, diagnosis using cancerous tissues, and decision-making of surgical approaches using both tissue types in patients with UC and cancer. Funding: Grants in Aid for Scientific Research (17K10628, 18K08591) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. Declaration of Interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors have no conflict of interests to disclose. Ethical Approval Statement: Specimen collection and experiments were approved by the Institutional Review Boards of all participating institutions. All participants provided a written informed consent for participation in research.

Solitary fibrous tumors occasionally present with hypoglycemia because of the excessive release of insulin-like growth factor II. We report the first case of pancreatic solitary fibrous tumor causing ectopic adrenocorticotropic hormone syndrome. An 82-year-old Japanese man presented with lower limb edema, uncontrolled hypertension, hypokalemia, and baseline hypercortisolism. Distal pancreatectomy was performed after the clinical diagnosis of a neuroendocrine tumor with ectopic secretion of adrenocorticotropic hormone. On histological examination, the tumor showed spindle cells in a fascicular arrangement. The diagnosis of the solitary fibrous tumor was confirmed by the identification of the NAB2-STAT6 fusion gene and positive immuno-histochemical staining for STAT6 and CD34. Using quantitative real-time polymerase chain reaction, mRNA that encoded proopiomelanocortin, precursor of adrenocorticotropic hormone, was detected. Proopiomelanocortin production through the demethylation of the promoter region Domain IV was detected. Pancreatic solitary fibrous tumors represent a new cause of ectopic adrenocorticotropic hormone syndrome.

Background Optical coherence tomography (OCT) is one of the tools trying to distinguish neoatherosclerosis from other neointimal tissue but its role has to be still validated. This study evaluated the diagnostic accuracy of OCT for characterization of lipid-atherosclerotic neointima following drug-eluting stent (DES) implantation. Methods Twelve stented coronary arteries from the 7 autopsy hearts were imaged by OCT. These OCT images were compared with histology. By OCT, the morphological appearances of neointima were classified into three patterns: homogeneous pattern, heterogeneous pattern with visible strut, or heterogeneous pattern with invisible strut. Results Of 21 histological cross-sections, 6 were categorized as homogeneous patterns (29%), 11 as heterogeneous patterns with visible stent strut (52%), and 4 as heterogeneous patterns with invisible stent strut (19%). All homogeneous patterns were composed of smooth muscle cells with collagen fibers. The heterogeneous patterns with visible stent strut included proteoglycan-rich myxomatous matrix and calcium deposition. On the other hand, the heterogeneous patterns with invisible stent strut comprised atheromatous tissue, including a large amount of foam cell accumulation (25%) or large fibroatheroma/necrotic core (75%) inside the stent struts within neointima. The optical attenuation coefficient was highest in the heterogeneous pattern with invisible stent strut due to scattering of light by atheromatous tissue. Conclusion The heterogeneous patterns with invisible stent strut on OCT imaging identify the presence of lipid-atherosclerotic tissue within neointima after DES. This may suggest the potential capability of OCT based on visualization of stent struts for discriminating atheromatous formation within neointima from other neointimal tissue.

To correlate both primary lesion maximum standardized uptake values (SUVmax) of FDG-PET/CT, and apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI) with clinicopathologic prognostic factors in patients with breast carcinoma.214 patients with 216 mass-type invasive breast carcinomas underwent whole-body FDG-PET/CT and 3-Tesla breast MRI including DWI before initial therapy. The primary tumor's SUVmax and ADC values were measured using FDG-PET/CT and DWI, respectively. Histologic analysis parameters included tumor size, expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67, nuclear grade, histology subtype, and axillary lymph node (LN) metastasis. The relationships among SUVmax, ADC values, and pathologic prognostic factors were evaluated.The mean SUVmax and ADCmean were 5.63±3.79 (range, 1.2-24.17) and 894±204×10(-6)mm(2)/s (range, 452-1550×10(-6)), respectively. There was a significant but weak inverse correlation between the SUVmax and ADCmean values (correlation coefficient r=-0.30, p0.0001). SUVmax was associated with numerous prognostic factors such as tumor size (p0.0001), expression levels of ER (p=0.00041), PR (p=0.00028), HER2 (p=0.00021), and Ki-67 (p0.0001), nuclear grade (p0.0001), histology subtype (p=0.00061), axillary LN metastasis (p0.0001), and TNM staging (p0.0001). Meanwhile, ADCmean value was associated with tumor size (p=0.013), expression of Ki-67 (p=0.0010), histology subtype (p=0.00013), axillary LN metastasis (p=0.00059), and TNM staging (p=0.0011).Primary tumor SUVmax on FDG-PET/CT has a stronger relationship with known prognostic parameters and may be a more useful for predicting the prognosis of breast carcinoma than ADC values.

Objectives This study sought to assess the accuracy of optical coherence tomography (OCT), gray-scale intravascular ultrasound (IVUS), and their combination for detecting thin-cap fibroatheromas (TCFA). Background The extent to which the imaging characteristics of OCT and IVUS correlate with histologically defined TCFA is unknown. Methods IVUS and OCT examinations identified focal plaques in 165 coronary arteries from 60 autopsy hearts. A total of 685 pairs of images of OCT and IVUS were compared with histology. By OCT, a TCFA was defined as a signal-poor region with diffuse borders and cap thickness Results With histology as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy for OCT-derived TCFA were 100%, 97%, 41%, 100%, and 98%, respectively. The corresponding numbers for IVUS-derived TCFA were 92%, 93%, 19%, 99%, and 93%, respectively. The histological findings underlying the false positive diagnoses of OCT for TCFA included large amounts of foam cell accumulation on the luminal surface, large amounts of microcalcifications at the surface, large amounts of hemosiderin accumulation, or organized thrombus. In contrast, histological causes of mischaracterization of TCFA by IVUS were mostly TCFA. When both OCT and IVUS criteria for TCFA were required to be met, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy were 92%, 99%, 69%, 99%, and 99%, respectively. Conclusions In the present study, neither OCT nor IVUS were optimal to detect TCFA. The combined use of OCT and IVUS may improve TCFA detection accuracy.

We experienced a rare case of uterine metastasis of non-small cell lung cancer in an 82-year-old Japanese woman revealed by detecting the same epidermal growth factor receptor (EGFR) gene mutation in both lung and endometrial biopsy specimens. The patient noticed abnormal genital bleeding at the first presentation. Further examination revealed huge masses in both lung and uterus. Biopsies from the lung and endometrium were performed. Although the pathological findings of both specimens showed similar adenocarcinomatous features including intracytoplasmic luminas, immunohistochemical analyses could not clarify whether these two tumors are lung metastasis of endometrial adenocarcinoma, uterine metastasis of lung adenocarcinoma or double primary adenocarcinomas of the lung and endometrium. Mutational analyses of EGFR gene using genomic DNA revealed that both lung and endometrial tumors had the same substitution mutation (L858R) at exon 21 which is often observed in lung adenocarcinomas. Since EGFR mutations are rarely detected in primary endometrial cancers and especially L858R mutation has not been reported in them, detection of the same L858R EGFR gene mutation in both lung and endometrial tumors strongly suggested that uterine tumor is the metastasis of lung adenocarcinoma. Mutational analyses might be useful to determine whether the tumor is primary or metastatic when the particular mutational types are observed in particular tumor types and/or particular organs.

We carried out an experiment on a 58-year-old man with multiple left lung tumors and swelling of multiple lymph nodes. For clinical staging and therapeutic purposes, bronchoalveolar lavage (BAL) cytology and lung biopsy were performed. The biopsy specimen revealed the left lower lung mass to be immunohistochemically ALK (anaplastic lymphoma kinase)-positive adenocarcinoma. Using the BAL specimen from the left lower lung, EML4 (echinoderm microtubule-associated protein-like 4)-ALK variant 1 fusion gene was detected by reverse transcription-polymerase chain reaction (RT-PCR). His past history showed that he had undergone an operation for lung adenocarcinoma of the right lower lobe 15 years before, and the pathological specimen at that time revealed that the lung adenocarcinoma with pleural invasion and single metastasis of mediastinal lymph node showed a mucinous cribriform pattern and/or signet-ring cell pattern. The typical histology led us to examine the ALK rearrangement in the primary lung cancer and mediastinal metastatic tumor. Immunohistochemistry (IHC) for ALK was positive, and ALK break apart fluorescence in situ hybridization (FISH) showed a positive result. Moreover, RT-PCR using formalin-fixed, paraffin-embedded tissue from the right lung cancer also demonstrated EML4-ALK variant 1 fusion gene. Although there is a possibility that the left lung cancer is de novo one with multiple metastases, detection of the same fusion gene of the very rare EML4-ALK variant 1 in both tumors suggests that the left cancer is a recurrence of the right lung cancer after an interval of 15 years.

We experienced a peculiar case of orbital mesenchymal tumor in a 22-year-old Japanese woman. The tumor showed a papillary proliferating pattern, but no typical hemangiopericytomatous staghorn vessels. The tumor was composed of round to oval shaped cells with oval nuclei and mild nuclear atypia. Abundant vascular cores were present in the central portion of papillary proliferations of tumor cells. Immunohistochemistry revealed that the tumor cells were positive for CD34 and bcl2. Moreover, they showed positive nuclear signals of STAT6, which have recently been shown to be specific for solitary fibrous tumors. In the literature, only one case of solitary fibrous tumor with papillary and retiform growth pattern has been reported, but the case partially showed the typical staghorn vessel pattern. Although the definite diagnosis is difficult in the settings of the unusual histology and the deficiency of NAB2-STAT6 fusion, it is possible that this STAT6-positive intraorbital papillary tumor is a very rare variant of solitary fibrous tumor.

Coronary high intensity plaque (HIP) detected by T1 weighted imaging (T1WI) may represent plaque instability. However, pathological findings of HIP remain unclear. Ten lesions from 10 patients with angina pectoris were evaluated by non-contrast T1WI. Signal intensity of coronary plaque to cardiac

Clear cell sarcoma is a unique tumor which has EWSR1-ATF1 or EWSR1-CREB1 fusion. Several patterns of EWSR1-ATF1 fusion are observed in clear cell sarcoma. Since type 5-7 fusions were reported recently, they are classified as type 1-7. We examined EWSR1-ATF1 and EWSR1-CREB1 fusions in a single case of clear cell sarcoma with lung metastasis in a 36-year-old Japanese man. As a result, we found only type 1 EWSR1-ATF1 fusion in the primary site, but 4 types of EWS-ATF1 fusion (type 1, 2, 5, 6) were detected in the metastatic site. These 4 types of fusion were completely identical to the recent report, but the case had the same fusion patterns in both primary and metastatic sites. In our case, increased splicing activity in the EWSR1-ATF1 fusion might be acquired at the metastatic site. There is another possibility that metastasis might develop through the increased splicing activity in the fusion.

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) failure. Recently, iron deficiency is reported to be prevalent in patients with PH. However, the mechanism by which iron deficiency occurs in patients with PH remains unknown. Here, we investigated the effects of dietary iron restriction on the development of monocrotaline-induced pulmonary vascular remodeling and the involved mechanisms. Male Sprague–Dawley rats were subcutaneously injected with monocrotaline (60 mg/kg). Afterwards, monocrotaline - injected rats were randomly divided into two groups and were given a normal diet ( n = 6) or an iron-restricted diet ( n = 6) for 4 weeks. Saline-injected rats given a normal diet were served as controls ( n = 6). Monocrotaline-injected rats showed pulmonary vascular remodeling, increased RV pressure, RV hypertrophy, and decreased RV ejection fraction, followed by RV failure after 4 weeks. In contrast, iron restriction attenuated the development of pulmonary vascular remodeling and RV failure. Of interest, expression of cellular iron transport protein, transferrin receptor 1 was increased in the pulmonary remodeled artery and the failing right ventricle of monocrotaline-injected rats, as compared with the controls. Moreover, a key regulator of iron homeostasis, hepcidin gene expression was increased in the failing right ventricle of monocrotaline-injected rats. Iron restriction attenuated the development of monocrotaline-induced pulmonary vascular remodeling and RV failure. Cellular iron transport might be involved in the pathophysiology of PH and PH induced RV failure.

The great majority of gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the c-kit gene, which encodes KIT receptor tyrosine kinase. Most of the mutations are located at exon 11, but some are at exon 9 or at other exons. Mutation types at exon 11 vary, while most mutations at exon 9 are a particular duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). Recently a duplication of Ser501Ala502 (KIT-Dup-Ser501Ala502) at exon 9 has been reported in two cases of pediatric mastocytosis and one case of adult mast cell leukemia. Although KIT-Dup-Ser501Ala502 had not been reported in GISTs, we found two GIST cases possessing the mutation in 45 GIST cases with exon 9 c-kit gene mutations, among a total of approximately 500 GIST cases examined. In this report, we briefly summarize clinicopathological findings of the two cases, and characterize the biology of the mutation. When autophosphorylation of KIT-Dup-Ser501Ala502 was examined by transient transfection of c-kit cDNA with Dup-Ser501Ala502 into CHO-K1 cells, KIT-Dup-Ser501Ala502 was ligand-independently activating. The inhibitory effect of selective tyrosine kinase inhibitors, imatinib and nilotinib, on KIT-Dup-Ser501Ala502 was examined and compared with that of KIT-Dup-Ala502Tyr503. Imatinib efficiently inhibited constitutive activation of KIT-Dup-Ser501Ala502 at a concentration of 0.1 μM, whereas it inhibited that of KIT-Dup-Ala502Tyr503 at a concentration of 10 μM. Constitutive activation of KIT-Dup-Ser502Ala503 was not inhibited by nilotinib even at a concentration of 10 μM but that of KIT-Dup-Ala501Tyr502 was almost completely inhibited at a concentration of 1 μM. The results suggest that imatinib and nilotinib could be more effective on GISTs with KIT-Dup-Ser501Ala502 than those with KIT-Dup-Ala502Tyr503. In fact, a patient with KIT-Dup-Ser501Ala502 showed long-term stable disease with administration of the usual dose of 400 mg imatinib. Although mutation sites of KIT-Dup-Ser501Ala502 and KIT-Dup-Ala502Tyr503 are closely located, imatinib- and nilotinib-sensitive KIT-Dup-Ser501Ala502 are distinguishable from KIT-Dup-Ala502Tyr503.

Myxoid/round cell liposarcomas are rare mesenchymal neoplasms. They preferentially occur in the lower extremity, and most of them have type 1 or type 2 DDIT3-FUS fusion gene. We report here a very rare case of myxoid/round cell liposarcoma of the paratesticular region with type 3 DDIT3-FUS fusion gene. A 46-year-old Japanese man noticed a gradually enlarged intrascrotal mass without pain. Surgical resection of 3.4 cm × 2.1 cm oval mass was carried out, and it was located in the right paratesticular region apart from the spermatic cord and epididymis. Histological examination of the tumor revealed ovoid cell proliferation with anastomosing vascular network and scattered lipoblasts. Genetic analysis elucidated that the tumor had a chromosomal translocation, type 3 DDIT3-FUS chimeric gene. The tumor was definitely diagnosed as myxoid/round cell liposarcoma of the paratesticular region.

We found a novel type germline mutation at exon 11 of the c-kit gene, which results in a substitution of Tyr to Cys at codon 553 of the c-kit gene product (KIT-Tyr553Cys), in a 68-year-old female patient with multiple gastrointestinal stromal tumors (GISTs). In the present study, we carried out mutational analysis in her family members to determine the carriers and characterized the mutation by introducing the corresponding mutation (murine KIT-Tyr552Cys) into expression vector possessing murine c-kit cDNA. Mutational analysis of peripheral blood leukocytes of her family members revealed that a 44-year-old son had the same mutation, but at present he had neither apparent symptoms nor images of multiple GISTs. By transfection with the expression vector possessing the murine mutant c-kit cDNA, interleukin-3-dependent Ba/F3 murine lymphoid cells started growing autonomously without any growth factors, indicating that the mutation was considered to be of gain-of-function. Imatinib, a small molecule of tyrosine kinase inhibitor, effectively inhibited autophosphorylation of KIT-Tyr552Cys. Nilotinib, another small molecule of the KIT inhibitor, also effectively inhibited autophosphorylation of KIT-Tyr552Cys. In fact, proliferation of Ba/F3 cells expressing KIT-Tyr552Cys was effectively inhibited by both imatinib and nilotinib. These findings indicate that the novel type human KIT-Tyr553Cys mutation is the cause of the present familial and multiple GISTs, and that both imatinib and nilotinib might effectively inhibit the growth of GISTs developing in the patients of this family.

Primary carcinoid tumor of the urinary bladder is a very rare neoplasm. We report here a case of primary carcinoid tumor of the urinary bladder with an unusual cytological feature in a 72-year-old Japanese man. A bladder polypoid mass was incidentally found by ultrasonography during the follow-up of a benign prostate hyperplasia. Histological examination of the transurethrally resected tissue revealed that the upper part of the mass was a tumor showing tubuloglandular anastomosing structures. Most of the tumor cells had peculiar subnuclear eosinophilic granules. The features of the granules were reminiscent of those observed in neuroendocrine cells of the intestine. The tumor cells were immunohistochemically positive for chromogranin A and synaptophysin. The tumor was diagnosed as carcinoid tumor of pure form of the urinary bladder. The lower part of the mass showed the findings of glandular cystitis, as its coexistence with carcinoid tumors of the bladder has often been described in previous reports.

Background It is unknown whether interleukin-18 (IL-18) participates in the pathophysiology of nonrheumatic aortic stenosis (NR-AS). Methods We examined IL-18 expression in human NR-AS valves by immunohistochemistry and Western blot analysis. Results Immunohistochemistry revealed that NR-AS valves showed increased IL-18 expression compared with controls. IL-18 receptor was also expressed in NR-AS valves. Western blot analysis showed that IL-18 was expressed as an active form in NR-AS valves. Furthermore, increased IL-18 expression was correlated with the advanced clinical severity of NR-AS. Conclusions IL-18 was expressed in the aortic valves and up-regulated in NR-AS valves. IL-18 may contribute to the pathophysiology of NR-AS.

The involvement of cyclooxygenase (COX)-2 in oral carcinogenesis and outcome of the patients is not fully understood. To determine whether COX-2 expression could serve as an indicator for them, we examined the expression of COX-2 and DNA topoisomerase (DNA-Topo) II alpha as an index of cell proliferating activity in precancerous and cancerous lesions of the oral mucosa. A 164 samples composed of 60 intraepithelial dysplasias (IEDs), 12 carcinomas in situ (CISs), 72 squamous cell carcinomas (SCCs) including 12 early invasive SCCs, 10 undifferentiated carcinomas (UCs), and 10 epithelial hyperplasias (EHPs) in the oral mucosa were examined immunohistochemically for COX-2 and DNA-Topo II alpha. Normal squamous epithelium as the control showed no COX-2 expression, whereas 41% of IEDs, 67% of CISs, 74% of SCCs, and 86% of UCs demonstrated increased COX-2 expression with elevated DNA-Topo II alpha labeling index (LI). High COX-2 expression was also observed in 61% of EHPs, but DNA-Topo II alpha LI was very low. Increased expression of COX-2 protein correlated with elevated DNA-Topo II alpha LI, indicating that COX-2 may contribute to malignant transformation and tumor growth. These two enzyme activities were increased as T, N, and M categories and stages proceeded. The patients with high expression of both COX-2 and DNA-Topo II alpha showed poor prognosis. Our results suggested that COX-2 expression become a possible indicator in oral carcinogenesis and may reflect the outcome of the patients.

Purpose To investigate CT and MR findings of giant cell tumors (GCTs) of the skull, an unusual site for such tumors. Materials and methods CT and MR features of five histologically proven giant cell tumors of the skull were retrospectively reviewed. We also reviewed 22 cases in the literature that included MR or CT findings. Results Three of the tumors originated from the temporal bone with predominantly medial extension, and the other two were centered in the body of the sphenoid bone and featured symmetrical soft tissue extension. CT images with bone window settings showed reactive bone changes for all three tumors of the temporal bone, suggesting slow growth for example, an expanded intradiploic space, expansive remodelling and development of foci of pressure erosion. GCTs of the sphenoid bone showed purely osteolytic changes without remodelling. Although the MR signals and enhancement patterns varied, all the tumors of the temporal bone had a markedly low intensity area on T2-weighted images, which was not seen in the tumors of the sphenoid bone. The findings for our cases generally corresponded to those reported in the literature. Conclusion Giant cell tumors of the skull have two preferential sites and may have characteristic tendencies as to their extent. Bone changes and MR signals appear to show differences between the two sites.

To date, the potency of pancreatic and duodenal homeobox gene 1 (PDX-1) in inducing differentiation into insulin-producing cells has been demonstrated in some cells and tissues. In order to carry out efficient screening of somatic tissues and cells that can transdifferentiate into beta-cell-like cells in response to PDX-1, we generated CAG-CAT-PDX1 transgenic mice carrying a transgene cassette composed of the chicken beta-actin gene (CAG) promoter and a floxed stuffer DNA sequence (CAT) linked to PDX-1 cDNA. When the mice were crossed with Alb-Cre mice, which express the Cre recombinase driven by the rat albumin gene promoter, PDX-1 was expressed in more than 50% of hepatocytes and cholangiocytes. The PDX-1 (+) livers expressed a variety of endocrine hormone genes such as insulin, glucagon, somatostatin, and pancreatic polypeptide. In addition, they expressed exocrine genes such as elastase-1 and chymotrypsinogen 1B. However, the mice exhibited marked jaundice due to conjugated hyperbilirubinemia, and the liver tissue displayed abnormal lobe structures and multiple cystic lesions. Thus, the in vivo ectopic expression of PDX-1 in albumin-producing cells was able to initiate but not complete the differentiation of liver cells into pancreatic cells. The conditional PDX-1 transgenic mouse system developed in this study appeared to be useful for efficient screening of PDX-1 responsive somatic tissues and cells.

Background & Aims: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c- kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) α, we examined whether GISTs without KIT mutations had a mutation of PDGFR α. Methods: Whole coding region of PDGFR α complementary DNA (cDNA) was sequenced in GISTs with or without KIT mutations. Mutant PDGFR α cDNA was transfected into 293T human embryonic kidney cells, and autophosphorylation of PDGFR α was examined. Proliferation of Ba/F3 murine lymphoid cells stably transfected with mutant PDGFR α cDNA was estimated by tritium thymidine incorporation. Wild-type KIT cDNA was cotransfected with mutant PDGFR α cDNA, and immunoprecipitation by anti-KIT antibody was performed. Inhibitory effect of Imatinib mesylate on activated PDGFR α was examined. Results: We found 2 types of constitutively activated mutations of PDGFR α, Val-561 to Asp or Asp-842 to Val, in 5 of 8 GISTs without KIT mutations but not in 10 GISTs with KIT mutations. Stable transfection of each mutation induced autonomous proliferation of Ba/F3 cells. Constitutively activated mutant PDGFR α bound and activated the cotransfected wild-type KIT. The constitutive activation of PDGFR α with Val-561 to Asp was inhibited effectively by Imatinib mesylate but that of PDGFR α with Asp-842 to Val was inhibited only weakly, even at the concentration of 10 μmol/L. Conclusions: The gain-of-function mutations of PDGFR α appear to play an important role in development of GISTs without KIT mutations.

A family with multiple gastrointestinal stromal tumors (GISTs), a new type of germline mutation of KIT gene, and dysphagia is reported. The mutation was observed at Asp-820 in tyrosine kinase (TK) II domain. Mutations in TK II domain have been found in mast cell and germ cell tumors but not in GISTs, and the present family members are the first reported cases of GISTs with TK II domain mutations, including sporadic GISTs. Because interleukin 3-dependent Ba/F3 murine lymphoid cells transfected with the mutant KIT complementary DNA grew autonomously without any growth factors and formed tumors in nude mice, the mutation was considered to be gain-of-function type. Family members with the germline KIT mutation reported dysphagia, but those without the mutation did not. The mechanism of dysphagia was examined with gastrointestinal fiberscopy, endoscopic ultrasonography, and esophageal manometry. No mechanical obstruction was found, and the esophagus was not remarkably dilated. In the family members with dysphagia, endoscopic ultrasonography at the esophagocardiac junction showed a thickened hyperechoic layer between the circular and longitudinal muscle layers, suggesting hyperplasia of interstitial cells of Cajal at the myenteric plexus layer. Manometry showed low resting lower esophageal sphincter pressure and abnormal simultaneous contractions of the esophagus without normal peristalsis. These findings indicate that the dysphagia of the present family is different from typical achalasia. This is the first report of familial dysphagia caused by germline gain-of-function mutation of the KIT gene at the TK II domain.

Background & Aims Methylation of specific microRNAs (miRNAs) often occurs in an age-dependent manner, as a field defect in some instances, and may be an early event in colitis-associated carcinogenesis. We aimed to determine whether specific mRNA signature patterns (MIR1, MIR9, MIR124, MIR137, MIR34B/C) could be used to identify patients with ulcerative colitis (UC) who are at increased risk for colorectal neoplasia. Methods We obtained 387 colorectal tissue specimens collected from 238 patients with UC (152 without neoplasia, 17 with dysplasia, and 69 with UC-associated colorectal cancer [UC-CRC]), from 2 independent cohorts in Japan between 2005 and 2015. We quantified methylation of miRNAs by bisulfite pyrosequencing analysis. We analyzed clinical data to determine whether miRNA methylation patterns were associated with age, location, or segment of the colorectum (cecum, transverse colon, and rectum). Differences in tissue miRNA methylation and expression levels were compared among samples and associated with cancer risk using the Wilcoxon, Mann-Whitney, and Kruskal–Wallis tests as appropriate. We performed a validation study of samples from 90 patients without UC and 61 patients with UC-associated dysplasia or cancer to confirm the association between specific methylation patterns of miRNAs in non-tumor rectal mucosa from patients with UC at risk of UC-CRC. Results Among patients with UC without neoplasia, rectal tissues had significantly higher levels of methylation levels of MIR1, MIR9, MIR124, and MIR137 than in proximal mucosa; levels of methylation were associated with age and duration of UC in rectal mucosa. Methylation of all miRNAs was significantly higher in samples from patients with dysplasia or CRC compared with samples from patients without neoplasia. Receiver operating characteristic analysis revealed that methylation levels of miRNAs in rectal mucosa accurately differentiated patients with CRC from those without. Methylation of MIR137 in rectal mucosa was an independent risk factor for UC-CRC. Methylation patterns of a set of miRNAs (panel) could discriminate discriminate UC patients with or without dysplasia or CRC in the evaluation cohort (area under the curve, 0.81) and the validation cohort (area under the curve, 0.78). Conclusions In evaluation and validation cohorts, we found specific miRNAs to be methylated in rectal mucosal samples from patients with UC with dysplasia or CRC compared with patients without neoplasms. This pattern also associated with patient age and might be used to identify patients with UC at greatest risk for developing UC-CRC. Our findings provide evidence for a field defect in rectal mucosa from patients with UC-CRC.

It is well known that coronary artery (CA) in maintenance dialysis patients demonstrates diffuse stenosis and severe calcified plaques. Recently, diabetic nephropathy is a major course of hemodialysis. Although previous study indicated medial calcification of muscular arteries in these patients

Loss-of-function mutations of the c-kit receptor tyrosine kinase (KIT) result in depletion of mast cells and interstitial cells of Cajal (ICCs). In contrast, gain-of-function mutations of KIT induce neoplasms of mast cells and ICCs. In humans, the sites of mutations are different between mast cell neoplasms and those of ICCs. The former were found in the juxtamembrane domain between the transmembrane and tyrosine kinase domains, and the latter in the tyrosine kinase domain. Moreover, the mechanism of constitutive activation is different. Point mutations and/or deletions in the juxtamembrane domain induced the KIT dimerization, and the dimerized KIT was activated. A point mutation at the particular aspartic acid in the tyrosine kinase domain induced spontaneous activation without forming dimers. Mutations of the c-kit gene are a good model for understanding the relationship between mutations and diseases in both humans and mice.

We evaluated the clonality of seborrheic keratoses using a polymorphism due to the random inactivation of one of two X chromosomes in females. Thirty-eight seborrheic keratoses obtained from the skin of females with polymorphism of the human androgen receptor (HUMARA) locus were examined by a fluorescent polymerase chain reaction procedure, which allowed accurate measurement of the peak intensities of each HUMARA allele. The epithelial portion of seborrheic keratosis and normal control epidermis adjacent to the seborrheic keratosis were removed by laser capture microdissection. As biopsied specimens of seborrheic keratoses contained small amounts of normal epidermis, the effect of digestion by a restriction enzyme (HhaI) recognizing the nonmethylated active sites was compared between seborrheic keratoses and normal control epidermis in only five seborrheic keratosis cases. Disappearance or significant reduction in intensity of one of two HUMARA alleles was observed after HhaI digestion in seborrheic keratoses, but not in the normal control epidermis. Although the skewing of the polymorphism was not corrected by the normal control epidermis in the remaining 33 seborrheic keratosis cases, one of two HUMARA peaks practically disappeared after HhaI digestion in 20 of 33 seborrheic keratosis cases. In total, 25 of 38 seborrheic keratoses were considered to be monoclonal. The histologic type of seborrheic keratoses did not affect clonality.

A 70-year-old woman was admitted to our hospital due to cardiogenic shock and died of heart failure 1 day after admission. She had a 12-year history of hemodialysis. Biodegradable-polymer biolimus-eluting stent (NOBORI, Terumo Corporation, Tokyo, Japan) was implanted in the left anterior