Publications by authors named "Yasuhiro Nakamura"

386 Publications

Clinicopathological Significance of Estrogen Receptor and Estrogen Synthesizing/Metabolizing Enzymes in Urothelial Carcinoma of Urinary Bladder.

Pathol Oncol Res 2021 15;27:589649. Epub 2021 Apr 15.

Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Sex-specific differences in the incidence of urinary bladder carcinomas are well known, and the possible involvement of sex steroids has been proposed. We previously reported the association of the loss of androgen receptors and androgen-producing enzymes with tumor progression of urinary bladder cancer patients. Clinically, the selective estrogen receptor modulators (SERMs) were reported to suppress the progression of these tumors but the status of estrogen receptors (ERs) has not been well studied in patients with bladder urinary cancer. Moreover, not only ERs but also estrogen-related enzymes, such as aromatase, steroid sulfatase (STS), and estrogen sulfotransferase (EST), have been reported in the biological/clinical behavior of various hormone-dependent carcinomas but not studied in urinary bladder carcinoma. Therefore, in this study, we immunolocalized ERs as well as estrogen metabolizing enzymes in urinary bladder carcinoma and performed immunoblotting and cell proliferation assays using the bladder urothelial carcinoma cell line, T24. The results revealed that the loss of STS and aromatase was significantly correlated with advanced stages of the carcinoma. studies also revealed that T24 cell proliferation rates were significantly ameliorated after treatment with estradiol or diarylpropionitrile (DPN). EST and aromatase were also significantly correlated with the nuclear grade of the carcinoma. The results of our present study, for the first time, demonstrated that biologically active estrogens that bind to ERs could suppress tumor progression and the inactive ones could promote its progression and the potential clinical utility of SERM treatment in selective patients with urinary bladder carcinoma.
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http://dx.doi.org/10.3389/pore.2021.589649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262212PMC
April 2021

Novel detection of the CAMTA1-WWTR1 fusion gene in extra-adrenal myelolipoma-like lesion: a case report.

Virchows Arch 2021 Jul 6. Epub 2021 Jul 6.

Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.

A mediastinal mass was incidentally detected by chest X-ray in a 44-year-old man. Computed tomography findings revealed that the mass was a possible malignancy in the right and middle mediastinum and was removed by surgical resection. Macroscopically, the resected specimen was a well-demarcated yellowish, brownish, and whitish mass. Microscopically, a solid lesion with cords of epithelioid cells in the extra-adrenal myelolipoma-like lesion was observed. Immunohistochemically, the solid lesion was positive for typical vascular markers and CAMTA1, the expression of which is highly specific for epithelioid hemangioendothelioma (EHE). The endothelial cells and bone marrow elements of myelolipoma-like lesion were also positive for CAMTA1. Fluorescence in situ hybridization examination detected the CAMTA1-WWTR1 fusion gene not only in the solid lesion but also in the endothelial cells and bone marrow elements of myelolipoma-like lesion. To our knowledge, this is the first report suggesting common genetic abnormality, CAMTA1-WWTR1 fusion, in cases of EHE and extra-adrenal myelolipoma.
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http://dx.doi.org/10.1007/s00428-021-03143-0DOI Listing
July 2021

Deficiency of Type I Platelet-Activating Factor-Acetylhydrolase Catalytic Subunits Causes an Increase in Body Weight.

Biol Pharm Bull 2021 ;44(7):920-925

Faculty of Pharma-sciences, Teikyo University.

Type I platelet-activating factor-acetylhydrolase (PAF-AH) forms a complex consisting of two catalytic subunits (α1 and/or α2) with a regulatory subunit (β). Although this protein was discovered as an enzyme that degrades an acetyl ester linked at the sn-2 position of platelet-activating factor (PAF), its physiological function remains unknown. In this study, to examine whether knockout mice lacking the catalytic subunits of this enzyme showed a different phenotype from that of wild-type mice, we measured and compared the body weights of knockout mice and control mice. The body weights of knockout mice were significantly increased compared to those of the control mice during 6 to 20 weeks from birth. Food intake was also significantly increased in knockout mice compared with control mice during these periods. Since a decrease in testis weight was reported in the knockout mice, we expected a decrease in testosterone levels. We measured and compared the amounts of testosterone in the serum and testis of knockout and control mice using liquid chromatography-tandem mass spectrometry, and found that testosterone levels in both the serum and testis were significantly decreased in the knockout mice compared with the control mice. These results suggest that a deficiency of type I PAF-AH catalytic subunits causes an increase in body weight, in part, due to reduced testosterone levels in male mice.
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http://dx.doi.org/10.1248/bpb.b20-00936DOI Listing
January 2021

A Solitary Necrotizing Sarcoid Granulomatosis-like Pulmonary Lesion Possibly Associated with Propionibacterium Acnes and Mycobacterium Avium.

Intern Med 2021 Jun 12. Epub 2021 Jun 12.

Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Japan.

We report a case of a pulmonary necrotizing sarcoid granulomatosis (NSG)-like lesion possibly associated with coinfection of Mycobacterium avium and Propionibacterium acnes. A solitary nodule in the right middle lobe of the lung was notable for coagulative necrosis with aggregates of sarcoid-like epithelioid granulomas. Small arteries were damaged by granulomas. Both M. avium and P. acnes were detected in the lesion. Furthermore, more P. acnes genomes were detected in the granulomas than in the non-lesion lung. These findings blur the pathophysiologic boundaries among NSG, sarcoidosis, and mycobacteriosis, and suggest that NSG needs to be recognized as continuous spectra of sarcoidosis/mycobcteriosis.
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http://dx.doi.org/10.2169/internalmedicine.7162-21DOI Listing
June 2021

Long-term resolution of invasive extramammary Paget's disease with multiple regional lymph node metastases solely with regional lymph node dissection.

J Dermatol 2021 Jun 12. Epub 2021 Jun 12.

Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, Japan.

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http://dx.doi.org/10.1111/1346-8138.16007DOI Listing
June 2021

Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study).

Jpn J Clin Oncol 2021 Jun 12. Epub 2021 Jun 12.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Background: Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma.

Methods: This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours.

Result: Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events.

Conclusion: The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.
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http://dx.doi.org/10.1093/jjco/hyab064DOI Listing
June 2021

Cellular Senescence in Human Aldosterone-Producing Adrenocortical Cells and Related Disorders.

Biomedicines 2021 May 18;9(5). Epub 2021 May 18.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on in situ senescence. We analyzed 30 surgical cases of aldosterone-producing adenoma (APA), 10 idiopathic hyperaldosteronism (IHA) and 19 normal adrenals (NA). CYP11B2 and senescence markers p16 and p21 were immunolocalized in all those cases above and results were correlated with histological/endocrinological findings. In the three cohorts examined, the zona glomerulosa (ZG) was significantly more senescent than other corticosteroid-producing cells. In addition, the ZG of adjacent non-pathological adrenal glands of APA and IHA had significantly higher p16 expression than adjacent non-pathological zona fasciculata (ZF), reticularis (ZR) and ZG of NA. In addition, laboratory findings of primary aldosteronism (PA) were significantly correlated with p21 status in -mutated tumors. Results of our present study firstly demonstrated that non-aldosterone-producing cells in the ZG were the most senescent compared to other cortical zones and aldosterone-producing cells in PA. Therefore, aldosterone production, whether physiological or pathological, could be maintained by suppression of cell senescence in human adrenal cortex.
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http://dx.doi.org/10.3390/biomedicines9050567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158118PMC
May 2021

Endoscopic Treatment of Sinonasal Leiomyosarcoma: A Case Report in Light of the Literature.

Yonago Acta Med 2021 May 15;64(2):217-221. Epub 2021 Apr 15.

Division of Pathology, Tohoku Medical and Pharmaceutical University, Sendai 981-8536, Japan.

A 49-year-old Japanese man presented with a rare case of sinonasal leiomyosarcoma with left nasal bleeding for 12 months. He had no history of irradiation or malignancies, including retinoblastoma. Preoperative histological examination suggested vascular leiomyoma. Complete resection with endoscopic surgery was performed. Histological examination during the operation suggested that the tumor was a leiomyoma. However, immunohistochemical staining for α smooth muscle actin and desmin were helpful in establishing a definitive diagnosis of sinonasal leiomyosarcoma. The resection margins were positive for tumor cells. Staging with CT of the neck and thorax, ultrasound of the abdomen, and MRI of the head ruled out metastases. Second endoscopic tumor resection surgery was performed for positive resection margins. The patient's condition was successfully managed with additional excision, and he remains well with no evidence of recurrence and metastasis 36 months after treatment. Endoscopic management should be considered in suitable cases.
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http://dx.doi.org/10.33160/yam.2021.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128653PMC
May 2021

Pathology of Aldosterone Biosynthesis and its Action.

Tohoku J Exp Med 2021 ;254(1):1-15

Department of Pathology, Tohoku University, Graduate School of Medicine.

Aldosterone plays pivotal roles in renin-angiotensin-aldosterone system in order to maintain the equilibrium of liquid volume and electrolyte metabolism. Aldosterone action is mediated by both mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive actions directly induced tissue injuries in its target organs such as myocardial and vascular fibrosis in addition to chronic kidney diseases. Excessive aldosterone actions were also reported to be involved in unbalanced electrolyte metabolism in inflammatory bowel disease and development of pulmonary diseases. Hyperaldosteronism is tentatively classified into primary and secondary types. Primary aldosteronism is more frequent and has been well known to result in secondary hypertension with subsequent cardiovascular damages. Primary aldosteronism is also further classified into distinctive subtypes and among those, aldosterone-producing adenoma is the most frequent one accounting for the great majority of unilateral primary aldosteronism cases. In bilateral hyperaldosteronism, aldosterone-producing diffuse hyperplasia and aldosterone-producing micronodules or nodules are the major subtypes. All these aldosterone-producing lesions were reported to harbor somatic mutations including KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which were all related to excessive aldosterone production. Among those mutations above, somatic mutation of KCNJ5 is the most frequent in aldosterone-producing adenoma and mostly composed of clear cells harboring abundant aldosterone synthase expression. In contrast, CACNA1D-mutated aldosterone-producing micronodules or aldosterone-producing nodules were frequently detected not only in primary aldosteronism patients but also in the zona glomerulosa of normal adrenal glands, which could eventually lead to an autonomous aldosterone production resulting in normotensive or overt primary aldosteronism, but their details have remained unknown.
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http://dx.doi.org/10.1620/tjem.254.1DOI Listing
January 2021

Histological and immunohistochemical characteristics and status studied by FISH in six incidentally detected cases of well-differentiated papillary mesothelioma of the peritoneum.

Indian J Pathol Microbiol 2021 Apr-Jun;64(2):277-281

Division of Pathology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial neoplasm, which is generally regarded as benign or indolent in terms of its clinical behavior. However, details about WDPM have remained relatively unknown. Therefore, in this study, we examined six incidentally detected cases of WDPM of the peritoneum. All six cases were surgically excised, without any additional therapeutic measures. None of the cases showed recurrence. All six cases presented single lesions and the tumor sizes ranged from 2 to 10 mm. Histologically, all six cases exhibited papillary proliferation of cytologically bland mesothelial cells with a fibroconnective tissue core. One of the cases (Case 6) presented small invasive foci in the stalk. The tumor cells were immunohistochemically positive for mesothelial markers and negative for GLUT-1, p53, and CD146. The Ki-67 labeling index of the tumor cells was lower than 5% at the hot spots. All samples were BAP1-positive. None of the samples presented p16 homozygous deletion, as assessed by fluorescence in situ hybridization (FISH). None of the patients deceased due to WDPM. However, in Case 3, death occurred due to pancreatic cancer. The results of this study indicate the importance of analyzing immunohistochemical markers and p16 status to diagnose WDPM accurately.
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http://dx.doi.org/10.4103/IJPM.IJPM_111_20DOI Listing
April 2021

Recent Development toward the Next Clinical Practice of Primary Aldosteronism: A Literature Review.

Biomedicines 2021 Mar 17;9(3). Epub 2021 Mar 17.

Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

For the last seven decades, primary aldosteronism (PA) has been gradually recognized as a leading cause of secondary hypertension harboring increased risks of cardiovascular incidents compared to essential hypertension. Clinically, PA consists of two major subtypes, surgically curable and uncurable phenotypes, determined as unilateral or bilateral PA by adrenal venous sampling. In order to further optimize the treatment, surgery or medications, diagnostic procedures from screening to subtype differentiation is indispensable, while in the general clinical practice, the work-up rate is extremely low even in the patients with refractory hypertension because of the time-consuming and labor-intensive nature of the procedures. Therefore, a novel tool to simplify the diagnostic flow has been recently in enormous demand. In this review, we focus on recent progress in the following clinically important topics of PA: prevalence of PA and its subtypes, newly revealed histopathological classification of aldosterone-producing lesions, novel diagnostic biomarkers and prediction scores. More effective strategy to diagnose PA based on better understanding of its epidemiology and pathology should lead to early detection of PA and could decrease the cardiovascular and renal complications of the patients.
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http://dx.doi.org/10.3390/biomedicines9030310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002562PMC
March 2021

Mycobacterium leprae promotes triacylglycerol de novo synthesis through induction of GPAT3 expression in human premonocytic THP-1 cells.

PLoS One 2021 26;16(3):e0249184. Epub 2021 Mar 26.

Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Itabashi-ku, Tokyo, Japan.

Mycobacterium leprae (M. leprae) is the etiological agent of leprosy, and the skin lesions of lepromatous leprosy are filled with numerous foamy or xanthomatous histiocytes that are parasitized by M. leprae. Lipids are an important nutrient for the intracellular survival of M. leprae. In this study, we attempted to determine the intracellular lipid composition and underlying mechanisms for changes in host cell lipid metabolism induced by M. leprae infection. Using high-performance thin-layer chromatography (HPTLC), we demonstrated specific induction of triacylglycerol (TAG) production in human macrophage THP-1 cells following M. leprae infection. We then used [14C] stearic acid tracing to show incorporation of this newly synthesized host cell TAG into M. leprae. In parallel with TAG accumulation, expression of host glycerol-3-phosphate acyltransferase 3 (GPAT3), a key enzyme in de novo TAG synthesis, was significantly increased in M. leprae-infected cells. CRISPR/Cas9 genome editing of GPAT3 in THP-1 cells (GPAT3 KO) dramatically reduced accumulation of TAG following M. leprae infection, intracellular mycobacterial load, and bacteria viability. These results together suggest that M. leprae induces host GPAT3 expression to facilitate TAG accumulation within macrophages to maintain a suitable environment that is crucial for intracellular survival of these bacilli.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249184PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997041PMC
March 2021

The Genotype-Based Morphology of Aldosterone-Producing Adrenocortical Disorders and Their Association with Aging.

Endocrinol Metab (Seoul) 2021 Feb 24;36(1):12-21. Epub 2021 Feb 24.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosteroneproducing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.
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http://dx.doi.org/10.3803/EnM.2021.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937858PMC
February 2021

The Liver Surface Is an Attractive Transplant Site for Pancreatic Islet Transplantation.

J Clin Med 2021 Feb 12;10(4). Epub 2021 Feb 12.

Division of Transplantation and Regenerative Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-0872, Japan.

In the current clinical islet transplantation, intraportal transplantation is regarded as the gold-standard procedure. However, in this procedure, 50 to 70% of the transplanted islets are immediately damaged due to a strong innate immune response based on islet-blood contact. We investigated the transplant efficiency of a novel method of liver surface transplantation using a syngeneic keratinocyte sheet to avoid islet-blood contact. To examine the influence of the keratinocyte sheet, substantial amounts of syngeneic islets (8 IEQs/g) were transplanted on the liver surface of diabetic rats, while marginal amounts of islets (4 IEQs/g) were transplanted via intraportal transplantation to compare the transplant efficiency. Blood glucose, intraperitoneal glucose tolerance, immunohistochemistry, and in vivo imaging findings of the cell sheet were evaluated. The study showed that islet transplantation to the liver surface immediately followed by a syngeneic keratinocyte sheet covering was effective for curing diabetic rats, while no rats were cured in the group without the cell sheet. Notably, islet grafts transplanted via this approach appeared to penetrate into the liver parenchyma. However, the transplant efficiency did not reach that of intraportal transplantation. Further refinements of this approach by introducing mesothelial or fibroblast cell sheets in combination with a preferable scaffold for islet grafts may help to improve the transplant efficiency.
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http://dx.doi.org/10.3390/jcm10040724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918755PMC
February 2021

Gender differences in human adrenal cortex and its disorders.

Mol Cell Endocrinol 2021 04 11;526:111177. Epub 2021 Feb 11.

Department of Pathology, Tohoku University Graduate School of Medicine, Japan. Electronic address:

The adrenal cortex plays pivotal roles in the maintenance of blood volume, responsiveness to stress and the development of gender characteristics. Gender differences of human adrenal cortex have been recently reported and attracted increasing interests. Gender differences occur from the developing stage of the adrenal, in which female subjects had more activated stem cells with higher renewal capacity resulting in gender-associated divergent structures and functions of cortical zonations of human adrenal. Female subjects generally have the lower blood pressure with the lower renin levels and ACE activities than male subjects. In addition, HPA axis was more activated in female than male, which could possibly contribute to gender differences in coping with various stressful events in our life. Of particular interest, estrogens were reported to suppress RAAS but activate HPA axis, whereas androgens had opposite effects. In addition, adrenocortical disorders in general occur more frequently in female with more pronounced adrenocortical hormonal abnormalities possibly due to their more activated WNT and PRK signaling pathways with more abundant activated adrenocortical stem cells present in female adrenal glands. Therefore, it has become pivotal to clarify the gender influence on both clinical and biological features of adrenocortical disorders. We herein reviewed recent advances in these fields.
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http://dx.doi.org/10.1016/j.mce.2021.111177DOI Listing
April 2021

Re: INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer.

Pathology 2021 Feb 29;53(2):292-293. Epub 2020 Dec 29.

Department of Pathology, Saitama Medical University International Medical Center, Hidaka, Japan.

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http://dx.doi.org/10.1016/j.pathol.2020.12.001DOI Listing
February 2021

Metastatic Renal Cell Carcinoma to the Left Sphenoid Sinus: A Case Report in Light of the Literature.

Yonago Acta Med 2020 Nov 15;63(4):368-371. Epub 2020 Oct 15.

Division of Pathology, Tohoku Medical and Pharmaceutical University, Sendai 981-0905, Japan.

A 79-year-old Japanese woman presented with a rare case of metastatic renal cell carcinoma to the left sphenoid sinus with left nasal bleeding. She had previously had right radical nephrectomy for renal cell carcinoma at the age of 64 years and brain and spinal cord infarction at 74 years. Endoscopic examination revealed no mass in the nasal cavity. CT and MRI revealed a tumor in the left sphenoid sinus. The size of the tumor increased gradually from 12 to 15 years after the radical nephrectomy. Complete resection with endoscopic surgery was performed without preoperative embolization. The tumor cells had clear cytoplasm and were arranged in a trabecular pattern lined by a layer of endothelial cells. These findings were identical to the pathological findings of the surgical specimen of the renal cell carcinoma from 15 years previous. A pathological diagnosis of metastatic renal cell carcinoma of clear cell type (grade 1) was made. PET-CT demonstrated no metastasis. The patient's condition was successfully managed with excision of the tumor, and she remains well with no evidence of recurrence and metastasis 36 months after treatment. Metastatic renal cell carcinoma to the sphenoid sinus is rare, but it might be considered in the differential diagnosis of masses in the paranasal sinus even long after initial treatment of renal cancer.
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http://dx.doi.org/10.33160/yam.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683906PMC
November 2020

Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma.

Front Endocrinol (Lausanne) 2020 10;11:587779. Epub 2020 Nov 10.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Pheochromocytomas (PHEOs) are relatively rare catecholamine-producing tumors derived from adrenal medulla. Tumor microenvironment (TME) including neoangiogenesis has been explored in many human neoplasms but not necessarily in PHEOs. Therefore, in this study, we examined tumor infiltrating lymphocytes (CD4 and CD8), tumor associated macrophages (CD68 and CD163), sustentacular cells (S100p), and angiogenic markers (CD31 and areas of intratumoral hemorrhage) in 39 cases of PHEOs in the quantitative fashion. We then compared the results with pheochromocytoma of the adrenal gland scaled score (PASS), grading system for pheochromocytoma and paraganglioma (GAPP) and the status of intra-tumoral catecholamine-synthesizing enzymes (TH, DDC, and PNMT) as well as their clinicopathological factors. Intratumoral CD8 (p = 0.0256), CD31 (p = 0.0400), and PNMT (p = 0.0498) status was significantly higher in PHEOs with PASS <4 than PASS ≧4. In addition, intratumoral CD8 lymphocytes were also significantly more abundant in well-than moderately differentiated PHEO according to GAPP score (p = 0.0108) and inversely correlated with tumor size (p = 0.0257). Intratumoral CD68 cells were significantly higher in PHEOs with regular or normal histological patterns than those not (p = 0.0370) and inversely correlated with tumor size (p = 0.0457). The status of CD163 was significantly positively correlated with that of CD8 positive cells (p = 0.0032). The proportion of intratumoral hemorrhage areas was significantly higher in PHEOs with PASS ≧4 (p = 0.0172). DDC immunoreactivity in tumor cells was significantly positively correlated with PASS score (p = 0.0356) and TH status was significantly higher in PHEOs harboring normal histological patterns (p = 0.0236) and cellular monotony (p = 0.0219) than those not. Results of our present study did demonstrate that abundant CD8 and CD68 cells could represent a histologically low-scored tumor. In particular, PHEOs with increased intratumoral hemorrhage should be considered rather malignant. In addition, abnormal catecholamine-producing status of tumor cells such as deficient PNMT and TH and increased DDC could also represent more aggressive PHEOs.
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http://dx.doi.org/10.3389/fendo.2020.587779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685215PMC
May 2021

Recent Advances in Histopathological and Molecular Diagnosis in Pheochromocytoma and Paraganglioma: Challenges for Predicting Metastasis in Individual Patients.

Front Endocrinol (Lausanne) 2020 27;11:587769. Epub 2020 Oct 27.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Pheochromocytomas and paragangliomas (PHEO/PGL) are rare but occasionally life-threatening neoplasms, and are potentially malignant according to WHO classification in 2017. However, it is also well known that histopathological risk stratification to predict clinical outcome has not yet been established. The first histopathological diagnostic algorithm for PHEO, "PASS", was proposed in 2002 by Thompson et al. Another algorithm, GAPP, was then proposed by Kimura et al. in 2014. However, neither algorithm has necessarily been regarded a 'gold standard' for predicting post-operative clinical behavior of tumors. This is because the histopathological features of PHEO/PGL are rather diverse and independent of their hormonal activities, as well as the clinical course of patients. On the other hand, recent developments in wide-scale genetic analysis using next-generation sequencing have revealed the molecular characteristics of pheochromocytomas and paragangliomas. More than 30%-40% of PHEO/PGL are reported to be associated with hereditary genetic abnormalities involving > 20 genes, including , and others. Such genetic alterations are mainly involved in the pathogenesis of pseudohypoxia, , and kinase signaling, and other intracellular signaling cascades. In addition, recurrent somatic mutations are frequently detected and overlapped with the presence of genetic alterations associated with hereditary diseases. In addition, therapeutic strategies specifically targeting such genetic abnormalities have been proposed, but they are not clinically applicable at this time. Therefore, we herein review recent advances in relevant studies, including histopathological and molecular analyses, to summarize the current status of potential prognostic factors in patients with PHEO/PGL.
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http://dx.doi.org/10.3389/fendo.2020.587769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652733PMC
May 2021

A Facelift Procedure for Resection of Benign Parapharyngeal Tumors.

Otolaryngol Pol 2020 Jun;74(5):1-5

Department of Otolaryngology, Head and Neck Surgery, Toho University Faculty of Medicine, Tokyo, Japan.

<b>Objective:</b> The feasibility, surgical outcomes and possible risks and complications encountered during a facelift procedure for patients with parapharyngeal space (PPS) tumor were analyzed. <br><b>Method:</b> This retrospective analysis examined 10 patients who underwent surgery for PPS tumor using a facelift incision at our institutes between April 2015 and August 2019. <br><b>Results:</b> This study included four retro-styloid (benign nerve sheath tumor) and six pre-styloid tumors (pleomorphic adenoma). Mean tumor dimensions were 4.1 x 4.2 x 3.8 cm respectively. None of the patients needed conversion to conventional open resection. Transient sensory changes in the auricle occurred in 30% of the patients; however, all recovered within four months. In all the patients, postoperative scars were fully concealed by the auricle and hair. No recurrences were detected during a mean follow-up period of 16.6 months. <br><b>Conclusion: </b>The facelift procedure provides adequate visualization, workspace and excellent cosmetic results in properly selected cases.
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http://dx.doi.org/10.5604/01.3001.0014.1614DOI Listing
June 2020

Intratumoral heterogeneity of the tumor cells based on in situ cortisol excess in cortisol-producing adenomas; ∼An association among morphometry, genotype and cellular senescence∼.

J Steroid Biochem Mol Biol 2020 11 28;204:105764. Epub 2020 Sep 28.

Department of Pathology, Tohoku University Graduate School of Medicine, Japan. Electronic address:

Cortisol-producing adrenocortical adenomas (CPAs) are associated with ACTH-independent Cushing's syndrome and histologically composed of two cellular subtypes: compact (lipid-poor) and clear (lipid-rich) tumor cells. However, the details of hormonal and biological activities of these tumor cells have remained unknown, especially in CPAs. CPAs frequently harbored unique histological features different from those of aldosterone-producing adenomas (APAs) including a senescent phenotype. Therefore, we explored the association between morphological features and the immunoreactivity of steroidogenic enzymes in CPAs with different genotypes and compared them with cellular senescence markers as well as clinicopathological factors of the cases. Hormonal activities (3βHSD, CYP21A, CYP17A1, CYP11B1 and DHEA-ST) and cellular senescence markers (p16, p21 and Ki-67) within different morphological features (clear and compact) were evaluated in 40 CPAs. CPA genotypes (PRKACA, GNAS and CTNNB1) were examined by Sanger sequencing and then compared them with the factors above. p21 immunoreactivity was significantly positively correlated with that of CYP21A (p = 0.0110), CYP17A1 (p = 0.0356) and DHEA-ST (p = 0.0420) but inversely with tumor size (p = 0.0015). CYP21A (p = 0.0016), CYP11B1 (p = 0.0001), CYP17A1 (p < 0.0001) and p16 (p = 0.0137) immunoreactivity were all significantly higher in compact cells than those in clear cells. CYP17A1 (p = 0.0056) and 3βHSD (p = 0.0437) immunoreactivity was significantly higher in PRKACA-mutated than wild type CPAs. p16 immunoreactivity and serum DHEA-S level were both significantly higher in GNAS-mutated than PRKACA-mutated (p = 0.0250) and wild type (p = 0.0180) CPAs. Results of our present study did demonstrate that compact tumor cells were hormonally active and more senescent than clear tumor cells in CPAs. PRKACA- and GNAS-mutated tumor cells were more hormonally active and senescent than those without mutations despite the similar morphological features. We herein proposed a novel histological classification of the tumor cell subtypes based on in situ cortisol excess, genotypes and the status of cell senescence in CPAs.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105764DOI Listing
November 2020

Repeated complete response with long-term control of BRAF-mutant melanoma by multiple rechallenges with dabrafenib plus trametinib.

Eur J Cancer 2020 11 18;139:37-40. Epub 2020 Sep 18.

Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, Japan.

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http://dx.doi.org/10.1016/j.ejca.2020.08.012DOI Listing
November 2020

Progressive plasmacytoid variant bladder cancer with retroperitoneal dissemination: An autopsy case report.

IJU Case Rep 2020 Sep 28;3(5):166-169. Epub 2020 May 28.

Division of Urology Faculty of Medicine Tohoku Medical and Pharmaceutical University Sendai Japan.

Introduction: Plasmacytoid urothelial carcinoma is a rare and aggressive variant of bladder cancer.

Case Presentation: A 75-year-old woman presented with plasmacytoid urothelial carcinoma with retroperitoneal dissemination was treated with chemotherapy. After an unsuccessful first-line chemotherapy with gemcitabine and cisplatin, we assessed circulating tumor cells; one such cell was found to be positive for programmed death-ligand 1. The patient received second-line chemotherapy with pembrolizumab. However, the tumor extended to the retroperitoneal organs, and the patient eventually died. Autopsy revealed a widespread diffuse scirrhous infiltration of the carcinoma into the retroperitoneum. However, distant metastasis was not observed.

Conclusion: The evaluation of circulating tumor cells and autopsy revealed a disease state of progressive plasmacytoid urothelial carcinoma treated with pembrolizumab.
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http://dx.doi.org/10.1002/iju5.12167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469833PMC
September 2020

Prediction of the invasive level of basal cell carcinomas in the facial area: Analysis of 718 Japanese cases.

J Dermatol Sci 2020 Sep 4;99(3):152-157. Epub 2020 Jul 4.

Department of Dermato-Oncology / Dermatology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.

Background: Basal cell carcinoma (BCC) is the most common skin cancer. While Mohs micrographic surgery is commonly accepted for BCC treatment, surgical excision with free margins is widely considered the best treatment modality for BCCs in Japan. However, little is known about the predictors of the invasion levels of BCCs.

Objective: To investigate the optimization of deep surgical margins by identifying factors significantly influencing the invasion levels of facial BCCs.

Methods: The tumor invasion level was defined as the deepest part of a tumor. Tumor thickness was measured from the top of the granular layer to the deepest extension of the tumor or from the ulcer base overlying the deepest point of invasion in ulcerated lesions. Factors independently associated with tumor thickness and invasion level were identified by multivariate analysis. Six variables were tested: age, sex, anatomical region (nose, orbit, others), histologic pattern (aggressive, non-aggressive), presence of pigmentation, and diameter.

Results: We included 718 cases of facial BCCs involving 705 Japanese patients. The most frequent anatomical region and histologic pattern were the nose and nodular pattern, respectively. Only tumor diameter showed a correlation with tumor thickness (β = 0.377, P < 0.001). Tumor diameter (AOR = 71.189, 95 % CI: 11.420-430.931, P = 0.01) and the following anatomical regions showed correlations with the invasion level: nose/others: AOR=2.769, 95 % CI: 1.235-6.493, P = 0.01; orbit/others: AOR=6.369, 95 % CI: 2.728-15.429, P < 0.001; orbit/nose: AOR=2.300, 95 % CI: 1.056-4.984, P = 0.04.

Conclusions: This study serves as a guide for optimizing deep surgical margins and planning surgery for facial BCCs considering independently associated factors.
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http://dx.doi.org/10.1016/j.jdermsci.2020.07.001DOI Listing
September 2020

Adrenal Corticomedullary Mixed Tumor Associated With the -G388R Variant.

J Endocr Soc 2020 Sep 21;4(9):bvaa101. Epub 2020 Jul 21.

Department of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan.

Adrenal corticomedullary mixed tumors (CMMTs) are extremely rare; with only 20 cases being reported to date, the pathogenesis has remained elusive. A 31-year-old woman developed gestational hypertension with psychiatric disturbances persistent to postpartum and was diagnosed with pheochromocytoma, for which adrenalectomy was performed. Histological findings showed mixed adrenocortical adenoma and pheochromocytoma. Double immunostaining of inhibin and INSM1 (insulinoma-associated protein 1) showed that the 2 tumor components had distinct functional properties. Exome analysis of peripheral leukocytes and tumor (singular, as anatomically it is only 1 mass) revealed a homozygous germline -G388R variant. As a readout of the variant, serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was detected only in the nucleus of adrenocortical adenoma component but not in the pheochromocytoma component. No tyrosine phosphorylation of STAT3 was detected. We report a case of CMMT with the germline -G388R variant. Although additional studies are required, our immunohistochemical analysis suggests that the variant may play a role in the development of the adrenocortical component within the pheochromocytoma, leading to CMMT.
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http://dx.doi.org/10.1210/jendso/bvaa101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417000PMC
September 2020

Assessment of suitable antihypertensive therapies: Combination with high-dose amlodipine/irbesartan vs triple combination with amlodipine/irbesartan/indapamide (ASAHI-AI study).

J Clin Hypertens (Greenwich) 2020 09 6;22(9):1577-1584. Epub 2020 Aug 6.

Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.

Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (-19.2/-9.2 mm Hg in Group 1 and -21.6/-8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients.
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http://dx.doi.org/10.1111/jch.13977DOI Listing
September 2020

Preoperative denosumab treatment with curettage may be a risk factor for recurrence of giant cell tumor of bone.

J Orthop Surg (Hong Kong) 2020 Jan-Apr;28(2):2309499020929786

Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Purpose: Giant cell tumor of bone (GCTB) is a local aggressive bone tumor, histologically classified as intermediate malignancy. Recently, the RANKL inhibitor, denosumab, was developed as a novel and effective treatment option for GCTB. Since the risk of preoperative use of denosumab with curettage had been previously reported, this study aimed to investigate the relationship between recurrences and clinicopathological features associated with adjuvant denosumab treatment in GCTB.

Methods: A total of 87 GCTB cases were treated at our institution. We reviewed 66 patients with conventional-type GCTB occurring in the extremities and analyzed 78 surgical treatments, including curettages and resections, with clinicopathological features and denosumab treatment.

Results: GCTB lesions, including 66 primary and 12 recurring, underwent surgical treatment like curettage and resection. Recurrence-free survivals in 78 GCTB surgeries were 78.7% in 3 years and 71.9% in 5 years. In the resected cases of GCTBs, there was no recurrence either with or without denosumab. In curettage cases, 3-year recurrence-free survivals were 0.0% ( = 3) in preoperative treatment of denosumab, 66.7% ( = 6) in postoperative treatment, and 76.6% ( = 43) in no treatment. Interestingly, three preoperative treatment cases demonstrated low MIB-1 index despite 100% recurrence. The other clinicopathological factors did not contribute much to the risk of recurrence in curettage cases.

Conclusion: Our findings revealed the use of denosumab in GCTB, prior to curettage, to possibly increase the risk of local recurrence. Together with previous reports, our finding might provide information for beneficial treatment of GCTB.
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http://dx.doi.org/10.1177/2309499020929786DOI Listing
February 2021

Detection of Macrophage Localization in the Abdominal Aortic Aneurysm Wall Using Ex Vivo Superparamagnetic Iron Oxide-Enhanced Magnetic Resonance Imaging.

Ann Vasc Surg 2020 Oct 18;68:344-350. Epub 2020 May 18.

Department of Surgery, Tohoku University Hospital, Sendai, Miyagi, Japan.

Background: Macrophages in the aneurysmal wall play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Superparamagnetic iron oxide (SPIO) is a macrophage-specific contrast agent that results in negative enhancement on magnetic resonance imaging (MRI). SPIO-enhanced MRI targeting the intraluminal thrombus of AAAs has been previously reported. However, macrophages in the media and adventitia of AAA wall have not been investigated in detail. This study aimed to evaluate macrophage localization using SPIO-enhanced MRI in the media and adventitia of AAA wall, as macrophages play a crucial role in AAA pathogenesis.

Methods: Here, we included study and control patients planning to undergo open surgery for AAA. The study patients received SPIO injection 2 days preoperatively (the SPIO group, n = 7), whereas the control patients did not receive this injection (the control group). Ex vivo MRI was performed on the harvested AAA wall in the SPIO group during the surgery. The concordance between the number of macrophages and berlin blue (BB)-stained areas was histologically evaluated in both groups. Moreover, the concordance between regions of interest in MR images and BB-stained areas was evaluated.

Results: The proportion of BB-stained macrophages was higher in the SPIO group (0.93; interquartile range [IQR], 0.83-0.95) than in the control group (0.03; IQR, 0.026-0.11) (P < 0.05), indicating uptake of SPIO by macrophages in the AAA wall. A significant positive correlation was found between the number of BB-stained macrophages and BB-stained areas using Kendall rank correlation coefficient in the SPIO group (τ = 0.58; P < 0.05). Significant correlations were found in the distributions of the region of interest of SPIO-enhanced MRI and BB-stained areas in the media and adventitia in 5 of 7 patients.

Conclusions: Macrophages present in the media and adventitia of the AAA wall showed an uptake of the SPIO contrast agent injected 2 days prior, which were then detected by ex vivo MRI. This suggests that SPIO-enhanced MR images help detect the localization of macrophages on the AAA wall, indicating its potential to serve as a novel index for AAA pathogenesis.
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http://dx.doi.org/10.1016/j.avsg.2020.04.067DOI Listing
October 2020