Publications by authors named "Mitsunori Yamakawa"

107 Publications

Metastatic Orbital Tumor From Breast Ductal Carcinoma With Neuroendocrine Differentiation Initially Presenting as Ocular Symptoms: A Case Report and Literature Review.

Front Endocrinol (Lausanne) 2021 22;12:625663. Epub 2021 Feb 22.

Department of Ophthalmology and Visual Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan.

Background: Orbital metastases from cancers of various organs can arise the hematogenous route, and many originate from breast, prostate, and lung cancers. Such metastatic orbital tumors may be diagnosed before the primary tumor. We have encountered a case of breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and responded to chemotherapy, with improvement in visual function.

Case Presentation: A woman in her fifties visited our ophthalmology department with a chief complaint of foreign body sensation and exophthalmos in her right eye. An elastic soft mass was palpated from the lateral orbit to the temporal region. A systemic examination revealed breast cancer and a metastatic orbital tumor. Excisional biopsy of the breast revealed a diagnosis of invasive ductal carcinoma with neuroendocrine differentiation, and immunohistochemical examination was negative for cytokeratin 7, making the case unusual. Chemotherapy was remarkably effective, and the tumor size decreased, resulting in improvement of visual function. Her general condition and quality of life are still good at present. We searched the PubMed English language literature focusing on metastatic orbital tumors from breast cancer in which ocular symptoms had been the initial presenting sign. No previous reports have documented neuroendocrine differentiation or cytokeratin 7 expression in isolated orbital metastases from breast cancer. Although it is not possible to be certain from this case alone, we speculated that some such cases might involve cytokeratin 7-negative invasive breast cancer with neuroendocrine differentiation.

Conclusion: We have described our experience of a very rare case of cytokeratin 7 negative breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and formed a solitary giant tumor initially manifesting as ocular symptoms.
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http://dx.doi.org/10.3389/fendo.2021.625663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937957PMC
February 2021

Developmental retardation in neonates of aldehyde reductase (AKR1A)-deficient mice is associated with low ascorbic acid and high corticosterone levels.

J Nutr Biochem 2021 05 4;91:108604. Epub 2021 Feb 4.

Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan. Electronic address:

Aldehyde reductase encoded by the Akr1a gene catalyzes the NADPH-dependent reduction of a variety of aldehyde compounds, and it plays a role in the biosynthesis of ascorbic acid (AsA) by converting D-glucuronate to L-gulonate. Although supplementing drinking water with AsA (1.5 mg/mL) ameliorates the fertility of Akr1a (KO) female mice, litter sizes in the KO mice are typically smaller than those for Akr1a (WT) mice, and about one-third of the neonates have a reduced stature. Half of the neonates in the smallest, developmentally retarded group died before weaning, and the remaining half (less than 6 g in weight) also barely grew to adulthood. While no difference was found in the number of fetuses between the KO and WT mice at 14.5-embryonic days, the sizes of the KO fetuses had already diverged. Among the organs of these retarded KO neonates at 30 d, the spleen and thymus were characteristically small. While an examination of spleen cells showed the normal proportion of immune cells, apoptotic cell death was increased in the thymus, which would lead to thymic atrophy in the retarded KO neonates. Plasma AsA levels were lower in the small neonates despite the fact that their mothers had received sufficient AsA supplementation, and the corticosterone levels were inversely higher compared to wild-type mice. Thus, insufficient AsA contents together with a defect in corticosterone metabolism might be the cause of the retarded growth of the AKR1A-deficient mice embryos and neonates.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108604DOI Listing
May 2021

Potential role of M2 TAMs around lymphatic vessels during lymphatic invasion in papillary thyroid carcinoma.

Sci Rep 2021 01 13;11(1):1150. Epub 2021 Jan 13.

Department of Diagnostic Pathology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

The aim of this study was to examine whether lymphatic invasion in papillary thyroid carcinoma (PTC) occurs when tumour-associated macrophages (TAMs) injure lymphatic vessels together with cancer cells. While there was no difference in the lymphatic vessel density in PTC and follicular thyroid carcinoma (FTC), the number of TAMs around the lymphatic vessels was increased in PTC compared to that in FTC. In particular, TAMs were observed together with cancer cells in lymphatic invasive lesions, and the number of M2 cells inside and outside the lymphatic vessels showed a significant correlation. MMP-2 mRNA was expressed in nonneoplastic stromal cells as well as cancer cells, and double immunofluorescence staining confirmed M2 positivity. Consequently, this study reveals that M2 TAMs around lymphatic vessels within the tumour border of PTC may be associated with the lymphatic invasion of cancer cells. This study represents a step forward in elucidating the mechanism of lymphatic invasion.
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http://dx.doi.org/10.1038/s41598-020-80694-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806843PMC
January 2021

Nodal histiocytic sarcoma with prominent eosinophilic infiltration: expression of eotaxin-2 on tumor cells.

Diagn Pathol 2021 Jan 12;16(1). Epub 2021 Jan 12.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

Background: Histiocytic sarcoma (HS) is a rare neoplasm showing morphological and immunophenotypic features of mature tissue histiocytes. We report a patient with nodal HS exhibiting prominent reactive eosinophilic infiltration.

Case Presentation: A 68-year-old man presented with intermittent left lower abdominal pain and weight loss over 3 months. A computed tomography scan revealed multiple abdominal nodules. Open biopsy of the mesenteric tumors was performed for definitive diagnosis. Histologically, the tumor was comprised of a diffuse noncohesive proliferation of pleomorphic large cells, including multinucleated cells. Neoplastic cells were positive for histiocytic markers (CD68, CD163, and LIGHT) and PD-L1 but lacked markers of Langerhans cells, follicular dendritic cells, and epithelial cells. Frequent reactive inflammatory cells were intermingled in the background. Interestingly, prominent eosinophilic infiltration was also noted. Spindle neoplastic cells were prone to be present around areas with little to no eosinophilic infiltration and exhibiting fibrosis and lymphatic vessel proliferation. Conversely, polygonal neoplastic cells were prone to be present around areas with relatively large amounts of eosinophilic infiltration without fibrosis or lymphatic vessel proliferation. Immunohistochemically, the tumor cells and reactive eosinophils expressed eotaxin-2 and eotaxin-3, respectively.

Conclusion: We revealed that eotaxins induced the selective migration of eosinophils into tissues in this case. These eosinophils may affect the tumor remodeling and tumor biology characteristics of HS, such as fibrosis and lymphatic vessel proliferation.
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http://dx.doi.org/10.1186/s13000-020-01061-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805230PMC
January 2021

Cytokeratin-positive interstitial reticulum cell (CIRC) tumor in the lymph node: a case report of the transformation from the epithelioid cell type to the spindle cell type.

Diagn Pathol 2020 Sep 26;15(1):121. Epub 2020 Sep 26.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan.

Background: Cytokeratin-positive interstitial reticulum cells (CIRCs), which are a subgroup of fibroblastic reticular cells (FRCs), are known to be present in the lymph nodes. There have been only a few cases of tumors derived from CIRCs.

Case Presentation: We have reported a new case involving a CIRC tumor in a 75-year-old man and reviewed the literature. The resected mediastinal lymph nodes showed epithelial-like proliferation of large atypical round and polygonal epithelioid cells. The tumor cells expressed CK8, CK18, CAM5.2, AE1/AE3, epithelial membrane antigen, vimentin, fascin, and some FRC markers, which is consistent with the diagnosis of a CIRC tumor. Following chemotherapy, the CIRC tumor was observed to have responded very well and became difficult to confirm on imaging, but a small cell lung carcinoma developed 12 months later. Chemoradiotherapy was performed, but the patient passed away 29 months after the initial diagnosis. The autopsy revealed the recurrence of the CIRC tumor, residual small cell lung carcinoma, and a very small latent carcinoma of the prostate. The relapsed CIRC tumor cells had a spindle shape; they were highly pleomorphic and had invaded the superior vena cava.

Conclusion: We first reported autopsy findings of CIRC tumors and demonstrated the transformation of the tumor from the epithelioid cell type to the spindle cell type.
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http://dx.doi.org/10.1186/s13000-020-01032-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519525PMC
September 2020

Iron loading exerts synergistic action via a different mechanistic pathway from that of acetaminophen-induced hepatic injury in mice.

Free Radic Res 2020 Sep 28;54(8-9):606-619. Epub 2020 Sep 28.

Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan.

Acetaminophen (APAP) overdose is a major cause of drug-induced acute liver failure. In such cases, free iron is released from lysosomes and is transported to mitochondria where it plays a pivotal role in APAP-induced liver injury. We previously reported that ascorbic acid (Asc) markedly mitigates APAP-induced hepatic damage in aldehyde reductase (Akr1a)-knockout (KO) mice that produce about 10% Asc as wild-type (WT) mice. However, the issue of the protective mechanism of Asc in association with the status of iron remains ambiguous. To gain additional insights into this issue, we examined effects of APAP (500 mg/kg) on female KO mice under conditions of iron loading. While the KO mice without AsA supplementation were more sensitive to APAP toxicity than the WT mice, FeSO loading (25 mg/kg) to WT mice aggravated the hepatic injury, which was a similar extent to that of the KO mice. Supplementation of Asc (1.5 mg/ml in the drinking water) ameliorated KO mice irrespective of iron status but did not change the iron-mediated increase in the lethality in the WT mice. Hepatic cysteine and glutathione levels declined to similar extents in all mouse groups at 3 h irrespective of the iron status and largely recovered at 18 h after the APAP treatment when liver damage was evident. Asc prominently mitigated APAP toxicity in KO mice irrespective of the iron status but had no effect on the synergistic action of iron and APAP in the WT mice, suggesting that the mechanism for the deteriorating action of loaded iron is different from that of APAP toxicity.
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http://dx.doi.org/10.1080/10715762.2020.1819996DOI Listing
September 2020

A Patient with 22q11.2 Deletion Syndrome Presenting with Systemic Skin Rash and Dermatopathic Lymphadenitis of Unusual Histology.

Am J Case Rep 2020 Aug 26;21:e924961. Epub 2020 Aug 26.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata City, Yamagata, Japan.

BACKGROUND Chromosome 22q11.2 deletion syndrome (22q11.2 DS) currently includes DiGeorge syndrome, conotruncal anomaly face syndrome, and velocardiofacial syndrome. We present the case of a male infant with 22q11.2 DS exhibiting generalized skin rash and dermatopathic lymphadenitis. CASE REPORT The patient was born at 40 weeks of gestation with interruption of aortic arch, ventricular septal defect, and thymic defect. Fluorescence in situ hybridization method performed on buccal smears detected the deletion of 22q11.2. On day of life 33, diffuse erythema appeared on the entire body. A skin biopsy detected vacuolar interface dermatitis with superficial perivascular infiltration. Laboratory examinations revealed eosinophilia and hypocalcemia. Clinically, cutaneous inflammation was correlated with the abnormal immune response in 22q11.2 DS. On day of life 210, the patient died due to sepsis caused by Pseudomonas aeruginosa. An autopsy revealed lymph nodes swellings in the bilateral axillar and subclavicular areas and around the bilateral iliac arteries. Histology of the lymph nodes demonstrated sparse distribution of atrophic germinal centers surrounded by wide zones of proliferating spindle cells, as well as macrophages, Langerhans cells, and interdigitating dendritic cells. Fontana-Masson staining revealed abundant melanin particles in the macrophages. Accordingly, we diagnosed this case as dermatopathic lymphadenitis. Interestingly, CD123 and CD56 double-positive spindle cells also proliferated around the germinal center. CONCLUSIONS This case had an unusual histological feature of dermatopathic lymphadenitis. Considering the wide variety of unusual immune conditions in 22q11.2 DS, the lymph nodes in the systemic skin inflammation may exhibit an extraordinary histology of spindle cells proliferation.
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http://dx.doi.org/10.12659/AJCR.924961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476748PMC
August 2020

[A case of fibrinogen storage disease with primary biliary cholangitis].

Nihon Shokakibyo Gakkai Zasshi 2020 ;117(8):726-732

Department of Gastroenterology, Faculty of Medicine, Yamagata University.

A 66-year-old woman was diagnosed as primary biliary cholangitis (PBC) and was previously hospitalized for ascites and jaundice. She came to our hospital for further examination of the liver by needle biopsy, which showed interface hepatitis that mainly comprised lymphocytes and inflammatory infiltrates in the bile duct in the portal area. On the other hand, numerous intracytoplasmic inclusions that were positive for fibrinogen immunostaining were seen in the lobular area. Finally, we histologically diagnosed as PBC with fibrinogen storage disease (FSD). FSD is rare disease that leads to liver damage caused by abnormal fibrinogen storage in the endoplasmic reticulum of hepatocytes, with only four cases reported in Japan until now.
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http://dx.doi.org/10.11405/nisshoshi.117.726DOI Listing
August 2020

Immunohistochemical staining as supportive diagnostic tool for pseudomyxoma peritonei arising from intraductal papillary mucinous neoplasm: A report of two cases and literature review.

Pancreatology 2020 Sep 7;20(6):1226-1233. Epub 2020 Jul 7.

Department of Surgery, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

Background/objectives: Pseudomyxoma peritonei (PMP) arising from an intraductal papillary mucinous neoplasm of the pancreas (IPMN) is a rare condition. The diagnosis of IPMN as the origin of PMP is mainly inferred from the clinical course and the exclusion of PMP from other organs. The pathological diagnosis has not yet been established. To evaluate the usefulness of immunohistochemical staining for the diagnosis of the primary lesion of PMP as IPMN.

Methods: There are 2 cases of PMP arising from IPMN between March 2010 and December 2019 at National Center for Global Health and Medicine. A PubMed search that reported PMP arising from IPMN identified 16 additional cases. Diagnostic methods and clinicopathological features of 18 cases were compared.

Results: Four cases including our two cases used immunohistochemical staining for the diagnosis of PMP arising from IPMN. The correspondence of the immunohistochemical staining between PMP and IPMN was shown in the three cases including previously reported two cases and one of our two cases to identify the primary lesion of PMP as IPMN. In addition, we revealed that the comparison of the immunostaining pattern of PMP with the representative immunostaining pattern of the candidate primary lesions is helpful for the diagnosis of the primary lesion of PMP.

Conclusions: Immunohistochemical staining is helpful to identify the primary lesion of PMP as IPMN.
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http://dx.doi.org/10.1016/j.pan.2020.06.008DOI Listing
September 2020

The distribution of macrophage subtypes and their relationship to bone morphogenetic protein 2 in calcified aortic valve stenosis.

Am J Transl Res 2020 15;12(5):1728-1740. Epub 2020 May 15.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine Yamagata, Japan.

Activation of the osteogenic signaling cascade (OSC) is thought to be involved in aortic valve stenosis. The aim of this study was to clarify the distribution of macrophage (M) subtypes in the calcified aortic valve and to clarify the relationship between osteoblast-like cells (OLC) and OSC activation. Thirty-six cases of calcified aortic valve were set as the calcification group, and six autopsy cases of aortic valve without pathological calcification comprised the noncalcification group. Aortic valve tissues were used in histological studies including single and double immunostaining to identify M subtypes, bone morphogenetic protein 2 (BMP2) and osteopontin, reverse transcription polymerase chain reaction (RT-PCR) for , (), and mRNAs and RT-PCR for mRNA. Ms positive for CD68, CD163, CD206, and HO-1 were significantly higher in the calcification group than in the noncalcification group (P < 0.01). Comparison of the positive cells in each section of the calcification group showed that cells of all M subtypes were found around calcifications. Osteopontin cells were also observed around calcifications. CD163/CD206 M2 and CD163/HO-1 Mox were significantly higher in the sponge layer in both groups. In double immunofluorescence, CD206 and a portion of HO-1 Ms expressed BMP2, and in RT-PCR, or mRNA was expressed in cases in which BMP2 was expressed. In RT-PCR, expression of mRNA was observed around calcifications. This work clarifies the distribution of M subtypes in calcified aortic valves. In addition, the results suggest that CD206 M2 and HO-1 Mox, which express BMP2 in calcified aortic valves, are OLC candidates.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270035PMC
May 2020

Diabetes mellitus exacerbates citrin deficiency via glucose toxicity.

Diabetes Res Clin Pract 2020 Jun 23;164:108159. Epub 2020 Apr 23.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan; Department of Pediatrics, Miyukikai Hospital, Kaminoyama, Japan. Electronic address:

Aims: Citrin is an aspartate/glutamate carrier that composes the malate-aspartate reduced nicotinamide adenine dinucleotide (NADH) shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD) and adult-onset type II citrullinemia (CTLN2). Hepatic glycolysis is essentially impaired in citrin deficiency and a low-carbohydrate diet was recommended. The lethal effect of infusion of glycerol- and fructose-containing osmotic agents was reported in these patients. Hyperalimentation was also reported to exacerbate CTLN2; however, glucose toxicity was unclear in citrin deficiency.

Methods: We studied two CTLN2 patients complicated with type 2 diabetes mellitus (DM), Case 1 presented with hyperammonemic encephalopathy accompanied with DM, while Case 2 presented with hyperammonemic encephalopathy relapse upon the onset of DM after several years' remission following supplementation with medium-chain triglycerides (MCT) and adherence to a low-carbohydrate diet.

Results: Insulin therapy with MCT supplementation and a low-carbohydrate diet improved hyperammonemia and liver function in Case 1. Additional insulin therapy improved hyperammonemia in Case 2.

Conclusion: Glucose is not toxic for citrin deficiency in normoglycemia because glucose uptake and metabolism by hepatocytes are limited in normoglycemia. However, glucose becomes toxic during persistent hyperglycemia and antidiabetic therapy is indispensable for CTLN2 patients with DM.
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http://dx.doi.org/10.1016/j.diabres.2020.108159DOI Listing
June 2020

A case of iatrogenic immunodeficiency-associated colonic lymphoma complicating ulcerative colitis.

Diagn Pathol 2020 Apr 7;15(1):34. Epub 2020 Apr 7.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.

Background: Ulcerative colitis (UC) is one of the major types of inflammatory bowel diseases and is associated with a significantly increased risk of not only lymphoproliferative disorders but also lymphomas, of which most cases are related to the long-term usage of immunosuppressants. Here, we demonstrate a very rare case of other iatrogenic immunodeficiency-associated colonic diffuse large B-cell lymphoma (Oii-DLBCL) complicating UC and rectal perforation. In addition, we reviewed the clinicopathological features of previous cases of DLBCL related to UC.

Case Presentation: A 68-year-old man was diagnosed with left-sided UC 26 months prior. Although he was followed by immunosuppressive therapy with azathioprine and infliximab, an emergency total proctocolectomy was performed due to rectal perforation. The resected specimen exhibited irregular wall thickening and elevated multinodular lesions extending from the mid-transverse colon to the rectum, measuring up to 52 cm in length. Histologically, the lesion was diagnosed as Oii-DLBCL and crypt abscess surrounded by mixed inflammatory cell was remained.

Conclusion: Oii-DLBCL complicating UC with rectal perforation is extremely rare. Macro- and microscopic findings are important for early diagnosis of the lesion.
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http://dx.doi.org/10.1186/s13000-020-00954-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137478PMC
April 2020

Good prognosis for follicular lymphoma with estrogen receptor α-positive follicular dendritic cells.

Hematol Oncol 2020 Aug 13;38(3):293-300. Epub 2020 Apr 13.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan.

Follicular lymphoma (FL) has a meshwork of follicular dendritic cells (FDCs). We previously demonstrated the presence of estrogen receptor alpha (ERα) CD23 FDCs in grades 1-2 FL. The significance of FDCs as a prognostic factor in FL remains unknown. The current study aimed to compare clinicopathological features, including prognosis, between FL with and without ERα FDCs. This study evaluated the clinicopathological significance of ERα expression in 70 FL patients by immunostaining. The presence of ERα mRNA on FDCs from 5 FL patients was confirmed by CD21/ERα double staining (immunohistochemistry and in situ hybridization). We defined patients with frequent ERα expression as the ERα group and those with infrequent ERα expression as the ERα group. Thirty-two patients were assigned to the ERα group (45.7%), and 38 patients were assigned to the ERα group (54.3%). Both overall survival (OS) and progression-free survival (PFS) were significantly better in the ERα group than in the ERα group (OS, log-rank, P = .0465; PFS, log-rank, P = .0336). Moreover, high ERα expression on FDCs was an independent prognostic factor for OS in both the univariate ([hazard ratio] HR, 0.163; P = .0260) and multivariate (HR, 0.050; P = .0188) analyses and for PFS in both the univariate (HR, 0.232; P = .0213) and multivariate (HR, 0.084; P = .0243) analyses. ERα mRNA expression was detected in CD21 FDCs within the neoplastic follicles of FL patients. In conclusion, a neoplastic follicular microenvironment with ERα-positive FDCs might affect the grade and presence of the follicular pattern of FL and improve patient prognosis.
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http://dx.doi.org/10.1002/hon.2730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496718PMC
August 2020

Relationships between recurrence patterns and subventricular zone involvement or CD133 expression in glioblastoma.

J Neurooncol 2020 Feb 4;146(3):489-499. Epub 2020 Feb 4.

Department of Neurosurgery, Faculty of Medicine, Yamagata University, 2-2 Iida-Nishi, Yamagata, Yamagata, 990-9585, Japan.

Introduction: We previously reported that CD133 expression correlated with the recurrence pattern of glioblastoma (GBM). Subventricular zone (SVZ) involvement may also be associated with distant recurrence in GBM. Therefore, we herein investigated whether the combined analysis of SVZ involvement and CD133 expression is useful for predicting the pattern of GBM recurrence.

Materials And Methods: We retrospectively analyzed 167 cases of GBM. Tumors were divided into four groups based on spatial relationships between contrast-enhanced lesions (CEL) and the SVZ or cortex (Ctx) on MRI. The initial recurrence pattern (local/distant) was obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by immunohistochemical, clinical (age, sex, KPS, Ki-67 labeling index, surgery, and MRI characteristics), and genetic (IDH1, MGMT, and BRAF) factors.

Results: The CD133 expression rate was higher in SVZ-positive tumors than in SVZ-negative tumors (P = 0.046). Distant recurrence was observed in 21% of patients, and no significant difference was noted in recurrence patterns among the four groups. However, strong CD133 expression was associated with a shorter time to distant recurrence in univariate, multivariate, and propensity-matched scoring analyses (P < 0.0001, P = 0.001, and P = 0.0084, respectively). In the combined analysis, distant recurrence was the most frequent (70%) in group III (SVZ-negative, Ctx-positive) GBM and those with high CD133 expression rates (≥ 15%).

Conclusion: An integrated analysis of CD133 expression and MRI-based tumor classification may be useful for predicting the recurrence pattern of GBM.
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http://dx.doi.org/10.1007/s11060-019-03381-yDOI Listing
February 2020

Effect of cold and hot compress on neutrophilic migration to the site of doxorubicin extravasation.

Int J Clin Exp Pathol 2019 1;12(4):1468-1477. Epub 2019 Apr 1.

Department of Diagnostic Pathology, Yamagata University Faculty of Medicine Yamagata, Japan.

In the present study, we investigated a part of the mechanism responsible for the effects of hot and cold compresses for extravasation of doxorubicin. We injected 20 μl of doxorubicin (DOX) (1 μg/μl) subcutaneously into the dorsal area in mice and observed the resulting skin lesions macroscopically and histologically from day 1 to day 14 thereafter in groups treated with a cold pack (18-20°C) and a hot pack (38-40°C) or left untreated (control). Immunofluorescence and RT-PCR for C5a receptor (CD88), interleukin-8 receptor (IL-8RA), and transient receptor potential cation channel subfamily V member 1 (TRPV1) were also performed. Macroscopic observation showed that the area of the skin lesion was significantly smaller in the cold group than in the control group, but was significantly larger in the hot group. The neutrophil count in the lesion was significantly higher in the hot group than in the cold (3 hrs) and control groups. The numbers of inflammatory cells expressing CD88 and IL-8RA were significantly lower in the cold group than that in the other groups at almost time points and in the hot groups at later time points, respectively. The number of nerve fascicles expressing TRPV1 was higher in the hot group than in the cold group on days 1, 3 and 14. mRNA for CD88, IL-8RA and TRPV1 was detectable by reverse transcription-polymerase chain reaction in both the cold and hot pack groups. Consequently, these results suggested that the cold pack for the extravasation of DOX might reduce inflammation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947076PMC
April 2019

Primary mesenchymal chondrosarcoma of the kidney without and fusion: A case report and review.

Oncol Lett 2020 Jan 22;19(1):885-891. Epub 2019 Nov 22.

Department of Urology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan.

Mesenchymal chondrosarcoma (MC) of the kidney is rare. To the best of our knowledge, the current report is the first case of a giant extraskeletal MC that arose primarily from the right kidney and mimicked renal cell carcinoma at the locally advanced stage (cT3bN0) with vena cava thrombus and multiple pulmonary arterial tumor emboli. Additionally, the literature on renal EMC is reviewed and the possibilities of oncogenic heterogeneity are discussed. A 64-year-old woman was admitted to Yamagata University Hospital for sudden onset of asymptomatic gross hematuria. CT revealed a 90 mm renal mass without calcification in the right kidney and tumor thrombus extending to the inferior vena cava. Radical nephrectomy with thrombectomy was performed. Lung metastasis was detected 2 months later. The patient received systemic chemotherapy, which was only marginally effective. She died of the malignancy 8 months after surgery. Microscopic examination of the tumor revealed typical histology of MC and a lack of and gene fusions in the tumor tissues. Not all MC patients may exhibit chromosomal alterations in the tumor, suggesting the presence of genetically heterogeneous pathways of MC oncogenesis. Further studies are required to confirm the present findings and reinforce the molecular diagnosis of MC.
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http://dx.doi.org/10.3892/ol.2019.11143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924144PMC
January 2020

Comparative study of HO-1 expressing synovial lining cells between RA and OA.

Mod Rheumatol 2021 Jan 22;31(1):133-140. Epub 2020 Jan 22.

Faculty of Medicine, Department of Pathological Diagnostics, Yamagata University, Yamagata, Japan.

Objectives: We aimed to clarify the characteristics of heme oxygenase (HO)-1 expressing cells in the synovium from rheumatoid arthritis (RA) and osteoarthritis (OA), and to investigate the co-expression of HO-1 and IgG-Fc/HLA-DR complex.

Methods: The characteristics of HO-1 expressing cells in the synovium were investigated by using immunohistochemistry. The co-expression of HO-1 and IgG-Fc/HLA-DR complex was examined by an proximity ligation assay (PLA) with immunofluorescence. HO-1 mRNA was investigated by reverse transcription-polymerase chain reaction.

Results: The number of HO-1 cells from the RA synovium is higher than that from OA synovium. The double positive cells of HO-1 and IgG-Fc/HLA-DR complex were detected by the PLA with immunofluorescence in RA synovium. HO-1 mRNA was detected in both RA and OA synovium.

Conclusion: A portion of HO-1 cells with IgG-Fc/HLA-DR complex in lining layer of RA may be concluded as one of antigen presenting cells in RA and may be involved in production of RF.
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http://dx.doi.org/10.1080/14397595.2019.1704976DOI Listing
January 2021

A case of myeloid sarcoma of the mandibular gingiva as extramedullary relapse of acute myeloid leukemia.

Oral Maxillofac Surg 2020 Mar 1;24(1):121-126. Epub 2019 Dec 1.

Department of Dentistry, Oral and Maxillofacial-Plastic and Reconstructive Surgery, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.

Purpose: Myeloid sarcoma (MS) is defined as a tumorous mass of myeloblasts or immature myeloid cells involving an extramedullary anatomic site. MS occurs in 3 to 8% of patients with acute myeloid leukemia. The overwhelming majority of MS occurs in the skin, bones, and gastrointestinal tract; intraoral MS (IMS) is extremely rare.

Methods: We describe a case of MS of the mandibular gingiva in a patient with acute myeloid leukemia that was in remission. We also present a review of the English and Japanese literature with a special focus on the management and prognosis of intraoral MS.

Results: The patient was discharged while in remission 8 months after the initial examination.

Conclusion: The prognosis of IMS is extremely poor in general, and a diagnostic delay can prevent adequate therapy by hematologists and oncologists. All dental clinicians must keep the possibility of IMS in mind and carefully examine all patients with AML.
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http://dx.doi.org/10.1007/s10006-019-00812-yDOI Listing
March 2020

Diagnostic utility of CD205 in breast cancer: Simultaneous detection of myoepithelial cells and dendritic cells in breast tissue by CD205.

Histol Histopathol 2020 May 16;35(5):481-488. Epub 2019 Sep 16.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan.

Background: CD205 can be used to detect myoepithelial cells (MECs) and dendritic cells (DCs) in breast tissue. However, the usefulness of CD205 immunostaining in the pathological diagnosis of breast tumors is not fully understood. The objective of this study was to re-evaluate CD205 co-expression with other MEC markers, such as p63 and CD10, in nonneoplastic and neoplastic breast tissue and to evaluate its pathological diagnostic utility in these types of breast cancer.

Material And Methods: Nonneoplastic breast tissue samples with a terminal duct lobular unit and duct were obtained from fibroadenoma and mastopathy patients. Neoplastic breast tissue samples included ductal carcinoma in situ (DCIS) (n=43) and invasive ductal carcinoma (IDC) (n=60), including the tubule-forming type (n=20). These specimens were investigated by CD205, p63, and CD10 immunostaining.

Results: In addition to p63 and CD10, CD205 was expressed on MECs in nonneoplastic breast and DCIS tissue samples; CD205 was simultaneously detected on DCs that had infiltrated DCIS and IDC tumor nests. CD205 was expressed on cancer cells themselves in only 7.3% of the breast cancer samples. The number of intratumoral CD205⁺ DCs in tubular IDC was significantly higher than that in DCIS (P<0.01).

Conclusion: Because CD205 was simultaneously detected on MECs and DCs in the same breast tissue sections, it may be useful for distinguishing tubular IDC from DCIS.
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http://dx.doi.org/10.14670/HH-18-164DOI Listing
May 2020

Impact of eIF4E phosphorylation at Ser209 via MNK2a on tumour recurrence after curative surgery in localized clear cell renal cell carcinoma.

Oncotarget 2019 Jun 18;10(40):4053-4068. Epub 2019 Jun 18.

Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.

We investigated the roles of eIF4E phosphorylation (Ser209) in tumour recurrence after curative nephrectomy for localized clear cell renal cell carcinoma (ccRCC). Expression of eIF4E, p eIF4E and MNKs (MAPK interacting kinases), was evaluated in surgical specimens obtained from consecutive non metastatic ccRCC patients ( = 290) by immunohistochemistry (IHC), immunoblotting, and qRT PCR at the protein and mRNA levels. In human RCC cell lines, the effects of eIF4E phosphorylation were examined using immunoblotting, proliferation, migration and invasion assays with pharmacological inhibitors (CGP57380 or ETP45835) and specific small interfering (si) RNAs against MNK1/2(a/b). In postoperative follow-up (median, 7.9 y), 40 patients experienced metastatic recurrence. In multivariate Cox analyses, higher IHC expression of p eIF4E in ccRCC significantly predicted a longer recurrence-free interval. eIF4E is phosphorylated mainly by MNK2a in tumour specimens and cell lines. In 786-O and A-498 cell lines, pharmacological inhibition of MNKs decreased p-eIF4E and increased vimentin and N cadherin but did not influence proliferation. Similarly, MNK2 or MNK2a inhibition with siRNA reduced p-eIF4E and enhanced vimentin translation, cell migration and invasion in the cell lines. MNK2a-induced eIF4E phosphorylation may suppress metastatic recurrence of ccRCC, partially due to vimentin downregulation at the translational level, consequently leading to inhibition of epithelial-mesenchymal transition.
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http://dx.doi.org/10.18632/oncotarget.27017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592294PMC
June 2019

Increasing Heme Oxygenase-1-Expressing Macrophages Indicates a Tendency of Poor Prognosis in Advanced Colorectal Cancer.

Digestion 2020 21;101(4):401-410. Epub 2019 May 21.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan,

Background: Many cancers express heme oxygenase-1 -(HO-1) at a higher frequency than healthy tissues, and this elevated expression is associated with cancer prognosis. Here, we aim to clarify the correlation between HO-1-expressing macrophage numbers and clinicopathological parameters of advanced colorectal cancer.

Materials And Methods: Formalin-fixed and paraffin-embedded tissues of patients with advanced colorectal cancer were used. To detect HO-1 expression in macrophages, immunohistochemistry was performed. The number of positive cells was measured. Furthermore, HO-1 mRNA in colorectal cancer was examined by reverse transcription polymerase chain reaction.

Results: Among the HO-1-negative and HO-1-positive groups, 58.02 and 85.00% of cases, respectively, were positive for lymph node metastasis. The disease-free survival (DFS) time was significantly shorter (p < 0.05) in the -HO-1-positive group (2.44 years) than in the HO-1-negative group (4.09 years). However, according to the Cox proportional-hazards regression model, the HO-1-positive group could not be a risk factor of poor prognosis. HO-1 mRNA expression was confirmed in colorectal normal and cancer tissues.

Conclusion: In this study, the correlation between HO-1-expressing macrophages and clinicopathological parameters in the tumor microenvironment of colorectal cancer was studied for the first time, and the expression was associated with lymph node metastasis and shortening of DFS.
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http://dx.doi.org/10.1159/000500225DOI Listing
April 2021

Expression of total and phospho 4EBP1 in metastatic and non-metastatic renal cell carcinoma.

Oncol Lett 2019 Apr 12;17(4):3910-3918. Epub 2019 Feb 12.

Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Yamagata 990-9585, Japan.

Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) is phosphorylated and activated by mammalian target of rapamycin complex 1, which serves as a regulator of cell growth, cell survival, metastasis and angiogenesis in many types of cancer. The aim of this study was to evaluate the role of phosphorylated 4EBP1 (p4EBP1) in primary renal cell carcinoma (RCC) as a biomarker in metastatic RCC (mRCC) and non-mRCC cohorts. Primary tumor tissue from 254 non-mRCC and 60 mRCC patients were immunohistochemically stained for t4EBP1 and p4EBP1. The disease-free interval (DFI) categorized by the expressions and clinical parameters were assessed by univariate and multivariate analysis in the non-mRCC cohort. Then, the cause-specific survival (CSS) was assessed in the mRCC cohort by the same methods as used in the non-mRCC cohort. In the non-mRCC cohort, patients with t4EBP1 expression had no RCC recurrence. Patients with p4EBP1 expression had the shorter DFI in univariate analysis (P=0.037). p4EBP1 and pT1b-4 expression levels were independent predictors for metastasis. In the mRCC cohort, intermediate/poor MSKCC risk, non-clear cell RCC, and no p4EBP1 expression were correlated with poor CSS on multivariate analysis. Expression of p4EBP1 could be a predictive biomarker for metastasis in non-mRCC patient cohort. By contrast, mRCC patients showing no p4EBP1 expression had shorter CSS than patients with p4EBP1 expression.
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http://dx.doi.org/10.3892/ol.2019.10033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403496PMC
April 2019

[Hypopituitarism associated with autoimmune pancreatitis: a case report].

Nihon Shokakibyo Gakkai Zasshi 2019;116(2):168-176

Department of Gastroenterology, Faculty of Medicine, Yamagata University.

We herein report the case of a 64-year-old male patient with hypopituitarism associated with autoimmune pancreatitis (AIP). The patient was previously diagnosed with AIP based on the presence of a swollen pancreas, elevated serum immunoglobulin G4, and narrowing of the pancreatic duct by imaging. Magnetic resonance imaging revealed a pituitary stem tumor, and loading test showed a decrease in the function of the anterior lobe suggesting severe failure of growth hormone secretion. Treatment with steroids was effective in reducing the pituitary lesion and improving the function of the anterior lobe. The present case illustrates the importance of pituitary function evaluation before steroid treatment in patients with AIP.
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http://dx.doi.org/10.11405/nisshoshi.116.168DOI Listing
June 2019

Differential expression of estrogen receptor-α on follicular dendritic cells from patients with grade 1-2 and grade 3 follicular lymphoma.

Hematol Oncol 2019 Apr 20;37(2):151-159. Epub 2019 Mar 20.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan.

Hormone therapy has been used for patients with estrogen receptor alpha (ERα)-positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B-cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1-3 of FL. Reverse transcription-polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα-positive cells strongly correlated with the width of GCs (r  = 0.81, P < 0.01) and the CD21-positive (r  = 0.69, P < 0.01) and CD23-positive (r  = 0.83, P < 0.01) FDC meshwork. The axillary lymph nodes had fewer ERα-positive cells, smaller GCs, and a looser CD21- and CD23-positive FDC meshwork with hormone therapy than without hormone therapy (P < 0.01). Neoplastic follicles of G1-2 FL had more ERα-positive cells and a larger CD23 FDC meshwork than those of G3 FL (P < 0.01). ERα mRNA was detected in both G1-2 FL and G3 FL by reverse transcription-polymerase chain reaction. In conclusion, these results suggested that antiestrogen hormone therapy may decrease the number of ERα-positive FDCs and that the responses mediated by the estrogen-ERα interaction on FDCs may differ between G1-2 FL and G3 FL.
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http://dx.doi.org/10.1002/hon.2577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593816PMC
April 2019

Expression of TRPM8 in human reactive lymphoid tissues and mature B-cell neoplasms.

Oncol Lett 2018 Nov 3;16(5):5930-5938. Epub 2018 Sep 3.

Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Yamagata 990-9585, Japan.

Transient receptor potential melastatin 8 (TRPM8) is a member of the transient receptor potential superfamily of Ca channels. The aim of the present study was to clarify TRPM8 expression in reactive lymphoid tissues and mature B-cell neoplasms. Reactive and neoplastic lymphoid tissues were used to evaluate TRPM8 expression by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). TRPM8 cells were frequently detected in the follicular light zone and marginal zone of reactive lymphoid tissues. Double immunostaining revealed that TRPM8 cells co-expressed cluster of differentiation (CD) 38, CD79a, CD138, interferon regulatory factor 4/melanoma associated antigen (mutated) 1, B cell CLL/lymphoma 6 and transmembrane activator and CAML interactor. TRPM8 neoplastic cells were frequently detected in plasma cell myeloma. The positive band of TRPM8 mRNA was confirmed by RT-PCR in cases of myeloma. The present study is, to the best of our knowledge, the first to demonstrate the expression of TRPM8 in reactive lymphoid tissues and mature B-cell neoplasms, revealing that TRPM8 is frequently expressed in pre-plasmablasts, plasmablasts, plasma cells and mature B-cell lymphomas that are likely to differentiate into plasma cells.
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http://dx.doi.org/10.3892/ol.2018.9386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176370PMC
November 2018

Levels of 4EBP1/eIF4E Activation in Renal Cell Carcinoma Could Differentially Predict Its Early and Late Recurrence.

Clin Genitourin Cancer 2018 10 8;16(5):e1029-e1058. Epub 2018 Jun 8.

Department of Urology, Yamagata University, Faculty of Medicine, Yamagata, Japan.

Background: The objective was to explore the predictive markers of late recurrence (LR) > 5 years after curative nephrectomy for renal cell carcinoma (RCC).

Patients And Methods: We retrospectively examined the data from 303 patients with localized clear cell RCC treated surgically at our institution from 1993 to 2011. Activation of the eukaryotic initiation factor (eIF)4E-binding protein 1 (4EBP1)/eIF4E axis at the mammalian target of rapamycin complex 1 (mTORC1) was evaluated in the tumor specimens. Weak, intermediate, and strong immunohistochemistry staining grades were defined for 4EBP1, phosphorylated 4EBP1, and eIF4E. The effects of clinicopathologic factors and activation level grades on tumor recurrence were analyzed using multivariate Cox regression models. To validate the present findings, we investigated clinical data from The Cancer Genome Atlas and protein/phosphoprotein data from corresponding patients from The Cancer Proteome Atlas.

Results: Of the 303 patients, 31 and 16 patients developed early recurrence (ER, ≤ 5 years) and LR, respectively. The activation levels were comparable among the subcategories of pathologic TN stage, Fuhrman grade, and microvascular and capsular invasion. Pathologic stage ≥ T1b, Fuhrman grade 3/4, and an intermediate or strong activation level correlated significantly with overall recurrence and ER. Strong activation of the axis and pathologic stage ≥ T1b were identified as independent predictors of LR. Only 2 patients with weak activation experienced recurrence (1 each with ER and LR). Similar results were confirmed by the analyses of The Cancer Genome Atlas and The Cancer Proteome Atlas data.

Conclusion: The activation level of the axis in RCC tissues could independently predict for recurrence and differentially affect the timing of recurrence.
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http://dx.doi.org/10.1016/j.clgc.2018.06.002DOI Listing
October 2018

Steroidogenesis in ovarian-like mesenchymal stroma of hepatic and pancreatic mucinous cystic neoplasms.

Hepatol Res 2018 Nov 16;48(12):989-999. Epub 2018 Jul 16.

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

Steroidogenesis In Hepatic Mucinous Cystic Neoplasm: Aim Mucinous cystic neoplasms (MCNs) occur in the ovary, pancreas, and retroperitoneum but very rarely in the liver. Mucinous cystic neoplasms are known to harbor ovarian-like mesenchymal stroma (OLS) expressing progesterone and estrogen receptors. In this study we evaluated steroidogenesis in OLS of 25 hepatic MCNs and 24 pancreatic MCNs. Methods Both steroid receptors and steroidogenic factors were immunohistochemically evaluated using H-scores and results were compared with those in 15 ovarian MCNs and 10 normal ovaries. Results Androgen receptor (AR) H-scores in OLS were significantly higher in hepatic, pancreatic, and ovarian MCN than those in normal ovaries. H-scores of cytochrome P450 17α-hydroxylase/c17-20 lyase (P450c17) and 5α-reductase-1 (5αRED-1) in the stroma were significantly higher in OLS of hepatic and pancreatic MCN than in the stroma of ovarian MCN and normal ovary. In tumor epithelium, AR H-scores were significantly higher in hepatic and pancreatic MCN than in ovarian MCN. In both hepatic and pancreatic MCN, a significant positive correlation was detected between AR H-score in the epithelium and P450c17 H-score in OLS (hepatic MCN: Pearson's r = 0.446, P = 0.025; pancreatic MCN: r = 0.432, P = 0.035). In pancreatic MCN, a significantly positive correlation was detected between AR H-score in the tumor epithelium and 5αRED-1 H-score in OLS (Pearson's r = 0.458, P = 0.024). Conclusions These results indicated that locally produced androgens in OLS could be pivotal for tumorigenesis of both hepatic and pancreatic MCN and influence epithelial cells, possibly in a paracrine fashion, which could represent biological significance of OLS in these neoplasms.
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http://dx.doi.org/10.1111/hepr.13201DOI Listing
November 2018

Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult-onset type II citrullinemia.

J Inherit Metab Dis 2018 09 12;41(5):777-784. Epub 2018 Apr 12.

Department of Pediatrics, Tsuruoka Municipal Shonai Hospital, Tsuruoka, Japan.

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.
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http://dx.doi.org/10.1007/s10545-018-0176-1DOI Listing
September 2018
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