Publications by authors named "Hiroko Ikeda"

263 Publications

Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies.

J Hum Genet 2021 May 6. Epub 2021 May 6.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs.
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http://dx.doi.org/10.1038/s10038-021-00932-yDOI Listing
May 2021

Physiological and pathological roles of the accommodation response in lower esophageal sphincter relaxation during wet swallows.

Sci Rep 2021 Apr 12;11(1):7898. Epub 2021 Apr 12.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, Japan.

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1-11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, - 0.6-6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5-44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18-28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice.
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http://dx.doi.org/10.1038/s41598-021-87052-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042112PMC
April 2021

De novo ATP1A3 variants cause polymicrogyria.

Sci Adv 2021 Mar 24;7(13). Epub 2021 Mar 24.

Department of Pediatrics, Tottori Prefectural Central Hospital, Tottori 680-0901, Japan.

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo variants in eight patients. Mutated causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with abnormalities.
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http://dx.doi.org/10.1126/sciadv.abd2368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990330PMC
March 2021

Neural EGFL like 2 expressed in myoepithelial cells and suppressed breast cancer cell migration.

Pathol Int 2021 Mar 3. Epub 2021 Mar 3.

Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.

Breast tissue has a branching structure that contains double-layered cells, consisting primarily of luminal epithelial cells inside and myoepithelial cells outside. Ductal carcinoma in situ (DCIS) still has myoepithelial cells surrounding the cancer cells. However, myoepithelial cells disappear in invasive ductal carcinoma. In this study, we detected expression of neural EGFL like (NELL) 2 and one of its receptors, roundabout guidance receptor (ROBO) 3, in myoepithelial and luminal epithelial cells (respectively) in normal breast tissue. NELL2 also was expressed in myoepithelial cells surrounding the non-cancerous intraductal proliferative lesions and DCIS. However, the expression level and proportion of NELL2-positive cells in DCIS were lower than those in normal and non-cancerous intraductal proliferative lesions. ROBO3 expression was decreased in invasive ductal carcinoma compared to that in normal and non-cancerous intraductal proliferative lesions. An evaluation of NELL2's function in breast cancer cell lines demonstrated that full-length NELL2 suppressed cell adhesion and migration in vitro. In contrast, the N-terminal domain of NELL2 increased cell adhesion in the early phase and migration in vitro in some breast cancer cells. These results suggested that full-length NELL2 protein, when expressed in myoepithelial cells, might serve as an inhibitor of breast cancer cell migration.
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http://dx.doi.org/10.1111/pin.13087DOI Listing
March 2021

Neuropeptide Y and glutamatergic mechanisms in the amygdala and ventral hippocampus differentially mediate impaired social behavior in diabetic mice.

Behav Brain Res 2021 May 19;405:113195. Epub 2021 Feb 19.

Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. Electronic address:

Though patients with diabetes mellitus are reported to show deficits in social interaction, the mechanisms of these impairments are unclear. The present study investigated the role of AMPA and neuropeptide Y (NPY) receptors in the ventral hippocampus (vHC) and basolateral amygdala (BLA) in the social behavior of diabetic mice. In the three-chamber test, streptozotocin (STZ)-induced diabetic mice showed impairment in social novelty preference, but not in sociability. Injection of the AMPA receptor antagonist NBQX into vHC or BLA each restored social novelty preference in STZ-induced diabetic mice. NPY content in amygdala, but not in vHC, of STZ-induced diabetic mice was increased relative to non-diabetic mice. In STZ-induced diabetic mice, injection of the NPY Y receptor antagonist BIIE 0246 into BLA restored social novelty preference, whereas injection of BIIE 0246 into vHC was without effect. Finally, in non-diabetic mice social novelty preference was impaired by the NPY Y receptor agonist NPY 13-36 injected into BLA and restored by co-injection of NBQX. These results indicate that in diabetic mice glutamatergic function is enhanced in both vHC and BLA, which impairs social novelty preference through AMPA receptors. In addition, they indicate that NPYergic function in BLA, but not vHC, is enhanced in diabetic mice, which impairs social novelty preference through NPY Y receptors.
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http://dx.doi.org/10.1016/j.bbr.2021.113195DOI Listing
May 2021

Durable response achieved using Pazopanib for germ tumor cells: A case report.

Mol Clin Oncol 2021 Mar 19;14(3):48. Epub 2021 Jan 19.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.

Germ cell tumors with somatic-type malignancy (GCTSTM) are rare, and patients with GCTSTM have extremely poor prognoses with a median survival of nine months. Somatic-type malignancy, which are mainly sarcomas, usually exhibit chemoresistance. The recommended therapy for GCTSTM is radical resection; however, Pazopanib, which is a multityrosine kinase inhibitor, has indicated therapeutic effects for some soft tissue sarcoma components. The current study reports the case of a 21-year-old Asian man who presented with GCTSTM after combined chemotherapy for a primary mediastinal germ cell tumor with multiple lung metastases. Despite the metastases, his disease was stable after continuous administration of Pazopanib for two years and then stopping the medication for four years. To the best of our knowledge, the current report is the first report of a durable response by Pazopanib for GCTSTM, which is a rare outcome.
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http://dx.doi.org/10.3892/mco.2021.2210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849064PMC
March 2021

Significant Improvement After Surgery for a Symptomatic Osteoblastoma in a Patient with Camurati-Engelmann Disease: Case Report and Literature Review.

Calcif Tissue Int 2021 Feb 8. Epub 2021 Feb 8.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Camurati-Engelmann disease (CED) is a rare, progressive diaphyseal dysplasia characterized as diaphyseal hyperostosis and sclerosis of the long bones. Corticosteroids, bisphosphonates, and losartan have been reported to be effective systemic medications used to reduce CED symptoms. There are no reports of osteoblastoma in patients with CED, and osteoblastoma in the distal radius is rare. We present a patient diagnosed with CED, based on radiological and histological examinations, at 11 years old. At 22 years old, she experienced severe pain in her right forearm and was treated with bisphosphonate, losartan, and prednisolone; however, the pain continued. An expansive and sclerotic lesion at the distal radius was observed on radiography. A follow-up plain radiograph indicated that the lesion was growing. Fluorodeoxyglucose positron emission tomography revealed solitary, intense radiotracer uptake, and a biopsy and surgical resection were performed due to suspected malignancy. Pathologic analysis showed anastomosing bony trabeculae rimmed by osteoblasts observed in a loose fibrovascular stroma. The lesion was diagnosed as an osteoblastoma. Following bone excision and artificial bone grafting, the patient's severe pain almost completely disappeared. At final follow-up, no evidence of osteoblastoma recurrence was noted. To our knowledge, this is the first case report of osteoblastoma arising in a patient with CED. Bone excision and artificial bone grafting may be a treatment option for local symptomatic osteoblastoma in patients with CED.
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http://dx.doi.org/10.1007/s00223-021-00813-8DOI Listing
February 2021

The number of osteoclasts in a biopsy specimen can predict the efficacy of neoadjuvant chemotherapy for primary osteosarcoma.

Sci Rep 2021 Jan 21;11(1):1989. Epub 2021 Jan 21.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa-city, Ishikawa, 920-8641, Japan.

Osteosarcoma is the most common primary malignant bone tumor, and its standard treatment is a combination of surgery and chemotherapy. A poor response to chemotherapy causes unfavorable oncological outcomes. We investigated the correlation between osteoclast differentiation in biopsy specimens and the efficacy of neoadjuvant chemotherapy in resected specimens. Forty-nine patients who underwent neoadjuvant chemotherapy and subsequent surgical treatment at our institution between 1999 and 2018 were enrolled. Using medical records, we investigated the age, sex, tumor size, location, subtype, staging, chemotherapy agents (doxorubicin, cisplatin, ifosfamide, and methotrexate), number of neoadjuvant chemotherapy courses, number of osteoclasts in biopsy specimens, and efficacy of neoadjuvant chemotherapy according to the Rosen and Huvos classification (Grade I-IV) in resected specimens. Univariate and multivariate analyses were performed to identify factors predictive of a good response in resected specimens after neoadjuvant chemotherapy. A good response (Grade III/IV) was detected in 25, while a poor response (Grade I/II) was detected in 24. According to the multivariate analysis, ≥ 46 years old (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.01-0.45; p < 0.01) and ≥ 5 mature osteoclasts in a biopsy specimen (OR, 36.9; 95% CI, 6.03-225; p < 0.01) were significantly associated with the neoadjuvant chemotherapy efficacy. The accuracy for predicting a good response to chemotherapy based on ≥ 5 osteoclasts in a biopsy specimen in patients < 46 years old was 85%. The number of mature osteoclasts in biopsy specimens is a simple factor for predicting the efficacy of chemotherapy before treatment, although further studies will be required to determine the underlying mechanism.
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http://dx.doi.org/10.1038/s41598-020-80504-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820005PMC
January 2021

Similar Recurrence Rate Between Gleason Score of Six at Positive Margin and Negative Margin After Radical Prostatectomy.

Anticancer Res 2021 Jan;41(1):509-516

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: To investigate whether surgical margin (SM) status would affect the biochemical recurrence (BCR) after robot-associated RP (RARP).

Patients And Methods: We evaluated BCR after RARP and the association between pre- and postoperative predictive factors and BCR.

Results: Positive SM (PSM) was observed in 97 out of 365 enrolled patients. On multivariate analysis, preoperative prostate specific antigen, biopsy Gleason score (GS), clinical stage, GS ≥7 at the PSM and pathological GS ≥7 were predictive factors for BCR. The 5-year BCR-free survival rate was 84.1% in the negative SM (NSM), 87.4% when GS=6 at the PSM, and 47.6% when GS ≥7 at the PSM. There was no statistically significant difference in BCR-free survival between the NSM group and GS=6 at the PSM group (p=0.966).

Conclusion: It would be desirable to evaluate GS at PSM when PSM is present in a specimen removed by RP.
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http://dx.doi.org/10.21873/anticanres.14802DOI Listing
January 2021

A phase I study of preoperative (neoadjuvant) chemotherapy with gemcitabine plus -paclitaxel for resectable pancreatic cancer.

Mol Clin Oncol 2021 Feb 14;14(2):26. Epub 2020 Dec 14.

Department of Hepato-Biliary-Pancreatic Surgery, Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.

Neoadjuvant chemotherapy (NAC) has become a standard treatment for borderline resectable pancreatic ductal adenocarcinoma (PDAC). The present study examined the maximum tolerated dose of NAC with gemcitabine plus -paclitaxel (GnP) in patients with resectable PDAC. Between 2015 and 2019, 39 patients with resectable PDAC were enrolled in the present study. GnP was administered for two 28-day cycles on days 1, 8 and 15. The planned doses for levels 1, 2 and 3 were 75, 100 and 125 mg/m, respectively, for -paclitaxel and 600, 800 and 1,000 mg/m, respectively, for gemcitabine. Dose-limiting toxicity (neutropenia, anemia, thrombocytopenia and/or liver injury) was observed in 44.4% of patients treated at dose level 1 (21 patients) and 60.0% of those treated at dose level 2 (18 patients). Therefore, the maximum tolerated dose was set as level 1. Six patients withdrew from protocol treatment because of non-hematologic adverse events (skin rash, pancreatitis and biliary tract infection). Among the 31 patients with pathologically confirmed PDAC, partial response, stable disease and disease progression were recorded in 4 (12.9%), 24 (77.4%) and 3 (9.7%) patients, respectively. NAC significantly reduced tumor size according to computed tomography, and CA19-9 levels and the F-fluorodeoxyglucose maximum standardized uptake value were decreased in positron emission tomography. No postoperative complications attributable to NAC were recognized. Among the 27 patients with PDAC who underwent resection, the pathological treatment effect was judged as grades Ia, Ib and II in 21 (77.8%), 4 (14.8%) and 2 (7.4%) patients, respectively. R0 resection was performed in 24 out of 27 patients (88.9%). Adjuvant chemotherapy with oral S-1 was administered to 21 out of 27 patients (77.8%). In conclusion, NAC with GnP was safe and feasible for resectable PDAC at dose level 1. In the future, verification of the long-term results of the present study will be necessary, and a phase II clinical trial is anticipated.
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http://dx.doi.org/10.3892/mco.2020.2188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783717PMC
February 2021

Bronchoesophageal fistula formation after three courses of nivolumab for carcinoma of unknown primary with a subgroup of lung squamous cell carcinoma.

Oxf Med Case Reports 2020 Dec 28;2020(12):omaa116. Epub 2020 Dec 28.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.

Immune checkpoint inhibitors (ICIs) are widely used in both monotherapy and combination chemotherapy for various types of cancers. Nivolumab is the most popular among ICIs, and the number of adapted malignant diseases for nivolumab is increasing. Bronchoesophageal fistula formation is a serious complication of the treatment for esophageal or lung cancer. However, the development of bronchoesophageal fistula as a complication of ICIs is obscure. A 59-year-old man who was diagnosed with carcinoma of unknown primary with a subgroup of lung squamous cell carcinoma had bronchoesophageal fistula formation after three cycles of nivolumab as the fourth line treatment. Before the initiation of nivolumab, he had received two esophageal stents and an angiogenesis inhibitor. These are known risk factors for fistula formation. This is a rare case showing that nivolumab monotherapy might induce bronchoesophageal fistulae. Therefore, clinicians should be aware of the factors related to fistula formation when using ICIs.
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http://dx.doi.org/10.1093/omcr/omaa116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768526PMC
December 2020

Roles of endothelial cells in the regulation of cell motility via lysophosphatidic acid receptor-2 (LPA) and LPA in osteosarcoma cells.

Exp Mol Pathol 2021 02 26;118:104596. Epub 2020 Dec 26.

Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan. Electronic address:

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA to LPA) exhibits a variety of biological responses. In tumor microenvironment, endothelial cells promote cancer cell functions. In this study, we investigated the roles of endothelial cells in the regulation of cell motile activity via LPA and LPA in human osteosarcoma MG-63 cells. In cell motility assay, the cell motile activity of MG-63 cells was markedly increased by the supernatants of endothelial F2 cells. MG-63 cell motility elevated by the supernatants was enhanced by GRI-977143 (LPA agonist) and reduced by (2S)-OMPT (LPA agonist). LPAR2 and LPAR3 expressions were increased in highly migratory MG63-CR7(F2) cells, which were generated from MG-63 cells by co-culture with F2 cell supernatants. MG63-CR7(F2) cell motility was stimulated by LPA treatment. In the presence of F2 cell supernatants, MG63-CR7(F2) cell motility was markedly enhanced by GRI-977143 and suppressed by (2S)-OMPT. Autotaxin (ATX) enzymatically converts lysophosphatidylcholine (LPC) to LPA. ATX expression was higher in MG63-CR(F2) cells than in MG-63 cells. MG63-CR7(F2) cell motility was markedly increased by LPC in comparison with MG-63 cells. In addition, MG63-CR(F2) cell motility was significantly stimulated by the supernatants of LPC treated F2 cells. The present results suggest that the activation of LPA signaling via LPA and LPA by endothelial cells is involved in the modulation of cell motile activity of MG-63 cells.
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http://dx.doi.org/10.1016/j.yexmp.2020.104596DOI Listing
February 2021

Central dopamine D receptors regulate plasma glucose levels in mice through autonomic nerves.

Sci Rep 2020 12 18;10(1):22347. Epub 2020 Dec 18.

Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.

Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the β adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.
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http://dx.doi.org/10.1038/s41598-020-79292-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749102PMC
December 2020

Low-grade myofibroblastic sarcoma of the levator scapulae muscle: a case report and literature review.

BMC Musculoskelet Disord 2020 Dec 10;21(1):836. Epub 2020 Dec 10.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.

Background: Low-grade myofibroblastic sarcoma (LGMS) is described as a distinct atypical myofibroblastic tumor often with fibromatosis-like features and predilection for the head and neck, especially the oral cavity and larynx. LGMS arising in the levator scapulae muscle is extremely rare.

Case Presentation: A 69-year-old woman was admitted to our hospital because she noticed a hard mass in her left neck six months prior. Magnetic resonance images (MRI) showed a soft tissue tumor of the left levator scapulae muscle. A core needle biopsy showed cellular fascicles or a storiform growth pattern of spindle-shaped tumor cells with minimally atypia. Immunohistochemistry revealed focally positive for α-smooth muscle actin (α-SMA), negative for S-100, and a low-grade spindle cell sarcoma was suspected. Following a biopsy, the tumor was resected with a wide surgical margin. Immunohistochemical staining was a positive for vimentin and α-SMA and negative for desmin, CD34, nuclear β-catenin, and h-caldesmon. LGMS diagnosis was determined based on the histopathological findings. The patient was alive with no evidence of disease eight years after the surgery.

Conclusions: To the best of our knowledge, this is the first case report of LGMS arising in the levator scapulae muscle. In addition to the case report, 48 reports with 103 LGMS cases are reviewed and discussed. In previous reports of LGMS, there were 43 females and 60 males, with a mean age of 43.0 years (range, 2-75). There were 13 (12.6%) patients aged < 18 years, 67 (65.1%) patients aged 18 to 59 years, and 23 (22.3%) patients aged ≥60 years. The average tumor size was 4.4 cm (range: 0.4-22.0). The commonest sites of LGMS was the tongue. Tumor growth patterns were evaluated in 52 cases, and 44 cases (84.6%) showed infiltrative growth patterns. Local recurrence was 26.7%, and distant metastasis was 4.4%. Because of the locally aggressive feature, it is important to diagnose LGMS with biopsy and to excise the tumor with an adequately wide margin.
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http://dx.doi.org/10.1186/s12891-020-03857-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731512PMC
December 2020

Diagnostic accuracies of intraoperative frozen section and permanent section examinations for histological grades during open biopsy of bone tumors.

Int J Clin Oncol 2021 Mar 23;26(3):613-619. Epub 2020 Nov 23.

Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan.

Background: A histological diagnosis obtained from an intraoperative frozen section (FS) during biopsy confirms the adequacy of tumor tissue in the specimen. However, some cases show a discrepancy among the intraoperative FS diagnosis, permanent section (PS) diagnosis of the biopsy specimen, and the final diagnosis of the excised tumor specimen. In this study, we retrospectively investigated the diagnostic accuracy of the FS and PS for different types of bone tumors.

Methods: This study included 377 patients with 411 bone tumors who underwent tumor excision after an open biopsy with intraoperative FS diagnosis. FS, PS, and final diagnoses of the patients were classified into benign tumors/tumor-like lesions, intermediate malignancies, and malignant tumors. To assess diagnostic accuracy, the histological grades in FS and PS diagnoses were compared with those in the final diagnoses.

Results: The overall diagnostic accuracies of FS and PS were 93% and 97%, respectively. The accuracy of FS and PS for histological grade was 84% and 93% for chondrogenic tumors, 90% and 96% for osteogenic tumors, 97% and 98% for osteoclastic giant cell-rich tumors, 100% and 100% for tumors of undefined neoplastic nature, and 95% and 99% for other bone tumors, respectively.

Conclusion: These data suggest that surgical planning based on PS diagnosis is recommended for chondrogenic and osteogenic tumors.
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http://dx.doi.org/10.1007/s10147-020-01836-1DOI Listing
March 2021

Increase in neuropeptide Y activity impairs social behaviour in association with glutamatergic dysregulation in diabetic mice.

Br J Pharmacol 2021 Feb 23;178(3):726-740. Epub 2020 Dec 23.

Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.

Background And Purpose: Patients with diabetes mellitus are reported to show a raised prevalence of mental disorders, which may be reflected in impaired social interaction. However, the mechanisms underlying such impairment in diabetes are unknown.

Experimental Approach: The present study investigated whether social interaction is impaired in diabetic mice and whether central neuropeptide Y (NPY) and glutamatergic function are involved in such impairment.

Key Results: In the three-chamber test, social novelty preference, but not sociability, was impaired in streptozotocin (STZ)-induced diabetic mice. The mRNA level of NPY in the hypothalamus was increased in STZ-induced diabetic mice. Injection of the NPY Y receptor agonist NPY 13-36 into naïve mice impaired social novelty preference, but not sociability, and this effect was inhibited by the Y receptor antagonist BIIE 0246. BIIE 0246 also reversed the impairment of social novelty preference in STZ-induced diabetic mice. Similarly, injection of the AMPA receptor agonist AMPA into naïve mice impaired social novelty preference, but not sociability, and this effect was inhibited by the AMPA receptor antagonist NBQX. Impairment of social novelty preference induced by NPY 13-36 was inhibited by NBQX, whereas impairment of social novelty preference induced by AMPA was not inhibited by BIIE 0246. Finally, impairment of social novelty preference in STZ-induced diabetic mice was reversed by NBQX.

Conclusion And Implications: These findings suggest that NPY neurons are activated in diabetic mice and that this may impair social novelty preference by promoting glutamatergic function through Y receptors.
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http://dx.doi.org/10.1111/bph.15326DOI Listing
February 2021

Clinical features and diagnostic imaging of cholangiolocellular carcinoma compared with other primary liver cancers: a surgical perspective.

Technol Cancer Res Treat 2020 Jan-Dec;19:1533033820948141

General and Digestive Surgery, 12857Kanazawa Medical University, Kahoku, Ishikawa, Japan.

Background And Objectives: Although cholangiolocellular carcinoma is considered a combined hepatocellular and cholangiocarcinoma, we feel that this classification is not appropriate. Therefore, we compared the diagnostic imaging findings, surgical prognosis, and pathological features of cholangiolocellular carcinoma with those of other combined hepatocellular and cholangiocarcinoma subtypes, hepatocellular carcinoma, and cholangiocarcinoma.

Methods: The study patients included 7 with classical type combined hepatocellular and cholangiocarcinoma; 8 with stem cell feature, intermediate type combined hepatocellular and cholangiocarcinoma; 13 with cholangiolocellular carcinoma; 58 with cholangiocarcinoma; and 359 with hepatocellular carcinoma. All patients underwent hepatectomy or living-related donor liver transplantation from 2001 to 2014.

Results: cholangiolocellular carcinoma could be distinguished from hepatocellular carcinom, other combined hepatocellular and cholangiocarcinoma subtypes, and cholangiocarcinoma by the presence of intratumoral Glisson's pedicle, hepatic vein penetration, and tumor-staining pattern on angiography-assisted CT. Cholangiolocellular carcinoma was associated with a significantly lower SUV-max than that of cholangiocarcinoma on FDG-PET. Hepatocellular carcinoma, classical type, and cholangiolocellular carcinoma had significantly better prognoses than stem cell feature, intermediate type and cholangiocarcinoma. A cholangiocarcinoma component was detected in cholangiolocellular carcinoma that progressed to the hepatic hilum, and the cholangiocarcinoma component was found in perineural invasion and lymph node metastases.

Conclusions: From the viewpoint of surgeon, cholangiolocellular carcinoma should be classified as a good-prognosis subtype of biliary tract carcinoma because of its tendency to differentiate into cholangiocarcinoma during its progression, and its distinctive imaging and few recurrence rates different from other combined hepatocellular and cholangiocarcinoma subtypes.
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http://dx.doi.org/10.1177/1533033820948141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592326PMC
October 2020

Surgically resected primary esophageal choriocarcinoma accompanied with Barrett's adenocarcinoma: a case report.

Surg Case Rep 2020 Sep 29;6(1):227. Epub 2020 Sep 29.

Department of Gastroenterological Surgery, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan.

Background: Choriocarcinomas are usually classified as either gestational or non-gestational. Primary choriocarcinomas in the gastrointestinal tract, especially primary choriocarcinomas in the esophagus, are extremely rare. We report a case of a rare primary esophageal choriocarcinoma mixed with squamous cell carcinoma-like components in association with Barrett's adenocarcinoma.

Case Presentation: A 58-year-old man visited the hospital, complaining of hematemesis and tarry stools. In emergency upper gastrointestinal endoscopy, a bleeding esophageal tumor was observed. Additionally, a contrast computed tomography (CT) scan showed a large hypervascular tumor 4.8 cm in diameter in the left kidney. He came to our institution for further examination and treatment of the esophageal tumor and kidney lesion. The patient had an easy bleeding elevated tumor 2 cm in diameter at the left wall of the middle thoracic esophagus and a left renal carcinoma. Histopathological diagnosis of the biopsy specimen of the esophageal tumor was a poorly differentiated carcinoma. However, a precise histological type diagnosis could not be obtained. In June 2016, mediastinoscopic transhiatal esophagectomy and posterior mediastinal gastric tube reconstruction were performed to treat his esophageal tumor. Histopathologically, most of the tumor comprised hCG-positive syncytiotrophoblasts. Therefore, we confirmed it as a primary esophageal choriocarcinoma. Furthermore, the tumor contained a poorly differentiated squamous cell carcinoma-like component that was also diagnosed as a choriocarcinoma using immunohistochemical staining and there was a small Barrett's esophageal adenocarcinoma lesion in the Barrett's epithelium near the tumor. Three months after surgery, a CT scan demonstrated multiple lung metastatic nodules and multiple intrahepatic masses. Needle biopsy from the lung nodule showed a choriocarcinoma. Despite chemotherapy, the metastatic choriocarcinoma regrew rapidly and multiple bone metastases appeared. He died because of his esophageal choriocarcinoma 13 months after primary resection.

Conclusions: We encountered an extremely rare case of esophageal choriocarcinoma combined with squamous cell carcinoma-like components in association with a simultaneous Barrett's adenocarcinoma that we followed for the entire course of his disease, from resection to end of life. Esophageal choriocarcinomas are rare with peculiar characteristics and very poor prognoses. Additional cases are needed to establish an appropriate future treatment.
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http://dx.doi.org/10.1186/s40792-020-00990-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524915PMC
September 2020

Clinical and genetic characteristics of patients with Doose syndrome.

Epilepsia Open 2020 Sep 23;5(3):442-450. Epub 2020 Jul 23.

Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama Japan.

Objective: To elucidate the genetic background and genotype-phenotype correlations for epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy (MAE) or Doose syndrome.

Methods: We collected clinical information and blood samples from 29 patients with MAE. We performed whole-exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant.

Results: We newly identified four variants: and missense variants and microdeletions at 2q24.2 involving and Xp22.31 involving . Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic-atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention-deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology.

Significance: MAE patients had genetic heterogeneity, and and emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic-atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.
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http://dx.doi.org/10.1002/epi4.12417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469791PMC
September 2020

Cooperation of G12/13 and Gi proteins via lysophosphatidic acid receptor-2 (LPA) signaling enhances cancer cell survival to cisplatin.

Biochem Biophys Res Commun 2020 11 31;532(3):427-432. Epub 2020 Aug 31.

Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan. Electronic address:

Lysophosphatidic acid (LPA) through six subtypes of G protein-coupled LPA receptors (LPA to LPA) mediates a variety of cancer cell functions. The aim of this study was to evaluate the cooperative effects of G12/13 and Gi proteins through LPA on cancer cell survival to cisplatin (CDDP). In cell survival assay, cells were treated with CDDP every 24 h for 2 days. The long-term CDDP treated (HT-CDDP) cells established from fibrosarcoma HT1080 cells were pretreated with an LPA agonist, GRI-977143. The cell survival rate to CDDP of HT-CDDP cells was significantly increased by GRI-977143. The elevated cell survival to CDDP was suppressed by LPA knockdown. Since G12/13 protein stimulates Rho-mediated signaling, RhoA and RhoC knockdown cells were generated from HT1080 cells (HT1080-RhoA and HT1080-RhoC cells, respectively). In the presence of GRI-977143, HT1080-RhoA and HT1080-RhoC cells showed the low cell survival rates to CDDP. On the other hand, Gi protein inhibits adenylyl cyclase (AC) activity. Before cell survival assay, cells were treated with a Gi protein inhibitor, pertussis toxin (PTX) for 24 h. The cell survival rate to CDDP of HT1080 cells was significantly reduced by PTX. Furthermore, when HT1080-RhoA and HT1080-RhoC cells were pretreated with PTX, the cell survival rates to CDDP of both cells were markedly inhibited by PTX. The present results suggest that cooperation of G12/13 and Gi proteins activated by LPA enhances the cell survival of HT1080 cells treated with CDDP.
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http://dx.doi.org/10.1016/j.bbrc.2020.08.087DOI Listing
November 2020

Multiple Malignant Lymphomas of the Bile Duct Developing after Spontaneous Regression of an Autoimmune Pancreatitis-like Mass.

Intern Med 2021 Feb 29;60(3):409-415. Epub 2020 Aug 29.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Japan.

We herein report a 67-year-old woman with malignant lymphomas of the bile duct that developed after regression of a pancreatic head mass. Computed tomography suggested the mass was pancreatic head cancer. Endoscopic ultrasonography showed a low-echoic mass with hyperechoic strands resembling autoimmune pancreatitis. Her serum IgG4 concentration was elevated to 674 mg/dL. After the pancreatic head mass spontaneously diminished, three masses were detected in the common bile duct. A biopsy of the major papilla revealed high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement. Systemic chemotherapy with rituximab plus etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin resulted in complete remission.
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http://dx.doi.org/10.2169/internalmedicine.5429-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925286PMC
February 2021

Intraoperative ultrasonography-guided surgery for malignant soft tissue tumor.

J Surg Oncol 2020 Dec 19;122(8):1791-1801. Epub 2020 Aug 19.

Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background And Objectives: A clear surgical margin is crucial for preventing the recurrence of soft tissue sarcomas (STSs). Recognizing the tumor border is difficult when the STS is impalpable or ill-defined. Ultrasonography (US) is a widely used diagnostic device that can visualize certain tumors intraoperatively. However, its usefulness for intraoperatively assessing STSs is unclear and was investigated here.

Methods: Our study comprised 19 patients with STSs that were impalpable, ill-defined, or beneath the fascia. All patients underwent intraoperative US (IOUS), with follow-up times ranging from 5 to 103 months (mean, 49 months).

Results: The mean age of the study participants was 56 years (range, 25-83 months). The most common histological diagnosis was undifferentiated pleomorphic sarcoma (UPS) (nine patients). The mean tumor size was 51 mm (range, 7-126 mm). According to the residual tumor classification, 18 tumors were microscopically negative (R0), including seven close to the fascia, and one was microscopically positive (R1). Local recurrence occurred in two cases (both classified as R0). The recurrence-free survival rate was 88.9% in 5 years.

Conclusions: IOUS-guided surgery is useful for visualizing STSs. Using this technique, STSs can be precisely localized, evaluated, and excised.
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http://dx.doi.org/10.1002/jso.26181DOI Listing
December 2020

Accuracy of histological grades from intraoperative frozen-section diagnoses of soft-tissue tumors.

Int J Clin Oncol 2020 Dec 10;25(12):2158-2165. Epub 2020 Aug 10.

Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.

Background: For excised tumor specimens, histological grades can differ between the biopsy diagnosis and the final diagnosis.

Methods: We retrospectively investigated the diagnostic accuracies of histological grades for frozen-section and permanent-section diagnoses from patients with soft-tissue tumors. Frozen-section, permanent-section, and final diagnoses were classified as benign tumors/tumor-like lesions, intermediate malignancies, or malignant tumors. Diagnostic accuracies of the histological grades from the frozen and permanent sections were evaluated by comparing the final diagnoses for the resected specimens.

Results: The diagnostic accuracies of the histological grades for the frozen- and permanent-section diagnoses were 95% (387/408 lesions) and 97% (395/408 lesions), respectively. Among the tumor types, the diagnostic accuracies of the histological grades for the frozen-section and permanent-section diagnoses were 84% and 87% for adipocytic tumors, 87% and 91% for fibroblastic/myofibroblastic tumors, 99% and 100% for nerve-sheath tumors, 98% and 98% for fibrohistiocytic tumors, 90% and 98% for tumors of uncertain differentiation, 100% and 100% for vascular tumors, and 97% and 98% for other tumors, respectively.

Conclusions: Histological grades from frozen-section diagnoses yielded low diagnostic accuracies in adipocytic and fibroblastic/myofibroblastic tumors. Treatment should be planned based on permanent-section diagnosis and radiological findings for these tumors.
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http://dx.doi.org/10.1007/s10147-020-01762-2DOI Listing
December 2020

Effect of total callosotomy on KCNQ2-related intractable epilepsy.

Brain Dev 2020 Sep 9;42(8):612-616. Epub 2020 Jun 9.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-2606, Japan.

Aim: To describe beneficial effects of callosotomy on KCNQ2-related intractable epilepsy.

Case Report: Our patient was a 10-year-old girl who had developed epilepsy during the neonatal period, accompanied by a suppression-burst pattern on the electroencephalography (EEG). The patient showed profound psychomotor developmental delay since early infancy. Daily seizures of versive posturing and ocular deviation were transiently controlled by carbamazepine and valproate at the age of 1 year; however, the seizures gradually increased to up to 50 times per day. Ictal EEG and positron emission tomography revealed an epileptic focus in the left frontal lobe at age 5 years. Total callosotomy resulted in marked reduction of epileptic seizures thereafter, as well as improved responses to external auditory and visual stimuli. Whole exome sequencing at age 9 identified a de novo missense variant in KCNQ2 (NM_172107.3:c.563A > C:p.(Gln188Pro)).

Conclusion: This case supports that epilepsy surgery could benefit children with epileptic encephalopathy, even with the etiology of channelopathy.
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http://dx.doi.org/10.1016/j.braindev.2020.05.005DOI Listing
September 2020

The Efficacy and Safety of a Promising Single-Channel Endoscopic Closure Technique for Endoscopic Treatment-Related Artificial Ulcers: A Pilot Study.

Gastrointest Tumors 2020 Apr 6;7(1-2):21-29. Epub 2019 Nov 6.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background/aims: It is important to appropriately manage patients with procedure-related artificial mucosal ulcers or procedure-related complications. Many endoscopic closure techniques have been reported; however, they often require the use of special devices. We developed a single-channel endoscopic closure technique (SCCT) that can be performed with conventional devices. In the present study, we describe the technique and evaluate its efficacy.

Methods: Twenty-five consecutive patients who underwent endoscopic treatment and whose artificial ulcer was closed using the SCCT were enrolled in this study. The technical success rate, number of clips for closure, procedure time, complication rate on the day of the procedure, clinical success rates on days 1 and 5, and incidence of severe stenosis of the gastrointestinal (GI) tract at 2 months after the procedure were evaluated.

Results: The median ulcer diameter was 20 mm. The tumor locations were the stomach ( = 19), jejunum ( = 1), and colon ( = 5). The technical success rate was 100% (25/25), and the rate of incomplete closure was 0% (0/25). Eight clips were needed on average. The median procedure time was 18 min (range 5-49 min). The complication rate was 0% (25/25). The clinical success rates on days 1 and 5 were 100% (19/19) and 100% (9/9), respectively. No patients presented stenosis as a late complication at 2 months after the procedure (0/25).

Conclusion: The SCCT could be applied in the treatment of artificial ulcers in several parts of the GI tract with a high clinical success rate and no complications. The SCCT appears to be a good option for closing artificial mucosal ulcers.
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http://dx.doi.org/10.1159/000503994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206593PMC
April 2020

Methylprednisolone pulse therapy in 31 patients with refractory epilepsy: A single-center retrospective analysis.

Epilepsy Behav 2020 08 6;109:107116. Epub 2020 May 6.

National Epilepsy Center, NHO, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan.

Purpose: We investigated the efficacy of methylprednisolone pulse therapy (MP) and responder characteristics in patients with refractory epilepsy.

Methods: We reviewed medical records of our center to identify patients with refractory epilepsy treated with MP other than continuous spikes and waves during slow sleep (CSWS), Landau-Kleffner syndrome (LKS), or Rasmussen's syndrome (RS) between 2004 and 2015. A course of MP consisted of intravenous methylprednisolone (30 mg/kg/day) on three consecutive days. Patients received multiple courses at intervals of four weeks. We examined seizure outcome, developmental outcome, antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptors (GluRs), cerebral spinal fluid (CSF)-albumin/serum-albumin ratio, and interictal electroencephalograms (EEGs). Responder to MP was defined as maintaining seizure reduction rate (SRR) ≥50% for three months after the first course of MP.

Results: Thirty-one consecutive patients treated with MP at our center were studied. Seizure types were focal onset impaired awareness seizure (FIAS) only (n = 23), FIAS with epileptic spasms (ES) (n = 7), and ES only (n = 1). Responder rate was 32.2% (10/31 patients), and seizure-free rate was 9.7% (3/31). Responders constituted 43.5% of patients without ES. No patient with ES was responder. Behavior and cognition also improved in 6 of 10 responders. History of seizure aggravation after inactivated vaccine before MP was found significantly higher rate in responder patients, comparing with nonresponder patients (p = 0.01).

Conclusion: Methylprednisolone pulse therapy may be considered for possible treatment in patients with focal epilepsy with drug-resistant seizures without ES, and it may improve cognitive function and behavioral comorbidities.
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http://dx.doi.org/10.1016/j.yebeh.2020.107116DOI Listing
August 2020

Gastric subtype of intraductal papillary neoplasm of the bile duct: The pathologic spectrum.

J Hepatobiliary Pancreat Sci 2020 Jul 13;27(7):402-413. Epub 2020 Jun 13.

Department of Diagnostic Pathology, Yonsei University Medical Center, Seoul, Korea.

Background And Aims: Intraductal papillary neoplasms of bile duct (IPNBs) remain a challenging entity to manage.

Methods: The pathologic spectrum of 34 gastric subtype of IPNB (gIPNB) cases was examined in consideration of the type 1 and 2 subclassification proposed by Japan-Korea consensus and compared with gastric subtype of pancreatic intraductal papillary mucinous neoplasm (gIPMN) (44 cases).

Results: Type 1 gIPNBs (17 cases) showed regular papillary foveola with variable tubular pyloric glands. Eight of the type 1 gIPNBs showed low-grade dysplasia. Type 2 cases (n = 17) showed complicated papillary and tubular structures and high-grade dysplastic foveola and pyloric glands. Foveolas were predominant in 15 cases, while pyloric glands were predominant in 10 cases, and considerable areas of foveolas and pyloric glands in the remaining: these three were found similarly in type 1 and 2 gIPNB. gIPMNs showed central foveola with a peripheral pyloric gland. Such a pattern was recognizable in type 1 but vague in type 2. Type 1 was frequently found in the intrahepatic bile ducts and showed abundant mucin, as in gIPMNs, while type 2 also occurred in the extrahepatic bile ducts and were pathologically more malignant.

Conclusion: Type 1 lesions shared features of gIPMN, while type 2 lesions differed from gIPMN and were more pathologically malignant.
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http://dx.doi.org/10.1002/jhbp.751DOI Listing
July 2020

The relation between anti-TGBFR1 immunohistochemical reaction and low Ki67, small tumor size and high estrogen receptor expression in invasive breast cancer.

Pathol Int 2020 Jun 26;70(6):330-339. Epub 2020 Feb 26.

Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.

Most breast cancers are derived from the luminal epithelium, which composes the inside of the breast ductal structure. Ductal carcinoma in situ (DCIS) leads to invasive ductal carcinoma, but noncancerous intraductal proliferative lesions are also a risk factor for ductal carcinoma. The transforming growth factor beta (TGFB) signaling pathway behaves as a tumor suppressor in the early stage of cancer, and conversely as a tumor growth factor in invasive stages in several cancers. In this study, we performed immunohistochemistry with an antibody that detects the cytoplasmic region of TGFB receptor 1 (TGFBR1) and elucidated TGFBR1 protein expression in luminal epithelial cells of noncancerous breast ducts and in several cases of DCIS and invasive carcinoma. TGFBR1 expression was higher in noncancerous breast tissue than in cancerous tissue, and a difference in expression was also seen among histological subtypes. Comparing the expression level of TGFBR1 in cancer cells and clinico-pathological parameters, cases expressing low TGFBR1 tended to show low estrogen receptor expression, large tumor size (≥10 mm), and a high Ki67 labeling index. These data suggested that TGFBR1 protein expression may be related to the suppression of breast cancer cell growth.
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http://dx.doi.org/10.1111/pin.12914DOI Listing
June 2020

GABAergic function in the lateral hypothalamus regulates feeding behavior: Possible mediation via orexin.

Neuropsychopharmacol Rep 2019 12 16;39(4):289-296. Epub 2019 Oct 16.

Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.

Aim: The lateral hypothalamus (LH) is known as the hunger center, but the mechanisms through which the LH regulates food intake are unclear. Since GABA neurons are reported to project to the LH, the present study investigated the role of GABAergic function in the LH in the regulation of feeding behavior.

Methods: GABA levels in the LH were measured by in vivo microdialysis. Food intake after drug injection into the LH was measured every 1 hour for 4 hours. The mRNA levels were measured using RT-PCR.

Results: Food intake significantly increased GABA levels in the LH, suggesting that food intake stimulates GABAergic function in the LH. Injection of the GABA receptor agonist muscimol into the LH significantly inhibited food intake, whereas injection of the GABA receptor antagonist bicuculline into the LH did not significantly affect food intake. The inhibitory effect of muscimol injected into the LH was blocked by co-administration of bicuculline. These results indicate that the stimulation of GABA receptors in the LH inhibits food intake. We next examined whether the stimulation of GABA receptors affects hypothalamic neuropeptides that are known to regulate feeding behavior. The injection of muscimol significantly decreased preproorexin mRNA in the hypothalamus.

Conclusion: These results indicate that food intake activates GABAergic function in the LH, which terminates feeding behavior by stimulating GABA receptors. Moreover, it is suggested that the stimulation of GABA receptors in the LH reduces food intake through inhibition of orexin neurons.
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http://dx.doi.org/10.1002/npr2.12080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292314PMC
December 2019