Publications by authors named "Keita Kai"

85 Publications

Infiltration of CD1a-positive dendritic cells in advanced laryngeal cancer correlates with unfavorable outcomes post-laryngectomy.

BMC Cancer 2021 Aug 30;21(1):973. Epub 2021 Aug 30.

Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga, Japan.

Background: The prognosis of advanced laryngeal cancer is unfavorable despite advances in multidisciplinary therapy. Dendritic cells (DCs) play a central role in antitumor immunity. Tumor-infiltrating CD1a DCs have been reported to be associated with clinical outcomes in carcinomas of various organs, but the clinical impact of CD1a DCs in laryngeal cancer remains to be unequivocally established.

Methods: We retrospectively analyzed the cases of 57 patients with Stage III or IV laryngeal cancer who underwent a total laryngectomy. Immunohistochemistry detection of CD1a, S100 and CD8 was performed on representative resected specimens. CD1a DCs, S100 DCs and CD8 cytotoxic T-lymphocytes (CTLs) were evaluated, and the cases divided into high and low groups according to the cut-off of the median values for each of these 3 parameters.

Results: Compared to the CD1a-low group, the CD1a-high group had more advanced cases and showed significantly worse disease-specific survival (DSS) (P = 0.008) and overall survival (OS) (P = 0.032). The analyses of S100 DCs and CD8 CTLs revealed no significant impact on clinical outcomes. However, multivariate analysis revealed that infiltration of CD1a DCs was an independent unfavorable prognostic factor for both DSS (P = 0.009) and OS (P = 0.013).

Conclusions: Our results demonstrated that the infiltration of CD1a DCs was associated with unfavorable clinical outcomes in patients with advanced laryngeal cancer who underwent a total laryngectomy as the initial treatment.
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http://dx.doi.org/10.1186/s12885-021-08715-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406956PMC
August 2021

Cytological Appearances of Ovarian Seromucinous Borderline Tumor in Ascites: Presentation of 2 Cases.

Acta Cytol 2021 20;65(5):440-447. Epub 2021 Jul 20.

Department of Pathology, Saga University Hospital, Saga, Japan.

Background: Seromucinous borderline tumor (SMBT) is a rare neoplasm which was newly defined in the 2014 WHO classification. Although the clinical and histopathological characteristics of SMBT have been well described, its cytological characteristics have not. We recently experienced 2 cases of SMBT which were defined by cytological findings of ascites.

Case Presentation: Case 1 was a 65-year-old Japanese woman. Preoperative imaging studies revealed abundant ascites and a cystic tumor, with a solid component measuring 13 cm on the left ovary. Radical surgery was performed during the intraoperative diagnosis of ovarian borderline tumor, made by histological examinations of frozen tumor sections. The cytological smears of preoperatively and intraoperatively collected ascites showed many atypical cells resembling reactive mesothelial cells. Alcian-blue staining of cell block sections revealed intracytoplasmic mucin, and the results of immunohistochemistry were consistent with SMBT. The final pathological diagnosis of tumor was SMBT. Case 2 was a 28-year-old Japanese woman. Preoperative imaging studies revealed a small amount of ascites and cystic tumors with solid components in the bilateral ovaries. She initially underwent fertility preservation surgery. SMBT was suspected by cytological examination of smears of intraoperatively collected ascites and the findings of cell block. She underwent additional radical surgery based on a final pathological diagnosis of SMBT.

Conclusion: In our experience, the tumor cells of SMBT in ascites mimicked reactive mesothelial cells. The nuclear atypia of SMBTs was intermediate between that of reactive mesothelial cells and serous carcinoma. The immunohistochemistry and mucin staining using cell block were very helpful for facilitating the cytodiagnosis of SMBT.
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http://dx.doi.org/10.1159/000517313DOI Listing
September 2021

Recognition and pathological features of periampullary region adenocarcinoma with an indeterminable origin.

Cancer Med 2021 06 19;10(11):3499-3510. Epub 2021 May 19.

Department of Pathology, Keio University School of Medicine, Tokyo, Japan.

Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer.
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http://dx.doi.org/10.1002/cam4.3809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178491PMC
June 2021

A deep learning model to detect pancreatic ductal adenocarcinoma on endoscopic ultrasound-guided fine-needle biopsy.

Sci Rep 2021 Apr 19;11(1):8454. Epub 2021 Apr 19.

Department of Pathology, Kurume University School of Medicine, Kurume, 830-0011, Japan.

Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.
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http://dx.doi.org/10.1038/s41598-021-87748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055968PMC
April 2021

Modification of the Thermal Spread by the Blade Shape of an Ultrasonically Activated Device.

World J Surg 2021 06 17;45(6):1698-1705. Epub 2021 Feb 17.

Department of Pathology, Saga University Hospital, Saga, Japan.

Background: Few studies have focused on the spread of thermal damage from different blade shapes of ultrasonically activated devices (USADs) used during minimally invasive surgery.

Methods: In vivo experiments using pig arteries, nerves, and mesentery were used to compare the thermal spread of two different blade types of USADs, non-tapered and tapered, under the same conditions. The tissue temperatures were monitored using a high-resolution infrared thermographic camera and calculated using an image analysis program. The spread of heat denaturation was measured histologically.

Results: The temperature was greater at the sides with greater curvature when non-tapered USADs were activated (artery, 1 s, 2 mm: - 0.92 ± 0.5 °C vs. - 0.44 ± 0.5 °C, P = 0.022). This effect was more prominent in the tapered type (artery, 1 s, 0/1/2 mm: 9.14 ± 3.7 °C vs. 28.3 ± 16.2 °C/0.5 ± 1.4 °C vs. 9.76 ± 6.2 °C/ - 0.12 ± 0.9 °C vs. 1.44 ± 1.9 °C, P = 0.044/0.016/0.038, respectively). The temperatures in the tapered USAD were significantly higher at some time- and distance-points than those in a non-tapered USAD (artery, 1 s, 0 mm, Less/1 s, 1 mm, Gre: 4.2 ± 2.9 °C vs. 9.14 ± 3.7 °C /0.36 ± 0.5 °C vs. 9.76 ± 6.2 °C, P = 0.047/0.027; nerve, 2 s, 0 mm, Gre: 6.54 ± 3.9 °C vs. 17.66 ± 6.2 °C, P = 0.012). A three-directional study revealed the thermal spread of the mesentery was greatest at the tip side of the non-tapered type USAD (4.55 ± 2.53 °C vs. 12.43 ± 4.03 °C/12.43 ± 4.03 °C vs. 5.04 ± 1.91 °C, P = 0.003/0.005).

Conclusions: The thermal spread changed according to the blade shape of the USAD. This knowledge can be applied to more meticulous and complicated procedures, reducing surgical morbidity.
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http://dx.doi.org/10.1007/s00268-021-05971-2DOI Listing
June 2021

Immunohistochemical analysis of the aggregation of CD1a-positive dendritic cells in resected specimens and its association with surgical outcomes for patients with gallbladder cancer.

Transl Oncol 2021 Jan 24;14(1):100923. Epub 2020 Oct 24.

Department of Pathology, Saga University Hospital, Nabeshima 5-1-1, Saga 849-8501, Japan; Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga, Japan.

Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis. Antigen-presenting dendritic cells (DCs) play a central role in antitumor immunity. DCs expressing CD1a (CD1a-DCs) are considered immature DCs. The aim of this study was to evaluate the clinical impact of CD1a-DC infiltration into GBC tissue. Seventy-five patients with GBC (excluding non-invasive and intramucosal cancer) were enrolled. Immunohistochemistry for CD1a, S100 and CD8 was performed using representative surgically resected specimens. The cases were divided into a high CD1a-DC group (27 cases, 36%) and low CD1a-DC group (48 cases, 64%) according to the degree of CD1a-DC infiltration/aggregation. The high CD1a-DC group contained fewer patients with distant metastasis (P = 0.039) and more patients given postoperative chemotherapy (P = 0.038). The high CD1a-DC group had significantly longer overall survival (P = 0.001) and disease-specific survival (P = 0.002) than the low CD1a-DC group. In contrast, S100-DC and CD8+ tumor-infiltrating lymphocyte statuses were without effect on OS or DSS. The results of multivariate analyses indicated that the degree of infiltration/aggregation of CD1a-DCs was an independent prognostic factor associated with a favorable prognosis after surgery.
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http://dx.doi.org/10.1016/j.tranon.2020.100923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590585PMC
January 2021

Accumulation of Astrocytic Aquaporin 4 and Aquaporin 1 in Prion Protein Plaques.

J Neuropathol Exp Neurol 2020 04;79(4):419-429

Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Gerstmann-Sträussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases.
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http://dx.doi.org/10.1093/jnen/nlaa010DOI Listing
April 2020

Development and Validation of a Nomogram for Early Detection of Malignant Gallbladder Lesions.

Clin Transl Gastroenterol 2019 10;10(10):e00098

Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.

Objectives: Preoperative decision-making for differentiating malignant from benign lesions in the gallbladder remains challenging. We aimed to create a diagnostic nomogram to identify gallbladder cancer (GBC), especially for incidental GBC (IGBC), before surgical resection.

Methods: A total of 587 consecutive patients with pathologically confirmed gallbladder lesions from a hospital were randomly assigned to a training cohort (70%) and an internal validation cohort (30%), with 287 patients from other centers as an external validation cohort. Radiological features were developed by the least absolute shrinkage and selection operator logistic regression model. Significant radiological features and independent clinical factors, identified by multivariate analyses, were used to construct a nomogram.

Results: A diagnostic nomogram was established by age, CA19.9, and 6 radiological features. The values of area under the curve in the internal and external validation cohorts were up to 0.91 and 0.89, respectively. The calibration curves for probability of GBC showed optimal agreement between nomogram prediction and actual observation. Compared with previous methods, it demonstrated superior sensitivity (91.5%) and accuracy (85.1%) in the diagnosis of GBC. The accuracy using the nomogram was significantly higher in GBC groups compared with that by radiologists in the training cohort (P < 0.001) and similarly in each cohort. Notably, most of the IGBC, which were misdiagnosed as benign lesions, were successfully identified using this nomogram.

Discussion: A novel nomogram provides a powerful tool for detecting the presence of cancer in gallbladder masses, with an increase in accuracy and sensitivity. It demonstrates an unprecedented potential for IGBC identification.
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http://dx.doi.org/10.14309/ctg.0000000000000098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884352PMC
October 2019

Frequent Detection of Pituitary-Derived PrPres in Human Prion Diseases.

J Neuropathol Exp Neurol 2019 10;78(10):922-929

Department of Neuropathology, Graduate School of Medical Sciences.

Human prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD), inherited prion diseases, and acquired human prion diseases are lethal neurodegenerative diseases. One of the major sources of iatrogenic Creutzfeldt-Jakob disease was human growth hormone (hGH-iCJD) derived from contaminated cadaveric pituitaries. The incidence of hGH-iCJD has decreased since changing from growth hormone extracted from human cadaveric pituitaries to recombinant pituitary hormones. However, extensive analysis on the localization and detecting of abnormal prion protein in the pituitary gland are limited. In this study, we examined 9 autopsied brains and pituitary glands from 6 patients with prion disease (3 Gerstmann-Sträussler-Scheinker disease, 2 sCJD, and 1 dura mater graft-associated CJD) and 3 individuals with nonprion diseases. Western blot analysis of pituitary samples demonstrated unique glycoforms of normal cellular prion protein with molecular weights of 30-40 kDa, which was higher than the typical 25-35 kDa prion protein in brains. Proteomic analysis also revealed prion protein approximately the molecular weight of 40 kDa in pituitary samples. Moreover, proteinase K-resistant Prion protein was frequently detected in pituitary samples of the prion diseases. Immunohistochemistry for Prion protein revealed mosaic cellular distribution preferentially in growth hormone- or prolactin-producing cells.
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http://dx.doi.org/10.1093/jnen/nlz075DOI Listing
October 2019

Decreased cytokeratin 7 expression correlates with the progression of cervical squamous cell carcinoma and poor patient outcomes.

J Obstet Gynaecol Res 2019 Nov 9;45(11):2228-2236. Epub 2019 Sep 9.

Department of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Aim: To identify potential biomarkers for tumor progression and patient outcomes in cervical squamous cell carcinoma.

Methods: We examined the expressions of CK7 and CK17 as potential markers of the squamo-columnar junction, and podoplanin as a basal cell marker using surgical and biopsy samples of patients in grade 3 cervical intraepithelial neoplasia (n = 30), operable invasive carcinoma (OP group, n = 53) and inoperable invasive carcinoma before radiotherapy and/or chemotherapy (RC group, n = 76).

Results: The positive rates of CK7 and podoplanin in invasive carcinoma were significantly lower than those in grade 3 cervical intraepithelial neoplasia (P = 0.001, P < 0.0001). The positive rates of CK7 and podoplanin in the RC group were significantly lower than those in the OP group (P < 0.0001, P = 0.04), while CK17 expression showed significantly higher positivity in the RC group than in the OP group (P < 0.0001). Negative CK7 expression showed a potential impact on overall survival in early-stage patients. In the RC group, the prevalence of cases with post-therapeutic residual carcinoma cells was higher in the CK7-negative group than in the positive group (P = 0.003). We found that decreased expression of CK7 could be a prognostic factor in early-stage cervical cancer patients.

Conclusion: This result may provide strategies and suggestions for new treatment options and follow-up practices in managing patients with cervical cancer.
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http://dx.doi.org/10.1111/jog.14108DOI Listing
November 2019

Primary mucoepidermoid carcinoma of the liver with CRTC1-MAML2 fusion: a case report.

Diagn Pathol 2019 Jul 27;14(1):84. Epub 2019 Jul 27.

Department of Anatomic Pathology Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

Background: CRTC1-MAML2 fusion is often detected in low- or intermediate-grade salivary mucoepidermoid carcinoma (MEC), and it is associated with a favorable clinical course. Primary MEC of the liver is an extremely rare, aggressive tumor, and no study has investigated CRTC1-MAML2 fusion.

Case Presentation: A 79-year-old Japanese female presented with an approx. 5-cm hepatic mass lesion. We surgically resected the lesion under the clinical diagnosis of intrahepatic cholangiocarcinoma. The histological and immunohistochemical findings were consistent with high-grade MEC, consisting of squamoid, mucin-producing, and intermediate tumor cells. Our RT-PCR analysis revealed the presence of CRTC1-MAML2 fusion. This fusion gene was further confirmed by direct sequencing. The patient is still alive almost 10 years after the surgery.

Conclusion: This is the first case report of primary MEC of the liver with CRTC1-MAML2 fusion, with long survival. The present case has significant implications for the entity of primary MEC of the liver which should be distinguished from adenosquamous carcinoma.
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http://dx.doi.org/10.1186/s13000-019-0863-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661078PMC
July 2019

Predictive value of the ratio of 8‑hydroxydeoxyguanosine levels between cancerous and normal tissues in patients with stage II/III colorectal cancer.

Oncol Rep 2019 May 22;41(5):3041-3050. Epub 2019 Mar 22.

Department of Surgery, Saga University Faculty of Medicine, Saga 849‑8501, Japan.

Reactive oxygen species (ROS) accumulation is known to induce carcinogenesis and accelerate cancer progression. 8‑Hydroxydeoxyguanosine (8‑OHdG) is a specific marker of ROS‑mediated DNA damage. Therefore, we analysed 8‑OHdG levels in cancerous and normal tissue DNA via enzyme‑linked immunosorbent assay (ELISA) using 97 tissue specimens obtained from surgically‑treated patients with stage II/III colorectal cancer (CRC). Additionally, 8‑OHdG levels in these tissues were also assessed via quantitative immunohistochemistry (qIHC). To eliminate individual background variables, the ratio of 8‑OHdG levels between cancerous and normal tissues was calculated using both techniques. A comparative analysis demonstrated that the 8‑OHdG ratio in DNA was significantly correlated with both lymph node metastasis and lymphatic invasion. Multivariate analysis revealed that a high 8‑OHdG ratio in DNA was independently correlated with poor prognosis. These results suggest that the 8‑OHdG ratio in DNA reflects ROS‑induced cancer progression. Conversely, a low 8‑OHdG ratio as estimated via qIHC was an independent factor for poor prognosis. In Kaplan‑Meier analysis, the combination of a high 8‑OHdG ratio in DNA (ELISA) and a low 8‑OHdG ratio in cytoplasm (qIHC) was associated with markedly worse patient prognosis than other combinations. Combined evaluation of the 8‑OHdG ratio using ELISA and qIHC may be pivotal for predicting surgical outcomes for patients with stage II/III CRC.
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http://dx.doi.org/10.3892/or.2019.7086DOI Listing
May 2019

Primary Chest Wall MYC/BCL6 Double-hit Lymphoma with t (3;7) (q27;p12) and t (8;14) (q24;q32) Translocations.

Intern Med 2019 Jul 28;58(14):2073-2077. Epub 2019 Mar 28.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan.

Primary chest wall lymphoma is rare and typically associated with chronic pleural inflammation. Double-hit lymphoma (DHL), which is defined as aggressive mature B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, is a highly aggressive malignancy that tends to have extranodal involvement and is resistant to standard immunochemotherapy. We herein report a 55-year-old man with no history of chronic pleural inflammation, diagnosed with primary chest wall DHL with MYC/BCL6 rearrangement, and harboring a unique BCL6 translocation, t (3;7) (q27;p12). After six courses of intensive chemotherapy, he has achieved complete remission. To our knowledge, this is the first case report of primary chest wall DHL.
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http://dx.doi.org/10.2169/internalmedicine.2532-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702014PMC
July 2019

Formalin fixation on HER-2 and PD-L1 expression in gastric cancer: A pilot analysis using the same surgical specimens with different fixation times.

World J Clin Cases 2019 Feb;7(4):419-430

Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.

Background: The needs for human epidermal growth factor receptor 2 (HER-2) and/or programmed death-ligand 1 (PD-L1) evaluations in gastric cancer are dramatically increasing. Although the importance of standardization of sample fixation has been widely recognized, most of the evidence regarding the fixation duration or type of fixing solution are based on breast cancer.

Aim: To investigate the real effects of fixation conditions on HER-2 testing or PD-L1 testing for gastric cancer using gastrectomy specimens.

Methods: Thirty-two patients who underwent gastrectomy for gastric cancer were enrolled. Their resected specimens were each divided into four pieces and fixed in four strictly controlled different durations (6 h, 24 h, and 48 h, and 1 wk) by 10% formalin ( = 22) or 10% neutral buffered formalin (NBF) ( = 10). Immunohistochemistry (IHC) of HER-2 and PD-1 was performed, and a pathology examination was conducted. In the HER-2-immunoreactive cases, all four specimens were subjected to dual-color in situ hybridization (DISH). Five cases were assessed as HER-2-positive by IHC and DISH. We used the cut-off values of 1%, 10%, and 50% to assess the IHC findings of PD-L1.

Results: No significant difference was observed in comparisons between the shorter fixation period groups (6 h, 24 h, and 48 h) and the prolonged fixation period (1 wk) group in the HER-2 and PD-L1 analyses. Although no significant difference was observed between 10% formalin and 10% NBF within 1 wk of fixation, the superiority of 10% NBF was confirmed in a long-term (> 3 mo) fixation in both the HER-2 and PD-L1 analyses.

Conclusion: In this small-numbered pilot study, prolonged fixation within 1 wk showed no inferiority in HER-2 or PD-L1 testing. However, a large-numbered prospective study is needed to obtain conclusive results.
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http://dx.doi.org/10.12998/wjcc.v7.i4.419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397813PMC
February 2019

Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma.

Histopathology 2019 Jul 16;75(1):63-73. Epub 2019 May 16.

Departments of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Aim: Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. An excess of iron in liver tissue causes oxidative stress, leading to hepatocellular carcinogenesis. Iron metabolism, which is regulated by a complex mechanism, is important for cancer cell survival. The aim of this study is to clarify the role of iron regulatory protein in the progression of HCC and in patient outcome.

Methods And Results: We first investigated the mRNA level of iron metabolism-related genes, including hepcidin, ferroportin 1 (FPN-1) and transferrin receptor (TFR)-1/2. TFR-1/2 protein expression was then evaluated in surgical specimens from 210 cases using immunohistochemistry, and we compared clinicopathological factors with TFR-1/2 expression. The mRNA expression levels of TFR-1 were significantly increased in HCC tissues compared with adjacent non-cancerous tissues (P = 0.0013), but there were no differences in other genes. High expression of TFR-1 in HCC was associated with the absence of alcohol abuse (P = 0.0467), liver cirrhosis (P < 0.0001), higher alpha-fetoprotein (AFP; P < 0.0001), smaller tumour size (P = 0.0022), poor histological differentiation (P < 0.0001) and morphological features (P < 0.0001). In contrast, high expression of TFR-2 in HCC was associated with lower AFP (P < 0.0001), well-differentiated histological grade (P < 0.0001) and morphological features (P = 0.0010). Multivariate analysis for both overall survival and recurrence-free survival indicated that high TFR-1 expression was a significant prognostic factor for poor outcome.

Conclusions: We found an inverse correlation of TFR-1 and TFR-2 expression in AFP and tumour differentiation. TFR-1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection.
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http://dx.doi.org/10.1111/his.13847DOI Listing
July 2019

Occult HBV infection status and its impact on surgical outcomes in patients with curative resection for HCV-associated hepatocellular carcinoma.

Hepatobiliary Surg Nutr 2018 Dec;7(6):443-453

Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan.

Background: We sought to clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and to determine whether OBI affects the surgical outcomes in curatively resected Japanese patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).

Methods: A total of 257 patients with HCV-related HCC who underwent curative surgical resection were enrolled. All enrolled patients were serologically negative for HBV surface antigen and positive for HCV antibody. DNA was extracted from formalin-fixed paraffin-embedded liver tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Surgical outcomes were evaluated according to overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS).

Results: OBI was identified in 15 of the 257 (5.8%) cases. In the multivariate analyses, the factors significantly correlated with OS were BMI >25 (P=0.0416), portal vein invasion (P=0.0065), and multiple tumors (P=0.0064). The only factor significantly correlated with DSS was T-stage (P=0.0275). The factors significantly correlated with DFS were liver fibrosis (P=0.0017) and T-stage (P=0.0001). The status of OBI did not show any significant correlation with OS, DSS or DFS, but a weak association with DSS (P=0.0603) was observed.

Conclusions: The prevalence of OBI was 5.8% in 257 cases of HCV-related HCC. Although a weak association between DSS and OBI was observed, and statistical analyses were limited by small number of OBI cases, no significant correlation between OBI and surgical outcomes was detected.
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http://dx.doi.org/10.21037/hbsn.2018.10.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295390PMC
December 2018

A case of osimertinib-resistant lung adenocarcinoma responded effectively to alternating therapy.

Ann Transl Med 2018 Dec;6(23):464

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.

We report a case of initial lung adenocarcinoma in which transformation to small cell lung carcinoma (SCLC) was observed after acquired resistance to the 3 generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and alternating treatment between chemotherapy and osimertinib was effective. A 61-year-old woman with EGFR mutation positive stage IV lung adenocarcinoma was administered 1 generation EGFR-TKI for 8 months as the first line therapy, then chemotherapy and 2 generation EGFR-TKI after progressive disease (PD). Four years after initial diagnosis, T790M was detected in a metastatic lesion of the right thoracic wall and osimertinib was prescribed. Although partial response (PR) was achieved, a new metastatic lesion appeared in the right pleurum near the diaphragm, in which SCLC characteristics were observed with elevation of pro-gastrin-releasing peptide (pro-GRP) at the time of PD under osimertinib. Osimertinib was discontinued and carboplatin plus irinotecan chemotherapy was chosen as the next treatment, leading to PR after 2 cycles. Subsequently, the right thoracic wall tumor harboring T790M and the right pleural tumor near the diaphragm showing transformation to SCLC exhibited opposite responses to therapy alternating between osimertinib and chemotherapy. It is concluded that extended disease control can be achieved by combining appropriate treatments according to the mechanisms of resistance inferred from precise genetic and pathological examination in real time.
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http://dx.doi.org/10.21037/atm.2018.11.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312808PMC
December 2018

Didactic surgical experience of thyroid metastasis from renal cell carcinoma: A case report.

World J Clin Cases 2018 Dec;6(15):1018-1023

Department of Otolaryngology Head and Neck Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.

Background: The optimal therapeutic strategy in treating thyroid metastasis from renal cell carcinoma (RCC) has not been clearly established. Here we describe a case of didactic surgical experience of the disease which caused massive intraoperative bleeding.

Case Summary: A 59-year-old male patient presented with a thyroid left lobe soft mass detected by chest computed tomography scans prior to the surgical treatment of RCC of the left kidney. The thyroid mass was initially considered to be benign, then he underwent left radical nephrectomy. One year after the nephrectomy, stereotactic radiosurgery was performed for brain metastasis. During follow-up, the thyroid nodule gradually grew, and the patient manifested swallowing discomfort. Under a clinical diagnosis of thyroid follicular neoplasm, left hemithyroidectomy was performed. Although hemithyroidectomy is usually a safe and straightforward procedure, massive bleeding from markedly developed tumor vessels made the operation very difficult. The thyroid tumor was finally diagnosed as metastasis from clear cell RCC.

Conclusion: For proper timing of the surgery, a clinician should take into consideration the possibility of thyroid metastasis of RCC when a thyroid lesion is found in patients with RCC or in patients with a previous history of RCC. We recommend that thyroid metastasis of RCC should be resected as early as possible even if a patient has other metastatic sites.
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http://dx.doi.org/10.12998/wjcc.v6.i15.1018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288516PMC
December 2018

The relationship between type 1 IFN and vasculopathy in anti-MDA5 antibody-positive dermatomyositis patients.

Rheumatology (Oxford) 2019 05;58(5):786-791

Department of Rheumatology, Saga University, Saga, Japan.

Objective: Based on the antibody profiles of inflammatory myositis patients, we investigated the type 1 IFN (T1-IFN) signature in serum and DM skin to determine the relationship between T1-IFN and vasculopathy in anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive DM patients.

Methods: We examined 47 patients with new-onset inflammatory myositis. We divided them into three groups: the anti-MDA5 antibody-positive patients (MDA5 group, n = 16), the anti-aminoacyl-tRNA synthetase antibody-positive patients (aminoacyl-tRNA synthetase group, n = 12), and the double-negative patients (n = 19). Serum T1-IFN signatures were revealed by a functional reporter assay, and we evaluated the T1-IFN signatures of skin based on Mx1 expression by immunohistochemistry.

Results: The numbers of patients with classical DM, clinically amyopathic DM and interstitial lung disease were 1, 15 and 13 in the MDA5 group, 2, 3 and 11 in the aminoacyl-tRNA synthetase group, and 10, 1 and 4 in the double-negative group, respectively. The signs of vasculopathies (i.e. palmer papules, skin ulcers and mononeuritis multiplex) were identified only in the MDA5 patients. Most of the MDA5 group showed the highest serum T1-IFN signatures among the three groups. In the histological analysis of DM skin, perivascular inflammations were significant in the MDA5 group. The MDA5 group's Mx1 expression was significantly strong, distributed in blood vessels and interstitial fibroblasts, and had spread to deep dermis.

Conclusion: Anti-MDA5 antibody-positive DM patients showed high T1-IFN signatures in serum and affected skin. The high T1-IFN signatures of the MDA5 antibody-positive DM patients in serum and deep vasculatures suggested that T1-IFN may have important roles in the vasculopathy of these patients.
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http://dx.doi.org/10.1093/rheumatology/key386DOI Listing
May 2019

Locally distributed multicentric plasmacytomas in the ileum secondary to lymphoma chemoimmunotherapy.

Ann Hematol 2019 Jun 8;98(6):1501-1503. Epub 2018 Nov 8.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

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http://dx.doi.org/10.1007/s00277-018-3543-yDOI Listing
June 2019

Oral ulceration: an unusual manifestation of lymphomatoid granulomatosis.

Ann Hematol 2019 May 3;98(5):1305-1307. Epub 2018 Oct 3.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

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http://dx.doi.org/10.1007/s00277-018-3506-3DOI Listing
May 2019

Primary Pulmonary Colloid Adenocarcinoma: How Can We Obtain a Precise Diagnosis?

Intern Med 2018 Dec 10;57(24):3637-3641. Epub 2018 Aug 10.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan.

A 76-year-old asymptomatic man was found to have a mass in the right lower lung field. Although the presence of a mucinous component in the majority of the tumor was shown by magnetic resonance imaging, the presence of cancer cells was suspected by contrast enhancement on computed tomography (CT) and based on the partial accumulation in the marginal regions of the tumor on fluorodeoxyglucose-positron emission tomography (FDG-PET). A transbronchial lung biopsy was non-diagnostic, but resection of the mass resulted in a diagnosis of colloid adenocarcinoma. The findings from combined contrast CT and FDG-PET may raise the suspicion of colloid adenocarcinoma and prompt the consideration of surgical resection.
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http://dx.doi.org/10.2169/internalmedicine.1153-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355410PMC
December 2018

Gastric adenocarcinoma of fundic gland type with signet-ring cell carcinoma component: A case report and review of the literature.

World J Gastroenterol 2018 Jul;24(26):2915-2920

Department of Pathology, Shin Koga Hospital, Kurume 830-8577, Japan.

A depressed lesion was found at a gastric angle of 76-year-old Japanese woman by esophagogastroduodenoscopy. Four years prior, she was diagnosed with a infection but no eradication was performed. The pathological diagnosis of biopsy specimens was signet-ring cell carcinoma. Endoscopic submucosal dissection (ESD) was performed. Histopathological examination of the ESD specimen revealed proliferation of well-differentiated tubular adenocarcinoma mimicking fundic gland cells at the deep layer of the lamina propria mucosae. These tumor cells expressed focally pepsinogen-I, diffusely MUC6, and scattered H/K ATPase according to immunohistochemistry. Therefore, we diagnosed this tumor as gastric adenocarcinoma of fundic gland type (GA-FG). Adjacent to the GA-FG, proliferation of signet-ring cell carcinoma which diffusely expressed MUC 2 and MUC 5AC was observed. Intestinal metaplasia was focally observed in the surrounding mucosa of the signet-ring cell carcinoma. To the best of our knowledge, this is the first case report of GA-FG with a signet-ring cell carcinoma component. The origin of signet-ring cell carcinoma, ., whether it accidentally arose from a non-neoplastic mucosa and coexisted with the GA-FG or dedifferentiated from the GA-FG is unclear at present. We expect the accumulation of similar cases and further analysis to clarify this issue.
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http://dx.doi.org/10.3748/wjg.v24.i26.2915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048433PMC
July 2018

High-dose Factor XIII administration induces effective hemostasis for trauma-associated coagulopathy (TAC) both in vitro and in rat hemorrhagic shock in vivo models.

J Trauma Acute Care Surg 2018 09;85(3):588-597

From the Division of Trauma Surgery and Surgical Critical Care, Saga University Hospital, Nabeshima Saga, Japan (F.N., S.I.); Department of Emergency Medicine, Saga University Hospital, Saga, Japan (H.K., T.M., Y.S.); and Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan (K.K.).

Background: Trauma-associated coagulopathy (TAC) is an early and primary complication in severe trauma patients. Factor XIII (FXIII) is reported to stabilize a clot in the late phase of the coagulation cascade. The goal of this study was to investigate whether the administration of FXIII improves the condition of TAC both in vitro and in vivo.

Methods: We evaluated the effects of different doses, including a very high dose of FXIII (3.6-32.4 IU/mL) on tissue-plasminogen activator-induced hyperfibrinolysis and the combined condition of dilutional coagulopathy and tissue-plasminogen activator-induced hyperfibrinolysis in vitro. The coagulation status was analyzed by rotational thromboelastometry (ROTEM) and Sonoclot. Then, we evaluated the effect of high-dose FXIII (300 IU/kg) for severe coagulopathy in vivo using a rat liver trauma model in which coagulopathy similar to TAC was observed. Survival time and the amount of intra-abdominal bleeding of rats were measured, and a coagulation test was also performed. Histologic evaluations of rats' lung and kidney after FXIII administration were completed.

Results: High-dose FXIII significantly improved clot strength as well as increased resistance to hyperfibrinolysis in vitro which was confirmed by ROTEM. Platelet function on Sonoclot was significantly increased by FXIII in a dose-dependent manner. Factor XIII significantly decreased the total amount of bleeding and prolonged the survival time compared to control (control vs FXIII: 108.9 ± 11.4 vs 32.6 ± 5.5 mL/kg; p < 0.001; 26.0 ± 8.8 vs 120 minutes, p < 0.001) in a rat model. Rotational thromboelastometry parameters and platelet function on Sonoclot were significantly improved in the FXIII (+) group compared to control. No adverse effects of FXIII were detected histologically.

Conclusion: Factor XIII not only generated stable clot resistance to hyperfibrinolysis but also enhanced platelet function by facilitating clot retraction. High-dose FXIII administration therapy has significant clinical impact for severe trauma accompanied with TAC.

Study Type: Human in vitro and rat in vivo experimental study.
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http://dx.doi.org/10.1097/TA.0000000000001998DOI Listing
September 2018

A dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features.

Pathol Int 2018 04 15;68(4):262-264. Epub 2018 Feb 15.

Department of Pathology, Saga University Hospital, Saga, Japan.

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http://dx.doi.org/10.1111/pin.12645DOI Listing
April 2018

Correlation between smoking habit and surgical outcomes on viral-associated hepatocellular carcinomas.

World J Gastroenterol 2018 Jan;24(1):58-68

Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.

Aim: To investigate the association between smoking habits and surgical outcomes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) (B-HCC) and hepatitis C virus (HCV)-related HCC (C-HCC) and clarify the clinicopathological features associated with smoking status in B-HCC and C-HCC patients.

Methods: We retrospectively examined the cases of the 341 consecutive patients with viral-associated HCC (C-HCC, = 273; B-HCC, = 68) who underwent curative surgery for their primary lesion. We categorized smoking status at the time of surgery into never, ex- and current smoker. We analyzed the B-HCC and C-HCC groups' clinicopathological features and surgical outcomes, ., disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS). Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. We also performed subset analyses in both patient groups comparing the current smokers to the other patients.

Results: The multivariate analysis in the C-HCC group revealed that current-smoker status was significantly correlated with both OS ( = 0.0039) and DSS ( = 0.0416). In the B-HCC patients, no significant correlation was observed between current-smoker status and DFS, OS, or DSS in the univariate or multivariate analyses. The subset analyses comparing the current smokers to the other patients in both the C-HCC and B-HCC groups revealed that the current smokers developed HCC at significantly younger ages than the other patients irrespective of viral infection status.

Conclusion: A smoking habit is significantly correlated with the overall and disease-specific survivals of patients with C-HCC. In contrast, the B-HCC patients showed a weak association between smoking status and surgical outcomes.
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http://dx.doi.org/10.3748/wjg.v24.i1.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757126PMC
January 2018

Occult hepatitis B virus infection and surgical outcomes in non-B, non-C patients with curative resection for hepatocellular carcinoma.

World J Hepatol 2017 Dec;9(35):1286-1295

Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.

Aim: To investigate the prevalence, clinicopathological characteristics and surgical outcomes of occult hepatitis B virus (HBV) infection (OBI) in patients with non-B, non-C (NBNC) hepatocellular carcinoma (HCC).

Methods: This study retrospectively examined the cases of 78 NBNC patients with curative resection for HCC for whom DNA could be extracted from formalin-fixed paraffin-embedded tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Possibly carcinogenetic factors such as alcohol abuse, diabetes mellitus, obesity and non-alcoholic steatohepatitis (NASH) were examined. Surgical outcomes were evaluated according to disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS).

Results: OBI was found in 27/78 patients (34.6%) with NBNC HCC. The OBI patients were significantly younger than the non-OBI cases at the time of surgery (average age 63.0 68.1, = 0.0334) and the OBI cases overlapped with other etiologies significantly more frequently compared to the non-OBI cases ( = 0.0057). OBI had no impact on the DFS, OS or DSS. Only tumor-related factors affected these surgical outcomes.

Conclusion: Our findings indicate that OBI had no impact on surgical outcomes. The surgical outcomes of NBNC HCC depend on early tumor detection; this reconfirms the importance of a periodic medical examination for individuals who have NBNC HCC risk factors.
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http://dx.doi.org/10.4254/wjh.v9.i35.1286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740092PMC
December 2017

Paraneoplastic Sarcoidosis in Multiple Myeloma.

Intern Med 2017 1;56(15):2049-2051. Epub 2017 Aug 1.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan.

Sarcoidosis predominantly affects the lungs, intrathoracic lymph nodes, and eyes; it less frequently affects the musculoskeletal system. We herein report a case of paraneoplastic sarcoidosis in a patient presenting with multiple myeloma. The patient developed ocular sarcoidosis and showed an increased F-fluorodeoxyglucose uptake in the mediastinal lymph nodes and vertebral column. A lymph node specimen showed the histological features of sarcoidosis, while an examination of the vertebral tumor revealed myeloma. Although the simultaneous occurrence of sarcoidosis and myeloma is extremely rare, our case indicates the importance of exculing any underlying malignancies before establishing a diagnosis of skeletal sarcoidosis when bone lesions are observed at unusual sites.
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http://dx.doi.org/10.2169/internalmedicine.56.8331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577085PMC
February 2018
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