Publications by authors named "Ichiro Murakami"

76 Publications

A case of mixed tumor formed by metastasis of urothelial carcinoma and malignant lymphoma to the same lymph nodes.

IJU Case Rep 2021 Sep 21;4(5):294-297. Epub 2021 Jun 21.

Departments of Department of Urology Kochi Medical School Nankoku Japan.

Introduction: Mixed tumor in the same lymph nodes is extremely rare and no previous reports have described mixed tumor comprising urothelial carcinoma and malignant lymphoma.

Case Presentation: A 71-year-old woman visited a local clinic with a main complaint of hematuria. Imaging revealed right hydronephrosis and a mid-ureter tumor shadow. Positron emission tomography-computed tomography showed high uptake of fluorodeoxyglucose in para-aortic lymph nodes. Abdominal para-aortic lymph node biopsy was performed. Pathology showed urothelial carcinoma and malignant lymphoma in the same lymph nodes, where a mixed tumor was diagnosed.

Conclusion: We encountered a case of mixed tumor of urothelial carcinoma and Hodgkin lymphoma, which metastasized to the same tissues.
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http://dx.doi.org/10.1002/iju5.12329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413221PMC
September 2021

The Expression of Insulin-Like Growth Factor 2 Messenger RNA-Binding Protein 3 in Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma.

Tohoku J Exp Med 2021 09;255(1):27-31

Department of Diagnostic Pathology, Kyoto University Hospital.

Langerhans cell neoplasms, which include Langerhans cell histiocytosis and Langerhans cell sarcoma, are tumors that originate from dendritic cells. Langerhans cell sarcoma is defined as a high-grade neoplasm with overtly malignant cytological features and the Langerhans cell-like phenotype, and generally has a poorer prognosis and more aggressive phenotype than Langerhans cell histiocytosis. Insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types; its expression is often associated with a poor prognosis and aggressive phenotype. Here, we used immunohistochemistry to evaluate IGF2BP3 expression in Langerhans cell neoplasms. IGF2BP3 expression was scored as negative (< 1%) or positive (≥ 1%) by immunohistochemistry. All 4 patients with Langerhans cell sarcoma (100%) and 6 of 22 pediatric (age < 18 years) patients with Langerhans cell histiocytosis (27.3%) had positive results for IGF2BP3; however, 16 of 22 pediatric patients with Langerhans cell histiocytosis (72.7%) and all 15 adult (age ≥ 18 years) patients with Langerhans cell histiocytosis (100%) had a negative result. Among patients with Langerhans cell histiocytosis, IGF2BP3 expression was independent of sex, location, prognosis, and BRAF V600E staining results. Taken together, these results indicate that IGF2BP3 expression may be a helpful marker for distinguishing Langerhans cell sarcoma from Langerhans cell histiocytosis in adult patients.
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http://dx.doi.org/10.1620/tjem.255.27DOI Listing
September 2021

Fascin-1 is associated with recurrence in solitary fibrous tumor/hemangiopericytoma.

Mol Clin Oncol 2021 Oct 8;15(4):199. Epub 2021 Aug 8.

Department of Diagnostic Pathology, Kochi University Hospital, Kochi University, Nankoku, Kochi 783-8505, Japan.

Fascin-1, an actin-bundling protein, is associated with poor prognosis in patients with various types of human carcinoma. However, research is limited on the role of fascin-1 in sarcoma. Solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are rare sarcomas derived from the mesenchyme. Although the prognosis of SFT/HPC is generally favorable, fatalities are possible with repeated recurrence and distant metastasis. The current study included a total of 20 Japanese patients, who were diagnosed with SFT/HPC and underwent surgery at Kochi University Hospital from January 2000 to December 2019. The statistical relationship between recurrence and the following variables were examined: Sex, age of onset, tumor origin, tumor size, necrosis, mitosis ≥1/10 high power field (HPF; magnification, x400), Ki-67 >5% and Fascin-1. A significant association was determined between recurrence and necrosis, mitosis ≥1/10 HPF (magnification, x400), Ki-67 >5%, and Fascin-1 ≥'strongly positive' (P<0.05). The results demonstrated that Fascin-1 immunostaining may be a highly effective and useful evaluation factor for predicting poor prognosis in patients with SFT/HPC, a fatal sarcoma of humans.
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http://dx.doi.org/10.3892/mco.2021.2361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375015PMC
October 2021

Prognostic significance of human papillomavirus 16 viral load level in patients with oropharyngeal cancer.

Cancer Sci 2021 Aug 12. Epub 2021 Aug 12.

Department of Microbiology and Infection, Kochi Medical School, Kochi University, Nankoku, Japan.

Human papillomavirus (HPV) infection in patients with oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant for better prognosis. However, there remain HPV-positive patients who have poor outcomes. The stratification strategy for detecting high-risk patients among those with HPV-positive OPSCC has not been well delineated, especially for Asian patients. We undertook a retrospective cohort study on the survival rate of 89 Japanese patients diagnosed with primary OPSCC. The tumors were concurrently analyzed for the presence of HPV E6 DNA/mRNA, viral DNA load, p16 expression, viral physical status, and viral variant lineage. Human papillomavirus 16 viral DNA was found in 45 (51%) OPSCCs. Human papillomavirus 16 DNA-positive OPSCCs with higher viral load (classified as HPV16 DNA-medium/high OPSCCs) showed significantly favorable overall survival and progression-free survival compared with HPV16 DNA-positive OPSCCs with lower viral load (<10 copies/cell; HPV16 DNA-low OPSCCs) and HPV16 DNA-negative OPSCCs. E6 mRNA expression was observed in all HPV16 DNA-medium/high OPSCCs but not in HPV16 DNA-low OPSCCs. Notably, p16-positive and HPV16 DNA-negative/low OPSCCs showed significantly worse survival than p16-positive and HPV16 DNA-medium/high OPSCCs and resembled HPV-unrelated OPSCCs with regard to survival and risk factor profile. Although not significant, a trend toward shorter survival was observed for HPV16-integrated OPSCCs. Phylogenetic analysis revealed two major types of HPV16 variants termed Asian (A4) and European (A1/A2/A3) variants, but no difference in survival between these variants was observed. Altogether, these findings suggest that HPV viral load is a potentially informative factor for more accurate risk stratification of patients with OPSCC.
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http://dx.doi.org/10.1111/cas.15105DOI Listing
August 2021

A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma.

Neoplasia 2021 Sep 28;23(9):939-950. Epub 2021 Jul 28.

Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan; Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, Japan; Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan. Electronic address:

An antibody-drug conjugate (ADC) is a promising therapeutic modality because selective and effective delivery of an anti-cancer drug is achieved by drug-conjugated antibody-targeting cancer antigen. Glypican 1 (GPC1) is highly expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC). Herein, we describe the usefulness of GPC1-targeting ADC. Humanized anti-GPC1 antibody (clone T2) was developed and conjugated with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC) linkers (humanized GPC1-ADC[MMAE]). Humanized GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC and ESCC cell lines via inducing cycle arrest in the G2/M phase and apoptosis in vitro. The binding activity of humanized GPC1-ADC(MMAE) with GPC1 was comparable with that of the unconjugated anti-GPC1 antibody. The humanized GPC1-ADC(MMAE) was effective in GPC1-positive BxPC-3 subcutaneously xenografted mice but not in GPC1-negative BxPC-3-GPC1-KO xenografted mice. To assess the bystander killing activity of the humanized GPC1-ADC(MMAE), a mixture of GPC1-positive BxPC-3 and GPC1-negative BxPC-3-GPC1-KO-Luc cells were subcutaneously inoculated, and a heterogenous GPC1-expressing tumor model was developed. The humanized GPC1-ADC(MMAE) inhibited the tumor growth and decreased the luciferase signal, measured with an in vivo imaging system (IVIS), which suggests that the suppression of the BxPC-3-GPC1-KO-Luc population. The humanized GPC1-ADC(MMAE) also inhibited the established liver metastases of BxPC-3 cells and significantly improved the overall survival of the mice. It exhibited a potent antitumor effect on the GPC1-positive PDAC and ESCC patient-derived xenograft (PDX) models. Our preclinical data demonstrate that GPC1 is a promising therapeutic target for ADC.
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http://dx.doi.org/10.1016/j.neo.2021.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340053PMC
September 2021

Anti-Glypican-1 Antibody-drug Conjugate as Potential Therapy Against Tumor Cells and Tumor Vasculature for Glypican-1-Positive Cholangiocarcinoma.

Mol Cancer Ther 2021 Sep 17;20(9):1713-1722. Epub 2021 Jun 17.

Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan.

Cholangiocarcinoma is a highly malignant cancer. Many patients need systemic chemotherapy to prevent tumor development and recurrence; however, their prognosis is poor due to the lack of effective therapy. Therefore, a new treatment option is urgently required. We recently identified glypican-1 (GPC1) as a novel cancer antigen of esophageal squamous cell carcinoma. We also demonstrated the efficacy and safety of GPC1-targeted ADC (GPC1-ADC) conjugating anti-GPC1 mAb possessing high internalization activity with monomethyl auristatin F (MMAF), which is a potent tubulin polymerizing inhibitor. In this study, we confirmed that GPC1 was highly expressed in cholangiocarcinoma cells and tissues. IHC analysis of 49 extrahepatic cholangiocarcinoma patient tumor specimens revealed high expression of GPC1 in 47% of patients. These patients demonstrated significantly poorer prognosis compared with the low-expression group in terms of disease-free survival and overall survival ( < 0.05). GPC1 was also expressed in tumor vessels of cholangiocarcinoma, but not on the vessels of nontumor tissues. MMAF-conjugated GPC1-ADC showed potent tumor growth inhibition against GPC1-positive cholangiocarcinoma cells and In a GPC1 knockout xenograft model, GPC1-ADC partially inhibited tumor growth. Vascular endothelial cells in tumor tissues of GPC1-negative xenograft mice expressed GPC1 and were arrested in the G-M phase of cell cycle by GPC1-ADC. GPC1-ADC exhibits direct as well as indirect antitumor effects via inhibition of tumor angiogenesis. Our preclinical data highlight GPC1-ADC as a promising therapy for GPC1-positive cholangiocarcinoma.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0015DOI Listing
September 2021

Tenosynovial and Cardiac Transthyretin Amyloidosis in Japanese Patients Undergoing Carpal Tunnel Release.

Circ Rep 2021 May 27;3(6):338-344. Epub 2021 May 27.

Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University Nankoku Japan.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a life-threatening progressive disease. Recent studies have shown that the detection of transthyretin (TTR) amyloid in tenosynovial tissue may play an important role in the diagnosis of cardiac amyloidosis. The aim of this study was to determine the prevalence of TTR amyloid deposits in surgical tissue of patients undergoing carpal tunnel surgery and to clarify the clinical significance of concomitant cardiac examination with Tc-labeled pyrophosphate (Tc-PYP) scintigraphy in those patients with TTR deposition. We evaluated 79 consecutive patients undergoing carpal tunnel release surgery and biopsy of tenosynovial tissue. The mean (±SD) age of the patients at surgery was 71.6±12.5 years (range 30-95 years); 32 patients (41%) were male. TTR amyloid deposition in tenosynovial tissue was observed in 27 patients (34%). Sixteen of those 27 patients underwent Tc-PYP scintigraphy. Of those 16 patients, 3 (19%) had Grade 2 uptake on Tc-PYP scintigraphy. None of the 3 patients with a diagnosis of ATTRwt-CA had apparent cardiac symptoms and left ventricular wall thickness >13 mm. Concomitant cardiac examination with Tc-PYP scintigraphy in patients who had TTR amyloid deposition in tenosynovial tissue resulted in the identification of 19% of patients with a diagnosis of ATTRwt-CA. This diagnostic approach seems to be useful for the early diagnosis of the disease.
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http://dx.doi.org/10.1253/circrep.CR-21-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180371PMC
May 2021

Synchronous bilateral renal cell carcinomas with differing histologies.

IJU Case Rep 2020 Sep 28;3(5):196-199. Epub 2020 Jun 28.

Department of Urology Kochi Medical School Nankoku Japan.

Introduction: Bilateral renal cell carcinomas with different histological types are rare. We report herein the first description of bilateral renal carcinomas with clear cell renal cell carcinoma and mucinous tubular and spindle cell carcinoma occurring synchronously.

Case Presentation: A 62-year-old man was referred to our hospital with bilateral renal tumors. The tumors on each side showed different findings from both contrast-enhanced computed tomography and magnetic resonance imaging. The tumors were partially resected. Histopathological and immunohistochemical examination of the left renal tumor diagnosed clear cell renal carcinoma. Histopathological and immunohistochemical examination of the right renal tumor diagnosed mucinous tubular and spindle cell carcinoma.

Conclusion: We encountered a case with clear cell renal cell carcinoma and mucinous tubular and spindle cell carcinoma occurring simultaneously in bilateral kidneys.
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http://dx.doi.org/10.1002/iju5.12186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469849PMC
September 2020

Recurrence of Solitary Fibrous Tumor/Hemangiopericytoma Could Be Predicted by Ki-67 Regardless of Its Origin.

Acta Med Okayama 2020 Aug;74(4):335-343

Department of Diagnostic Pathology, Kochi University, Nankoku, Kochi 783-8505, Japan.

Since the discovery of the NAB2-STAT6 gene fusion in 2013, solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) have been considered the same disease. STAT6 nuclear stain is approved as a highly sensitive and specific marker to diagnose SFT/HPC from other tumors with similar histology. As the next step, detection of fusion variants that may predict clinical malignancy of SFT/HPC has been attempted. However, no fusion variants with a clear relation to malignancy have been identified. In this study, the clinical and histological backgrounds of 23 Japanese patients diagnosed with SFT/HPC from 2000 to 2019 at Kochi University Hospital were examined to identify factors potentially related to recurrence. A significant relationship to recurrence was detected for mitosis ≥ 1/10 HPF (400×), necrosis, and Ki-67>5%. These findings indicate that a deliberate investigation of histological features such as mitosis and necrosis is crucial for the clinical observation of SFT/ HPC patients. In addition, Ki-67 was revealed to be a useful parameter to predict recurrence in SFT/HPC patients.
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http://dx.doi.org/10.18926/AMO/60372DOI Listing
August 2020

[Recurrent High-grade Astroblastoma Treated with Stereotactic Radiotherapy:A Case Report].

No Shinkei Geka 2020 Feb;48(2):151-158

Department of Neurosurgery, Kochi Medical School.

Introduction: Astroblastoma is a rare, supratentorial glial tumor, occurring predominantly in children and young adults. However, treatment strategies have not yet been established for this rare disease.

Case Presentation: A 6-year-old boy presented with headache and nausea. CT and MRI revealed a left frontal mass lesion with slight edema and macrocalcifications. Gross tumor resection was performed. Histological examination found neoplastic cells with astroblastic characteristics, and a striking perivascular array of pseudorosettes. The final diagnosis was high-grade astroblastoma. MRI 13 months after surgery suggested local recurrence, and an enlargement was found 3 months later. Stereotactic radiotherapy(SRT)was performed. MRI after SRT showed enhanced cyst formation around the tumor bed, suggesting tumor recurrence. However, 11C-methionine positron emission tomography(PET)revealed radiation necrosis. The last follow-up MRI 15 months after SRT showed no further recurrence.

Conclusion: Astroblastoma is rare, therefore, no optimal management is known. SRT may be effective to treat recurrent astroblastomas. 11C-methionine PET/CT was useful to differentiate metastatic disease from radiation necrosis.
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http://dx.doi.org/10.11477/mf.1436204152DOI Listing
February 2020

Human Polyomavirus 6 with the Asian-Japanese Genotype in Cases of Kimura Disease and Angiolymphoid Hyperplasia with Eosinophilia.

J Invest Dermatol 2020 08 23;140(8):1650-1653.e4. Epub 2020 Jan 23.

Department of Microbiology and Infection, Kochi Medical School, Kochi University, Kochi, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.12.027DOI Listing
August 2020

Lymph node retrieval after colorectal cancer surgery: a comparative study of the efficacy between the conventional manual method and a new fat dissolution method.

Surg Today 2020 Jul 7;50(7):726-733. Epub 2020 Jan 7.

Department of Surgery, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.

Purpose: This study compared the efficacy of two different methods for lymph node (LN) searching after colorectal cancer surgery: the fat dissolution and the conventional manual method.

Methods: For the fat dissolution method, we used a commercially available solution of collagenase and lipase (FD group). The primary endpoint was the number of identified LNs in the FD group compared to an historical control (control group) after adjusting by propensity score matching.

Results: Using 37 matched patients from each group, we identified 20.6 ± 7.2 LNs using the fat dissolution method compared to 13.5 ± 5.9 using the conventional method (t test, P < 0.01). Three patients in the FD group received an inappropriate LN examination in terms of number, while the number of the retrieved LNs was < 12 in 12 patients in the control group. The mean diameter of LNs without metastasis was 3.2 ± 1.9 mm in the FD group, and 40% of metastasis cases were found in LNs < 5 mm in diameter. A pathological examination confirmed that using the fat resolution method did not change the morphological or immunochemical staining findings.

Conclusion: We demonstrated that fat dissolution had a positive impact on the number of retrieved LNs after colorectal cancer surgery without disturbing the microscopic observation.
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http://dx.doi.org/10.1007/s00595-019-01944-0DOI Listing
July 2020

Clinicopathologic study of deciduoid mesothelioma using SMARCB1/INI1 immunohistochemistry and fluorescence in situ hybridization.

Hum Pathol 2019 11 22;93:23-29. Epub 2019 Aug 22.

Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.

Deciduoid mesothelioma is a rare variant of epithelioid mesothelioma. Malignant rhabdoid tumors, renal medullary carcinoma, and some synovial sarcomas show a loss of SMARCB1/INI1 protein, a member of the SWI/SNF chromatin-remodeling complex. All of those tumors are known to have rhabdoid cells. Some mesothelioma cases, such as those of the deciduoid type, have also been reported to possess such rhabdoid features. Since this topic has not been studied in malignant mesothelioma, we analyzed the immunohistochemical expression of SMARCB1/INI1 in malignant mesotheliomas [45 epithelioid type (including 9 deciduoid type), 12 biphasic type, and 17 sarcomatoid type]. We employed (a) SMARCB1/INI1 immunohistochemistry, using an antibody to the INI1 gene product and (b) Fisher exact test, logistic regression analysis, the Kaplan-Meier method, and the Wilcoxon test for survival analysis for prognostic factor evaluation (SAS 9.4; SAS Institute, Cary, NC). The results showed that 17 of 74 (23%) malignant mesothelioma cases (epithelioid: 24%; biphasic; 8%; sarcomatoid; 29%) had reduced SMARCB1/INI1 expression. Reduced SMARCB1/INI1 expression appeared to be more frequent in the deciduoid type (67%), of which there were admittedly only a few cases, than in either the epithelioid type (14%) or biphasic type (8%), whether or not rhabdoid cells were present, but not different between the deciduoid and sarcomatoid types. However, there was no statistically significant difference in prognosis between malignant mesotheliomas with reduced versus preserved SMARCB1/INI1 protein expression. The results suggest that in differential diagnosis, cases with reduced SMARCB1/INI1 protein expression should not be excluded from a diagnosis of malignant mesothelioma.
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http://dx.doi.org/10.1016/j.humpath.2019.08.016DOI Listing
November 2019

Vocal cord inflammatory myofibroblastic tumor with mucoid deposits harboring TIMP3-ALK fusion: A potential diagnostic pitfall.

Pathol Int 2019 Jun 18;69(6):366-371. Epub 2019 Jun 18.

Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Pilsen, Czech Republic.

A 35-year-old Japanese man who had experienced hoarseness for 10 years presented with a vocal cord lesion. A gross examination revealed a left vocal cord polyp occupying two-thirds of the vocal space. The endoscopically resected lesion contained scattered atypical fibroblastic, stellate, or ganglion-like cells with mucoid stroma. Vacuolated cells were also seen. Lymphoplasmacytic infiltrate was largely undetectable. A vocal cord polyp was first suspected, but well-differentiated liposarcoma and inflammatory myofibroblastic tumor (IMT) were included in the differential diagnoses. The tumor cells were positive for anaplastic lymphoma kinase (ALK), calponin, and vimentin, and negative for other smooth muscle markers by immunohistochemistry. Structures resembling myofibroblasts were not observed by electron microscopy, which confirmed abundant rough endoplasmic reticulum in the tumor cells and accumulated lipid droplets in some tumor cells. ALK gene rearrangement was detected by fluorescence in situ hybridization, and TIMP3-ALK fusion was confirmed by 5' rapid amplification of cDNA ends. We diagnosed the lesion as an IMT, and an ALK-rearranged stellate cell tumor may be postulated. This is the first report of a fusion partner gene of ALK in a case of laryngeal IMT.
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http://dx.doi.org/10.1111/pin.12796DOI Listing
June 2019

Intrahepatic bile duct adenoma in a patient with gastric cancer.

Int Cancer Conf J 2019 Jan 12;8(1):7-11. Epub 2018 Sep 12.

Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505 Japan.

We report a case of intrahepatic bile duct adenoma (BDA) detected during laparoscopic distal gastrectomy for gastric cancer. A 70-year-old man was referred to our hospital for the treatment of gastric cancer. Esophagogastroduodenoscopy revealed an irregular, nodular, and elevated lesion on the greater curvature side of the middle third of the stomach. Abdominal contrast-enhanced computed tomography showed wall thickening with homogeneous enhancement in the middle part of the stomach, and no lesions in the liver. The patient underwent laparoscopic distal gastrectomy with regional lymphadenectomy, and during the operation a small whitish nodule was observed on the lateral segment of the liver surface. The lesion was excised by partial resection of the liver for the purpose of both histological diagnosis and treatment. Pathological examination of the liver lesion revealed no structural or cellular atypia, no stromal invasion, and immunohistochemical positivity for CK7 and CK19, but negativity for p53. The final diagnosis was well-differentiated adenocarcinoma invading the gastric serosal layer without lymph node metastasis, and intrahepatic BDA measuring 0.4 × 0.3 cm. Following surgery, the patient remained symptom-free without evidence of recurrence for 5 months. To the best of our knowledge, this is the first case of BDA with gastric cancer. Because it is difficult to distinguish BDA from other liver tumors including metastatic cancer due to its characteristically small size and lack of specific morphological features on standard imaging, surgical resection should be considered as the most suitable approach for both accurate diagnosis and treatment.
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http://dx.doi.org/10.1007/s13691-018-0345-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498292PMC
January 2019

Generation and characteristics of a novel "double-hit" high grade B-cell lymphoma cell line DH-My6 with / and / gene arrangements and potential molecular targeted therapies.

Oncotarget 2018 Sep 11;9(71):33482-33499. Epub 2018 Sep 11.

Department of Microbiology and Infection, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.

"Double-hit" lymphoma (DHL) is a high-grade B-cell lymphoma that harbors concurrent and or rearrangements. Because cases of / DHL are uncommon, most reported conclusions have been based on cases of / DHL. Lack of experimental / DHL models continues to hinder the pathophysiologic and therapeutic investigations of this disorder. We herein describe a novel / DHL cell line, designated DH-My6, carrying both the - and - fusion genes. Interruptions of and expressions using short interfering RNAs and chemical inhibitors led to significant attenuation of DH-My6 cell growth. Greater antitumor effects were found when the cells were treated with a combination of MYC and BCL6 inhibitors. Moreover, the PLK1 inhibitor volasertib and the HDAC inhibitor vorinostat synergized strongly when combined with the bromodomain inhibitor JQ1. DH-My6 is a new well-validated / DHL cell line that will provide a useful model for studies of the pathogenesis and therapeutics for the less common DHL tumor type. The rationale for approaches targeting both MYC and BCL6, and in combination with PLK1 or HDAC inhibitors for superior suppression of the aggressive / DHL warrants further testing in a preclinical model.
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http://dx.doi.org/10.18632/oncotarget.26060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173362PMC
September 2018

Merkel cell polyomavirus and Langerhans cell neoplasm.

Cell Commun Signal 2018 08 22;16(1):49. Epub 2018 Aug 22.

AP-HP Hôpital Necker-Enfants Malades, University Paris Descartes (Paris 5), 75006, Paris, France.

Background: The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual's reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.

Methods: We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups' data.

Results: We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS/MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH.

Conclusion: We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.
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http://dx.doi.org/10.1186/s12964-018-0261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103986PMC
August 2018

Lymph node retrieval after dissolution of surrounding adipose tissue for pathological examination of colorectal cancer.

Oncol Lett 2018 Feb 14;15(2):2495-2500. Epub 2017 Dec 14.

Cancer Treatment Center, Kochi Medical School Hospital, Kochi 783-8505, Japan.

Examination of >12 lymph nodes (LNs) is important for the diagnostic accuracy of nodal status following resection of colorectal cancer. In the present study, the efficacy of a fat dissolution technique for LN retrieval was evaluated using resected colon and rectum mesentery. First, the resected mesentery was searched for LNs by inspection and palpation immediately after surgery. Subsequently, fat dissolution liquid was applied to the remnant fat and the LN search was repeated. The primary endpoint was whether the second assessment would increase the number of evaluated LNs. Recruitment of 20 patients was planned. The study was conducted after institutional review board approval and written informed consent was obtained. Among 20 participants, 1 patient was excluded because LN dissection was not performed. The median number of LNs identified at the first and second assessments was 13 and 6, respectively, producing a significant increase in total LNs evaluated (13 vs. 20, respectively; P<0.01; paired t-test). One positive node was identified among the additionally identified LNs (0.9%, 1/107). The second assessment increased the number of LNs assessed to >12 in 4 patients, and although staging was not changed, the treatment was potentially altered in 2 stage II patients. The maximum diameter of the additionally obtained LNs was significantly smaller compared with those from the first assessment (4 vs. 7.7 mm, respectively; P<0.01; Wilcoxon signed-rank test). After the fat dissolution technique, the tumor cells were satisfactorily stained by carcinoembryonic antigen and cytokeratin-20. In conclusion, applying fat dissolution liquid to the remnant adipose tissue of the mesentery of the colon and rectum identified additional LNs. This method should be considered when insufficient LNs are identified after conventional LN retrieval.
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http://dx.doi.org/10.3892/ol.2017.7629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777345PMC
February 2018

Hepatic stellate cells derived from the nestin-positive cells in septum transversum during rat liver development.

Med Mol Morphol 2018 Dec 29;51(4):199-207. Epub 2018 Jan 29.

Department of Pathology, Kochi University Hospital, 185-1 Kohasu, Okoh, Nankoku, Kochi, 783-8505, Japan.

Hepatic stellate cells (HSCs) play a principal role in Vitamin A metabolism and are considered the major matrix-producing cell type in the diseased liver. Rat HSCs are identified by immunohistochemistry with myogenic or mesenchymal (desmin, vimentin, and alpha-smooth muscle actin) or neural (e.g., GFAP or neuronal cell adhesion molecule) markers. Embryonic origin of rat HSCs was determined using these markers. Nestin, an intermediate filament protein originally identified in neuronal stem or progenitor cells, is widely used as a stem cell marker, including hepatic stem cells in adult rat livers. Additionally, nestin is reportedly expressed in activated HSCs during liver injury and hepatic regeneration. However, little is known about nestin expression in rat fetal liver HSCs. The present study aimed to clarify nestin-positive HSC expression during rat liver development. At embryonic day (ED) 10.5, nestin expression in mesenchymal cells adjacent to the liver bud was detected by immunohistochemistry. At ED 11.5, nestin-positive cells were also detected in desmin-positive cells appearing and increasing in intensity by ED 16.5. However, nestin-positive cells in the parenchyma decreased by ED 20.5 or later. These findings reveal that the nestin-positive HSCs during rat liver development originate from nestin-positive mesenchymal cells in the septum transversum.
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http://dx.doi.org/10.1007/s00795-018-0183-1DOI Listing
December 2018

Questiomycin A stimulates sorafenib-induced cell death via suppression of glucose-regulated protein 78.

Biochem Biophys Res Commun 2017 10 12;492(1):33-40. Epub 2017 Aug 12.

Science Research Center, Kochi University, Kochi 783-8505, Japan. Electronic address:

Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat owing to the lack of effective chemotherapeutic methods. Sorafenib, the first-line and only available treatment for HCC, extends patient overall survival by several months, with a response rate below 10%. Thus, the identification of an agent that enhances the anticancer effect of sorafenib is critical for the development of therapeutic options for HCC. Endoplasmic reticulum (ER) stress response is one of the methods of sorafenib-induced cell death. Here we report that questiomycin A suppresses expression of GRP78, a cell-protective ER chaperone protein. Analysis of the molecular mechanisms of questiomycin A revealed that this compound stimulated GRP78 protein degradation in an ER stress response-independent manner. Cotreatment with sorafenib and questiomycin A suppressed GRP78 protein expression, which is essential for the stimulation of sorafenib-induced cell death. Moreover, our in vivo study demonstrated that the coadministration of sorafenib and questiomycin A suppressed tumor formation in HCC-induced xenograft models. These results suggest that cotreatment with sorafenib and questiomycin A is a novel therapeutic strategy for HCC by enhancing sorafenib-dependent ER stress-induced cell death, and downregulation of GRP78 is a new target for the stimulation of the therapeutic effects of sorafenib in HCC.
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http://dx.doi.org/10.1016/j.bbrc.2017.08.042DOI Listing
October 2017

Aberrant expression of AID and AID activators of NF-κB and PAX5 is irrelevant to EBV-associated gastric cancers, but is associated with carcinogenesis in certain EBV-non-associated gastric cancers.

Oncol Lett 2017 Jun 3;13(6):4133-4140. Epub 2017 Apr 3.

Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8503, Japan.

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric cancer characterized by clinicopathological features including lymphoepithelioma-like histology. Aberrant expression of activation-induced cytidine deaminase (AID) as a genomic modulator was demonstrated through pathogen-related nuclear factor κB (NF-κB) signaling in -associated gastric cancer. To elucidate whether or not AID expression is relevant to carcinogenesis in EBVaGC, immunohistochemical expression of AID and AID-regulatory factors between EBVaGC and EBV-non-associated gastric carcinoma (GC) were evaluated, each using 15 cases of GC with lymphoid stroma (GCLS) and other types of GC. Aberrant expression of AID, NF-κB and paired box 5 (PAX5) were significantly decreased in EBVaGC (0/11, 1/11 and 1/11) compared with in EBV-non-associated GC (7/19, 12/19 and 11/19) (P=0.025, 0.005 and 0.01, respectively); however, no significant difference in c-Myb proto-oncogene expression was identified. AID expression was also decreased in EBV-associated GCLS (0/10) compared with in EBV-non-associated GCLS (3/5). Unexpectedly, decreased expression of NF-κB and PAX5 was observed in GCLS (1/15 and 2/15) compared with in GC without LS (12/15 and 10/15) (P<0.001 and P=0.003, respectively). Decreased AID expression observed in EBVaGC is consistent with the reported molecular characterization of hypermethylation and rare somatic gene mutation in EBVaGC. Only PAX5 was identified to be significantly associated with venous invasion (P=0.022). The results of the present study suggest that pathogen-induced AID expression may be irrelevant to carcinogenesis of EBVaGC, whereas it contributes to carcinogenesis in certain types of EBV-non-associated GC.
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http://dx.doi.org/10.3892/ol.2017.5978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452920PMC
June 2017

Killer cell immunoglobulin-like receptor 2DL4 is expressed in and suppresses the cell growth of Langerhans cell histiocytosis.

Oncotarget 2017 Jun;8(23):36964-36972

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

Killer cell immunoglobulin-like receptor (KIR) 2DL4 (CD158d) is a receptor for human leukocyte antigen-G. The function of KIR2DL4 has been reported in human natural killer cell lymphoma and mastocytosis, but not in Langerhans cell histiocytosis (LCH). Herein, we examined the expression and function of KIR2DL4 in LCHs. In pathological specimens, 27 of 36 LCH cases (75.0%) were immunohistochemically positive for KIR2DL4. Its expression was independent of age, gender, location, multi- or single-system, and the status of BRAFV600E immunostaining. We also confirmed the expression of KIR2DL4 mRNA and protein in the human LCH-like cell lines ELD-1 and PRU-1. KIR2DL4 protein was distributed in the membrane and cytoplasm of ELD-1 cells, but only in the cytoplasm of PRU-1 cells. An agonistic antibody against KIR2DL4 reduced phosphorylation of extracellular signal-regulated kinases (ERKs) and suppressed the cell growth of ELD-1 cells in a Src homology region 2 domain-containing phosphatase-2 dependent manner, but it had no effect in PRU-1 cells. These results suggest that KIR2DL4-mediated ERK suppression is a possible therapeutic target for LCH cells.
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http://dx.doi.org/10.18632/oncotarget.16936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514884PMC
June 2017

Epstein-Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease.

Viral Immunol 2017 04 23;30(3):240-249. Epub 2017 Mar 23.

1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .

Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein-Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity. We showed that the EBV reactivation induces the production of every isotype of Ig and suggested that the Ig production was catalyzed by AID through LMP1 and NF-κB. The results that the amount of IgM was significantly larger compared with IgG suggested the polyclonal B cell activation due to LMP1. We proposed the pathway of EBV reactivation induced Ig production; B cells newly infected with EBV are activated by polyclonal B cell activation and produce Igs through plasma cell differentiation induced by EBV reactivation. LMP1-induced AID enabled B cells to undergo class-switch recombination to produce every isotype of Ig. According to this mechanism, EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases.
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http://dx.doi.org/10.1089/vim.2016.0179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393416PMC
April 2017

Acute undifferentiated leukemia (stem cell acute leukemia) showing differentiation to Langerhans cell-like cells in lymph nodes.

Rinsho Ketsueki 2017 ;58(1):26-31

Department of Pathology, Tottori Prefectural Central Hospital.

A 75-year-old woman was referred to our hospital with suspected leukemia. Complete blood count demonstrated WBC 3,810/µl with 26% blasts, Hb of 11.7 g/dl and Plt of 18.0×10/µl. Bone marrow aspiration revealed blasts (86.3%) with expressions of CD34, CD7, TdT, CD33, and CD117. MPO was negative. Chromosomal analysis of the bone marrow showed isolated trisomy 10 in all leukemic cells (20/20). Swelling of superficial lymph nodes was also observed. Cervical lymph node biopsy revealed leukemic blasts which had the same phenotype as those in the bone marrow except that proliferation of Langerhans cell-like cells (LCs) was observed in the paracortex. LCs had pale cytoplasm and grooved nuclei, and were positive for both CD1a and S100 protein. Trisomy 10 was detected in both the leukemic blasts and the LCs by fluorescence in situ hybridization. This rare case strongly suggests leukemic cells to differentiate into LCs.
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http://dx.doi.org/10.11406/rinketsu.58.26DOI Listing
May 2017

Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumors.

Pol J Pathol 2017;68(4):284-290

The entity of hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated RCC has been proposed and integrated into the recent International Society of Urologic Pathology (ISUP) of renal tumors. This tumor is characterized by presence of cutaneous and/or uterine leiomyomas and RCC and autosomal dominant hereditary form. Grossly, HLRCC arising in the kidney show the solid tumor with frequent partial cystic area. Microscopically, the tumor typically shows papillary RCC, type 2, with eosinophilic large nucleoli reminiscent of cytomegaloviral inclusion and perinuclear clearing/haloes. Immunohistochemically, tumor cells show the overexpression for 2SC and reduced expression of FH. Germline mutation of fumarate hydratase (FH) gene, the HLRCC responsible gene mapped to chromosome 1q43, has been identified in patients with HLRCC. As the renal cancer in patients with HLRCC generally behave aggressively even in a small size, complete surgical resection and retroperitoneal lymph node resection should be performed promptly when the tumor is discovered. The surveillance of renal tumor in FH gene germline mutation-positive patients should be started from the early age using ultrasound sonography or magnetic resonance imaging.
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http://dx.doi.org/10.5114/pjp.2017.73920DOI Listing
June 2018

Thyrotropin Receptor Antibody (TRAb)-IgM Levels Are Markedly Higher Than TRAb-IgG Levels in Graves' Disease Patients and Controls, and TRAb-IgM Production Is Related to Epstein-Barr Virus Reactivation.

Viral Immunol 2016 Oct 16;29(8):459-463. Epub 2016 Aug 16.

1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .

Graves' disease is an autoimmune thyroid disorder that mainly presents as hyperthyroidism and is caused by thyrotropin receptor antibodies (TRAbs) that stimulate thyroid-stimulating hormone receptors. We previously reported that Graves' disease patients and healthy controls both had Epstein-Barr virus (EBV)-infected TRAb-positive B cells and the EBV-reactivated induction of these B cells in cultures may induce the production of TRAbs. In the present study, we quantified serum TRAb-IgG and TRAb-IgM levels in 34 Graves' disease patients and 15 controls using ELISA to elucidate the mechanisms underlying EBV-related antibody production. As expected, TRAb-IgG and TRAb-IgM levels were higher in Graves' disease patients than in controls; however, TRAb-IgM levels were significantly higher than those of TRAb-IgG levels, whereas total IgM levels were lower than total IgG levels. On the other hand, the enhanced production of TRAb-IgM was frequently observed in patients with EBV reactivation. These results are consistent with the fact that the percentage of autoreactive IgM B cells are higher than that of autoreactive IgG B cells, and support the EBV-related polyclonal B cell activation. It is necessary to clarify the biological characteristics of TRAb-IgM and the relationship between TRAb isotypes and the biology of Graves' disease.
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http://dx.doi.org/10.1089/vim.2016.0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307640PMC
October 2016

Aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms.

Pathology 2016 Aug 14;48(5):467-82. Epub 2016 Jun 14.

Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

The Polycomb repressive complex-2 members (EZH2, EED, SUZ12 and EZH1) are important regulators of haematopoiesis, cell cycle and differentiation. Over-expression of EZH2 has been linked to cancer metastases and poor prognosis. Detailed information on the expression of other members in normal and neoplastic lymphoid tissue remains to be elucidated. Immunohistochemical and immunofluorescent analyses of 156 samples from haematopoietic neoplasms patients and 27 haematopoietic cell lines were used. B-cell neoplasms showed a significant over-expression of EZH2, EED and SUZ12 in the aggressive subtypes compared to the indolent subtypes and normal tissue (p = 0.000-0.046) while expression of EZH1 was decreased in mantle cell lymphoma compared to normal tissue (p = 0.011). T/NK-cell neoplasms also showed significant over-expression of EZH2, EED and SUZ12 (p = 0.000-0.002) and decreased expression of EZH1 (p = 0.001) compared to normal cells. EZH2 and EZH1 have opposite expression patterns both in normal and neoplastic lymphoid tissues as well as an opposite relation to Ki-67. These results were supported by western blotting analyses. Immunofluorescent staining revealed a difference in the intracellular localisation of EZH1 compared to other members. These evidences suggest that EZH2 and EZH1 are important in the counter-balancing mechanisms controlling proliferation/resting of lymphoid cells. The disruption of the balanced EZH2/EZH1 ratio may play important roles in the pathogenesis of lymphomas.
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http://dx.doi.org/10.1016/j.pathol.2016.05.002DOI Listing
August 2016

Renal oncocytoma, small cell variant, with pseudorosettes, showing cyclin D1 expression and tubulovesicular cristae of mitochondria.

Pathol Int 2016 Jul 13;66(7):409-10. Epub 2016 Apr 13.

Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Japan.

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http://dx.doi.org/10.1111/pin.12410DOI Listing
July 2016

Low prevalence of Merkel cell polyomavirus with low viral loads in oral and maxillofacial tumours or tumour-like lesions from immunocompetent patients: Absence of Merkel cell polyomavirus-associated neoplasms.

Mol Clin Oncol 2015 Nov 31;3(6):1301-1306. Epub 2015 Aug 31.

Division of Molecular Pathology, Department of Pathology, Tottori University, Yonago, Tottori 683-8503, Japan.

It was recently demonstrated that ~80% of Merkel cell carcinomas (MCCs) harbour a novel polyomavirus, Merkel cell polyomavirus (MCPyV). MCPyV has been detected in various human tissue samples. However, previous studies on the prevalence of MCPyV in oral tumours or tumour-like lesions are incomplete. To address this issue, we measured MCPyV DNA quantity using quantitative polymerase chain reaction (qPCR) in 327 oral tumours or tumour-like lesions and 54 jaw tumours or cyst lesions from 381 immunocompetent patients, as well as in 4 oral lesions from 4 immunosuppressed patients. qPCR revealed a low MCPyV prevalence (25/381, 6.6%) with low viral loads (0.00024-0.026 copies/cell) in oral and maxillofacial tumours and tumour-like lesions from immunocompetent patients. The prevalence was 7/176 (4.0%) in invasive squamous cell carcinomas (SCCs) [2/60 (3.33%) SCCs of the tongue, 4/52 (7.7%) SCCs of the gingiva and 1/19 (5.3%) SCCs of the floor of the mouth], 1/10 (10%) in dysplasias, 1/5 (20%) in adenocarcinomas, 2/13 (15.4%) in adenoid cystic carcinomas, 1/10 (10%) in non-Hodgkin's lymphomas, 3/10 (30%) in lipomas, 3/5 (60%) in neurofibromas, 1/3 (33.3%) in Schwannomas, 2/12 (16.7%) in Warthin's tumours, 2/11 (18.2%) in pyogenic granulomas, 1/14 (7.1%) in radicular cysts and 1/12 (8.3%) in ameloblastomas. The prevalence in lesions from immunosuppressed patients (1/4, 25%) was higher compared with that in lesions from immunocompetent patients (25/381, 6.6%), but the difference was not statistically significant. To the best of our knowledge, this study was the first to report prevalence data of MCPyV in tumours and cysts of the jaws (2/54, 3.7%). These data indicated absence of MCPyV-related tumours or tumour-like lesions in the oral cavity and jaws and suggested that the detected MCPyV DNA was derived from non-neoplastic background tissues with widespread low-level MCPyV infection.
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http://dx.doi.org/10.3892/mco.2015.629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665147PMC
November 2015

Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis.

Hum Pathol 2016 Feb 23;48:1-8. Epub 2015 Oct 23.

Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan. Electronic address:

Merkel cell carcinoma (MCC) is a clinically aggressive neuroendocrine skin cancer; 80% of the cases are associated with the Merkel cell polyomavirus (MCPyV). We previously reported that MCPyV-negative MCCs have more irregular nuclei with abundant cytoplasm and significantly unfavorable outcomes than do MCPyV-positive MCCs. These results suggest that some cell adhesion or structural stabilization molecules are differently expressed depending on MCPyV infection status. Thus, we investigated the association of prognosis or MCPyV infection status in MCCs with cell adhesion molecule 1 (CADM1)/differentially expressed in adenocarcinoma of the lung protein 1 (DAL-1)/membrane protein, palmitoylated 3 (MPP3) tripartite complex and mal T-cell differentiation protein (MAL) expression, which play important roles in cell adhesion and oncogenesis and are related to cancer outcomes in various malignancies, to elucidate the role of these molecules. We analyzed the pathological and molecular characteristics of 26 MCPyV-positive and 15 MCPyV-negative MCCs. Univariate Cox regression analysis showed that advanced age (hazard ratio [HR], 8.249; P = .007) and high CADM1 expression (HR, 5.214; P = .012) were significantly unfavorable overall survival parameters, whereas MCPyV infection (HR, 0.043, P < .001) and lower MAL expression (HR, 0.273; P = .018) were significantly favorable. On multivariate analysis, only MCPyV infection was significantly favorable for overall survival (HR, 0.04; P = .005). Hypermethylation of CADM1, DAL-1, and MAL promoters was detected in 1 of 18, 15 of 27, and 1 of 13 cases, respectively. Double immunostaining for cytokeratin 20 and CADM1, DAL-1, or MAL showed that nonneoplastic Merkel cells expressed DAL-1 and MAL but not CADM1. This study revealed that MCPyV-negative MCCs significantly expressed higher CADM1 and lower MAL than MCPyV-positive MCCs; these expression levels were markedly related to unfavorable outcomes. These data will give us important insights to develop novel molecular target therapies for MCCs.
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http://dx.doi.org/10.1016/j.humpath.2015.09.030DOI Listing
February 2016
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