Publications by authors named "Jun-Ichiro Ikeda"

85 Publications

The Use of Deep Learning-Based Computer Diagnostic Algorithm for Detection of Lymph Node Metastases of Gastric Adenocarcinoma.

Int J Surg Pathol 2022 Jul 27:10668969221113475. Epub 2022 Jul 27.

Center for Frontier Medical Engineering, 12737Chiba University, Chiba, Japan.

The diversifying modalities of treatment for gastric cancer raise urgent demands for the rapid and precise diagnosis of metastases in regional lymph nodes, thereby significantly impact the workload of pathologists. Meanwhile, the recent advent of whole-slide scanners and deep-learning techniques have enabled the computer-assisted analysis of histopathological images, which could help to alleviate this impact. Thus, we developed a deep learning-based diagnostic algorithm to detect lymph node metastases of gastric adenocarcinoma and evaluated its performance. We randomly selected 20 patients with gastric adenocarcinoma who underwent surgery as definitive treatment and were found to be node metastasis-positive. HEMATOXYLIN-eosin (HE) stained glass slides, including a total of 51 metastasis-positive nodes, were retrieved from the specimens of these cases. Other slides with 776 metastasis-negative nodes were also retrieved from other twenty cases with the same disease that were diagnosed as metastasis-negative by the final pathological examinations. All glass slides were digitized using a whole-slide scanner. A deep-learning algorithm to detect metastases was developed using the data in which metastasis-positive parts of the images were annotated by a well-trained pathologist, and its performance in detecting metastases was evaluated. Cross-validation analysis indicated an area of 0.9994 under the receiver operating characteristic curve. Free-response receiver operating characteristic curve (FROC) analysis indicated a sensitivity of 1.00 with three false positives. Further evaluation using an independent dataset also showed similar level of accuracies. This deep learning-based diagnosis-aid system is a promising tool that can assist pathologists involved in gastric cancer care and reduce their workload.
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http://dx.doi.org/10.1177/10668969221113475DOI Listing
July 2022

Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis.

Int J Clin Oncol 2022 Jun 15. Epub 2022 Jun 15.

Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles.

Methods: Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation CDx was investigated.

Results: In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion.

Conclusions: Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.
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http://dx.doi.org/10.1007/s10147-022-02195-9DOI Listing
June 2022

Adenocarcinoma arising in an adrenohepatic fusion-related cyst.

Pathol Int 2022 Jun 13. Epub 2022 Jun 13.

Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/pin.13238DOI Listing
June 2022

Clinicopathological and Genomic Features of Pediatric Intracranial Myxoid Mesenchymal Tumor with both of Gene Fusion and Mutation: A Case Report and Comparison with Adult Cases in the Literature.

NMC Case Rep J 2022 18;9:101-109. Epub 2022 May 18.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan.

Intracranial myxoid mesenchymal tumors (IMMTs) with family gene fusion are rare brain neoplasms characterized by gene fusion between the gene and one of the cyclic AMP response element-binding (CREB) family transcription factor (, , or ) genes. Although half of reported cases are pediatric, the clinical, histologic, and genomic features of IMMTs with rearrangement in pediatric populations are not yet well clarified. Here we describe the case of a 7-year-old girl who presented with seizures due to an extra-axial tumor in the left parietal convexity. Gross total resection was achieved, and the tumor displayed a multilobular structure with solid hypercellular and myxoid hypocellular areas, separated by a variable amount of stroma. The hypercellular areas consisted of round to polygonal cells, whereas the myxoid areas were ovoid to spindled cells. Immunophenotypically, the tumor cells were positive for vimentin, desmin, and EMA. Next-generation sequencing of tumoral DNA revealed gene fusion and a pathogenic mutation of . No recurrence was detected 9 months after resection, without chemotherapy or radiotherapy. In comparison to other pediatric and adult patients with rearrangement, many clinical, radiological, and immunohistochemical features were shared. However, signs of elevated intracranial pressure were more frequently observed, and postoperative radiation was less frequently administered for pediatric patients. Gross total resection (GTR) was the key prognostic factor for better disease control especially among pediatric patients. Further reports of cases with rearrangement with detailed genetic profiles are essential for clarifying the oncogenic pathway and establishing a standard treatment strategy.
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http://dx.doi.org/10.2176/jns-nmc.2021-0385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177164PMC
May 2022

Case of pigmented onychomatricoma: A relationship between dermoscopic and pathological findings.

J Dermatol 2022 May 26. Epub 2022 May 26.

Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan.

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http://dx.doi.org/10.1111/1346-8138.16474DOI Listing
May 2022

pneumonia in an immunocompetent patient developing a subacute disease course with central consolidation.

Respir Med Case Rep 2022 1;37:101659. Epub 2022 May 1.

Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba, 260-8670, Japan.

pneumonia (PCP) typically occurs in immunocompromised individuals and rarely presents in immunocompetent individuals. A 55-year-old man was referred to our hospital with cough and anorexia that persisted for 2 months. Chest computed tomography revealed bilateral central consolidation. He was diagnosed with PCP via bronchoscopy. His symptoms and imaging findings improved with the administration of only trimethoprim and sulfamethoxazole. Although he had non-alcoholic fatty liver disease, there were no other complications that could potentially cause immunodeficiency. It should be noted that PCP in immunocompetent individuals can have a subacute disease course presenting with bilateral central consolidation.
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http://dx.doi.org/10.1016/j.rmcr.2022.101659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097713PMC
May 2022

Ovarian Malignant Mixed Germ Cell Tumor Composed Mainly of a Polyembryoma Pattern With Vasculogenic Mesenchymal Tumor Components.

Int J Gynecol Pathol 2022 Apr 12. Epub 2022 Apr 12.

Ovarian germ cell tumors composed of numerous well-formed embryonal bodies have been described as exhibiting a "polyembryoma pattern." In addition, some germ cell tumors are occasionally concomitant with neoplastic vascular proliferation. These include angiosarcomas and the recently reported mediastinal vasculogenic mesenchymal tumors. A 9-yr-old Japanese girl underwent surgery for a right ovarian tumor. Histologically, the polyembryoma pattern, nongestational choriocarcinoma, and vasculogenic lesions characterized by a neoplastic repetition of embryonic vasculogenesis have been intermingled. The polyembryoma pattern consisted of numerous complete and incomplete embryonal bodies and glandular structures resembling adult-type and fetal-type intestines. Vasculogenic lesions were composed of variously developed neoplastic vessels within the myxomatous stroma, which extended well beyond one low-power (40×) microscopic field. We concluded that the vasculogenic lesion in our case was the ovarian counterpart of the mediastinal vasculogenic mesenchymal tumor. After the surgery, the patient was administered adjuvant chemotherapy and was alive with no evidence of recurrence or other malignancy at 28 mo postsurgery.
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http://dx.doi.org/10.1097/PGP.0000000000000867DOI Listing
April 2022

Exploring microsatellite instability in patients with advanced hepatocellular carcinoma and its tumor microenvironment.

JGH Open 2021 Nov 1;5(11):1266-1274. Epub 2021 Oct 1.

Department of Diagnostic Pathology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Immune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability-high (MSI-H) by using tumor samples from advanced HCC patients eligible for systemic therapy.

Methods: MSI-H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD-L1, CD8, VEGF, and HLA-class1 was evaluated by immunohistochemistry. Whole-exome sequencing was performed for MSI-H tumor samples.

Results: Of 50 patients, one (2.0%) was confirmed with MSI-H. In the MSI-H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8 lymphocytes, and low expression of VEGF were identified. Although PD-L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR-21 and miR-155 overexpression and hypermethylation of the gene.

Conclusion: We identified a very small number of MSI-H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI-H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI-H in HCC and to analyze tumor microenvironments.
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http://dx.doi.org/10.1002/jgh3.12660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593775PMC
November 2021

Henoch-Schonlein Purpura After Cardiac Device Removal for Staphylococcus Aureus Infective Endocarditis.

Circ J 2022 03 16;86(4):722. Epub 2021 Nov 16.

Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine.

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http://dx.doi.org/10.1253/circj.CJ-21-0772DOI Listing
March 2022

Successful allogeneic bone marrow transplantation after massive gastrointestinal bleeding in a patient with myelodysplastic syndrome associated with intestinal Behçet-like disease.

Leuk Res Rep 2021 29;16:100278. Epub 2021 Oct 29.

Department of Hematology, Chiba University Hospital, Chiba, Japan.

A 45-year-old woman was diagnosed with myelodysplastic syndrome (MDS) with trisomy 8 and Behçet-like disease (BLD) with multiple colorectal ulcers. Nonspecific inflammatory cells were infiltrated in the intestinal mucosa, whereas fluorescence in situ hybridization (FISH) analysis revealed only sporadic trisomy 8-positive cells. She presented massive lower gastrointestinal bleeding early after bone marrow transplantation but achieved long-term remission of both MDS and BLD. This is the first report of massive gastrointestinal bleeding after transplantation for MDS with BLD. Based on FISH analysis, dysregulation of systemic inflammation may be involved in BLD rather than direct invasion by trisomy 8-positive MDS clones.
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http://dx.doi.org/10.1016/j.lrr.2021.100278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572864PMC
October 2021

Expression of tertiary lymphoid structure in deferred cytoreductive nephrectomy of metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

IJU Case Rep 2021 Nov 16;4(6):355-358. Epub 2021 Aug 16.

Urology Graduate School of Medicine Chiba University Chiba Japan.

Introduction: Tertiary lymphoid structure expression and immune checkpoint inhibitors have been attracting attention, and their relationship with renal cell carcinoma is controversial.

Case Presentation: Two patients with nivolumab plus ipilimumab treatment response for metastatic renal cell carcinoma underwent cytoreductive nephrectomy and regional lymph node dissection. In both cases, the renal tumor site expressed tertiary lymphoid structures. Despite the absence of treatment after a deferred cytoreductive nephrectomy and the short postoperative observation period, the patients still survived.

Conclusion: Tertiary lymphoid structures were expressed in deferred cytoreductive nephrectomy specimen in cases treated with nivolumab plus ipilimumab.
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http://dx.doi.org/10.1002/iju5.12347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560443PMC
November 2021

Solid serous neoplasm of the pancreas with locally aggressive behaviors.

Pathol Int 2021 Nov 9;71(11):795-797. Epub 2021 Sep 9.

Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/pin.13163DOI Listing
November 2021

Recurrent Cerebral Infarcts Associated with Uterine Adenomyosis: Successful Prevention by Surgical Removal.

Intern Med 2022 Mar 4;61(5):735-738. Epub 2021 Sep 4.

Department of Neurology, Graduate School of Medicine, Chiba University, Japan.

Hypercoagulability associated with malignant tumors causes thrombosis, termed Trousseau's syndrome, but is rarely associated with benign gynecological tumors, such as myoma and adenomyosis. We herein report a 47-year-old Japanese woman with uterine adenomyosis who developed multiple cerebral infarcts during menstruation. Edoxaban was initially used for prevention but failed to prevent recurrence of thrombosis. However, hysterectomy and bilateral salpingo-oophorectomy resulted in the successful prevention of recurrence of cerebral infarct for five years without antiplatelet or anticoagulant agents. In our patient, the surgical removal of adenomyosis was highly effective for preventing thrombosis in a patient with adenomyosis.
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http://dx.doi.org/10.2169/internalmedicine.7320-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8943379PMC
March 2022

Genetic profiles of Barrett's esophagus and esophageal adenocarcinoma in Japanese patients.

Sci Rep 2021 09 3;11(1):17671. Epub 2021 Sep 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670, Japan.

The genetic characteristics of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) in the Japanese population is unclear. This study aims to investigate the genetic characteristics from nondysplastic BE (NDBE) to early EAC in Japan. Clinical information was collected. Moreover, the genetic profile of NDBE without concurrent dysplasia, early EAC, and surrounding BE were also investigated using endoscopic biopsy samples and formalin-fixed, paraffin-embedded specimens from Japanese patients by targeted next-generation sequencing. Immunohistochemical staining for p53 was also performed for EAC lesions. Targeted NGS was performed for 33 cases with 77 specimens. No significant difference exists in the NDBE group between the number of putative drivers per lesion in the short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE) [0 (range, 0-1) vs. 0 (range, 0-1). p = 1.00]. TP53 putative drivers were found in two patients (16.7%) with nondysplastic SSBE. TP53 was the majority of putative drivers in both BE adjacent to EAC and EAC, accounting for 66.7% and 66.7%, respectively. More putative drivers per lesion were found in the EAC than in the NDBE group [1 (range, 0-3) vs. 0 (range, 0-1). p < 0.01]. The genetic variants of TP53 in the Japanese early EAC were similar to those in western countries. However, TP53 putative drivers were detected even in Japanese patients with nondysplastic SSBE. This is significant because such nondysplastic SSBE might have higher risk of progressing to high-grade dysplasia or EAC. The risks of progression may not be underestimated and appropriate follow-ups may be necessary even in patients with SSBE.Trial registration: This study was registered at the University Hospital Medical Information Network (UMIN000034247).
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http://dx.doi.org/10.1038/s41598-021-97249-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417273PMC
September 2021

Genetic subtype classification using a simplified algorithm and mutational characteristics of diffuse large B-cell lymphoma in a Japanese cohort.

Br J Haematol 2021 12 10;195(5):731-742. Epub 2021 Aug 10.

Department of Hematology, Chiba University Hospital, Chiba, Japan.

Recent large-scale genetic studies have proposed a new genetic classification of diffuse large B-cell lymphoma (DLBCL), which is clinically and biologically heterogeneous. However, the classification methods were complicated to be introduced into clinical practice. Here we retrospectively evaluated the mutational status and copy number changes of 144 genes in 177 Japanese patients with DLBCL, using targeted DNA sequencing. We developed a simplified algorithm for classifying four genetic subtypes-MYD88, NOTCH2, BCL2, and SGK1-by assessing alterations in 18 representative genes and BCL2 and BCL6 rearrangement status, integrating the significant genes from previous studies. In our cohort and another validation cohort from published data, the classification results in our algorithm showed close agreement with the other established algorithm. A differential prognosis among the four groups was observed. The NOTCH2 group showed a particularly poorer outcome than similar groups in previous reports. Furthermore, our study revealed unreported genetic features in the DLBCL subtypes that are mainly reported in Japanese patients, such as CD5-positive DLBCL and methotrexate-associated lymphoproliferative disorders. These results indicate the utility of our simplified method for DLBCL genetic subtype classification, which can facilitate the optimisation of treatment strategies. In addition, our study highlights the genetic features of Japanese patients with DLBCL.
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http://dx.doi.org/10.1111/bjh.17765DOI Listing
December 2021

ICAM1-Negative Intravascular Large B-Cell Lymphoma of the Pituitary Gland: A Case Report and Literature Review.

AACE Clin Case Rep 2021 Jul-Aug;7(4):249-255. Epub 2021 Feb 9.

Department of Endocrinology, Hematology and Gerontology, Chiba University Hospital, Chiba, Japan.

Objective: Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive type of B-cell lymphoma with large cells growing within the lumen of blood vessels. Although previous reports revealed highly variable symptoms resulting from small-vessel occlusion by neoplastic cells in a variety of organs, there are few reports of IVLBCL with pituitary involvement.

Method: We present a case of IVLBCL with pituitary infiltration from our institution together with a literature review of similar cases to better understand this rare case of IVLBCL involving the pituitary gland.

Results: Our case and the pertinent literature demonstrated that IVLBCL with pituitary involvement predominantly occurred in women at a mean age of 64 years, and most of them showed panhypopituitarism that was reversible after standard therapy of rituximab-containing chemotherapy with intrathecal methotrexate. Notably, the pituitary biopsy in our case revealed that atypical large B-cells found within blood vessels and the pituitary gland were negative for intercellular adhesion molecule 1. Intercellular adhesion molecule 1-negative lymphoid cells may have contributed to panhypopituitarism by extravasation into the pituitary tissues, which do not have a blood-brain barrier and receive abundant blood flow.

Conclusion: IVLBCL of the pituitary gland is a rare lymphoma with nonspecific manifestations and a dismal prognosis. Recognition of the clinicopathological features is necessary for early clinical diagnosis and appropriate treatment.
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http://dx.doi.org/10.1016/j.aace.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282537PMC
February 2021

Metabolic, immunohistochemical, and genetic profiling of a cerebellar liponeurocytoma with spinal dissemination: a case report and review of the literature.

Brain Tumor Pathol 2021 Jul 17;38(3):257-262. Epub 2021 Jun 17.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba, 260-8670, Japan.

Cerebellar liponeurocytoma (cLNC), categorized as a World Health Organization grade II tumor, is a rare neoplasm characterized by advanced neuronal/neurocytic differentiation and focal lipid accumulation in neuroepithelial tumor cells. However, the expression and genetic profiling of cLNC have been poorly studied. A 44-year-old woman with a three-year history of cerebellar ataxia and numbness in lower extremities underwent radiological examination revealing multiple contrast-enhancing tumors at the floor of the fourth ventricle and in the lower vermis, and spinal dissemination. The high uptake of 11 C-methionine in positron emission tomography (Met-PET) supported the preoperative cLNC diagnosis. Subtotal removal of the tumor around the obex and inferior vermis was performed. Histologically, the tumor was composed of small, uniform cells with round nuclei in a sheet-like fashion. Tumor cells were diffusely reactive for the neuronal markers synaptophysin and neurofilament. Vacuolate cells with a displacement of nuclei suggested the accumulation of lipid, which was further supported by immunohistochemical staining of S-100. These findings confirmed the diagnosis of cLNC. Next-generation sequencing of tumoral DNA detected a splice site mutation in the ATRX gene. Further reports of cLNC cases with detailed expression and genetic profiles are essential for precise diagnosis and clarifying the oncogenic pathway in cLNC.
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http://dx.doi.org/10.1007/s10014-021-00405-2DOI Listing
July 2021

The heavy chain of 4F2 antigen promote prostate cancer progression via SKP-2.

Sci Rep 2021 06 1;11(1):11478. Epub 2021 Jun 1.

Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan.

The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc's impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.
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http://dx.doi.org/10.1038/s41598-021-90748-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169706PMC
June 2021

Characteristics of benign adrenocortical adenomas with 18F-FDG PET accumulation.

Eur J Endocrinol 2021 Jun 5;185(1):155-165. Epub 2021 Jun 5.

Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Introduction: Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated.

Methods: To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers).

Results: All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation.

Discussion: A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation.

Conclusion: Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.
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http://dx.doi.org/10.1530/EJE-20-1459DOI Listing
June 2021

Bronchiolitis obliterans after stem cell transplantation for hematologic malignancies rescued by lung transplantation: A report of two cases.

Respir Investig 2021 Jul 18;59(4):559-563. Epub 2021 Apr 18.

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Bronchiolitis obliterans syndrome (BOS) occurring after hematopoietic stem cell transplantation (HSCT) for hematologic malignancies is a progressive and refractory disease, and lung transplantation (LTx) seems to be the only promising treatment. We report two cases of BOS after HSCT, which showed distinct clinical courses and were successfully treated with LTx. The respiratory symptoms and function of the two patients progressively deteriorated to a critical level during the waiting period. In one patient, recurrent and intractable pneumothoraxes consistent with thoracic air-leak syndrome (TALS) occurred, which were associated with pleuroparenchymal fibroelastosis. TALS could accelerate clinical deterioration, thus permitting a shorter waiting period for LTx.
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http://dx.doi.org/10.1016/j.resinv.2021.03.007DOI Listing
July 2021

Sialadenoma Papilliferum of the Bronchus: An Unrecognized Bronchial Counterpart of the Salivary Gland Tumor With Frequent BRAF V600E Mutations.

Am J Surg Pathol 2021 05;45(5):662-671

Departments of Anatomic Pathology.

Sialadenoma papilliferum (SP) is a rare benign tumor of the salivary glands, and only 3 unequivocal cases of SP arising in the bronchus have been reported. We herein describe the histomorphologic and molecular features of 4 bronchial SP cases and discuss the differential diagnosis of this entity and the relationship with its clinicopathologic mimics, in particular, glandular papilloma and mixed squamous cell and glandular papilloma (GP/MP). We encountered 2 male and 2 female patients with bronchial SP (mean: 66.8 y old). All 4 tumors arose in the central bronchus and were characterized by a combination of surface exophytic endobronchial papillary proliferation and a submucosal multicystic component with complex architecture. The neoplastic epithelium consisted predominantly of nonciliated stratified columnar cells with ciliated, squamous, and mucinous cells present focally. While 2 tumors (50%) harbored a BRAF V600E mutation by molecular and immunohistochemical analysis, similar to GP/MP, no KRAS, HRAS, AKT1, or PIK3CA mutations were detected in any of the cases. Two patients were treated with limited resection, while 2 patients underwent lobectomy based on the diagnosis of adenocarcinoma or possible squamous cell carcinoma in situ in the preoperative biopsy. All survived without recurrence or metastasis for 23 to 122 months after treatment. SP can develop in the central bronchus as the bronchial counterpart of the salivary gland tumor and should be considered in the differential diagnosis of endobronchial tumors. In addition, some histologic resemblance and frequent BRAF V600E mutation raise the possibility of SP and GP/MP being on the same disease spectrum.
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http://dx.doi.org/10.1097/PAS.0000000000001657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035241PMC
May 2021

Steroid metabolites for diagnosing and predicting clinicopathological features in cortisol-producing adrenocortical carcinoma.

BMC Endocr Disord 2020 Nov 23;20(1):173. Epub 2020 Nov 23.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Approximately 60% of adrenocortical carcinomas (ACC) are functional, and Cushing's syndrome is the most frequent diagnosis that has been revealed to have a particularly poor prognosis. Since 30% of ACC present steroid hormone-producing disorganization, measurement of steroid metabolites in suspected ACC is recommended. Previous reports demonstrated that steroid hormone precursors or their urine metabolites, which can be assessed using liquid chromatography tandem mass spectrometry (LC-MS/MS) or gas chromatography mass spectrometry (GC-MS) respectively, are useful for distinguishing ACC from cortisol-producing adenomas (CPA); however, despite high precision, LC-MS/MS and GC-MS require a highly trained team, are expensive and have limited capacity.

Methods: Here, we examined 12 serum steroid metabolites using an immunoassay, which is a more rapid and less costly method than LC-MS/MS, in cortisol-producing ACC and CPA. Further, the correlation of each steroid metabolite to the classification stage and pathological status in ACC was analyzed.

Results: Reflecting disorganized steroidogenesis, the immunoassay revealed that all basal levels of steroid precursors were significantly increased in cortisol-producing ACC compared to CPA; in particular, 17-hydroxypregnenolone (glucocorticoid and androgen precursor) and 11-deoxycorticosterone (mineralocorticoid precursor) showed a large area under the ROC curve with high sensitivity and specificity when setting the cut-off at 1.78 ng/ml and 0.4 mg/ml, respectively. Additionally, a combination of androstenedione and DHEAS also showed high specificity with high accuracy. In cortisol-producing ACC, 11-deoxycortisol (glucocorticoid precursor) showed significant positive correlations with predictive prognostic factors used in ENSAT classification, while testosterone showed significant positive correlations to the Ki67-index in both men and women.

Conclusion: Less expensive and more widely available RIA and ECLIA may also biochemically distinguish ACC from CPA and may predict the clinicopathological features of ACC.
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http://dx.doi.org/10.1186/s12902-020-00652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686776PMC
November 2020

Coexistence of Marfan-like Connective Tissue Disease with Morphologic Left Ventricular Non-compaction.

Intern Med 2020 Dec 4;59(23):3039-3044. Epub 2020 Aug 4.

Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Japan.

We treated a man with co-incident Marfan-like connective tissue disease with morphologic left ventricular non-compaction (LVNC). He underwent valve-sparing aortic root replacement because of aortic root dilation at 43 years old. Pathological findings of the aorta revealed cystic medio-necrosis, consistent with Marfan syndrome. He developed congestive heart failure caused by LVNC at 47 years old. His daughter had scoliosis, and he had several physical characteristics suggestive of Marfan syndrome. We herein report a rare case of a patient who had Marfan-like connective disease with an LVNC appearance.
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http://dx.doi.org/10.2169/internalmedicine.5100-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759706PMC
December 2020

Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine.

Nat Metab 2020 01 13;2(1):81-96. Epub 2020 Jan 13.

Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Serine racemase (SRR) catalyses not only the racemization but also the dehydration of L-serine and D-serine, resulting in the formation of pyruvate and ammonia. Although SRR activity is important in the central nervous system, SRR has not been linked to cancer metabolism before. Here we show that SRR supports proliferation of colorectal-cancer cells. We find that SRR expression is upregulated in colorectal adenoma and adenocarcinoma lesions compared with non-neoplastic mucosa in human colorectal-cancer specimens. SRR-mediated dehydration of serine contributes to the pyruvate pool in colon-cancer cells, enhances proliferation, maintains mitochondrial mass and increases basal reactive oxygen species production, which has anti-apoptotic effects. Moreover, SRR promotes acetylation of histone H3 by maintaining intracellular acetyl-CoA levels. Inhibition of SRR suppresses growth of colorectal tumours in mice and augments the efficacy of 5-fluorouracil treatment. Our findings highlight a previously unknown mechanism through which a racemase supports cancer-cell growth and suggest that SRR might be a molecular target for colorectal-cancer therapy.
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http://dx.doi.org/10.1038/s42255-019-0156-2DOI Listing
January 2020

Androgenetic Complete Hydatidiform Moles With p57KIP2-Positive Immunostaining.

Am J Clin Pathol 2020 11;154(6):776-783

Departments of Reproductive Medicine, Chiba, Japan.

Objectives: Complete hydatidiform moles (CHMs) are androgenetic and have a high rate of progression to gestational trophoblastic neoplasia (GTN). CHMs are negative when immunostained for p57KIP2 protein, the product of the maternally expressed gene on chromosome 11p15.5, whereas biparental partial hydatidiform moles and hydropic abortion are positive for p57KIP2. This study presents two cases of p57KIP2-positive androgenetic CHMs and explores the cause of this inconsistency.

Methods: Androgenetic CHMs were diagnosed using multiplex short tandem repeat polymorphism analysis. Single-nucleotide polymorphism arrays were performed for molecular karyotyping.

Results: Among the consecutive 188 androgenetic CHMs, two cases were positive for p57KIP2. The first case remitted spontaneously, whereas the second case developed into low-risk GTN. The first case was positive for p57KIP2 in all villi. The karyotype was 48,XX,+7,+11, with the additional chromosome 11 confirmed to be of maternal origin. The second case presented a mosaic of both positively and negatively stained villi. The karyotype was 46,XX.

Conclusions: The cause of one of the CHMs was trisomy with an additional maternal chromosome 11. Although rare, the confirmation of p57KIP2-positive androgenetic CHM status is necessary to manage GTN risk.
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http://dx.doi.org/10.1093/ajcp/aqaa096DOI Listing
November 2020

Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer.

Cancer Sci 2020 Apr 27;111(4):1407-1416. Epub 2020 Feb 27.

Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially-methylated genes between responders and non-responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression-free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC.
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http://dx.doi.org/10.1111/cas.14338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156782PMC
April 2020

Development of localized cul-de-sac endometrioid carcinoma associated with deep infiltrating endometriosis during remission of early endometrial cancer.

Gynecol Oncol Rep 2020 Feb 9;31:100526. Epub 2019 Dec 9.

Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

•A cul-de-sac endometrioid carcinoma adjacent to extraovarian endometriosis was identified during remission of endometrial cancer.•The origin of the cul-de-sac tumor was malignant transformation of deep infiltrating endometriosis.•Endometriosis-related cancer was identified in a woman with endometrial cancer during remission.•Hyperestrogenism due to infertility treatment may contribute to malignant transformation of deep infiltrating endometriosis.
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http://dx.doi.org/10.1016/j.gore.2019.100526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926206PMC
February 2020

Possible malignant transformation of arteriovenous malformation to angiosarcoma: case report and literature review.

J Surg Case Rep 2019 Dec 23;2019(12):rjz375. Epub 2019 Dec 23.

Department of Plastic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Angiosarcoma is a rare malignant tumour, which accounts for 1-2% of all malignant soft-tissue tumours. Most cases of angiosarcoma arise spontaneously, and malignant transformation of vascular malformation to angiosarcoma is extremely rare. We describe the case of a 70-year-old woman with a massive arteriovenous malformation in her shoulder, which gradually enlarged, despite repeated surgeries and radiation therapy over 53 years. She also presented with rapidly growing haemorrhagic masses in her oral cavity. Excision biopsy was performed, and the pathohistological diagnosis was angiosarcoma. Positron emission tomography-computed tomography revealed high fluorodeoxyglucose accumulation in the oral cavity and right shoulder, the latter of which was consistent with the location of the arteriovenous malformation. The masses in the oral cavity were diagnosed as metastatic angiosarcoma from the right shoulder, where the massive arteriovenous malformation was suspected to have malignantly transformed. This report describes a possible case of malignant transformation of arteriovenous malformation to angiosarcoma.
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http://dx.doi.org/10.1093/jscr/rjz375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926386PMC
December 2019

Publisher Correction: Decomposition and oxidation of methionine and tryptophan following irradiation with a nonequilibrium plasma jet and applications for killing cancer cells.

Sci Rep 2019 Nov 27;9(1):18140. Epub 2019 Nov 27.

Joining and Welding Research Institute, Osaka University, Ibaraki, Osaka, 567-0047, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-54737-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879489PMC
November 2019
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