酒井 康弘

Background and aims: Capillary Cup® is a novel finger-stick blood collection device equipped with separation float technology to effectively isolate plasma and blood cell layers. This study aimed to evaluate its analytical equivalence compared to venipuncture sampling in clinical chemistry, complete blood count, and hemoglobin A1c testing. Methods: Blood samples were collected from 63 healthy participants for clinical chemistry and hemoglobin A1c tests and 67 for complete blood count tests. Discrepancies between the Capillary Cup® and venipuncture sampling results were analyzed using the 2025 Clinical Laboratory Improvement Amendments (CLIA) acceptance limits and total allowable error (TEA) thresholds. Results: The Capillary Cup® samples showed strong linear correlations with venipuncture samples across proteins, transaminases, kidney function markers, lipids, C-reactive protein, blood cell and platelet counts, white blood cell differentials, hemoglobin, hematocrit, and Wintrobe's indices (r = 0.740–0.999, P < 0.0001). Hemoglobin A1c was accurately measured alongside other clinical chemistry markers in a single kit (r = 0.976, P < 0.0001). All values met the 2025 CLIA acceptance limits, and most also met the TEA thresholds. Minor deviations were observed for creatinine, triglycerides, and C-reactive protein, as well as for platelet counts—potentially affected by activation and aggregation—but all remained within acceptance limits and demonstrated preserved linearity. Conclusions: The Capillary Cup® provides analytically equivalent results to venipuncture for all tested parameters. It is easy to use, reduces waste, and is a potential alternative for at-home health monitoring, addressing challenges in venous access, and reducing iatrogenic blood loss risk in clinical practice.

The effectiveness of immune checkpoint inhibitors is diminished by the presence of myeloid-derived suppressor cells (MDSCs). Recent studies indicate that the NLR family pyrin domain-containing 3 (NLRP3) inflammasome regulates MDSC function, thereby reducing the efficacy of immune checkpoint inhibitors. However, the specific mechanism by which NLRP3 expression induces the immunosuppressive effects in MDSCs remains unclear. Here, we demonstrate that the adenosine triphosphate (ATP)–NLRP3 inflammasome axis enhances the immunosuppressive effects of MDSCs. We found that ATP increases the mRNA levels of immunosuppressive molecules in MDSCs, leading to the suppression of T cell proliferation. Additionally, we showed the efficacy of a novel immune checkpoint therapy that combines an ATP receptor inhibitor (P2X7 receptor inhibitor), an NLRP3 inhibitor, and an anti-PD-L1 antibody (Ab). This combination treatment significantly inhibited tumor growth compared to treatment with only the NLRP3 inhibitor and anti-PD-L1 Ab. These results suggest that the ATP–NLRP3 axis enhances the immunosuppressive effect of MDSCs. In conclusion, this study elucidates the mechanism through which MDSCs acquire immunosuppressive functions, potentially informing the development of novel cancer immunotherapies.

Background/Objectives: Differentiating thoracic malignant tumors, such as epithelioid malignant pleural mesothelioma (EMPM) and non-small-cell lung carcinoma (NSCLC), primarily comprising lung adenocarcinoma (LAC) and lung squamous cell carcinoma (LSCC), remains a challenge in routine pathological diagnosis. This study aimed to evaluate whether podoplanin (PDPN) immunohistochemistry combined with scanning electron microscopy (SEM) using the NanoSuit-correlative light and electron microscopy (CLEM) methods could serve as a reliable tool for distinguishing these thoracic malignancies. Methods/Results: Initially, PDPN expression was assessed by immunohistochemical analysis in 11 EMPM, 100 LAC, and 23 LSCC cases. PDPN positivity was predominantly observed in the cell membrane and was significantly more frequent in EMPM (100%) than in LAC (2%; p &lt; 0.0001) or LSCC (43.5%; p = 0.0018). Subsequently, field emission–SEM (FE-SEM) observations of PDPN-positive sites on immunohistochemical slides, conducted using the NanoSuit-CLEM method, revealed distinctive ultrastructural features. EMPM exhibited densely packed, elongated microvilli, whereas such structures were absent in LAC and LSCC. Furthermore, analysis of thick-cut sections (20 μm) demonstrated extensive microvilli coverage characteristic of EMPM. Conclusions: These findings suggest that the combined approach of PDPN immunohistochemistry and FE-SEM observation of PDPN-positive sites, using the NanoSuit-CLEM method, constitutes an effective diagnostic strategy for enhancing the accuracy of distinguishing EMPM from NSCLCs.

Prospero homeobox protein 1 (PROX1) is aberrantly expressed in tumors, including neuroendocrine neoplasms (NENs); however, the detailed expression pattern remains elusive. This study aimed to immunohistochemically assess PROX1 expression. Immunohistochemistry (IHC) for PROX1 was performed on tissue microarrays of normal tissues (n = 107), NENs (n = 152) (small cell lung carcinoma [SCLC], lung carcinoid [LC], gastroenteropancreatic-NEN [GEP-NEN], esophageal neuroendocrine carcinoma [ENEC], medullary thyroid carcinoma [MTC], neuroblastoma [NB], and pheochromocytoma [PHEO]), and non-NENs (n = 469). In normal tissues, PROX1 was expressed in lymphatic endothelial cells and a subset of epithelial cells in the gastrointestinal tract and the distal convoluted tubules. In NENs, the positive expression was observed in the nucleus of tumor cells in 19/26 SCLC (73.1%), 13/16 LC (81.3%), 10/15 GEP-NEN (66.7%), 2/2 ENEC (100%), 17/43 MTC (39.5%), 1/25 NB (4.0%), and 0/25 PHEO (0%). Although PROX1 was negative in many non-NENs, our analysis revealed high expression in certain cases with medulloblastoma and one case with juvenile granulosa cell tumor. PROX1 was expressed in specific cases with epithelial NENs and some cases with non-NENs. Analysis of PROX1 should provide insights into the molecular characteristics of distinct tumors.

DNA is frequently damaged by genotoxic stresses such as ionizing radiation, reactive oxygen species, and nitrogen species. DNA damage is a key contributor to cancer initiation and progression, and thus the precise and timely repair of these harmful lesions is required. Recent studies revealed transcription as a source of genome instability, and transcription-coupled DNA damage has been a focus in cancer research. Impaired mRNA export is closely related to DNA damage through R-loop formation. The molecular machineries of transcription-coupled DNA damage have been extensively analyzed in Saccharomyces cerevisiae. However, the molecular basis of these phenomena in higher eukaryotes remains elusive. In this review, we focus on the relationship between deregulated mRNA export through the transcription-export-2 (TREX-2) complex and cancer development. Particularly, the expression of germinal center-associated nuclear protein (GANP), a molecular scaffold in the TREX-2 complex, is highly associated with tumorigenesis in mice and humans. Although the deregulated expression of other components in the TREX-2 complex might affect cancer development, we have directly demonstrated the significance of GANP in tumorigenesis using genetically modified mice. Additionally, we describe recent evidence for medical applications demonstrating that the downregulation of the other components may be a good candidate for a chemotherapeutic target in terms of reducing the side effects.

STIL is a regulatory protein essential for centriole biogenesis, and its dysregulation has been implicated in various diseases, including malignancies. However, its role in non-small-cell lung carcinoma (NSCLC) remains unclear. In this study, we examined STIL expression and its potential association with chromosomal numerical abnormalities (CNAs) in NSCLC using The Cancer Genome Atlas (TCGA) dataset, immunohistochemical analysis, and in vitro experiments with NSCLC cell lines designed to overexpress STIL. TCGA data revealed upregulated STIL mRNA expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of NSCLC. Immunohistochemical analysis of cases from our hospital (LUAD, n = 268; LUSC, n = 98) revealed STIL protein overexpression. To elucidate the functional role of STIL, an inducible STIL-overexpressing H1299 NSCLC cell line was generated. Overexpression of STIL in these cells promoted centrosome amplification, leading to chromosomal instability. Finally, analysis of arm-level chromosomal copy number alterations from the TCGA dataset revealed that elevated STIL mRNA expression was associated with CNAs in both LUAD and LUSC. These findings suggest that STIL overexpression is associated with CNAs in NSCLC, likely through centrosome amplification, which is linked to chromosomal instability and might represent a potential therapeutic target for NSCLC treatment.

Background: Androgen receptor signaling inhibitors (ARSIs) have been used to treat patients with metastatic prostate cancer (PC) and castration‐resistant prostate cancer (CRPC). In this study, we aimed to identify novel serum extracellular vesicle (EV)‐based biomarkers to diagnose ARSI‐resistance and therapeutic targets for ARSI‐resistant CRPC. Methods: Total RNA contained in serum EVs from 5 cases of CRPC before ARSI treatment and after acquiring ARSI‐resistance was subjected to RNA‐sequencing. The expression changes of selected RNAs contained in EVs were confirmed in 48 cases of benign prostatic hyperplasia (BPH) and 107 PC using reverse transcription‐quantitative PCR (RT‐qPCR) and compared with tissue RNA expression using public datasets. Results: RNA‐sequencing revealed that mitochondrial oxidative phosphorylation (OXPHOS)‐related genes were increased in EVs after acquiring ARSI‐resistance. Among them, RT‐qPCR and datasets analysis demonstrated that SDHB mRNA was upregulated after acquiring ARSI‐resistance in EVs and ARSI‐exposed PC tissue compared to ARSI‐naïve EVs and tissue, respectively. SDHB mRNA levels both in EVs and tissue were increased in localized PC compared with BPH and decreased in advanced PC. Tissue expression of SDHB mRNA was significantly correlated with those of other OXPHOS‐related genes. SDHB mRNA in EVs (EV‐SDHB) was elevated among 3 out of 7 ARSI‐treating patients with stable PSA levels who later progressed to ARSI‐resistant CRPC. Conclusions: The levels of OXPHOS‐related mRNAs in EVs correlated with those in PC tissue, among which SDHB mRNA was found to be a novel biomarker to diagnose ARSI‐resistance. EV‐SDHB may be useful for early diagnosis of ARSI‐resistance.

Background: Mutations in the TP53 tumor suppressor gene are well-established drivers of colorectal cancer (CRC) development. However, data on the prevalence of TP53 variants and their association with consensus molecular subtype (CMS) classification in patients with CRC from Rwanda are currently lacking. This study addressed this knowledge gap by investigating TP53 mutation status concerning CMS classification in a CRC cohort from Rwanda. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue blocks were obtained from 51 patients with CRC at the University Teaching Hospital of Kigali, Rwanda. Exons 4 to 11 and their flanking intron-exon boundaries in the TP53 gene were sequenced using Sanger sequencing to identify potential variants. The recently established immunohistochemistry-based classifier was employed to determine the CMS of each tumor. Results: Sequencing analysis of cancerous tissue DNA revealed TP53 pathogenic variants in 23 of 51 (45.1%) patients from Rwanda. These variants were predominantly missense types (18/23, 78.3%). The most frequent were c.455dup (p.P153Afs*28), c.524G > A (p.R175H), and c.733G > A (p.G245S), each identified in three tumors. Trinucleotide sequence context analysis of the 23 mutations (20 of which were single-base substitutions) revealed a predominance of the [C > N] pattern among single-base substitutions (SBSs) (18/20; 90.0%), with C[C > T]G being the most frequent mutation (5/18, 27.8%). Furthermore, pyrimidine bases (C and T) were preferentially found at the 5ʹ flanking position of the mutated cytosine (13/18; 72.2%). Analysis of CMS subtypes revealed the following distribution: CMS1 (microsatellite instability-immune) (6/51, 11.8%), CMS2 (canonical) (28/51, 54.9%), CMS3 (metabolic) (9/51, 17.6%), and CMS4 (mesenchymal) (8/51, 15.7%). Interestingly, the majority of TP53 variants were in the CMS2 subgroup (14/23; 60.1%).

Lung neuroendocrine neoplasms (NENs) are a diverse group of tumors characterized by neuroendocrine (NE) differentiation. Among lung NENs, lung carcinoid (LC) is a rare tumor with unique characteristics. Recent research has highlighted the importance of transcription factors (TFs) in establishing gene expression programs in lung NENs such as small cell lung carcinoma. However, the TFs that control the gene expression of LC are largely unknown. In this study, we report the expression and potential function of a TF called Prospero homeobox protein1 (PROX1) in LC. Publicly available transcriptome data suggested that PROX1 was highly expressed in LC tissues, which was confirmed by immunohistochemical analysis on a tissue microarray. Knockdown of PROX1 did not impact the cellular viability of an LC-derived cell line, NCI-H727. Meanwhile, transcriptome analysis revealed that PROX1 knockdown altered the expression of genes involved in NE differentiation. ASCL1, CHGA, CALCA, and LINC00261 were suggested as downstream genes of PROX1. These findings indicate that PROX1 may play an important role in the NE identity of LC by regulating the expression of key target genes.

Background: Common marmosets (Callithrix jacchus) are widely used as primate experimental models in biomedical research. Duodenal dilation with chronic vomiting in captive common marmosets is a recently described life-threatening syndrome that is problematic for health control. However, the pathogenesis and cause of death are not fully understood. Case presentation: We report two novel necropsy cases in which captive common marmosets were histopathologically diagnosed with gastric emphysema (GE) and pneumatosis intestinalis (PI). Marmoset duodenal dilation syndrome was confirmed in each case by clinical observation of chronic vomiting and by gross necropsy findings showing a dilated, gas-filled and fluid-filled descending duodenum that adhered to the ascending colon. A diagnosis of GE and PI was made on the basis of the bubble-like morphology of the gastric and intestinal mucosa, with histological examination revealing numerous vacuoles diffused throughout the lamina propria mucosae and submucosa. Immunostaining for prospero homeobox 1 and CD31 distinguished gas cysts from blood and lymph vessels. The presence of hepatic portal venous gas in case 1 and possible secondary bacteremia-related septic shock in case 2 were suggested to be acute life-threatening abdominal processes resulting from gastric emphysema and pneumatosis intestinalis. Conclusions: In both cases, the gross and histopathological findings of gas cysts in the GI tract walls matched the features of human GE and PI. These findings contribute to clarifying the cause of death in captive marmosets that have died of gastrointestinal diseases.

Perturbation of genes is important for somatic hypermutation to increase antibody affinity during B-cell immunity; however, it may also promote carcinogenesis. Previous studies have revealed that transcription is an important process that can induce DNA damage and genomic instability. Transciption-export-2 (TREX-2) complex, which regulates messenger RNA (mRNA) nuclear export, has been studied in the budding yeast Saccharomyces cerevisiae; however, recent studies have started investigating the molecular function of the mammalian TREX-2 complex. The central molecule in the TREX-2 complex, that is, germinal center-associated nuclear protein (GANP), is closely associated with antibody affinity maturation as well as cancer etiology. In this review, we focus on carcinogenesis, lymphomagenesis, and teratomagenesis caused by transcription-coupled DNA damage through GANP and other components of the TREX-2 complex. We review the basic machinery of mRNA nuclear export and transcription-coupled DNA damage. We then briefly describe the immunological relationship between GANP and the affinity maturation of antibodies. Finally, we illustrate that the aberrant expression of the components of the TREX-2 complex, especially GANP, is associated with the etiology of various solid tumors, lymphomas, and testicular teratoma. These components serve as reliable predictors of cancer prognosis and response to chemotherapy.

Long non-coding RNA (lncRNA) plays an important role in the regulation of gene expression in normal and cancer cells. We previously discovered a novel tumor-suppressive lncRNA, DRAIC, in prostate cancer cells. Subsequent studies have demonstrated that DRAIC is dysregulated in various malignancies and exhibits a tumor-suppressive or pro-oncogenic function. However, details regarding its expression pattern in normal and cancerous tissues remain largely unknown. In this study, we performed chromogenic in situ hybridization (CISH) using RNAscope technology to assess DRAIC expression in formalin-fixed paraffin-embedded (FFPE) specimens. In the neuroendocrine-differentiated cancer cell line VMRC-LCD, CISH revealed a diffuse localization of DRAIC in the cytoplasm as well as specific accumulation in the nuclear compartment. DRAIC expression was comprehensively analyzed using tissue microarrays containing 89 normal and 155 tumor tissue samples. DRAIC was weakly expressed in normal epithelial cells of the colon, bronchiole, kidney, prostate, and testis. Conversely, DRAIC was moderately to highly expressed in some cancer tissues, including prostate adenocarcinoma, invasive ductal carcinoma of the breast, neuroendocrine carcinoma of the esophagus, lung adenocarcinoma, and small cell lung carcinoma. While DRAIC knockdown did not affect VMRC-LCD cellular viability and invasive ability, gene expression related to the neuroendocrine and cancer-related pathways was altered. Our expression analysis revealed the specific expression pattern of DRAIC in normal and cancerous FFPE tissues. The results presented here may lead to the elucidation of additional novel functions of DRAIC.

Background and aims: Gastric cancer (GC) is associated with chronic gastritis. To evaluate the risk, the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) system was constructed and showed a higher GC risk in stage III or IV patients, determined by the degree of intestinal metaplasia (IM). Although the OLGIM system is useful, evaluating the degree of IM requires substantial experience to produce precise scoring. Whole-slide imaging is becoming routine, but most artificial intelligence (AI) systems in pathology are focused on neoplastic lesions. Methods: Hematoxylin and eosin-stained slides were scanned. Images were divided into each gastric biopsy tissue sample and labeled with an IM score. IM was scored as follows: 0 (no IM), 1 (mild IM), 2 (moderate IM), and 3 (severe IM). Overall, 5753 images were prepared. A deep convolutional neural network (DCNN) model, ResNet50, was used for classification. Results: ResNet50 classified images with and without IM with a sensitivity of 97.7% and specificity of 94.6%. IM scores 2 and 3, involved as criteria of stage III or IV in the OLGIM system, were classified by ResNet50 in 18%. The respective sensitivity and specificity values of classifying IM between scores 0 and 1 and 2 and 3 were 98.5% and 94.9%, respectively. The IM scores classified by pathologists and the AI system were different in only 438 images (7.6%), and we found that ResNet50 tended to miss small foci of IM but successfully identified minimal IM areas that pathologists missed during the review. Conclusions: Our findings suggested that this AI system would contribute to evaluating the risk of GC accuracy, reliability, and repeatability with worldwide standardization.

Background/Aim: We aimed to evaluate the changes of androgen receptor (AR) signaling-related long non-coding RNAs (lncRNAs) in serum extracellular vesicles (EVs) from prostate cancer (PC) patients, in order to identify novel biomarkers for AR axis-targeted therapy (ARAT)-resistance among castration-resistant PC (CRPC) patients. Patients and Methods: EVs were isolated from 2 patients before and after acquiring ARAT-resistance. RNA profiling of EVs was performed by RNA-sequencing. The expression levels of selected lncRNAs in EVs were analyzed by digital droplet PCR (ddPCR) in 58 localized and 14 metastatic PC patients at diagnosis, 7 ARAT-naïve and 6 ARAT-resistant CRPC patients. LncRNA H19 expression in PC tissue was examined using published data. In order to analyze the role of H19, the prognosis was analyzed in PC patients and proteomic analysis was performed in 22Rv1 PC cells. Results: RNA-sequencing revealed that AR-regulated RNAs were most enriched in EVs after acquiring ARAT-resistance. Among them, up-regulation of AR signaling-related lncRNAs (PCAT1, H19, HOXA-11AS, ZEB1-AS1, ARLNC1, PART1, CTBP1-AS and PCA3) was confirmed by ddPCR. H19 contained in EVs (EV-H19) was significantly increased among ARAT-resistant patients compared to ARAT-naïve CRPC or metastatic PC patients. In PC tissue, H19 was negatively correlated with AR protein and AR-activity score and up-regulated in neuroendocrine CRPC tissue with low AR expression. Furthermore, EV-H19 expression was significantly associated with worse outcome to androgen-deprivation therapy. Proteomic analysis demonstrated that H19 knockdown enhanced PC-related protein expression. Conclusion: EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.

Testicular teratomas are the major histologic type of testicular germ cell tumors and their incidence continues to grow. Moreover, teratomas can develop from undifferentiated cells in induced pluripotent stem (iPS) cell transplantation therapy, seriously hampering the progress of regenerative medicine. Germinal center-associated nuclear protein (GANP) is thought to be important to the biogenetic control of primordial germ cells and is among the genes susceptible to testicular germ cell tumors. Thus, we analyzed the expression of GANP in human testicular postpubertal-type teratomas and established a novel mouse model to reveal the association between GANP and teratomagenesis. We analyzed 31 cases of human testicular postpubertal-type teratomas and, in all cases, GANP was overexpressed. The aberrant expression was also detected in germ cell neoplasia in situ accompanied by the teratoma. GANP expression was particularly high in the epithelia of the epidermis, cutaneous appendages, and trachea-like ciliated epithelium. To further clarify the association between GANP and teratomagenesis, we established a novel teratomagenesis mouse model (CAG-ganpTg mice). In the GANP−teratoma mice, GANP-overexpressing teratomas were more frequent at the testes and the middle portion of the uterus than has been seen in the previously established mouse models. In conclusion, GANP is overexpressed in testicular postpubertal-type teratomas and is an essential teratomagenic factor. We also found that CAG-ganpTg mice are useful mouse models of teratomagenesis that mimics human midline teratomas and that teratomas may originate from the overexpression of GANP in primordial germ cells.

Background: Various vaccine adjuvants have been developed to eliminate HBV from patients with chronic HBV infection. In addition, spermidine (SPD), a type of polyamine, has been reported to enhance the activity of immune cells. In the present study, we investigated whether the combination of SPD and vaccine adjuvant enhances the HBV antigen-specific immune response to HBV vaccination. Methods: Wild-type and HBV-transgenic (HBV-Tg) mice were vaccinated 2 or 3 times. SPD was orally administered in drinking water. Cyclic guanosine monophosphate–AMP (cGAMP) and nanoparticulate CpG-ODN (K3-SPG) were used as the HBV vaccine adjuvants. The HBV antigen-specific immune response was evaluated by measuring the HBsAb titer in blood collected over time and the number of interferon-γ producing cells by enzyme-linked immunospot assay. Results: The administration of HBsAg + cGAMP + SPD or HBsAg + K3-SPG + SPD significantly enhanced HBsAg-specific interferon-γ production by CD8 T cells from wild-type and HBV-Tg mice. The administration of HBsAg, cGAMP, and SPD increased serum HBsAb levels in wild-type and HBV-Tg mice. In HBV-Tg mice, the administration of SPD + cGAMP or SPD + K3-SPG with HBV vaccination significantly reduced HBsAg levels in the liver and serum. Conclusions: These results indicate that the combination of HBV vaccine adjuvant and SPD induces a stronger humoral and cellular immune response through T-cell activation. These treatments may support the development of a strategy to completely eliminate HBV.

A previous study revealed that treatment with the anticoagulant heparin attenuated concanavalin A (ConA)-induced liver injury. The administration of spermidine (SPD) increased urokinase-type plasminogen activator (uPA) levels in the serum. uPA is clinically used for the treatment of some thrombotic diseases such as cerebral infarction. Therefore, SPD may attenuate ConA-induced liver injury that is exacerbated by blood coagulation. The present study investigated the effect of SPD on liver injury in mice with autoimmune hepatopathy induced by ConA. A model of liver injury was created by intravenous injection of ConA into mice. SPD was administered in free drinking water and was biochemically and pathologically examined over time. The administration of SPD to ConA-treated mice significantly reduced liver injury. However, SPD treatment upregulated the mRNA expression of TNF-α and IFN-γ in the livers of ConA-treated mice. In contrast, the mRNA expression of tissue factor in the livers of SPD-treated mice was decreased after ConA injection. The frequency of lymphocytes and lymphocyte activation were not affected by SPD administration in ConA-treated mice. SPD treatment increased uPA levels in the serum and decreased the level of D-dimer in ConA-treated mice. Moreover, SPD decreased fibrin in the livers of ConA-treated mice. These results indicated that SPD treatment increased anticoagulant ability by increasing of uPA and attenuated ConA-induced liver injury.

Background/Aim: Cancer cells with high anchorage independence can survive and proliferate in the absence of adhesion to the extracellular matrix. Under anchorage-independent conditions, cancer cells adhere to each other and form aggregates to overcome various stresses. In this study, we investigated the cytomorphology and gene expression signatures of oral cancer cell aggregates. Materials and Methods: Two oral cancer-derived cell lines, SAS and HSC-3 cells, were cultured in a low-attachment plate and their cytomorphologies were observed. The transcriptome between attached and detached SAS cells was examined using gene expression microarrays. Subsequently, gene enrichment analysis and Ingenuity Pathway Analysis were performed. Gene expression changes under attached, detached, and re-attached conditions were measured via RT-qPCR. Results: While SAS cells formed multiple round-shaped aggregates, HSC-3 cells, which had lower anchorage independence, did not form aggregates efficiently. Each SAS cell in the aggregate was linked by desmosomes and tight junctions. Comparative transcriptomic analysis revealed 1,698 differentially expressed genes (DEGs) between attached and detached SAS cells. The DEGs were associated with various functions and processes, including cell adhesion. Moreover, under the detached condition, the expression of some epithelial genes (DSC3, DSP, CLDN1 and OCLN) were up-regulated. The changes in both cytomorphology and epithelial gene expression under the detached condition overall returned to their original ones when cells re-attached. Conclusion: The results suggest specific cytomorphological and gene expression changes in oral cancer cell aggregates. Our findings provide insights into the mechanisms underlying anchorage-independent oral cancer cell aggregation and reveal previously unknown potential diagnostic and therapeutic molecules.

The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10−5). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis.

Purpose: Malignant pleural mesothelioma (MPM) is a malignant neoplasm of the pleura caused by asbestos exposure. For diagnosis of MPM, immunohistochemistry using multiple markers is recommended to rule out differential diagnoses, such as pulmonary adenocarcinoma. However, the specificity of currently used markers is not fully satisfactory. We previously developed a monoclonal antibody named S1, which recognizes 6-sulfo sialyl Lewis x, an L-selectin ligand expressed on high endothelial venules. During the screening process, we discovered that this antibody stained normal pleural mesothelium. This finding prompted us to hypothesize that the epitope recognized by S1 might serve as a new diagnostic marker for MPM. Methods: To test this hypothesis, we immunostained human MPM (n = 22) and lung adenocarcinoma (n = 25) tissues using S1 antibody. Results: 77.3% of MPM were S1 positive, and if limited to epithelioid type, the positivity rate was 100%, while that of lung adenocarcinoma was only 36.0%. Statistical analysis revealed a significant difference in the S1 positivity rate between each disease. Furthermore, immunohistochemistry using a series of anti-carbohydrate antibodies combined with glycosidase digestion revealed the structure of sulfated glycans expressed in MPM to be 6-sulfo sialyl N-acetyllactosamine attached to core 2-branched O-glycans. Conclusion: We propose that the S1 glycoepitope could serve as a new diagnostic marker for MPM.

Sarcoidosis is a rare disease of isolated or diffuse granulomatous inflammation. Although any organs can be affected by sarcoidosis, cardiac sarcoidosis is a fatal disorder, and it is crucial to accurately diagnose it to prevent sudden death due to dysrhythmia. Although endomyocardial biopsy is invasive and has limited sensitivity for identifying granulomas, it is the only modality that yields a definitive diagnosis of cardiac sarcoidosis. It is imperative to develop novel pathological approaches for the precise diagnosis of cardiac sarcoidosis. Here, we aimed to discuss commonly used diagnostic criteria for cardiac sarcoidosis and to summarize useful and novel histopathologic criteria of cardiac sarcoidosis. While classical histologic observations including noncaseating granulomas and multinucleated giant cells (typically Langhans type) are the most important findings, others such as microgranulomas, CD68+ CD163− pro-inflammatory (M1) macrophage accumulation, CD4/CD8 T-cell ratio, Cutibacterium acnes components, lymphangiogenesis, confluent fibrosis, and fatty infiltration may help to improve the sensitivity of endomyocardial biopsy for detecting cardiac sarcoidosis. These novel histologic findings are based on the pathology of cardiac sarcoidosis. We also discussed the principal histologic differential diagnoses of cardiac sarcoidosis, such as tuberculosis myocarditis, fungal myocarditis, giant cell myocarditis, and dilated cardiomyopathy.

A Japanese man in the present study experienced acute weakness in his right leg as a two year old. The strength in his leg gradually recovered and developed, and he could play golf and climb mountains up to around the age of 50. From approximately 55 years of age, he became unable to stand up from a stooped position. Muscle weakness and atrophy spread to his right arm, and an electromyography revealed a neurogenic pattern in his lower and upper extremities. The patient was diagnosed as having post-poliomyelitis syndrome (PPS). Numbness in both the legs and pain in the buttocks occurred after 60 years of age. Computed tomography and magnetic resonance imaging at that time revealed spondylosis and protrusion of an osteophye in lower thoracic vertebrae compressing the second lumbar segment of the spinal cord. He died of malignant lymphoma and acute interstitial pneumonia at 80 years of age. Pathological examination revealed transverse myelopathy at the second lumbar segment of the spinal cord and total necrosis. The anterior horn and the intermediate zone of the third and fourth lumbar segments of the spinal cord on the right side were atrophic and diffusely gliotic. An oval-shaped plaque-like lesion was observed in the right anterior horn at the third and fourth lumbar segments of the spinal cord. Neurons and synaptophysin immunoreactivity had completely disappeared in the plaque-like lesion. A striking spread of vimentin-immunoreactive cells was found corresponding to the lesion, while glial fibrillary acidic protein-immunoreactive astrocytes existed evenly in the anterior horn and intermediate zone on both sides of the third and fourth lumber segments of the spinal cord. Virological examination using the autopsied materials was negative for poliovirus. Neither transactivation response DNA-binding protein of 43 kDa-immunoreactive inclusion nor Bunina body was seen in the spinal cord. The present paper demonstrates new findings of a noteworthy response of the vimentin-immunoreactive cells within the peculiar "plaque-like lesion" in the PPS.

Breast cancer, the most common malignancy among women, is closely associated with mutations in the tumor suppressor gene BRCA. DSS1, a component of the TRanscription–EXport-2 (TREX-2) complex involved in transcription and mRNA nuclear export, stabilizes BRCA2 expression. DSS1 is also related to poor prognosis in patients with breast cancer owing to the induction of chemoresistance. Recently, BRCA2 was shown to be associated with the TREX-2 component PCID2, which prevents DNA:RNA hybrid R-loop formation and transcription-coupled DNA damage. This study aimed to elucidate the involvement of these TREX-2 components and BRCA2 in the chemosensitivity of breast carcinomas. Our results showed that compared with that in normal breast tissues, DSS1 expression was upregulated in human breast carcinoma, whereas PCID2 expression was comparable between normal and malignant tissues. We then compared patient survival time among groups divided by high or low expressions of DSS1, BRCA2, and PCID2. Increased DSS1 expression was significantly correlated with poor prognosis in recurrence-free survival time, whereas no differences were detected in the high and low BRCA2 and PCID2 expression groups. We performed in vitro analyses, including propidium iodide nuclear staining, single-cell gel electrophoresis, and clonogenic survival assays, using breast carcinoma cell lines. The results confirmed that DSS1 depletion significantly increased chemosensitivity, whereas overexpression conferred chemoresistance to breast cancer cell lines; however, BRCA2 expression did not affect chemosensitivity. Similar to DSS1, PCID2 expression was also inversely correlated with chemosensitivity. These results strongly suggest that DSS1 and PCID2 depletion is closely associated with increased chemosensitivity via BRCA2-independent DNA damage. Together with the finding that DSS1 is not highly expressed in normal breast tissues, these results demonstrate that DSS1 depletion confers a druggable trait and may contribute to the development of novel chemotherapeutic strategies to treat DSS1-depleted breast carcinomas independent of BRCA2 mutations.

A well-differentiated neuroendocrine tumor (WDNET) of the urinary bladder is an exceedingly rare neoplasm. Here, we report a case of WDNET of the urinary bladder and present the histological and immunohistochemical findings. A 42-year-old man presented with gross hematuria. A 1-cm polypoid lesion was removed from the urinary bladder by transurethral resection. On histological analysis, uniform tumor cells with round nuclei and stippled chromatin, arranged in a gland-like pattern, were noted. Immunohistochemical analysis revealed that the tumor cells were diffusely immunoreactive for synaptophysin and chromogranin A. The Ki67 labeling index was 1 %. Less than 1% of the tumor cells were immunoreactive for p53. The lesion was diagnosed as WDNET of the urinary bladder. Although the histology of WDNETs of the urinary bladder is similar to that of those arising in other organs, a histopathological diagnosis is often challenging due to its rarity. Furthermore, WDNETs should be considered in the differential diagnosis of glandular lesions, such as cystitis glandularis and adenocarcinoma of the urinary bladder.

AI has led to extraordinary medical breakthroughs, one of which is the digitisation of pathological slides which negates the need for classical optical microscopes. Also thanks to AI, clinicians and researchers can access great swathes of data that can be used to enhance understanding of diseases and improve patient outcomes. In his research, Dr Yasuhiro Sakai is exploring the possibilities facilitated by AI and big data, with a focus on gastric cancer. He has established the Japan Pathology AI Diagnostics Project (JP-AID) and is collaborating with Dr Mai Iwaya and Professor Kensaku Mori, with input from other researchers based at Shinshu University, Fujita Health University, Nagoya University and the National Institute of Informatics. The researchers are using AI to evaluate the risk factors of gastric cancer, including the degree of chronic gastritis, neutrophil infiltration and intestinal metaplasia. In using AI, the researchers aim to overcome limitations associated with the 'Updated Sydney System (USS)', which is a pathological scoring system for gastritis. Limitations of the USS are that the scoring system is subjective and in order to produce precise scoring, substantial gastrointestinal pathology experience is required. Sakai and the team are using AI to create new methods for evaluating gastritis that are efficient and will save time for pathologists.

40代男性に認められたまれな食道原発の滑膜肉腫の1例を報告する。上部消化管内視鏡検査により食道に有茎性の隆起性病変を認め，外科的切除が施行された。 病理組織学的に腺腔形成性の異型上皮様細胞と異型紡錘形細胞の増殖からなり，免疫組織化学的に前者はcytokeratin（AE1/AE3），EMAに陽性，後者はvimentin，CD99に 陽性で，両者ともにTLE1に陽性を呈した。FISHおよびRT-PCRにてSYT-SSXI融合遺伝子の存在が確認され，食道原発の二相型滑膜肉腫と診断した。

Germinal center-associated nuclear protein (GANP) is a unique and multifunctional protein that plays a critical role in cell biology, neurodegenerative disorders, immunohematology, and oncogenesis. GANP is an orthologue of Saccharomyces Sac3, one of the components of the transcription export 2 (TREX-2) complex and a messenger RNA (mRNA) nuclear export factor. GANP is widely conserved in all mammals, including humans. Although GANP was originally discovered as a molecule upregulated in the germinal centers of secondary lymphoid follicles in peripheral lymphoid organs, it is expressed ubiquitously in many tissues. It serves numerous functions, including making up part of the mammalian TREX-2 complex; mRNA nuclear export via nuclear pores; prevention of R-loop formation, genomic instability, and hyper-recombination; and B-cell affinity maturation. In this review, we first overview the extensive analyses that have revealed the basic functions of GANP and its ancestor molecule Sac3, including mRNA nuclear export and regulation of R-loop formation. We then describe how aberrant expression of GANP is significantly associated with cancer development. Moreover, we discuss a crucial role for GANP in B-cell development, especially affinity maturation in germinal centers. Finally, we illustrate that overexpression of GANP in B cells leads to lymphomagenesis resembling Hodgkin lymphoma derived from germinal center B cells, and that GANP may be involved in transdifferentiation of B cells to macrophages, which strongly affects Hodgkin lymphomagenesis.

Phosphaturic mesenchymal tumor（以下PMT）は腫瘍が産生する線維芽細胞増殖因子23（FGF23）による腫瘍性骨軟化症を伴う稀な腫瘍である。PMTは組織学的に多彩な像を示し，様々な疾患との鑑別を要する。今回我々は選択的な静脈血サンプリ ングによるFGF23測定が原発巣の特定に役立ったPMTの1例を経験した。PMTの正確な診断には，特徴的な臨床像と組織学的所見に加え，血中FGF23値の測定と免疫 染色t適切な画像情報に基づく総合的な判断が重要である。

Hodgkin lymphoma (HL) is one of the most difficult neoplasms in terms of cytopathological research owing to the lack of established cytological murine models. Although HL is believed to be of lymphoid germinal center B-cell origin, HL cells exhibit unique biphenotypic characteristics of B cells and macrophages. B-cell/macrophage biphenotypic cells have also been identified in the spleen of Lyn-deficient mice. Moreover, Lyn-targeting germinal center-associated nuclear protein (GANP)-transgenic mice (Ig-ganpTg mice) spontaneously develop a lymphoid tumor. We aimed to investigate whether the lymphoid tumor developed in Ig-ganpTg mice exhibit biphenotypic characteristics of B cells/macrophages that correspond to human HL. Here, we demonstrated GANP overexpression in human HL cells and found that it may regulate transdifferentiation between B cells and macrophages. We also demonstrated that tumors were comparable with B-cell/macrophage biphenotypic Hodgkinoid lymphomas. The tumor cells expressed macrophage-related F4/80, CD68, and CD204 as well as cytoplasmic B220 and µ-/κ-chains; in addition, these cells exhibited phagocytic activity. These cells also expressed transcripts of CD30; c-fms; and the cytokines monocyte chemoattractant protein (MCP)-1, MCP-5, RANTES, tumor necrosis factor-α and thrombopoietin associated with macrophages as well as granulocyte/macrophage colony-stimulating factor, interleukin (IL)-4, IL-10, IL-12, and IL-13. Ig-ganpTg mice represent a novel cytological model for the study of cytopathological etiology and oncogenesis of HL.

目的：当施設における唾液腺細胞診ミラノシステムの運用と有用性の検討を行った。方法:唾液腺および頸部腫瘤に対する穿刺細胞診施行106例中、組織診断が得られた70例についてミラノシステムを用いて検討し、各診断カテゴリーにおけるrisk of malignancy(ROM)を算出し、細胞診断と組織診断の不一致例について検討した。 成績：70例の内訳は「不適正」16例(以下ROM0%)、「非腫瘍性」3例(33%)、「意義不明な異型」9例(56%)、「良性腫瘍」20例(0%)、「良悪性不明な腫瘍」8例(63%)、「悪性の疑い」4例(100%)、「悪性」10例(100%)であった。富リンパ球性病変、低悪性の癌腫は判定が困難であった。対象を頸部リンパ節を除く唾液腺病変に限るとAUS、SUMPカテゴリーのROMは低下した。 結論：ミラノシステムは不適正の判断を明確化し、従来の鑑別困難をAUS、SUMPとして、臨床医にROMに基づく適切な取り扱い指針を示すことが可能である。ミラノシステムは唾液腺病変を対象としているが、実臨床ではリンパ節を区別して穿刺することは容易でなく、臨床像との対比や補助診断を用いてROMを下げる努力をすべきである。

For the long-term survival of a patient with renal cell carcinoma and a vena cava tumor thrombus, total resection is desired: inoperable patients are sometimes treated with drugs. The effect of the presurgical use of nivolumab, an anti-programmed cell death 1 (PD-1) antibody drug, has been described. Our patient had inoperable renal cancer with an inferior vena cava tumor thrombus. We were able to downsize the tumor to operable size by administrating nivolumab. The patient underwent a nephrectomy and thrombectomy safely. Pathological findings revealed papillary renal cell carcinoma type 2. No viable cells were identified in the removed thrombus. Anti-programmed cell death ligand 1 was expressed on the cell membrane in approximately 20% of the tumor cells, and PD-1 positive tumor-ifiltrating immune cells had infiltrated particularly at the edge of the tumor. This case indicates the positive effect of the presurgical use of nivolumab for advanced papillary renal cell carcinoma.

Unfortunately, many societies are ageing rapidly and the numbers of patients suffering from lifestyle or age induced conditions like cardiovascular disease or cancer is increasing. This places a huge burden on the field of pathology. In Japan, the healthcare system is being stretched even further as the percentage of doctors who specialise in pathology has dropped. In addition, the job of the pathologist is difficult. It requires a vast body of knowledge as to what any one condition might look like in a tissue sample or what effects it may have on levels of proteins and cells. They are taxed even further because there is usually no straightforward answer to these questions – each patient will present symptoms or 'pathologies' that are unique to them and which look slightly different from the textbook cases. Training and hiring will not address the growing demand and so, like many areas of healthcare, pathology is turning to AI. In many cases, AI technology in medical imaging is now being developed by commercial enterprises and entrepreneurial companies. Our JP-AID project however, has a great leg-up in insider knowledge. Our members consist mostly of expert pathologists and engineers working at universities and national institutes, not as employees in commercial enterprises, therefore we know the realities, the difficulties, the needs and demands of frontline pathologists in detail. This knowledge is invaluable when it comes to designing an AI diagnostic technology that can be used on a large scale. Our key objective is not only to develop, but also to utilise AI technology, and no one can utilise AI on a large scale because they don't recognise the infrastructure for the active reinforcement of AI. We create pathology AI as well as a tele-pathology network that can not only connect hospitals but also serve as a source for AI training materials and provide an existing infrastructure to disseminate the benefits of JP-AID.

Objective: Helicobacter pylori eradication is expected to prevent gastric cancer. However, morphological alterations after eradication often hinder accurate diagnosis. Therefore, we evaluated endoscopic and histological changes in gastric tumors after eradication of H. pylori in a time-dependent manner. Methods: We classified 144 cases of endoscopic submucosal dissection (ESD) of early gastric cancer into the following categories: (i) patients positive for H. pylori with no eradication history, (ii) patients positive for H. pylori who underwent ESD 2 months after eradication, (iii) patients negative for H. pylori with an eradication history of at least 6 months before ESD, and (iv) patients negative for H. pylori with an unknown history. We compared endoscopic and histological factors between the groups. Results: The characteristics of cancers positive for H. pylori were exploding shape, superficial high-grade atypical epithelium, and a surface proliferating zone. H. pylori eradication induced a series of endoscopic and histological changes, including shape ­depression, appearance of surface regenerative and lower-grade atypical epithelium, and a downward shift of the proliferative zone within a period as short as 2 months. Conclusion: H. pylori eradication rapidly causes cancer regression and leads to tumor shrinkage, diminished atypism, and shortened proliferative zone, resulting in drastic morphological changes.

Dr Yasuhiro Sakai, surgical pathologist, and Dr Kazuhiko Kuwahara, immunopathologist, are studying other important biological indicators of breast cancer and have made groundbreaking headway. Their research focuses on investigating the causes of sporadic, or non-hereditary, breast cancer. As sporadic breast cancer is a multifactorial disease, it is difficult to separate out the various biological processes behind its origins. However, slowly, as if assembling a puzzle piece by piece, it is possible to uncover significant findings that have the potential to bring about novel therapeutic approaches in the future. Specifically, Sakai and Kuwahara are working with the germinal centre B-cell-associated nuclear protein (GANP) gene, and examining how its alteration affects the development of sporadic breast cancer. 'Immunologically, GANP is associated with maturation and activation of B lymphocytes. Amazingly, it also contributes to DNA damage and may arise various malignant tumours,' states Sakai. By studying GANP's effect on B lymphocytes, or B cells responsible for a body's immunity, Sakai and Kuwahara are discerning how B lymphocyte maturation is related to the initiation of cancer formation. In doing so, they are joining the fields of tumour pathology and immunology.

Rationale: Pneumatosis intestinalis (PI) and hepatic portal venous gas (HPVG) are rare but potentially lethal conditions in which gas pathologically accumulates in the portal vein and intestinal wall, respectively. Proposed mechanisms include flatus escaping through an injured intestinal mucosa into the submucosa and thence into the portal venous system, or bacterial translocation (BT) of gas-forming enteric microorganisms from the gut into and through the intestinal wall to other organs. However, there has been no clear histopathological evidence to support these hypotheses. Patient concerns: A 61-year-old man underwent sigmoidectomy for colonic adenocarcinoma. Postoperatively, he developed paralytic ileus and then had a sudden cardiopulmonary arrest. Diagnoses: PI and HPVG were found at autopsy, presumably caused by the postoperative paralytic ileus and associated with BT of gas-forming organisms. Interventions: Cardiopulmonary resuscitation was unsuccessful. Outcomes: Postmortem imaging indicated the presence of massive PI and HPVG. At autopsy, there was marked intestinal emphysema with diffuse ischemic mucosal necrosis and severe pneumatosis in the stomach and intestine and marked gaseous dilation of the intrahepatic portal veins. Postmortem bacterial cultures revealed enteric bacteria in the peripheral blood and liver tissue. Lessons: Postoperative ileus leading to intestinal mucosal damage may be associated with BT of gas-forming enteric bacteria and the rapid onset of PI and HPVG with a lethal outcome.

Langerhans cell sarcoma (LCS) is an extremely rare malignant dendritic cell neoplasm with Langerhans cell differentiation. Conventional cytology, based on cell morphology alone, cannot render a cytological diagnosis of LCS because immunochemical analysis is essential to identify the Langerhans cell immunophenotype. We present a case illustrating the value of liquid‐based cytology with immunocytochemistry as compared with conventional cytology, along with histological and immunohistochemical findings. A 92‐year‐old woman presented with a 1‐month history of progressive right cervical lymphadenopathy. Cytology of a fine needle aspiration sample from the right superior internal jugular lymph node revealed proliferation of atypical, pleomorphic, and histiocytoid cells with one or more irregular‐shaped nuclei. Compared with conventional cytology, liquid‐based cytology demonstrated more clustered and spatial cells, slightly less marked nuclear atypia, more intense light green staining of the cytoplasm, and a clearer background. Immunocytochemical analysis of the abnormal cells revealed expression of vimentin, CD1a, langerin, CD68, and S‐100. The combined morphologic and immunocytochemical results strongly indicated LCS. Histological and immunohistochemical examination of a subsequent excisional biopsy specimen closely coincided with the results of liquid‐based cytology. Thus, this technique, including the use of immunocytochemistry, is very useful and valuable for the pathological diagnosis of nonepithelial and hematopoietic neoplasms. There are subtle but considerable differences in cell morphology between conventional and liquid‐based cytology; these differences include clusterability, spatial findings, dyeability, and atypism as illustrated in this case of LCS.

Peripheral neuropathy occurs in approximately 5% of the patients with lymphoma. Two major causes of peripheral neuropathy associated with lymphoma are neurolymphomatosis and paraneoplastic neuropathy such as demyelinating neuropathy. The differential diagnosis between neurolymphomatosis and demyelinating neuropathy is difficult, because electrophysiological findings suggestive of demyelination are frequently observed even in patients with neurolymphomatosis. Here, we report a patient with de novo CD5‐positive diffuse large B‐cell lymphoma (DLBCL) who presented with Guillain–Barré syndrome (GBS)‐like neuropathy. Demyelination due to paraneoplastic neuropathy was clinically suspected. However, autopsy demonstrated that the cause of the neuropathy was neurolymphomatosis. Clinical courses of neurolymphomatosis vary and neurolymphomatosis cases presenting with GBS‐like neuropathy are reported. In addition, DLBCL is the most frequent histological type of malignant lymphoma that develops neurolymphomatosis. Furthermore, “CD5‐positive” DLBCL may tend to develop neurolymphomatosis. If a patient with “CD5‐positive” DLBCL develops peripheral neuropathy, neurolymphomatosis should be considered and imaging studies performed and, if possible, nerve tissue biopsy, regardless of clinical symptoms of the neuropathy. To our knowledge, this is the first report of a patient with de novo CD5‐positive DLBCL with neurolymphomatosis who presented with GBS‐like neuropathy.

Renal metastasis at diagnosis with neuroblastoma is rare. We present a 14-month-old boy who was diagnosed with high-risk neuroblastoma with multiple metastases, including bilateral kidneys. He received five cycles of induction chemotherapy and high-dose chemotherapy with autologous peripheral blood stem cell transplantation. All of the lesions shrank, and magnetic resonance imaging indicated that some of the metastases had disappeared. However, there were residual masses in the bilateral kidneys, and histological examination revealed the presence of tumor cells. Therefore, the patient underwent unrelated cord blood stem cell transplantation, which involved killer-ligand incompatibility in the graft-versus-host direction, in addition to human leukocyte antigen C and DRB1 mismatches. Three months later, tumor progression occurred from the residual mass in the sacral canal and a new lesion in the pancreas. Although tumor progression could not be controlled by additional chemotherapy and local radiotherapy, the metastatic nodules in bilateral kidneys did not increase in size before his death. To the best of our knowledge, this is the first report of neuroblastoma with bilateral renal metastases in the English medical literature. In addition, this case suggests that the combination of chemotherapy and immunotherapy may inhibit the progression of the renal lesions under certain conditions.

背景：未分化子宮肉腫は，2014 年WHOの子宮内膜間質腫瘍の組織学的分類で，初めて提唱された疾患名である．そして，その鑑別診断の一つが，全く治療法が異なる未分化癌である．本例は，液状検体法（LBC 法）を導入した子宮内膜細胞診断が「肉腫疑い」で，術前の子宮内膜組織診断が「未分化癌」であった未分 化子宮肉腫である． そこで，なぜ，子宮内膜細胞診（LBC 法）が子宮内膜組織診に比べ，摘出腫瘍の組織を反映したかを考察 したので報告する． 症例：52 歳，女性．主訴は不正出血．子宮内膜細胞診像は，孤立散在性に出現する多形性細胞で，核所見 はきわめて異型が強かった．子宮内膜組織診像は，大部分が赤血球でごく一部に蜂巣状に発育した腫瘍細胞 を認めるのみであった．本例の診断において，子宮内膜細胞診（LBC 法）が有効であった理由は，溶血操作 により赤血球に邪魔されず腫瘍細胞を容易に観察できたことと，標本を複数枚作製し免疫染色により間葉系 への分化傾向を証明できたことである． 結論：出血を伴う巨大な腫瘍を形成する未分化子宮肉腫では，子宮内膜組織診に加え子宮内膜細胞診（LBC 法）を併用することが術前診断の一助となりうると考えられる．

背景：右下顎骨および甲状腺左葉からの Liquid based cytology（LBC）で原発巣と組織型が短期間に診断 できたことで，治療の奏効につながった TX肺癌症例を経験したので報告する． 症例：80 歳代，女性．右頬部腫脹と疼痛を主訴に当院を受診した．頭頸部CT・MRI・FDG-PET検査で右 下顎骨，第一頸椎および甲状腺左葉に腫瘤を認めたが，両肺野に病変はなく，当初原発不明癌が疑われた． 右下顎腫瘍の生検術が施行され，同時に採取された LBC 標本から上皮性結合を有する腫瘍塊を認め，免疫染色で TTF-1，Napsin Aが陽性であった．これらの所見は甲状腺左葉の LBC 標本にも認められ，同様の結果は 右下顎の組織診でも追認されたことより，最終的に右下顎骨と甲状腺左葉転移を伴ったTX肺癌（腺癌，Stage Ⅳ）と診断できた．さらに，LBC 残余検体から EGFR遺伝子変異がすみやかに検出されたことで，早期の gefitinib 治療につながり奏効した． 結論：LBC は迅速，簡便，低侵襲性，かつ細胞の保存にも優れることから，原発巣不明症例の診断にも組 織診に先駆けて積極的に活用されるべきと考えられた．