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Background Biliary atresia is a rare paediatric biliary obliteration disease with unknown aetiology, and is the most common indication for paediatric liver transplantation (LT). However, no consensus for predicting Kasai portoenterostomy (KP) outcomes using liver histological findings exists. Ki67 is a popular biomarker for measuring and monitoring cellular proliferation. Methods Ki67 (clone, MIB‐1) liver parenchyma expression was measured by immunohistochemical staining of samples from living donors and patients with biliary atresia to assess its value in predicting outcomes after KP. Results Of 35 children with biliary atresia, 13 were native liver survivors (NLS), 17 were non‐NLS, and five had primary LT. The median proportion of Ki67 immunostained areas in donors and patients with biliary atresia at KP was 0·06 and 0·99 per cent respectively. Univariable analysis identified a high proportion of Ki67 areas, high Ki67 cell numbers and high Ki67‐positive/leucocyte common antigen‐positive cell numbers at KP as significant predictors of poor native liver survival after KP (hazard ratio 9·29, 3·37 and 12·17 respectively). The proportion of Ki67 areas in the non‐NLS group was significantly higher than that in the NLS group (1·29 versus 0·72 per cent respectively; P = 0·001), and then decreased at LT (0·32 per cent versus 1·29 per cent at KP; P

We used polymethylmethacrylate (PMMA) particles to investigate the relationship between particle properties and biological responses of macrophages. In a previous study, we reported that biological response of these immune cells was activated by a specific PMMA particle size. In this study, biological responses of macrophages to particle parameters other than and in conjunction with size were evaluated. However, particle size as a biologically active factor of the biological response has not been characterized in detail. Here, macrophage viability and proinflammatory cytokine production were investigated to elucidate the relationship between particle size, added volume, and added surface area, and the biological response of macrophages. Decrease of cell viability was observed when relatively large particles were tested (5.6–19.3 μm). Production of proinflammatory cytokines was elicited by 5.6- and 9.6-μm particles. Cell death occurred when the added volume exceeded 1×105 μm3 per cell. Proinflammatory cytokines were produced upon stimulation with added volume between 1×105 and 4.5×105 μm3 per cell. Cell death was elicited when the added surface area per cell exceeded 1×105 μm2 and proinflammatory cytokines were produced with the added surface area per cell between 1×105 and 3×105 μm2. These results suggested that biologically active factors exert their effect through added volume and added surface area rather than through particle size. This work will contribute to biological responses after total joint replacement since particles generated in the joint as a result of load bearing lead to tissue reaction and joint loosening.

Ultra-high molecular weight polyethylene (UHMWPE) wear particles from artificial joints induce osteolysis and the subsequent loosening of implants. Studies have reported that particles in the size range of 0.1–10 μm are the most biologically active in macrophage immune response. To develop prosthetic joints with greater longevity and durability, it is crucial to understand the deleterious effects of wear particles. In this study, to evaluate the effects of particle size on the activities of human monocyte-derived macrophages (HMDMs), seven differently sized particles of polymethylmethacrylate (PMMA), in the range of 0.1–20 μm, were prepared. Viability and the secretion of cytokines were evaluated after phagocytosis of each size particles by HMDMs. Differences in the viability of HMDMs after phagocytosis of particles sized 0.16–9.6 μm were statistically significant. Proinflammatory cytokine production of both tumor necrosis factor-α and interleukin-6 by HMDMs was strongly induced by 0.8 μm PMMA particles. Consistent with the fact that macrophages are known to respond to pathogens measuring approximately 1.0 μm in size, in this study, PMMA particles measuring 0.8 μm in size induced an immune response. This work provides fundamental data for the designing of surface profiles of prosthetic joints, Which may expect the lower incidence of immune response.

Glioblastoma (GBM) is the central nervous system tumor with the most aggressive behavior, and no definitive therapy has yet been found. The tumor microenvironment of GBM is immunosuppressive and is considered a 'cold tumor' with low lymphocytic infiltration, but is characterized by a high proportion of glioma-associated macrophages/microglia (GAMs). GAMs promote tumor growth and also affect treatment resistance in GBM. In this review, we describe the origin and classification of GAMs in humans and describe the mechanisms of their activation and the cell-cell interactions between tumor cells and GAMs. We also describe the history of GAM detection methods, especially immunohistochemistry, and discusses the merits and limitations of these techniques. In addition, we summarized chemotactic factors for GAMs and the therapies targeting these factors. Recent single-cell RNA analysis and spatial analysis add new insights to our previous knowledge of GAMs. Based on these studies, GBM therapies targeting GAMs are expected to be further developed.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non-Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by Spi1, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non-germinal center B-cell-like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional Spi1 knockout mice using Cγ1-Cre mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B-cell lymphomas. In contrast, no wild-type mice developed B-cell lymphoma. In addition, RNA-seq analysis of lymphoma cells from Cγ1-Cre Spi1 F/F mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral-transduced Spi1 rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B-cell lymphoma development., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Immune checkpoint inhibitors are effective in treating microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). Pathological complete response to immune checkpoint inhibitors for MSI-H metastatic CRC have been described in several reports. Liver metastasis is known to predict resistance to ani-programmed death 1 (PD-1)/PD-1 ligand 1 (PD-L1) therapy in several cancers, including CRC., Case Report: Herein, we report the case of a 23-year-old man with MSI-H colorectal liver metastasis who exhibited a pathological complete response to pembrolizumab following systemic chemotherapies. Pathological examination of the primary lesion revealed strong HLA-class I and HLA-DR expression in cancer cells. Elevated PD-L1 expression was observed in areas of increased CD8-postive T cell infiltration. Additional pathological study of regional lymph nodes showed increased PD-L1 and CD169 expression., Conclusion: A detailed pathological examination revealed PD-L1 expression not only in the primary CRC lesion but also in regional lymph nodes. Recent studies have highlighted the significance of regional lymph nodes in anti-cancer immune responses. Therefore, pathological studies using resected lymph nodes might be beneficial for predicting the response of anti-PD-1/PD-L1 therapy., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Fusobacterium nucleatum inhabits the oral cavity and affects the progression of gastrointestinal cancer. Our prior findings link F. nucleatum to poor prognosis in oesophageal squamous cell carcinoma via NF-κB pathway. However, its role in oesophagogastric junction and gastric adenocarcinoma remains unexplored. We investigated whether F. nucleatum influences these cancers, highlighting its potential impact., Methods: Two cohorts of EGJ and gastric adenocarcinoma patients (438 from Japan, 380 from the USA) were studied. F. nucleatum presence was confirmed by qPCR, FISH, and staining. Patient overall survival (OS) was assessed based on F. nucleatum positivity. EGJ and gastric adenocarcinoma cell lines were exposed to F. nucleatum to study molecular and phenotypic effects, validated in xenograft mouse model., Results: In both cohorts, F. nucleatum-positive EGJ or gastric adenocarcinoma patients had notably shorter OS. F. nucleatum positivity decreased in more acidic tumour environments. Cancer cell lines with F. nucleatum showed enhanced proliferation and NF-κB activation. The xenograft model indicated increased tumour growth and NF-κB activation in F. nucleatum-treated cells. Interestingly, co-occurrence of F. nucleatum and Helicobacter pylori, a known risk factor, was rare., Conclusions: F. nucleatum can induce the NF-κB pathway in EGJ and gastric adenocarcinomas, leading to tumour progression and poor prognosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The tumor suppressor TP53 gene, the most frequently mutated gene in human cancers, produces the product tumor protein p53, which plays an essential role in DNA damage. p53 protein mutations may contribute to tumorigenesis by loss of tumor suppressive functions and malignancy of cancer cells via gain-of-oncogenic functions. We previously reported that mutant p53 proteins form aggregates and that cytoplasmic p53 aggregates were associated with poor prognosis in human ovarian cancer. However, the prognostic impact of p53 aggregation in other tumors including lung squamous cell carcinoma (SCC) is poorly understood. Here, we demonstrated that lung SCC cases with cytoplasmic p53 aggregates had a significantly poor clinical prognosis. Analysis via patient-derived tumor organoids (PDOs) established from lung SCC patients and possessing cytoplasmic p53 aggregates showed that eliminating cytoplasmic p53 aggregates suppressed cell proliferation. RNA sequencing and transcriptome analysis of p53 aggregate-harboring PDOs indicated multiple candidate pathways involved in p53 aggregate oncogenic functions. With lung SCC-derived cell lines, we found that cytoplasmic p53 aggregates contributed to cisplatin resistance. This study thus shows that p53 aggregates are a predictor of poor prognosis in lung SCC and suggests that detecting p53 aggregates via p53 conventional immunohistochemical analysis may aid patient selection for platinum-based therapy., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

CD74 is a transmembrane protein that functions as a specialized chaperone of HLA class II and CD74 in tumor cells was suggested to be involved in cell proliferation in several kinds of malignant tumors. CD74 is also known to be expressed in macrophages, therefore, we investigated the CD74 expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemistry of CD74 indicated that CD74 was expressed not only in cancer cells but also macrophages. CD74 was detected in surface membrane and cytoplasm of cancer cells in 92 of 94 cases (98%) and of 87 of 94 cases (93%). CD74 was expressed both in cancer cells and TAMs in 86 of 94 cases (91%). In vitro studies using cancer cell lines and monocyte-derived macrophages stimulated by anti-CD74 antibodies showed that CD74 signal accelerated cancer cell proliferation and macrophage activation. However, macrophage activation via CD74 signal did not influence macrophage-mediated cancer cell growth. RNA-sequence of macrophages stimulated by anti-CD74 antibodies indicated that CD74 signal was associated to inflammatory responses in macrophages. In conclusion, we examined the expression and functional significance of CD74 in ccRCC using tissue specimens and cell culture studies. The function of CD74 was suggested to be different in cancer cells and in macrophages, and further studies are necessary to clarify the functional significance of CD74 in ccRCC., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1-methylguanosine modification at position nine of various cytoplasmic tRNAs. Pathogenic mutations in TRMT10A cause intellectual disability, microcephaly, diabetes, and short stature in humans, and generate cytotoxic tRNA fragments in cultured cells; however, it is not clear how TRMT10A supports codon translation or brain functions. Here, we generated Trmt10a null mice and showed that tRNAGln(CUG) and initiator methionine tRNA levels were universally decreased in various tissues; the same was true in a human cell line lacking TRMT10A. Ribosome profiling of mouse brain revealed that dysfunction of TRMT10A causes ribosome slowdown at the Gln(CAG) codon and increases translation of Atf4 due to higher frequency of leaky scanning of its upstream open reading frames. Broadly speaking, translation of a subset of mRNAs, especially those for neuronal structures, is perturbed in the mutant brain. Despite not showing discernable defects in the pancreas, liver, or kidney, Trmt10a null mice showed lower body weight and smaller hippocampal postsynaptic densities, which is associated with defective synaptic plasticity and memory. Taken together, our study provides mechanistic insight into the roles of TRMT10A in the brain, and exemplifies the importance of universal tRNA modification during translation of specific codons., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages.

The tumor microenvironment of hepatoblastoma (HB), the most common pediatric liver tumor, predominantly exhibits a myeloid immune landscape. in which tumor-associated macrophages (TAMs) are considered the core component. The crosstalk between TAMs and HB cells markedly influences tumor behavior. TAM-derived factors are involved in tumor proliferation and vascular invasion. On the other hand, HB cell secretome attracts, stimulates, and reprograms TAMs to be immunosuppressive in favor of tumor invasion, rather than their innate role in combating tumor growth, such crosstalk sometimes forms bidirectional feedback loops, making the tumor more virulent and resistant to routine therapeutics. Consequently, TAMs are the common denominator of most suggested HB immunotherapeutic strategies. Macrophage immune checkpoint inhibitors, macrophage-mediated antibody-dependent cellular phagocytosis, and the novel chimeric antigen receptor macrophage therapy (CAR Mφ) are currently under trial. In this review, we will summarize the significance of TAMs and their potential role as a therapeutic target in HB., (© 2024 The Societies and John Wiley & Sons Australia, Ltd.)

Bone fractures represent a common health problem, particularly in an increasingly aging population. Bioresorbable magnesium (Mg) alloy-based implants offer promising alternatives to traditional metallic implants for the treatment of bone fractures because they eliminate the need for implant removal after healing. The Mg-Y-rare-earth (RE)-Zr alloy WE43, designed for orthopedic implants, has received European Conformity mark approval. However, currently, WE43 is not clinically used in certain countries possibly because of concerns related to RE metals. In this study, we investigated the use of a RE-free alloy, namely, Mg-Zn-Zr alloy (ZK30), as an implant for bone fractures. Hydrofluoric acid (HF) treatment was performed to improve the corrosion resistance of ZK30. HF-treated ZK30 (HF-ZK30) exhibited lower corrosion rate and higher biocompatibility than those of WE43 in in vitro experiments. After implanting a rod of HF-ZK30 into the fractured femoral bones of mice, HF-ZK30 held the bones and healed the fracture without deformation. Treatment results of HF-ZK30 were comparable to those of WE43, indicating the potential of HF-ZK30 as a bioresorbable and safe implant for bone repair., (© 2024 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

There are numerous macrophages and dendritic cells in lymph nodes (LNs). Recent studies have highlighted that sinus macrophages (SMs) in LNs possess antigen-presenting capabilities and are related to anti-cancer immune responses. In this study, we assessed the distribution of SMs in mesenteric LNs removed during surgery for colorectal cancer. A marked reduction of SMs was noted in elderly patients, particularly those over 80 years old. We observed a disappearance of CD169-positive cells in LNs where SMs were reduced. In silico analysis of publicly available single-cell RNA sequencing data from LNs revealed that CD169-positive macrophages express numerous genes associated with antigen presentation and lymphocyte proliferation, similar to dendritic cells' functions. In conclusion, our study demonstrates that SMs, potentially crucial for immune activation, diminish in the LNs of elderly patients. This reduction of SMs may contribute to the immune dysfunction observed in the elderly.

Interleukin 32 (IL-32) is a proinflammatory cytokine secreted from several kinds of cancer cells. In the present study, we investigated the significance of IL-32 in lung adenocarcinoma by immunohistochemistry and bioinformatics analysis. IL-32 was positive in cancer cells of 21 cases (9.2%) of total 228 cases. Increased IL-32 gene expression was linked to worse clinical course in TCGA analysis, however, IL-32 expression in immunohistochemistry was not associated to clinical course in our cohort. It was also found that high IL-32 expression was seen in cases with increased lymphocyte infiltration. In vitro studies indicated that IFN-γ induced gene expression of IL-32 and PD1-ligands in lung adenocarcinoma cell lines. IL-32, especially IL-32β, also induced overexpression of PD1-ligands in human monocyte-derived macrophages. Additionally, Cancer-cell-derived IL-32 was elevated by stimulation with anticancer agents. In conclusion, IL-32 potentially induced by inflammatory conditions and anticancer therapy and contribute to immune escape of cancer cells via development the immunosuppressive microenvironment. IL-32 might be a target molecule for anti-cancer therapy., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Background: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade., Methods: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated., Results: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control., Conclusions: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Follow-up is recommended for an asymptomatic unilocular hepatic cystic lesion without wall-thickness and nodular components. A few liver cystic lesions represent biliary cystic neoplasms, which are difficult to differentiate from simple cysts with benign mural nodules on imaging alone., Case Presentation: An 84-year-old woman with a history of simple liver cyst diagnosed one year prior was admitted for evaluation of a developed mural nodule in the cystic lesion. She had no specific symptoms and no abnormalities in blood tests except for carcinoembryonic antigen (5.0 ng/mL) and carbohydrate antigen (43.5 U/mL) levels. Contrast-enhanced computed tomography revealed a well-defined, low-attenuation lesion without a septum that had enlarged from 41 to 47 mm. No dilation of the bile duct was observed. A gradually enhancing mural nodule, 14 mm in diameter, was confirmed. MRI revealed a uniform water-intense cystic lesion with a mural nodule. This was followed by T2-enhanced imaging showing peripheral hypointensity and central hyperintensity. Enhanced ultrasonography revealed an enhanced nodule with a distinct artery within it. A needle biopsy of the wall nodule or aspiration of intracystic fluid was not performed to avoid tumor cell spillage. The possibility of a neoplastic cystic tumor could not be ruled out, so a partial hepatectomy was performed with adequate margins. Pathologically, the cystic lesion contained a black 5 mm nodule consisting of a thin, whitish fibrous wall and dilated vessels lined by CD31 and CD34 positive endothelial cells. The final diagnosis was a rare cavernous hemangioma within a simple liver cyst., Conclusions: Cavernous hemangiomas mimicking well-enhanced mural nodules can arise from simple liver cysts. In less malignant cases, laparoscopic biopsy or percutaneous targeted biopsy of the mural nodules, together with needle ablation, may be recommended to avoid unnecessary surgery., (© 2024. The Author(s).)

Background/aim: The long-term use of proton pump inhibitors (PPIs) has been reported to be strongly associated with the development of fundic gland polyps (FGPs). Conversely, a few cases of gastric hyperplastic polyps (GHPs) associated with PPI use have been reported. We experienced a case of PPI-associated multiple GHPs with uncontrollable bleeding., Case Report: A 64 year old man with a history of rheumatoid arthritis presented to the hospital with complaints of vertigo and black stools. Blood tests revealed anemia and hypoproteinemia. Esophagogastroduodenoscopy (EGD) showed blood and black residue accumulated in the stomach. The source of the bleeding was multiple hyperplastic polyps. Bleeding could be stopped even with fasting, and total blood transfusions amounted to 28 units of RBCs were required in 18 days. After the cessation of PPI, EGD showed that the polyps had almost disappeared. Pathological diagnosis of resected polyp was hyperplastic polyp, which was characterized by capillary hyperplasia and edema. Gastrin receptors were over-expressed in the foveolar epithelium and not in the capillaries. Methotrexate (MTX)-induced portal hypertensive gastroenteropathy was revealed during follow-up. We consider that the effect of portal hypertension may have caused the capillary hyperplasia., Conclusion: Although PPI-related polyps are usually fundic gland polyps and do not cause life-threatening adverse events, we experienced PPI-related GHPs in which hemostasis was difficult to control., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Hypoxia is a common feature of solid tumors. However, the impact of hypoxia on immune cells within tumor environments remains underexplored. Carbonic anhydrase 9 (CA9) is a hypoxia-responsive tumor-associated enzyme. We previously noted that regardless of human CA9 (hCA9) expression, hCA9-expressing mouse renal cell carcinoma RENCA (RENCA/hCA9) presented as a "cold" tumor in syngeneic aged mice. This study delves into the mechanisms behind this observation. Gene microarray analyses showed that RENCA/hCA9 cells exhibited elevated mouse serpinB9, an inhibitor of granzyme B, relative to RENCA cells. Corroborating this, RENCA/hCA9 cells displayed heightened resistance to antigen-specific cytotoxic T cells compared with RENCA cells. Notably, siRNA-mediated serpinB9 knockdown reclaimed this sensitivity. In vivo tests showed that serpinB9 inhibitor administration slowed RENCA tumor growth, but this effect was reduced in RENCA/hCA9 tumors, even with adjunctive immune checkpoint blockade therapy. Further, inducing hypoxia or introducing the mouse CA9 gene upregulated serpinB9 expression, and siRNA-mediated knockdown of the mouse CA9 gene inhibited the hypoxia-induced induction of serpinB9 in the original RENCA cells. Supernatants from RENCA/hCA9 cultures had lower pH than those from RENCA, suggesting acidosis. This acidity enhanced serpinB9 expression and T cell apoptosis. Moreover, coculturing with RENCA/hCA9 cells more actively prompted T cell apoptosis than with RENCA cells. Collectively, these findings suggest hypoxia-associated CA9 not only boosts serpinB9 in cancer cells but also synergistically intensifies T cell apoptosis via acidosis, characterizing RENCA/hCA9 tumors as "cold.", (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Given that gastric small cell neuroendocrine carcinoma (SCNEC) is notably more aggressive than conventional adenocarcinoma, and a platinum-based regimen aligned with the treatment for pulmonary SCNEC is advocated when chemotherapy is needed, ensuring an accurate pathological diagnosis is paramount., Case Report: A 63-year-old man, examined for melena, underwent gastroscopy which revealed a total circumferential Borrmann type 3 lesion extending from the pylorus to the antrum of the stomach. He underwent a distal gastrectomy with D2 lymphadenectomy. The microscopic examination revealed SCNEC with a minor adenocarcinoma component. Immunohistochemically, the SCNEC was diffusely positive for synaptophysin, CD56, and INSM1, very focally positive for chromogranin A, and negative for leukocyte common antigen, CD3, and CD20. A significant observation in this case was the complete negativity for epithelial markers including keratin (CK7, CK8, CK20, CAM5.2, and AE1/AE3) and epithelial membrane antigen., Conclusion: Diffuse positivity for neuroendocrine markers, negativity for other lineage markers, and a transition from the adenocarcinoma component, if present, serve as significant diagnostic clues for gastric SCNEC with loss of epithelial markers expression. SCNEC should not be excluded solely based on the negative result for epithelial markers., Competing Interests: All Authors have no conflicts of interest to declare in relation to this study., (Copyright 2024, International Institute of Anticancer Research.)

Background: Immunohistochemistry for p53 was a well-established method for cancer diagnosis in pathology. Aberrant cytoplasmic p53 positivity reflects the accumulation of p53 aggregates, which has been shown to be associated with chemoresistance and to be a predictive marker of a worse clinical course in ovarian cancer., Case Report: A 65-year-old Japanese man was diagnosed with lung cancer, and surgical resection was performed. Multiple metastasis were found 21 months post-surgery. The lesions were resistant to chemotherapy, and he succumbed to the disease 29 months post-surgery. The resected primary lesion was pathologically diagnosed as squamous cell carcinoma, with notable cytoplasmic p53 positivity indicated by immunohistochemistry., Conclusion: Notable aberrant cytoplasmic accumulation of p53 aggregate was observed in the cancer cells of this case. Chemotherapy was ineffective for the recurrent lesions, suggesting a role of p53 aggregates in chemoresistance. Pathological analysis of p53 via immunohistochemistry may be useful in predicting chemoresistance of lung squamous cell carcinoma., Competing Interests: All Authors have no conflicts of interest to declare in relation to this study., (Copyright 2024, International Institute of Anticancer Research.)

Serpinb9 is an inhibitor of granzyme B and is potentially involved in the immune escape of tumor cells. In the present study, bioinformatics analysis using open databases suggested that SerpinB9 is overexpressed in testicular embryonal carcinoma. Immunohistological analysis was performed on 28 cases of testicular germ cell tumors to investigate the relationship between SerpinB9 expression in testicular germ cell tumors and the tumor immune environment. SerpinB9 was significantly upregulated in the non-seminoma group and inversely correlated with the number of tumor-infiltrating CD8-positive cells. In addition, yolk sac tumors were characterized by the loss of human leukocyte antigen-class I expression. These findings suggest that SerpinB9 contributes to the immune escape of testicular germ cell tumors. Targeting therapy for SerpinB9 might therefore be useful in immunotherapy for testicular germ cell tumors resistant to immune checkpoint inhibitors., (© 2023. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Purpose: In this research, we analyzed the expression of serpinB9 in hepatoblastoma and investigated the factors which enhance its expression., Method: SerpinB9 expression in hepatoblastoma cell lines and macrophages co-cultured with each other or stimulated by anticancer agents was examined using RT-qPCR and western blotting. Immunohistochemistry for SerpinB9 in hepatoblastoma specimens was performed. Single-cell RNA-sequence data for hepatoblastoma from an online database were analyzed to investigate which types of cells express SerpinB9., Result: HepG2, a hepatoblastoma cell line, exhibited increased expression of SerpinB9 when indirectly co-cultured with macrophages. Immunohistochemistry for the specimens demonstrated that serpinB9 is positive not in hepatoblastoma cells but in macrophages. Single-cell RNA sequence analysis in tissues from hepatoblastoma patients showed that macrophages expressed SerpinB9 more than tumor cells did. Co-culture of macrophages with hepatoblastoma cell lines led to the enhanced expression of SerpinB9 in both macrophages and cell lines. Anticancer agents induced an elevation of SerpinB9 in hepatoblastomas cell lines., Conclusion: In hepatoblastoma, SerpinB9 is thought to be more highly expressed in macrophages and enhanced by interaction with hepatoblastoma cell., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A 56-year-old man referred to our hospital for cecum cancer. Enhanced computed tomography (CT) found swollen reginal lymph nodes and liver metastasis. Magnetic Resonance Imaging (MRI) revealed a solitary lesion on liver (S2). We performed a laparoscopic ileocolic resection and liver partial resection. Tumor pathology showed that these tumors were moderate-differentiated adenocarcinoma (pT3N2bM1 Stage IVA). Genetic examination revealed MSI-high, KRAS wild type, and BRAF wild type. After surgery, two liver metastases were found in S4 and S7 as new lesion in EOB-MRI. We started chemotherapy with the FOLFOFIRI plus bevacizumab regimen, but two liver metastases were enlarged after six cycles of chemotherapy. As a second-line treatment, nivolumab and ipilimumab combination therapy was started. After three cycles of these therapy, both of these tumors shrinkage were observed. We performed laparoscopic liver resection. In specimens, there were no malignant cells. Pathological study revealed that in the initial surgery specimen, PD-L1 protein was detected in both primary and metastatic lesions, and HLA-DR, CK5/6 in liver. No recurrence was observed at 6 months after the surgery. In conclusion, we reported the case of anticancer drug-resistant MSI-high colon cancer liver metastasis was resected after treatment with immune-checkpoint inhibitors and a pathological complete response was found., (© 2023. Japanese Society of Gastroenterology.)

The prognosis of osteosarcoma (OS) has remained stagnant over the past two decades, requiring the exploration of new therapeutic targets. Cytokines, arising from tumor-associated macrophages (TAMs), a major component of the tumor microenvironment (TME), have garnered attention owing to their impact on tumor growth, invasion, metastasis, and resistance to chemotherapy. Nonetheless, the precise functional role of TAMs in OS progression requires further investigation. In this study, we investigated the interaction between OS and TAMs, as well as the contribution of TAM-produced cytokines to OS advancement. TAMs were observed to be more prevalent in lung metastases compared with that in primary tumors, suggesting their potential support for OS progression. To simulate the TME, OS and TAMs were co-cultured, and the cytokines resulting from this co-culture could stimulate OS proliferation, migration, and invasion. A detailed investigation of cytokines in the co-culture conditioned medium (CM) revealed a substantial increase in IL-8, establishing it as a pivotal cytokine in the process of enhancing OS proliferation, migration, and invasion through the focal adhesion kinase (FAK) pathway. In an in vivo model, co-culture CM promoted OS proliferation and lung metastasis, effects that were mitigated by anti-IL-8 antibodies. Collectively, IL-8, generated within the TME formed by OS and TAMs, accelerates OS proliferation and metastasis via the FAK pathway, thereby positioning IL-8 as a potential novel therapeutic target in OS., (© 2024. The Author(s).)

Histiocytic neoplasms (HNs) include juvenile xanthogranuloma, Erdheim-Chester disease, Rosai-Dorfman disease, ALK-positive histiocytosis, and histiocytic sarcoma in the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours. These entities are clinicopathologically distinctive, and typical histological findings have been established. However, the common feature of a proliferation of histiocytic cells often leads to morphological overlap among HNs, and also necessitates a differential diagnosis from several non-HNs or non-neoplastic conditions. In this review, we provide a brief summary of the clinical findings, molecular features, histopathologies, and immunophenotypes of HNs, as well as to discuss their differential diagnosis.

Lymph nodes are secondary lymphoid organs localized throughout the body that typically appear as bean-like nodules. Numerous antigen-presenting cells, including dendritic cells and macrophages, that mediate host defense responses against pathogens, such as bacteria and viruses, reside within lymph nodes. To react to cancer cell-derived antigens in a variety of cancers, antigen-presenting cells induce cytotoxic T lymphocytes (CTLs). In relation to anticancer immune responses, macrophages in the lymph node sinus have been of particular interest because a number of studies involving both human specimens and animal models have reported that lymph node macrophages expressing CD169 play a key role in activating anticancer CTLs. Recent studies have indicated that dysfunction of lymph node macrophages potentially contributes to immune suppression in elderly patients and immunological "cold" tumors. Therefore, in anticancer therapy, the regulation of lymph node macrophages is a potentially promising approach.

Background/aim: CXCL10, a member of the CXC chemokine family, plays a crucial role in immune response by facilitating the chemotaxis of CXCR3-positive immune cells. We examined the expression of CXCL10 to unravel its functional significance in colorectal cancer., Materials and Methods: Bioinformatics analysis was performed to investigate CXCL10 expression and its clinicopathological relevance. Subsequently, we examined the correlation between the serum levels of CXCL10 and its expression within cancer tissues., Results: Analysis of the TCGA database revealed that elevated CXCL10 expression in CRC tissues correlates with improved long-term survival and is inversely associated with lymph node infiltration and metastasis. Insights from Gene Ontology and Kyoto Encyclopedia of Genes and Genomes further established a connection between increased CXCL10 and co-regulated gene expression with enhanced immune activation and regulation, mediated by the inhibition of the NOD-like receptor signaling pathway. Single-cell analysis pinpointed myeloid cells and macrophages as the primary sources of CXCL10. Immunohistochemical assessments revealed that a subset of cancer cells and macrophages are positive for CXCL10 expression. CXCL10-positive cells are predominantly located at the invasive front of the tumor. Intriguingly, our findings reveal an inverse correlation between serum CXCL10 levels and its expression in cancer tissues., Conclusion: The expression of CXCL10 may play a role in mediating the inflammatory responses at the invasive front in colorectal cancer and is observed to be inversely correlated with serum CXCL10 levels. It is pivotal to elucidate the distinct roles of CXCL10 in colorectal cancer, particularly different functions of cancer-tissue CXCL10 from serum CXCL10., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Sinus macrophages in draining lymph nodes (DLNs) are involved in anti-tumor immune reactions. CD169 (Sialoadhesin, Siglec-1) is expressed on sinus macrophages and is considered a surrogate marker for the immunostimulatory phenotype of macrophages. In this study, the significance of sinus macrophages in immunotherapy was evaluated using mouse models. Treatment with anti-programmed death-ligand 1 (PD-L1) antibody suppressed the subcutaneous tumor growth of MC38 and E0771 cells but was not effective against MB49 and LLC tumors. Decreased cytotoxic T-lymphocyte (CTL) infiltration in tumor tissues and CD169 expression in sinus macrophages were observed in MB49 and LLC cells compared to corresponding parameters in MC38 and E0771 cells. The anti-tumor effects of the anti-PD-L1 antibody on MC38 and E0771 cells were abolished when sinus macrophages in DLNs were depleted, suggesting that sinus macrophages are involved in the therapeutic effect of the anti-PD-L1 antibody. Naringin activated sinus macrophages. Naringin inhibited tumor growth in MB49- and LLC-bearing mice but did not affect that in MC38- and E0771-bearing mice. The infiltration of CTLs in tumor tissues and their activation were increased by naringin, and this effect was impaired when sinus macrophages were depleted. Combination therapy with naringin and anti-PD-L1 antibody suppressed MB49 tumor growth. In conclusion, CD169-positive sinus macrophages in DLNs are critical for anti-tumor immune responses, and naringin suppresses tumor growth by activating CD169-positive sinus macrophages and anti-tumor CTL responses. The activation status of sinus macrophages has been suggested to differ among tumor models, and this should be investigated in future studies., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Immunotherapies that target programmed cell death protein 1 (PD-1) signals are standard therapies for advanced-stage lung cancer, and the expression of programmed death-ligand 1 (PD-L1) in cancer tissue predicts immunotherapy efficacy. Although programmed death-ligand 2 (PD-L2) is expressed in cancer cells and macrophages, similar to PD-L1, its significance in lung cancer is unclear. Double immunohistochemistry analyses using anti-PD-L2 and anti-PU.1 antibodies were carried out on tissue array sections from 231 cases of lung adenocarcinoma, and PD-L2 expression in macrophages was evaluated. High PD-L2 expression in macrophages was associated with longer progression-free survival (PFS) and cancer-specific survival (CSS) and observed more often in females, non-heavy smokers, and patients with epidermal growth factor receptor (EGFR) mutations and those at a lower disease stage. Significant correlations were found more frequently in patients with EGFR mutations. Cell culture studies revealed that cancer cell-derived soluble factors induced PD-L2 overexpression in macrophages, suggesting the involvement of the JAK-STAT signaling pathway. The present findings suggest that PD-L2 expression in macrophages predicts PFS and CSS in lung adenocarcinoma without immunotherapy., (© 2023. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

The role of sinus macrophages (SMs) in anticancer immune responses has received considerable interest in recent years, but the types of molecules that are expressed in human SMs have not yet been clarified in detail. We therefore sought to identify dendritic cell (DC)- or macrophage-related molecules in SMs in human lymph nodes (LNs). SMs are strongly positive for Iba-1, CD163, CD169, and CD209. CD169 (clone SP216) reacted with almost all SMs, mainly in the cell surface membrane, while CD169 (clone HSn 7D2) reacted with a subpopulation of SMs, mainly in the cytoplasm, with a significant increase observed after IFN-α stimulation. The immunoreactivity of clone HSn 7D2 was markedly reduced after transfection with small interfering RNA against CD169, while that of clone SP216 was slightly reduced. The induction of CCL8 and CXCL10 messenger RNA (mRNA) expression by IFN-α was confirmed using cultured macrophages and RT-qPCR, but fluorescence in situ hybridization did not detect CCL8 and CXCL10 mRNA expression in SMs. Single-cell RNA sequence data of LNs indicated that the highest level of CXCL10 gene expression occurred in monocytes. In conclusion, we found that CD209, also known as DC-related molecule, was expressed in human SMs. The heterogeneity observed in CD169 reacted with cone HSn 7D2 and SP216 was potentially due to the modification of CD169 protein by IFN stimulation. Further, no expression of CXCL10 mRNA in SMs suggested that SMs might be resident macrophages., (© 2023 The Societies and John Wiley & Sons Australia, Ltd.)

Although pregnant women's fish consumption is beneficial for the brain development of the fetus due to the DHA in fish, seafood also contains methylmercury (MeHg), which adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women's sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier study revealed that DHA and its metabolite 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) produced by cytochrome P450s (P450s) and soluble epoxide hydrolase (sEH) can suppress MeHg-induced cytotoxicity in mouse primary neuronal cells. In the present study, DHA supplementation to pregnant mice suppressed MeHg-induced impairments of pups' body weight, grip strength, motor function, and short-term memory. DHA supplementation also suppressed MeHg-induced oxidative stress and the decrease in the number of subplate neurons in the cerebral cortex of the pups. DHA supplementation to dams significantly increased the DHA metabolites 19,20-epoxydocosapentaenoic acid (19,20-EDP) and 19,20-DHDP as well as DHA itself in the fetal and infant brains, although the expression levels of P450s and sEH were low in the fetal brain and liver. DHA metabolites were detected in the mouse breast milk and in human umbilical cord blood, indicating the active transfer of DHA metabolites from dams to pups. These results demonstrate that DHA supplementation increased DHA and its metabolites in the mouse pup brain and alleviated the effects of MeHg on fetal brain development. Pregnant women's intake of fish containing high levels of DHA (or DHA supplementation) may help prevent MeHg-induced neurotoxicity in the fetus., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We previously demonstrated the relationship of human microbiome Fusobacterium nucleatum with unfavorable clinical outcomes and inferior chemotherapeutic responses in esophageal cancer. Global DNA methylation is associated with the occurrence and development of various cancers. In our previous study, LINE-1 hypomethylation (i.e., global DNA hypomethylation) was associated with a poor prognosis in esophageal cancer. As the gut microbiota may play crucial roles in the DNA methylation of host cells, we hypothesized that F. nucleatum might influence LINE-1 methylation levels in esophageal cancer., Methods: We qualified the F. nucleatum DNA using a quantitative PCR assay and LINE-1 methylation via a pyrosequencing assay using formalin-fixed paraffin-embedded specimens from 306 esophageal cancer patients., Results: Intratumoral F. nucleatum DNA was detected in 65 cases (21.2%). The LINE-1 methylation scores ranged from 26.9 to 91.8 (median = 64.8) in tumors. F. nucleatum DNA was related to the LINE-1 hypomethylation of tumor lesions in esophageal cancer (P < 0.0001). The receiver operating characteristic curve analysis showed that the area under the curve was 0.71 for F. nucleatum positivity. Finally, we found that the impact of F. nucleatum on clinical outcomes was not modified by LINE-1 hypomethylation (P for interaction = 0.34)., Conclusions: F. nucleatum alters genome-wide methylation levels in cancer cells, which may be one of the mechanisms by which F. nucleatum affects the malignant behavior of esophageal cancer., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Immune checkpoint inhibitors (ICIs) are attracting increasing attention as a novel and potentially curative therapy for microsatellite instability-high (MSI-H) colorectal cancer (CRC)., Case Report: An 80-year-old female visited our hospital with complaints of lower abdominal pain due to bowel obstruction caused by descending colon cancer. After 1 month of metallic stent detention, she underwent radical surgery, although laparotomy showed broad peritoneal dissemination. Based on the genetic finding of MSI-H status, pembrolizumab therapy was administered in two cycles. Unfortunately, the therapy was ineffective, and the patient died after being discharged 5 months after surgery., Conclusion: The findings in this case of MSI-H CRC with a poor response to an ICI suggest the importance of confirming HLA status, including beta-2-microglobulin and HLA expression, before starting ICI therapy in cases of MSI-H CRC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: This study investigated the expression of interleukin 32 (IL-32) in hepatoblastoma, the most common primary pediatric liver tumor, and its possible roles in tumorigenesis., Methods: IL-32 expression was investigated in two hepatoblastoma cell lines (Hep G2 and HuH 6) in the steady state and after co-culture with macrophages by RNA-seq analysis and RT-qPCR, and after stimulation with chemotherapy. Cultured macrophages were stimulated by IL-32 isoforms followed by RT-qPCR and western blot analysis. IL-32 immunohistochemical staining (IHC) was performed using specimens from 21 hepatoblastoma patients. Clustering analysis was also performed using scRNA-seq data downloaded from Gene Expression Omnibus., Results: The IL-32 gene is expressed by hepatoblastoma cell lines; expression is upregulated by paracrine cell-cell communication with macrophages, also by carboplatin and etoposide. IL-32 causes protumor activation of macrophages with upregulation of PD-L1, IDO-1, IL-6, and IL-10. In the patient pool, IHC was positive only in 48% of cases. However, in the downloaded dataset, IL-32 gene expression was negative., Conclusion: IL-32 was detected in hepatoblastoma cell lines, but not in all hepatoblastoma patients. We hypothesized that stimulation such as chemotherapy might induce expression of IL-32, which might be a critical mediator of chemoresistance in hepatoblastoma through inducing protumor activation in macrophages., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cholangiocarcinoma (CCA) is an aggressive malignant tumor of bile duct epithelia. Recent evidence suggests the impact of cancer stem cells (CSC) on the therapeutic resistance of CCA; however, the knowledge of CSC in CCA is limited due to the lack of a CSC model. In this study, we successfully established a stable sphere-forming CCA stem-like cell, KKU-055-CSC, from the original CCA cell line, KKU-055. The KKU-055-CSC exhibits CSC characteristics, including: (1) the ability to grow stably and withstand continuous passage for a long period of culture in the stem cell medium, (2) high expression of stem cell markers, (3) low responsiveness to standard chemotherapy drugs, (4) multilineage differentiation, and (5) faster and constant expansive tumor formation in xenograft mouse models. To identify the CCA-CSC-associated pathway, we have undertaken a global proteomics and functional cluster/network analysis. Proteomics identified the 5925 proteins in total, and the significantly upregulated proteins in CSC compared with FCS-induced differentiated CSC and its parental cells were extracted. Network analysis revealed that high mobility group A1 (HMGA1) and Aurora A signaling through the signal transducer and activator of transcription 3 pathways were enriched in KKU-055-CSC. Knockdown of HMGA1 in KKU-055-CSC suppressed the expression of stem cell markers, induced the differentiation followed by cell proliferation, and enhanced sensitivity to chemotherapy drugs including Aurora A inhibitors. In silico analysis indicated that the expression of HMGA1 was correlated with Aurora A expressions and poor survival of CCA patients. In conclusion, we have established a unique CCA stem-like cell model and identified the HMGA1-Aurora A signaling as an important pathway for CSC-CCA., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Carpal tunnel syndrome (CTS) is considered an early sign of cardiac amyloidosis (CA) because amyloid deposition is often confirmed in the tenosynovium removed during carpal tunnel release (CTR); however, the prevalence of concomitant CA is unclear., Methods and results: We prospectively examined 700 patients who underwent CTR and evaluated amyloid deposition after tenosynovium removal. Amyloid deposition was observed in 261 (37%) patients, who were significantly older and predominantly male (P<0.05). Of them, 120 agreed to cardiac screening. We performed 99 m Tc-labeled pyrophosphate ( 99 m Tc-PYP) scintigraphy in 12 patients who met either of the following criteria: (1) interventricular septal diameter (IVSd) ≥14 mm or (2) 12 mm ≤ IVSd < 14 mm with above-normal limits in high-sensitivity cardiac troponin T (hs-cTnT). Six patients (50%) had positive findings on 99 m Tc-PYP scintigraphy and were diagnosed with wild-type transthyretin CA. Concomitant CA was observed in 6/120 (5%) CTR patients with amyloid deposition and 50% (6/12) in patients with left ventricular hypertrophy (≥12 mm) with increased hs-cTnT levels., Conclusions: Amyloid deposition was frequently observed in the removed tenosynovium of elderly men with CTS. Cardiac screening may be useful for early diagnosis of CA in patients undergoing CTR with amyloid deposition.

Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare RCC subtype, and FH-deficient RCC may be misdiagnosed as another type of RCC, such as type 2 papillary RCC or collecting duct carcinoma. FH and 2-succinocysteine (2SC) are useful diagnostic markers for FH-deficient RCC and can be measured using immunohistochemistry (IHC)., Case Report: A 30-year-old female with 3-month history of fatigue and left-flank mass was diagnosed with a 20×13×10 cm left-side renal mass with massive inferior vena cava (IVC) tumor thrombus that extended into the right atrium. She underwent nephrectomy and IVC thrombectomy, and a pathological diagnosis of type 2 papillary RCC was made. Four months after the surgery, computed tomography scan showed multiple liver metastases not observed immediately after surgery. Systemic treatment with sorafenib was initiated; however, she did not respond and died 3 months after treatment. Subsequent re-review of hematoxylin and eosin-stained sections indicated morphologic characteristics consistent with FH-deficient RCC, and IHC staining was negative for FH but positive for 2SC, indicating a diagnosis of FH-deficient RCC. Further immunological analyses revealed the loss of HLA-class I, b2 microglobulin, and HLA-DR antigens in cancer cells. In addition, a few CD8-positive cytotoxic T cells and CD163-positive tumor-associated macrophages were noted., Conclusion: An immunosuppressive tumor microenvironment that facilitates cancer immune evasion might be associated with the rapid progression and poor prognosis in our patient. Further investigation of the tumor immune microenvironment in patients with FH-deficient RCC is warranted., Competing Interests: All Authors have no conflicts of interest to declare in relation to this study., (Copyright 2023, International Institute of Anticancer Research.)

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma., (© 2023. The Author(s).)

Immune checkpoint inhibitors (ICIs) have recently improved the prognosis of various cancers. By contrast, some immune-related adverse events (irAEs) caused by ICIs are fatal and have become problematic. The pathogenesis of irAEs remains unknown and must be elucidated to establish biomarkers. This study investigated plasma cytokine, chemokine, and anti-CD74 autoantibody levels in patients with renal cell carcinoma (RCC) and analyzed their association with irAEs. In a discovery cohort of 13 patients, plasma levels of chemokine (C-X-C motif) ligand (CXCL) 1, IL-17A, IL-1β, IL-6, IL-8, CXCL10, MCP-1, and TNFα were measured at baseline and post-dose 1. Only CXCL10, at post-dose 1 but not at baseline, was significantly associated with grade 2 or higher irAEs (P = 0.0413). Plasma CXCL10 levels were then measured at baseline and post-dose 1 in an extended cohort of 43 patients with RCC who received ICI-based treatment. Higher plasma CXCL10 levels both at baseline and post-dose1 were significantly associated with the occurrence of grade 2 or higher irAEs (P = 0.0246 and 0.0137, respectively). Plasma CXCL13 levels, which we measured in a previous study, were significantly higher in patients with grade 2 or higher irAEs at baseline but not at post-dose 1 (P = 0.0037 and 0.052, respectively). No significant association between plasma anti-CD74 autoantibody level and both irAE pneumonitis and any grade 2 or higher irAE was observed. In conclusion, plasma CXCL10 is significantly associated with the occurrence of irAEs in patients with RCC treated with ICIs. CXCL10 is a potential predictive and on-treatment biomarker for irAEs., (© 2023 The Societies and John Wiley & Sons Australia, Ltd.)

Tumor-associated macrophages (TAMs) are the most prominent immune cells in the breast cancer microenvironment, and the protumor functions of TAMs are thought to affect cancer progression and resistance to anticancer therapy. Numerous studies using human breast cancer samples, cell lines, and murine breast cancer models have revealed details of the mechanisms by which the protumor functions of TAMs are activated. Recent advances have highlighted the significant involvement of TAMs in the resistance of breast cancer cells to immunotherapy. Tumor-associated macrophages express a number of immunosuppressive genes, and single-cell sequence analyses of human and murine cancer samples have helped elucidate the mechanism of TAM-induced immunosuppression. As TAMs are considered suitable targets for anticancer therapies, we summarized the protumor functions of TAMs and the potential of anticancer therapies targeting TAMs, with a focus on breast cancer research., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Tumor-associated macrophage (TAM)-derived IL-6 is involved in small-cell lung cancer (SCLC) progression and chemoresistance via the activation of signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. This study aimed to identify natural compounds that suppress cell-cell interactions between TAMs and SCLC cells by inhibiting STAT3 activation. We used a library of natural compounds to identify candidate agents possessing anti-SCLC effects by inhibiting macrophage-induced tumor proliferation. SBC-3 and SBC-5, human SCLC cell lines, were used for in vitro experiments. Furthermore, we assessed the efficacy of these candidate agents in a murine xenograft model of human SCLC. Among the natural compounds examined, onionin A (ONA) inhibited IL-6-induced STAT3 activation and SCLC cell proliferation. ONA also reduced the secretion of IL-6 from macrophages and interfered with the direct effect of cell-cell interactions between macrophages and SCLC cells. Furthermore, ONA administration suppressed tumor progression in a tumor-bearing mouse model. ONA was identified as the most useful candidate for targeting cell-cell interactions between cancer cells and TAMs for anti-SCLC therapy., (© 2023. The Author(s).)

Aims: Mismatch-repair deficiency and microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC) is treated with programmed death (PD)-1 antibody regardless of PD-ligand (L)1 expression in tumor cells. We previously found that abundant CD169 + macrophages in regional lymph node (RLN) sinuses and CD8 + tumor-infiltrating lymphocytes (TILs) positively correlated in CRC and were associated with a favorable prognosis. However, associations between dMMR/MSI-H CRC and CD8 + TILs or prognoses vary among studies. In this study, we attempted to compare the association between MMR status, CD169 + macrophages in RLNs, CD8 + TILs, PD-L1 scores, and prognoses in CRC., Methods and Results: We immunostained 83 surgically resected CRC tumors that we previously analyzed for MMR proteins, and identified 9 that were dMMR. The number of CD169 + macrophages in RLNs and CD8 + TILs significantly correlated with overall survival, whereas MMR status did not. The number of cells positive for the TIL markers CD3, CD4, CD8, and TIA-1, and macrophage markers CD68 and CD169 in RLNs did not significantly differ between groups according to MMR status. Furthermore, combined positive scores (CPS) for PD-L1 expression in five of nine dMMR CRCs were all <1. We found that dMMR in CRC did not correlate with numbers of CD169 + macrophages in RLNs or CD8 + TILs., Conclusions: CRC with CD169 + macrophages in RLNs and abundant CD8 + TILs indicates a better prognosis and it should be immunologically classified as a different antitumor group from dMMR CRC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)