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Morphological and functional heterogeneity are found in tumors, with the latter reflecting the different levels of resistance against antitumor therapies. In a therapy‐resistant subpopulation, the expression levels of differentiation markers decrease, and those of immature markers increase. In addition, this subpopulation expresses genes involved in drug metabolism, such as aldehyde dehydrogenase 1A1 (ALDH1A1). Because of their similarity to stem cells, cells in the latter therapy‐resistant subpopulation are called cancer stem cells (CSCs). Like normal stem cells, CSCs were originally thought not to arise from non‐CSCs, but this hierarchical model is too simple. It is now believed that CSCs are generated from non‐CSCs. The plasticity of tumor phenotypes between CSCs and non‐CSCs causes difficulty in completely curing tumors. In this review, focusing on ALDH1A1 as a marker for CSCs or immature tumor cells, the dynamics of ALDH1A1‐expressing tumor cells and their regulatory mechanisms are described, and the plausible regulatory mechanisms of plasticity of ALDH1A1 expression phenotype are discussed. Genetic mutations are a significant factor for tumorigenesis, but non‐mutational epigenetic reprogramming factors yielding tumor heterogeneity are also crucial in determining tumor characteristics. Factors influencing non‐mutational epigenetic reprogramming in tumors are also discussed. [ABSTRACT FROM AUTHOR]

Objectives: To compare iodine content (IC) of solitary lung cancer using dynamic measurements of CT attenuation (Hounsfield Units, HU) and to correlate their quantitative CT data with expressions of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and hypoxia-inducible factor-1α (HIF-1α) using immunostaining methods. Methods: This study included 18 patients with adenocarcinoma, who undergone dual energy dynamic multiphase CT to examine solitary lung nodules (6 part-solid and 12 solid nodules). Tumor size was 21.1 mm±8.1 (9-39mm) [Mean±SD (range)]. Contrast volume was determined by weight (2ml/kg). Contrast volume and injection rate were 110.5 ml±17.2 (80-144ml) and 1.84ml/s±0.30 (1.3-2.4ml/s), respectively. Enhancement values ([CT value at each delayed scan-CT value at unenhanced scan]) and net enhancement values ([peak CT value-CT value at unenhanced scan]) were calculated in HU from 65keV monochromatic image. IC at each delayed scan was measured in mg/cm(3) from the iodine-water material decomposition pair on the advantage workstation VolumeShare4. Immunostaining using VEGF, EGFR, and HIF-1α was performed by two pathologists, who evaluated the expression level of them subjectively. Statistical analyses were performed with rank correlation tests and regression analysis. Results: IC at 2- and 3-minute delayed scan (x) and immunostaining score of HIF-1α (y) showed a significantly positive correlation (r=0.64 and 0.52, p=0.004 and 0.03): regression equation, y=1.34+0.58x and y=1.51+0.55x, respectively. Conclusions: Dual-energy dynamic multiphase CT can measure iodine content in lung adenocarcinoma. Iodine content at 2- and 3-minute delayed scan might correlate with the expression level of HIF-1α. [ABSTRACT FROM AUTHOR]

The clinical significance of human papillomavirus (HPV) in neck node metastasis from cancer of unknown primary (CUP) is not well established. We aimed to address the relationship of HPV status between node metastasis and the primary tumor, and also the relevance of HPV status regarding radiographically detected cystic node metastasis in head and neck squamous cell carcinoma (HNSCC) and CUP. HPV DNA was examined in 68 matched pairs of node metastasis and primary tumor, and in node metastasis from 27 CUPs. In surgically treated CUPs, p16 was examined immunohistochemically. When tonsillectomy proved occult tonsillar cancer in CUP, HPV DNA and p16 were also examined in the occult primary. Cystic node metastasis on contrast-enhanced computed tomography scans was correlated with the primary site and HPV status in another series of 255 HNSCCs and CUPs with known HPV status. Node metastasis was HPV-positive in 19/37 (51%) oropharyngeal SCCs (OPSCCs) and 10/27 (37%) CUPs, but not in non-OPSCCs. Fluid was collected from cystic node metastasis using fine needle aspiration in two OPSCCs and one CUP, and all fluid collections were HPV-positive. HPV status, including the presence of HPV DNA, genotype, and physical status, as well as the expression pattern of p16 were consistent between node metastasis and primary or occult primary tumor. Occult tonsillar cancer was found more frequently in p16-positive CUP than in p16-negative CUP (odds ratio (OR), 39.0; 95% confidence interval (CI), 1.4–377.8; P = 0.02). Radiographically, cystic node metastasis was specific to OPSCC and CUP, and was associated with HPV positivity relative to necrotic or solid node metastasis (OR, 6.2; 95% CI, 1.2–45.7; P = 0.03). In conclusion, HPV status remains unchanged after metastasis. The occult primary of HPV-positive CUP is most probably localized in the oropharynx. HPV status determined from fine needle aspirates facilitates the diagnosis of cystic node metastasis. [ABSTRACT FROM AUTHOR]

Distinguishing primary ovarian cancer from metastatic colorectal cancer is often difficult by a conventional pathological examination alone. We assessed the usefulness of p53 gene mutation analysis for the differential diagnosis of ovarian adenocarcinoma. A 66-year-old woman suffered multiple organ metastases, including the liver, para-aortic lymph node, and right ovary, following an operation for advanced sigmoid colon cancer. She underwent ovarian resection after effective chemotherapy against the liver and para-aortic lymph node cancer. Histological analysis suggested primary ovarian cancer. Therefore, we applied p53 gene mutation analysis for the differential diagnosis of primary versus metastatic ovarian cancer from sigmoid colon cancer. The direct sequence of the p53 gene demonstrated the same gene mutation in codon 211 (ACT to ATT) in both the sigmoid colon and ovarian cancers. According to the International Agency for Research on Cancer TP53 mutation database, this type of p53 mutation in colorectal cancer and ovarian cancer is 0.13% (5/3,693) and 0% (0/1,494), respectively. Therefore, we determined that the ovarian tumor was metastatic. Although p53 gene mutation analysis has been applied in some cases, this modality is very useful for the differential diagnosis of primary and metastatic cancer. [ABSTRACT FROM AUTHOR]

Soft tissue sarcomas (STS) are rare mesenchymal neoplasms with a variety of histological subtypes. However, in Japan, data on the clinical characteristics and prognostic profiles of these tumors are lacking. The purpose of the present study was to clarify the clinical features and outcomes of Japanese patients with retroperitoneal and abdominal STS. We reviewed and analyzed retrospectively the data for 82 patients who underwent surgery for retroperitoneal and abdominal STS at Osaka University and affiliated hospitals from 2000 to 2007. The factors analyzed included patient demographics and clinical features. The histological subtypes included leiomyosarcoma in 32 patients (39.0%), liposarcoma in 30 (36.6%), malignant fibrous histiocytoma in 10 (12.2%), and other miscellaneous subtypes in 10 (12.2%). The overall survivals were 92, 69, and 62%, respectively, at 1, 3, and 5 years after primary surgery. The overall survival of patients with low-grade sarcoma was significantly better than that of patients with high-grade sarcoma. Complete resection was done in 63 patients (77%) and their recurrence-free survivals were 73, 34, and 23%, respectively, at 1, 3, and 5 years after the surgery. Subgroup analysis of differences between leiomyosarcoma and liposarcoma revealed that liposarcomas were mainly located in the retroperitoneum and leiomyosarcomas were located equally in the retroperitoneum and abdominal cavity. The tumor size of liposarcomas was larger than that of leiomyosarcomas; however, the recurrence-free survival was better in patients with liposarcoma than in those with leiomyosarcoma. Our results showed the clinical features and prognoses of retroperitoneal and abdominal STS in Japan. Further large-scale nationwide studies are required to clarify the detailed clinical behavior of retroperitoneal and abdominal STS in Japan. [ABSTRACT FROM AUTHOR]

Introduction: Small bowel adenocarcinoma is a rare malignancy associated with a poor prognosis and there is little evidence of effective treatment. Recurrent small bowel adenocarcinoma is an intractable disease for which there is little information available regarding its treatment by palliative therapy. We present a case of recurrent small bowel adenocarcinoma successfully treated by cytoreductive surgery and palliative chemotherapy.Case Presentation: We report the case of a 72-year-old Japanese female who developed a peritoneal metastasis from recurrent small bowel adenocarcinoma after curative resection and adjuvant chemotherapy with S-1 and polysaccharide K. She underwent cytoreductive surgery followed by chemotherapy with folinic acid/fluorouracil/oxaliplatin and folinic acid/fluorouracil/irinotecan with polysaccharide K. Subsequently, no sign of a recurrence was observed 42 months after the second operation.Conclusion: To the best of our knowledge, this is the first case report of the successful treatment of peritoneal metastasis from small bowel adenocarcinoma by cytoreductive surgery and combination chemotherapy (folinic acid/fluorouracil/oxaliplatin and folinic acid/fluorouracil/irinotecan with polysaccharide K). [ABSTRACT FROM AUTHOR]

Abstract: Enhanced expression of valosin-containing protein (VCP) correlates with invasiveness and metastatic potential of cancer cells; therefore its transcriptional regulation could be a new target for cancer therapy. Here, the mechanism for transactivation of VCP promoter by E74-like factor 2 (ELF2), a transcription factor which enhances VCP transcription, was investigated. There was a highly conserved region among species in VCP promoter with one proven motif for ELF2 binding. However, the mutation at this motif did not obviously change the promoter activity. Further survey revealed another ELF2 binding motif in the upstream of the conserved region. The promoter activity was modestly reduced when this upstream motif was mutated, and completely abolished when both upstream and downstream motifs were mutated. Chromatin immunoprecipitation assay revealed that ELF2 bound both upstream and downstream motifs. These findings indicate that ELF2 transactivates VCP promoter through binding to two motifs, with a predominant contribution of the upstream one. [Copyright &y& Elsevier]

Abstract: Cancer stem cells are supposed to be resistant to apoptosis, but information for this is quite limited. Cancer stem cells are usually isolated as dye-effluxing cells with Hoechst 33342 staining, called side-population (SP) cells. Because Hoechst 33342 dye itself induces apoptosis, the SP cells isolated by such method are not suitable for evaluation of apoptosis. For accurate assessment, SP cells must be isolated without Hoechst 33342. Here, we found that CD55 was highly expressed in SP cells of two mammary gland carcinoma cell lines. Then, the high expression of CD55 was used for isolation of cancer stem cells among mammary carcinoma cell lines as a surrogate character. Cells expressing high level of CD55 (CD55hi) were resistant to apoptosis induced by serum depletion as in the case of SP cells. In ceramide-inducing apoptosis, CD55hi cells showed high tolerance. Anti-apoptotic molecules such as Bcl-2 were abundantly expressed in both SP cells and CD55hi cells. These findings indicated that SP cells as revealed to be CD55hi cells were tolerant to apoptosis. The high expression of CD55 may be a useful character for SP cells in evaluating their functions. [Copyright &y& Elsevier]

Abstract: X-ray repair cross-complementing gene 1 (XRCC1) is involved in base excision repair (BER) through interaction with other BER enzymes, and polymorphisms in XRCC1 appear to increase the risk of various cancers. We evaluated how three XRCC1 polymorphisms, Arg194Trp, Arg280His and Arg399Gln, affect the extent of DNA damage and repair using the micronucleus assay. XRCC1 cDNAs containing the wild-type sequence and the three polymorphisms were overexpressed in EM9 cells, which lack the full sequence needed to perform XRCC1 functions. Normal human XRCC1 cDNA corrected the defect in EM9 cells. Only XRCC1 cDNA containing the Arg399Gln polymorphism did not fully correct the DNA repair defect in EM9 cells. These results indicate that the Arg399Gln polymorphism, but not the Arg194Trp or Arg280His polymorphism, influences the ability of XRCC1 to repair DNA. This study may provide a model that can be used to evaluate the functional significance of polymorphisms in DNA repair genes. [Copyright &y& Elsevier]

Mast cells generate eicosanoids that are linked to asthma and other inflammatory diseases. A basic-helix-loop-helix leucine zipper transcription factor termed MITF is essential for the development of mast cells. Although other substances also linked to inflammatory reactions (such as various proteases and serotonin) require MITF for their expression, the role of MITF in eicosanoid generation has not been studied. We examined eicosanoid generation in bone marrow-derived mast cells (BMMCs) of tg/tg mice that lack MITF. Most eicosanoids generated by BMMCs are either prostaglandin (PG) D2 or leukotriene C4. The former is synthesized via the cyclooxygenase pathway, whereas the latter is synthesized via the 5-lipoxygenase pathway. In response to stimulation with IgE and antigens, BMMCs of tg/tg mice synthesized leukotriene C4 normally. However, neither immediate nor delayed PGD2 production was detected in these BMMCs. This indicates that MITF is a transcription factor that specifically activates the cyclooxygenase pathway, but not the 5-lipoxygenase pathway. Significant decreases in expression of hematopoietic PGD2 synthase (hPGDS, a terminal synthase for PGD2) were observed at both mRNA and protein levels in tg/tg BMMCs. MITF transactivated the hPGDS gene via a CACCTG motif located in the promoter region. MITF appeared to be essential for generation of PGD2 by enhancing expression of the hPGDS gene in BMMCs. [ABSTRACT FROM AUTHOR]

MITF is a basic helix-loop-helix leucine zipper-type transcription factor and is important for development of mast cells. MITF encoded by Miwh allele (Miwh-MITF) was mutated at a single amino acid of basic domain, and possessed a deficient but apparent DNA-binding ability. Here, we characterized the unique effects of Miwh-MITF on the expression of mast cell-related genes. The expression level of mouse mast cell protease (mMCP)-4, -5, and -6 genes in Miwh/Miwh cultured mast cells (CMCs) was intermediate between levels of normal (+/+) CMCs and tg/tg CMCs, which did not express any MITFs. Miwh-MITF appeared to show the positive transactivation effect through the remaining DNA-binding ability. On the other hand, the expression level of tryptophan hydroxylase gene was lower in Miwh/Miwh CMCs than in tg/tg CMCs, suggesting the inhibitory effect of Miwh-MITF on the transactivation. Miwh-MITF possessed dual abnormal effects on transactivation of mast cell-related genes. [Copyright &y& Elsevier]

The mi transcription factor (MITF) is a basic helix–loop–helix leucine zipper (bHLH-Zip) transcription factor and encoded by the mi locus of mice. Double gene dose of mutant allele at the mi locus results the decrease of mast cells and phenotypic abnormalities of mast cells. Various mutations have been reported at the mi locus. We divided them to null and inhibitory mutations. The tg is a typical null mutation due to the insertion of a transgene into the promoter region of MITF gene. Adult mice of tg/tg genotype can easily obtained and are a potentially useful tool for studying development and function of mast cells. [Copyright &y& Elsevier]

The development of mast cells is controlled through the cooperative effects of growth factors and nuclear transcription factors. The signals generated by the binding of stem cell factor (SCF) to c-kit receptor tyrosine kinase (KIT) are essential for their development and survival. A double gene dose of mutant alleles at either the SCF or KIT locus results in a decrease of mast cells. A double gene dose of mutant alleles at the mi transcription factor (MITF) locus also results in mast cell deficiency. Although the phenotype of the few mast cells remaining in SCF and KIT mutant mice appeared to be normal, the phenotype of mast cells was abnormal in MITF mutant mice. We describe here the abnormalities of mast cells observed in MITF mutant mice.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

MITF is a basic helix-loop-helix leucine zipper transcription factor, which is important for normal phenotypic expression of mast cells. Three isoforms of MITF have been known in mice, MITF-A, -H, and -M. Since cultured mast cells (CMCs) are useful for studying the function of MITF, we examined isoforms of MITF expressed in CMCs using 5′-RACE, and found a new isoform of MITF, MITF-E. We assessed the relative mRNA amount of various MITF isoforms with reverse transcription-PCR. When the mRNA amount of MITF-E was used as a standard, that of MITF-M was ∼10%, that of MITF-H was ∼1%, and that of MITF-A was ∼0.1%. Although MITF-E was the preferential isoform in CMCs, peritoneal mast cells expressed only MITF-M. The expression profile of MITF isoforms appeared to be influenced by the developing process of mast cells. [Copyright &y& Elsevier]

We have used various mouse mutants for studying the development of mast cells. The bone marrow origin of mast cells was shown by using giant granules of beige mice as a marker. Mast cell-deficient W/W[sup v] and Sl/Sl[sup d] mice are useful for investigation of the developmental processes. The mi locus encodes a member of the basic helix-loop-helix-leucine zipper protein family of transcription factors (MITF), and mast cells of mi/mi mice showed phenotypic abnormalities. Mast cells of mi/mi mice synthesized the mutant mi-MITF in normal amounts, and mi-MITF showed an inhibitory effect on the transcription of various mast cell-specific genes. On the other hand, mice of tg/tg possess the transgene insertional mutation in the 5′ flanking region of the mi gene and do not express any MITFs. Genes whose transcription was suppressed were more numerous in mast cells of mi/mi mice than in those of tg/tg mice. The comparison between phenotypes of mi/mi mast cells and those of tg/tg mast cells gave some insights into the regulation of mast cell phenotypes by transcription factors.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Thymic carcinoma is a rare type of tumor originating in the thymus, making up about 15–20% of all thymic epithelial tumors. It typically has a poor prognosis, especially in advanced stages, with low 5-year survival rates. Cases where the cancer recurs more than 10 years after surgery are extremely uncommon. Additionally, there are very few reports about the outcomes of patients who undergo aortic resection as part of their treatment for thymic carcinoma. Case presentation: A 68-year-old male was diagnosed with thymic squamous cell carcinoma classified as Masaoka stage III following the detection of an anterior mediastinal mass during a routine health examination. The patient underwent preoperative treatment, which included two cycles of chemotherapy (cisplatin and docetaxel) and 60 Gy of mediastinal radiotherapy, followed by an extensive surgical procedure comprising extended thymectomy, resection of the ascending aorta and superior vena cava, and wedge resection of the right upper lobe. Postoperative pathological examination revealed ypT3N0M0 disease, corresponding to ypStage IIIa disease, and the patient remained disease-free for 10 years. However, at 11 years after surgery, imaging revealed new nodules in the left lung. Surgical resection confirmed these nodules as metastatic lesions originating from the thymic carcinoma. Conclusions: This case highlights the critical need for long-term monitoring of thymic carcinoma patients, extending beyond the standard 5-year follow-up due to the potential for late recurrence, even in initially disease-free patients. Furthermore, our findings indicate that aortic resection, when carefully selected, can contribute to favorable long-term outcomes in advanced cases. This report enhances the limited literature on the long-term prognosis of thymic carcinoma, particularly following major vascular resection, and underscores the importance of a multidisciplinary approach to optimize patient management and improve outcomes. [ABSTRACT FROM AUTHOR]

Antibodies are extensively used in biomedical research, clinical fields, and disease treatment. However, to enhance the reproducibility and reliability of antibody-based experiments, it is crucial to have a detailed understanding of the antibody's target specificity and epitope. In this study, we developed a high-throughput and precise epitope analysis method, DECODE (Decoding Epitope Composition by Optimized-mRNA-display, Data analysis, and Expression sequencing). This method allowed identifying patterns of epitopes recognized by monoclonal or polyclonal antibodies at single amino acid resolution and predicted cross-reactivity against the entire protein database. By applying the obtained epitope information, it has become possible to develop a new 3D immunostaining method that increases the penetration of antibodies deep into tissues. Furthermore, to demonstrate the applicability of DECODE to more complex blood antibodies, we performed epitope analysis using serum antibodies from mice with experimental autoimmune encephalomyelitis (EAE). As a result, we were able to successfully identify an epitope that matched the sequence of the peptide inducing the disease model without relying on existing antigen information. These results demonstrate that DECODE can provide high-quality epitope information, improve the reproducibility of antibody-dependent experiments, diagnostics and therapeutics, and contribute to discover pathogenic epitopes from antibodies in the blood. Epitope analysis methods allow for a detailed understanding of antibody target specificity, but are often limited in their resolution and comprehensiveness. This study develops a high-throughput epitope analysis method called DECODE that provides single amino acid resolution for antibodies that recognize linear epitopes. [ABSTRACT FROM AUTHOR]

Osteopontin (Opn) and polyoma enhancer-binding protein (PEBP) 2αA/core binding factor (CBFA) 1 have been suggested to play important roles in ossification. The overlapping localization of opn and PEBP2αA/CBFA1 mRNA, and the marked decrease of opn mRNA expression in PEBP2αA knockout mice, indicated that the transcription of opn gene was controlled by PEBP2αA. In the present study, we determined the direct regulation of PEBP2αA on the opn promoter activity. Opn promoter activity was markedly enhanced by PEBP2αA and ETS1 in a synergistic manner. The synergistic effect was diminished when either the PEBP2αA or ETS1 binding site was mutated, or the spatial arrangement of these sites was mutated by a 4-nt insertion. The distance between these sites was important for transactivation but not protein-DNA binding. The direct interaction between PEBP2αA and ETS1 was depended on protein-DNA binding. These results suggested that the specific spatial arrangement of both sites and direct interaction between PEBP2αA and ETS1, were essential for promoter function. Furthermore, endogenous opn mRNA was decreased with the introduction of dominant negative PEBP2αA to MC3T3/E1 cells expressing endogenous PEBP2αA, ETS1 and opn. These findings suggest that PEBP2αA and ETS1 cooperate in vivo to regulate expression of the opn gene in the skeletal tissue. Cell type-specific regulation of Opn gene expression will also be discussed. [ABSTRACT FROM AUTHOR]

Micropapillary adenocarcinoma (MPC) is an aggressive histological subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited a gene expression signature similar to that of lung MPC. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC. [ABSTRACT FROM AUTHOR]

Clinical cancer genomic testing based on next‐generation sequencing can help select genotype‐matched therapy and provide diagnostic and prognostic information. Pathological tissue from malignant tumors obtained during routine practice are frequently used for genomic testing. This article is aimed to standardize the proper handling of pathological specimens in practice for genomic medicine based on the findings established in "Guidelines on the handling of pathological tissue samples for genomic medicine (in Japanese)" published by The Japanese Society of Pathology (JSP) in 2018. The two‐part practical guidelines are based on empirical data analyses; Part 1 describes the standard preanalytic operating procedures for tissue collection, processing, and storage of formalin‐fixed paraffin‐embedded (FFPE) samples, while Part 2 describes the assessment and selection of FFPE samples appropriate for genomic testing, typically conducted by a pathologist. The guidelines recommend that FFPE sample blocks be used within 3 years from preparation, and the tumor content should be ≥30% (minimum 20%). The empirical data were obtained from clinical studies performed by the JSP in collaboration with leading Japanese cancer genome research projects. The Japanese Ministry of Health, Labour, and Welfare (MHLW) recommended to comply with the JSP practical guidelines in implementing cancer genomic testing under the national health insurance system in over 200 MHLW‐designated core and cooperative cancer genome medicine hospitals in Japan. [ABSTRACT FROM AUTHOR]

Background: Cholesterol granuloma (CG) is a benign entity characterized by the presence of cholesterol crystals and foreign body giant cells. This condition can be attributed to cholesterol crystals that are deposited in the tissues and react with foreign body giant cells, resulting in granuloma formation. Lesions commonly develop in the otolaryngeal region, such as the middle ear. However, crystals rarely form in the thymus, accounting for 1% of all mediastinal tumors. Herein, we present five cases of mediastinal CG. Case presentation: The patients were aged 49–61 (mean, 55.4) years. Among them, three were men and two women. One patient had fever, and four patients were asymptomatic. The patients' lesions were detected during follow-up of other diseases or medical examinations showing the presence of abnormal chest shadows. The patients did not have a history of trauma or surgery. All lesions were located within the thymus gland. Three patients presented with multifocal lesions and two with a single lesion. Four patients had contrast effect on computed tomography scan. Four patients had abnormal fluorodeoxyglucose accumulation (mean maximum standardized uptake value, 4.67) on positron emission tomography-computed tomography. Four patients underwent complete surgical resection. The size of the resected lesions ranged from 1.8 to 5.1 (mean, 3.24) cm. Histologically, all patients presented with small nodules with cholesterol clefts and foreign body giant cells and histiocyte infiltration within the thymic tissue. The postoperative course was excellent. None of the patients who underwent complete resection presented with recurrence. Moreover, the patient who underwent partial resection did not have lesion enlargement. Conclusions: CG in the thymus is clinically challenging to differentiate from malignant lesions, and histologic diagnosis via surgical resection is required. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Although metabolic dysfunction‐associated steatotic liver disease (MASLD) patients with a Fib‐4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high‐risk populations requiring follow‐up is needed. We explored the utility of serum levels of growth differentiation factor‐15 (GDF15), a cell stress‐responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. Methods: Serum GDF15 levels were measured in 518 biopsy‐performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. Results: In the biopsy‐MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib‐4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high‐GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib‐4 index <1.3 or low‐GDF15 rarely developed liver cancer, high‐GDF15 patients with a Fib‐4 index >1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high‐GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low‐GDF15 patients, whether limited to high‐Fib‐4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib‐4 index >1.3, 2.7% had a Fib‐4 index >1.3 and >1.75 ng/mL GDF15. Conclusions: Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance. [ABSTRACT FROM AUTHOR]

Although deep vein thrombosis, as well as subsequent pulmonary embolism, is one of the major and fatal complications in cases of malignant neoplasm, it most often occurs after the diagnosis or treatment of the tumor. On the other hand, malignant tumors that develop with deep vein thrombosis as a specific initial symptom are extremely rare. Here, we report a case of angiosarcoma of the iliac vein, whose initial symptom was dyspnea due to pulmonary embolism. Although angiosarcoma arising directly from major blood vessels is rare, literature reviews, as well as our case, indicate that thromboembolism is an important initial symptom related to angiosarcoma from thick blood vessels and may contribute to immediate diagnosis and therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology. Methods: Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes. Results: We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1–4) were one woman and three men with a mean age of 53.75 years (range: 15–74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1–3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases. Conclusions: We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated. [ABSTRACT FROM AUTHOR]

Background: Cell- or tissue-based regenerative therapy is an attractive approach to treat heart failure. A tissue patch that can safely and effectively repair damaged heart muscle would greatly improve outcomes for patients with heart failure. In this study, we conducted a preclinical proof-of-concept analysis of the efficacy and safety of clinical-grade human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches. Methods: A clinical-grade hiPSC line was established using peripheral blood mononuclear cells from a healthy volunteer that was homozygous for human leukocyte antigens. The hiPSCs were differentiated into cardiomyocytes. The obtained hiPSC-CMs were cultured on temperature-responsive culture dishes for patch fabrication. The cellular characteristics, safety, and efficacy of hiPSCs, hiPSC-CMs, and hiPSC-CM patches were analyzed. Results: The hiPSC-CMs expressed cardiomyocyte-specific genes and proteins, and electrophysiological analyses revealed that hiPSC-CMs exhibit similar properties to human primary myocardial cells. In vitro and in vivo safety studies indicated that tumorigenic cells were absent. Moreover, whole-genome and exome sequencing revealed no genomic mutations. General toxicity tests also showed no adverse events posttransplantation. A porcine model of myocardial infarction demonstrated significantly improved cardiac function and angiogenesis in response to cytokine secretion from hiPSC-CM patches. No lethal arrhythmias were observed. Conclusions: hiPSC-CM patches are promising for future translational research and may have clinical application potential for the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Background: There has been little information on the actual diagnosis of pulmonary lesions in patients with a history of urinary tract transitional cell carcinoma (TCC) and short- and long- outcomes of pulmonary resection for these patients. Methods: In the present study, the data of 37 consecutive patients with a history of TCC who underwent pulmonary resection for solitary pulmonary lesions were reviewed, and the clinical factors and short- and long-term outcomes were analyzed. Results: The study population included 35 male patients, and 2 female patients. The mean age was 72.5 years. Twenty patients (80%) were smokers and showed a high incidence of chronic obstructive pulmonary disease. Pulmonary lesions and primary TCC were detected simultaneously in 5 patients and metachronously in 32 patients. The median interval between treatment for primary TCC and the detection of pulmonary lesion was 43 months. The mean tumor diameter was 23 mm. The types of resection included lobectomy (n = 19), segmentectomy (n = 8), and partial resection (n = 10). Twelve of 37 patients (32%) developed postoperative complications. The pathological diagnoses included primary lung cancer (n = 28), pulmonary metastasis from TCC (n = 7), and others (n = 2). The 5-year overall survival rate for all patients was 72%. The 5-year overall survival rate of patients with primary lung cancer was 74%, while that of patients with pulmonary metastasis from TCC was 57%. Conclusions: Surgery can be proactively considered for treating pulmonary lesions in patients with a previous history of TCC, as it provides favorable long-term outcomes. [ABSTRACT FROM AUTHOR]

Background: Mediastinal lymphatic tumors are relatively rare. The prognosis is poor but has improved due to recent advances in treatment strategies. Herein, we report a case of mediastinal lymphoma diagnosed using surgical biopsy, which was complicated by mediastinal mass syndrome due to general anesthesia. Case presentation: A 25-year-old man with cough, fever, dyspnea, and night sweats was transferred to our hospital for resection of a large anterior mediastinal tumor. Although his preoperative diagnosis was WHO type B1 thymoma, the clinical findings suggested a lymphoma. A repeat surgical biopsy was performed under general anesthesia. Immediately after extubation, the patient developed acute respiratory failure with hypolucency of the right lung field on chest radiography. He was reintubated immediately and was diagnosed with negative pressure pulmonary edema in the right lung. He was managed with positive-pressure ventilation and his respiratory distress resolved within 5 days. Pathological examination of surgical specimens confirmed the diagnosis of lymphoma. Conclusion: Surgical biopsy is useful for the diagnosis of mediastinal tumors. However, the risk of perioperative mediastinal mass syndrome should be carefully assessed before administering general anesthesia. [ABSTRACT FROM AUTHOR]

Retinal gliosis (RG) is a rare intraocular disease characterized by the proliferation of Müller cells within the retina. This case report describes a 3-year-old Japanese boy with RG and osseous metaplasia, a condition where bone-like tissue forms within the eye. The boy presented with a white pupil and was diagnosed with RG based on clinical imaging and histology. The report suggests that intraocular ossification may progress more quickly than previously thought and provides new insights into the mechanism of ossification in RG. [Extracted from the article]

In this study, we aimed to investigate the relationship between out-of-hospital natural death (OHND) and ambient temperature and examine the seriousness of the impact of the coronavirus disease-2019 (COVID-19) pandemic on this relationship. We used data from the Osaka Prefectural Office of Medical Examiners between 2018 and 2022 and performed a retrospective observational study. A Poisson regression model was applied to examine the relationship between OHND and temperature in Osaka City. The relative risk of OHND at 5 °C and 32 °C compared to the minimum mortality temperature increased from 1.81 in the pre-COVID-19 period to 2.03 in the post-COVID-19 period at 5 °C and from 1.29 in the pre-COVID-19 period to 1.60 in the post-COVID-19 period at 32 °C. The increase in relative risk per 1 °C increase from the pre- to post-COVID-19 period was 1.0551 (rate ratio [RR], p = 0.003) in the hot environment and 1.0233 (RR, p = 0.013) in the cold environment, which was larger than that in the hot environment. Although the risk of OHND increased at both temperatures, the change in OHND risk during post-COVID-19 was larger in the hot environment than in the cold environment, implicating the effect of pandemics in the current scenario of global warming. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative condition that presents with several neurological symptoms, such as cerebellar ataxia, parkinsonism, and cognitive impairment. It is caused by a CTA/CTG repeat expansion on chromosome 13q21 (ataxin 8 opposite strand [ATXN8OS]). However, the pathological significance of this expansion remains unclear. Moreover, abnormal CTA/CTG repeat expansions in ATXN8OS have also been reported in other neurodegenerative diseases, including progressive supranuclear palsy. In this study, we analyzed all available autopsy cases in Japan to investigate common pathological features and profiles of tau pathology in each case. Severe neuronal loss in the substantia nigra and prominent loss of Purkinje cells, atrophy of the molecular layer, and proliferation of Bergmann glia in the cerebellum were common features. Regarding tauopathy, one case presented with progressive supranuclear palsy‐like 4‐repeat tauopathy in addition to mild Alzheimer‐type 3‐ and 4‐repeat tauopathy. Another case showed 3‐ and 4‐repeat tauopathy accentuated in the brainstem. The other two cases lacked tauopathy after extensive immunohistochemical studies. The present study confirmed common pathological features of SCA8 as degeneration of the substantia nigra in addition to the cerebellum. Our study also confirmed unique tauopathy in two of four cases, indicating the necessity to further collect autopsy cases. [ABSTRACT FROM AUTHOR]

Our findings lead us to strongly recommend that (i) genetic analysis should be performed in patients with polyneuropathy of unknown etiology, and (ii) that RNAi therapy should be started as early as possible in patients with genetically confirmed ATTRv amyloidosis. In contrast, excessive amyloid deposits were visible in the heart and sympathetic ganglia, and moderate amyloid deposits were found in several organs even after the periodic administration of patisiran for 21 months, likely because therapy was initiated at a late stage of the disease. Sural nerve biopsy showed no amyloid deposits in the endoneurium or perineurium, but a small amount of amyloid deposition was visible on the vessel wall by Congo red staining (Supplementary Figure S2). Although TTR synthesis in hepatocytes was significantly reduced, massive amyloid deposits were found in some organs, even after RNAi therapy, likely because of the late initiation of the therapy. [Extracted from the article]

Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3ʹ splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia. [ABSTRACT FROM AUTHOR]

We report an autopsy case of progressive supranuclear palsy (PSP‐Richardson syndrome). The individual had been enrolled in a phase 2 trial and received a monoclonal tau antibody (tilavonemab, ABBV‐8E12); he died of intrahepatic cholangiocarcinoma and gastrointestinal bleeding during the clinical trial. Neuropathological examination demonstrated neuronal loss, gliosis, and widespread deposits of phosphorylated tau in the neurofibrillary tangles, tufted astrocytes, coiled bodies, and threads, which mainly occurred in the inferior olive nucleus, dentate nucleus of the cerebellum, substantia nigra, midbrain tegmentum, subthalamic nuclei, globus pallidus, putamen, and precentral gyrus, confirming typical PSP pathology. Phosphorylated tau was also found to accumulate in Betz cells, Purkinje cells, and pencil fibers in the basal ganglia. In conclusion, no additional changes or pathological modifications, which were expected from immunotherapy targeting tau, were visible in the present case. [ABSTRACT FROM AUTHOR]

Background: Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates in non-lymphoid tissues, which are associated with improved prognosis in some cancer types. This study aimed to investigate the clinical significance of TLSs in oesophageal cancer (EC). Methods: In a series of 316 EC surgical specimens from two different institutes, we evaluated the density and maturity of peritumoral TLSs using haematoxylin/eosin, immunohistochemistry, and multiplex immunofluorescence staining. We analysed the association between TLSs and clinicopathological parameters. The clinical significance of TLSs was further evaluated in a different cohort of 34 patients with recurrent EC treated with anti-PD-1 antibody. Results: Tumours with high TLS density predominantly consisted of matured TLSs. High TLS density was significantly associated with less advanced tumour stage, absence of lymphatic/vascular invasion, better serum nutrition parameters (neutrophils count, albumin, neutrophil-to-lymphocyte ratio, and prognostic nutritional index), and prolonged survival. This survival trend was more remarkable in cases with matured TLSs, which represented an increased population of CD138+ plasma cells. In the second EC cohort, TLS density predicted the clinical response to anti-PD-1 antibody and patient survival. Conclusion: The density and maturity of peritumoral TLSs are useful parameters for predicting long-term survival and response to anti-PD-1 antibody treatment in EC patients. [ABSTRACT FROM AUTHOR]

Background and Aim: Cold snare polypectomy is commonly performed to remove small colorectal polyps. Accidental resection of carcinomas during this procedure has been reported. Herein, we aimed to clarify the clinicopathological features and clinical course of colorectal carcinomas resected by cold snare polypectomy. Methods: This multicenter retrospective cohort study was conducted at 10 Japanese healthcare centers. Of the colorectal lesions resected by cold snare polypectomy between April 2016 and March 2020, lesions pathologically diagnosed as carcinoma were reviewed. Centralized histology (based on the Vienna classification) and endoscopic reviews were performed. The study endpoints were endoscopic features and clinical outcomes of cold snare polypectomy‐resected colorectal carcinomas (Vienna category ≥4.2). Results: We reviewed 74 of the 70 693 lesions resected by cold snare polypectomy. After a central pathological review, 68 lesions were diagnosed as carcinomas. The Japan Narrow‐band imaging Expert Team (JNET) classification type 2B, lesion size ≥6 mm, and multinodular morphology were the significant endoscopic predictors of carcinoma resected by cold snare polypectomy. No adverse events related to the procedure occurred. Sixty‐three lesions were diagnosed as carcinomas within the mucosal layer, and 34 were curative resections. Of the five carcinoma lesions with submucosal invasion, additional surgery revealed remnant cancer tissues in one lesion. No local or metastatic recurrence was observed during follow‐up. Conclusions: Although most of the carcinomas resected by cold snare polypectomy were within the mucosal layer, few lesions invading the submucosa were identified. Careful pre‐procedural endoscopic evaluation, especially focusing on the JNET classification and multinodular morphology, is recommended. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine tumors of the thymus (NETTs) are rare and have a poor prognosis. Complete resection would be the best method to achieve a radical cure, although a standardized treatment method has not been established. Additionally, no standard criteria have been developed to determine the necessity of tumor resection alone or total thymectomy, and the same is true for lymph node dissection. We reviewed 40 patients who underwent surgical resection, including lymph node dissection and biopsy. The overall survival (OS) rate was better in the resected cases but with no significant differences in histological grade and pathological stage. NETTs frequently develop lymph node metastasis; thus, lymph node dissection seems necessary to achieve complete resection, especially for local control. Recurrence frequently occurs, but complete resection and multidisciplinary treatment would be effective because of the relatively good OS. Background: Neuroendocrine tumors of a thymus (NETTs) are rare, accounting for approximately 2–5% of all thymic epithelial tumors, and have a poor prognosis due to frequent lymph nodes or distant metastasis. Methods: We retrospectively reviewed the clinicopathological background and outcomes of 40 patients who underwent resection or surgical biopsy with histologically diagnosed NETTs from 1986 to 2022. Results: The most common pathological type was atypical carcinoid. Surgical resection was performed in 35 patients, with lymph node dissection in 33 and surgical biopsy in five. The overall survival (OS) rate for all patients was 81.4% and 52.3% at 5 and 10 years, respectively. The 2-year survival rate was 20% for the biopsy group, which was significantly worse than that of the resected group (p < 0.001). The relapse-free survival rates were 61.7% and 37.6% at 5 and 10 years, respectively, in 34 patients with complete resection. The univariate analysis revealed better the OS rate in the resected cases but with no significant differences between histological grade, lymph node metastasis, tumor size, or Ki67 index. Conclusions: Surgical complete resection is considered to improve prognosis regardless of histologic type. NETTs frequently develop lymph node metastasis, thus, lymph node dissection seems necessary for complete resection. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from three individuals with ICI-related T1D, and their histopathological data were compared those from three patients who had received ICI therapy but did not develop T1D (non-T1D) and seven normal glucose-tolerant subjects as control subjects. All ICI-related T1D patients had susceptible HLA haplotypes. In ICI-related T1D, the β-cell area decreased and the α-cell area increased compared with non-T1D and control subjects. The number of CD3-positive cells around islets increased in ICI-related T1D and non-T1D compared with control subjects, while the number of CD68-positive cells around islets increased in ICI-related T1D compared with non-T1D and control subjects. The expression ratios of programmed death-ligand 1 (PD-L1) on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while PD-L1 expression was observed in most cells of pancreatic islets in control subjects. This study, therefore, indicates that ICI therapy itself could reduce PD-L1 expression on islets in all subjects, which may be related to β-cell vulnerability. In addition, we showed that absence of PD-L1 expression on β-cells, genetic susceptibility, and infiltration of macrophages as well as T lymphocytes around islets might be responsible for T1D onset. ARTICLE HIGHLIGHTS: Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. Pancreatic histological findings of ICI-related T1D patients were compared with those of patients who had received ICI therapy but did not develop T1D (non-T1D) and control subjects. Programmed death-ligand 1 expression on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while it was observed in control subjects. Patients with ICI-related T1D had T1D-susceptible HLA haplotypes and islet inflammation. ICIs may decrease programmed death-ligand 1 expression on islets, and its absence and additional islet inflammation in genetically susceptible patients can lead to development of T1D. [ABSTRACT FROM AUTHOR]

main-duct intraductal papillary mucinous neoplasm (IPMN). The topics discussed include the classification of IPMN types, the challenges in determining the extent of resection in cases with diffuse main pancreatic duct dilatation, and the possibility that the dilatation in the remnant pancreatic head is derived from a secondary effect of the IPMN lesion in the resected pancreas.

The state of microglial activation provides important information about the central nervous system. However, a reliable index of microglial activation in histological samples has yet to be established. Here, we show that microglial activation induces topological changes of Iba1 localization that can be detected by analysis based on homology theory. Analysis of homology was applied to images of Iba1-stained tissue sections, and the 0-dimentional Betti number (b0: the number of solid components) and the 1-dimentional Betti number (b1: the number of windows surrounded by solid components) were obtained. We defined b1/b0 as the Homology Value (HV), and investigated its validity as an index of microglial activation using cerebral ischemia model mice. Microglial activation was accompanied by changes to Iba1 localization and morphology of microglial processes. In single microglial cells, the change of Iba1 localization increased b1. Conversely, thickening or retraction of microglial processes decreased b0. Consequently, microglial activation increased the HV. The HV of a tissue area increased with proximity to the ischemic core and showed a high degree of concordance with the number of microglia expressing activation makers. Furthermore, the HV of human metastatic brain tumor tissue also increased with proximity to the tumor. These results suggest that our index, based on homology theory, can be used to correctly evaluate microglial activation in various tissue images. [ABSTRACT FROM AUTHOR]

One of the known histological patterns of endometrioid carcinoma (EC) in uterine corpus cancer is MELF (microcystic, elongated, and fragmented). MELF is associated with lymphovascular invasion and lymph node metastasis. Besides MELF, it is also known that squamous differentiation (SD) often occurs in EC. SD is known to be no significant difference in the frequency of lymph node metastasis in EC. However, there have been no previous reports on the association between MELF and SD. In this research, we investigated the presence of SD in MELF using an antibody to CK5. We examined 28 cases of EC with MELF pattern, in which 15 cases showed SD. Moreover, the relation of lymph node metastasis to SD was examined. Lymph node dissection was performed in 27 out of 28 cases. Among them, 12 cases showed lymph node metastasis. The ratio of lymph node metastasis was significantly higher in EC with SD (64.3 %, 9 in 14 cases) than EC without SD (23.1 %, 3 in 13 cases). In this study, we first showed the association between SD and MELF and that MELF with SD is associated with a high ratio of lymph node metastasis. It is clinically relevant to recognize that MELF with SD is aggressive with a high ratio of lymph node metastasis. [ABSTRACT FROM AUTHOR]

Interstitial pneumonia (IP) is a refractory disease that causes severe inflammation and fibrosis in the interstitium of the lungs, often resulting in the development of lung cancer (LC) during treatment. Previous studies have demonstrated that the prognosis of LC complicated by IP is inferior to that of LC without IP. It is therefore of the utmost importance to gain a deeper understanding of the heterogeneity of such tumors. In the present study, we conducted spatial transcriptome analysis of squamous cell carcinoma arising from IP. The results suggested involvement of the glucocorticoid receptor pathway in treatment resistance. Immunostaining of squamous cell carcinoma specimens from patients with IP demonstrated that the tumors expressed NR3C1 to varying degrees. Furthermore, higher NR3C1 expression levels were associated with a significantly increased risk of recurrence. Our results point to a novel subtype of lung squamous cell carcinoma. Further analysis of the molecular mechanisms associated with this subtype may facilitate the development of novel diagnostic criteria and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Cardiac remodeling has no established therapies targeting inflammation. CD4+ T-cell subsets have been reported to play significant roles in healing process after ischemic myocardial injury, but their detailed mechanisms of activation remain unknown. To explore immune reactions during cardiac remodeling, we applied a non-surgical model of coronary heart disease (CHD) induced by a high-fat diet (HFD-CHD) in SR-BI−/−/ApoeR61h/h mice. Flow cytometry analyses throughout the period of progressive cardiac dysfunction revealed that CD4+ T Helper 1 (Th1) cells were predominantly activated in T-cell subsets. Probucol was reported to attenuate cardiac dysfunction after coronary artery ligation model (ligation-MI) in rats. To determine whether probucol suppress cardiac remodeling after HFD-CHD, we treated SR-BI−/−/ApoeR61h/h mice with probucol. We found treatment with probucol in HFD-CHD mice reduced cardiac dysfunction, with attenuated activation of Th1 cells. RNA-seq analyses revealed that probucol suppressed the expression of CXCR3, a Th1-related chemokine receptor, in the heart. XCR1+ cDC1 cells, which highly expresses the CXCR3 ligands CXCL9 and CXCL10, were predominantly activated after HFD-CHD. XCR1+ cDC1 lineage skewing of pre-DC progenitors was observed in bone marrow, with subsequent systemic expansion of XCR1+ cDC1 cells after HFD-CHD. Activation of CXCR3+ Th1 cell and XCR1+ cDC1 cells was also observed in ligation-MI. Notably, post-MI depletion of XCR1+ cDC1 cells suppressed CXCR3+ Th1 cell activation and prevented cardiac dysfunction. In patient autopsy samples, CXCR3+ Th1 and XCR1+ cDC1 cells infiltrated the infarcted area. In this study, we identified a critical role of XCR1+ cDC1-activated CXCR3+ Th1 cells in ischemic cardiac remodeling. [Display omitted] • Th1 cells were predominantly activated and recruited to the ischemic area after HFD-CHD and ligation-MI. • XCR1+ cDC1 cells could be involved in activating Th1 cells via CXCL9/CXCL10-CXCR3 axis. • In bone marrow, XCR1+ cDC1 lineage skewing of pre-DC progenitors was observed after HFD-CHD and ligation-MI. • XCR1+ cDC1 depletion suppressed CXCR3+ Th1-cell chemotaxis and prevented cardiac dysfunction after ligation-MI. [ABSTRACT FROM AUTHOR]

Colloid adenocarcinoma of the lung is a rare subtype of lung adenocarcinoma, accounting for only about 0.24% of lung cancers. Because of its rarity, long‐term postoperative prognostic reports are limited. In this report, we describe a case of colloid adenocarcinoma of the lung with a 5‐year recurrence‐free follow‐up. The patient is a 66‐year‐old woman. During postoperative follow‐up for ovarian cancer, chest CT showed a 45 × 30 mm sized mass in the left lung with mixed low‐absorption areas inside that were suspicious of cystic lesion. We suspected metastatic lung tumour, and performed lower lobectomy. Pathological examination revealed pale tumour cells forming a glandular lumen with internal mucus production. Based on the results of immunostaining we diagnosed colloid adenocarcinoma of the lung. She received postoperative adjuvant chemotherapy and is alive 4 years postoperatively without recurrence. Colloid adenocarcinoma of the lung, even if large, may have a good prognosis if completely resected. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapeutic options for rare cancers are frequently limited and less effective than for common cancers. Therefore, novel therapeutic strategies to treat rare cancers are urgently required. Our clinical study on rare cancers showed that the biweekly WT1 Trio peptide vaccine comprising two WT1-cytotoxic T lymphocyte (CTL)-peptides and one WT1-helper T lymphocyte-peptide induced more robust immune responses targeting WT1 than the weekly WT1-CTL peptide (WT1-235) vaccine. In addition, the safety of WT1 Trio was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer (TC). Fifteen (33.3%) of the 45 patients with recurrent or advanced rare cancers, including malignant glioma, soft-tissue sarcoma, TC, and malignant pleural mesothelioma, achieved stable disease after 3 months of protocol treatment. Therefore, since WT1 is widely overexpressed in rare cancers, WT1-targeted immunotherapy may be a therapeutic strategy for rare cancers. No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers. [ABSTRACT FROM AUTHOR]

Carney–Stratakis syndrome (CSS) is a familial syndrome characterized by gastrointestinal stromal tumors (GISTs) and paragangliomas, often at multiple sites. A 34‐year‐old woman who had undergone resection of gastric GISTs, liver metastases, and a retroperitoneal paraganglioma in her previous hospital was referred to our hospital due to recurrence after 5 years. She presented with two gastric GISTs, a liver tumor, and a peritoneal tumor. As molecular‐targeted agents are reported to be ineffective against CSS‐related GISTs, we selected surgical resection for the recurrence. We performed laparoscopic local gastrectomy, liver S7 subsegmentectomy, and peritoneal tumor resection. Pathological findings revealed multiple gastric GISTs with liver metastasis and a paraganglioma. The laparoscopic approach could be performed safely, less invasively, and it could be more effective in such cases. This is the first case report of laparoscopic resection for recurrent CSS‐related GISTs and paragangliomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Cervical cancer is the most common frequent gynecological malignancy. The incidence has decreased owing to screening programs and human papillomavirus vaccination; however, the incidence of adenocarcinoma has recently increased in some countries, especially in the young population. Adenocarcinoma treated with definitive radiotherapy, the recommended approach for treating locally advanced cervical cancer, has a lower response and survival rate than squamous cell carcinoma. Our study aimed to assess the response to definitive radiotherapy by histological subtype and to investigate prognostic factors of adenocarcinoma according to the uniform staging system and histological classification. We confirmed that 52 patients with adenocarcinoma responded significantly less to definitive radiotherapy and had shorter survival times than 275 patients with squamous cell carcinoma. In the adenocarcinoma population, univariate and multivariate analyses showed that gastric-type adenocarcinoma was an independent poor prognostic factor associated with response to definitive radiotherapy. The pathogenesis of gastric-type adenocarcinoma must be investigated to overcome its poor response to treatment and establish novel therapeutic strategies for it. We aimed to evaluate the response to definitive radiotherapy (RT) for cervical cancer based on histological subtypes and investigate prognostic factors in adenocarcinoma (AC). Of the 396 patients treated with definitive RT between January, 2010 and July, 2020, 327 patients met the inclusion criteria, including 275 with squamous cell carcinoma (SCC) and 52 with AC restaged based on the 2018 International Federation of Gynecology and Obstetrics staging system. Patient characteristics, response to RT, and prognoses of SCC and AC were evaluated. The complete response (CR) rates were 92.4% and 53.8% for SCC and AC, respectively (p < 0.05). Three-year overall survival and progression-free survival (PFS) rates of SCC were significantly higher than those of AC (88.6% vs. 74.1%, p < 0.05 and 76.3% vs. 59.3%, p < 0.05, respectively). Among the AC population, univariate and multivariate analyses were performed to examine prognostic factors associated with non-complete response (CR). In the multivariate analysis, gastric-type adenocarcinoma (GAS) was associated with non-CR in AC (adjusted odds ratio, 12.2; 95% confidence interval 1.0–145.6; p < 0.05). The 3-year PFS rate in patients with GAS was significantly lower than that in patients with other histological types of AC (44.4% vs. 66.7%, p < 0.05). Definitive RT for cervical cancer was significantly less effective for AC than for SCC. GAS was the only independent prognostic factor associated with non-CR in AC. [ABSTRACT FROM AUTHOR]

Background and Aim: Sessile serrated lesions (SSLs) act as precursors to colorectal cancer, sometimes harbor carcinomas, and are sometimes incompletely resected. We aimed to evaluate local recurrence after endoscopic resection of SSL ≥10 mm. Methods: This prospective, single‐arm, observational study was performed at eight Japanese tertiary institutions. Colorectal lesions ≥10 mm were resected endoscopically, and the pathological diagnosis was either an SSL or hyperplastic polyp (HP). Follow‐up colonoscopy was performed 1 year later, and the local recurrence was evaluated by biopsy. Results: From October 2018 to September 2021, 104 cases with 123 lesions were registered. Among the pathologically diagnosed 105 SSLs and 18 HPs, 95 and 7 lesions were diagnosed as SSLs and HPs, respectively, by central pathological review. Among the 104 endoscopically diagnosed SSLs, 86 were diagnosed as SSLs, whereas among the 11 endoscopically diagnosed HPs, two were diagnosed as HPs by central pathological review (the rest were SSLs). Among the 95 patients with 113 lesions who underwent follow‐up colonoscopy, resection scars were identified in 95 (84%) lesions. Three (3.1%; 95% confidence interval 0.6–8.7%) local recurrences were diagnosed pathologically among 98 pathologically diagnosed SSLs. Two (6%) local recurrences were diagnosed in patients with SSLs ≥20 mm. Conclusions: The local recurrence rate after endoscopic resection of SSLs ≥10 mm was 3.1%. Careful follow‐up is recommended after endoscopic resection of large SSLs. Endoscopically diagnosed HPs ≥10 mm were sometimes pathologically diagnosed as SSL and should be considered for resection. [ABSTRACT FROM AUTHOR]

During tumorigenesis, certain tissues are colonized by mutant clones with oncogenic driver mutations as precancer lesions. These mutations can facilitate clonal expansion and may contribute to malignant transformation. The molecular features of low-grade non-muscle invasive bladder cancer (NMIBC) and high-grade bladder cancer are so distinct that they are thought to follow different evolutionary tumorigenesis pathways. Although NMIBC accounts for most bladder tumors, the somatic mutation patterns in "precancer" urothelium of patients with NMIBC remain unclear. Here, we analyzed specimens of normal urothelium and bladder tumors from patients with low-grade and high-grade NMIBC and investigated the genomic evolution of the cancer. Somatic mutations were analyzed using 50 oncogene-targeted sequences and droplet digital polymerase chain reaction for TERT promoter mutations. Somatic mutations in TERT promoter, FGFR3, and CDKN2A were characteristically identified in the normal urothelium of patients with NMIBC. These mutations, consistently identified in both tumor and normal specimens, likely affect clonal expansion during the malignant transformation of NMIBC. Though larger samples and comprehensive study are warranted to confirm our results, the difference in mutational landscape of the precancerous urothelium of patients with bladder cancer could offer deeper understandings of genomic evolution in bladder tumorigenesis. [ABSTRACT FROM AUTHOR]