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Abstract The cellular origin of clear cell ovarian carcinoma (CCOC), a major histological subtype of ovarian carcinoma remains elusive. Here, we explored the candidate cellular origin and identify molecular subtypes using integrated genomic/epigenomic analysis. We performed whole exome-sequencing, microarray, and DNA methylation array in 78 CCOC samples according to the original diagnosis. The findings revealed that ARID1A and/or PIK3CA mutations were mutually exclusive with DNA repair related genes, including TP53, BRCA1, and ATM. Clustering of CCOC and other ovarian carcinomas (n = 270) with normal tissues from the fallopian tube, ovarian surface epithelium, endometrial epithelium, and pelvic peritoneum mesothelium (PPM) in a methylation array showed that major CCOC subtypes (with ARID1A and/or PIK3CA mutations) were associated with the PPM-lile cluster (n = 64). This cluster was sub-divided into three clusters: (1) mismatch repair (MMR) deficient with tumor mutational burden-high (n = 2), (2) alteration of ARID1A (n = 51), and (3) ARID1A wild-type (n = 11). The remaining samples (n = 14) were subdivided into (4) ovarian surface epithelium-like (n = 11) and (5) fallopian tube-like (considered as high-grade serous histotype; n = 3). Among these, subtypes (1–3) and others (4 and 5) were found to be associated with immunoreactive signatures and epithelial-mesenchymal transition, respectively. These results contribute to the stratification of CCOC into biological subtypes.

Abstract Variations in color and texture of histopathology images are caused by differences in staining conditions and imaging devices between hospitals. These biases decrease the robustness of machine learning models exposed to out-of-domain data. To address this issue, we introduce a comprehensive histopathology image dataset named PathoLogy Images of Scanners and Mobile phones (PLISM). The dataset consisted of 46 human tissue types stained using 13 hematoxylin and eosin conditions and captured using 13 imaging devices. Precisely aligned image patches from different domains allowed for an accurate evaluation of color and texture properties in each domain. Variation in PLISM was assessed and found to be significantly diverse across various domains, particularly between whole-slide images and smartphones. Furthermore, we assessed the improvement in domain shift using a convolutional neural network pre-trained on PLISM. PLISM is a valuable resource that facilitates the precise evaluation of domain shifts in digital pathology and makes significant contributions towards the development of robust machine learning models that can effectively address challenges of domain shift in histological image analysis.

In pathology, various tissue and cell components play diverse biological roles. The morphology of each component can vary markedly with differentiation status or pathological conditions, making it critical for understanding diseases. Traditional computational pathology methods typically employ patch-based feature extraction, which aggregates visual features across entire images. However, this approach does not differentiate between tissue types, limiting component analysis. To address this limitation, we introduce a novel concept in pathology image analysis, namely segment representation learning, and present an algorithm, SegRep, for this purpose. SegRep uses a unique dual-masking strategy that combines input masking and feature map masking. This approach effectively removes external influences for the targeted segment, identified via a segmentation model or manual annotation, allowing for the extraction of segment-specific feature representations. In addition, SegRep utilizes a self-supervised learning algorithm to achieve optimized segment representation. We evaluated SegRep’s efficacy in clustering and classification tasks using a dataset of human gastric cancer samples. The results demonstrate SegRep’s superior capability in extracting feature vectors that are highly specific to different pathology image segments. Compared with traditional methods, SegRep shows significant improvements in accuracy and specificity in both clustering and classification tasks. Segment representations obtained via SegRep can offer a more detailed and insightful perspective on computational pathology, paving the way for advanced applications in the field.

Abstract Renal cell carcinoma (RCC) comprises several histological types characterised by different genomic and epigenomic aberrations; however, the molecular pathogenesis of each type still requires further exploration. We perform whole-genome sequencing of 128 Japanese RCC cases of different histology to elucidate the significant somatic alterations and mutagenesis processes. We also perform transcriptomic and epigenomic sequencing to identify distinguishing features, including assay for transposase-accessible chromatin sequencing (ATAC-seq) and methyl sequencing. Genomic analysis reveals that the mutational signature differs among the histological types, suggesting that different carcinogenic factors drive each histology. From the ATAC-seq results, master transcription factors are identified for each histology. Furthermore, clear cell RCC is classified into three epi-subtypes, one of which expresses highly immune checkpoint molecules with frequent loss of chromosome 14q. These genomic and epigenomic features may lead to the development of effective therapeutic strategies for RCC.

Adenocarcinoma is a common histological type of ulcerative colitis-associated cancer (UCAC), whereas neuroendocrine carcinoma (NEC) is extremely rare. UCAC is generally diagnosed at an advanced stage, even with regular surveillance colonoscopy. A 41-year-old man with a 17-year history of UC began receiving surveillance colonoscopy at the age of 37 years; 2 years later, dysplasia was detected in the sigmoid colon, and he underwent colonoscopy every 3 to 6 months. Approximately 1.5 years thereafter, a flat adenocarcinoma lesion occurred in the rectum. Flat lesions with high-grade dysplasia were found in the sigmoid colon and surrounding area. The patient underwent laparoscopic total proctocolectomy and ileal pouch-anal anastomosis with ileostomy. Adenocarcinoma was diagnosed in the sigmoid colon and NEC in the rectum. One year postoperation, recurrence or metastasis was not evident. Regular surveillance colonoscopy is important in patients with long-term UC. A histological examination of UCAC might demonstrate NEC.

Background: The nucleic acid quality from formalin-fixed paraffin-embedded (FFPE) tumor vary among samples, resulting in substantial variability in the quality of comprehensive cancer genomic profiling tests. The objective of the study is to investigate how nucleic acid quality affects sequencing quality. We also examined the variations in nucleic acid quality among different hospitals or cancer types. Methods: Three nucleic acid quality metrics (ddCq, Q-value, and DV200) and five sequencing quality metrics (on-target rate, mean depth, coverage uniformity, target exon coverage, and coverage of the housekeeping gene) were examined using 585 samples from the Todai OncoPanel, a dual DNA–RNA panel. Results: In the DNA panel, ddCq served as an indicator of sequencing depth and Q-value reflected the uniformity of sequencing across different regions. It was essential to have favorable values not only for ddCq but also for Q-value to obtain ideal sequencing results. For the RNA panel, DV200 proved to be a valuable metric for assessing the coverage of the housekeeping genes. Significant inter-hospital differences were observed for DNA quality (ddCq and Q-value), but not for RNA quality (DV200). Differences were also observed among cancer types, with Q-value being the lowest in lung and the highest in cervix, while DV200 was the highest in lung and the lowest in bowel. Conclusions: We demonstrated distinct characteristics and high predictive performances of ddCq, Q-value, and DV200. Variations were observed in the nucleic acid quality across hospitals and cancer types. Further study is warranted on preanalytical factors in comprehensive cancer genomic profiling tests.

Abstract Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remain elusive. In this study, we examine the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we find that the directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. The elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further demonstrate that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.

Background: Hunner-type interstitial cystitis (HIC) is an immunological, chronic inflammatory disease. The efficacy of corticosteroid as a treatment for HIC is unclear. Objective: To assess the efficacy and safety of low-dose oral prednisolone (PSL) treatment for patients with refractory HIC. Design, setting, and participants: This retrospective observational study reviewed the clinical outcomes of 31 patients with refractory HIC who received oral PSL daily (initial dose, 5.0 or 7.5 mg) for at least 12 mo between 2016 and 2023. The dose was tapered to the minimum that maintained symptom relief during follow-up. Outcome measurements and statistical analysis: Treatment outcomes were evaluated using a seven-graded global response assessment (scores ≥+2, moderately or markedly improved, were defined as treatment response), O’Leary and Sant symptom and problem indices (OSSI/OSPI), overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, a quality of life (QOL) score, and frequency-volume chart variables. Related complications were also documented. Results and limitations: The mean follow-up period was 20.1 ± 14.6 mo. The overall response rates at 1, 3, 6, 9, and 12 mo at doses of 6.7, 6.7, 5.2, 4.0, and 3.0 mg were 38.7%, 48.4%, 54.8%, 61.3%, and 64.5%, respectively. Compared with baseline, OSSI/OSPI and pain intensity improved significantly from 1 mo after PSL induction. The OABSS, QOL score, urinary frequency, and voided volume improved significantly from 9 mo after PSL induction. No patients discontinued treatment due to adverse events, although hypertension and glucose intolerance occurred in two patients, but these were resolved by temporal medications. Conclusions: This study showed that low-dose oral PSL significantly improves bladder pain, urinary symptoms, and QOL in patients with HIC, without serious adverse events. Further prospective evaluation is warranted to verify the potential efficacy and safety of low-dose PSL for HIC. Patient summary: This retrospective observational study reviewed the clinical outcomes of 31 patients suffering from refractory Hunner-type interstitial cystitis treated with low-dose oral prednisolone. Low-dose prednisolone improved bladder pain, urinary symptoms, and quality of life significantly, without serious adverse events. The response rate of 64.5% at 12 mo was comparable with the rates reported in previous studies that used higher doses of prednisolone. This study provides a rationale for further prospective evaluation of low-dose prednisolone for this intractable disease.

Abstract Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with neurofibromatosis type 2 (NF2) have not been fully elucidated. This study investigated meningiomas' clinical, histological, and molecular characteristics in NF2 patients. A long-term retrospective follow-up (13.5 ± 5.5 years) study involving total 159 meningiomas in 37 patients with NF2 was performed. Their characteristics were assessed using immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in patients with NF2 were compared with those in 189 sporadic NF2-altered meningiomas in 189 patients. Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/year. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade I meningiomas in patients with NF2 were more frequent than in sporadic NF2-altered meningiomas (92.9% vs. 80.9%). Transcriptomic analysis for patients with NF2/sporadic NF2-altered WHO grade I meningiomas (n = 14 vs. 15, respectively) showed that tumours in NF2 patients still had a higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this enhanced immune response by identifying myeloid cell infiltration, particularly in macrophages. Clinical, histological, and transcriptomic analyses of meningiomas in patients with NF2 demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited a marked immune response by identifying myeloid cell infiltration, particularly of macrophages.

Abstract Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post‐operative survival outcomes. To test this hypothesis, we utilised a multi‐institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease‐free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09–1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10–1.46). Compared to cases with 0–2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09–1.51) and 1.47 (95% CI, 1.22–1.78), respectively (ptrend

Abstract Bone metastases (BMs) of prostate cancer (PCa) have been considered predominantly osteoblastic, but non-osteoblastic (osteolytic or mixed osteoblastic and osteolytic) BMs can occur. We investigated the differences in prostate MRI and clinical findings between patients with osteoblastic and non-osteoblastic BMs. Between 2014 and 2021, patients with pathologically proven PCa without a history of other malignancies were included in this study. Age, Gleason score, prostate-specific antigen (PSA) density, normalized mean apparent diffusion coefficient and normalized T2 signal intensity (nT2SI) of PCa, and Prostate Imaging Reporting and Data System category on MRI were compared between groups. A multivariate logistic regression analysis using factors with P-values

Abstract Background Small cell carcinoma of the uterine cervix (SCCC) is a rare and highly malignant human papillomavirus (HPV)‐associated cancer in which human genes related to the integration site can serve as a target for precision medicine. The aim of our study was to establish a workflow for precision medicine of HPV‐associated cancer using patient‐derived organoid. Methods Organoid was established from the biopsy of a patient diagnosed with HPV18‐positive SCCC. Therapeutic targets were identified by whole exome sequencing (WES) and RNA‐seq analysis. Drug sensitivity testing was performed using organoids and organoid‐derived mouse xenograft model. Results WES revealed that both the original tumor and organoid had 19 somatic variants in common, including the KRAS p.G12D pathogenic variant. Meanwhile, RNA‐seq revealed that HPV18 was integrated into chromosome 8 at 8q24.21 with increased expression of the proto‐oncogene MYC. Drug sensitivity testing revealed that a KRAS pathway inhibitor exerted strong anti‐cancer effects on the SCCC organoid compared to a MYC inhibitor, which were also confirmed in the xenograft model. Conclusion In this study, we confirmed two strategies for identifying therapeutic targets of HPV‐derived SCCC, WES for identifying pathogenic variants and RNA sequencing for identifying HPV integration sites. Organoid culture is an effective tool for unveiling the oncogenic process of rare tumors and can be a breakthrough for the development of precision medicine for patients with HPV‐positive SCCC.

Objectives: The prolonged presence of infectious SARS-CoV-2 in deceased patients with COVID-19 has been reported. However, infectious virus titers have not been determined. Such information is important for public health, death investigation, and handling corpses. The aim of this study was to assess the level of SARS-CoV-2 infectivity in the corpses of patients with COVID-19. Methods: We collected 11 nasopharyngeal swabs and 19 lung tissue specimens from 11 autopsy cases with COVID-19 in 2021. We then investigated the viral genomic copy number by real-time reverse transcription-polymerase chain reaction and infectious titers by cell culture and virus isolation. Results: Infectious virus was present in six of 11 (55%) cases, four of 11 (36%) nasopharyngeal swabs, and nine of 19 (47%) lung specimens. The virus titers ranged from 6.00E + 01 plaque-forming units/ml to 2.09E + 06 plaque-forming units/g. In all cases in which an infectious virus was found, the time from death to discovery was within 1 day and the longest postmortem interval was 13 days. Conclusion: The corpses of patients with COVID-19 may have high titers of infectious virus after a long postmortem interval (up to 13 days). Therefore, appropriate infection control measures must be taken when handling corpses.

Summary: The stomach is an important digestive organ with various biological functions. However, because of the complexity of its cellular and glandular composition, its precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequencing (scRNA-seq) and subcellular-level spatial transcriptomics analysis of the human stomach and constructed the largest dataset to date: a stomach encyclopedia. This dataset consists of approximately 380,000 cells from scRNA-seq and the spatial transcriptome, enabling integrated analyses of transcriptional and spatial information of gastric and metaplastic cells. This analysis identified LEFTY1 as an uncharacterized stem cell marker, which was confirmed through lineage tracing analysis. A wide variety of cell-cell interactions between epithelial and stromal cells, including PDGFRA+BMP4+WNT5A+ fibroblasts, was highlighted in the developmental switch of intestinal metaplasia. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies of development, aging, and carcinogenesis.

Abstract Aim Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable prognostic indicator. This study aimed to analyze the pathological and biological features of DN. Materials and Methods A total of 81 RCC tumors, including 33 cases of DN and 48 cases of tumor necrosis without DN features (ghost necrosis [GN]), were enrolled in this study. We compared the number of neutrophils; the activation of cell death pathways, including ferroptosis, NETosis, and apoptosis; the rate of epithelial‐mesenchymal transition (EMT); and proliferation status using immunohistochemistry. We further assessed the effect of the necrosis type on systemic inflammation. Results DN tumors had a significantly higher number of neutrophils in both areas around the necrotic foci and far from the necrotic foci. Ferroptosis status did not differ between DN and GN; however, DN tumors had significantly larger areas exhibiting cell detritus with neutrophil extracellular traps (NETs) detected by citrullinated histone H3 (citH3) than GN tumors. DN tumors also had more apoptotic cells within areas around the necrotic foci. There was no significant difference between the EMT and proliferation status between DN and GN groups. Systemic inflammation markers including C‐reactive protein (CRP), CRP‐to‐albumin ratio (CRP/Alb), platelet‐to‐lymphocyte ratio (PLR), and hemoglobin were significantly higher in patients with DN. In addition, some of these inflammation markers (CRP/Alb and PLR) significantly decreased after surgery. Conclusions DN in RCC is characterized by NETs production and systemic inflammation.

Colonic metastasis from ovarian cancer is extremely rare, with only seven reported cases. A 77-year-old woman who had previously undergone surgery for ovarian cancer was admitted to a local hospital with anal bleeding. Histopathological analysis confirmed the presence of adenocarcinoma. Colonoscopy revealed a descending colon tumor. The patient was diagnosed with Union for International Cancer Control T3N0M0 descending colon cancer or colon metastasis of the ovarian cancer. Laparoscopic left colectomy was performed; intraoperative frozen section diagnosis confirmed metastasis from ovarian cancer, and the absence of invasion to the serosal surface suggested hematogenous metastasis. This is the first case of colonic metastasis from ovarian cancer that was diagnosed using an intraoperative frozen section and laparoscopically treated.

Background and Aims: Although Helicobacter pylori is the most important bacterial carcinogen in gastric cancer (GC), GC can emerge even after H. pylori eradication. Studies suggest that various constituents of the gastric microbiome may influence GC development, but the role of individual pathogens is unclear. Methods: Human gastric mucosal samples were analyzed by 16SrRNA sequencing to investigate microbiome composition and its association with clinical parameters, including GC risk. Identified bacteria in the stomach were cocultured with gastric epithelial cells or inoculated into mice, and transcriptomic changes, DNA damage, and inflammation were analyzed. Bacterial reads in GC tissues were examined together with transcriptomic and genetic sequencing data in the cancer genome atlas dataset. Results: Patients after Helicobacter pylori eradication formed 3 subgroups based on the microbial composition revealed by 16SrRNA sequencing. One dysbiotic group enriched with Fusobacterium and Neisseria species was associated with a significantly higher GC incidence. These species activated prooncogenic pathways in gastric epithelial cells and promoted inflammation in mouse stomachs. Sugar chains that constitute gastric mucin attenuate host-bacteria interactions. Metabolites from Fusobacterium species were genotoxic, and the presence of the bacteria was associated with an inflammatory signature and a higher tumor mutation burden. Conclusion: Gastric microbiota in the dysbiotic stomach is associated with GC development after H. pylori eradication and plays a pathogenic role through direct host-bacteria interaction.

Abstract Infection with certain viruses is an important cause of cancer. The Pan‐Cancer Analysis of Whole Genomes (PCAWG) Consortium recently analyzed the whole‐genome sequencing (WGS) data from 2656 cases across 21 cancer types, and indicated that Epstein–Barr virus (EBV) is detected in many different cancer cases at a higher frequency than previously reported. However, whether EBV‐positive cancer cases detected by WGS‐based screening correspond to those detected by conventional histopathological techniques is still unclear. In this study, to elucidate the involvement of EBV in various cancers, we reanalyzed the WGS data of the PCAWG cohort combined with the analysis of clinical samples of gastric and pancreatic cancer in our cohort. Based on EBV copy number in each case, we classified tumors into three subgroups: EBV‐High, EBV‐Low, and EBV‐Negative. The EBV‐High subgroup was found to be EBV‐positive in the cancer cells themselves, whereas the EBV‐Low subgroup was EBV‐positive in the surrounding lymphocytes. Further, the EBV‐Low subgroup showed a significantly worse prognosis for both gastric cancer and across cancer types. In summary, we classified tumors based on EBV copy number and found a unique cancer subgroup, EBV‐positive in the surrounding lymphocytes, which was associated with a poor prognosis.

Abstract Chronic kidney disease (CKD) affects kidney cancer patients’ mortality. However, the underlying mechanism remains unknown. M2-like macrophages have pro-tumor functions, also exist in injured kidney, and promote kidney fibrosis. Thus, it is suspected that M2-like macrophages in injured kidney induce the pro-tumor microenvironment leading to kidney cancer progression. We found that M2-like macrophages present in the injured kidney promoted kidney cancer progression and induced resistance to anti-PD1 antibody through its pro-tumor function and inhibition of CD8+ T cell infiltration. RNA-seq revealed Slc7a11 was upregulated in M2-like macrophages. Inhibition of Slc7a11 with sulfasalazine inhibited the pro-tumor function of M2-like macrophages and synergized with anti-PD1 antibody. Moreover, SLC7A11-positive macrophages were associated with poor prognosis among kidney cancer patients. Collectively, this study dissects the characteristic microenvironment in the injured kidney that contributed to kidney cancer progression and anti-PD1 antibody resistance. This insight offers promising combination therapy with anti-PD1 antibody and macrophage targeted therapy.

Atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP), proposed in a recent NIH consensus overview, is a rare precursor entity of malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) patients. Only one report on imaging findings of ANNUBP is available. Herein, we present the case of a 19-year-old female, diagnosed with a mediastinal tumor by chance, who visited to our hospital. She had café-au-lait spots on her trunk and a past history of resected neurofibroma. Her family also had café-au-lait spots; therefore, an NF1-induced tumor was strongly suspected. MRI revealed a paravertebral mass of 7.5 cm in size consisting of an inner rim with low T2 signal intensity and an outer rim with high T2 intensity, which was similar to a target sign, adjacent to the pulmonary veins; the center of the tumor was well enhanced by gadolinium, and the peripheral region was myxoid and slightly enhanced. FDG-PET showed high FDG uptake, SUVmax of 8.5, although the peripheral region represented low FDG accumulation. CT-guided needle biopsy was repeated because of the suspicion of an MPNST, which resulted in the histopathological diagnosis of ANNUBP. Marginal tumor resection was performed, and the final post-resection histopathological diagnosis was ANNUBP transformed from neurofibroma; the region of ANNUBP lost p16 immunostaining, although it was retained in the peripheral region of the neurofibroma. There has been no recurrence or metastasis 1 year after treatment. In conclusion, ANNUBP could be represented as a well-enhanced homogeneous mass on MRI and a high FDG accumulated region on FDG PET/CT, as seen in MPNST, in NF1 patients.

Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.

Abstract We aimed to identify prognostic factors of cancer-specific survival (CSS) in non-metastatic castration-resistant prostate cancer (M0CRPC) patients. The final analysis of this retrospective cohort included 82 patients who were diagnosed as M0CRPC between 1998 and 2018 at the University of Tokyo Hospital. CRPC was defined as prostate-specific antigen (PSA) progression (increased PSA ≥ 25% and ≥ 2 ng/mL above the nadir or detection of a metastatic lesion). The median value of age and PSA at the time of CRPC were 76 (range 55–94) years and 2.84 (range 2.04–22.5) ng/mL, respectively. The median follow-up time from CRPC diagnosis was 38 (range 3–188) months. The prognostic factors of CSS were ‘PSA doubling time (PSADT) ≤ 3 months’, ‘time to CRPC diagnosis from the start of androgen deprivation therapy (TTCRPC) ≤ 12 months’, of which TTCRPC was a novel risk factor of CSS. In the multivariate analysis, ‘PSADT ≤ 3 months’ and TTCRPC ≤ 12 months’ remained as statistically significant predictors of CSS. Novel risk stratification was developed based on the number of these risk factors. The high-risk group showed a hazard ratio of 4.416 (95% confidence interval 1.701–11.47, C-index = 0.727).

Summary: Patients with von Hippel-Lindau disease (vHL) are at risk of developing spatially and temporally multiple clear cell renal cell carcinomas (ccRCCs), which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient. Here, we perform whole-exome and RNA sequencing, digital gene expression, and immunohistochemical analyses for 81 samples from 51 ccRCCs of 10 patients with vHL. Inherited ccRCCs are clonally independent and have less genomic alterations than sporadic ccRCCs. Hierarchical clustering of transcriptome profiles shows two clusters with distinct immune signatures: immune hot and cold clusters. Interestingly, not only samples from the same tumors but also different tumors from the same patients tend to show a similar immune signature, whereas samples from different patients frequently exhibit different signatures. Our findings reveal the genetic and immune landscape of inherited ccRCCs, demonstrating the relevance of host factors in shaping anti-tumor immunity.

Abstract Background Endometriosis is assumed to be involved in ovarian cancer development, which is called endometriosis-associated ovarian cancer (EAOC). Uterine endometrial cells may be the cell of origin of EAOC. Accumulated carcinogenic changes in the uterine endometrial cells may increase the risk of developing EAOC. To further understand the pathogenesis of EAOCs, we focused on the clinicopathological characteristics of EAOCs in endometrial cancer patients with concomitant endometriosis. Methods We retrospectively reviewed 376 patients who were surgically treated for stage I–III endometrial cancer. Clinicopathological characteristics were compared between patients with and without endometriosis. Furthermore, the incidence of simultaneous endometrial and ovarian cancer (SEOC) and the histological characteristics of SEOC were compared between the two groups. Results Among 376 patients with endometrial cancer, 51 had concomitant endometriosis. Patients with endometriosis were significantly younger and more frequently had endometrioid G1/G2 tumors than those without endometriosis. The incidence of SEOCs was significantly higher in endometrial cancer patients with endometriosis than those without it (p

Stereotactic frame-based brain tumor biopsy (SFB) is a potent diagnostic tool considering its minimal invasiveness, though its diagnostic power and safety for brainstem lesions remain to be discussed. Here, we aimed to examine the usefulness of SFB for brainstem tumors. Twenty-two patients with brainstem tumors underwent 23 SFBs at our institution during 2002–2021. We retrospectively analyzed patient characteristics, tumor pathology, surgical procedures, and outcomes, including surgery-related complications and the diagnostic value. Seven (32%) tumors were located from the midbrain to the pons, eleven (50%) in the pons only, and four (18%) from the pons to the medulla oblongata. The target lesions were in the middle cerebellar peduncles in sixteen procedures (70%), the cerebellum in four (17%), the inferior cerebellar peduncles in two (9%), and the superior cerebellar peduncles in one (4%). A definitive diagnosis was made in 21 patients (95%) at the first SFB. The diagnoses were glioma in seventeen (77%) cases, primary central nervous system lymphoma in four (18%), and a metastatic brain tumor in one (5%). The postoperative complications (cranial nerve palsy in three [13%] cases, ataxia in one [4%]) were all transient. SFB for brainstem tumors yields a high diagnostic rate with a low risk of morbidity.

Cardiac fibrosis is a hallmark of heart failure. Here the authors use single-cell RNA-sequencing, spatial transcriptomics, and genetic manipulations, to show that Htra3 regulates cardiac fibrosis by keeping fibroblasts quiescent and by degrading TGF-beta.

Introduction Complete resection is the only possible treatment for cholangiocarcinoma in the extrahepatic biliary tree (eCCA), although current imaging modalities are limited in their ability to accurately diagnose longitudinal spread. We aimed to develop fluorescence imaging techniques for real-time identification of eCCA using an enzyme-activatable probe, which emits fluorescence immediately after activation by a cancer-specific enzyme. Methods Using lysates and small tissue fragments collected from surgically resected specimens, we selected the most specific probe for eCCA from among 800 enzyme-activatable probes. The selected probe was directly sprayed onto resected specimens and fluorescence images were acquired; these images were evaluated for diagnostic accuracy. We also comprehensively searched for enzymes that could activate the probe, then compared their expression levels in cancer and non-cancer tissues. Results Analyses of 19 samples (four cancer lysates, seven non-cancer lysates, and eight bile samples) and 54 tissue fragments (13 cancer tissues and 41 non-cancer tissues) revealed that PM-2MeSiR was the most specific fluorophore for eCCA. Fluorescence images of seven patients were obtained; these images enabled rapid identification of cancerous regions, which closely matched histopathology findings in four patients. Puromycin-sensitive aminopeptidase was identified as the enzyme that might activate the probe, and its expression was upregulated in eCCA. Discussion/Conclusion Fluorescence imaging with PM-2MeSiR, which may be activated by puromycin-sensitive aminopeptidase, yielded generally high accuracy. This technique may be useful for real-time identification of the spread of eCCA during surgery and endoscopic examinations.

Abstract NF2 alteration is the most commonly–found genetic abnormality in meningiomas and is known to initiate events for aggressive-type meningiomas. Whereas the prognosis of meningiomas differs depending on their epigenomic/transcriptomic profile, the effect of NF2 alteration on the prognosis of benign meningiomas is not fully elucidated. This study aimed to probe the importance of NF2 alteration in prognosis of WHO grade I meningiomas. A long-term retrospective follow-up (5.3 ± 4.5 years) study involving 281 consecutive WHO grade I meningioma patients was performed. We assessed tumour recurrence in correlation with extent of resection (EOR), histopathological findings, tumour location, and NF2 alteration. “NF2 meningioma” was defined as meningiomas with presence of NF2 mutation and/or 22q loss. Overall, NF2 meningioma per se was not a predictor of prognosis in the whole cohort; however, it was a predictor of recurrence in supratentorial meningiomas, together with EOR and Ki-67. In a striking contrast, NF2 meningioma showed a better prognosis than non-NF2 meningioma in infratentorial lesion. Supratentorial NF2 meningiomas had higher Ki-67 and forkhead box protein M1 expression than those of others, possibly explaining the worse prognosis in this subtype. The combination of NF2 alteration, high Ki-67 and supratentorial location defines subgroup with the worst prognosis among WHO grade I meningiomas. Clinical connotation of NF2 alteration in terms of prognosis of WHO grade I meningioma differs in an opposite way between supratentorial and infratentorial tumors. Integrated anatomical, histopathological, and genomic classifications will provide the best follow-up schedule and proactive measures.

Abstract Understanding the tumor microenvironment (TME) and anti-tumor immune responses in gastric cancer are required for precision immune-oncology. Taking advantage of next-generation sequencing technology, the feasibility and reliability of transcriptome-based TME analysis were investigated. TME of 30 surgically resected gastric cancer tissues was analyzed by RNA-Seq, immunohistochemistry (IHC) and flow cytometry (FCM). RNA-Seq of bulk gastric cancer tissues was computationally analyzed to evaluate TME. Computationally analyzed immune cell composition was validated by comparison with cell densities established by IHC and FCM from the same tumor tissue. Immune cell infiltration and cellular function were also validated with IHC and FCM. Cell proliferation and cell death in the tumor as assessed by RNA-Seq and IHC were compared. Computational tools and gene set analysis for quantifying CD8+ T cells, regulatory T cells and B cells, T cell infiltration and functional status, and cell proliferation and cell death status yielded an excellent correlation with IHC and FCM data. Using these validated transcriptome-based analyses, the immunological status of gastric cancer could be classified into immune-rich and immune-poor subtypes. Transcriptome-based TME analysis is feasible and is valuable for further understanding the immunological status of gastric cancer.

Abstract This study assessed the effect of magnifying endoscopy with narrow-band imaging (M-NBI) on the endoscopic differential diagnosis between intramucosal gastric carcinomas and adenomas with matched characteristics. Associations between magnified endoscopic findings and pathological high-grade cellular and architectural atypia were also investigated. In total, the records of 50 adenomas and 50 intramucosal well-differentiated adenocarcinomas matched by tumor size (≥ 20 mm or

Abstract Background Pseudomyxoma peritonei is a rare disease condition mainly caused by primary mucinous tumors from the appendix and rarely from the ovary, such as when mucinous ovarian tumors arise from within a teratoma. Molecular analyses of pseudomyxoma from the appendix showed that KRAS and GNAS pathogenic variants are common genetic features of pseudomyxoma peritonei. However, the origin of the tumors is difficult to be identified via genetic variants alone. This study presents a case of pseudomyxoma peritonei of ovarian origin, which was diagnosed by comprehensive genomic profiling with ploidy analysis in a series of primary, recurrent, and autopsy tumor specimens. Case presentation A 40-year-old woman was diagnosed with Stage IC2 mucinous ovarian tumor of borderline malignancy with mature cystic teratoma, upon clinical pathology. Immunohistochemical analysis suggested that the mucinous tumor was derived from the intestinal component of an ovarian teratoma. Three years later, intraperitoneal recurrence was detected, which subsequently progressed to pseudomyxoma peritonei. Genomic analysis detected KRAS (G12D), GNAS (R201C), and FBXW7 (R367*) variants in the primary tumor. In addition, the tumor showed aneuploidy with loss of heterozygosity (LOH) in all its chromosomes, which suggested that the primary ovarian tumor was derived from germ cells. Existence of one Barr body suggested the existence of uniparental disomy of the tumors throughout the genome, instead of a haploid genotype. All three pathogenic variants remained positive in the initial recurrent tumor, as well as in the paired DNA from the whole blood in pseudomyxoma peritonei. The pathogenic variant of KRAS (G12D) was also identified in the autopsy specimen of the appendix by droplet digital polymerase chain reaction. Conclusions This study pathologically and genetically confirmed that the primary ovarian borderline tumor was derived from the intestinal component of an ovarian teratoma, and that the subsequent pseudomyxoma peritonei progressed from the primary ovarian tumor. Integrative genomic analysis was useful to identify cellular origin of tumors, as well as to precisely interpret the process of disease progression.

ABSTRACT Although it has been 2.5 years since the coronavirus disease 2019 (COVID-19) pandemic began, the transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a dead infected body remains unclear, and in Japan, bereaved family members are often not allowed to view in person a loved one who has died from COVID-19. In this study, we analyzed the possibility of SARS-CoV-2 transmission from a dead body using a hamster model. We also analyzed the effect of “angel care”––in which the pharynx, nostrils, and rectum are plugged––and embalming on reducing transmissibility from dead bodies. We found that SARS-CoV-2 could be transmitted from the bodies of animals that had died within a few days of infection; however, angel care and embalming were effective in preventing transmission from the dead bodies. These results suggest that protection from infection is essential when in contact with a SARS-CoV-2-infected dead body and that sealing the cavities of a dead body is an important infection control step if embalming is not performed. IMPORTANCE We found that SARS-CoV-2 could be transmitted from a dead body, presumably via postmortem gases. However, we also found that postmortem care, such as plugging the pharynx, nostrils, and rectum or embalming the corpse, could prevent transmission from the dead body. These results indicate that protection from infection is essential when handling infected corpses and that appropriate care of SARS-CoV-2-infected corpses is important.

Abstract Immune checkpoint inhibitor (ICI) therapy is widely used but effective only in a subset of gastric cancers. Epstein–Barr virus (EBV)-positive and microsatellite instability (MSI) / mismatch repair deficient (dMMR) tumors have been reported to be highly responsive to ICIs. However, detecting these subtypes requires costly techniques, such as immunohistochemistry and molecular testing. In the present study, we constructed a histology-based deep learning model that aimed to screen this immunotherapy-sensitive subgroup efficiently. We processed whole slide images of 408 cases of gastric adenocarcinoma, including 108 EBV, 58 MSI/dMMR, and 242 other subtypes. Many images generated by data augmentation of the learning set were used for training convolutional neural networks to establish an automatic detection platform for EBV and MSI/dMMR subtypes, and the test sets of images were used to verify the learning outcome. Our model detected the subgroup (EBV + MSI/dMMR tumors) with high accuracy in test cases with an area under the curve of 0.947 (0.901–0.992). This result was slightly better than when EBV and MSI/dMMR tumors were detected separately. In an external validation cohort including 244 gastric cancers from The Cancer Genome Atlas database, our model showed a favorable result for detecting the “EBV + MSI/dMMR” subgroup with an AUC of 0.870 (0.809–0.931). In addition, a visualization of the trained neural network highlighted intraepithelial lymphocytosis as the ground for prediction, suggesting that this feature is a discriminative characteristic shared by EBV and MSI/dMMR tumors. Histology-based deep learning models are expected to be used for detecting EBV and MSI/dMMR gastric cancers as economical and less time-consuming alternatives, which may help to effectively stratify patients who respond to ICIs.

Endometrial stromal sarcoma is a rare uterine mesenchymal neoplasm, and extrauterine endometrial stromal sarcoma is even rarer, with a limited number of case reports. In the present report, we present a case of low-grade extrauterine endometrial stromal sarcoma originating from the mesentery in a 49-year-old woman, without endometrial stromal sarcoma in the uterus or evidence of endometriosis. The tumor was diagnosed using recombination of the JAZF1 gene by fluorescence in situ hybridization. Computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography showed a 13 cm, primarily polycystic, mass containing a contrast-enhancing solid component with restricted diffusion and mild 18F-fluorodeoxyglucose uptake. A large cystic component may be a characteristic feature of extrauterine endometrial stromal sarcoma, given the low pressure from the surrounding tissues.

Primary intracranial spindle cell sarcoma is an extremely rare mesenchymal tumor, the molecular pathogenesis of which is poorly understood. Because of the lack of specific markers, diagnosis sometimes relies on ruling out all possible differential diagnoses, often making it difficult to reach a definitive diagnosis. In this case study, we report a 69 year-old female patient for whom the integration of multi-layered molecular analyses contributed to making the diagnosis. The disease exhibited aggressive clinical behavior, requiring two sequential surgeries because of rapid regrowth within a short period. Primary and recurrent tumors exhibited similar histological features, in which spindle-shaped cells arranged in interlacing fascicles without any specific architectures, implicating sarcomatous tumors. In immunohistochemistry testing, tumor cells were immunopositive for vimentin but lacked any specific findings that contribute to narrowing down the differential diagnoses. Seeking further diagnostic clues, we performed DNA methylation-based analysis. The copy number analysis revealed MDM2 gene amplification and loss of heterozygosity of 22q. Moreover, dimension reduction clustering analysis implicated a methylation pattern comparable to aggressive types of sarcomas. In addition, an in-house next-generation sequencing panel (“Todai-OncoPanel”) analysis identified somatic mutations in DICER1, NF2 , and ATRX genes. Taken all together, we finally made the diagnosis of primary intracranial spindle cell sarcoma, DICER1 -mutant, with MDM2 gene amplification. This case report suggests that even for the tumors with insufficient morphological and immuno-histological diagnostic clues, integration of multi-layered molecular analyses can contribute to making the diagnoses as well as to understanding the rare tumors by elucidating unexpected genetic and epigenetic features.

Postmortem computed tomography (CT) is currently a well-known procedure and helps in postmortem investigations. In this case report, we report a unique postmortem CT finding: delayed cerebral enhancement associated with the antemortem infusion of contrast medium. A 72-year-old female lost consciousness at a restaurant and was taken to a hospital in an ambulance. Despite resuscitation efforts, she died of hypoxic–ischemic encephalopathy caused by cardiac arrest. About 6 h before her death, she underwent enhanced antemortem CT of the head. No abnormal enhancement was observed in the cerebral parenchyma. Then, 11 h after her death, she underwent unenhanced postmortem CT, which showed bilateral hyperdense caudate nucleus and putamina, due to residual iodinated contrast medium, in addition to other characteristic findings of hypoxic–ischemic encephalopathy. The mechanism underlying this phenomenon could be the destruction of the blood–brain barrier, and/or selective vulnerability, due to hypoxic–ischemic changes in the gray matter. Enhancement of basal ganglia on postmortem CT due to antemortem infusion of iodinated contrast medium might suggest hypoxic–ischemic encephalopathy, which should be noted in postmortem CT interpretations.

The mechanisms by which in vivo expression of the Yamanaka transcription factors (OSKM) renders somatic cells permissive for differentiation remain unclear. Here, the authors show that in vivo reprogramming using OSKM generates germ cell tumors and drives acquisition of totipotency-like features in somatic cells through DMRT1.

Introduction Intravesical Bacillus Calmette–Guerin immunotherapy is known to prevent recurrence of bladder cancer, but it can cause tuberculosis infections as an adverse event. Case presentation A 75‐year‐old man visited our hospital due to hematuria. The patient was diagnosed with bladder cancer and underwent transurethral resection of the bladder tumor. Postoperatively, the patient received Bacillus Calmette–Guerin immunotherapy. One year later, we performed transurethral surgery and prostate biopsy because of cystoscopic findings showing nodulous lesions in the bladder and an elevated serum prostate‐specific antigen level. The patient presented with high fever and malaise since the surgery. After careful examination, the patient was diagnosed with miliary tuberculosis caused by Mycobacterium bovis. The pathology of the bladder and prostate revealed acid‐fast bacilli collection by Ziehl–Neelsen staining. Conclusion The surgery exacerbated the local infection into a systemic infection. The risk of developing miliary tuberculosis should be considered at transurethral surgery or prostate biopsy in patients after intravesical Bacillus Calmette–Guerin immunotherapy.

Abstract Background Ectopic decidua is the presence of decidual tissue outside the uterus. Ectopic decidua of the appendix is a rare entity that can present with abdominal symptoms mimicking appendicitis. We report a case of a 39-year-old female patient at 27 weeks gestational age with a 2-day history of right lower quadrant abdominal pain. Case presentation The patient was referred to our hospital with suspicion of either acute appendicitis or threatened rupture of the uterus, the latter of which was considered unlikely following close examination. Therefore, she underwent emergency appendectomy via laparotomy. Microscopic examination revealed decidual tissue with myxoid degeneration in the subserosal layer of the tip side of the appendix, without endometriosis, which was compatible with ectopic decidua (deciduosis). Conclusions Because it is extremely difficult to distinguish ectopic decidua of the appendix from acute appendicitis, even with various imaging modalities, we should be aware that ectopic decidua of the appendix is a differential diagnosis for acute appendicitis in pregnant women.

Lung hepatoid adenocarcinoma (HAC) is a rare primary lung carcinoma pathologically characterized by hepatocellular carcinoma-like tumor cells, the majority of which produce alpha-fetoprotein (AFP). The clinical prognosis of lung HAC is generally poor, and effective therapeutic regimens for inoperable or recurrent cases have not been established. Here, we report a case of AFP-producing lung HAC with brain metastasis with long-term disease control, treated with the 5-fluorouracil-derived regimen S-1. The patient was a 66-year-old male admitted to the hospital with alexia. Chest X-ray revealed a massive tumor in the left upper lobe, and a head CT scan revealed a metastasis in the left parietal lobe. The laboratory data showed a remarkably elevated AFP level (97,561 ng/mL). Pathological assessment of the resected brain tumor revealed HAC, which was compatible with the lung biopsies. Together with the absence of other metastatic lesions, a final diagnosis of primary lung HAC, stage IV T4N3M1b, was given. The patient first underwent non-small cell lung cancer chemotherapy regimens (carboplatin and paclitaxel as the first line, and pemetrexed as the second line), but had clinical progression. After third-line oral S-1 (tegafur/gimeracil/oteracil) administration, the serum AFP level significantly dropped and the patient achieved long-term disease control without relapse, surviving more than 19 months after disease presentation. The autopsy result was consistent with the diagnosis of primary lung HAC, and immunohistochemical staining was AFP+, glypican 3+, and spalt-like transcription factor 4+. Here, we report the case of a rare primary lung HAC with apparent disease control on S-1 therapy, together with a literature review.

PURPOSEWe aimed to investigate the clinical and magnetic resonance imaging (MRI) characteristics of uterine adenomyosis, in which there is an extensive area of high signal intensity in the myometrium on T2-weighted MRI.METHODSThis retrospective radiographic study reviewed a case series of six patients (mean age, 36 years) with adenomyosis. These patients were selected because, unlike in classical adenomyosis, T2-weighted images showed a larger area of high signal intensity than that of low signal intensity in the myometrium. The morphology of the myometrial lesions, patterns of contrast enhancement (n=4), intramyometrial hemorrhaging, diffusion restriction (n=5), endometrial lesions, and imaging findings after treatment (n=3) were evaluated on MRI.RESULTSThe patients’ clinical symptoms included vaginal bleeding and severe anemia. Four were administered hormonal therapy, one underwent hysterectomy, and one underwent enucleation. On T2-weighted images, all showed endometrial thickening and a high signal intensity area in the myometrium that was divided up by a mesh of low signal intensity bands, with an appearance reminiscent of a fish caught in a net. Other findings included gradual centripetal enhancement with contrast defects in multicystic areas (4/4), an intramyometrial hemorrhage (1/6), and increased diffusion (5/5). Following hormonal therapy, the uteruses decreased in size and were similar to those of classical adenomyosis on MRI (3/3). The lesions were diagnosed as adenomyosis with a proliferation of adenomyotic glandular tissue and a proliferative endometrial polyp.CONCLUSIONThis case series suggests that there is a subgroup of uterine adenomyosis that shows a characteristic “fish-in-a-net” appearance on T2-weighted images.

Tissue clearing has revolutionised histology, but limited penetration of antibodies and stains into thick tissue segments is still a bottleneck. Here, the authors characterise optically cleared tissue as an electrolyte gel and apply this knowledge to stain the entirety of thick tissue samples.

Serum amyloid A (SAA) is an acute phase protein, which undergoes structural changes and deposits in the extracellular matrix, causing organ damage. Systemic AA amyloidosis is a relatively common amyloid subtype among the more than 30 amyloid subtypes, but the mechanism of amyloid fibril formation remains unclear. In this study, we investigated the tissue distribution of SAA derived peptides in formalin-fixed paraffin embedded (FFPE) specimens of human myocardium with amyloidosis using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). In the whole SAA protein, four trypsin-digested peptides in the range of SAA2-67 were visualized and the N-terminal peptide; SAA2-15, was selectively localized in the Congo red-positive region. The C-terminal peptides; SAA47-62, SAA48-62, and SAA63-67 were detected not only in the Congo red-positive region but also in the surrounding negative region. Our results demonstrate that the N-terminal SAA2-15 plays a critical role in the formation of AA amyloid fibril, as previously reported. Roles of the C-terminal peptides require further investigation.

CD70 – a ligand protein of CD27 on lymphocytes – is expressed in a large spectrum of malignancies. It is an attractive target for antibody-based therapy and several clinical trials are currently being conducted. However, there is no evidence regarding the expression of CD70 and its relationship with expression of programmed death ligand-1 (PD-L1) and CD27+ tumor-infiltrating lymphocytes (TIL) in formalin-fixed paraffin-embedded (FFPE) tissues of thymic tumors. FFPE tissues of thymic squamous cell carcinoma (TSCC) (operative specimens, n = 31; biopsy specimens, n = 11), thymoma (n = 60), thymic carcinoid (n = 3), and lung squamous cell carcinoma (LSCC) (n = 30) were analyzed immunohistochemically. Immunoreactivity for CD70 was semi-quantitatively scored according to the proportion of positive tumor cells. Moreover, the densities of CD27-positive intratumoral TIL (iTIL) and stromal TIL of TSCC were assessed and survival was compared. Most TSCC cases (87%; 27/31) were CD70-positive. In contrast, all thymoma and thymic carcinoid cases were CD70-negative. In LSCC cases, CD70-positivity was significantly lower than TSCC cases (20%; 6/30). Biopsy and resected specimens obtained from the same patients demonstrated a consistent staining pattern (6/6 patients). The proportion of CD70-positive TSCC was comparable with those of CD5 (87%) and CD117 (90%). Correlation between CD70 and PD-L1 expression score was observed. There was no significant difference in survival between the CD70-high and CD70-low expression groups. Meanwhile, patients with CD27-positive iTIL-high tumors exhibited better survival than those with iTIL-low tumors. This tendency was weaker in the CD70-high subset. CD70 immunohistochemistry is useful in diagnosing TSCC. CD70 may prevent anti-tumor immunity via CD27. Immunotherapy targeting the CD70–CD27 axis may be a promising option for the treatment of TSCC.

The histopathological findings of the glomeruli from whole slide images (WSIs) of a renal biopsy play an important role in diagnosing and grading kidney disease. This study aimed to develop an automated computational pipeline to detect glomeruli and to segment the histopathological regions inside of the glomerulus in a WSI. In order to assess the significance of this pipeline, we conducted a multivariate regression analysis to determine whether the quantified regions were associated with the prognosis of kidney function in 46 cases of immunoglobulin A nephropathy (IgAN). The developed pipelines showed a mean intersection over union (IoU) of 0.670 and 0.693 for five classes (i.e., background, Bowman’s space, glomerular tuft, crescentic, and sclerotic regions) against the WSI of its facility, and 0.678 and 0.609 against the WSI of the external facility. The multivariate analysis revealed that the predicted sclerotic regions, even those that were predicted by the external model, had a significant negative impact on the slope of the estimated glomerular filtration rate after biopsy. This is the first study to demonstrate that the quantified sclerotic regions that are predicted by an automated computational pipeline for the segmentation of the histopathological glomerular components on WSIs impact the prognosis of kidney function in patients with IgAN.

IntroductionRadical resection is the only curative treatment for pancreatic cancer, which is a life-threatening disease. However, it is often not easy to accurately identify the extent of the tumor before and during surgery. Here we describe the development of a novel method to detect pancreatic tumors using a tumor-specific enzyme-activatable fluorescence probe.MethodsTumor and non-tumor lysate or small specimen collected from the resected specimen were selected to serve as the most appropriate fluorescence probe to distinguish cancer tissues from noncancerous tissues. The selected probe was sprayed onto the cut surface of the resected specimen of cancer tissue to acquire a fluorescence image. Next, we evaluated the ability of the probe to detect the tumor and calculated the tumor-to-background ratio (TBR) by comparing the fluorescence image with the pathological extent of the tumor. Finally, we searched for a tumor-specific enzyme that optimally activates the selected probe.ResultsUsing a library comprising 309 unique fluorescence probes, we selected GP-HMRG as the most appropriate activatable fluorescence probe. We obtained eight fluorescence images of resected specimens, among which four approximated the pathological findings of the tumor, which achieved the highest TBR. Finally, dipeptidyl-peptidase IV (DPP-IV) or a DPP-IV-like enzyme was identified as the target enzyme.ConclusionThis novel method may enable rapid and real-time visualization of pancreatic cancer through the enzymatic activities of cancer tissues.

Abstract Background Cancers of unknown primary origin (CUPs) are reported to be the 3-4th most common causes of cancer death. Recent years have seen advances in mutational analysis and genomics profiling. These advances could improve accuracy of diagnosis of CUPs and might improve the prognosis of patients with CUPs. Case presentation A 76-year old male with an adenocarcinoma of unknown primary origin in the lung presented with another tumor of the palate mucosa. The tumor cells in the pleural effusion were all negative for immunohistochemical markers (TTF-1 and Napsin A) and lung-specific oncogenic driver alterations (EGFR mutation and ALK translocation). The tumor of the palate mucosa was likewise identified as an adenocarcinoma, and the cells showed cytological similarities with the tumor cells in the pleural effusion; TTF-1, Napsin A, EGFR mutation and ALK translocation were all negative. This result suggested that origins of the tumors of the palate mucosa and in the lung were the same, even though the origin had not yet been determined. Next, we addressed whether the tumor of the palate mucosa was a primary tumor or not. Secretory carcinoma (SC), which is a common type of minor salivary gland tumor (MSGT), was suspected; however, mammaglobin was negative and ETV6-NTRK3 (EN) fusion was not observed. Other MSGTs were excluded based on histological and immunohistochemical findings. Furthermore, an additional examination demonstrated an oncogenic KRAS mutation at codon 12 (p.G12D) in both palate tumor and in pleural effusion. KRAS mutation is known to exist in one-third of lung adenocarcinomas (LUADs), but quite rare in MSGTs. The possibility of metastasis from other organs was considered unlikely from the results of endoscopic and imaging studies. This result indicated that the primary site of the CUP was indeed the lung, and that the tumor of the palate mucosa was a metastasis of the LUAD. Conclusions A tumor of the palate mucosa that showed diagnostic difficulties was determined to be a metastatic LUAD by genomic alterations and histopathological findings.