稲村 健太郎

Neuroendocrine carcinoma (NEC) is a rare and aggressive malignancy derived from multiple body parts, with the urogenital organs being the second-largest extrapulmonary sites. The detailed mechanism of bladder NEC pathogenesis remains unknown. We reviewed data from 23 patients diagnosed with NEC from urogenital organs (bladder and prostate) and conducted targeted sequencing of 523 cancer-related genes, focusing on bladder NEC. While 14 cases featured a pure NEC histology, the remaining nine cases included NEC histology mixed with other tumors, such as urothelial carcinoma (UC) or adenocarcinoma. Median overall survival in the entire cohort was 11.1 months, and survival curves were comparable between pure NEC and NEC of mixed appearance. Major mutations detected in the NEC component were in TP53 (38%), TERT promoter (31%), PIK3CA (25%), histone-modification genes (19%), and RB1 (19%). The BARD1 frameshift variant related to homologous recombination was also detected in one patient. More than half of the patients had a high total mutational burden (TMB; ≥10), including two with a TMB ≥45. Intriguingly, at least one identical gene variant in driver genes was detected between NEC and non-NEC (UC) components in the four bladder specimens analyzed. These results highlight the possibility of shared genetic background between bladder NEC and UC. Additionally, several cases harbored druggable gene alterations as presented by TMB-high. Our presentation of the histopathological and molecular features of NEC may help clarify the underlying mechanisms and contribute to efficient treatment of the disease.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors that occur in the adrenal medulla and extra-adrenal tissues, respectively. The prognosis and tumor microenvironment (TME) of pseudohypoxic PPGL as a major entity have not been fully described. Based on the clinical database of 65 patients with PPGL, we assessed the morphological features as well as the immunohistochemistry of pseudohypoxia-related proteins (SDHB and CAIX) and TME-related immune cell markers. Furthermore, we compared the relapse-free survival (RFS) rates in localized patients between the pathological subgroups. Among 50 available specimens, 84% and 30% of the cases exhibited at least one morphological adverse feature including vascular/capsular invasion and a Ki-67 index > 3%, respectively. The SDHB and CAIX positivity rates were 81% and 51%. Concerning the immune cell markers, the CD163-positive cell numbers were higher in hypoxia-associated PPGL composed of SDHB-negative or CAIX-positive cases than in non-hypoxia PPGL (median 66 vs. 23/mm2). Concerning prognosis, RFS rates were significantly lower in cases with Ki-67 indices > 3% and SDHB-negativity than in those with Ki-67 indices ≤ 3% and SDHB-positivity (3-year rate: 64% vs. 100%, P < 0.001; 57% vs. 100%, P = 0.03). In contrast, RFS was comparable between CAIX-positive and CAIX-negative PPGL cases. Our analyses suggested that SDHB-deficient PPGL exhibited a higher incidence of relapse. Furthermore, M2 macrophage infiltration in TME might be crucial in pseudohypoxic PPGL pathogenesis.

Colibactin, a genotoxin produced by Escherichia coli strains harboring the polyketide synthetase (pks) gene cluster, causes DNA damage and somatic mutations. pks+E. coli is enriched in primary colorectal cancer (CRC) and is associated with clonal driver mutations, but its role in CRC liver metastasis is unclear. We assessed the association of pks+ E. coli in CRC liver metastasis tissues with systemic and local immune responses and the number of organs involved in recurrence using specimens and clinicopathological data from 239 patients with CRC liver metastasis who underwent metastasectomy. The levels of pks+E. coli in fresh-frozen specimens were quantified as "very low" (<50th percentile), "low" (50th to 75th percentiles), and "high" (>75th percentile) using a digital PCR. Immunohistochemical analysis of tumor-infiltrating immune cells was performed using tissue microarrays. Systemic inflammation was evaluated using serum C-reactive protein (CRP) levels. pks+E. coli was detected in 66.7% (157 of 239) liver metastasis tissues. Higher levels of pks+E. coli were associated with decreased serum CRP levels and reduced densities of CD4+ cells and CD163+ cells in the tumor-immune microenvironment. The "high" pks+ E. coli group had fewer metastatic organs involved than the "very low" pks+ E. coli group (mean number of organs: 1.00 vs. 1.23). These findings suggest that pks+E. coli play a modulating role in CRC metastasis.

The presence of Fusobacterium nucleatum is associated with an immunosuppressive tumor immune microenvironment (TIM) in primary colorectal cancer (CRC), contributing to tumor progression. Its persistence in CRC liver metastasis tissues raises questions about its role in modulating local and systemic immune responses and influencing recurrence patterns. This retrospective cohort study of 218 patients with CRC liver metastasis investigated the association of F. nucleatum in CRC liver metastasis tissues with systemic inflammation, TIM alterations, and the number of metastatic organs involved in recurrence. Two-step polymerase chain reaction (PCR), including digital PCR, detected F. nucleatum in 42% (92/218) of fresh-frozen specimens of CRC liver metastases. Compared with the F. nucleatum-none group, the F. nucleatum-high group showed higher C-reactive protein levels (0.82 vs. 0.22 mg/dL; Ptrend = 0.02), lower numbers of CD8+ cells (33.2 vs. 65.3 cells/mm2; Ptrend = 0.04) and FOXP3+ cells (11.3 vs. 21.7 cells/mm2; Ptrend = 0.01) in the TIM, and a greater number of metastatic organs involved in recurrence (1.6 vs. 1.1; p < 0.001). The presence of F. nucleatum in CRC liver metastasis tissues was associated with increased systemic inflammation, TIM alterations, and a greater number of metastatic organs involved in recurrence. These findings suggest a potential contribution of F. nucleatum to the metastatic propensity of CRC cells and could inform future research to enhance understanding of the interaction between tumor, host, and microbes in the metastatic process.

INTRODUCTION: NUT carcinoma is a rare cancer associated with a poor prognosis. Because of its rarity, its diagnosis is challenging and is usually made by excluding other diagnoses. Immunohistochemical analysis is a reliable technique that contributes to a correct diagnosis, but overestimating the expression of neuroendocrine (NE) markers may result in an incorrect diagnosis. In this study, we established the immunohistochemical phenotypes of NUT carcinoma compared with tumors that mimic its phenotype to identify potential diagnostic pitfalls. METHODS: Eight cases of NUT carcinoma were examined along with eight basaloid squamous cell carcinomas and thirteen cases of small cell carcinoma using an immunohistochemical panel consisting of various antibodies. RESULTS: Of the eight NUT carcinomas, three patients had a smoking history. All the cases examined for INSM1 were positive (6/6, 100%), although the staining was somewhat weak. Among the NE markers, synaptophysin was variably positive in two NUT carcinomas (2/6, 33%); however, all cases were negative for ASCL1, chromogranin A, and CD56. Moreover, the squamous cell markers, p40 and CK5/6, were weakly expressed in 4/6 (67%) and 3/6 (50%) of the NUT carcinomas, respectively. CONCLUSIONS: For tumors with an ambiguous morphology, applying the neuroendocrine phenotype of NUT carcinoma may be misleading; particularly, when distinguishing it from small-cell carcinoma. Similarly, null or weak expression of squamous cell markers may be observed in NUT carcinoma, but this differs from squamous cell carcinoma, which consistently demonstrates strong positivity for squamous cell markers.

Inverted urothelial papilloma (IUP) is a benign neoplasm characterized by a downgrowth of the urothelium beneath the surface of morphologically normal urothelial cells; however, the molecular features of IUP and their association with clinicopathological characteristics are unclear. In this study, we aimed to investigate the mutational landscape, clinicopathological features, genotype-phenotype associations, and spread patterns of IUP. We performed targeted next-generation sequencing of 39 consecutive IUP cases, the largest series investigated to date, and identified oncogenic driver mutations in RAS family genes in 34 cases (87%). HRAS mutations were the most prevalent (28 cases), which included Q61R (15 cases), followed by KRAS (5 cases) and NRAS (1 case) mutations. Characteristic mutations observed in urothelial carcinoma, including those in FGFR3, TP53, or the TERT promoter, were absent. HRAS-mutated IUPs were associated with a history of smoking (P = 0.017) and streaming morphology (P < 0.001), corresponding to the trabecular subtype. In contrast, all KRAS-mutated IUPs occurred in never-smoking patients (P = 0.001) and showed cystic changes in morphology (P = 0.005), corresponding to the glandular subtype. RAS Q61R immunohistochemistry visually revealed the neoplastic nature of the overlying cells and distinct spread patterns of IUP cells within the surface, including pseudoinfiltrative spread. No recurrence or carcinoma development was observed in any of the IUP cases during the follow-up period. Thus, we confirmed the importance of RAS pathway activation in IUP pathogenesis, an association between RAS family gene mutations and IUP subtypes, and the spread patterns of IUP cells within the surface.

AIM: Vessels encapsulating tumor clusters (VETC) represents an adverse prognostic morphological feature of hepatocellular carcinoma (HCC), which is associated with an immunosuppressive tumor immune microenvironment (TIM). However, the underlying factors characterizing the TIM in HCC with a VETC pattern (VETC-positive HCC) remain uncertain. Oncostatin M (OSM), a pleiotropic cytokine of the interleukin-6 family, regulates various biological processes, including inflammation, proliferation, and invasiveness of tumor cells. We aimed to test a hypothesis that OSM is associated with the immunosuppressive TIM of VETC-positive HCC. METHODS: A total of 397 consecutive HCC patients with curative-intent hepatectomy were included. OSM-positive cells and inflammatory cells including CD4-, CD8-, CD163-, and FOXP3-positive cells were immunohistochemically evaluated. We compared VETC-positive and VETC-negative HCCs in terms of the number of these cells. RESULTS: We found the VETC pattern in 62 patients (15.6%). Our analysis revealed a significant decrease in the expression of arginase-1, a marker associated with mature hepatocyte differentiation, in VETC-positive HCC (p = 0.046). The number of tumor-infiltrating OSM-positive cells was significantly low in VETC-positive HCC (p = 0.0057). Notably, in VETC-positive HCC, the number of OSM-positive cells was not associated with vascular invasion, whereas in VETC-negative HCC, an increase in the number of OSM-positive cells was associated with vascular invasion (p = 0.042). CONCLUSIONS: We identified an association between a decrease in OSM-positive cells and the VETC pattern. Additionally, our findings indicate that VETC-positive HCC is characterized by low hepatocyte differentiation and OSM-independent vascular invasion. These findings highlight the potential interaction between VETC-positive HCC cells and their TIM through the reduction of OSM-expressing cells.

Female urethral adenocarcinoma has attracted attention as a rare tumor type based on its differential pathogenesis from its male counterpart. However, to date, our knowledge concerning its immunohistochemical and morphological characteristics remains limited due to the small number of cases studied. In this study, nine consecutive cases of female urethral adenocarcinoma were used for immunohistochemical and morphological characterization of the tumor based on semi-comprehensive immunohistochemical analysis and detailed morphological evaluations. Our immunohistochemical assay revealed two subtypes of female urethral adenocarcinoma with distinctive staining patterns: the CDX2- and PAX8-expressing subtypes. The former stained positive for other intestinal markers (e.g., HNF4α and TFF1) as well (7 of 7 cases); the latter stained negative for these intestinal markers (0 of 2 cases) but stained positive for clear cell carcinoma markers (e.g., Napsin A and HNF1β) (2 of 2 cases). Regarding cytokeratins, the former displayed a CK7- and CK20-positive immunoprofile (7 of 7 cases); the latter exhibited a CK7-positive and CK20-negative immunoprofile (2 of 2 cases). Morphologically, CDX2- and PAX8-expressing subtypes resembled intestinal-type adenocarcinoma and clear cell carcinoma (occurring in gynecological organs), respectively. The semi-comprehensive immunoprofiling data presented in this study can potentially contribute to the correct diagnosis of this rare tumor type. Finally, our study represents an important basis for future investigations aiming to further elucidate the details and origin of female urethral adenocarcinoma, and it can potentially contribute to developing diagnostic and therapeutic strategies for treating this malignancy.

Hepatocellular carcinomas (HCCs) with biliary/progenitor cell features frequently show increased programmed death-ligand 1 (PD-L1) expression, but their response to immunotherapy is not high. One possible explanation for this phenomenon could be the loss of major histocompatibility complex (MHC) class I expression on tumor cells, which impairs the presentation of tumor antigens to cytotoxic T cells. However, the potential correlation between MHC class I loss, biliary/progenitor cell features, and the tumor-immune microenvironment remains largely unexplored. Herein, we hypothesized that MHC class I loss could be associated with biliary/progenitor cell features and potentially impact the tumor-immune microenvironment. To evaluate this hypothesis and gain insight into the characteristics of tumor cells and the tumor-immune microenvironment in HCCs with MHC class I loss, we examined a consecutive series of 397 HCC cases. MHC class I loss was observed in 32 HCCs (8.1%). Lipid-less cytologic morphology was significantly associated with MHC class I loss (P = 0.02). CK19 expression and decreased ARG1 expression, both known as biliary/progenitor cell features, were significantly associated with MHC class I loss (P < 0.05). PD-L1 expression was irrelevant to the MHC class I status. HCCs with MHC class I loss exhibited significantly lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ cells than those with intact MHC class I (all Ps < 0.01). Our study reveals an association between MHC class I loss, biliary/progenitor cell features, and a "cold" tumor-immune microenvironment in HCCs. These insights highlight the potential impact of MHC class I loss on tumor cells and the tumor-immune microenvironment.

The microbiota is widely recognized to influence diverse biological processes, including metabolism, neurological and cardiovascular functions, the inflammatory response and immunity [...].

INTRODUCTION: In Lynch syndrome, urothelial cancer is the third most common cancer, following colorectal and endometrial cancers. Little is known, however, about the efficacy of immune checkpoint inhibitors in the treatment of metastatic urothelial cancer in Lynch syndrome. CASE PRESENTATION: A 49-year-old patient with metastatic urothelial cancer underwent pembrolizumab therapy after platinum-containing chemotherapy. The efficacy of the pembrolizumab therapy was good. Her lung and bone metastatic lesions disappeared in imaging studies and her back pain decreased dramatically. Pathogenic mutations of MSH2 and BRCA2 were found in the DNA extracted from her tumor, and subsequent genetic analysis confirmed the germline pathogenic variant of MSH2. As such, this case was genetically diagnosed as Lynch syndrome. CONCLUSION: We report metastatic urothelial cancer in a patient with Lynch syndrome who demonstrated a radiological complete response to pembrolizumab therapy. Accurate genetic diagnosis can provide useful information to both the patient and their relatives.

INTRODUCTION: Prostatic large-cell neuroendocrine carcinoma is poorly studied. Although several case reports are available, information on the clinicopathological characteristics of this disease is limited, particularly for the de novo (hormone-naive) type. Herein, we report an extremely rare de novo case of this disease with a good prognosis despite a multi-metastatic status. CASE PRESENTATION: An 83-year-old male patient presented with a high serum prostate-specific antigen level and was found to have de novo prostatic large-cell neuroendocrine carcinoma with an adenocarcinoma component upon pathological examination. Diagnosed with stage pT4cN1cM1c, he underwent chemo-hormonal therapy using a luteinizing hormone-releasing hormone antagonist and combined etoposide and cisplatin, which achieved a partial response. The patient has survived for 20 months without progression. CONCLUSION: Although prostatic large-cell neuroendocrine carcinoma is known for its aggressive clinical behavior, the de novo type with an adenocarcinoma component may be sensitive to hormonal therapy and achieve a good prognosis.

The incidence of non-alcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is increasing along with the growing prevalence of metabolic disorders. In this subset, few useful biomarkers are available to narrow down the high-risk group for recurrence. This study aimed to evaluate the prognostic impact of decreased ARG1 (arginase-1), which is pathologically known as a marker reflecting hepatocyte differentiation, in NANV-HCC. Besides, its relationship with biliary/progenitor cell markers, whose expressions are associated with poor prognosis, was also assessed. To reveal the clinicopathological association of decreased ARG1 expression in NANV-HCC, we investigated 99 patients who underwent curative-intent hepatectomy for NANV-HCC. Tissue microarrays were employed for immunohistochemical analysis. A total of 21 NANV-HCC cases (21%; 21/99) showed decreased ARG1 expression. Decreased ARG1 expression was an independent prognostic factor for both poor DFS (hazard ratio 2.17; 95% confidence interval 1.15-4.09; p = 0.02) and OS (hazard ratio 4.09; 95% confidence interval 1.71-9.80; p = 0.002). In addition, decreased ARG1 expression was significantly associated with expressions of biliary/progenitor cell markers, CK19 and CD56 (p < 0.01). As cytologic features of tumor cells, decreased ARG1 expression was significantly associated with lipid-less cytologic morphology (p = 0.045). These findings indicate that decreased ARG1 expression is a predictive phenotype of postoperative recurrence with poor prognosis in patients with NANV-HCC. Decreased ARG1 expression may be a precursor or overlapping feature with biliary/progenitor cell marker expressions in NANV-HCC.

Cancer is generally regarded as a localised disease, with the well-established role of the tumour microenvironment. However, the realm of cancer goes beyond the tumour microenvironment, and cancer should also be regarded as a systemic and environmental disease. The exposome (ie, the totality of exposures), which encompasses diets, supplements, smoking, alcohol, other lifestyle factors, medications, etc, likely alters the microbiome (inclusive of bacteria, viruses, archaea, fungi, parasites, etc) and immune system in various body sites and influences tumour phenotypes. The systemic metabolic/inflammatory status, which is likely influenced by exposures and intestinal physiological changes, may affect tissue microenvironment of colorectum and any other organs. Germline genomic factors can modify disease phenotypes via gene-by-environment interactions. Although challenges exist, it is crucial to advance not only basic experimental research that can analyse the effects of exposures, microorganisms and microenvironmental components on tumour evolution but also interdisciplinary human population research that can dissect the complex pathogenic roles of the exposome, microbiome and immunome. Metagenomic, metatranscriptomic and metabolomic analyses should be integrated into well-designed population research combined with advanced methodologies of artificial intelligence and molecular pathological epidemiology. Ideally, a prospective cohort study design that enables biospecimen (such as stool) collection before disease detection should be considered to address reverse causation and recall biases. Robust experimental and observational research together can provide insights into dynamic interactions between environmental exposures, microbiota, tumour and immunity during carcinogenesis processes, thereby helping us develop precision prevention and therapeutic strategies to ultimately reduce the cancer burden.

BACKGROUND: Understanding the gene alteration status of primary lung cancers is important for determining treatment strategies, but gene testing is both time-consuming and costly, limiting its application in clinical practice. Here, potential therapeutic targets were selected by predicting gene alterations in cytologic specimens before conventional gene testing. METHODS: This was a retrospective study to develop a cytologic image-based gene alteration prediction model for primary lung cancer. Photomicroscopic images of cytology samples were collected and image patches were generated for analyses. Cancer-positive (n = 106) and cancer-negative (n = 32) samples were used to develop a neural network model for selecting cancer-positive images. Cancer-positive cases were randomly assigned to training (n = 77) and validation (n = 26) data sets. Another neural network model was developed to classify cancer images of the training data set into 4 groups: anaplastic lymphoma kinase (ALK)-fusion, epidermal growth factor receptor (EGFR), or Kirsten rat sarcoma viral oncogene homologue (KRAS) mutated groups, and other (None group), and images of the validation data set were classified. A decision algorithm to predict gene alteration for cases with 3 probability ranks was developed. RESULTS: The accuracy and precision for selecting cancer-positive patches were 0.945 and 0.991, respectively. Predictive accuracy for the EGFR and KRAS groups in the validation data set was ~0.95, whereas that for the ALK and None groups was ~0.75 and ~ 0.80, respectively. Gene status was correctly predicted in the probability rank A cases. The model extracted characteristic conventional cytologic findings in images and a novel specific feature was discovered for the EGFR group. CONCLUSIONS: A gene alteration prediction model for lung cancers by machine learning based on cytologic images was successfully developed.

BACKGROUND&AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES&RESULTS: We performed RNA-seq of tumor tissues in 113 nonviral HCC patients and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into 3 molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with CTNNB1 mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T-cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Steatotic HCC patients, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

Introduction: The eight TNM classification of lung tumors provides a more precise prediction of prognosis than previous classification systems, especially in T1 tumors, the invasion size of which are less than or equal to 3 cm. T1 is divided into T1a (6-10 mm), T1b (11-20 mm), and T1c (21-30 mm), but the relationship between pathologic T (pT)1 categories and other pathologic factors has not been thoroughly evaluated. Methods: Surgically resected pulmonary adenocarcinomas (N = 551) were extracted on the basis of computed tomography-based tumor size measurements, including 302 pT1a to c cases (pT1a: n = 98, pT1b: n = 156, and pT1c: n = 48). Pathologic factors, including a minor component of micropapillary or solid subtype, were analyzed by new T categories. Recurrence-free and disease-specific survivals (DSSs) were evaluated using univariable and multivariable analyses and Cox proportional hazards models. Results: Lymphatic invasion, vascular invasion, and nodal metastasis increased remarkably from pT1a to pT1c, step-wisely. Visceral pleural invasion was elevated from 7% (6-10 mm) to 33% (21-30 mm) along with an increase in invasion size. Recurrence-free survival (RFS) and DSS relevantly deteriorated from the group of pathologic stages 0, IA1, and IA2 to the group IA3 and IB. Multivariable analysis revealed that lymph node metastasis and solid components were independent prognostic factors for both RFS and DSS in pT1a to c cases. Conclusions: The new TNM classification precisely predicts prognosis. Tumor invasion size is closely associated with lymphatic and vascular invasion, nodal metastasis, and visceral pleural invasion. As a minor component, solid subtype was a potent adverse prognostic factor affecting both RFS and DSS after surgery in T1 categories.

Myxoid liposarcoma (MLPS) is genetically characterized by FUS-DDIT3 or EWSR1-DDIT3 gene fusion and the high frequency of hotspot mutations (C228T or C250T) in the promoter region of telomerase reverse transcriptase (TERT) that encodes the TERT protein. The latter leads to telomerase reactivation, a mechanism of telomere maintenance. Although the TERT promoter hotspot mutation is a poor prognostic factor in various tumors, its effect on MLPS has not been reported in detail. In the present study, we examined the clinicopathological characteristics, prognosis, and telomere maintenance mechanisms in 83 primary tumor samples of MLPS, which were resected surgically at the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan, from 2008 to 2020. TERT promoter hotspot mutations were observed in 77% (63/82) cases, and alternative lengthening of telomeres (ALT) was absent in all cases. Among the cases without TERT promoter hotspot mutations, TERT rearrangements, and minor point mutations in the TERT promoter region were found in 3 and 2 cases, respectively. TERT mRNA expression was observed consistently even in patients for whom no genomic TERT aberrations were detected, and the presence of TERT promoter hotspot mutation did not correlate significantly with either overall and metastasis-free survival (P = .56, P = .83, respectively) or clinicopathological features. Therefore, patients with MLPS characteristically shows TERT expression and a high prevalence of TERT aberrations. Our findings suggest that TERT aberration is not prognostic factor, but might occur at an early stage and play a key role in tumorigenesis.

The incidence of non-alcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is increasing along with the growing prevalence of metabolic disorders. In this subset, few useful biomarkers are available to narrow down the high-risk group for recurrence. This study aimed to evaluate the prognostic impact of decreased ARG1 (arginase-1), which is pathologically known as a marker reflecting hepatocyte differentiation, in NANV-HCC. Besides, its relationship with biliary/progenitor cell markers, whose expressions are associated with poor prognosis, was also assessed. To reveal the clinicopathological association of decreased ARG1 expression in NANV-HCC, we investigated 99 patients who underwent curative-intent hepatectomy for NANV-HCC. Tissue microarrays were employed for immunohistochemical analysis. A total of 21 NANV-HCC cases (21%; 21/99) showed decreased ARG1 expression. Decreased ARG1 expression was an independent prognostic factor for both poor DFS (hazard ratio 2.17; 95% confidence interval 1.15-4.09; p = 0.02) and OS (hazard ratio 4.09; 95% confidence interval 1.71-9.80; p = 0.002). In addition, decreased ARG1 expression was significantly associated with expressions of biliary/progenitor cell markers, CK19 and CD56 (p < 0.01). As cytologic features of tumor cells, decreased ARG1 expression was significantly associated with lipid-less cytologic morphology (p = 0.045). These findings indicate that decreased ARG1 expression is a predictive phenotype of postoperative recurrence with poor prognosis in patients with NANV-HCC. Decreased ARG1 expression may be a precursor or overlapping feature with biliary/progenitor cell marker expressions in NANV-HCC.

ABSTRACT: Nonalcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is considered to occur in steatotic livers; however, emerging evidence indicates that a subset of NANV-HCC occurs in nonsteatotic livers. Currently, little information is available regarding this subset. This study sought to provide the clinical and pathological features of NANV-HCC in nonsteatotic livers.We retrospectively investigated the clinicopathological features of 101 consecutive patients with NANV-HCC treated with a curative-intent hepatectomy. A background liver with <5% steatosis by area was regarded as a nonsteatotic liver. Survivals of patient subgroups were estimated using the Kaplan-Meier method, and log-rank tests were conducted to assess the survival difference. Multivariate analysis was performed with the Cox proportional hazards method.Overall, 34 of 101 patients with NANV-HCC were found to have a nonsteatotic liver. Vascular invasion of the tumor was more frequently observed in patients with a nonsteatotic liver than in those with a steatotic liver (P = .03). The extent of lobular inflammation and fibrosis did not differ between patients with and without steatosis in the liver. NANV-HCC with a nonsteatotic liver was independently associated with a shorter disease-free survival (DFS) (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.21-3.80; P = .009) and a shorter overall survival (OS) (HR 2.79; 95% CI 1.27-6.16; P = .01) than NANV-HCC with a steatotic liver.The absence of steatosis in the liver is independently associated with shorter DFS and OS in patients with NANV-HCC. Our findings indicate that nonsteatotic liver can be a surrogate phenotype of aggressive NANV-HCC.

BACKGROUND: Reports on the prognostic significance of serum γ-glutamyltransferase (GGT) in men with metastatic castration-resistant prostate cancer (mCRPC) are limited. In addition, GGT expression status in cancer tissues has not been well characterized regardless of cancer types. METHODS: This retrospective study included 107 consecutive men with mCRPC receiving docetaxel therapy. The primary endpoints were associations of serum GGT with overall survival (OS) and prostate-specific antigen (PSA) response. The secondary endpoint was an association of serum GGT with progression-free survival (PFS). Additionally, GGT expression status was immunohistochemically semi-quantified using tissue microarrays. RESULTS: A total of 67 (63%) men died during follow-up periods (median 22.5 months for survivors). On multivariable analysis, high Log GGT was independently associated with adverse OS (HR 1.49, p = 0.006) as were low hemoglobin (HR 0.79, p = 0.002) and high PSA (HR 1.40, p < 0.001). In contrast, serum GGT was not significantly associated with PSA response or PFS. Moreover, incorporation of serum GGT into established prognostic models (i.e., Halabi and Smaletz models) increased their C-indices for predicting OS from 0.772 to 0.787 (p = 0.066) and from 0.777 to 0.785 (p = 0.118), respectively. Furthermore, there was a positive correlation between serum and tissue GGT levels (ρ = 0.53, p = 0.003). CONCLUSIONS: Serum GGT may be a prognostic biomarker in men with mCRPC receiving docetaxel therapy. GGT overexpression by prostate cancer cells appears to be responsible for the elevation of GGT in the serum.

Introduction: Metastatic renal cell carcinoma is treated with various regimens. As their outcomes are improving and follow-up periods are growing longer, the rate of unusual visceral metastases may increase. Case presentation: A 68-year-old man diagnosed with lung, pancreatic, and renal metastases 9 years after left partial nephrectomy and a diagnosis of pT1a clear cell renal cell carcinoma started molecular targeted therapy using sunitinib. Nine years after the initiation of targeted therapy, a mass lesion in the esophagus was revealed by follow-up computed tomography, and endoscopic mucosal resection of the esophageal metastatic lesion was performed. One year later, a bladder tumor was detected by follow-up computed tomography. The patient underwent transurethral resection of the bladder tumor. Histological evaluation of both resected specimens disclosed clear cell renal cell carcinoma. Conclusion: We present a valuable case of metachronous esophagus and bladder metastases from renal cell carcinoma in a long-term follow-up.

The microbiota influences human health and the development of diverse diseases, including cancer. Microbes can influence tumor initiation and development in either a positive or negative manner. In addition, the composition of the gut microbiota affects the efficacy and toxicity of cancer therapeutics as well as therapeutic resistance. The striking impact of microbiota on oncogenesis and cancer therapy provides compelling evidence to support the notion that manipulating microbial networks represents a promising strategy for treating and preventing cancer. Specific microbes or the microbial ecosystem can be modified via a multiplicity of processes, and therapeutic methods and approaches have been evolving. Microbial manipulation can be applied as an adjunct to traditional cancer therapies such as chemotherapy and immunotherapy. Furthermore, this approach displays great promise as a stand-alone therapy following the failure of standard therapy. Moreover, such strategies may also benefit patients by avoiding the emergence of toxic side effects that result in treatment discontinuation. A better understanding of the host-microbial ecosystem in patients with cancer, together with the development of methodologies for manipulating the microbiome, will help expand the frontiers of precision cancer therapeutics, thereby improving patient care. This review discusses the roles of the microbiota in oncogenesis and cancer therapy, with a focus on efforts to harness the microbiota to fight cancer.

PURPOSE: We aimed to investigate atypical papillary renal cell carcinoma (PRCC) presenting with early contrast enhancement and late washout and to investigate the correlation between the CT attenuation value of the corticomedullary phase (CMP) of contrast-enhanced CT in PRCCs and the endothelial cell counts of these tumors. METHODS: Twenty-two patients with pathologically confirmed PRCC were enrolled in this study. PRCCs were categorized into 18 typical PRCCs and 4 atypical PRCCs. The CT attenuation value of the lesion in the CMP was measured in the maximal section of the tumor using the region of interest. Microvessel density (MVD) was evaluated as a histopathologic parameter using tissue specimens immunohistochemically stained with an anti-ERG antibody. The CT attenuation value and MVD were compared between atypical and typical PRCCs using the Mann-Whitney U test, where p < 0.05 was considered significant. The correlations between CT attenuation value and MVD were evaluated in all PRCCs using single linear regression analysis. RESULTS: The mean CT attenuation value and the MVD were significantly higher in atypical than in typical PRCCs. Correlation analyses revealed a weak positive correlation between the CT attenuation value and MVD. CONCLUSIONS: We confirmed several cases of atypical PRCC that present with early contrast enhancement, such as clear cell renal cell carcinoma. In addition, a positive correlation was found between the CT attenuation value in the CMP of PRCCs and the vascular endothelial cell count.

BACKGROUND: Prostate cancer spans a broad spectrum from indolent to deadly disease. In the management of prostate cancer, diagnostic biopsy specimens are important sources of data that inform the selection of treatment. B7-H3 (CD276), an immune checkpoint molecule, has emerged as a promising immunotherapy target. B7-H3 expression is related to adverse clinical outcomes in various types of cancer; however, little is known concerning the association between tumor B7-H3 expression in diagnostic biopsy specimens and clinical outcome in patients with metastatic prostate cancer. METHODS: We evaluated tumor B7-H3 expression levels in diagnostic biopsy specimens from 135 patients with metastatic prostate cancer and 113 patients with localized prostate cancer. RESULTS: High B7-H3 expression was more frequently observed in patients with metastatic cancer than in those with localized cancer (31 vs. 12%; p = 0.0003). In patients with localized cancer, the B7-H3 expression status was not associated with biochemical recurrence-free survival. However, among patients with metastatic cancer, high B7-H3 expression was independently associated with high disease-specific mortality (multivariable hazard ratio [HR] = 2.72; p = 0.047) and overall mortality rates (multivariable HR = 2.04; p = 0.025). CONCLUSIONS: Tumor B7-H3 expression in diagnostic biopsy specimens may be a useful biomarker for identifying highly aggressive metastatic prostate cancer. Given the potential utility of anti-B7-H3 immunotherapy, this information may aid in stratifying prostate cancer based on its responsiveness to B7-H3-targeted treatment.