Clinicopathologic and Molecular Characteristics of HER2 (ERBB2)-Altered Non-Small Cell Lung Cancer: Implications for Precision Medicine.

The heterogeneous relationship between protein expression, amplification, and mutations in human epidermal growth factor receptor 2 (HER2) in non-small cell lung cancer (NSCLC) and the optimal methods for detecting these alterations remain unclear. We aimed to elucidate the clinicopathological and molecular characteristics of HER2-altered NSCLC and investigate practical approaches for identifying patients who might benefit from HER2-targeted therapies. Using next-generation sequencing data from 1680 individuals, we searched for patients with HER2-altered NSCLCs, including amplifications and mutations. Clinicopathological data and tissue slides were reviewed. Immunohistochemistry (IHC) and silver in situ hybridization were performed according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Our analysis identified 89 (5.3%) patients with HER2-altered NSCLCs, comprising 30 (1.8%) with amplification and 59 (3.6%) mutations, and they were compared with 165 control patients. Of the 59 HER2-mutated cases, 52 harbored tyrosine kinase domain (TKD) mutations, primarily HER2 exon 20 insertions. HER2 TKD alterations were associated with younger age, female sex, nonsmoking status, adenocarcinoma with a micropapillary pattern, lung-to-lung metastasis, and poor overall survival. The 33 patients with TKD mutations and 3 with non-TKD point mutations showed incomplete or complete membranous HER2 immunoreactivity (1+ and 2+, 61.07%). Six patients exhibiting amplifications had an IHC score of ≤2+ despite their high copy numbers and concomitantly displayed other actionable EGFR, KRAS, SMARCA4, and other HER2 mutations. These HER2-altered NSCLCs with molecular coalterations showed heterogeneous patterns through HER2 IHC and silver in situ hybridization. Therefore, next-generation sequencing should be used to identify HER2 mutations in patients with NSCLC who present with concomitant alterations. In addition, the above clinicopathological characteristics and HER2 IHC results can be valuable determinants for identifying patients with HER2-altered NSCLC. These insights hold promise for the development of more effective diagnostic and therapeutic strategies for this complex subset of NSCLC patients.

Digital Validation in Breast Cancer Needle Biopsies: Comparison of Histological Grade and Biomarker Expression Assessment Using Conventional Light Microscopy, Whole Slide Imaging, and Digital Image Analysis.

Given the widespread use of whole slide imaging (WSI) for primary pathological diagnosis, we evaluated its utility in assessing histological grade and biomarker expression (ER, PR, HER2, and Ki67) compared to conventional light microscopy (CLM). In addition, we explored the utility of digital image analysis (DIA) for assessing biomarker expression. Three breast pathologists assessed the Nottingham combined histological grade, its components, and biomarker expression through the immunohistochemistry of core needle biopsy samples obtained from 101 patients with breast cancer using CLM, WSI, and DIA. There was no significant difference in variance between the WSI and CLM agreement rates for the Nottingham grade and its components and biomarker expression. Nuclear pleomorphism emerged as the most variable histologic component in intra- and inter-observer agreement (kappa ≤ 0.577 and kappa ≤ 0.394, respectively). The assessment of biomarker expression using DIA achieved an enhanced kappa compared to the inter-observer agreement. Compared to each observer's assessment, DIA exhibited an improved kappa coefficient for the expression of most biomarkers with CLM and WSI. Using WSI to assess prognostic and predictive factors, including histological grade and biomarker expression in breast cancer, is acceptable. Furthermore, incorporating DIA to assess biomarker expression shows promise for substantially enhancing scoring reproducibility.

Comparison between Peritumoral and Intratumoral Budding in Colorectal Cancer.

Tumor budding (TB) is classified, based on location, into peritumoral budding (PTB) or intratumoral budding (ITB). This study aimed to evaluate the relationship between PTB and ITB in colorectal cancers (CRCs). PTB and ITB were investigated and subsequently divided into high and low groups. CRCs were divided into three groups: (1) high PTB/ITB, (2) high PTB or ITB, and (3) low PTB/ITB. The clinicopathological and prognostic significances were evaluated according to the three tumor budding (TB) groups. High PTB/ITB and low PTB/ITB were identified in 32 (12.0%) and 135 (50.8%) patients, respectively. A total of 99 patients (37.2%) were found to have high PTB or ITB. TB was significantly correlated with lymphatic and perineural invasion, lymph node metastasis, metastatic lymph node ratio, distant metastasis, and a higher pTNM stage. A significant correlation was found between high PTB and high ITB (p = 0.010). The amount of PTB was found to increase significantly with the amount of ITB (p < 0.001) in a linear regression test. Patients with high PTB/ITB had worse overall and recurrence-free survival than those with high PTB or ITB. Conversely, patients with low PTB/ITB had better overall and recurrence-free survival rates than those with high PTB or ITB. However, there was no significant difference in overall and recurrence-free survival between patients with high PTB/low ITB and high ITB/low PTB (p = 0.336 and p = 0.623, respectively). In summary, the presence of TB, regardless of PTB or ITB, was significantly correlated with aggressive tumor behavior and a worse prognosis than the absence of TB. Additionally, the present study demonstrated that it is feasible to stratify the prognosis of patients based on whether they have both PTB and ITB or only one of the two.

Physiologically-based pharmacokinetic model for evaluating gender-specific exposures of N-nitrosodimethylamine (NDMA).

N-nitrosodimethylamine (NDMA) is classified as a human carcinogen and could be produced by both natural and industrial processes. Although its toxicity and histopathology have been well-studied in animal species, there is insufficient data on the blood and tissue exposures that can be correlated with the toxicity of NDMA. The purpose of this study was to evaluate gender-specific pharmacokinetics/toxicokinetics (PKs/TKs), tissue distribution, and excretion after the oral administration of three different doses of NDMA in rats using a physiologically-based pharmacokinetic (PBPK) model. The major target tissues for developing the PBPK model and evaluating dose metrics of NDMA included blood, gastrointestinal (GI) tract, liver, kidney, lung, heart, and brain. The predictive performance of the model was validated using sensitivity analysis, (average) fold error, and visual inspection of observations versus predictions. Then, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty of the single model predictions. The developed PBPK model was applied for the exposure simulation of daily oral NDMA to estimate blood concentration ranges affecting health effects following acute-duration (≤ 14 days), intermediate-duration (15-364 days), and chronic-duration (≥ 365 days) intakes. The results of the study could be used as a scientific basis for interpreting the correlation between in vivo exposures and toxicological effects of NDMA.

Clinicopathological Significances of Peritumoral Budding in Colorectal Cancer: A Detailed Analysis Based on Mucinous and Micropapillary Pattern.

The present study aimed to evaluate the correlations between peritumoral tumor budding (PTB) and the clinicopathological characteristics of colorectal cancer (CRC) according to histological components. The PTBs were investigated and divided into high and low groups. The clinicopathological significance and prognostic implications of PTB in CRC were evaluated. High PTB was found in 104 of 266 CRCs (39.1%). High PTB was significantly correlated with left-sided tumors, lymphatic invasion, lymph node metastasis, distant metastasis, and high pTNM stage. However, there was no significant correlation between PTB and the other clinicopathological characteristics. PTB was significantly higher in CRCs without the mucinous component than those with the mucinous component (p = 0.008). However, there was no significant difference between CRCs with and without the micropapillary pattern (p = 0.123). Patients with high PTB had worse recurrence-free survival than those with low PTB (p = 0.031). In the subgroup analysis based on histological components, a significant correlation between PTB and recurrence-free survival was found in CRC with a micropapillary pattern but not in those without a micropapillary pattern (p = 0.010 and p = 0.178, respectively). These findings indicate that high PTB is significantly correlated with aggressive tumor behaviors and worse survival in patients with CRC. However, the prognostic implications of PTB can differ according to histological components.

Diagnostic roles of PAX8 immunohistochemistry in ovarian tumors.

OBJECTIVE: This study aimed to elucidate the diagnostic roles of PAX8 immunohistochemistry in various ovarian tumors. METHODS: We searched through the PubMed database and selected the eligible studies to perform the meta-analysis. The PAX8 immunohistochemical expression rates of various ovarian tumors, including primary and metastatic carcinomas, were analyzed. In addition, the subgroup analysis based on tumor behaviors was performed. RESULTS: The PAX8 expression rates were 0.056 (95% confidence interval [CI] 0.008-0.307), 0.400 (95% CI 0.228-0.600), 0.741 (95% CI 0.578-0.857), and 0.738 (95% CI 0.666-0.799) in normal ovary and benign, borderline, and malignant ovarian tumors, respectively. The PAX8 expression rates of serous and transitional cell carcinomas were 0.937 (95% CI 0.882-0.967) and 0.918 (95% CI 0.841-0.959). In addition, the PAX8 expression rate of mucinous carcinomas was 0.393 (95% CI 0.285-0.512). However, metastatic carcinomas showed a significantly lower PAX8 expression rate than primary ovarian cancers (P < 0.001 in the meta-regression test). In cytologic specimens, PAX8 expression rates of serous and endometrioid carcinomas were 0.905 (95% CI 0.832-0.948) and 0.714 (95% CI 0.327-0.928), respectively. CONCLUSION: PAX8 expression rate was significantly higher in serous ovarian tumors than in mucinous ovarian tumors. In addition, PAX8 expression rates were significantly higher in primary ovarian cancers than in metastatic carcinomas.

Significance of Tumor-Stroma Ratio (TSR) in Predicting Outcomes of Malignant Tumors.

Background and Objectives: The present study aimed to elucidate the distribution and the prognostic implications of tumor-stroma ratio (TSR) in various malignant tumors through a meta-analysis. Materials and Methods: This meta-analysis included 51 eligible studies with information for overall survival (OS) or disease-free survival (DFS), according to TSR. In addition, subgroup analysis was performed based on criteria for high TSR. Results: The estimated rate of high TSR was 0.605 (95% confidence interval (CI) 0.565-0.644) in overall malignant tumors. The rates of high TSR ranged from 0.276 to 0.865. The highest rate of high TSR was found in endometrial cancer (0.865, 95% CI 0.827-0.895). The estimated high TSR rates of colorectal, esophageal, and stomach cancers were 0.622, 0.529, and 0.448, respectively. In overall cases, patients with high TSR had better OS and DFS than those with low TSR (hazard ratio (HR) 0.631, 95% CI 0.542-0.734, and HR 0.564, 95% CI 0.0.476-0.669, respectively). Significant correlations with OS were found in the breast, cervical, colorectal, esophagus, head and neck, ovary, stomach, and urinary tract cancers. In addition, there were significant correlations of DFS in breast, cervical, colorectal, esophageal, larynx, lung, and stomach cancers. In endometrial cancers, high TSR was significantly correlated with worse OS and DFS. Conclusions: The rate of high TSR was different in various malignant tumors. TSR can be useful for predicting prognosis through a routine microscopic examination of malignant tumors.

Analgesic efficacy of median nerve stimulation in mice with chemotherapy-induced peripheral neuropathymodulation of brain-derived neurotrophic factor expression.

OBJECTIVE: Chemotherapeutic agents such as docetaxel (DTX) can trigger chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by unbearable pain. This study was designed to investigate the analgesic effect and related neuronal mechanism of low-frequency median nerve stimulation (LFMNS) on DTX-induced tactile hypersensitivity in mice. METHODS: To produce CIPN, DTX was administered intraperitoneally 4 times, once every 2 d, to male ICR mice. LFMNS was performed on the wrist area, and the pain response was measured using von Frey filaments on both hind paws. Western blot and immunofluorescence staining were performed using dorsal root ganglion and spinal cord samples to measure the expression of brain-derived neurotrophic factor (BDNF). RESULTS: Repeated LFMNS significantly attenuated the DTX-induced abnormal sensory response and suppressed the enhanced expression of BDNF in the DRG neurons and spinal dorsal area. CONCLUSIONS: LFMNS might be an effective non-pharmaceutical option for treating patients suffering from CIPN regulating the expression of peripheral and central BDNF.

Prognostic Implication of EBV Infection in Gastric Carcinomas: A Systematic Review and Meta-Analysis.

Background and objectives: This study aims to elucidate the prognostic implications of Epstein-Barr virus (EBV) infection in gastric carcinomas (GCs) through a systematic review and meta-analysis. Materials and Methods: In total, 57 eligible studies and 22,943 patients were included in this meta-analysis. We compared the prognoses of EBV-infected and non-infected GC patients. The subgroup analysis was performed based on the study location, molecular classification, and Lauren's classification. This study was checked according to the PRISMA 2020. The meta-analysis was performed using the Comprehensive Meta-Analysis software package. Results: EBV infection was found in 10.4% (95% confidence interval (CI) 0.082-0.131) of GC patients. The EBV-infected GC patients had a better overall survival compared with the EBV-non-infected GC patients (hazard ratio (HR) 0.890, 95% CI 0.816-0.970). In the subgroup analysis based on molecular classification, no significant differences were found between EBV+ and microsatellite instability and microsatellite stable (MSS)/EBV- subgroups (HR 1.099, 95% CI 0.885-1.364 and HR 0.954, 95% CI 0.872-1.044, respectively). In the diffuse type of Lauren's classification, EBV-infected GCs have a better prognosis compared with the EBV-non-infected GCs (HR 0.400, 95% CI 0.300-0.534). The prognostic impact of EBV infection was found in the Asian and American subgroups but not in the European subgroup (HR 0.880, 95% CI 0.782-0.991, HR 0.840, 95% CI 0.750-0.941, and HR 0.915, 95% CI 0.814-1.028). Conclusions: EBV infection is a favorable survival factor for GCs. However, the prognostic implications of EBV infection in the new molecular classification are not clear.

Clinicopathological implications of histological mapping in radical prostatectomy specimens.

OBJECTIVE: The present study aims to elucidate the clinicopathological implications of histological mapping in radical prostatectomy specimens. METHODS: This study included 76 prostatic cancers with histological mapping. The examined characteristics from the histological mappings were the largest tumor dimension, distance from the tumor core to resection margin, tumor dimension from the apex to base, tumor volume, tumor surface area, and proportion of the tumor. In addition, these histological parameters from the histological mapping were compared between patients with positive surgical margin (PSM) and negative surgical margin (NSM). RESULTS: Patients with PSM were significantly correlated with a higher Gleason score and pT stage than those with NSM. Among the histological characteristics from mappings, there were significant correlations between PSM and the largest tumor dimension, tumor volume, tumor surface area, and proportion of tumor (P < 0.001, P < 0.001, P < 0.001, and P = 0.017, respectively). The distance from the tumor core to the resection margin was significantly longer with PSM than with NSM (P = 0.024). According to the linear regression test, the tumor volume, tumor surface area, and largest tumor dimension were significantly correlated with Gleason score and grade (P = 0.019, P = 0.036, and P = 0.016, respectively). There were no significant differences in the histological factors between the apical and non-apical involved subgroups. CONCLUSION: Various clinicopathological characteristics assessed from the histological mappings, such as the tumor volume, tumor surface area, and proportion of the tumor, can be useful for interpreting PSM after radical prostatectomy.

A Standardized Pathology Report for Gastric Cancer: 2nd Edition.

The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.

A standardized pathology report for gastric cancer: 2nd edition.

The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.

Prognostic Implications of Intratumoral Budding in Colorectal Cancer: Detailed Analysis Based on Tumor-Infiltrating Lymphocytes.

BACKGROUND: This study aims to understand the clinical and pathological importance of intratumoral budding (ITB) in colorectal cancer (CRC) and its relationship with tumor-infiltrating lymphocytes (TILs). CRCs can be classified into hot (high immunoscore (IS)) and cold (low IS) tumors. METHODS: We investigated the number of ITBs in a hotspot area and categorized them into high-ITB (≥5) and low-ITB (<5) groups. The clinicopathological significance of ITB in human CRCs was evaluated, and a detailed analysis based on tumor-infiltrating lymphocytes (TILs) was also performed. RESULTS: High ITB was identified in 59 of 266 CRC cases (22.2%). High ITB significantly correlated with a poorly differentiated tumor, lympho-vascular invasion, perineural invasion, higher pT stage, lymph node metastasis, and higher metastatic lymph node ratio. High ITB was also significantly correlated with a low IS and low CD8-positive lymphocytic infiltrate. The number of ITBs was substantially higher in the low-IS group than in the high-IS group (3.28 ± 3.31 vs. 2.19 ± 2.59; p = 0.005). High ITB significantly correlated with worse overall survival (p = 0.004). In the low-IS group, CRCs with high ITB had a significantly worse prognosis than those with low ITB (p = 0.021). However, there was no significant difference in prognosis between the high- and low-ITB groups in the high-IS group (p = 0.498). CONCLUSIONS: Taken together, high ITB was significantly correlated with aggressive tumor behaviors and worse survival in patients with CRCs. In addition, ITB can be useful for the prognostic stratification of CRCs with low IS.

Clinicopathological Significances and Prognostic Role of Intratumoral Budding in Colorectal Cancers.

BACKGROUND: This study aims to evaluate the clinicopathological significance and prognostic implications of intratumoral budding (ITB) in colorectal cancers (CRCs) through a meta-analysis. METHODS: We performed the meta-analysis using 13 eligible studies and investigated the rates of CRCs with high ITB. The correlation between ITB and clinicopathological characteristics, including disease-free survival, was evaluated. RESULTS: The estimated rate of CRCs with high ITB was 0.233 (95% confidence interval (CI) 0.177-0.299) in overall CRCs. High ITB was significantly correlated with tumor grade, lymphatic invasion, perineural invasion, pT stage, and lymph node metastasis. In addition, ITBs were more frequently found in medullary and signet-ring cell carcinomas than in conventional adenocarcinomas and mucinous carcinomas. However, the high ITB rate was not correlated with tumor border, tumor-infiltrating lymphocytes, or microsatellite instability. CRCs with a good response after neoadjuvant therapy revealed a lower rate of high ITB than those with a poor response (hazard ratio (HR) 0.114, 95% CI 0.070-0.179 vs. 0.321, 95% CI 0.204-0.467). In addition, CRCs with high ITB had a worse disease-free survival than those with low ITB (HR 1.426, 95% CI 1.092-1.863). CONCLUSIONS: The ITB was significantly correlated with aggressive tumor behaviors and a worse prognosis in CRCs. The detection of ITB, as a histological parameter, can be useful for predicting clinicopathologic features and the prognosis of CRC.

Impacts of Outdoor Particulate Matter Exposure on the Incidence of Lung Cancer and Mortality.

Background and objectives: Long-term exposure to air pollution has been associated with lung cancer. This study aimed to evaluate the relative risk (RR) and hazard ratio (HR) of lung cancers and the prognostic implication of outdoor particulate matter (PM) pollution using a meta-analysis. Materials and Methods: We performed the meta-analysis using 19 eligible studies and evaluated the PMs, dividing into PM smaller than 2.5 µm (PM2.5) and PM smaller than 10 µm (PM10). In addition, subgroup analyses, based on the increment of PM exposure, location, sex, smoking history, and tumor histology, were performed. Results: Lung cancer was significantly increased by exposure to PM2.5 (RR 1.172, 95% confidence interval (CI) 1.002-1.371), but not PM10 exposure. However, there was no significant correlation between PM10 exposure and the incidence of lung cancers (RR 1.062, 95% CI 0.932-1.210). The all-cause and lung-cancer-specific mortalities were significantly increased by PM2.5 exposure (HR 1.1.43, 95% CI 1.011-1.291 and HR 1.144, 95% CI 1.002-1.307, respectively). However, PM10 exposure significantly increased the all-cause mortality, but not the lung-cancer-specific mortality. The lung-cancer-specific mortality was significantly increased by PM10 per 12.1 µg/m3 increment and in the Europe area. Conclusions: PM2.5 significantly increased lung cancer and the all-cause and lung-cancer-specific mortalities, whereas PM10 did not increase lung cancer or lung-cancer-specific mortality. However, PM10 increased the all-cause mortality and the PM10 per 12.1 µg/m3 increment and PM10 in the Europe area may increase the lung-cancer-specific mortality.

Characterization of Poorly Cohesive and Signet Ring Cell Carcinomas and Identification of PTPRM as a Diagnostic Marker.

Background and aims. Signet ring cell (SRC) and poorly cohesive (PC) gastric carcinomas are morphologically similar but exhibit different biological behavior. We compared the clinical and molecular characteristics of SRC and PC carcinomas. Methods. Diffuse-type gastric cancer (GC) cases were classified into SRC carcinomas (>90% of SRCs), PC carcinomas (<10% of SRCs), and combined PC/SRC carcinomas (≤90% but ≥10% of SRCs). The gene expression patterns in SRC and PC carcinomas were examined by transcriptome and protein immunohistochemistry analyses, and diagnostic and prognostic biomarkers were identified. Results. SRC and PC carcinomas showed significantly different clinical behaviors but shared common RNA expression patterns. PC carcinomas showed an increased expression of genes related to cancer progression. Among genes differentially expressed between PC and SRC carcinomas, protein tyrosine phosphatase receptor type M (PTPRM) was overexpressed in PC and related to unfavorable clinical factors. Conclusion. We found that PC and SRC carcinomas had distinct clinical characteristics and should be classified as different carcinoma types. PTPRM was identified as a potential diagnostic and prognostic biomarker for PC carcinomas and could represent a potential therapeutic target.

Sigma-1 receptor increases intracellular calcium in cultured astrocytes and contributes to mechanical allodynia in a model of neuropathic pain.

Recent studies have revealed that glial sigma-1 receptor (Sig-1R) in the spinal cord may be a critical factor to mediate sensory function. However, the functional role of Sig-1R in astrocyte has not been clearly elucidated. Here, we determined whether Sig-1Rs modulate calcium responses in primary cultured astrocytes and pathological changes in spinal astrocytes, and whether they contribute to pain hypersensitivity in naïve mice and neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve in mice. Sig-1R was expressed in glial fibrillary acidic protein (GFAP)-positive cultured astrocytes. Treatment with the Sig-1R agonist, PRE-084 or neurosteroid dehydroepiandrosterone (DHEA) increased intracellular calcium responses in cultured astrocytes, and this increase was blocked by the pretreatment with the Sig-1R antagonist, BD-1047 or neurosteroid progesterone. Intrathecal administration of PRE-084 or DHEA for 10 days induced mechanical and thermal hypersensitivity and increased the number of Sig-1R-immunostained GFAP-positive cells in the superficial dorsal horn (SDH) region of the spinal cord in naïve mice, and these changes were inhibited by administration with BD-1047 or progesterone. In CCI mice, intrathecal administration of BD-1047 or progesterone at post-operative day 14 suppressed the developed mechanical allodynia and the number of Sig-1R-immunostained GFAP-positive cells that were increased in the SDH region of the spinal cord following CCI of the sciatic nerve. These results demonstrate that Sig-1Rs play an important role in the modulation of intracellular calcium responses in cultured astrocytes and pathological changes in spinal astrocytes and that administration of BD-1047 or progesterone alleviates the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced mechanical allodynia.

Standardization of the pathologic diagnosis of appendiceal mucinous neoplasms.

Although the understanding of appendiceal mucinous neoplasms (AMNs) and their relationship with disseminated peritoneal mucinous disease have advanced, the diagnosis, classification, and treatment of AMNs are still confusing for pathologists and clinicians. The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists (GPSG-KSP) proposed a multicenter study and held a workshop for the "Standardization of the Pathologic Diagnosis of the Appendiceal Mucinous Neoplasm" to overcome the controversy and potential conflicts. The present article is focused on the diagnostic criteria, terminologies, tumor grading, pathologic staging, biologic behavior, treatment, and prognosis of AMNs and disseminated peritoneal mucinous disease. In addition, GPSG-KSP proposes a checklist of standard data elements of appendiceal epithelial neoplasms to standardize pathologic diagnosis. We hope the present article will provide pathologists with updated knowledge on how to handle and diagnose AMNs and disseminated peritoneal mucinous disease.

Clinicopathological Significances of Tumor-Stroma Ratio (TSR) in Colorectal Cancers: Prognostic Implication of TSR Compared to Hypoxia-Inducible Factor-1α Expression and Microvessel Density.

The present study aimed to elucidate the clinicopathological significance and prognostic implications of tumor-stroma ratio (TSR) in colorectal cancers (CRCs). TSRs were investigated in 266 human CRC specimens. The correlations between TSR and clinicopathological characteristics and survival were evaluated. The hypoxia-inducible factor-1α (HIF-1α) immunohistochemical expression of tumor cells and microvessel density (MVD) of stroma were compared between stroma-low and stroma-high subgroups. Results: Stroma-low was found in 185 of 266 CRCs (69.5%). Stroma-low was significantly correlated with less frequent vascular and perineural invasion and distant metastasis than stroma-high. HIF-1α of tumor cells was more highly expressed in the stroma-high subgroup than in the stroma-low subgroup. In addition, MVD was significantly higher in the stroma-high subgroup compared to the stroma-low subgroup. The stroma-low rate was increased considerably in CRCs with a mucinous component and decreased in CRCs with a micropapillary component. There were significant correlations between stroma-low and better overall and recurrence-free survivals. Similar to the literature, we observed that stroma-low was significantly correlated with favorable tumor behaviors and better survival. The microscopic examination of TSR can be useful for predicting the prognosis of CRC patients.

Plasma fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxachola-4,6-dien-24-oic acid indicate severity of liver cirrhosis.

Two 3-oxo-Δ4 fetal bile acids, 3-oxachola-4,6-dien-24-oic acid (1) and 7α-hydroxy-3-oxochol-4-en-24-oic acid (2), occur normally in the human fetus but remain elevated in neonates and children with severe cholestatic liver disease due to an autosomal recessive inborn error of metabolism affecting Δ4-3-oxo-steroid 5ß-reductase (AKR1D1). Relatively little is known about 1 and 2 in adult patients with liver disease. The chemical synthesis of 1 and 2 is therefore described and their quantitation in plasma by ultrarapid chromatography-triple quadrupole mass spectrometry. Plasma concentrations of 1 and 2 were investigated in 25 adult patients with varying degrees of liver cirrhosis with and without hepatocellular carcinoma (HCC). Highly statistically significant correlations (P < 0.0001) were found between severity of liver cirrhosis, determined by the Child-Pugh and MELD scores, with plasma 1 and 2 concentrations, both alone and combined. The presence of HCC did not influence these correlations. Plasma cholic, chenodeoxycholic, deoxycholic, lithocholic or ursodeoxycholic acids, free and as their glycine or taurine conjugates, did not correlate with Child-Pugh or MELD score when corrected for multiple comparisons. These findings demonstrate that plasma levels of fetal bile acids 3-oxachola-4,6-dien-24-oic acid and 7α-hydroxy-3-oxochol-4-en-24-oic acid and likely deteriorating AKR1D1 activity indicate the severity of liver cirrhosis measured by the Child-Pugh and MELD scores.