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.

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.

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.

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.

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.

Gender differences in pharmacokinetics of perfluoropentanoic acid using non-linear mixed-effect modeling in rats.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been used in various industrial applications for many years. Long-chain PFASs are ubiquitous in wildlife and are reported to have a long elimination half-life in biological systems. Moreover, significant gender difference exists in the elimination of PFASs, where less is eliminated in male than in female. Recently, PFASs manufacturers and agencies have tried to replace the use of long-chain PFASs with short-chain PFASs, since they are expected to exhibit less bioaccumulation potential. Nevertheless, the potential risk and the pharmacokinetic (PK) characteristics of the short-chain PFASs still remain unknown. This study aims to fill the knowledge gap on short-chain PFASs, perfluoropentanoic acid (PFPeA), in terms of its PK properties using non-linear mixed-effect modeling and to explore gender differences in rats. Animal studies were carried out following oral or intravenous administration of PFPeA in male and female rats at a dose of 0.5-10 mg/kg. Plasma, urine, feces and nine tissues were collected and analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. PK findings revealed that the clearance and the inter-compartmental clearance were 1.75 and 3.12 times higher in female rats than in male rats, respectively. According to the result, PFPeA is eliminated more rapidly in female rats than in male rats. Also, the tissue distribution study confirmed that distribution characteristics exhibited gender difference. This study provides scientific evidence for conducting further investigation into short-chain PFASs, biomonitoring plans and decision making regarding human health risk assessment.

Clinicopathological Significance of EBV-Infected Gastric Carcinomas: A Meta-Analysis.

Background and objectives: The present study aims to elucidate the clinicopathologic significance of Epstein-Barr virus (EBV) infection in gastric carcinomas (GCs) through a meta-analysis. Materials and Methods: Sixty-one eligible studies were included in the present meta-analysis. The included patients, with and without EBV infection, were 2063 and 17,684, respectively. We investigated the clinicopathologic characteristics and various biomarkers, including programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs). Results: The estimated EBV-infected rate of GCs was 0.113 (95% confidence interval (CI): 0.088-0.143). The EBV infection rates in GC cells were 0.138 (95% CI: 0.096-0.194), 0.103 (95% CI: 0.077-0.137), 0.080 (95% CI: 0.061-0.106), and 0.042 (95% CI: 0.016-0.106) in the population of Asia, America, Europe, and Africa, respectively. There was a significant difference between EBV-infected and noninfected GCs in the male: female ratio, but not other clinicopathological characteristics. EBV infection rates were higher in GC with lymphoid stroma (0.573, 95% CI: 0.428-0.706) than other histologic types of GCs. There were significant differences in high AT-rich interactive domain-containing protein 1A (ARID1A) and PD-L1 expressions, and high CD8+ TILs between EBV-infected and noninfected GCs. Conclusions: Our results showed that EBV infection of GCs was frequently found in male patients and GCs with lymphoid stroma. EBV infection was significantly correlated with ARID1A and PD-L1 expressions and CD8+ TILs in GCs.

Metastatic Lymph Node Ratio (mLNR) is a Useful Parameter in the Prognosis of Colorectal Cancer; A Meta-Analysis for the Prognostic Role of mLNR.

Background and objectives: The presenting study aimed to elucidate the prognostic role of the metastatic lymph node ratio (mLNR) in patients with colorectal cancer (CRC), using a meta-analysis. Materials and Methods: Using data from 90,274 patients from 14 eligible studies, we performed a meta-analysis for the correlation between mLNR and survival rate. Besides, subgroup analyses were performed, based on tumor stage, tumor location, and mLNR. Results: A high mLNR showed significant correlation with worse overall survival and disease-free survival rates in CRC patients (hazard ratio (HR), 1.617, 95% confidence interval (CI) 1.393-1.877, and HR 2.345, 95% CI 1.879-2.926, respectively). In patients with stage III, who had regional LN metastasis, the HRs were 1.730 (95% CI 1.266-2.362) and 2.451 (95% CI 1.719-3.494) for overall and disease-free survival, respectively. According to tumor location, rectal cancer showed a worse survival rate when compared to colon cancer. In the analysis for overall survival, when mLNR was 0.2, HR was the highest across the different subgroups (HR 5.040, 95% CI 1.780-14.270). However, in the analysis for disease-free survival, the subgroup with an mLNR < 0.2 had a higher HR than the other subgroups (HR 2.878, 95% CI 1.401-5.912). Conclusions: The mLNR may be a useful prognostic factor for patients with CRC, regardless of the tumor stage or tumor location. Further studies are necessary for the detailed criteria of mLNR before its application in daily practice.

Suppression of c-Myc enhances p21WAF1/CIP1 -mediated G1 cell cycle arrest through the modulation of ERK phosphorylation by ascochlorin.

Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, other genes such as the proto-oncogene c-Myc are promising targets for anticancer therapy. In the present study, we provide evidence that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 cell cycle arrest and p21WAF1/CIP1 expression by downregulating of c-Myc protein expression. Ascochlorin promoted the G1 arrest, upregulated p53 and p21WAF1/CIP1 , and downregulated c-Myc in HCT116 cells. In p53-deficient cells, ascochlorin enhanced the expression of G1 arrest-related genes except p53. Small interfering RNA (siRNA) mediated c-Myc silencing indicated that the transcriptional repression of c-Myc was related to ascochlorin-mediated modulation of p21WAF1/CIP1 expression. Ascochlorin suppressed the stabilization of the c-Myc protein by inhibiting ERK and P70S6K/4EBP1 phosphorylation, whereas it had no effect on c-Myc degradation mediated by PI3K/Akt/GSK3ß. The ERK inhibitor PD98059 and siRNA-mediated ERK silencing induced G1 arrest and p21WAF1/CIP1 expression by downregulating c-Myc in p53-deficient cells. These results indicated that ascochlorin-induced G1 arrest is associated with the repression of ERK phosphorylation and c-Myc expression. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for ERK/c-Myc.

t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists.

A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki=0.1nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

Brd4 is displaced from HPV replication factories as they expand and amplify viral DNA.

Replication foci are generated by many viruses to concentrate and localize viral DNA synthesis to specific regions of the cell. Expression of the HPV16 E1 and E2 replication proteins in keratinocytes results in nuclear foci that recruit proteins associated with the host DNA damage response. We show that the Brd4 protein localizes to these foci and is essential for their formation. However, when E1 and E2 begin amplifying viral DNA, Brd4 is displaced from the foci and cellular factors associated with DNA synthesis and homologous recombination are recruited. Differentiated HPV-infected keratinocytes form similar nuclear foci that contain amplifying viral DNA. We compare the different foci and show that, while they have many characteristics in common, there is a switch between early Brd4-dependent foci and mature Brd4-independent replication foci. However, HPV genomes encoding mutated E2 proteins that are unable to bind Brd4 can replicate and amplify the viral genome. We propose that, while E1, E2 and Brd4 might bind host chromatin at early stages of infection, there is a temporal and functional switch at later stages and increased E1 and E2 levels promote viral DNA amplification, displacement of Brd4 and growth of a replication factory. The concomitant DNA damage response recruits proteins required for DNA synthesis and repair, which could then be utilized for viral DNA replication. Hence, while Brd4 can enhance replication by concentrating viral processes in specific regions of the host nucleus, this interaction is not absolutely essential for HPV replication.

Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists.

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K(i(CAP))=0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists.

A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

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.

Sex, age, and species differences of perfluorooctanoic acid modeled by flow- versus permeability-limited physiologically-based pharmacokinetic models.

This study aimed to investigate sex, age, and species differences of perfluorooctanoic acid (PFOA) using physiologically-based pharmacokinetic (PBPK) models in rats and humans. PBPK models were generally developed as either flow- or permeability-limited models. The flow-limited model is cost-effective and allows for human PK prediction through simple allometric scaling, while the permeability-limited model can incorporate detailed information on the disposition process through in vitro-in vivo extrapolation (IVIVE). PFOA was administered via oral or intravenous administration with 5 mg/kg in male and female rats of different ages and the data was used to develop the PBPK models. Our results showed that both models successfully captured sex differences in rats, while only the flow-limited model with male rats and the permeability-limited model with both male and female rats provided comparable predictions in the human clinical study. More than the flow-limited model, the permeability-limited model effectively explained sex differences in rats and species differences through IVIVE. Additionally, the ontogeny-based mechanistic description of PFOA disposition enabled the interpretation of age- and sex-dependent pharmacokinetics. Although the flow-limited PBPK model lacked mechanistic interpretability compared to the permeability-limited model, it demonstrated reliable human prediction through simple allometric scaling. In conclusion, the permeability PBPK model could interpret age, sex, and species differences and it could improve the accuracy of human prediction.

Cytochrome P450 regulation by α-tocopherol in Pxr-null and PXR-humanized mice.

The pregnane X receptor (PXR) has been postulated to play a role in the metabolism of α-tocopherol owing to the up-regulation of hepatic cytochrome P450 (P450) 3A in human cell lines and murine models after α-tocopherol treatment. However, in vivo studies confirming the role of PXR in α-tocopherol metabolism in humans presents significant difficulties and has not been performed. PXR-humanized (hPXR), wild-type, and Pxr-null mouse models were used to determine whether α-tocopherol metabolism is influenced by species-specific differences in PXR function in vivo. No significant difference in the concentration of the major α-tocopherol metabolites was observed among the hPXR, wild-type, and Pxr-null mice through mass spectrometry-based metabolomics. Gene expression analysis revealed significantly increased expression of Cyp3a11 as well as several other P450s only in wild-type mice, suggesting species-specificity for α-tocopherol activation of PXR. Luciferase reporter assay confirmed activation of mouse PXR by α-tocopherol. Analysis of the Cyp2c family of genes revealed increased expression of Cyp2c29, Cyp2c37, and Cyp2c55 in wild-type, hPXR, and Pxr-null mice, which suggests PXR-independent induction of Cyp2c gene expression. This study revealed that α-tocopherol is a partial agonist of PXR and that PXR is necessary for Cyp3a induction by α-tocopherol. The implications of a novel role for α-tocopherol in Cyp2c gene regulation are also discussed.

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.

Application of Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung and Trachea Exposure of Pyronaridine and Artesunate in Hamsters.

A fixed-dose combination of pyronaridine and artesunate, one of the artemisinin-based combination therapies, has been used as a potent antimalarial treatment regimen. Recently, several studies have reported the antiviral effects of both drugs against severe acute respiratory syndrome coronavirus two (SARS-CoV-2). However, there are limited data on the pharmacokinetics (PKs), lung, and trachea exposures that could be correlated with the antiviral effects of pyronaridine and artesunate. The purpose of this study was to evaluate the pharmacokinetics, lung, and trachea distribution of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) using a minimal physiologically-based pharmacokinetic (PBPK) model. The major target tissues for evaluating dose metrics are blood, lung, and trachea, and the nontarget tissues were lumped together into the rest of the body. The predictive performance of the minimal PBPK model was evaluated using visual inspection between observations and model predictions, (average) fold error, and sensitivity analysis. The developed PBPK models were applied for the multiple-dosing simulation of daily oral pyronaridine and artesunate. A steady state was reached about three to four days after the first dosing of pyronaridine and an accumulation ratio was calculated to be 1.8. However, the accumulation ratio of artesunate and dihydroartemisinin could not be calculated since the steady state of both compounds was not achieved by daily multiple dosing. The elimination half-life of pyronaridine and artesunate was estimated to be 19.8 and 0.4 h, respectively. Pyronaridine was extensively distributed to the lung and trachea with the lung-to-blood and trachea-to-blood concentration ratios (=Cavg,tissue/Cavg,blood) of 25.83 and 12.41 at the steady state, respectively. Also, the lung-to-blood and trachea-to-blood AUC ratios for artesunate (dihydroartemisinin) were calculated to be 3.34 (1.51) and 0.34 (0.15). The results of this study could provide a scientific basis for interpreting the dose-exposure-response relationship of pyronaridine and artesunate for COVID-19 drug repurposing.

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.