ABSTRACT
Despite several screening levels for NDMA reported in water, soil, air, and drugs, the human risk assessment using biomonitoring concentrations has not been performed. In this study, gender-specific exposure guidance values were determined in humans, then biomonitoring measurements in healthy Korean subjects (32 men and 40 women) were compared to the exposure guidance values to evaluate the current exposure level to NDMA. For the human risk assessment of NDMA, the gender-specific physiologically based pharmacokinetic (PBPK) model was developed in humans using proper physiological parameters, partition coefficients, and biochemical parameters. Using the PBPK model, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty on the single model predictions. The PBPK modeling and Monte Carlo simulation allowed the estimation of the relationship between external dose and blood concentration for the risk assessment. The procedure for the human risk assessment was summarized as follows: (1) estimating a steady-state blood concentration (Cavg) corresponding to the daily no observed adverse effect level (NOAEL) administration in rats; (2) applying uncertainty factors (UFs) for deriving the human Cavg; (3) determining the exposure guidance values as screening criteria; (4) interpreting the human biomonitoring measurements by forward and reverse dosimetry approaches. Using the biomonitoring concentrations, current daily exposures to NDMA were estimated to be 3.95 µg/day/kg for men and 10.60 µg/day/kg for women, respectively. The result of the study could be used as a basis for implementing further risk management and regulatory decision-making for NDMA.
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Molecular studies have identified various treatment-related prognostic molecules to enhance the effectiveness of colorectal cancer (CRC) treatment and improve survival rates. The expression of cathepsin V in gastrointestinal cancer cells prompted an investigation into its potential as a prognostic indicator for CRC. The evaluation of cathepsin V expression and its clinicopathological significance was conducted through immunohistochemistry in a tissue microarray, encompassing 142 CRC and normal colorectal tissues. Overall and disease-free survival rates, based on cathepsin V expression levels, were assessed using the Kaplan-Meier method and compared utilizing the log-rank test. Univariate and multivariate analyses, employing a Cox proportional hazards model, were performed to identify prognostic factors. Cathepsin V expression exhibited no correlation with age, sex, tumor location, tumor size, or histological grade. However, it was significantly correlated with depth of tumor invasion, regional lymph node (LN) metastasis, distant metastasis, and lymphovascular involvement (all p<0.001). Overall and disease-free survival rates were significantly better with low cathepsin V expression than with high expression (p<0.001). Univariate analysis identified several prognostic factors, including histological grade (low vs. high), tumor size (≤ vs. >5â¯cm), tumor depth (T1 vs. ≥T2), regional LN metastasis, distant metastasis, tumor-node-metastasis (TNM) stage (Stage I vs ≥II), lymphovascular involvement, and cathepsin V expression. Multivariate analysis revealed that tumor depth, distant metastasis, and cathepsin V expression are independent predictors of poor survival. Cathepsin V is frequently expressed in CRC, and its high expression is associated with poor prognosis. Therefore, cathepsin V is a useful prognostic marker for CRC.
ABSTRACT
Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (Vss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × Wb) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials.
Subject(s)
Artemisinins , Artesunate , Drug Repositioning , Naphthyridines , Artesunate/pharmacokinetics , Artesunate/pharmacology , Drug Repositioning/methods , Animals , Rats , Dogs , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Artemisinins/pharmacokinetics , Species Specificity , Humans , Models, Biological , Male , Antimalarials/pharmacokinetics , Antimalarials/pharmacologyABSTRACT
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 5â¯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.
Subject(s)
Caprylates , Fluorocarbons , Models, Biological , Permeability , Species Specificity , Caprylates/pharmacokinetics , Fluorocarbons/pharmacokinetics , Animals , Male , Female , Humans , Rats , Age Factors , Rats, Sprague-Dawley , Sex Factors , Administration, Oral , Sex CharacteristicsABSTRACT
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.
Subject(s)
Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Precision Medicine , Receptor, ErbB-2 , Humans , Female , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Male , Middle Aged , Aged , Adult , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Aged, 80 and over , Immunohistochemistry , High-Throughput Nucleotide Sequencing , Gene AmplificationABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Carcinogens , Dimethylnitrosamine , Rats , Humans , Animals , Dimethylnitrosamine/toxicity , Carcinogens/toxicity , Tissue Distribution , Lung , Liver , Models, BiologicalABSTRACT
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.
ABSTRACT
It has been suggested that stress responses induced by fasting have analgesic effects on nociception by elevating the levels of stress-related hormones, while there is limited understanding of pain control mechanisms. Here, we investigated whether acute or intermittent fasting alleviates formalin-induced pain in mice and whether spinal orexin A (OXA) plays a role in this process. 6, 12, or 24 h acute fasting (AF) and 12 or 24 h intermittent fasting (IF) decreased the second phase of pain after intraplantar formalin administration. There was no difference in walking time in the rota-rod test and distance traveld in the open field test in all groups. Plasma corticosterone level and immobility time in the forced swim test were increased after 12 h AF, but not after 12 h IF. 12 h AF and IF increased not only the activation of OXA neurons in the lateral hypothalamus but also the expression of OXA in the lateral hypothalamus and spinal cord. Blockade of spinal orexin 1 receptor with SB334867 restored formalin-induced pain and spinal c-Fos immunoreactivity that were decreased after 12 h IF. These results suggest that 12 h IF produces antinociceptive effects on formalin-induced pain not by corticosterone elevation but by OXA-mediated pathway.
Subject(s)
Acute Pain , Mice , Animals , Orexins/pharmacology , Formaldehyde/toxicity , Intermittent Fasting , Corticosterone/pharmacology , Analgesics/pharmacology , Spinal Cord/metabolism , Orexin Receptors/metabolismABSTRACT
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.
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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.
Subject(s)
Colorectal Neoplasms , Endometrial Neoplasms , Stomach Neoplasms , Female , Humans , Prognosis , Proportional Hazards Models , Disease-Free SurvivalABSTRACT
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.
Subject(s)
Antineoplastic Agents , Peripheral Nervous System Diseases , Rats , Mice , Male , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Rats, Sprague-Dawley , Median Nerve/metabolism , Mice, Inbred ICR , Pain , AnalgesicsABSTRACT
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.
Subject(s)
Carcinoma , Epstein-Barr Virus Infections , Stomach Neoplasms , Humans , Epstein-Barr Virus Infections/complications , Prognosis , Herpesvirus 4, Human , Microsatellite Instability , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Angiotensin-converting enzyme inhibitor (ACEi) inhibits the catalysis of angiotensin I to angiotensin II and the degradation of substance P (SP) and bradykinin (BK). While the possible relationship between ACEi and SP in nociceptive mice was recently suggested, the effect of ACEi on signal transduction in astrocytes remains unclear. OBJECTIVES: This study examined whether ACE inhibition with captopril or enalapril modulates the levels of SP and BK in primary cultured astrocytes and whether this change modulates PKC isoforms (PKCα, PKCßI, and PKCε) expression in cultured astrocytes. METHODS: Immunocytochemistry and Western blot analysis were performed to examine the changes in the levels of SP and BK and the expression of the PKC isoforms in primary cultured astrocytes, respectively. RESULTS: The treatment of captopril or enalapril increased the immunoreactivity of SP and BK significantly in glial fibrillary acidic protein-positive cultured astrocytes. These increases were suppressed by a pretreatment with an angiotensin-converting enzyme. In addition, treatment with captopril increased the expression of the PKCßI isoform in cultured astrocytes, while there were no changes in the expression of the PKCα and PKCε isoforms after the captopril treatment. The captopril-induced increased expression of the PKCßI isoform was inhibited by a pretreatment with the neurokinin-1 receptor antagonist, L-733,060, the BK B1 receptor antagonist, R 715, or the BK B2 receptor antagonist, HOE 140. CONCLUSIONS: These results suggest that ACE inhibition with captopril or enalapril increases the levels of SP and BK in cultured astrocytes and that the activation of SP and BK receptors mediates the captopril-induced increase in the expression of the PKCßI isoform.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Captopril , Receptors, Bradykinin , Substance P , Animals , Mice , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Astrocytes , Captopril/pharmacology , Enalapril , Peptidyl-Dipeptidase A , Protein Kinase C-alpha , Receptors, Bradykinin/metabolism , Substance P/pharmacologyABSTRACT
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.
ABSTRACT
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.
Subject(s)
Margins of Excision , Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Prostatectomy/methods , Neoplasm Grading , Neoplasm Recurrence, Local/pathology , Prostate-Specific AntigenABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.