Remarkable remission of symptomatic dermatomyositis after curative breast cancer surgery.

Dermatomyositis (DM) is an autoimmune disease that causes proximal muscle weakness in the extremities leading to severe immobility and dysphagia. Approximately 20% of patients with DM are positive for anti-TIF-1γ antibody and frequently accompanied by malignant tumors. Although DM remission after tumor resection has been reported, the indications for surgery in patients with severe DM are unknown. Herein, we report a case of a 79-year-old Japanese woman who presented with breast cancer and anti-TIF-1γ antibody-positive DM. She became bedridden shortly after DM onset. Although pulsed steroid therapy, intravenous immunoglobulin, tacrolimus, and endocrine therapy with fulvestrant did not improve her symptoms, tumor resection with axillary lymph node dissection resulted in complete remission of the DM after 8 months. Immunohistochemistry revealed high expression of TIF-1γ in cancer cells, both in the primary tumor and axillary lymph nodes. Since the serum levels of anti-TIF-1γ antibody decreased after the surgery, the existence of breast cancer with TIF-1γ expression may have contributed to the worsening of DM. The present case suggests that curative surgery should be considered as a treatment option even if the patient has severe symptoms, such as immobility and dysphagia. Careful discussions with patients and multidisciplinary collaboration are essential to make surgery feasible, particularly for those with severe symptomatic DM.

Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.

AIMS: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function. METHODS: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates. RESULTS: A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m2 ). The final kinetic-pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased. CONCLUSIONS: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.

Comparison of the efficacy of anti-diabetic medications as add-on to metformin in type 2 diabetes mellitus from a real-world database.

BACKGROUND: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A1c levels. METHODS: This retrospective cohort study used a medical information database in Japan. Non-insulin anti-hyperglycemic agents with different mechanisms of action were classified into eight drug classes. A monotherapy cohort and a combination therapy added to the metformin cohort were defined. The change in hemoglobin A1c levels was evaluated to compare the treatment effect between the cohorts. RESULTS: A total of 13,359 patients with type 2 diabetes mellitus in the monotherapy cohort and 1,064 in the metformin combination therapy cohort were identified. A comparison of the change from baseline HbA1c level by drug class between the two cohorts showed a similar trend. Among those treated with dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter-2 inhibitor, no clinically significant difference was observed between the two cohorts (0.00% and -0.07% for unadjusted, 0.15% and -0.03% for propensity score matching-adjusted, and 0.09% and -0.01% for inverse probability treatment weighting-adjusted analysis). CONCLUSIONS: According to the results of this study, the effect of dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor added to metformin seems to be additive with respect to the reduction in hemoglobin A1c.

Performance of dedicated breast PET in breast cancer screening: comparison with digital mammography plus digital breast tomosynthesis and ultrasound.

OBJECTIVE: To compare the diagnostic performance of dedicated breast positron emission tomography (dbPET) in breast cancer screening with digital mammography plus digital breast tomosynthesis (DM-DBT) and breast ultrasound (US). METHODS: Women who participated in opportunistic whole-body PET/computed tomography cancer screening programs with breast examinations using dbPET, DM-DBT, and US between 2016-2020, whose results were determined pathologically or by follow-up for at least 1 year, were included. DbPET, DM-DBT, and US assessments were classified into four diagnostic categories: A (no abnormality), B (mild abnormality), C (need for follow-up), and D (recommend further examination). Category D was defined as screening positive. Each modality's recall rate, sensitivity, specificity, and positive predictive value (PPV) were calculated per examination to evaluate their diagnostic performance for breast cancer. RESULTS: Out of 2156 screenings, 18 breast cancer cases were diagnosed during the follow-up period (10 invasive cancers and eight ductal carcinomas in situ [DCIS]). The recall rates for dbPET, DM-DBT, and US were 17.8%, 19.2%, and 9.4%, respectively. The recall rate of dbPET was highest in the first year and subsequently decreased to 11.4%. dbPET, DM-DBT, and US had sensitivities of 72.2%, 88.9%, and 83.3%; specificities of 82.6%, 81.4%, and 91.2%; and PPVs of 3.4%, 3.9%, and 7.4%, respectively. The sensitivities of dbPET, DM-DBT, and US for invasive cancers were 90%, 100%, and 90%, respectively. There were no significant differences between the modalities. One case of dbPET-false-negative invasive cancer was identified in retrospect. DbPET had 50% sensitivity for DCIS, while that of both DM-DBT and US was 75%. Furthermore, the specificity of dbPET in the first year was the lowest among all periods, and modalities increased over the years to 88.7%. The specificity of dbPET was significantly higher than that of DM-DBT (p < 0.01) in the last 3 years. CONCLUSIONS: DbPET had a compatible sensitivity to DM-DBT and breast US for invasive breast cancer. The specificity of dbPET was improved and became higher than that of DM-DBT. DbPET may be a feasible screening modality.

Hyperkalemia by eplerenone or esaxerenone in the presence or absence of clarithromycin in hypertensive patients: a retrospective observational cohort study.

OBJECTIVE: Mineralocorticoid receptor antagonists (MRAs), eplerenone and esaxerenone, cause hyperkalemia dose-dependently. We investigated the cytochrome P450 3A4-mediated drug-drug interaction between the MRAs and clarithromycin. METHODS: This retrospective observational study included adult hypertensive patients with MRA plus clarithromycin or MRA alone with a propensity score matching (1:1). The difference in serum potassium level (ΔK, maximum level - baseline level) between groups was compared using the Mann-Whitney U -test. Linear regression analysis was used to detect variables that correlated with ΔK in patients with MRA plus clarithromycin. RESULTS: After propensity score matching (each nine patients), serum potassium level was elevated after treatment with MRA plus clarithromycin [4.3 (3.5 to 5.1) meq/l to 4.9 (4.0 to 5.5) meq/l, P  = 0.0234] and MRA alone [4.3 (4.0 to 4.7) meq/l to 4.6 (4.4 to 5.2) meq/l, P  = 0.0469]. Although there was no significant difference in ΔK between groups [MRA plus clarithromycin: 0.5 (0.1 to 1.1) meq/l vs. MRA alone: 0.3 (0.1 to 1.2) meq/l, P  = 0.7231], ΔK was significantly higher in esaxerenone plus clarithromycin than in esaxerenone alone [0.6 (0.5 to 1.1) meq/l vs. 0.1 (0.1 to 0.2) meq/l, P  = 0.0495]. Conversely, clarithromycin did not show a significant effect on ΔK in patients with eplerenone [0.4 (-0.2 to 1.2) meq/l vs. 0.8 (0.1 to 1.3) meq/l, P  = 0.5745]. A positive correlation was found between ΔK and age in patients with MRA plus clarithromycin ( y  = 0.03 ×  x - 1.38, r  = 0.71, P  = 0.0336). CONCLUSION: The drug-drug interaction between MRAs and clarithromycin was evident, particularly in esaxerenone. Serum potassium levels should be closely monitored in older patients.

Reproducibility assessment of uptake on dedicated breast PET for noise discrimination.

OBJECTIVES: Dedicated breast PET (dbPET) systems have improved the detection of small breast cancers but have increased false-positive diagnoses due to an increased chance of noise detection. This study examined whether reproducibility assessment using paired images helped to improve noise discrimination and diagnostic performance in dbPET. METHODS: This study included 21 patients with newly diagnosed breast cancer who underwent [18F]FDG-dbPET and contrast-enhanced breast MRI. A 10-min dbPET data scan was acquired per breast, and two sets of reconstructed images were generated (named dbPET-1 and dbPET-2, respectively), each of which consisted of randomly allocated 5-min data from the 10-min data. Uptake spots higher than the background were indexed for the study with visual assessment. All indexed uptakes on dbPET-1 were evaluated using dbPET-2 for reproducibility. MRI findings based on the Breast Imaging-Reporting and Data System (BI-RADS) 2013 were used as the gold standard. Uptake spots that corresponded to BI-RADS 1 on MRI were considered noise, while those with BI-RADS 4b-6 were considered malignancies. The diagnostic performance of dbPET for malignancy was evaluated using four different criteria: any uptake on dbPET-1 regarded as positive (criterion A), a subjective visual assessment of dbPET-1 (criterion B), reproducibility assessment between dbPET-1 and dbPET-2 (criterion C), and a combination of B and C (criterion D). RESULTS: A total of 213 indexed uptake spots were identified on dbPET-1, including 152, 15, 6, 6, and 34 lesions classified as BI-RADS MRI categories 1, 2, 4b, 4c, and 5, respectively. Overall, 31.9% of the index uptake values were reproducible. All malignant lesions were reproducible, whereas 93.4% of noise was not reproducible. The sensitivities for malignancy for criteria A, B, C, and D were 100%, 91.3%, 100%, and 91.3%, respectively, with positive predictive values (PPVs) of 21.4%, 68.9%, 67.6%, and 82.4%, respectively. CONCLUSIONS: Our results demonstrated that reproducibility assessment helped reduce false-positive findings caused by noise on dbPET without lowering the sensitivity for malignancy. While subjective visual assessment was also efficient in increasing PPV, it occasionally missed malignant uptake.

Multiparametric imaging of breast cancer: An update of current applications.

Imaging plays an indispensable role in the diagnosis and treatment of breast cancer. Several new imaging tools are currently being developed for clinical use to improve diagnostic performance and tumor response evaluation. Abbreviated magnetic resonance imaging (MRI) allows shortening scanning time without penalizing diagnostic performances. Ultrafast dynamic contrast-enhanced MRI is a new approach that provides kinetic information and helps identify breast lesions developed in breast with marked background parenchymal enhancement. Intravoxel incoherent motion and kurtosis are parameters of diffusion-weighted imaging (DWI) that bring useful information in breast cancer. High-resolution DWI, allows morphological assessment of lesions without using a contrast agent. High-resolution breast positron emission tomography provides detailed metabolic information on small breast cancer. Photoacoustic imaging utilizes hemoglobin as an intrinsic contrast agent and depicts fine -branching structure of the tumor vessels related to cancer. It is important that experts in breast imaging understand the advantages and limitations of these new techniques in order to offer optimal imaging to each patient.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of the Analgesic Effects of Pentazocine Using Perioperative Real-World Data.

Pentazocine (PTZ) is a widely used drug for postoperative pain. It should be administered at appropriate dosing intervals not only because of its morphine-like side effects but also because frequent inappropriate dosing can lead to dependence. Although perioperative patients reportedly have nonnegligible effects on placebo drugs and postoperative wound healing, no pharmacokinetic (PK)/pharmacodynamic (PD) model has been established and simulated using real-world data for the perioperative period. This study aimed to perform PTZ modeling and simulation and to establish an indicator of the timing of drug efficacy evaluation in clinical practice. Participants were in-hospital orthopedic surgery patients who received 15 mg of PTZ within 48 h postoperatively. Pain severity was assessed using the numerical rating scale (NRS). A two-compartment model was selected for the population PK model and an indirect response model for the PK/PD model. Using these models, a virtual population of 1000 patients with Painbase NRS of 5 and 6 and body weights of 40, 80, and 120 kg were treated with single and multiple PTZ administrations (4, 8, and 24 h apart) of 15 mg. Simulation results indicate that its analgesic efficacy should be evaluated within 1 h after administration of 15 mg of PTZ. Additional doses should be considered every 8-12 h in postoperative patients with Painbase NRS of 5 weighing 40-80 kg. Simulation using the PK/PD model developed in this study may provide useful information for determining the analgesic effects and timing of the dosing interval after PTZ administration in perioperative patients.

External Evaluation of a Bayesian Warfarin Dose Optimization Based on a Kinetic-Pharmacodynamic Model.

Warfarin is a representative anticoagulant with large interindividual variability. The published kinetic-pharmacodynamic (K-PD) model allows the prediction of warfarin dose requirement in Swedish patients; however, its applicability in Japanese patients is not known. We evaluated the model's predictive performance in Japanese patients with various backgrounds and relationships using Bayesian parameter estimation and sampling times. A single-center retrospective observational study was conducted at Tokyo Women's Medical University, Medical Center East. The study population consisted of adult patients aged >20 years who commenced warfarin with a prothrombin time-international normalized ratio (PT-INR) from June 2015 to June 2019. The published K-PD model modified by Wright and Duffull was assessed using prediction-corrected visual predictive checks, focusing on clinical characteristics, including age, renal function, and individual prediction error. The external dataset included 232 patients who received an initial warfarin daily dose of 3.2 ± 1.28 mg with 2278 PT-INR points (median [range] follow-up period of 23 d [7-28]). Prediction-corrected visual predictive checks carried a propensity for underprediction. Additionally, age >60 years, body mass index ≤25 kg/m2, and estimated glomerular filtration rate ≤60 mL/min/1.73 m2 had a pronounced tendency to underpredict PT-INR. However, Bayesian prediction using four prior observations reduced underprediction. To improve the prediction performance of these special populations, further studies are required to construct a model to predict warfarin dose requirements in Japanese patients.

Development of a simple method for measuring tedizolid concentration in human serum using HPLC with a fluorescent detector.

ABSTRACT: The objective of the present study was to develop a method to measure tedizolid (TZD) concentration for studying target concentration intervention, pharmacokinetics, and pharmacodynamics of TZD. We established a high-performance liquid chromatography-fluorescence detector assay to measure the TZD concentration in serum for clinical application. Chromatographic separation was carried out on a 5 µm octadecyl silane hypersil column 150 mm × 4.6 mm. The mobile phase consisted of 0.1 M phosphoric acid and methanol (60:40, pH 7.0). Detection was performed at 300 nm and 340 nm for the excitation and emission wavelengths, respectively. The average retention times of TZD and the internal standard were 12.9 and 8.8 min, respectively. High linearity was exhibited over a concentration range of 0.025 to 10.0 µg/mL for TZD (R2 > 0.999). The intra- and inter-assay accuracies of TZD were 99.2% to 107.0% and 99.2% to 107.7%, respectively. The lower limit of quantitation and the lower limit of detection for TZD measurement were 0.025 and 0.01 µg/mL, respectively. The extraction recoveries of TZD were 100.4% to 114.1%.The high-performance liquid chromatography method developed in this study could separate the analytes with a single eluent (isocratic system), within a total run time of 15 min. Both TZD and IS were well separated, without interference from the peaks. Sharp peaks were observed in the chromatograms; problems such as double peaks, shoulder peaks, and broadened peaks were not observed. The proposed method showed acceptable analytical performance and could be used to evaluate serum TZD concentrations in patients.

A Proposed Dedicated Breast PET Lexicon: Standardization of Description and Reporting of Radiotracer Uptake in the Breast.

Dedicated breast positron emission tomography (dbPET) is a new diagnostic imaging modality recently used in clinical practice for the detection of breast cancer and the assessment of tumor biology. dbPET has higher spatial resolution than that of conventional whole body PET systems, allowing recognition of detailed morphological attributes of radiotracer accumulation within the breast. 18F-fluorodeoxyglucose (18F-FDG) accumulation in the breast may be due to benign or malignant entities, and recent studies suggest that morphology characterization of 18F-FDG uptake could aid in estimating the probability of malignancy. However, across the world, there are many descriptors of breast 18F-FDG uptake, limiting comparisons between studies. In this article, we propose a lexicon for breast radiotracer uptake to standardize description and reporting of image findings on dbPET, consisting of terms for image quality, radiotracer fibroglandular uptake, breast lesion uptake.

Usefulness and Prospects of Sentinel Lymph Node Biopsy for Patients With Breast Cancer Using the Medical Imaging Projection System.

BACKGROUND: The Medical Imaging Projection System (MIPS) projects indocyanine green (ICG) fluorescence images directly on the surgical field using a projection mapping technique. We conducted an observational study of sentinel lymph node (SLN) biopsy using the prototype MIPS; we found a high identification rate. However, the number of SLN-positive cases was small, and the sensitivity could not be evaluated. The aim of this study was to investigate the clinical usefulness of the MIPS assisted ICG fluorescence method using commercially available equipment. METHODS: This was a retrospective observational study. Patients with primary breast cancer who underwent SLN biopsy using the MIPS at Kyoto University Hospital from April to December 2020 were included in the study. The primary endpoints were the identification rate of SLNs and detection of positive SLNs by the MIPS. The secondary endpoint was the number of SLNs excised using the MIPS per patient. We also conducted a questionnaire survey focused on the utility of the MIPS; it involved doctors with an experience in using the MIPS. RESULTS: Seventy-nine patients (84 procedures) were included in the study. In 60 (71%) procedures, both the radioisotope (RI) method and MIPS were used. At least one SLN could be detected by the MIPS in all the procedures, with an identification rate of 100% (95% confidence interval 95.6-100%). A total of 19 (7%) positive SLNs were removed, which were identifiable by the MIPS. Among 57 patients in whom the MIPS and RI methods were used, there was no positive SLN only identified by the RI method. The results of the questionnaire survey showed that the MIPS enabled the operator and assistant to share the ICG fluorescence image in the surgical field and to communicate with each other easily. CONCLUSION: The current study demonstrated that the identification rate of SLNs using the MIPS was high, and the MIPS can be used for detecting positive SLNs. It was suggested that the MIPS will be useful in learning SLN biopsy procedures.

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

An artificial neural network-pharmacokinetic model and its interpretation using Shapley additive explanations.

We developed a method to apply artificial neural networks (ANNs) for predicting time-series pharmacokinetics (PKs), and an interpretable the ANN-PK model, which can explain the evidence of prediction by applying Shapley additive explanations (SHAP). A previous population PK (PopPK) model of cyclosporin A was used as the comparison model. The patients' data were used for the ANN-PK model input, and the output by ANN was the clearance (CL). The estimated CL value from the ANN were substituted into the one-compartment with one-order absorption model, the concentrations were calculated, and the parameters of ANN were updated by the back-propagation method. Kernel SHAP was applied to the trained model and the SHAP value of each input was calculated. The root mean squared error for the PopPK model and the ANN-PK model were 41.1 and 31.0 ng/ml, respectively. The goodness of fit plots for the ANN-PK model represented more convergence to y = x compared with that for the PopPK model, with good model performance for the ANN-PK model. The most influential factors on CL output were age and body weight from the evaluation using Kernel SHAP, and these factors were incorporated into the PopPK model as the significant covariates of CL. The ANN-PK model could handle time-series data and showed higher prediction accuracy then the conventional PopPK model, and the scientific validity for the model could be evaluated by applying SHAP. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? A black-box property of an artificial neural network (ANN) decreases the scientific confidence of the model, and making it difficult to utilize the ANN in the medical field. Moreover, difficulty in handling the time-series data is a significant problem for applying the ANN for pharmacometrics study. WHAT QUESTION DID THIS STUDY ADDRESS? How can we apply the ANN for predicting the time-series pharmacokinetics (PKs) , and confirm the scientific validity of the ANN model? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Using the ANN in combination with a conventional compartment (ANN-PK) model enabled to handle the time-series PK data, and the predicting performance of the model was higher than that of the population PK model. Furthermore, we could evaluate the scientific validity of the ANN model by applying the Shapley additive explanations. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? We expect that our study will contribute to develop the interpretable ANN model, which can predict the time-series PKs, drug efficacies, and side effects with high prediction performance.

Quantitative analysis of an impact of P-glycoprotein on edoxaban's disposition using a human physiologically based pharmacokinetic (PBPK) model.

The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 - 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively.

Invasive solid papillary carcinoma with neuroendocrine differentiation of the breast: a case report and literature review.

BACKGROUND: Solid papillary carcinoma (SPC) of the breast is a rare breast cancer that accounts for less than 1% of all breast cancers. The optimal clinical management of SPC remains controversial. Here, we report a case of invasive SPC with neuroendocrine differentiation in addition to review of the current literature. CASE PRESENTATION: A premenopausal 46-year-old female presented with a mass in her left breast that tended to increase in size over a 10-month period. Mammography and ultrasonography revealed a mass in the left upper-inner quadrant. The resulting images suggested a category 3 breast tumor according to the Breast Imaging Reporting and Data System (BI-RADS). A core needle biopsy (CNB) was performed, and the pathological findings showed a solid papillary pattern and atypical cells suggestive of noninvasive SPC. After a left partial mastectomy and sentinel lymph node biopsy (SLNB), the specimens were sent for histopathological analysis for further investigation. Postoperative pathological findings suggested invasive SPC. Whole-breast radiation therapy and adjuvant hormonal therapy were performed as postoperative treatments. Three years after surgery, multiple lung metastases were detected, and the patient was treated with a gonadotropin-releasing hormone agonist and an aromatase inhibitor. Five months later, multiple liver metastases and bone metastases appeared, and oral 5-fluorouracil was chosen for the subsequent treatment. The patient has been treated for 5 years to date, and she is continuing to take oral 5-fluorouracil and is alive without any further disease progression. CONCLUSIONS: We report a rare case of premenopausal invasive SPC with multiple metastases. Further study is needed to clarify the molecular characteristics and clinical behaviors of SPC and to explore the optimal treatment strategy.

Establishment of a clinically relevant specification for dissolution testing using physiologically based pharmacokinetic (PBPK) modeling approaches.

This paper presented how to establish a clinically relevant specification (CRS) using in silico physiologically based pharmacokinetic (PBPK) modeling. Three different formulations of model drug products were used in the clinical studies in order to distinguish between bioequivalent (BE) batches from non-BE batches. A human PBPK model was constructed by integrating the clinical and non-clinical observations by using GastroPlusTM software. The developed model was verified by the comparison between human PK behavior observed in clinical studies and human PK behavior predicted from the software. The simulation results were obtained by using the dissolution profiles showing clinically relevant discriminatory power as input variables for the developed PBPK model. For three investigated formulations, the simulated PK behavior was comparable to the PK behavior observed in clinical studies. In addition, in silico BE simulation studies confirmed that the verified PBPK model can successfully reproduce the clinical study results. In conclusion, a CRS was established with the BE simulation by using the verified PBPK model, in order to detect and reject non-BE batches of drug products. The establishment of the CRS is useful for a quality control and finding optimal formulation to accomplish target PK behavior, safety, and efficacy.

Estrogen Induces Mammary Ductal Dysplasia via the Upregulation of Myc Expression in a DNA-Repair-Deficient Condition.

Mammary ductal dysplasia is a phenotype observed in precancerous lesions and early-stage breast cancer. However, the mechanism of dysplasia formation remains elusive. Here we show, by establishing a novel dysplasia model system, that estrogen, a female hormone, has the potential to cause mammary ductal dysplasia. We injected estradiol (E2), the most active form of estrogen, daily into scid mice with a defect in non-homologous end joining repair and observed dysplasia formation with cell proliferation at day 30. The protooncogene Myc is a downstream target of estrogen signaling, and we found that its expression is augmented in mammary epithelial cells in this dysplasia model. Treatment with a Myc inhibitor reduced E2-induced dysplasia formation. Moreover, we found that isoflavones inhibited E2-induced dysplasia formation. Our dysplasia model system provides insights into the mechanistic understanding of breast tumorigenesis and the development of breast cancer prevention.

Application of a hemodialysis clearance prediction model using quantitative structure-pharmacokinetic relationship analysis.

Hemodialysis (HD) is a method used to remove biogenic substances or blood components that cause disease and some drugs used by patients to treat their diseases. Therefore, dosing schedule must be planned according to HD clearance (CLHD ) when medical treatment is provided to patients receiving HD. We aimed to clarify the physical properties (eg, octanol-water partition coefficient and molecular electronegativity) or pharmacokinetic parameters (eg, volume of distribution) of compounds affecting CLHD and to construct a mathematical model to predict CLHD . The analysis covered individual CLHD data for nine compounds from the literature. The molecular descriptors which are physical properties or pharmacokinetic parameters were calculated using the structural formula of each compound, and searched for factors related to CLHD among the calculated 148 molecular descriptors. Nonlinear mixed-effects model analysis with CLHD as objective variable and molecular descriptors as explanatory variable was conducted to examine the factor affecting CLHD and develop a model for predicting CLHD . The logarithm of the brain/blood partition coefficient was detected as a factor affecting CLHD . The predictive accuracy of CLHD using the constructed mathematical model with the logarithm of the brain/blood partition coefficient as explanatory variable was adequate.

Preoperative vascular mapping for anterolateral thigh flap surgeries: A clinical trial of photoacoustic tomography imaging.

BACKGROUND: Photoacoustic tomography (PAT) is a noninvasive vascular imaging modality that uses near-infrared pulse laser beams and ultrasound (US) to visualize vessels. We previously demonstrated the utility of PAT for visualizing anterolateral thigh (ALT) perforators in a clinical study of 10 thighs in 5 healthy adults. Evaluation of the correlation between PAT and US findings showed that PAT had comparable diagnostic potential but was superior in visualizing subcutaneous microvessels; however, there was no comparison with intraoperative findings. In this study, we used a newly developed technique to transfer a PAT image to a body-attachable transparent sheet to compare PAT and intraoperative findings. METHODS: Eight patients were recruited in this prospective study. Patient age ranged from 32 to 79 years (average 60). Seven ALT flaps were applied in head and neck reconstruction. One flap was elevated in chest wall reconstruction. Each PAT scan of an 18 cm × 13.5 cm region took approximately 5 min. Acquired data were processed three-dimensionally using a novel imaging software program. Perforator vessel data from PAT imaging were traced and corrected for projection onto medical film sheets. The correlation between the perforator stem portions predicted by PAT and the intraoperative findings at the level of the fascia-penetrating points was evaluated, and distal branching patterns were analyzed. RESULTS: PAT imaging showed 16 perforators in 8 thighs. Intraoperative surgical findings revealed that all the perforator penetrating points at the deep fascia level matched the PAT findings within 10 mm. None of the eight ALT flaps demonstrated postoperative complications. The perforator complexes were classified as type I in three cases (19%), type II in eight cases (50%), and type III in five cases (31%). CONCLUSIONS: PAT imaging matched the intraoperative findings within 10 mm. Preoperative vascular evaluation allows for the creation of a vascular map for facilitating ALT flap surgeries.