Population pharmacokinetics of mirvetuximab soravtansine in patients with folate receptor-α positive ovarian cancer: The antibody-drug conjugate, payload and metabolite.

AIMS: Mirvetuximab soravtansine is a first-in-class antibody-drug conjugate recently approved for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). METHODS: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed-effects modelling approach. Stepwise covariate modelling was performed to identify covariates. RESULTS: We developed a semi-mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S-methyl-DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated. CONCLUSION: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

Using machine learning-based radiomics to differentiate between glioma and solitary brain metastasis from lung cancer and its subtypes.

OBJECTIVE: To establish a machine learning-based radiomics model to differentiate between glioma and solitary brain metastasis from lung cancer and its subtypes, thereby achieving accurate preoperative classification. MATERIALS AND METHODS: A retrospective analysis was conducted on MRI T1WI-enhanced images of 105 patients with glioma and 172 patients with solitary brain metastasis from lung cancer, which were confirmed pathologically. The patients were divided into the training group and validation group in an 8:2 ratio for image segmentation, extraction, and filtering; multiple layer perceptron (MLP), support vector machine (SVM), random forest (RF), and logistic regression (LR) were used for modeling; fivefold cross-validation was used to train the model; the validation group was used to evaluate and assess the predictive performance of the model, ROC curve was used to calculate the accuracy, sensitivity, and specificity of the model, and the area under curve (AUC) was used to assess the predictive performance of the model. RESULTS: The accuracy and AUC of the MLP differentiation model for high-grade glioma and solitary brain metastasis in the validation group was 0.992, 1.000, respectively, while the sensitivity and specificity were 1.000, 0.968, respectively. The accuracy and AUC for the MLP and SVM differentiation model for high-grade glioma and small cell lung cancer brain metastasis in the validation group was 0.966, 1.000, respectively, while the sensitivity and specificity were 1.000, 0.929, respectively. The accuracy and AUC for the MLP differentiation model for high-grade glioma and non-small cell lung cancer brain metastasis in the validation group was 0.982, 0.999, respectively, while the sensitivity and specificity were 0.958, 1.000, respectively. CONCLUSION: The application of machine learning-based radiomics has a certain clinical value in differentiating glioma from solitary brain metastasis from lung cancer and its subtypes. In the HGG/SBM and HGG/NSCLC SBM validation groups, the MLP model had the best diagnostic performance, while in the HGG/SCLC SBM validation group, the MLP and SVM models had the best diagnostic performance.

Value of Multimodal Diffusion-weighted Imaging in Preoperative Evaluation of Ki-67 Expression in Endometrial Carcinoma.

PURPOSE: To investigate the value of multimodal diffusion weighted imaging (DWI) in preoperative evaluation of Ki-67 expression of endometrial carcinoma (EC). MATERIALS AND METHODS: Patients who had undergone pelvic DWI, intravoxel incoherent motion (IVIM), and diffusion kurtosis imaging (DKI) sequence MRI scan before surgery were retrospectively enrolled. Single index model, double index model, and DKI were used for post-processing of the DWI data, and the apparent diffusion coefficient (ADC), real diffusion coefficient (D), pseudo diffusion coefficient (D*), perfusion fraction (f), non-Gaussian mean diffusion kurtosis (MK), mean diffusion coefficient (MD) and anisotropy fraction (FA) were calculated and compared between the Ki-67 high (≥50%) and low (<50%) expression groups. RESULTS: Forty-two patients with a median age of 56 (range 37 - 75) years were enrolled, including 15 patients with a high Ki-67 (≥50%) expression and 27 with a low Ki-67 (<50%) expression. The MK (0.91 ± 0.12 vs. 0.76 ± 0.12) was significantly (P<0.05) higher while MD (0.99 ± 0.17 vs. 1.16 ± 0.22), D (0.55 ± 0.06 vs. 0.62 ± 0.08), and f (0.21 vs. 0.28) were significantly (P<0.05) lower in the high than in the low expression group. The combined model of MK, MD, D, and f-values had the largest area under the curve (AUC) value of 0.869 (95% CI: 0.764-0.974), sensitivity 0.733 and specificity 0.852, followed by the MK value with an AUC value 0.827 (95% CI: 0.700-0.954), sensitivity 0.733 and specificity 0.815. CONCLUSIONS: IVIM and DKI have certain diagnostic values for preoperative evaluation of the EC Ki-67 expression, and the combined model has the highest diagnostic efficiency.

Values of MRI Imaging Presentations in the Hepatobiliary Phase, DWI and T2WI Sequences in Predicting Pathological Grades of Intrahepatic Mass-Forming Cholangiocarcinoma.

Objective: To retrospectively investigate the value of various MRI image menifestations in the hepatobiliary phase (HBP), DWI and T2WI sequences in predicting the pathological grades of intrahepatic mass-forming cholangiocarcinoma (IMCC). Materials and Methods: Forty-three patients of IMCCs confirmed by pathology were enrolled including 25 cases in well- or moderately-differentiated group and 18 cases in poorly-differentiated group. All patients underwent DWI, T2WI and HBP scan. The Chi square test was used to compare the differences in the general information. Logistic regression analysis was used to analyze the risk factors in predicting the pathological grade of IMCCs. Results: The maximal diameter of the IMCC lesion was < 3 cm in 11 patients, between 3 cm and 6 cm in 15, and > 6 cm in 17. Sixteen cases had intrahepatic metastasis, including 5 in the well- or moderately-differentiated group and 11 in the poorly-differentiated group. Seventeen (39.5%) patients presented with target signs in the DWI sequence, including 9 in the well- or moderately-differentiated group and 8 in the poorly-differentiated group. Twenty (46.5%) patients presented with target signs in the T2WI sequence, including 8 in the well- or moderately-differentiated group and 12 in the poorly-differentiated group. Nineteen cases (54.3%) had a complete hypointense signal ring, including 13 in the well- or moderately-differentiated group and 6 in the poorly-differentiated group. Sixteen (45.7%) cases had an incomplete hypointense signal ring, including 5 in the well- or moderately-differentiated group and 11 in the poorly-differentiated group. The lesion size, intrahepatic metastasis, T2WI signal, and integrity of a hypointense signal ring in HBP were statistically significantly different between two gourps. T2WI signal, presence or non-presence of intrahepatic metastasis, and integrity of hypointense signal ring were the independent influencing factors for pathological grade of IMCC. Conclusion: Target sign in T2WI sequence, presence of intrahepatic metastasis and an incomplete hypointense-signal ring in HBP are more likely to be present in poorly-differentiated IMCCs.

Influencing Factors of Hope Among Chinese Patients With Hematological Malignancies From the Perspective of Positive Psychology: A Cross-sectional Study.

BACKGROUND: Hope is an important resource and reserve for patients with hematological malignancies to cope with stress. Through analyzing hope levels and its influencing factors, this study provides evidence for developing psychological interventions for this population. OBJECTIVE: The aim of this study was to explore the influencing factors of hope in patients with hematological malignancies. METHODS: A cross-sectional study including 165 participants with hematological malignancies was performed from November 2019 through June 2020 in a tertiary hospital in Beijing, China. The Adult Dispositional Hope Scale, UCLA Loneliness Scale, Simplified Coping Style Questionnaire, Self-esteem Scale, and Big Five Short-Form Scale were used to evaluate each variable. Regression analysis was conducted to explore the influencing factors of hope. RESULTS: The total mean hope level (40.39 ± 4.32) was significantly lower than the national norm. Multiple stepwise regression analysis indicated that openness ( ß = .38, P < .001), neuroticism ( ß = -0.25, P < .001), rigor ( ß = -0.15, P = .043), self-esteem ( ß = .33, P < .001), positive response ( ß = .22, P < .001), negative response ( ß = .12, P = .039), and residential region ( ß = .17, P = .002) were significantly associated with the total hope level among patients with hematological malignancies. Self-esteem and openness were positively correlated with the total mean hope score and its 3 subdimensions. CONCLUSION: The hope level was relatively low in patients with hematological malignancies. Hope level was affected by individual personality traits, coping styles, self-esteem, and loneliness. IMPLICATION FOR PRACTICE: Attention should be drawn to the relationship between the hope level and positive psychological characteristics among patients with hematological malignancies. Our study supports the need to develop tailored and effective interventions to improve the level of hope among this patient population.

A study of minimum segment width parameter on VMAT plan quality, delivery accuracy, and efficiency for cervical cancer using Monaco TPS.

PURPOSE: The purpose of this study was to study the influence of the minimum segment width (MSW) on volumetric modulated arc therapy (VMAT) plan quality, delivery accuracy, and efficiency for cervical cancer treatment. METHODS: Nineteen patients with cervical cancer were randomly selected to design VMAT plans. Three VMAT plans were generated for each patient incorporating MSWs of 0.5, 1.0, and 1.5 cm while other planning parameters remained constant using the Monaco treatment planning system (TPS) with 6 MV X rays delivered from an Elekta Synergy linear accelerator. Plan quality and delivery efficiency were evaluated based on dose-volume histograms (DVHs), control points, monitor units (MUs), dosimetric measurement verification results, and plan delivery time. RESULTS: Except for the small difference in target dose coverage and maximum dose, there were no statistically significant differences between the other dosimetric parameters in the planning target volumes. The 1.0 and 1.5 cm MSW plans showed lower maximum doses to the spinal cord than the 0.5 cm plan; doses to other organs at risks were similar regardless of MSWs. The mean reductions of total MUs when compared with the 0.5 cm plan were 14.5 ± 6.1% and 20.9 ± 7.9% for MSWs of 1.0 and 1.5 cm, respectively. The calculated gamma indices using the 3% and 3 mm criteria were 96.2 ± 0.6%, 97.0 ± 0.6%, and 97.6 ± 0.6% for the 0.5, 1.0 and 1.5 cm MSW plans, respectively. The plan delivery times decreased with increasing MSWs (p < 0.05). CONCLUSION: Increasing the MSW allows for improved plan delivery accuracy and efficiency without significantly affecting the VMAT plan quality. MSWs of 1.0 and 1.5 cm improved the plan quality, delivery accuracy, and efficiency for cervical VMAT radiation therapy.

Absolute quantification of E1, ubiquitin-like proteins and Nedd8-MLN4924 adduct by mass spectrometry.

Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins regulate a variety of important cellular processes by forming covalent conjugates with target proteins or lipids. Ubl conjugation is catalyzed by a cascade of proteins including activating enzymes (E1), conjugating enzymes (E2), and in many cases ligation enzymes (E3). The discovery of MLN4924 (Brownell et al., Mol Cell 37: 102-111, 1), an investigational small molecule that is a mechanism-based inhibitor of NEDD8-activating enzyme (NAE), reveals a promising strategy of targeting E1/Ubl pathway for therapeutic purposes. In order to better understand, the biochemical dynamics of Ubl conjugation in cells and tissues, we have developed a mass spectrometry-based method to quantify E1 and Ubls using isotope-labeled proteins as internal standards. Furthermore, we have used the described method to quantify levels of the covalent Nedd8-inhibitor adduct formed in MLN4924 treated cells and tissues. The Nedd8-MLN4924 adduct is a tight-binding inhibitor of NAE, and its cellular concentration represents an indirect pharmacodynamic readout of NAE/Nedd8 pathway inhibition.

Kallikrein gene transfer induces angiogenesis and further improves regional cerebral blood flow in the early period after cerebral ischemia/reperfusion in rats.

AIMS: The aims of this study were to find out whether kallikrein could induce angiogenesis and affect the cerebral blood flow (rCBF) in the early period after cerebral ischemia/reperfusion (CI/R). METHODS: The adenovirus carried human tissue kallikrein (HTK) gene was administrated into the periinfarction region after CI/R. At 12, 24, and 72 h after treatments, neurological deficits were evaluated; expression of HTK and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry staining; the infarction volume was measured; and rCBF was examined by( 14) C-iodoantipyrine microtracing technique. RESULTS: The expression of VEGF was enhanced significantly in pAdCMV-HTK group than controls over all time points (P < 0.05). Furthermore, the rCBF in pAdCMV-HTK group increased markedly than controls at 24 and 72 h after treatment (P < 0.05), and the improved neurological deficit was accompanied by reduced infarction volume in pAdCMV-HTK group 24 and 72 h posttreatment. CONCLUSION: In the early period after CI/R, kallikrein could induce the angiogenesis and improve rCBF in periinfarction region, and further reduce the infarction volume and improve the neurological deficits.

[Characteristics of virulence gene in Vibrio parahaemolyticus strains isolated from clinical patients and environment in Hangzhou, China].

OBJECTIVES: To investigate the characteristics of virulence gene in Vibrio parahaemolyticus strains isolated from clinical patients and environment in Hangzhou, China. METHODS: Thermostable direct hemolysin gene (tdh) and thermostable direct hemolysin-related hemolysin gene (trh) were determined in a total of 174 strains of V. parahaemolyticus isolated from patients and environment (seafood) in Hangzhou area by PCR. RESULTS: The tdh was found in 92 out of 94 V. parahaemolyticus strains from food poisoning patients and in 33 out of 34 strains from sporadic diarrhea patients, and trh was not detected in all above clinical strains. Meanwhile the tdh was negative in all V. parahaemolyticus strains from environment, and the trh was also negative except one strain with urease activity. All strains with trh negative had no the activity of urease. CONCLUSIONS: The V. parahaemolyticus strains from food poisoning patients and sporadic diarrhea patients are tdh positive and trh negative. The V. parahaemolyticus strains with tdh negative and almost trh positive in environment might be a potential pathogen in Hangzhou.