Combining Multistaged Filters and Modified Segmentation Network for Improving Lung Nodules Classification.

Advancements in computational technology have led to a shift towards automated detection processes in lung cancer screening, particularly through nodule segmentation techniques. These techniques employ thresholding to distinguish between soft and firm tissues, including cancerous nodules. The challenge of accurately detecting nodules close to critical lung structures such as blood vessels, bronchi, and the pleura highlights the necessity for more sophisticated methods to enhance diagnostic accuracy. This paper proposed combined processing filters for data preparation before using one of the modified Convolutional Neural Networks (CNN) as the classifier. With refined filters, the nodule targets are solid, semi-solid, and ground glass, ranging from low-stage cancer (cancer screening data) to high-stage cancer. Furthermore, two additional works were added to address juxta-pleural nodules while the pre-processing end and classification are done in a 3-dimensional domain in opposition to the usual image classification. The accuracy output indicates that even using a simple Segmentation Network if modified correctly, can improve the classification result compared to the other eight models. The proposed sequence total accuracy reached 99.7%, with 99.71% cancer class accuracy and 99.82% non-cancer accuracy, much higher than any previous research, which can improve the detection efforts of the radiologist.

Multiple thoracic intramedullary schwannoma: A case report.

INTRODUCTION AND IMPORTANCE: Schwannoma's are benign but clinically progressive tumours. Mostly, they present as intradural extramedullary and as a single lesion. They are quite rare in the intramedullary region and multiple lesions. We report a rare case of Multiple Intramedullary Schwannoma in the thoracic region. The aim of this study to inform an uncommon case of intramedullary schwannoma and support an appropriate preoperative diagnostic. CLINICAL PRESENTATION: A 43-year-old female patient was admitted with gradual onset weakness of both lower limbs (4/2) for last two months. Magnetic resonance imaging (MRI) scan disclosed an intramedullary tumour at the thoracal 11th and 12th vertebral levels. It measured 30x20x15 mm and 20x20x12 mm. Complete total resection of multiple lesions was done. Schwanoma's was confirmed based on the histopathological finding. The patient was discharged on 4th day post operative with both leg power 5/5 and needed to medical rehabilitation. Follow-up examination 1 months after surgery revealed favourable, neurological condition (modified McCormick scale: grade I). CLINICAL DISCUSSION: Intramedullary schwannoma is often misdiagnosed as other types of intramedullary tumour. Schwannomas are usually benign and have well defined cleavage plane. Total resection achievable in most cases, offers the best clinical outcome and avoids subsequent recurrence. CONCLUSION: Preoperative diagnosis of intramedullary schwannoma will help establish the optimum medical and surgical treatment and the prognosis. Timely surgery before permanent neurological deficit and gross total resection is recommended to achieve good clinical outcome.

Implementing Natural Image Quality Evaluator for Performance Indicator on Noise Artefacts Recovery in CT Scan.

The two most common evaluators for CT scan denoising are Peak Signal to Noise Ratio (PSNR) and Structural Similarity Index (SSIM). This paper offers an alternative evaluator by utilizing of Natural Image Quality Evaluator (NIQE) assessment to determine the performance of denoising work on noise artefact. The noise artefact was obtained during the cancer screening process and had a particular noise density pattern across the image. NIQE is one of the blind image assessments which rely on the measurable deviation of image patch as a reference; it can determine the improved quality of denoising image. Due to the method of comparison in NIQE, the two parameters: patch size and sharpness threshold, will play an essential part in getting the score compared with the result from the other evaluators (PSNR and SSIM).

Exposure-safety and exposure-efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors.

The antibody-drug conjugate (ADC) tisotumab vedotin (TV) received accelerated approval from the US Food and Drug Administration for treatment of adults with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. A population pharmacokinetic (PK) model, developed using dosing data from four clinical TV studies, was used to estimate individual exposure and explore safety and efficacy exposure-response (ER) relationships. Because PK analysis showed no appreciable accumulation of TV and monomethyl auristatin E (MMAE) with repeated dosing, cycle 1 exposure metrics and predicted average concentrations from time zero until end of the cycle in which an event occurred (CavgLast ) were used for ER analyses. The probability of achieving objective response increased significantly as the ADC cycle 1 maximum serum concentration (Cmax ) increased. The probability of treatment-related adverse events (AEs) leading to dose modification increased significantly as ADC cycle 1 area under the concentration-time curve (AUC) increased. Number of grade 2+ ocular AEs increased significantly as ADC cycle 1 AUC, Cmax , and ADC CavgLast increased. MMAE cycle 1 AUC predicted risk of serious treatment-related AEs. The relationship between ADC exposure and efficacy end points suggests ADC treatment was associated with clinically meaningful response across the observed exposures; greater exposure was associated with increased efficacy. The relationship between ADC and MMAE exposure and safety end points suggests increased exposure was associated with increased AE risk. These results align with clinical findings showing TV 2 mg/kg (≤200 mg for patients ≥100 kg) every 3 weeks is efficacious and tolerable for patients with r/mCC.

Image Recovery from Synthetic Noise Artifacts in CT Scans Using Modified U-Net.

Computed Tomography (CT) is commonly used for cancer screening as it utilizes low radiation for the scan. One problem with low-dose scans is the noise artifacts associated with low photon count that can lead to a reduced success rate of cancer detection during radiologist assessment. The noise had to be removed to restore detail clarity. We propose a noise removal method using a new model Convolutional Neural Network (CNN). Even though the network training time is long, the result is better than other CNN models in quality score and visual observation. The proposed CNN model uses a stacked modified U-Net with a specific number of feature maps per layer to improve the image quality, observable on an average PSNR quality score improvement out of 174 images. The next best model has 0.54 points lower in the average score. The score difference is less than 1 point, but the image result is closer to the full-dose scan image. We used separate testing data to clarify that the model can handle different noise densities. Besides comparing the CNN configuration, we discuss the denoising quality of CNN compared to classical denoising in which the noise characteristics affect quality.

Population pharmacokinetic analysis for tisotumab vedotin in patients with locally advanced and/or metastatic solid tumors.

Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) for treatment of solid tumors expressing tissue factor with accelerated approval from the US Food and Drug Administration for treatment of recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. This study describes development of a population pharmacokinetic (PK) model to assess the PK profile of tisotumab vedotin and microtubule-disrupting agent monomethyl auristatin E (MMAE) using data from 399 patients with solid tumors across four phase I/II trials. The ADC-MMAE model describes ADC and MMAE concentrations following intravenous administration of tisotumab vedotin. This four-compartment model comprises a two-compartment ADC model with parallel linear and Michaelis-Menten elimination, a delay compartment, and a one-compartment MMAE model. Nonspecific linear clearance of ADC was 1.42 L/day, central volume of distribution (Vc ) was 3.10 L, and median terminal half-life of ADC was 4.04 days. Apparent clearance of MMAE was 42.8 L/day, and apparent volume of distribution was 2.09 L. Terminal slope of the MMAE concentration-time curve was defined by the delay compartment rate with a half-life of 2.56 days. Patients with higher body weight and lower albumin concentration had faster ADC clearance. Male patients and those with higher body weight and lower albumin concentration had higher Vc . Body weight was the most influential covariate influencing distribution and elimination of ADC and MMAE, thus supporting weight-based dosing of tisotumab vedotin. Presence of antidrug antibodies (detected in 3.3% of patients) did not affect key PK parameters or exposures for ADC and MMAE.

Neuroangiography patterns and anomalies of middle cerebral artery: A systematic review.

BACKGROUND: As the largest and most complex cerebral artery, the middle cerebral artery (MCA) patterns and anomalies are not fully reported. At present, there is confusion about the criteria for the different subtypes. The study of MCA patterns and anomalies is important because variants such as accessories or duplicates represent a high risk of failure during endovascular embolization or navigation during treatment for ischemic stroke. This study conducted a systematic review of studies on the neuroangiography patterns and anomalies of MCA. METHODS: We conducted a systematic review of four articles online databases and included English articles from PubMed, the Cochrane Library, Directory of Open Access Journals, and EBSCOhost. RESULTS: The proportion of the MCA branching pattern was 1.9% (range from 0% to 6.3%) for monofurcation, 1.0% (range from 0% to 1.4%) for tetrafurcation, 69.9% (range from 58.1% to 92.7%) for bifurcation, and 27% (ranging from 7.3% to 40.4%) for trifurcation. The proportion of MCA anomalies for accessory is 0.03% (range from 0% to 1%), duplication is 0.17% (range from 0% to 3%), and fenestration is 0.15% (range from 0% to 2%). CONCLUSION: The proportions of the branching pattern and anomalies of MCA based on the systematic review are described in this study. This study is the first to systematically review the neuroangiography pattern of MCA and neuroangiography variations/anomalies of MCA in the literature.

Lack of QT Prolongation for 2'-O-Methoxyethyl-Modified Antisense Oligonucleotides Based on Retrospective Exposure/Response Analysis of Ten Phase 1 Dose-Escalation Placebo-Controlled Studies in Healthy Subjects.

The potential of QT prolongation of ten 2'-O-methoxyethyl-modified (2'-MOE) antisense oligonucleotides (ASOs) was evaluated retrospectively via exposure/response (ER) analysis using data from Phase 1 clinical studies in healthy subjects. All Phase 1 studies were double-blind, placebo-controlled, single and multiple ascending dose studies designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of the ASOs in healthy subjects. The active doses in these studies ranged from 50 to 450 mg administered by subcutaneous (SC) injection in single and multiple ascending dose cohorts. Two of the ten studies also included 2-h intravenous (IV) infusions up to 600 mg. Electrocardiogram (ECG) measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline (ΔQTcF) and the mean time-matched placebo (ΔΔQTcF) with PK plasma exposure when available was evaluated using a linear mixed-effects approach. There was no evidence for QTc prolongation associated with increasing plasma concentrations in healthy subjects, including exposures with treatment up to 450 mg administered SC or 600 mg by IV infusions, and concentrations that are 4-20 times the Cmax of the therapeutic dose, as assessed by both ΔQTcF and ΔΔQTcF. The ER analysis of the relationship between drug plasma concentration and ΔΔQTcF showed that the slope of the regression line was close to zero, and the upper bound of the 90% confidence interval at twice the mean observed (or predicted) Cmax (2 × Cmax) of the clinical therapeutic dose (ie, the highest clinically relevant plasma concentration) was well below 10 ms for all 10 compounds evaluated. Therefore, no concentration-dependent effect on QT prolongation was observed for any one of the ten 2'-MOE ASOs evaluated in Phase 1 studies. These results confirmed that 2'-MOE ASOs, as a chemical class, do not cause QT prolongation at clinically relevant dose levels.

Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations.

Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Qp = 0.572 L/h, QCSF = 0.069 L/h, CLp = 2.50 L/h, CLCSF = 0.133 L/hr, VCSF = 0.441 L, Vp = 32.0 L, Vsystemic_tissue = 429 L, and VCNS_tissue = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on VCSF , Vp , and CLp . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.

Disposition and Pharmacokinetics of a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Human Lipoprotein (a) in Monkeys.

Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency due to receptor-mediated uptake into hepatocyte. The disposition and pharmacokinetics of ISIS 681257, a GalNAc3-conjugated ASO, were studied in monkeys. Following subcutaneous (SC) injection, ISIS 681257 was rapidly absorbed into the systemic circulation, with peak plasma levels observed within hours after dosing. After reaching Cmax, plasma concentrations rapidly declined in a multiexponential manner and were characterized by a dominant initial rapid distribution phase in which drug transferred to tissues from circulation, followed by a much slower terminal elimination phase (half-life of 4 weeks). Intact ISIS 681257 is the major full-length oligonucleotide species in plasma (≥70%). In tissues, the conjugated-GalNAc sugar moiety was rapidly metabolized, leaving the fully unconjugated form as the only full-length oligonucleotide detected at 48 h after dosing. Unconjugated ISIS 681257 cleared slowly from tissues with a half-life of 4 weeks. ISIS 681257 was highly bound to plasma proteins (>97% bound), which limited its urinary excretion. Disposition of ISIS 681257 in plasma and liver appeared nonlinear over the 1-40 mg/kg dose range studied. The plasma and liver tissue concentration data were well described by a population based mixed-effects modeling approach with Michaelis-Menten uptake from plasma to liver. Safety data from the study and the good exposure, as well as the extended half-life of the unconjugated ASO in the liver, support further development and less frequent dosing in Phase I clinical study.

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy.

PURPOSE: Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products. METHODS: In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h). RESULTS: Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported. CONCLUSIONS: Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.

No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

PURPOSE: The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. METHODS: In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. RESULTS: In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. CONCLUSIONS: Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.

Dose response of umeclidinium administered once or twice daily in patients with COPD: a pooled analysis of two randomized, double-blind, placebo-controlled studies.

Umeclidinium (UMEC) is an inhaled long-acting muscarinic antagonist approved in the US and EU for the once-daily (QD) treatment of chronic obstructive pulmonary disease (COPD); it is not indicated for the treatment of asthma. To fully characterize the dose-response relationship of UMEC in patients with COPD, a pooled analysis of data from two randomized, placebo-controlled, cross-over, dose-ranging studies was performed, evaluating UMEC at doses of 15.6-1000 mcg QD and 15.6-250 mcg twice daily (BID). The primary endpoint was trough forced expiratory volume in one second (FEV(1)) at the end of each study's treatment period (Day 8/Day 15). A population model-based analysis using total daily UMEC dose was used for the primary analysis comparing QD and BID dosing. A physiological effect (E(max)) model was optimal in defining the relationship between UMEC dose and the primary endpoint, demonstrating a clear monotonic dose response over QD and BID dosing regimens. UMEC doses ≥62.5 mcg QD were differentiated from lower doses and BID dosing did not provide benefit over QD dosing. The potency (ED(50)) estimate was 33 mcg with QD dosing. These data indicate that UMEC 62.5 mcg and 125 mcg QD provide lung function benefits that warrant further investigation for the treatment of COPD.

A multi-route model of nicotine-cotinine pharmacokinetics, pharmacodynamics and brain nicotinic acetylcholine receptor binding in humans.

The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

Twenty-four hour human urine and serum profiles of bisphenol a during high-dietary exposure.

By virtue of its binding to steroid hormone receptors, bisphenol A (BPA, the unconjugated bioactive monomer) is hypothesized to be estrogenic when present in sufficient quantities in the body, raising concerns that widespread exposure to BPA may impact human health. To better understand the internal exposure of adult humans to BPA and the relationship between the serum and urinary pharmacokinetics of BPA, a clinical exposure study was conducted. Blood and urine samples were collected approximately hourly over a 24-h period from 20 adult volunteers who ingested 100% of one of three specified meals comprising standard grocery store food items for breakfast, lunch, and dinner. The volunteers' average consumption of BPA, estimated from the urinary excretion of total BPA ((TOT)BPA = conjugated BPA + BPA), was 0.27 µg/kg body weight (range, 0.03-0.86), 21% greater than the 95th percentile of aggregate exposure in the adult U.S. population. A serum time course of (TOT)BPA was observable only in individuals with exposures 1.3-3.9 times higher than the 95th percentile of aggregate U.S. exposure. The (TOT)BPA urine concentration T(max) was 2.75 h (range, 0.75-5.75 h) post-meal, lagging the serum concentration T(max) by ∼1 h. Serum (TOT)BPA area under the curve per unit BPA exposure was between 21.5 and 79.0 nM•h•kg/µg BPA. Serum (TOT)BPA concentrations ranged from less than or equal to limit of detection (LOD, 1.3 nM) to 5.7 nM and were, on average, 42 times lower than urine concentrations. During these high dietary exposures, (TOT)BPA concentrations in serum were undetectable in 83% of the 320 samples collected and BPA concentrations were determined to be less than or equal to LOD in all samples.