RESUMO
This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.
Assuntos
Biofarmácia , Modelos Biológicos , Biofarmácia/métodos , Humanos , Solubilidade , Preparações Farmacêuticas/química , Excipientes/química , Química Farmacêutica/métodosRESUMO
Blood is a highly complex fluid with rheological properties that have a significant impact on various flow phenomena. In particular, it exhibits a non-Newtonian elongational viscosity that is comparable to polymer solutions. In this study, we investigate the effect of three different anticoagulants, namely EDTA (ethylene diamine tetraacetic acid), heparin, and citrate, on the elongational properties of both human and swine blood. We observe a unique two stage thinning process and a strong dependency of the characteristic relaxation time on the chosen anticoagulant, with the longest relaxation time and thus the highest elongational viscosity being found for the case of citrate. Our findings for the latter are consistent with the physiological values obtained from a dripping droplet of human blood without any anticoagulant. Furthermore, our study resolves the discrepancy found in the literature regarding the reported range of characteristic relaxation times, confirming that the elongational viscosity must be taken into account for a full rheological characterization of blood. These results have important implications for understanding blood flow in various physiological, pathological and technological conditions.
Assuntos
Anticoagulantes , Anticoagulantes/farmacologia , Anticoagulantes/química , Humanos , Suínos , Animais , Viscosidade Sanguínea/efeitos dos fármacos , Ácido Edético/química , Ácido Edético/farmacologia , Heparina/farmacologia , Heparina/química , Viscosidade , Ácido Cítrico/química , Sangue/efeitos dos fármacos , ReologiaRESUMO
Red blood cells (RBC), the primary carriers of oxygen in the body, play a crucial role across several biomedical applications, while also being an essential model system of a deformable object in the microfluidics and soft matter fields. However, RBC behavior in viscoelastic liquids, which holds promise in enhancing microfluidic diagnostic applications, remains poorly studied. We here show that using viscoelastic polymer solutions as a suspending carrier causes changes in the clustering and shape of flowing RBC in microfluidic flows when compared to a standard Newtonian suspending liquid. Additionally, when the local RBC concentration increases to a point where hydrodynamic interactions take place, we observe the formation of equally-spaced RBC structures, resembling the viscoelasticity-driven ordered particles observed previously in the literature, thus providing the first experimental evidence of viscoelasticity-driven cell ordering. The observed RBC ordering, unaffected by polymer molecular architecture, persists as long as the surrounding medium exhibits shear-thinning, viscoelastic properties. Complementary numerical simulations reveal that viscoelasticity-induced repulsion between RBCs leads to equidistant structures, with shear-thinning modulating this effect. Our results open the way for the development of new biomedical technologies based on the use of viscoelastic liquids while also clarifying fundamental aspects related to multibody hydrodynamic interactions in viscoelastic microfluidic flows.
Assuntos
Elasticidade , Eritrócitos , Eritrócitos/citologia , Viscosidade , Humanos , Hidrodinâmica , MicrofluídicaRESUMO
BACKGROUND: In recent years, the production of inclusion bodies that retain substantial catalytic activity was demonstrated. These catalytically active inclusion bodies (CatIBs) are formed by genetic fusion of an aggregation-inducing tag to a gene of interest via short linker polypeptides. The resulting CatIBs are known for their easy and cost-efficient production, recyclability as well as their improved stability. Recent studies have outlined the cooperative effects of linker and aggregation-inducing tag on CatIB activities. However, no a priori prediction is possible so far to indicate the best combination thereof. Consequently, extensive screening is required to find the best performing CatIB variant. RESULTS: In this work, a semi-automated cloning workflow was implemented and used for fast generation of 63 CatIB variants with glucose dehydrogenase of Bacillus subtilis (BsGDH). Furthermore, the variant BsGDH-PT-CBDCell was used to develop, optimize and validate an automated CatIB screening workflow, enhancing the analysis of many CatIB candidates in parallel. Compared to previous studies with CatIBs, important optimization steps include the exclusion of plate position effects in the BioLector by changing the cultivation temperature. For the overall workflow including strain construction, the manual workload could be reduced from 59 to 7 h for 48 variants (88%). After demonstration of high reproducibility with 1.9% relative standard deviation across 42 biological replicates, the workflow was performed in combination with a Bayesian process model and Thompson sampling. While the process model is crucial to derive key performance indicators of CatIBs, Thompson sampling serves as a strategy to balance exploitation and exploration in screening procedures. Our methodology allowed analysis of 63 BsGDH-CatIB variants within only three batch experiments. Because of the high likelihood of TDoT-PT-BsGDH being the best CatIB performer, it was selected in 50 biological replicates during the three screening rounds, much more than other, low-performing variants. CONCLUSIONS: At the current state of knowledge, every new enzyme requires screening for different linker/aggregation-inducing tag combinations. For this purpose, the presented CatIB toolbox facilitates fast and simplified construction and screening procedures. The methodology thus assists in finding the best CatIB producer from large libraries in short time, rendering possible automated Design-Build-Test-Learn cycles to generate structure/function learnings.
Assuntos
Automação Laboratorial , Ensaios de Triagem em Larga Escala , Reprodutibilidade dos Testes , Teorema de Bayes , Corpos de Inclusão , AutomaçãoRESUMO
The Gárdos channel (KCNN4) and Piezo1 are the best-known ion channels in the red blood cell (RBC) membrane. Nevertheless, the quantitative electrophysiological behavior of RBCs and its heterogeneity are still not completely understood. Here, we use state-of-the-art biochemical methods to probe for the abundance of the channels in RBCs. Furthermore, we utilize automated patch clamp, based on planar chips, to compare the activity of the two channels in reticulocytes and mature RBCs. In addition to this characterization, we performed membrane potential measurements to demonstrate the effect of channel activity and interplay on the RBC properties. Both the Gárdos channel and Piezo1, albeit their average copy number of activatable channels per cell is in the single-digit range, can be detected through transcriptome analysis of reticulocytes. Proteomics analysis of reticulocytes and mature RBCs could only detect Piezo1 but not the Gárdos channel. Furthermore, they can be reliably measured in the whole-cell configuration of the patch clamp method. While for the Gárdos channel, the activity in terms of ion currents is higher in reticulocytes compared to mature RBCs, for Piezo1, the tendency is the opposite. While the interplay between Piezo1 and Gárdos channel cannot be followed using the patch clamp measurements, it could be proved based on membrane potential measurements in populations of intact RBCs. We discuss the Gárdos channel and Piezo1 abundance, interdependencies and interactions in the context of their proposed physiological and pathophysiological functions, which are the passing of small constrictions, e.g., in the spleen, and their active participation in blood clot formation and thrombosis.
Assuntos
Eritrócitos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária , Reticulócitos , Transporte Biológico , Cálcio/metabolismo , Eritrócitos/metabolismo , Reticulócitos/metabolismo , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Canais Iônicos/metabolismoRESUMO
The distribution of red blood cells (RBCs) in the microcirculation determines the oxygen delivery and solute transport to tissues. This process relies on the partitioning of RBCs at successive bifurcations throughout the microvascular network, and it has been known since the last century that RBCs partition disproportionately to the fractional blood flow rate, therefore leading to heterogeneity of the hematocrit (i.e., volume fraction of RBCs in blood) in microvessels. Usually, downstream of a microvascular bifurcation, the vessel branch with a higher fraction of blood flow receives an even higher fraction of RBC flux. However, both temporal and time-average deviations from this phase-separation law have been observed in recent studies. Here, we quantify how the microscopic behavior of RBC lingering (i.e., RBCs temporarily residing near the bifurcation apex with diminished velocity) influences their partitioning, through combined in vivo experiments and in silico simulations. We developed an approach to quantify the cell lingering at highly confined capillary-level bifurcations and demonstrate that it correlates with deviations of the phase-separation process from established empirical predictions by Pries et al. Furthermore, we shed light on how the bifurcation geometry and cell membrane rigidity can affect the lingering behavior of RBCs; e.g., rigid cells tend to linger less than softer ones. Taken together, RBC lingering is an important mechanism that should be considered when studying how abnormal RBC rigidity in diseases such as malaria and sickle-cell disease could hinder the microcirculatory blood flow or how the vascular networks are altered under pathological conditions (e.g., thrombosis, tumors, aneurysm).
Assuntos
Eritrócitos , Modelos Cardiovasculares , Hematócrito , Microcirculação/fisiologia , Velocidade do Fluxo Sanguíneo/fisiologiaRESUMO
BACKGROUND: Internationally, colorectal cancer screening participation remains low despite the availability of home-based testing and numerous interventions to increase uptake. To be effective, interventions should be based on an understanding of what influences individuals' decisions about screening participation. This study investigates the association of defensive information processing (DIP) with fecal immunochemical test (FIT)-based colorectal cancer screening uptake. METHODS: Regression modeling of data from a cross-sectional survey within a population-based FIT screening program was conducted. The survey included the seven subdomains of the McQueen DIP measure. The primary outcome variable was the uptake status (screening user or nonuser). Multivariable logistic regression was used to estimate the odds ratio (OR) for screening nonuse by DIP (sub)domain score, with adjustments made for sociodemographic and behavioral factors associated with uptake. RESULTS: Higher scores (equating to greater defensiveness) on all DIP domains were significantly associated with lower uptake in the model adjusted for sociodemographic factors. In the model with additional adjustments for behavioral factors, the suppression subdomains of "deny immediacy to be tested" (OR, 0.53; 95% confidence interval [CI], 0.43-0.65; p < .001) and "self-exemption" (OR, 0.80; 95% CI, 0.68-0.96; p < .001) independently predicted nonuse of FIT-based screening. CONCLUSIONS: This is the first study outside the United States that has identified DIP as a barrier to colorectal cancer screening uptake, and it is the first focused specifically on FIT-based screening. The findings suggest that two suppression barriers, namely denying the immediacy to be tested and self-exempting oneself from screening, may be promising targets for future interventions to improve uptake.
Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Estados Unidos , Estudos Transversais , Inquéritos e Questionários , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/prevenção & controle , Programas de Rastreamento , Sangue Oculto , ColonoscopiaRESUMO
OBJECTIVE: People from ethnic minority backgrounds are less likely to attend colonoscopy, following faecal immunochemical test screening, and are more likely to be diagnosed with colorectal cancer at an advanced stage as a result. The aim of this research was to explore the barriers and facilitators to attending colonoscopy, perceived by ethnic minority groups living in the United Kingdom. METHODS: Semi-structured online and telephone interviews were conducted with thirty men and women of Black-African (n = 5), Black-Caribbean (n = 5), South Asian (n = 10) and White British (n = 10) descent. Participants were eligible for screening, but had not necessarily been invited for colonoscopy. All interviews were conducted in the participant's first language and were assessed using Framework-analysis, in line with a conceptual framework developed from previous interviews with healthcare professionals. RESULTS: Five thematic groups of barriers and facilitators were developed: 'Locus of control', 'Cultural attitudes and beliefs', 'Individual beliefs, knowledge and personal experiences with colonoscopy and cancer', 'Reliance on family and friends' and 'Health concerns'. Differences were observed, between ethnic groups, for: 'Locus of control', 'Cultural attitudes and beliefs' and 'Reliance on family and friends'. Black and South Asian participants frequently described the decision to attend colonoscopy as lying with 'God' (Muslims, specifically), 'the doctor', or 'family' (Locus of control). Black and South Asian participants also reported relying on friends and family for 'language, transport and emotional support' (Reliance on family and friends). Black-African participants, specifically, described cancer as 'socially taboo' (Cultural attitudes and beliefs). CONCLUSIONS: The results highlight several targets for culturally-tailored interventions to make colonoscopy more equitable.
Assuntos
Neoplasias Colorretais , Etnicidade , Masculino , Humanos , Feminino , Etnicidade/psicologia , Grupos Minoritários/psicologia , Minorias Étnicas e Raciais , Detecção Precoce de Câncer/psicologia , Neoplasias Colorretais/diagnóstico , Colonoscopia , Pesquisa Qualitativa , Conhecimentos, Atitudes e Prática em SaúdeRESUMO
Bifurcations and branches in the microcirculation dramatically affect blood flow as they determine the spatiotemporal organization of red blood cells (RBCs). Such changes in vessel geometries can further influence the formation of a cell-free layer (CFL) close to the vessel walls. Biophysical cell properties, such as their deformability, which is impaired in various diseases, are often thought to impact blood flow and affect the distribution of flowing RBCs. This study investigates the flow behavior of healthy and artificially hardened RBCs in a bifurcating microfluidic T-junction. We determine the RBC distribution across the channel width at multiple positions before and after the bifurcation. Thus, we reveal distinct focusing profiles in the feeding mother channel for rigid and healthy RBCs that dramatically impact the cell organization in the successive daughter channels. Moreover, we experimentally show how the characteristic asymmetric CFLs in the daughter vessels develop along their flow direction. Complimentary numerical simulations indicate that the buildup of the CFL is faster for healthy than for rigid RBCs. Our results provide fundamental knowledge to understand the partitioning of rigid RBC as a model of cells with pathologically impaired deformability in complex in vitro networks.
Assuntos
Eritrócitos , Microfluídica , Eritrócitos/fisiologia , Microcirculação/fisiologia , Deformação EritrocíticaRESUMO
We report a study on granular matter with and without small additions of silicon oil, under low-frequency and large amplitude oscillatory shear strain under constant normal pressure, by running experiments with a rotational rheometer with a cup-and-plate geometry. We analysed the expansion with the Chebyshev polynomials of the orthogonal decomposition of stress-strain Lissajous-Bowditch loops. We found the onset of the strain amplitude for the yielding regime indicated a regime change from filament-like structures of grains to grain rearrangements for the dry granulate and from oscillations to the breaking and regeneration of liquid bridges for wet granulates. We have shown that this viscoelastic dynamics can be characterized by a noise temperature following Sollich et al. (Phys Rev Lett https://doi.org/10.1103/PhysRevLett.78.2020 , 1997). The analysis of the first harmonics of the Chebyshev expansion showed that the state of disorder of dry and wet granular matter in pre-yielding and yielding regimes involved ensembles of different inherent states; thus, each of them was governed by a different noise temperature. The higher-order harmonics of the Chebyshev expansion revealed a proportionality between the viscous nonlinearity and the variation in the elastic nonlinearity induced by the deformation, which shows the coupling between the elastic deformation and the viscous flow of mesoscopic-scale structures.
Assuntos
Pós , Temperatura , ViscosidadeRESUMO
The goal of our study was to examine the intention to get vaccinated using predictors from the 5C Model of vaccination attitudes, the Theory of Planned Behavior (TPB) and the Health Belief Model (HBM). Between August and November 2020, an online survey was delivered to 1428 participants in the UK and Germany (mean age = 40.6; 57% women), assessing socio-demographic and health factors, general vaccination attitudes, TBP and HBM variables, and COVID-19 vaccination intention. Vaccination intentions did not differ by country or survey period. Predictors of intention with the highest explanatory power in a relative weight analysis were confidence, collective responsibility (5C) perceived behavioral control, social norms, attitudes (especially negative affect & TPB cognitions), and perceived benefits (HBM). Women reported lower intention, although the effect size was small. Predictors from the TPB and HBM were effective to explain the intention to receive COVID-19 vaccines over and above socio-demographic variables, health-related factors and general vaccination attitudes. The results are interpreted in the context of current vaccination campaigns. Messages promoting sense of autonomy and control over the decision to get vaccinated, approval from significant others and reassurance that getting vaccinated will not be associated with fear or other negative feelings are important facilitators of vaccine uptake.
Assuntos
COVID-19 , Intenção , Humanos , Feminino , Adulto , Masculino , Vacinas contra COVID-19/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , COVID-19/prevenção & controle , Comportamentos Relacionados com a Saúde , VacinaçãoRESUMO
Low perceived risk of is associated with a low probability of engaging in risk preventive behaviours. Temporal framing has been suggested to make the risk seem higher, as narrower time frames appear to increase perceived risk and intentions to engage in risk-preventive behaviours. In two online experiments, we tested how manipulating risk information about colorectal cancer (CRC) influenced risk perception and preventive behaviours. 902 men and women aged 45-54 were recruited from an English online panel. Study 1 (N = 132) investigated how communicating CRC mortality instead of incidence rates influences risk perception, using both yearly and daily frames. In study 2 (N = 770), CRC incidence was described as occurring yearly, daily or hourly. The primary outcome measures were risk perception, intention to engage in preventive behaviours and whether participants chose to read information about ways to reduce CRC risk or skip it to finish the survey. Study 1 did not find a difference in intentions based on information about the risk of developing vs the risk of dying of CRC. Study 2 found that, while communicating CRC incidence occurring as every day increased information-seeking behaviour compared to every year and every hour (57.4% vs 45.9% vs 45.6%, p = 0.012), individuals in the daily condition were less likely to get all comprehension questions right (69.9% vs 78.2% vs 85.0%, respectively, p = 0.015). Temporal framing had no impact on perceived risk or intentions to engage in risk-reducing behaviours. While manipulating risk information in terms of temporal framing did not increase perceived risk, it may influence people's decision to engage with the information in the first place.
Assuntos
Neoplasias Colorretais , Intenção , Masculino , Humanos , Feminino , Inquéritos e Questionários , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controleRESUMO
Background: "Artificial intelligence" and "big data" increasingly take the step from just being interesting concepts to being relevant or even part of our lives. This general statement holds also true for transfusion medicine. Besides all advancements in transfusion medicine, there is not yet an established red blood cell quality measure, which is generally applied. Summary: We highlight the usefulness of big data in transfusion medicine. Furthermore, we emphasize in the example of quality control of red blood cell units the application of artificial intelligence. Key Messages: A variety of concepts making use of big data and artificial intelligence are readily available but still await to be implemented into any clinical routine. For the quality control of red blood cell units, clinical validation is still required.
RESUMO
The dynamics of single red blood cells (RBCs) determine microvascular blood flow by adapting their shape to the flow conditions in the narrow vessels. In this study, we explore the dynamics and shape transitions of RBCs on the cellular scale under confined and unsteady flow conditions using a combination of microfluidic experiments and numerical simulations. Tracking RBCs in a comoving frame in time-dependent flows reveals that the mean transition time from the symmetric croissant to the off-centered, nonsymmetric slipper shape is significantly faster than the opposite shape transition, which exhibits pronounced cell rotations. Complementary simulations indicate that these dynamics depend on the orientation of the RBC membrane in the channel during the time-dependent flow. Moreover, we show how the tank-treading movement of slipper-shaped RBCs in combination with the narrow channel leads to oscillations of the cell's center of mass. The frequency of these oscillations depends on the cell velocity, the viscosity of the surrounding fluid, and the cytosol viscosity. These results provide a potential framework to identify and study pathological changes in RBC properties.
RESUMO
BACKGROUND: Colorectal cancer (CRC) screening is less effective at reducing cancer incidence in the proximal colon compared to the distal colorectum. We aimed to identify adenoma characteristics associated with proximal colon cancer (PCC). METHODS: Endoscopy and pathology data for patients with ≥1 adenoma detected at baseline colonoscopy were obtained from 17 UK hospitals between 2001 and 2010. Multivariable Cox regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for PCC, and, for comparison, distal CRC incidence, by adenoma characteristics. RESULTS: Among 18,431 patients, 152 and 105 developed PCC and distal CRC, respectively, over a median follow-up of 9.8 years. Baseline adenoma characteristics positively associated with PCC incidence included number (≥3 vs. < 3: aHR 2.10, 95% CI: 1.42-3.09), histology (tubulovillous/villous vs. tubular: aHR 1.61, 95% CI: 1.10-2.35) and location (any proximal vs. distal only: aHR 1.70, 95% CI: 1.20-2.42), for which there was borderline evidence of heterogeneity by subsite (p = 0.055). Adenoma dysplasia (high vs. low grade) was associated with distal CRC (aHR 2.42, 95% CI: 1.44-4.04), but not PCC (p-heterogeneity = 0.023). CONCLUSIONS: Baseline adenoma number, histology and proximal location were independently associated with PCC and may be important to identify patients at higher risk for post-polypectomy PCC.
Assuntos
Adenoma , Neoplasias do Colo , Neoplasias Colorretais , Adenoma/epidemiologia , Adenoma/patologia , Adenoma/cirurgia , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/cirurgia , Colonoscopia , Neoplasias Colorretais/patologia , Humanos , Incidência , Estudos Retrospectivos , Fatores de RiscoRESUMO
The erythrocyte sedimentation rate is one of the oldest medical diagnostic methods whose physical mechanisms remain debatable today. Using both light microscopy and mesoscale cell-level simulations, we show that erythrocytes form a soft-particle gel. Furthermore, the high volume fraction of erythrocytes, their deformability, and weak attraction lead to unusual properties of this gel. A theoretical model for the gravitational collapse is developed, whose predictions are in agreement with detailed macroscopic measurements of the interface velocity.
Assuntos
Eritrócitos , Modelos Teóricos , Sedimentação SanguíneaRESUMO
The investigation of cell shapes mostly relies on the manual classification of 2D images, causing a subjective and time consuming evaluation based on a portion of the cell surface. We present a dual-stage neural network architecture for analyzing fine shape details from confocal microscopy recordings in 3D. The system, tested on red blood cells, uses training data from both healthy donors and patients with a congenital blood disease, namely hereditary spherocytosis. Characteristic shape features are revealed from the spherical harmonics spectrum of each cell and are automatically processed to create a reproducible and unbiased shape recognition and classification. The results show the relation between the particular genetic mutation causing the disease and the shape profile. With the obtained 3D phenotypes, we suggest our method for diagnostics and theragnostics of blood diseases. Besides the application employed in this study, our algorithms can be easily adapted for the 3D shape phenotyping of other cell types and extend their use to other applications, such as industrial automated 3D quality control.
Assuntos
Eritrócitos/citologia , Microscopia Confocal/métodos , Redes Neurais de Computação , Automação , Estudos de Casos e Controles , Eritrócitos/imunologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: To assess if systematic (SBx) vs. transrectal or transperineal mpMRI-ultrasound targeted combined with systematic (TBx + SBx) biopsy confer different effects on treatment delay to radical prostatectomy measured as Gleason grade group (GGG) upgrade of prostate cancer (PCa). MATERIALS AND METHODS: We relied on a multi-institutional cohort of localized PCa patients who underwent RP in Martini-Klinik, Hamburg, or Prostate Center Northwest, Gronau, between 2014 and 2022. Analyses were restricted to PCa GGG 1-3 diagnosed at SBx (n = 4475) or TBx + SBx (n = 1282). Multivariable logistic regression modeling (MVA) predicting RP GGG upgrade of ≥ 1 was performed separately for SBx and TBx + SBx. RESULTS: Treatment delay to RP of < 90, 90-180 and 180-365 days was reported in 59%, 35% and 6.2% of SBx and in 60%, 34% and 5.9% of the TBx + SBx patients, respectively. Upgrade to GGG ≥ 4 at RP was detected in 15% of SBx patients and 0.86% of TBx patients. In MVA performed for SBx, treatment delay yielded independent predictor status (OR 1.17 95% CI 1.02-1.39, p = 0.028), whereas for TBx + SBx MVA, statistical significance was not achieved. CONCLUSION: Treatment delay remained independently associated with radical prostatectomy GGG upgrade after adjustment for clinical variables in the patients diagnosed with SBx alone, but not in those who received combined TBx + SBx. These findings can be explained through inherent misclassification rates of SBx, potentially obfuscating historical observations of natural PCa progression and potential dangers of treatment delay. Thus, mpMRI-guided combined TBx + SBx appears mandatory for prospective delay-based examinations of PCa.
Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/diagnóstico por imagem , Próstata/cirurgia , Próstata/patologia , Estudos Prospectivos , Tempo para o Tratamento , Biópsia Guiada por Imagem , Prostatectomia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: To assess suitability of Comprehensive Complication Index (CCI®) vs. Clavien-Dindo classification (CDC) to capture 30-day morbidity after robot-assisted radical cystectomy (RARC). MATERIALS AND METHODS: A total of 128 patients with bladder cancer (BCa) undergoing intracorporeal RARC with pelvic lymph node dissection between 2015 and 2021 were included in a retrospective bi-institutional study, which adhered to standardized reporting criteria. Thirty-day complications were captured according to a procedure-specific catalog. Each complication was graded by the CDC and the CCI®. Multivariable linear regression (MVA) was used to identify predictors of higher morbidity. RESULTS: 381 complications were identified in 118 patients (92%). 55 (43%), 43 (34%), and 20 (16%) suffered from CDC grade I-II, IIIa, and ≥ IIIb complications, respectively. 16 (13%), 27 (21%), and 2 patients (1.6%) were reoperated, readmitted, and died within 30 days, respectively. 31 patients (24%) were upgraded to most severe complication (CCI® ≥ 33.7) when calculating morbidity burden compared to corresponding CDC grade accounting only for the highest complication. In MVA, only age was a positive estimate (0.44; 95% CI = 0.03-0.86; p = 0.04) for increased cumulative morbidity. CONCLUSION: The CCI® estimates of 30-day morbidity after RARC were substantially higher compared to CDC alone. These measurements are a prerequisite to tailor patient counseling regarding surgical approach, urinary diversion, and comparability of results between institutions.
Assuntos
Procedimentos Cirúrgicos Robóticos , Robótica , Neoplasias da Bexiga Urinária , Derivação Urinária , Cistectomia/efeitos adversos , Cistectomia/métodos , Humanos , Morbidade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Derivação Urinária/métodosRESUMO
OBJECTIVE: To compare surgical, oncological and functional outcomes between obese vs. normal-weight prostate cancer (PCa) patients treated with robotic-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: We assessed 4555 consecutive RARP patients from a high-volume center 2008-2018. Analyses were restricted to normal-weight vs. obese patients (≥ 30 kg/m2). Multivariable cox regression analyses (MVA) assessed the effect of obesity on biochemical recurrence (BCR), metastatic progression (MP), erectile function and urinary continence recovery. Analyses were repeated after propensity score matching. RESULTS: Before matching, higher rates of pathological Gleason Grade group ≥ 4 (14 vs. 18%; p = 0.004) and pT3 stage (33 vs. 35%; p = 0.016) were observed in obese patients, with similar observations for surgery time, blood loss and 30-day wound- and surgical complication rates. For normal-weight vs. obese patients, BCR- and MP-free rates were 86 vs. 85% (p = 0.97) and 97.5 vs.97.8% (p = 0.8) at 48 months. Similarly, rates of erectile function at 36 months and urinary continence at 12 months were 56 vs. 49% (p = 0.012) and 88 vs. 85% (p = 0.003), respectively. Before and after propensity score matching, obesity had no effect on BCR or MP, but a negative effect on erectile function (matched HR 0.87, 95%CI 0.76-0.99; p = 0.029) and urinary continence recovery (matched HR 0.91, 95%CI 0.84-0.98; p = 0.014). CONCLUSIONS: Obesity did not represent a risk factor of BCR or MP after RARP despite higher rates of adverse pathological features. However, obesity was associated with higher risk of perioperative morbidity and impaired functional outcomes. Such information is integral for patient counselling. Thus, weight loss before RARP should be encouraged.