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We have developed a computer-model-based approach to quantitatively diagnose the causes of metabolic acid-base disorders in critically-ill patients. We use an interstitial-plasma-erythrocyte (IPE) model that is sufficiently detailed to accurately calculate steady-state changes from normal in fluid volumes and electrolyte concentrations in a given patient due to a number of causes of acid-base disorders. Normal fluid volumes for each patient are determined from their sex, height and weight using regression equations derived from measured data in humans. The model inputs (electrolyte masses and volumes) are altered to simulate the laboratory chemistry of each critically-ill patient. In this process, the model calculates changes in body-fluid volumes, osmolality and yields the individual values of IPE base excess (BE(IPE)) attributed to changes due to: (1) fluid dilution/contraction, (2) gain or loss of Cl(-), (3) hyper- or hypoalbuminemia, (4) presence of unmeasured ions, (5) gain of lactate, (6) gain or loss of phosphate, (7) gain or loss of calcium and magnesium, (8) gain or loss of potassium and (9) gain or loss of sodium. We use critically-ill patient data to show how our new approach is more informative and much simpler to interpret as compared to the approaches of Siggaard-Andersen or Stewart. We demonstrate how the model can be used at the bedside to diagnose acid-base disorders and suggest appropriate treatment. Hence, this new approach gives clinicians a new tool for diagnosing disorders and specifying fluid-therapy options for critically-ill patients. [ABSTRACT FROM AUTHOR]

Acid-base disorders are currently analyzed and treated using a bicarbonate-centered approach derived from blood studies prior to the advent of digital computers, which could solve computer models capable of quantifying the complex physicochemical nature governing distribution of water and ions between fluid compartments. An alternative is the Stewart approach, which can predict the pH of a simple mixture of ions and electrically charged proteins; hence, the role of extravascular fluids has been largely ignored. The present study uses a new, comprehensive computer model of four major fluid compartments, based on a recent blood model, which included ion binding to proteins, electroneutrality constraints, and other essential physicochemical laws. The present model predicts quantitative respiratory acid-base buffering behavior in the whole body, as well as determining roles of each compartment and their species, particularly compartmental electrically charged proteins, largely responsible for buffering. The model tested an early theory that H + was conserved in the body fluids; hence, when changing Pco 2 states, intracellular buffering could be predicted by net changes in bicarbonate and protein electrical charge in the remaining fluids. Even though H + is not conserved in the model, the theory held in simulated respiratory disorders. Model results also agreed with a second part of the theory, that ion movements between cells and interstitial fluid were linked with H + buffering, but by electroneutrality constraints, not necessarily by some membrane-related mechanisms, and that the strong ion difference (SID), an amalgamation of ionic electrical charges, was approximately conserved when going between equilibrium states caused by Pco 2 changes in the body-fluid system. NEW & NOTEWORTHY For the first time, a physicochemically based, whole body, four-compartment, computer model was used to study respiratory whole body acid-base buffering. An improved approach to quantify acid-base buffering, previously used by this author, was able to determine contributions of the various compartmental fluids to whole body buffering. The model was used to test, for the first time, three fundamental theories of whole body acid-base homeostasis, namely, H + -conservation, its linkage to ion transport, and strong ion difference conservation.

This paper describes two new features 1 ) development of physicochemically based, two-compartment models describing acid-base-state changes in normal and abnormal blood and 2 ) use of model results to view and describe physicochemical properties of blood, in terms of Pco 2 as the causative independent variable and effected [H + ] changes as the dependent variable. Models were derived from an in vitro experimental study, where normal blood was made both hypoproteinemic and hyperalbuminemic and then equilibrated with CO 2 . Strong-ion gap (SIG) values were selected to match model and experimental pH. The effect of individual physicochemical factors affecting blood acid-base-state were evaluated from their induced changes on buffer curve linearized slope (β H+ ) and [H + ] curve shift at 40 mmHg ([H + ] 40 ). Model findings were: 1 ) in severe hypoproteinemia, hemoglobin enhances buffering (decreases β H+ ), whereas albumin compromises it, resulting in an almost unchanged β H+ ; [H + ] 40 decreases (alkalemia) due to hypoalbuminemia. 2 ) Severe hyperalbuminemia greatly increases both β H+ and [H + ] 40 , hence, compromising buffering and causing a severe acidemia. 3 ) Pco 2 -induced changes in the electrical-charge concentration of hemoglobin are the principal factor responsible for maintaining normal buffering characteristics in hypoproteinemia and hyperalbuminemia. 4 ) SIG values are a third Pco 2 -independent characteristic of blood acid-base state and 5 ) the quantities, β H +, [H + ] 40 , and SIG, derived from a [H + ] vs. Pco 2 perspective, are a more informative and intuitive way to characterize blood acid-base state. NEW & NOTEWORTHY This study represents the most up-to-date, physicochemical, multi-compartment computer model of the processes involved in determining the acid-base buffering state of blood. Previous models lack this capability, notably by being single compartment and/or lacking electroneutrality and osmotic constraints. Model results, analyzed from a different perspective of dependent [H + ] changes resulting from independent Pco 2 changes, provide a new set of Pco 2 -independent parameters, characteristic of blood buffering properties.

An equilibrium model was developed to understand interrelated, physicochemical mechanisms leading to blood pH and electrolyte distribution changes in patients because of venovenous extracorporeal membrane oxygenation (ECMO) and carbon dioxide removal. The model consists of plasma and red cell compartments between which water and small ions can move to establish an equilibrium state. Governing forces are as follows: 1) ionic electroneutrality in each compartment; 2) osmotic equilibrium between compartments; 3) mass balance of small ions other than bicarbonate; 4) oxygen (O 2 )-dependent hemoglobin (Hb)-Cl binding in red cells; 5) albumin binding to Cl - , Ca 2+ , and Mg 2+ in plasma; and 6) chemical equilibria of carbonates and phosphates in each compartment. The model was constructed and validated using recent clinical ECMO inlet and exit blood-pH and electrolyte concentration data. The model closely described pH and electrolyte concentration changes in both states, which validated the model. The model was then used to predict CO 2 and O 2 saturation-induced changes in pH and electrolyte concentrations. It was found that O 2 -dependent Hb-Cl binding had a much lesser effect on blood acid-base status changes and electrolyte shifts during ECMO than previously thought. The model showed that the Cl-shift and Gibbs-Donnan equilibrium effects, characterized by pH and electrolyte distribution changes during ECMO, were primarily caused by changes in pH-induced electrical charge on mainly Hb and other constrained ions in red cells. These insights can improve understanding of the same factors acting when blood traverses the lung., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

This study contrasts the abilities and mechanisms of two physicochemical, mathematical models to predict experimental bicarbonate kinetics, hence, buffer transport, during a hemodialysis (HD) treatment in chronic renal failure patients. The existing Sargent model assumes that the body fluids can be described as a single, homogeneous extracellular fluid (EC) compartment whose volume decreases because of a constant ultrafiltration rate during HD. Bicarbonate and acetate transport between HD fluid and the EC compartment are by convection and diffusion with acetate metabolized in that compartment. The new model formulated in this study assumes the same conditions as Sargent et al., but constrains ion concentrations in the EC to be electrically neutral at all times. This constraint requires inclusion in the EC of other transportable small ions, Na+, K+, Cl- and unidentified, anionic organic acids in addition to an electrical charge on impermeable albumin. The findings are that the new electroneutrality model predicts plasma bicarbonate-concentration kinetics as closely as the Sargent model, but bicarbonate transport is an unlikely mechanism. Rather, the findings are better explained by rapid interconversion of CO2 and bicarbonate in this simplified EC compartment model. The results of this study bring into question the ability of the Sargent et al. hypothesized H+-mobilization model to explain buffer-transport kinetics during HD., Competing Interests: Disclosure: The author has no conflicts of interest to report., (Copyright © ASAIO 2021.)

This study answers criticisms by Waniewski et al. of the recent paper by Wolf on peritoneal transport kinetic models. Their criticisms centre on the accuracy of the data used for model fits, the hypothesis presented, which involves changes in glucose membrane parameters at high peritoneal glucose concentration and on the necessary techniques required to achieve accurate model parameter estimation. In response, this article shows that (1) the mean values previously captured from graphical depictions of Heimburger et al. are not different than those captured from the recent Waniewski et al. graphs, (2) a much simpler hypothesis is proposed, which centres on intraperitoneal pressure-induced lymph flow during the dialysis dwell and (3) the finding that the new model predictions, with only two constant parameter values, as estimated by the Powell algorithm, give a closer fit than the Waniewski model, which uses many time-varying parameters. The current findings again bring into question of the validity of their vasodilation hypothesis, leading to transient changes in capillary surface area during the dwell.

To investigate mechanisms of acid-base changes during peritoneal dialysis (PD), a mathematical model was developed that describes kinetics of peritoneal bicarbonate, CO2, and pH during the dwell with both high and low lactate-containing dialysis fluids. The model was based on a previous modification of the Rippe 3-Pore model of water and solute kinetic transport across the peritoneal membrane during the PD dwell. A central feature of the present modification is an electroneutrality constraint on peritoneal-fluid ion concentrations, which results in the conclusion that peritoneal bicarbonate-concentration kinetics are entirely dependent on the kinetics of the other ions. This new model was able to closely predict peritoneal bicarbonate-concentration kinetics during the dwell. Predictions of total peritoneal bicarbonate-mass kinetics were greater than those of porous, transmembrane bicarbonate transport, suggesting that a portion of bicarbonate comes from CO2 transport, both porous and nonporous and then a partial conversion to bicarbonate. Fitting the model to experimental pH data during the dwell, required addition of a peritoneal CO2 mass-conservation constraint, coupled with the description for peritoneal bicarbonate kinetics. Predicted pH kinetics during the dwell, closely mimicked the experimental data. The conclusion was that the mechanisms describing peritoneal bicarbonate and pH kinetics during PD must include 1) electroneutrality of peritoneal fluid, 2) porous transport of bicarbonate and CO2, 3) nonporous transport of CO2, and 4) CO2 conversion to bicarbonate. These mechanisms are quite different and more complex than the bicarbonate-centered, lactate to acid-generation mechanisms previously proposed., Competing Interests: Disclosures: The authors have no conflicts of interest to report., (Copyright © ASAIO 2020.)

Background: Contemporary selection criteria for men with prostate cancer (PC) suitable for active surveillance (AS) are unsatisfactory, leading to high disqualification rates based on tumor misclassification. Conventional biopsy protocols are based on standard 12-core transrectal ultrasound (TRUS) biopsy., Objective: To assess the value of magnetic resonance imaging (MRI)/TRUS fusion biopsy over 4-yr follow-up in men on AS for low-risk PC., Design, Setting, and Participants: Between 2010 and 2018, a total of 273 men were included. Of them, 157 men with initial 12-core TRUS biopsy and 116 with initial MRI/TRUS fusion biopsy were followed by systematic and targeted transperineal MRI/TRUS fusion biopsies based on Prostate Cancer Research International Active Surveillance criteria. MRI from follow-up MRI/TRUS fusion biopsy was assessed using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) scoring system., Outcome Measurements and Statistical Analysis: AS-disqualification rates for patients on AS initially diagnosed by either 12-core TRUS biopsy or by MRI/TRUS fusion biopsy were compared using Kaplan-Meier estimates, log-rank tests, and regression analyses. We also analyzed the influence of negative primary MRI and PRECISE scoring to predict AS disqualification using Kaplan-Meier estimates, log-rank tests, and receiver operating characteristic (ROC) curve analysis., Results and Limitations: Of men diagnosed by 12-core TRUS biopsy, 59% were disqualified from AS based on the results of subsequent MRI/TRUS fusion biopsy. In the initial MRI fusion biopsy cohort, upgrading occurred significantly less frequently (19%, p<0.001). ROC curve analyses demonstrated good discrimination for the PRECISE score with an area under the curve of 0.83. No men with a PRECISE score of 1 or 2 (demonstrating absence or downgrading of lesions in follow-up MRI) were disqualified from AS. In our cohort, a negative baseline MRI scan was not a predictor of nondisqualification from AS. Limitations include transperineal approach and extended systematic biopsies used with MRI/TRUS fusion biopsy, which may not be representative of other centers., Conclusions: MRI/TRUS fusion biopsies allow a reliable risk classification for patients who are candidates for AS. The application of the PRECISE scoring system demonstrated good discrimination., Patient Summary: In this study, we investigated the value of multiparametric magnetic resonance imaging (MRI) and MRI/transrectal ultrasound (TRUS) fusion biopsies for the assessment of active surveillance (AS) reliability using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation criteria. Standard TRUS biopsies lead to significant underestimation of prostate cancer. In contrast, MRI/TRUS fusion biopsies allowed for a more reliable risk classification. For appropriate inclusion into AS, men should receive either an initial or a confirmatory MRI/TRUS fusion biopsy., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Waniewski postulated a transient increase in peritoneal capillary surface area to fit their model predictions to experimental data of Heimburger measured in renal failure (RF) patients undergoing peritoneal dialysis (PD) but with only a 3.86% glucose dialysis fluid. The present aim is to propose a new mathematical model of the patient PD procedure that could closely fit the complete Heimburger measurement set without this postulate., Methods: The three-pore model of Rippe was used to describe transient changes in peritoneal volume and solute concentrations during a PD dwell. The predialysis, RF patient, plasma solute concentrations were assumed to remain constant during the dwell. The model was validated using the 3.86% glucose Heimburger measurements. Permeability surface area product parameters were chosen to match only the end-dwell peritoneal fluid glucose concentration and the end-dwell amounts of urea, creatinine, and Na + removed from this simulated patient group. Then, this model was used to predict additional measurements by Heimburger on two other patient groups dialyzed with glucose concentrations of 2.27% and 1.36%, respectively. Parameters were unchanged when simulating these other patient groups., Results: To match the shape of the transient changes in drained volume and dialysis fluid glucose concentration for the 3.86% glucose group, it was necessary for only one parameter, the effective radius of glucose, to vary linearly in proportion to the dialysis fluid glucose concentration. This description was unchanged in the other two groups., Conclusion: Postulated transient increases in peritoneal capillary surface area were unnecessary to predict the entire Heimburger measurements.

Physicochemical models have played an important role in understanding, diagnosing, and treating acid-base disorders for more than 100 years. This review focuses on recent complex models, solved using computers, and shows how these models provide new understanding and diagnostic approaches in acid-base disorders. These advanced models use the following physicochemical principles: (1) chemical equilibrium, (2) conservation of mass, (3) electroneutrality, and (4) osmotic equilibrium to describe the steady-state distribution of H 2 O and ions in the four major body-fluid spaces, cells, interstitium, plasma, and erythrocytes, and show how this distribution is changed by fluid infusions and losses through renal and gastrointestinal physiological processes. Illustrations of model use with a new comprehensive diagnostic approach are the understanding of an important clinical situation, saline acidosis, and the diagnosis of a patient with diabetic ketoacidosis. This new approach predicts a patient's whole-body base excess and partitions this value into 10 individual values, producing the disorder. These data and other data produced by the diagnostic model described in this review provide much more extensive insight than previous approaches., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To quantitatively assess 12-month prostate volume (PV) reduction based on T2-weighted MRI and immediate post-treatment contrast-enhanced MRI non-perfused volume (NPV), and to compare measurements with predictions of acute and delayed ablation volumes based on MR-thermometry (MR-t), in a central radiology review of the Phase I clinical trial of MRI-guided transurethral ultrasound ablation (TULSA) in patients with localized prostate cancer., Materials and Methods: Treatment day MRI and 12-month follow-up MRI and biopsy were available for central radiology review in 29 of 30 patients from the published institutional review board-approved, prospective, multi-centre, single-arm Phase I clinical trial of TULSA. Viable PV at 12 months was measured as the remaining PV on T2-weighted MRI, less 12-month NPV, scaled by the fraction of fibrosis in 12-month biopsy cores. Reduction of viable PV was compared to predictions based on the fraction of the prostate covered by the MR-t derived acute thermal ablation volume (ATAV, 55°C isotherm), delayed thermal ablation volume (DTAV, 240 cumulative equivalent minutes at 43°C thermal dose isocontour) and treatment-day NPV. We also report linear and volumetric comparisons between metrics., Results: After TULSA, the median 12-month reduction in viable PV was 88%. DTAV predicted a reduction of 90%. Treatment day NPV predicted only 53% volume reduction, and underestimated ATAV and DTAV by 36% and 51%., Conclusion: Quantitative volumetry of the TULSA phase I MR and biopsy data identifies DTAV (240 CEM43 thermal dose boundary) as a useful predictor of viable prostate tissue reduction at 12 months. Immediate post-treatment NPV underestimates tissue ablation., Key Points: • MRI-guided transurethral ultrasound ablation (TULSA) achieved an 88% reduction of viable prostate tissue volume at 12 months, in excellent agreement with expectation from thermal dose calculations. • Non-perfused volume on immediate post-treatment contrast-enhanced MRI represents only 64% of the acute thermal ablation volume (ATAV), and reports only 60% (53% instead of 88% achieved) of the reduction in viable prostate tissue volume at 12 months. • MR-thermometry-based predictions of 12-month prostate volume reduction based on 240 cumulative equivalent minute thermal dose volume are in excellent agreement with reduction in viable prostate tissue volume measured on pre- and 12-month post-treatment T2w-MRI.

This study addresses the clinically important relationship between the decreases in plasma Na + and the increases in plasma glucose concentrations seen in diabetes and other hyperglycemic syndromes. This plasma 'Na + correction factor', is generally accepted as 1.6mM Na + per 100mg% glucose (0.29mM/mM in SI units) assuming osmotic equilibrium, although much larger numbers have been measured in experiments on normal humans. To resolve this controversy, a mathematical model of whole-body fluid-electrolyte balance was used to perform the experiment wherein plasma glucose concentration was increased to diabetic levels and the plasma Na + concentration changes assessed, without the complications seen in human experiments. The findings, based on osmotic grounds, were that the factor 1) was significantly <1.6, approaching 1 in some cases, 2) depended upon the anthropometry of the subject; it was inversely proportional to the ratio of extracellular to total body water, which increases with higher fat content and 3) was approximately linear up to glucose concentrations of about 800mg%, but decreased up to 10% for higher glucose concentrations. To explain the experimental data, a hypothesis of Na + sequestration in cells was incorporated in the model, resulting in close prediction of measured transient Na + changes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To investigate parametric changes in the apparent diffusion coefficient (ADC) at multiple timepoints during and after completion of primary proton and carbon ion irradiation of prostate cancer (PCa) as compared with normal-appearing prostate parenchyma., Materials and Methods: In all, 92 patients with histologically confirmed PCa received either proton or carbon ion hypofractionated radiotherapy (RT). All were prospectively evaluated with diffusion-weighted magnetic resonance imaging (DWI-MRI) at five timepoints: baseline, day 10 during therapy and 6 weeks, 6 months, and 18 months after treatment. Linear mixed models (LMM) were used to evaluate the effects of radiation, antihormonal therapy, time, and type of particle irradiation on manual ADC measurements. ADC differences related to prostate-specific antigen (PSA) relapse according to PSA thresholds and to Vancouver rules and Phoenix criteria were examined using LMM and unpaired Student's t-test., Results: A measurable and continuous increase of tumor ADC measurements from baseline (1.194 × 10 -3 mm 2 /s) during (1.350 × 10 -3 mm 2 /s, day 10, P = 0.006) and after treatment (1.355/1.430/1.490 × 10 -3 mm 2 /s, week 6 / month 6 / month 18, P = 0.001/<0.001/<0.001) was found. ADC values of normal-appearing control tissue remained unchanged. Androgen deprivation (P ≥ 0.320), different PSA thresholds (P = 0.634), and PSA relapse criteria according to Vancouver rules (P ≥ 0.776) had no effect. A weak association between 18-month measurements and Phoenix criteria (P = 0.046) was found., Conclusion: ADC parametric changes were distinct in tumor tissue, highlighting the ability of diffusion MRI to evaluate different aspects of the microscopic pathophysiology. Although promising, their use as noninvasive imaging biomarkers requires further validation., Level of Evidence: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:850-860., (© 2017 International Society for Magnetic Resonance in Medicine.)

We aimed to evaluate the sensitivity and specificity of 8 biochemical scanning tools in signalling the presence of unmeasured anions. We used blood gas and biochemical data from 15 patients during and after cardio-pulmonary bypass. Sampling time-points were pre-bypass (T1), 2 min post equilibration with priming fluid containing acetate and gluconate anions (T2), late bypass (T3) and 4 h after surgery (T4). We calculated the anion gap (AG), albumin-corrected anion gap (AGc), whole blood base excess (BE) gap, plasma BE gap, standard BE gap and the strong ion gap (SIG), plus 2 new indices-the unmeasured ion index (UIX) and unmeasured plasma anions according to the interstitial, plasma and erythrocyte acid-base model (IPEua). Total measured plasma concentrations of acetate and gluconate [XA] were proxies for unmeasured plasma anions. [XA] values (mmol/L) were 1.41 (0.87) at T1, 11.73 (3.28) at T2, 4.80 (1.49) at T3 and 1.36 (0.73) at T4. Corresponding [albumin] values (g/L) were 32.3 (2.0), 19.8 (2.6), 21.3 (2.5) and 29.1 (2.3) respectively. Only the AG failed to increase significantly at T2 in response to a mean [XA] surge of >10 mEq/L. At an [XA] threshold of 6 mEq/L, areas under receiver -operator characteristic curves in rank order were IPEua and UIX (0.88 and 0.87 respectively), SIG (0.81), AGc (0.79), standard BE gap (0.77), plasma BE gap (0.71), BE gap (0.70) and AG (0.59). Similar ranking hierarchies applied to positive and negative predictive values. We conclude that during acute hemodilution UIX and IPEua are superior to the anion gap (with and without albumin correction) and 4 other indices as scanning tools for unmeasured anions.

The hemoglobin-dilution method (HDM) has been used to estimate changes in vascular volumes in patients because direct measurements with radioisotopes are time-consuming and not practical in many facilities. The HDM requires an assumption of initial blood volume, repeated measurements of plasma hemoglobin concentration, and the calculation of the ratio of hemoglobin measurements. The statistics of these ratio distributions resulting from measurement error are ill-defined even when the errors are normally distributed. This study uses a "Monte Carlo" approach to determine the distribution of these errors. The finding was that these errors could be closely approximated with a log-normal distribution that can be parameterized by a geometric mean ( X ) and a dispersion factor ( S ). When the ratio of successive Hb concentrations is used to estimate blood volume, normally distributed hemoglobin measurement errors tend to produce exponentially higher values of X and S as the SD of the measurement error increases. The longer tail of the distribution to the right could produce much greater overestimations than would be expected from the SD values of the measurement error; however, it was found that averaging duplicate and triplicate hemoglobin measurements on a blood sample greatly improved the accuracy.

Background: Multiparametric magnetic resonance imaging (mpMRI) and MRI fusion targeted biopsy (FTB) detect significant prostate cancer (sPCa) more accurately than conventional biopsies alone., Objective: To evaluate the detection accuracy of mpMRI and FTB on radical prostatectomy (RP) specimen., Design, Setting and Participants: From a cohort of 755 men who underwent transperineal MRI and transrectal ultrasound fusion biopsy under general anesthesia between 2012 and 2014, we retrospectively analyzed 120 consecutive patients who had subsequent RP. All received saturation biopsy (SB) in addition to FTB of lesions with Prostate Imaging Reporting and Data System (PI-RADS) score ≥2., Outcome Measurements and Statistical Analysis: The index lesion was defined as the lesion with extraprostatic extension, the highest Gleason score (GS), or the largest tumor volume (TV) if GS were the same, in order of priority. GS 3+3 and TV ≥1.3ml or GS ≥3+4 and TV ≥0.55ml were considered sPCa. We assessed the detection accuracy by mpMRI and different biopsy approaches and analyzed lesion agreement between mpMRI and RP specimen., Results and Limitations: Overall, 120 index and 71 nonindex lesions were detected. Overall, 107 (89%) index and 51 (72%) nonindex lesions harbored sPCa. MpMRI detected 110 of 120 (92%) index lesions, FTB (two cores per lesion) alone diagnosed 96 of 120 (80%) index lesions, and SB alone diagnosed 110 of 120 (92%) index lesions. Combined SB and FTB detected 115 of 120 (96%) index foci. FTB performed significantly less accurately compared with mpMRI (p=0.02) and the combination for index lesion detection (p=0.002). Combined FTB and SB detected 97% of all sPCa lesions and was superior to mpMRI (85%), FTB (79%), and SB (88%) alone (p<0.001 each). Spearman's rank correlation coefficient for index lesion agreement between mpMRI and RP was 0.87 (p<0.001). Limitations included the retrospective design, multiple operators, and nonblinding of radiologists., Conclusions: MpMRI identified 92% of index lesions compared with RP histopathology. The combination of FTB and SB was superior to both approaches alone, reliably detecting 97% of sPCa lesions., Patient Summary: Multiparametric magnetic resonance imaging detects the index lesion accurately in 9 of 10 patients; however, the combined biopsy approach, while missing less significant cancer, comes at the cost of detecting more insignificant cancer., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Magnetic resonance imaging-guided transurethral ultrasound ablation (MRI-TULSA) is a novel minimally invasive technology for ablating prostate tissue, potentially offering good disease control of localized cancer and low morbidity., Objective: To determine the clinical safety and feasibility of MRI-TULSA for whole-gland prostate ablation in a primary treatment setting of localized prostate cancer (PCa)., Design, Setting, and Participants: A single-arm prospective phase 1 study was performed at three tertiary referral centers in Canada, Germany, and the United States. Thirty patients (median age: 69 yr; interquartile range [IQR]: 67-71 yr) with biopsy-proven low-risk (80%) and intermediate-risk (20%) PCa were treated and followed for 12 mo., Intervention: MRI-TULSA treatment was delivered with the therapeutic intent of conservative whole-gland ablation including 3-mm safety margins and 10% residual viable prostate expected around the capsule., Outcome Measurements and Statistical Analysis: Primary end points were safety (adverse events) and feasibility (technical accuracy and precision of conformal thermal ablation). Exploratory outcomes included quality of life, prostate-specific antigen (PSA), and biopsy at 12 mo., Results and Limitations: Median treatment time was 36min (IQR: 26-44) and prostate volume was 44ml (IQR: 38-48). Spatial control of thermal ablation was ±1.3mm on MRI thermometry. Common Terminology Criteria for Adverse Events included hematuria (43% grade [G] 1; 6.7% G2), urinary tract infections (33% G2), acute urinary retention (10% G1; 17% G2), and epididymitis (3.3% G3). There were no rectal injuries. Median pretreatment International Prostate Symptom Score 8 (IQR: 5-13) returned to 6 (IQR: 4-10) at 3 mo (mean change: -2; 95% confidence interval [CI], -4 to 1). Median pretreatment International Index of Erectile Function 13 (IQR: 6-28) recovered to 13 (IQR: 5-25) at 12 mo (mean change: -1; 95% CI, -5 to 3). Median PSA decreased 87% at 1 mo and was stable at 0.8 ng/ml (IQR: 0.6-1.1) to 12 mo. Positive biopsies showed 61% reduction in total cancer length, clinically significant disease in 9 of 29 patients (31%; 95% CI, 15-51), and any disease in 16 of 29 patients (55%; 95% CI, 36-74)., Conclusions: MRI-TULSA was feasible, safe, and technically precise for whole-gland prostate ablation in patients with localized PCa. Phase 1 data are sufficiently compelling to study MRI-TULSA further in a larger prospective trial with reduced safety margins., Patient Summary: We used magnetic resonance imaging-guided transurethral ultrasound to heat and ablate the prostate in men with prostate cancer. We showed that the treatment can be targeted within a narrow range (1mm) and has a well-tolerated side effect profile. A larger study is under way., Trial Registration: NCT01686958, DRKS00005311., (Copyright © 2016. Published by Elsevier B.V.)

Background: Active surveillance (AS) is commonly based on standard 10-12-core prostate biopsies, which misclassify ~50% of cases compared with radical prostatectomy. We assessed the value of multiparametric magnetic resonance imaging (mpMRI)-targeted transperineal fusion-biopsies in men under AS., Methods: In all, 149 low-risk prostate cancer (PC) patients were included in AS between 2010 and 2015. Forty-five patients were initially diagnosed by combined 24-core systematic transperineal saturation biopsy (SB) and MRI/transurethral ultrasound (TRUS)-fusion targeted lesion biopsy (TB). A total of 104 patients first underwent 12-core TRUS-biopsy. All patients were followed-up by combined SB and TB for restratification after 1 and 2 years. All mpMRI examinations were analyzed using PIRADS. AS was performed according to PRIAS-criteria and a NIH-nomogram for AS-disqualification was investigated. AS-disqualification rates for men initially diagnosed by standard or fusion biopsy were compared using Kaplan-Meier estimates and log-rank tests. Differences in detection rates of the SB and TB components were evaluated with a paired-sample analysis. Regression analyses were performed to predict AS-disqualification., Results: A total of, 48.1% of patients diagnosed by 12-core TRUS-biopsy were disqualified from AS based on the MRI/TRUS-fusion biopsy results. In the initial fusion-biopsy cohort, upgrading occurred significantly less frequently during 2-year follow-up (20%, P<0.001). TBs alone were significantly superior compared with SBs alone to detect Gleason-score-upgrading. NPV for Gleason-upgrading was 93.5% for PIRADS⩽2. PSA level, PSA density, NIH-nomogram, initial PIRADS score (P<0.001 each) and PIRADS-progression on consecutive MRI (P=0.007) were significant predictors of AS-disqualification., Conclusions: Standard TRUS-biopsies lead to significant underestimation of PC under AS. MRI/TRUS-fusion biopsies, and especially the TB component allow more reliable risk classification, leading to a significantly decreased chance of subsequent AS-disqualification. Cancer detection with mpMRI alone is not yet sensitive enough to omit SB on follow-up after initial 12-core TRUS-biopsy. After MRI/TRUS-fusion biopsy confirmed AS, it may be appropriate to biopsy only those men with suspected progression on MRI.

Purpose: To characterize parametric changes measured by sequential dynamic contrast enhanced perfusion MRI (DCE-MRI) during primary proton and carbon ion irradiation of prostate cancer using a novel hypofractionated raster scan technique to determine the potential of pharmacokinetic analysis for monitoring treatment effects of this novel irradiation scheme., Materials and Methods: Ninety-two patients were evaluated prospectively with DCE-MRI at baseline, day 10 during therapy, and 6weeks, 6months and 18months after treatment completion. After motion correction and co-registration to morphological T2-weighted images, tumors and normal appearing contralateral parenchyma (NACP) were segmented manually on T2W images and ROI statistics calculated for pharmacokinetic parameters K(trans), kep and ve using the standard Tofts model., Results: The volume transfer constant (K(trans), p<0.001/p=0.010) and the leakage space partial volume (ve, p<0.001/p=0.005) showed a statistically significant increase during therapy with protons and carbon ions, respectively. Parametric increases occurred only in patients naive to antihormonal therapy (AHT), and were maximal 10days after the begining of treatment. The rate constant (kep) showed a significant increase only for proton, but not for carbon irradiation (p=0.021). Statistically significant differences between PC and NACP were observed for all parameters (p<0.001). AHT naïve patients with persistent PSA elevation above 1ng/ml at 12months experienced statistically significant elevation of K(trans) and ve compared to those with PSA suppression (p=0.04/p=0.023)., Conclusion: DCE parametric changes following ion particle irradiation of the prostate have not been previously reported. Their development into potential non-invasive imaging biomarkers for assessment of treatment response and efficacy is expected to be aided by the data on the magnitude and temporal evolution of parametric responses of cancer and normal tissue during and after therapy presented here, especially the changes of K(trans) and ve during therapy and their different measurement levels within tumors and in normal appearing contralateral tissue., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the diagnostic performance of an automated analysis tool for the assessment of prostate cancer based on multiparametric magnetic resonance imaging (mpMRI) of the prostate., Methods: A fully automated analysis tool was used for a retrospective analysis of mpMRI sets (T2-weighted, T1-weighted dynamic contrast-enhanced, and diffusion-weighted sequences). The software provided a malignancy prediction value for each image pixel, defined as Malignancy Attention Index (MAI) that can be depicted as a colour map overlay on the original images. The malignancy maps were compared to histopathology derived from a combination of MRI-targeted and systematic transperineal MRI/TRUS-fusion biopsies., Results: In total, mpMRI data of 45 patients were evaluated. With a sensitivity of 85.7% (with 95% CI of 65.4-95.0), a specificity of 87.5% (with 95% CI of 69.0-95.7) and a diagnostic accuracy of 86.7% (with 95% CI of 73.8-93.8) for detection of prostate cancer, the automated analysis results corresponded well with the reported diagnostic accuracies by human readers based on the PI-RADS system in the current literature., Conclusion: The study revealed comparable diagnostic accuracies for the detection of prostate cancer of a user-independent MAI-based automated analysis tool and PI-RADS-scoring-based human reader analysis of mpMRI. Thus, the analysis tool could serve as a detection support system for less experienced readers. The results of the study also suggest the potential of MAI-based analysis for advanced lesion assessments, such as cancer extent and staging prediction.

Purpose: The purpose of this study was to compare safety and feasibility of proton therapy with that of carbon ion therapy in hypofractionated raster-scanned irradiation of the prostate, in a prospective randomized phase 2 trial., Methods and Materials: In this trial, 92 patients with localized prostate cancer were enrolled. Patients were randomized to receive either proton therapy (arm A) or carbon ion therapy (arm B) and treated with a total dose of 66 Gy(relative biological effectiveness [RBE]) administered in 20 fractions (single dose of 3.3 Gy[RBE]). Patients were stratified by the use of antihormone therapy. Primary endpoint was the combined assessment of safety and feasibility. Secondary endpoints were specific toxicities, prostate-specific antigen progression-free survival (PFS), overall survival (OS), and quality of life (QoL)., Results: Ninety-one patients completed therapy and have had a median follow-up of 22.3 months. Among acute genitourinary toxicities, grade 1 cystitis rates were 34.1% (39.1% in A; 28.9% in B) and 17.6% grade 2 (21.7% in A; 13.3% in B). Seven patients (8%) required urinary catheterization during treatment due to urinary retention, 5 of whom were in arm A. Regarding acute gastrointestinal toxicities, 2 patients treated with protons developed grade 3 rectal fistulas. Grade 1 radiation proctitis occurred in 12.1% (13.0% in A; 11.1% in B) and grade 2 in 5.5% (8.7% in A; 2.2% in B). No statistically significant differences in toxicity profiles between arms were found. Reduced QoL was evident mainly in fatigue, pain, and urinary symptoms during therapy and 6 weeks thereafter. All European Organization for Research and Treatment of Cancer QLQ-C30 and -PR25 scores improved during follow-up., Conclusions: Hypofractionated irradiation using either carbon ions or protons results in comparable acute toxicities and QoL parameters. We found that hypofractionated particle irradiation is feasible and may be safe. Due to the occurrence of gel in the rectal wall and the consecutive occurrence of 2 rectal fistulas, we stopped using the insertion of spacer gel. Longer follow-up is necessary for evaluation of PFS and OS. (Ion Prostate Irradiation (IPI); NCT01641185; ClinicalTrials.gov.)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: On February 26th, 2013 the patient law became effective in Germany. Goal of the lawmakers was a most authoritative case law for liability of malpractice and to improve enforcement of the rights of the patients. The following article contains several examples detailing legal situation. By no means should these discourage those persons who treat patients. Rather should they be sensitized to to various aspects of this increasingly important field of law. To identify relevant sources according to judicial standard research was conducted including first- and second selection. Goal was the identification of jurisdiction, literature and other various analyses that all deal with liability of malpractice and patient law within the field of Interventional Radiology--with particular focus on transarterial chemoembolization of the liver and related procedures. In summary, 89 different sources were included and analyzed. The individual who treats a patient is liable for an error in treatment if it causes injury to life, the body or the patient's health. Independent of the error in treatment the individual providing medical care is liable for mistakes made in the context of obtaining informed consent. Prerequisite is the presence of an error made when obtaining informed consent and its causality for the patient's consent for the treatment. Without an effective consent the treatment is considered illegal whether it was free of treatment error or not. The new patient law does not cause material change of the German liablity of malpractice law., Key Points: •On February 26th, 2013 the new patient law came into effect. Materially, there was no fundamental remodeling of the German liability for medical malpractice. •Regarding a physician's liability for medical malpractice two different elements of an offence come into consideration: for one the liability for malpractice and, in turn, liability for errors made during medical consultation in the process of obtaining informed consent. •Forensic practice shows that patients frequently enforce both offences concurrently., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To investigate the value of multiparametric magnetic resonance imaging (mpMRI) and to predict extracapsular extension (ECE), seminal vesicle (SV) infiltration, and a negative surgical margin (SM) status at radical prostatectomy (RP) for different prostate cancer (PC) risk groups., Patients and Methods: In the study, 805 men underwent 3 tesla mpMRI without endorectal coil before MRI/transrectal ultrasonography-fusion guided prostate biopsy. MRIs were analyzed using the prostate imaging reporting and data system. The cohort was classified into risk groups according to National Comprehensive Cancer Network (NCCN) criteria. Of 132 men who subsequently underwent RP, pathologic stage and SM status at RP were used as reference. Retrospectively, we investigated a European Society of Urogenital Radiology (ESUR) score for ECE and SV-infiltration. Statistical analyses included regression analyses, receiver operating characteristics (ROC), and Youden Index to assess an ESUR-score cutoff., Results: Area under the curve in ROC curve analyses was 0.82 for ESUR-ECE score to detect pT(3a)-disease and 0.77 for ESUR-SV score for pT(3b). Using a cutoff of 4 for ECE and of 2 for SV, the positive predictive value of the ECE-score for harboring pT(3) was 50.0%, 90.0%, and 88.8% for the low-, intermediate- and high-risk cohort. Retrospectively, the use of the ESUR-ECE score preoperatively would have changed the initial surgical plan, according to NCCN criteria, in 31.1% of patients. In the high-risk subgroup, 9/35 (25.7%) patients were correctly assessed as not harboring pT(3) by imaging (ECE score <4), and would have allowed secure robot-assisted radical prostatectomy and nerve-sparing surgery (NSS). When T3 suspicion on preoperative MRI would be taken into account, intraoperative frozen-sections (IFS) might avoid positive SM in 12/18 high-risk patients and an oncologic secure NSS in 8/20 intermediate-risk patients., Conclusion: Prediction of pT(3) disease is crucial to plan NSS and to achieve negative SM in RP. Standardized ECE scoring on mpMRI is an independent predictor of pT(3) and may help to plan RP with oncologic security, even in high-risk patients. In addition, it allows more accurate selection of a subgroup of patients for systematic and MRI-guided IFS.

Background: The objective of this study was to analyze the potential of prostate magnetic resonance imaging (MRI) and MRI/transrectal ultrasound-fusion biopsies to detect and to characterize significant prostate cancer (sPC) in the anterior fibromuscular stroma (AFMS) and in the transition zone (TZ) of the prostate and to assess the accuracy of multiparametric MRI (mpMRI) and biparametric MRI (bpMRI) (T2w and diffusion-weighted imaging (DWI))., Methods: Seven hundred and fifty-five consecutive patients underwent prebiopsy 3 T mpMRI and transperineal biopsy between October 2012 and September 2014. MRI images were analyzed using PIRADS (Prostate Imaging-Reporting and Data System). All patients had systematic biopsies (SBs, median n=24) as reference test and targeted biopsies (TBs) with rigid software registration in case of MRI-suspicious lesions. Detection rates of SBs and TBs were assessed for all PC and sPC patients defined by Gleason score (GS)⩾3+4 and GS⩾4+3. For PC, which were not concordantly detected by TBs and SBs, prostatectomy specimens were assessed. We further compared bpMRI with mpMRI., Results: One hundred and ninety-one patients harbored 194 lesions in AFMS and TZ on mpMRI. Patient-based analysis detected no difference in the detection of all PC for SBs vs TBs in the overall cohort, but in the repeat-biopsy population TBs performed significantly better compared with SBs (P=0.004 for GS⩾3+4 and P=0.022 for GS⩾4+3, respectively). Nine GS⩾4+3 sPCs were overlooked by SBs, whereas TBs missed two sPC in men undergoing primary biopsy. The combination of SBs and TBs provided optimal local staging. Non-inferiority analysis showed no relevant difference of bpMRI to mpMRI in sPC detection., Conclusions: MRI-targeted biopsies detected significantly more anteriorly located sPC compared with SBs in the repeat-biopsy setting. The more cost-efficient bpMRI was statistically not inferior to mpMRI in sPC detection in TZ/AFMS.

A mathematical model of whole-body acid-base and fluid-electrolyte balance was used to provide information leading to the diagnosis and fluid-therapy treatment in patients with complex acid-base disorders. Given a set of measured laboratory-chemistry values for a patient, a model of their unique, whole-body chemistry was created. This model predicted deficits or excesses in the masses of Na(+), K(+), Cl(-) and H2O as well as the plasma concentration of unknown or unmeasured species, such as ketoacids, in diabetes mellitus. The model further characterized the acid-base disorder by determining the patient's whole-body base excess and quantitatively partitioning it into ten components, each contributing to the overall disorder. The results of this study showed the importance of a complete set of laboratory measurements to obtain sufficient accuracy of the quantitative diagnosis; having only a minimal set, just pH and PCO2, led to a large scatter in the predicted results. A computer module was created that would allow a clinician to achieve this diagnosis at the bedside. This new diagnostic approach should prove to be valuable in the treatment of the critically ill.

Background: (68)Ga-DOTATOC-PET/CT is a well-established method for detecting and targeting the volume definition of meningiomas prior to radiotherapy. Moreover, there is evidence that this method is able to detect meningiomas with higher sensitivity than the goldstandard MRI. Since the hybrid PET/MRI scanner became available in the past few years, the next stage of development could consequently evolve by evaluating the feasibility of a hybrid PET/MRI scanner using (68)Ga-DOTATOC for detecting meningiomas., Methods: Fifteen patients received (68)Ga-DOTATOC-PET/CT (0.5 h post injection [p.i.]) followed by PET/MRI 2 hours p.i. Both investigations were analyzed separately and then compared with respect to image quality, detection of intracranial meningiomas, and radiotracer uptake values (RUVs). In addition, ratios between radiotracer uptake in meningiomas and pituitary glands were compared between both PET/CT and PET/MRI., Results: Overall, 33 intracranial meningiomas were detected. All were visible with high contrast in both PET/CT and PET/MRI. (68)Ga-DOTATOC-PET/MRI provided flawless image quality without artefacts. Calculated RUV in meningiomas, as well as the ratios of RUVs in meningiomas to those of pituitary glands, were higher in PET/CT. As a result, meningiomas can be distinguished from pituitary glands better in early images., Conclusions: (68)Ga-DOTATOC-PET/MRI provided flawless image quality and presented an ideal combination of high sensitivity/specificity (PET) and the best possible morphological visualization of meningiomas (MRI). In addition, excellent detection of meningiomas is already possible at 0.5 hours p.i. Later images do not improve the distinction between pituitary gland and adjacent meningiomas. However, RUVs need to be carefully compared between both imaging modalities., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To compare sensitivity of whole-body Computed Tomography (wb-CT) and whole-body Magnetic Resonance Imaging (wb-MRI) with Projection Radiography (PR) regarding each method's ability to detect osteolyses in patients with monoclonal plasma cell disease., Patients and Methods: The bone status of 171 patients was evaluated. All patients presented with multiple myeloma (MM) of all stages, monoclonal gammopathy of unknown significance (MGUS) or solitary plasmacytoma. Two groups were formed. Group A consisted of 52 patients (26 females, 26 males) with an average age of 62 years (range, 45-89 years) who received, both, PR and wb-CT as part of their diagnostic work-up. Group B comprised 119 patients (58 females, 61 males) averaging 57 years of age (range, 20-80 years) who received, both, PR and wb-MRI. Two experienced radiologists were blinded regarding the disease status and assessed the number and location of osteolyses in consensus. A distinction was made between axial and extra-axial lesions., Results: In group A, wb-CT revealed osteolyses in 12 patients (23%) that were not detected in PR. CT was superior in detecting lesions in patients with osteopenia and osteoporosis. Compared with PR, wb-CT was significantly more sensitive in detecting osteolyses than PR (p<0.001). This was particularly true for axial lesions. Additionally, CT revealed clinically relevant incidental findings in 33 patients (63%). In group B, wb-MRI revealed lesions in 19 patients (16%) that were not detected in PR. All lesions detected by PR were also detected by wb-MRI and wb-CT. Wb-MRI and wb-CT are each superior to PR in detecting axial lesions., Conclusion: Wb-CT can detect 23% more focal lesions than PR, especially in the axial skeleton. Therefore, this imaging method should be preferred over PR in the diagnostic work-up and staging of patients with monoclonal plasma cell disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)