Glomerular filtration rate measurement during platinum treatment for urothelial carcinoma: optimal methods for clinical practice.

BACKGROUND: We assessed the accuracy of four estimated glomerular filtration rate (eGFR) methods: MDRD, Cockcroft-Gault, CKD-EPI, and Wright. METHOD: The four methods were compared to measure GFR (mGFR) in patients with urothelial urinary tract cancer (T2-T4bNxMx) receiving platinum-based chemotherapy at Rigshospitalet, Copenhagen, from January 2019 to December 2021. Using standardized assays, creatinine values were measured, and mGFR was determined using Technetium-99 m diethylenetriaminepentaacetic acid (Tc-99 m-DTPA) or Cr-51-ethylenediaminetetraacetic acid (Cr-51-EDTA) plasma clearance. Patients (n = 146) with both mGFR and corresponding creatinine values available were included (n = 345 measurements). RESULTS: The CKD-EPI method consistently demonstrated superior accuracy, with the lowest Total Deviation Index of 21.8% at baseline and 22.9% for all measurements compared to Wright (23.4% /24.1%), MDRD (26.2%/25.5%), and Cockcroft-Gault (25.x%/25.1%). Bland Altman Limits of agreement (LOA) ranged from - 32 ml/min (Cockcroft-Gault) to + 33 ml/min (MDRD), with CKD-EPI showing the narrowest LOA (- 27 ml/min to + 24 ml/min and lowest bias (0.3 ml/min). Establishing an eGFR threshold at 85 ml/min-considering both the lower limit of agreement (LOA) and the minimum cisplatin limit at 60 ml/min-allows for the safe omission of mGFR in 30% of patients in this cohort. CONCLUSION: CKD-EPI equation emerged as the most suitable for estimating kidney function in this patient group although not meeting benchmark criteria. We recommend its use for initial assessment and ongoing monitoring, and suggest mGFR for patients with a CKD-EPI estimated GFR below 85 ml/min. This approach could reduce costs and decrease laboratory time for 30% of our UC patients.

Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs).

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.

Multiple endocrine neoplasia type 2: A review.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

Validation of a clinically applicable device for fast and accurate quantification of blood volume.

INTRODUCTION: Determination of blood volume (BV) using the dual-isotope (e.g., 99m Tc-labeled red blood cells [99m Tc-RBC] and 125 I-labeled human serum albumin [125 I-HSA]) injection method is limited in medicine due to the long isotope half-life. However, BV has been determined in laboratory settings for 100 years using the carbon monoxide (CO)-rebreathing-based procedure, which allows frequent BV measurements. METHODS: We investigated the reliability and accuracy of a semi-automated CO-rebreathing device by comparing it against the dual-isotope methodology and its ability to detect a known blood removal. In study A, BV was determined three times in ~2 h; twice using the device with rebreathing protocols lasting 2 (CO2min ) and 10 min (CO10min ) and once with the dual-isotope technique. In study B, the accuracy of the device was assessed by its ability to detect a 2% removal of BV. RESULTS: A good correlation was observed between both the CO-rebreathing protocols (r2 = 0.89-0.98; p < 0.001) and the dual-isotope approach (r2 = 0.89-0.95; p < 0.001). In absolute terms BV was 425 ± 263 mL and 491 ± 388 mL lower (p < 0.001) when quantified with the dual-isotope compared to the CO-rebreathing protocols. When reducing BV by 132 ± 25 mL (2%), the device quantified a lower (p < 0.001) BV of 150 ± 45 mL. CONCLUSION: This study emphasizes that the semi-automated device accurately determines small changes (i.e., 2%) in BV and that a high correlation with the dual-isotope methodology exists. The findings are clinically relevant owing to the method's simple and fast nature (the absence of radioactive tracers and reduced time requirements, i.e., ~15 min vs. ~180 min) and the possibility for repeated measurements within a single day.

Rapid decline in 51Cr-ethylenediaminetetraacetic acid-measured renal function during the first weeks following liver transplantation.

BACKGROUND: Renal dysfunction is a serious late complication after liver transplantation (LTX), but there are no studies addressing the early changes associated with this complication. METHODS: We prospectively studied glomerular filtration rate (GFR) before and at 1, 3 and 12 weeks after LTX using 51Cr-labelled ethylenediaminetetraacetic acid clearance in 37 adult consecutive patients who underwent non-acute first LTX. RESULTS: The mean (±SD) age was 49.5 ± 9.5 years, and the male:female sex ratio was 21:16. Diagnoses were autoimmune liver diseases (17), alcoholic cirrhosis (10) and other diseases (10). Immunosuppressive treatment consisted predominantly of triple-drug therapy. A total of 27 of the 37 patients were eligible for GFR analysis at all times. The mean (±SD) GFR was 86 ± 26 mL/min/1.73 m2 before LTX, and 77 ± 30 mL/min/1.73 m2 at 1 week, 64 ± 27 mL/min/1.73 m2 at 3 weeks and 64 ± 23 mL/min/1.73 m2 at 12 weeks after LTX, comparable to a reduction in mean GFR compared with baseline values of 10% (P = 0.1907), 25% (P = 0.0010) and 26% (P = 0.0007). Age and number of blood transfusions during surgery were identified as risk factors for this decline as well as gender, but not pre-transplant diagnosis, model of end-stage liver disease score, cold ischaemia time or post-transplant area under the curve tacrolimus during Days 0-14. CONCLUSIONS: Using measured rather than estimated GFR, our results show that severe renal impairment occurs during the first week after LTX. These results emphasize the need for more studies addressing renoprotective treatment strategies.

Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: a longitudinal cohort study.

BACKGROUND: Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. METHODS: This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. RESULTS: In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1-13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of -0.8 ± 0.2 with an annual slope of -0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin-creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. CONCLUSIONS: ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.

Heavy-load resistance exercise during chemotherapy in physically inactive breast cancer survivors at risk for lymphedema: a randomized trial.

Background: Due to long-standing concerns that heavy-load lifting could increase the risk of developing lymphedema, breast cancer survivors have been advised to refrain from resistance exercise with heavy loads. This study prospectively evaluated the effect of heavy-load resistance exercise on lymphedema development in women receiving chemotherapy for breast cancer.Material and Methods: Physically inactive women receiving adjuvant chemotherapy for breast cancer (n = 153) were randomized to a HIGH (supervised, multimodal exercise including heavy-load resistance exercise: 85-90% 1 repetition maximum [RM], three sets of 5-8 repetitions) versus LOW (pedometer and one-on-one consultations) 12-week intervention. Outcomes (baseline, 12 and 39 weeks) included lymphedema status (extracellular fluid [bioimpedance spectroscopy] and inter-arm volume % difference [dual-energy X-ray absorptiometry], lymphedema symptoms [numeric rating scale 0-10]), upper-extremity strength (1 RM), and quality of life domains (EORTC- BR23). Linear mixed models were used to evaluate equivalence between groups for lymphedema outcomes (equivalence margins for L-Dex, % difference and symptoms scale: ±5, ±3% and ±1, respectively). Superiority analysis was conducted for muscle strength and quality of life domains.Results: Postintervention equivalence between groups was found for extracellular fluid (0.4; 90% CI -2.5 to 3.2) and symptoms of heaviness (-0.2; -0.6 to 0.2), tightness (-0.1; -0.8 to 0.6) and swelling (0.2; -0.4 to 0.8). Nonequivalence was found for inter-arm volume % difference (-3.5%; -17.3 to 10.3) and pain (-0.7; -1.3 to 0), favoring HIGH. Strength gains were superior in the HIGH versus LOW group (3 kg; 1 to 5, p < .05). Further, clinically relevant reductions in breast (-11; -15 to -7) and arm (-6; -10 to -1) symptoms were found in the HIGH group.Conclusion: Findings suggest that physically inactive breast cancer survivors can benefit from supervised heavy-load resistance exercise during chemotherapy without increasing lymphedema risk. Trial registration: ISRCTN13816000.

Relation between invasive hemodynamics and measured glomerular filtration rate by 51Cr-EDTA clearance in advanced heart failure.

The interaction between hemodynamics and kidney function in heart failure (HF) is incompletely understood. We investigated the association between invasive hemodynamic parameters and measured glomerular filtration rate (mGFR) by plasma clearance of 51-chromium-labeled ethylenediamine tetra-acetic acid (51Cr-EDTA) in patients with advanced HF and tested the hypothesis that patients with reduced mGFR have lower cardiac index (CI) and mean arterial pressure (MAP) as well as higher central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP). We retrospectively studied 242 patients (mean age 50 ± 13 years) referred for evaluation for heart transplantation or implantation of a left ventricular assist device with a left ventricular ejection fraction < 45% on optimal medical therapy, who underwent right heart catheterization (RHC) and measurement of 51Cr-EDTA clearance. Mean mGFR was 63 ± 21 mL/min/1.73 m2, CI was 2.3 ± 0.7 L/min/m2, PCWP was 21 ± 9 mmHg, and CVP was 10.3 ± 5.2 mmHg. Univariate analysis demonstrated a significant correlation between mGFR and CI (r2 = 0.030, p = .007) and CVP (r2 = 0.017, p = .049) but not between mGFR and MAP or PCWP. In multivariate analyses, none of the hemodynamic variables remained significantly associated with mGFR. While CVP and CI were correlated with mGFR in univariate analysis the results of analyses adjusted for multiple covariates suggest that hemodynamics are only correlated to renal function in advanced HF to a modest degree challenging the hypothesis that renal dysfunction in HF mainly is a consequence of renal congestion.

Differential effects of age and sex on insulin sensitivity and body composition in adolescent offspring of women with type 1 diabetes: results from the EPICOM study.

AIMS/HYPOTHESIS: The aim of this study was to investigate the influence of age and sex on insulin sensitivity and insulin secretion in the adolescent offspring of women with type 1 diabetes, compared with the background population. METHODS: This was a prospective nationwide follow-up study (Epigenetic, Genetic and Environmental Effects on Growth, Cognitive Functions and Metabolism in Offspring of Women with Type 1 Diabetes [EPICOM]) in a Danish population. We examined 278 offspring of women with type 1 diabetes from the Danish Diabetes Association Register born during 1993-1999 (index offspring) and 303 control offspring, identified through the Danish Central Office of Civil Registration and matched to the index offspring with respect to date of birth, sex and postal code. The offspring had an overall mean age of 16.7 years (range 13.0-20.4 years). The main outcomes were age-related changes in fasting OGTT-derived indices for insulin sensitivity (BIGTT-SI0-30-120, Matsuda index, HOMA-IR) and insulin secretion (acute insulin response [BIGTT-AIR0-0-30-120], insulinogenic index, HOMA of insulin secretory function [HOMA-ß], disposition index) and physical activity (International Physical Activity Questionnaire). In addition, we determined total body fat (TBF) percentage using dual-energy x-ray absorptiometry. RESULTS: We observed significantly lower insulin sensitivity in index offspring compared with control offspring, increasing with age. The differences were attenuated after adjustment for TBF percentage, but were still significant at 17 and 18 years of age. We also observed decreased disposition index and insulin secretion-sensitivity index-2 in index offspring at the same age, but we found no significant differences in other indices of insulin secretion compared with control offspring. With age, TBF percentage became increasingly more divergent between index and control offspring, and was consistently higher among female but not male index offspring. CONCLUSIONS/INTERPRETATION: Differences in insulin sensitivity between the offspring of women with type 1 diabetes and control offspring increased with age. This was only partially explained by higher adiposity in the index offspring. TRIAL REGISTRATION: ClinicalTrials.gov NCT01559181.

Radioactive Seed Localization or Wire-guided Localization of Nonpalpable Invasive and In Situ Breast Cancer: A Randomized, Multicenter, Open-label Trial.

OBJECTIVE: To compare the rate of positive resection margins between radioactive seed localization (RSL) and wire-guided localization (WGL) after breast conserving surgery (BCS). BACKGROUND: WGL is the current standard for localization of nonpalpable breast lesions in BCS, but there are several difficulties related to the method. METHODS: From January 1, 2014 to February 4, 2016, patients with nonpalpable invasive breast cancer or DCIS visible on ultrasound were enrolled in this randomized, multicenter, open-label clinical trial, and randomly assigned to RSL or WGL. The primary outcome was margin status after BCS. Secondary outcomes were duration of the surgical procedure, weight of surgical specimen, and patients' pain perception. Analyses were performed by intention-to-treat (ITT) and per protocol. RESULTS: Out of 444 eligible patients, 413 lesions representing 409 patients were randomized; 207 to RSL and 206 to WGL. Twenty-three did not meet inclusion criteria, chose to withdraw, or had a change in surgical management and were excluded. The remaining 390 lesions constituted the ITT population. Here, resection margins were positive in 23 cases (11.8%) in the RSL group compared with 26 cases (13.3%) in the WGL group (P = 0.65). The per-protocol analysis revealed no difference in margin status (P = 0.62). There were no significant differences in the duration of the surgical procedure (P = 0.12), weight of the surgical specimen (P = 0.54) or the patients' pain perception (P = 0.28). CONCLUSION: RSL offers a major logistic advantage, as localization can be done several days before surgery without any increase in positive resection margins compared with WGL.

A randomized double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

BACKGROUND: Elevated serum levels of luteinizing hormone and slightly decreased serum levels of testosterone (mild Leydig cell insufficiency) is a common hormonal disturbance in testicular cancer (TC) survivors. A number of studies have shown that low serum levels of testosterone is associated with low grade inflammation and increased risk of metabolic syndrome. However, so far, no studies have evaluated whether testosterone substitution improves metabolic dysfunction in TC survivors with mild Leydig cell insufficiency. METHODS/DESIGN: This is a single-center, randomized, double-blind, placebo-controlled study, designed to evaluate the effect of testosterone replacement therapy in TC survivors with mild Leydig cell insufficiency. Seventy subjects will be randomized to receive either testosterone replacement therapy or placebo. The subjects will be invited for an information meeting where informed consent will be obtained. Afterwards, a 52-weeks treatment period begins in which study participants will receive a daily dose of transdermal testosterone or placebo. Dose adjustment will be made three times during the initial 8 weeks of the study to a maximal daily dose of 40 mg of testosterone in the intervention arm. Evaluation of primary and secondary endpoints will be performed at baseline, 26 weeks post-randomization, at the end of treatment (52 weeks) and 3 months after completion of treatment (week 64). DISCUSSION: This study is the first to investigate the effect of testosterone substitution in testicular cancer survivors with mild Leydig cell insufficiency. If positive, it may change the clinical handling of testicular cancer survivors with borderline low levels of testosterone. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02991209 (November 25, 2016).

Renal deterioration after spinal cord injury is associated with length of detrusor contractions during cystometry-A study with a median of 41 years follow-up.

AIMS: To investigate which urodynamic parameters are associated with renal deterioration over a median of 41 years follow-up after traumatic spinal cord injury. METHODS: Medical records of patients with a traumatic spinal cord injury sustained 1944-1975 were reviewed from time of injury until 2012. Patients who attended regular renography and/or renal clearance examinations and had minimum one cystometry and pressure-flow study were included. Renal deterioration was diagnosed as split renal function ≤30% in one kidney or relative glomerular filtration rate ≤51% of expected according to age and gender. Detrusor function, presence of detrusor sphincter dyssynergia, maximum detrusor pressure, post-void residual volume, and cystometric bladder capacity were obtained. In patients with detrusor overactivity, a detrusor overactivity/cystometry ratio was calculated using duration of detrusor contraction(s) during filling cystometry divided by total duration of filling cystometry. RESULTS: A total of 73 patients were included in the study, and the median follow-up time was 41 years after injury (range 24-56). Sixty-four patients (88%) used reflex triggering or bladder expression as bladder emptying method for the longest period after injury. During follow-up 60% changed to clean intermittent catheterization. The majority of the patients (68%) had neurogenic detrusor overactivity. In 35 patients, a detrusor-overactivity/cystometry ratio could be calculated and a detrusor overactivity/cystometry ratio > 0.33 was significantly associated with renal deterioration (P < 0.02). No significant association was found between maximum detrusor pressure or other urodynamic parameters and renal deterioration. CONCLUSIONS: Duration of detrusor overactivity longer than one third of the duration of cystometry is associated with renal deterioration after spinal cord injury.

A randomized cross-over trial to detect differences in arm volume after low- and heavy-load resistance exercise among patients receiving adjuvant chemotherapy for breast cancer at risk for arm lymphedema: study protocol.

BACKGROUND: In an effort to reduce the risk of breast cancer-related arm lymphedema, patients are commonly advised to avoid heavy lifting, impacting activities of daily living and resistance exercise prescription. This advice lacks evidence, with no prospective studies investigating arm volume changes after resistance exercise with heavy loads in this population. The purpose of this study is to determine acute changes in arm volume after a session of low- and heavy-load resistance exercise among women undergoing adjuvant chemotherapy for breast cancer at risk for arm lymphedema. METHODS/DESIGN: This is a randomized cross-over trial. PARTICIPANTS: Women receiving adjuvant chemotherapy for breast cancer who have undergone axillary lymph node dissection will be recruited from rehabilitation centers in the Copenhagen area. INTERVENTION: Participants will be randomly assigned to engage in a low- (two sets of 15-20 repetition maximum) and heavy-load (three sets of 5-8 repetition maximum) upper-extremity resistance exercise session with a one week wash-out period between sessions. OUTCOME: Changes in extracellular fluid (L-Dex score) and arm volume (ml) will be assessed using bioimpedance spectroscopy and dual-energy x-ray absorptiometry, respectively. Symptom severity related to arm lymphedema will be determined using a visual analogue scale (heaviness, swelling, pain, tightness). Measurements will be taken immediately pre- and post-exercise, and 24- and 72-hours post-exercise. SAMPLE SIZE: A sample size of 20 participants was calculated based on changes in L-Dex scores between baseline and 72-hours post exercise sessions. DISCUSSION: Findings from this study are relevant for exercise prescription guidelines, as well as recommendations regarding participating in activities of daily living for women following surgery for breast cancer and who may be at risk of developing arm lymphedema. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97332727 . Registered 12 February 2015.

Reliability of estimated glomerular filtration rate in patients treated with platinum containing therapy.

Estimates of glomerular filtration rate (eGFR) are widely used when administering nephrotoxic chemotherapy. No studies performed in oncology patients have shown whether eGFR can safely substitute a measured GFR (mGFR) based on a marker method. We aimed to assess the validity of four major formulas based on PCr (Cockcroft-Gault, MDRD, Wright and CKD-EPI) in comparison to mGFR in an oncology setting. Patients included had disseminated germ cell cancer and received conventional chemotherapy: bleomycin, etoposide and cisplatin. The mGFR of the patients was compared to all estimates with focus on bias (median percentage error), precision (median absolute percentage error) and accuracy (p10 and p30). The precision of carboplatin dosage based on eGFR was calculated. Data on mGFR, eGFR, and PCr were available in 390 patients, with a total of ∼ 1,600 measurements. Median PCr and mGFR synchronically decreased after chemotherapy, yielding high bias and low precision of most estimates. Post-chemotherapy, bias ranged from -0.2% (MDRD after four cycles) to 33.8% (CKD-EPI after five cycles+), precision ranged from 11.6% (MDRD after four cycles) to 33.8% (CKD-EPI after five cycles+) and accuracy (p30) ranged from 37.5% (CKD-EPI after five cycles+) to 86.9% (MDRD after four cycles). Although MDRD appeared acceptable after chemotherapy because of high accuracy, this equation underestimated GFR in all other measurements. Before and years after treatment, Cockcroft-Gault and Wright offered best results. Precision of carboplatin dosage was low. In conclusion, bias, precision and accuracy were unacceptable in all equations due to a synchronous decrease of PCr and mGFR during chemotherapy.

Techniques to Assess the Effect of Sodium-Glucose Cotransporter 2 Inhibitors on Blood Volume in Patients with Diabetic Kidney Disease.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a kidney protective effect in patients with diabetic kidney disease. Several mechanisms have been proposed, but why precisely SGLT2 inhibition has a kidney protective effect is incompletely understood. Clinical trials using SGLT2 inhibitors have found them to induce a rapid weight loss likely due to loss of sodium and subsequently fluid. While SGLT2 inhibitors are reported to increase hematocrit, it remains unknown whether the natriuretic and aquaretic effect reduces patient's blood volume and whether this could partly explain its kidney protective effects. A blood volume reduction could induce several beneficial effects with reduction in arterial and venous blood pressure as two central mechanisms. The aim of this paper was to review current techniques for assessing patient blood volume that could enhance our understanding of SGLT2 inhibitors' physiological effects. SUMMARY: Changes induced by SGLT2 inhibitors on erythrocyte volume and plasma volume can be assessed by tracer dilution techniques that include radioisotopes, indocyanine green (ICG) dye, or carbon monoxide (CO). Techniques with radioisotopes can provide direct estimates of both erythrocyte volume and plasma volume but are cumbersome procedures and the radiation exposure is a limitation for repeated measures in clinical studies. Methods more suitable for repeated assessment of erythrocyte and plasma volume include dilution of injected ICG dye or dilution of inhaled CO. ICG dye requires higher precision with timed blood samples and provides only a direct estimate of plasma volume wherefrom erythrocyte volume is estimated. Inhalation of CO is a time-effective and automated method that provides measure of the total hemoglobin mass wherefrom erythrocyte and plasma volumes are estimated. KEY MESSAGES: A kidney protective effect has been observed in clinical trials with SGLT2 inhibitors, but the underlying mechanisms are not fully understood. Significant weight loss within weeks has been reported in the SGLT2 inhibitor trials and could be related to a reduction in blood volume secondary to increased natriuresis and aquaresis. Alterations in blood volume compartments can be quantified by tracer dilution techniques and further improve our understanding of kidney protection from SGLT2 inhibitors.

Intravascular volumes and the influence on anemia assessed by a carbon monoxide rebreathing method in patients undergoing maintenance hemodialysis.

INTRODUCTION: Fluid overload is a major challenge in hemodialysis patients and might cause hypervolemia. We speculated that hemodialysis patients reaching dry weight could have undetected hypervolemia and low hemoglobin (Hb) concentration (g/dL) due to hemodilution. METHODS: The study included hemodialysis patients (n = 22) and matched healthy controls (n = 22). Blood volume, plasma volume, red blood cell volume, and total Hb mass were determined using a carbon monoxide (CO)-rebreathing method in hemodialysis patients reaching dry weight and controls. Blood volume measurements were also obtained by a dual-isotope labeling technique in a subgroup for validation purposes. FINDINGS: In the hemodialysis group, the median specific blood volume was 89.3 mL/kg (interquartile range [IQR]: 76.7-95.4 mL/kg) and was higher than in the control group (79.9 mL/kg [IQR: 70.4-88.0 mL/kg]; p < 0.037). The median specific plasma volume was 54.7 mL/kg (IQR: 47.1-61.0 mL/kg) and 44.0 mL/kg (IQR: 38.7-49.5 mL/kg) in the hemodialysis and control groups, respectively (p < 0.001). Hb concentration was lower in hemodialysis patients (p < 0.001), whereas no difference in total Hb mass was observed between groups (p = 0.11). A correlation was found between blood volume measured by the CO-rebreathing test and the dual-isotope labeling technique in the control group (r = 0.83, p = 0.015), but not the hemodialysis group (r = 0.25, p = 0.60). DISCUSSION: The hemodialysis group had increased specific blood volume at dry weight due to high plasma volume, suggesting a hypervolemic state. However, correlation was not established against the dual-isotope labeling technique underlining that the precision of the CO-rebreathing test should be further validated. The total Hb mass was similar between hemodialysis patients and controls, unlike Hb concentration, which emphasizes that Hb concentration is an inaccurate marker of anemia among hemodialysis patients.

Long-term effects of high-dose systemic corticosteroids on growth and bone mineral density in patients treated for childhood interstitial lung disease (chILD).

BACKGROUND: Children's interstitial lung disease (chILD) is a rare and potentially life-threatening condition. For many chILD conditions, systemic corticosteroids (sCCS) are considered the primary treatment despite a broad spectrum of potential side effects. AIM: We aimed to determine the long-term effects of sCCS treatment on growth, bone mineral density (BMD), and body composition after chILD. MATERIALS AND METHODS: This descriptive cross-sectional single-center study included patients diagnosed with chILD before the age of 18 years treated with sCCS in the period 1998-2020. Dual-energy X-ray absorptiometry, anthropometric measurements, bone age determination, and blood tests were performed in 53 (55% males) of 89 eligible patients. RESULTS: Median (range) age was 19.3 (6.4;30.7 years). Participants received a median (range) cumulative sCCS dose of 1144 (135; 6178) mg over a 2.0 (0.1; 13.8) years period and latest dose was administered 11.7 (1.2; 19.6) years before follow-up. Mean delta height (height standard deviation scores [SDS] - target height SDS) was reduced at sCCS treatment initiation (mean: -0.55, 95% confidence interval [CI]: -0.91; -0.20, p < .005) and at sCCS treatment cessation (mean: -0.86, 95% CI:-1.22; -0.51, p < .001), but normalized in the majority at follow-up (mean: -0.29, 95% CI:-0.61; 0.03, p = .07). Mean (SD) BMD z-score for the spine and whole body was -0.34 (1.06) and 0.52 (1.13), with no significant correlation to sCCS dose. Excess body fat (>30% in females, >25% in males) was found in 58% of patients. CONCLUSION: Long-term treatment with sCCS did not cause significant long-term reduction of height but showed subtle effects on fat mass percentage and BMD. Given the severity of chILD, the observed long-term effects of sCCS on growth and BMD appear acceptable.

Successful liver transplantation as rescue therapy in a patient with metastases from a vasoactive intestinal peptide producing neuroendocrine tumor.

This case report presents a 40-year-old patient with a vasoactive intestinal peptide (VIP) secreting high grade (Ki-67 39%) neuroendocrine tumor (NET) from the pancreas, for whom successful liver transplantation (LT) was carried out 8 years after resection of the primary tumor due to massive liver metastases. The transplantation was done as rescue therapy due to rapid progression and a devastating clinical condition requiring intravenous supplementation for 20 hours daily. The latest imaging carried out 18 months after transplantation is without signs of recurrence, and the patient is in good health with undetectable levels of VIP. According to the guidelines, LT is only recommended if Ki-67 is <20% and if there has been tumor control for more than 6 months prior to transplantation. Our case illustrates that LT is an option that should be considered for selected NET patients without extrahepatic involvement regardless of tumor grade and clinical condition.

Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. METHOD: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. RESULTS: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). CONCLUSIONS: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Responses to Medical Treatment in 192 Patients with Pancreatic Neuroendocrine Neoplasms Referred to the Copenhagen Neuroendocrine Tumour Centre in 2000-2020.

BACKGROUND: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. AIM: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. METHODS: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). RESULTS: Median OS was 36 (95% CI: 26-46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9-9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1-7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). CONCLUSION: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide.