Inhaled prostacyclin therapy in the acute respiratory distress syndrome: a randomized controlled multicenter trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. METHODS: We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride (Placebo). The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. RESULTS: Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. CONCLUSIONS: The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. TRIAL REGISTRATION: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

Impact of different immunosuppressive protocols on clinical outcomes in obese kidney transplant recipients: a propensity score-matched analysis.

BACKGROUND: Although obesity has become a significant problem in transplantation medicine, the impact of different immunosuppressive protocols on clinical outcomes in obese transplant recipients remains unclear. METHODS: We performed an analysis of the Scientific Registry of Transplant Recipients database. Kidney transplant recipients were categorized according to body mass index (BMI) categories and immunosuppressive protocols: (i) tacrolimus/mycophenolate mofetil (Tac-MMF), (ii) mTOR-inhibitor/Tac (mTORi-Tac), (iii) mTORi/cyclosporin (mTORi-Cyc) and (iv) mTORi-MMF. RESULTS: Graft recipients with advanced obesity (BMI ≥35 kg/m2) exhibited significantly lower rates of acute rejection during the first year after transplantation in the mTORi-Tac (6.4%) group compared with Tac-MMF (11.2%). Obesity class 1 (30 < BMI < 35 kg/m2) was associated with a significant risk of acute rejection for the mTORi-Tac group [obesity class 1 hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.21-2.62, P = .003]. A similar trend was observed in the Tac-MMF group for advanced obesity HR 1.29; 95% CI 0.96-1.73, P = .087). For the Tac-MMF group, recipients with both overweight and obesity had significantly impaired survival due to cardiovascular events and also increased mortality due to infection in advanced obesity. Combination of mTORi and calcineurin inhibitor was associated with lower rejection rates and stable long-term kidney function while reducing cardiovascular side effects linked to calcineurin inhibitors in obese kidney graft recipients. CONCLUSION: These results are critical for the growing number of obese graft recipients and warrant prospective evaluation.

COVID-19 does not influence functional status after ARDS therapy.

RATIONALE: Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. OBJECTIVES: A total of 144 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. METHODS: Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. MEASUREMENTS: Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. MAIN RESULTS: The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. CONCLUSIONS: Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity. Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity.

What difference does multiple imputation make in longitudinal modeling of EQ-5D-5L data? Empirical analyses of simulated and observed missing data patterns.

PURPOSE: Although multiple imputation is the state-of-the-art method for managing missing data, mixed models without multiple imputation may be equally valid for longitudinal data. Additionally, it is not clear whether missing values in multi-item instruments should be imputed at item or score-level. We therefore explored the differences in analyzing the scores of a health-related quality of life questionnaire (EQ-5D-5L) using four approaches in two empirical datasets. METHODS: We used simulated (GR dataset) and observed missingness patterns (ABCD dataset) in EQ-5D-5L scores to investigate the following approaches: approach-1) mixed models using respondents with complete cases, approach-2) mixed models using all available data, approach-3) mixed models after multiple imputation of the EQ-5D-5L scores, and approach-4) mixed models after multiple imputation of EQ-5D 5L items. RESULTS: Approach-1 yielded the highest estimates of all approaches (ABCD, GR), increasingly overestimating the EQ-5D-5L score with higher percentages of missing data (GR). Approach-4 produced the lowest scores at follow-up evaluations (ABCD, GR). Standard errors (0.006-0.008) and mean squared errors (0.032-0.035) increased with increasing percentages of simulated missing GR data. Approaches 2 and 3 showed similar results (both datasets). CONCLUSION: Complete cases analyses overestimated the scores and mixed models after multiple imputation by items yielded the lowest scores. As there was no loss of accuracy, mixed models without multiple imputation, when baseline covariates are complete, might be the most parsimonious choice to deal with missing data. However, multiple imputation may be needed when baseline covariates are missing and/or more than two timepoints are considered.

Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification.

Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in TP53, FGFR3, TP53, ERCC2, PIK3CA, PTEN and STAG2. We reviewed and analyzed the clinical and histological data of 45 patients with a consensus diagnosis of PUN-LMP (n = 8), non-invasive LG-PUC (n = 23), and HG-PUC (n = 14). The proliferation index and mitotic count assessed with MIB-1 and P-HH3 staining, respectively correlated with grading and clinical behavior. Targeted sequencing confirmed frequent FGFR3 mutations in non-invasive papillary tumors and identified mutations in TP53 as high-risk. Cluster analysis of the different immunohistochemical and molecular parameters allowed a clear separation in two different clusters: cluster 1 corresponding to PUN-LMP and LG-PUC (low MIB-1 and mitotic count/FGFR3 and STAG2 mutations) and cluster 2, HG-PUC (high MIB-1 and mitosis count/CK20 +++ expression, FGFR3 WT and TP53 mutation). Further analysis is required to validate and analyze the reproducibility of these clusters and their biological and clinical implication.

Modifiable Risk-factors for Keratinocyte Cancers in Australia: A Case-control Study.

Keratinocyte cancer is the most common malignancy in Caucasians. The aim of this study was to investigate risk-factors responsible for development of keratinocyte cancer in Australia. A case-control study was conducted, including 112 cases of squamous cell carcinoma (SCC), 95 cases of basal cell carcinoma (BCC) and 122 controls. Freckling during adolescence (SCC: odds ratio (OR) 1.04, p < 0.01; BCC: OR 1.05, p < 0.01), propensity to sunburn (SCC: OR 2.75, p = 0.01, BCC: OR 2.68 p = 0.01) and high cumulative sun-exposure (SCC: OR 2.43, p = 0.04; BCC: OR 2.36 p = 0.04) were independent risk-factors for both SCC and BCC. This study provides further evidence that a sun-sensitive phenotype and excessive sun-exposure during adulthood contribute to the risk of developing keratinocyte cancer. Wearing a hat, long-sleeved shirts, and sunscreen did not significantly reduce the risk of keratinocyte cancer in this study.

Successful treatment of thrombotic microangiopathy associated with dengue infection: A case report and literature review.

Dengue infection has been associated with multiple renal complications, including glomerulonephritis, acute tubular necrosis, tubulointerstitial nephritis, and thrombotic microangiopathy (TMA), this last one being a rare complication of dengue, with only a few reported cases. TMA associated with dengue can be explained by an alteration in the activity of the enzyme ADAMTS13, leading to thrombotic thrombocytopenic purpura; or it can be secondary to direct or indirect endothelial injury by the virus, which leads to hemolytic uremic syndrome. Here, we present a case of severe TMA, not related to ADAMTS13, which was clearly associated with dengue infection.

Lipocalina asociada con gelatinasa del neutrófilo como predictor de disfunción del injerto a un año del trasplante renal.

INTRODUCCIÓN: Estudios recientes sugieren que la lipocalina asociada con la gelatinasa del neutrófilo urinaria (NGALu) es superior a la creatinina para la detección temprana de la disfunción del injerto renal, pero son pocos los estudios que evalúan su utilidad como predictor a largo plazo de dicha función. OBJETIVO: Explorar si los valores de NGALu en las primeras 48 horas después del trasplante renal predicen la función del injerto a largo plazo. MÉTODO: Cohorte prospectiva en la que se evaluaron los valores de NGALu a las 2, 12, 24 y 48 horas postrasplante renal. RESULTADOS: Se valoraron 79 pacientes trasplantados renales. Al año de seguimiento, 30.4 de los pacientes presentó disfunción del injerto. No se encontraron diferencias estadísticamente significativas entre los valores de NGALu y la función a un año del injerto renal (p = 0.65); el análisis multivariado mostró que ningún valor de NGALu fue un marcador predictor de disfunción del injerto a un año del trasplante renal. CONCLUSIÓN: Los valores de NGALu obtenidos en las primeras 48 horas postrasplante no se asociaron con disfunción del injerto a un año del trasplante renal. INTRODUCTION: Recent studies suggest that urinary neutrophil gelatinase-associated lipocalin (uNGAL) is superior to creatinine for renal graft dysfunction early detection, but there are only few studies assessing its usefulness as long-term predictor of said function. OBJECTIVE: To explore if uNGAL values within the first 48 hours after kidney transplantation predict graft function on the long term. METHOD: Prospective cohort, where uNGAL values were assessed at 2, 12, 24 and 48 hours post-kidney transplantation. RESULTS: Seventy-nine kidney transplant recipients were evaluated. At one year of follow-up, 30.4% of patients had graft dysfunction. No statistically significant differences were found between the uNGAL values and the renal graft function at one year (p = 0.65); the multivariate analysis showed that no uNGAL value was a predictor marker of graft dysfunction at one year of kidney transplantation. CONCLUSION: The uNGAL values obtained within the first 48 hours post-transplant were not associated with graft dysfunction at one year of kidney transplantation.

Malakoplakia after kidney transplantation: Case report and literature review.

Malakoplakia is a granulomatous disease associated with an infectious etiology, usually involving the urinary tract. It reveals itself as a recurrent urinary tract infection (r-UTI), and in some cases, it is associated with impairment of renal function. Immunosuppression is one of its main associated factors, and it has been increasingly described in patients with solid organ transplantation (SOT), mainly kidney transplantation. Macroscopically, it can form masses and sometimes it may be confused with neoplasia, which is why histological findings are fundamental for the diagnosis. Here, we present a case of bladder malakoplakia, manifested by r-UTI from Escherichia coli in a patient with renal transplantation, refractory to long-term antibiotic treatment and reduction in immunosuppression, which resolved after surgical management. We also summarize the clinical characteristics of malakoplakia and compare them with previous reports in the literature on SOT.

Surgical Outcomes in Octogenarians with Heart Failure and Reduced Ejection Fraction following Isolated Coronary Artery Bypass Grafting-A Propensity Score Matched Analysis.

Background/Objectives: The demographic shift towards an aging population necessitates a reevaluation of surgical interventions like coronary artery bypass grafting (CABG) in octogenarians. This study aims to elucidate the outcomes of CABG in octogenarians with heart failure and reduced ejection fraction (HFrEF), a group traditionally considered at high risk for such procedures. Methods: Conducted across four academic hospitals in Germany from 2017 to 2023, this retrospective multicenter study assessed 100 patients (50 octogenarians ≥80 years and 50 non-octogenarians <80 years) with HFrEF undergoing isolated CABG. Through propensity score matching, the study aimed to compare the incidence of major adverse cardiac and cerebrovascular events (MACCEs), as well as other clinical endpoints, between the two groups. Statistical analyses included chi-square, ANOVA, Mann-Whitney U test, Cox regression, and logistic regression, aiming to identify significant differences in outcomes. Results: The study revealed no significant difference in the combined incidence of MACCEs between octogenarians and non-octogenarians (OR: 0.790, 95% CI: 0.174-3.576, p = 0.759). Mortality rates were similar across groups (7% each, p = 1.000), as were occurrences of postoperative myocardial infarction (2% each, p = 1.000) and stroke (3% total). Secondary outcomes like delirium (17% total, no significant age group difference, p = 0.755), acute kidney injury (18% total, p = 0.664), and the need for dialysis (14% total, p = 1.000) also showed no differences between age groups. Interestingly, non-octogenarians required more packed red blood cells during their stay (p = 0.008), while other postoperative care metrics, such as hospital and ICU length of stay and ventilation hours, were comparable across groups. Conclusion: This multicenter study highlights that CABG is a viable and safe surgical option for octogenarians with HFrEF, challenging prior assumptions about the elevated risks associated with performing this procedure in older patients. The absence of significant differences in the incidence of MACCEs and other postoperative complications across age groups emphasizes the importance of careful patient selection and perioperative management. These findings advocate for a more inclusive approach to surgical treatment for octogenarians with HFrEF, suggesting that age alone should not be a determinant for CABG eligibility. This study contributes critical insights into optimizing care for a high-risk demographic, indicating a need for tailored guidelines that accommodate the aging population with complex cardiac conditions.

Influence of Obesity on Short-Term Surgical Outcomes in HFrEF Patients Undergoing CABG: A Retrospective Multicenter Study.

Background: This retrospective multicenter study investigates the impact of obesity on short-term surgical outcomes in patients with heart failure and reduced ejection fraction (HFrEF) undergoing coronary artery bypass grafting (CABG). Given the rising global prevalence of obesity and its known cardiovascular implications, understanding its specific effects in high-risk groups like HFrEF patients is crucial. Methods: The study analyzed data from 574 patients undergoing CABG across four German university hospitals from 2017 to 2023. Patients were stratified into 'normal weight' (n = 163) and 'obese' (n = 158) categories based on BMI (WHO classification). Data on demographics, clinical measurements, health status, cardiac history, intraoperative management, postoperative outcomes, and laboratory insights were collected and analyzed using Chi-square, ANOVA, Kruskal-Wallis, and binary logistic regression. Results: Key findings are a significant higher mortality rate (6.96% vs. 3.68%, p = 0.049) and younger age in obese patients (mean age 65.84 vs. 69.15 years, p = 0.003). Gender distribution showed no significant difference. Clinical assessment scores like EuroScore II and STS Score indicated no differences. Paradoxically, the preoperative left ventricular ejection fraction (LVEF) was higher in the obese group (32.04% vs. 30.34%, p = 0.026). The prevalence of hypertension, COPD, hyperlipidemia, and other comorbidities did not significantly differ. Intraoperatively, obese patients required more packed red blood cells (p = 0.026), indicating a greater need for transfusion. Postoperatively, the obese group experienced longer hospital stays (median 14 vs. 13 days, p = 0.041) and higher ventilation times (median 16 vs. 13 h, p = 0.049). The incidence of acute kidney injury (AKI) (17.72% vs. 9.20%, p = 0.048) and delirium (p = 0.016) was significantly higher, while, for diabetes prevalence, there was an indicating a trend towards significance (p = 0.051) in the obesity group, while other complications like sepsis, and the need for ECLS were similar across groups. Conclusions: The study reveals that obesity significantly worsens short-term outcomes in HFrEF patients undergoing CABG, increasing risks like mortality, kidney insufficiency, and postoperative delirium. These findings highlight the urgent need for personalized care, from surgical planning to postoperative strategies, to improve outcomes for this high-risk group, urging further tailored research.

Unraveling the Predictors for Delirium and ICU Stay Duration in Patients with Heart Failure and Reduced Ejection Fraction (HFrEF) Undergoing Coronary Artery Bypass Grafting-A Multicentric Analysis.

Objective: This study assesses predictors for postoperative delirium (POD) and ICU stay durations in HFrEF patients undergoing CABG, focusing on ONCAB versus OPCAB surgical methods. Summary Background Data: In cardiac surgery, especially CABG, POD significantly impacts patient recovery and healthcare resource utilization. With varying incidences based on surgical techniques, this study provides an in-depth analysis of POD in the context of HFrEF patients, a group particularly susceptible to this complication. Methods: A retrospective analysis of 572 patients who underwent isolated CABG surgery with a preoperative ejection fraction under 40% was conducted at four German university hospitals. Patients were categorized into ONCAB and OPCAB groups for comparative analysis. Results: Age and Euro Score II were significant predictors of POD. The ONCAB group showed higher incidences of re-sternotomy (OR: 3.37), ECLS requirement (OR: 2.29), and AKI (OR: 1.49), whereas OPCAB was associated with a lower incidence of delirium. Statistical analysis indicated a significant difference in ICU stay durations between the two groups, influenced by surgical complexity and postoperative complications. Conclusions: This study underscores the importance of surgical technique in determining postoperative outcomes in HFrEF patients undergoing CABG. OPCAB may offer advantages in reducing POD incidence. These findings suggest the need for tailored surgical decisions and comprehensive care strategies to enhance patient recovery and optimize healthcare resources.

Apixaban versus Aspirin for Embolic Stroke of Undetermined Source.

BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

Development and Validation of a New Score to Assess the Risk of Posttransplantation Diabetes Mellitus in Kidney Transplant Recipients.

Background: Posttransplantation diabetes mellitus (PTDM) is a serious complication of solid organ transplantation. It is associated with major adverse cardiovascular events, which are a leading cause of morbidity and mortality in transplant patients. This study aimed to develop and validate a score to predict the risk of PTDM in kidney transplant recipients. Methods: A single-center retrospective cohort study was conducted in a tertiary care hospital in Medellín, Colombia, between 2005 and 2019. Data from 727 kidney transplant recipients were used to develop a risk prediction model. Significant predictors with competing risks were identified using time-dependent Cox proportional hazard regression models. To build the prediction model, the score for each variable was weighted using calculated regression coefficients. External validation was performed using independent data, including 198 kidney transplant recipients from Tübingen, Germany. Results: Among the 727 kidney transplant recipients, 122 developed PTDM. The predictive model was based on 5 predictors (age, gender, body mass index, tacrolimus therapy, and transient posttransplantation hyperglycemia) and exhibited good predictive performance (C-index: 0.7 [95% confidence interval, 0.65-0.76]). The risk score, which included 33 patients with PTDM, was used as a validation data set. The results showed good discrimination (C-index: 0.72 [95% confidence interval, 0.62-0.84]). The Brier score and calibration plot demonstrated an acceptable fit capability in external validation. Conclusions: We proposed and validated a prognostic model to predict the risk of PTDM, which performed well in discrimination and calibration, and is a simple score for use and implementation by means of a nomogram for routine clinical application.

Early initiation of antibiotic therapy and short-term outcomes in preterm infants: a single-centre retrospective cohort analysis.

BACKGROUND: Sepsis is one of the most important complications in preterm infants. For this reason, many such infants receive antibiotics during their hospital stay. However, early antibiotic therapy has also been associated with adverse outcome. It is yet largely unclear if the time of onset of antibiotic therapy influences the outcome. We here investigated whether the timing of initiation of antibiotic therapy plays a role in the association between antibiotic exposure and short-term outcome. METHODS: Retrospective analysis of data from 1762 very low birthweight infants born in a German neonatal intensive care unit (NICU) between January 2004 and December 2021. RESULTS: Antibiotics were administered to 1214 of the 1762 (68.9%) infants. In 973 (55.2%) of the 1762 of infants, antibiotic therapy was initiated within the first two postnatal days. Only 548 (31.1%) infants did not have any antibiotic prescription during their stay in the NICU. Antibiotic exposure at every timepoint was associated with an increased risk of all short-term outcomes analysed in univariable analyses. In multivariable analyses, initiation of antibiotic therapy within the first two postnatal days and initiation between postnatal days 3 and 6 was independently associated with an increased risk of developing bronchopulmonary dysplasia (BPD) (OR 3.1 and 2.8), while later initiation of antibiotic therapy was not. CONCLUSION: Very early initiation of antibiotic therapy was associated with an increased risk of BPD. Due to the study design, no conclusions on causality can be drawn. If confirmed, our data suggest that an improved identification of infants at low risk of early-onset sepsis is needed to reduce antibiotic exposure.

Deep learning-based scoring of tumour-infiltrating lymphocytes is prognostic in primary melanoma and predictive to PD-1 checkpoint inhibition in melanoma metastases.

BACKGROUND: Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma. METHODS: We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy. FINDINGS: We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival. INTERPRETATION: Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Dual-Time-Point Posttherapy 177Lu-PSMA-617 SPECT/CT Describes the Uptake Kinetics of mCRPC Lesions and Prognosticates Patients' Outcome.

177Lu-PSMA-617 is an effective therapeutic option in metastasized castration-resistant prostate cancer (mCRPC). However, some patients progress under treatment. We hypothesized that the tracer kinetics within the metastases may influence the therapy effectiveness and tested this hypothesis by analyzing uptake parameters on 2 consecutive posttherapy SPECT/CT scans. Methods: mCRPC patients treated with 177Lu-PSMA-617 and with available posttherapy SPECT/CT imaging (24 and 48 h after the first treatment) were enrolled retrospectively. Volumes of interest were defined on lymph node metastasis (LNM) and bone metastasis (BM) on both SPECT/CT scans. The reduction of the percentage injected dose (%IDred) between the 2 SPECT/CT scans was computed. We compared %IDred of responders (prostate-specific antigen drop ≥ 50% after 2 cycles of 177Lu-PSMA-617) and nonresponders. We tested the association of %IDred with progression-free survival and overall survival (OS) using a univariate Kaplan-Meier (KM) analysis and a multivariate Cox regression model. Results: Fifty-five patients (median age, 73 y; range, 54-87 y) were included. %IDred in LNM and BM was greater in nonresponders than in responders (for LNM, 36% in nonresponders [interquartile range (IQR), 26%-47%] vs. 24% in responders [IQR, 12%-33%] [P = 0.003]; for BM, 35% in nonresponders [IQR, 27%-52%] vs. 18% in responders [IQR, 15%-29%] [P = 0.002]). For progression-free survival, in KM analysis, greater %IDred in LNM (P = 0.008) and BM (P = 0.001) was associated with shorter survival, whereas in multivariate analysis, only %IDred in LNM was retained (P = 0.03). In univariate KM analysis of OS, greater %IDred in BM was associated with shorter survival (P = 0.002). In multivariate OS analysis, BM %IDred (P = 0.009) was retained. Conclusion: The 177Lu-PSMA-617 clearance rate from mCRPC metastases appears to be a relevant prognosticator of response and survival, with faster clearing possibly signaling a shorter radiopharmaceutical residence time and absorbed dose. Dual-time-point analysis appears to be a feasible and readily available approach to estimate the likelihood of response and patients' survival.

Impact of early antibiotic exposure on the risk of colonization with potential pathogens in very preterm infants: a retrospective cohort analysis.

BACKGROUND: Sepsis is one of the most important complications in preterm infants. For this reason, most preterm infants receive antibiotics during their first postnatal week. Since 2013, a weekly colonization screening has been installed in German neonatal intensive care units (NICUs), including multi-drug resistant organisms (MDRO) and pathogens with increased epidemic potential. We here investigated the impact of early antibiotic exposure on the colonization with these pathogens. METHODS: Data from 1407 preterm infants with gestational age < 32 + 0 weeks and born in three NICUs in Germany between January 2014 and December 2019 were analysed. RESULTS: Antibiotics were administered to 911/1407 (64.7%) participating infants during their first postnatal week. Screening-targeted pathogens were detected in 547/1407 (38.9%). Early antibiotic exposure did not increase the risk of colonization with screening-targeted pathogens. The only independent risk factor for colonisation with potential pathogens was the admitting hospital. Interestingly, longer antibiotic therapy (> 7 days) decreased the risk for acquiring pathogens with increased epidemic potential. CONCLUSION: Early antibiotic exposure did not impact the risk for colonization with MDRO or highly epidemic pathogens in preterm infants. Further studies are needed to identify risk factors for the acquisition of MDRO and highly epidemic pathogens and potential associations with long-term outcome.

Nephrotic syndrome as a manifestation of thrombotic microangiopathy due to long-term use of sunitinib.

Nephrotic syndrome in patients with cancer may be related to the primary malignancy or chemotherapeutic therapy. Solid organ cancers may cause membranous glomerulonephritis which is manifested by nephrotic syndrome; other less common histologic presentations include focal and segmental glomerulosclerosis and minimal change disease. In addition, chemotherapy agents may cause renal toxicity by affecting the small blood vessels, glomeruli, tubules, and interstitium. Tyrosine kinase inhibitors such as sunitinib may cause endothelial and podocyte damage leading to thrombotic microangiopathy affecting only the kidney and manifested by proteinuria and hypertension. We report a case of an elderly man with gastrointestinal stromal tumor (GIST) on treatment with sunitinib who had as a complication a thrombotic microangiopathy manifested with nephrotic syndrome and a hypertension of difficult control, which was finally controlled by stopping this drug but had a fatal outcome due to its malignancy.

Early Tumor Size Reduction of at least 10% at the First Follow-Up Computed Tomography Can Predict Survival in the Setting of Advanced Melanoma and Immunotherapy.

RATIONALE AND OBJECTIVES: Early tumor size reduction (TSR) has been explored as a prognostic factor for survival in patients with advanced melanoma in clinical trials. The purpose of this analysis is to validate, in a routine clinical milieu, the predictive capacity of TSR by 10% for overall survival (OS) and progression-free survival (PFS) and to compare its predictive performance with the RECIST 1.1 criteria. MATERIALS AND METHODS: This retrospective study was approved by the local ethics committee. A total of 152 patients with both CT before immunotherapy initiation and at first response evaluation after immunotherapy initiation were included. Prior to statistical analysis, treatment response was trichotomized as follows: Complete response and/or partial response, stable disease and progressive disease. Furthermore, response was dichotomized regarding TSR (TSR ≥ 10% and TSR < 10%). Kaplan-Meier survival estimates, Cox regression and Harrel's concordance index (C-index) were computed for prediction of overall survival and progression-free survival. RESULTS: Tumor size reduction by at least 10% significantly differentiated between patients with increased survival from the ones with decreased survival (median OS: TSR ≥ 10%: 2137 days vs. TSR < 10%: 263 days) (p < 0.001) (median PFS: TSR ≥ 10%: 590 days vs. TSR < 10%: 11 days) (p < 0.001). RECIST 1.1. criteria had a slightly higher C-index for overall survival reflecting a slight superior predictive capacity (RECIST: 0.69 vs TSR: 0.64) but a similar predictive capacity regarding progression-free survival (both: 0. 63). CONCLUSION: Early tumor size reduction serves as a simple-to-use metric which can be implemented on the first follow-up CT. Tumor size reduction by at least 10% can be considered an additional biomarker predictive of overall survival and progression-free survival in routine clinical care and not only in the context of clinical trials in patients with advanced melanoma undergoing immunotherapy. Nevertheless, RECIST-based criteria should remain the main tool of treatment response assessment until results of prospective studies validating the TSR method are available.