Real-life experience with sorafenib for advanced and refractory desmoid-type fibromatosis.

BACKGROUND: In recent years, there has been a change in the therapeutic landscape of desmoid-type fibromatosis (DF). Watchful waiting is now preferred over initial local treatments such as surgery and radiotherapy. Systemic treatment is considered for progressive or symptomatic disease. The aim of this study is to review real-life data on the use of sorafenib in DF. METHODS: We established a retrospective dataset of patients treated with sorafenib in our centre, Ghent University Hospital, for progressive DF. Patient demographics, disease characteristics, response to therapy using Response Evaluation Criteria in Solid Tumours 1.1 criteria and toxicity according to CTCAE v5.0 were assessed. RESULTS: Eleven patients with DF were treated with sorafenib between 2020 and 2024. Median treatment duration was 20.4 months (95% confidence interval [CI], 10.0-NR). 36.4% achieved partial response, 54.5% stable disease and 9.1% progressive disease. For three patients, the treatment is ongoing. The median time to objective response rate is 15.0 months (95% CI, 8.8-NR). The majority (81.8%) experienced grade 2 toxicity, and one third of patients grade 3 toxicity (36.4%). The most common all-grade adverse event was skin toxicity (hand-foot syndrome, pruritus and rash) (90.9%). Nine patients (81.8%) needed dose reduction with a median time to first reduction of 1.1 months (95% CI, 0.5-NR). One patient stopped treatment due to toxicity. INTERPRETATION: Real-life data on the use of sorafenib in the treatment of DF is consistent with published data in clinical trial setting. Sorafenib is an effective treatment option for progressive DF although associated with significant toxicity and the need for rapid dose reduction.

Vaginal morbidity, sexual functioning, and health-related quality of life in cervical cancer survivors: a cross-sectional multicenter study (VAMOS).

PURPOSE: To compare sexual/vaginal functioning between early cervical cancer (ECC) and locally advanced cervical cancer (LACC) survivors. METHODS: VAMOS was a multicenter, cross-sectional, questionnaire, noninferiority study including ECC patients treated with surgery and, if clinically indicated, adjuvant (chemo)radiotherapy and LACC patients treated with neoadjuvant (chemo)radiotherapy followed by surgery. Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-CX24, and Female Sexual Functioning Index (FSFI) questionnaires. Clinical reported outcomes (ClinROs) consisted of vaginal morbidity scored according to the CTCAE v4.0 scoring system. RESULTS: One hundred forty-three patients were included. Compared to ECC patients (n = 97), LACC patients (n = 46) were significantly less sexually active in the 4 weeks prior to completion of the questionnaires (65% vs. 41%; p = .005). The primary endpoint was not met: LACC patients reported a higher mean score (more problems) for sexual/vaginal functioning than ECC patients, with a non-clinically relevant mean difference of 6.38 ([95% CI: - 6.41, 19.17]; p = .570 for noninferiority). Regarding the secondary endpoints, the prevalence of sexual dysfunction between the two groups did not differ significantly (p = 0.124). Compared to ECC patients, LACC patients did not have significantly more vaginal morbidity (adjusted odds ratio [OR] 1.51 [95% CI: 0.22, 10.29]; p = .674). Moreover, there was poor agreement between any vaginal morbidity and sexual dysfunction (Cohen's kappa of 0.17). CONCLUSION: Compared to ECC survivors, LACC survivors were significantly less sexually active and reported equivalent or worse sexual/vaginal functioning, although the proportion of patients with sexual dysfunction was similar. Clinical assessment of vaginal morbidity was poorly correlated with sexual dysfunction.

The obesity paradox in critically ill patients: a causal learning approach to a casual finding.

BACKGROUND: While obesity confers an increased risk of death in the general population, numerous studies have reported an association between obesity and improved survival among critically ill patients. This contrary finding has been referred to as the obesity paradox. In this retrospective study, two causal inference approaches were used to address whether the survival of non-obese critically ill patients would have been improved if they had been obese. METHODS: The study cohort comprised 6557 adult critically ill patients hospitalized at the Intensive Care Unit of the Ghent University Hospital between 2015 and 2017. Obesity was defined as a body mass index of ≥ 30 kg/m2. Two causal inference approaches were used to estimate the average effect of obesity in the non-obese (AON): a traditional approach that used regression adjustment for confounding and that assumed missingness completely at random and a robust approach that used machine learning within the targeted maximum likelihood estimation framework along with multiple imputation of missing values under the assumption of missingness at random. 1754 (26.8%) patients were discarded in the traditional approach because of at least one missing value for obesity status or confounders. RESULTS: Obesity was present in 18.9% of patients. The in-hospital mortality was 14.6% in non-obese patients and 13.5% in obese patients. The raw marginal risk difference for in-hospital mortality between obese and non-obese patients was - 1.06% (95% confidence interval (CI) - 3.23 to 1.11%, P = 0.337). The traditional approach resulted in an AON of - 2.48% (95% CI - 4.80 to - 0.15%, P = 0.037), whereas the robust approach yielded an AON of - 0.59% (95% CI - 2.77 to 1.60%, P = 0.599). CONCLUSIONS: A causal inference approach that is robust to residual confounding bias due to model misspecification and selection bias due to missing (at random) data mitigates the obesity paradox observed in critically ill patients, whereas a traditional approach results in even more paradoxical findings. The robust approach does not provide evidence that the survival of non-obese critically ill patients would have been improved if they had been obese.

Prediction of delayed graft function after kidney transplantation: comparison between logistic regression and machine learning methods.

BACKGROUND: Predictive models for delayed graft function (DGF) after kidney transplantation are usually developed using logistic regression. We want to evaluate the value of machine learning methods in the prediction of DGF. METHODS: 497 kidney transplantations from deceased donors at the Ghent University Hospital between 2005 and 2011 are included. A feature elimination procedure is applied to determine the optimal number of features, resulting in 20 selected parameters (24 parameters after conversion to indicator parameters) out of 55 retrospectively collected parameters. Subsequently, 9 distinct types of predictive models are fitted using the reduced data set: logistic regression (LR), linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), support vector machines (SVMs; using linear, radial basis function and polynomial kernels), decision tree (DT), random forest (RF), and stochastic gradient boosting (SGB). Performance of the models is assessed by computing sensitivity, positive predictive values and area under the receiver operating characteristic curve (AUROC) after 10-fold stratified cross-validation. AUROCs of the models are pairwise compared using Wilcoxon signed-rank test. RESULTS: The observed incidence of DGF is 12.5 %. DT is not able to discriminate between recipients with and without DGF (AUROC of 52.5 %) and is inferior to the other methods. SGB, RF and polynomial SVM are mainly able to identify recipients without DGF (AUROC of 77.2, 73.9 and 79.8 %, respectively) and only outperform DT. LDA, QDA, radial SVM and LR also have the ability to identify recipients with DGF, resulting in higher discriminative capacity (AUROC of 82.2, 79.6, 83.3 and 81.7 %, respectively), which outperforms DT and RF. Linear SVM has the highest discriminative capacity (AUROC of 84.3 %), outperforming each method, except for radial SVM, polynomial SVM and LDA. However, it is the only method superior to LR. CONCLUSIONS: The discriminative capacities of LDA, linear SVM, radial SVM and LR are the only ones above 80 %. None of the pairwise AUROC comparisons between these models is statistically significant, except linear SVM outperforming LR. Additionally, the sensitivity of linear SVM to identify recipients with DGF is amongst the three highest of all models. Due to both reasons, the authors believe that linear SVM is most appropriate to predict DGF.

Pooled analysis of patients with inherited prion disease caused by two- to twelve-octapeptide repeat insertions in the prion protein gene (PRNP).

Inherited prion diseases caused by two- to twelve-octapeptide repeat insertions (OPRIs) in the prion protein gene (PRNP) show significant clinical heterogeneity. This study describes a family with two new cases with a 4-OPRI mutation and two asymptomatic mutation carriers. The pooled analysis summarizes all cases reported in the literature to date and describes the relation between survival, age of onset, number of OPRI and codon 129 polymorphism. MEDLINE and Google Scholar were queried from database inception up to December 31, 2022. Age of onset was compared per number of OPRI and per codon 129 polymorphism using the Kruskal-Wallis and Wilcoxon-Mann-Whitney tests, respectively. Disease duration was modeled non-parametrically by a Kaplan-Meier model and semi-parametrically by a Cox model. This study comprised 164 patients. Lower number of OPRI and presence of valine (cis-V) versus methionine (cis-M) on codon 129 were associated with an older age of onset (P < 0.001 and P = 0.025, respectively) and shorter disease duration (P < 0.001 and P = 0.003, respectively). Within patients with 5- or more OPRI codon cis-V remained significantly associated with a shorter disease duration. Codon 129 homozygosity versus heterozygosity was not significantly associated with age of onset or disease duration (P = 0.076 and P = 0.409, respectively). This study summarized the largest cohort of patients with two- to twelve-OPRI to date. Lower number of OPRI and codon 129 cis-V is associated with an older age of onset and shorter disease duration, while homozygosity or heterozygosity on codon 129 was not.

Incidence, evolution and risk factors of hypophosphatemia in patients with solid tumors receiving ferric carboxymaltose: a retrospective cohort study.

OBJECTIVES: Ferric carboxymaltose (FCM) is increasingly used in the management of cancer-related anemia, yet it may cause hypophosphatemia. This retrospective study describes the incidence, evolution and risk factors of hypophosphatemia in a cohort of patients with solid tumors receiving FCM. METHODS: Serum phosphorus concentration was assessed longitudinally using a random intercepts model. The probability of developing hypophosphatemia, as graded by CTCAE version 4.0, was investigated using a multi-state model. Transition hazards were modeled non-parametrically and semi-parametrically by a Cox model. Causal marginal risk differences between baseline interventions on serum phosphorus and/or FCM dose were obtained via G-computation. RESULTS: In 174 ambulatory patients with solid tumors receiving FCM at two university hospitals between October 2020 and September 2021, the risk of developing moderate-to-severe hypophosphatemia was 36.0% (95% confidence interval (CI) 28.2-43.9%) and peaked within 16 days after first FCM administration. The average duration of moderate-to-severe hypophosphatemia was 12.4 days. After adjustment for confounders, lower baseline serum phosphorus (adjusted hazard ratio (aHR) 0.88 per 0.1 mmol/L increase, 95% CI 0.79-0.98) and higher FCM dose (first dose: aHR 1.12 per 1 mg/kg increase, 95% CI 1.01-1.25; second dose: aHR 1.06 per 1 mg/kg increase, 95% CI 1.00-1.13) significantly increased the hazard of moderate-to-severe hypophosphatemia. CONCLUSION: Approximately one out of three ambulatory patients with solid tumors may develop moderate-to-severe hypophosphatemia after FCM administration. Baseline serum phosphorus and FCM dose may be modifiable risk factors that should be considered for intervention in order to mitigate the risk of hypophosphatemia.

Clinical decision-making in older patients with cancer: a cross-sectional single-centre study to assess the impact of clinical judgement and patient preferences.

OBJECTIVE: The heterogeneity in the population of older patients with cancer makes clinical decision-making difficult. We investigated the agreement between the G8 score and clinical judgment in frailty assessments, determined the impact of a life-expectancy calculator, and explored patient and caregiver preferences towards the treatment goal. METHODS: Patients aged ≥75 years in need of new oncological treatment were prospectively enrolled between June 2020 and February 2021. Frailty was estimated by the oncologist and caregiver and compared to the G8 estimation. We examined whether the oncologist changed the fit/frail estimation based on life expectancy calculated using the ePrognosis tool. The main treatment goals, either longevity or quality of life (QoL), from the patient's and caregiver's perspective were noted and compared. RESULTS: Forty-nine patients were included in the analysis. Comparison of the oncologist's and the caregiver's frailty estimation with the G8 assessment showed agreement and a Kappa coefficient of 58.3% (0.231) and 60% (0.255), respectively. The ePrognosis score and the odds of change in the frailty estimation by the oncologist showed no correlation. Regarding preferences, 28 (57.1%) and 17 (34.7%) patients and eighteen (47.3%) and seventeen (44.7%) caregivers chose longevity and QoL, respectively. The observed agreement and Kappa coefficient were 78.8% and 0.578. CONCLUSION: Compared to the G8 assessment, frailty was underestimated by both oncologists and caregivers. Most of the patients chose longevity over QoL, and the preferences between the patient and the caregiver matched in the majority of cases.

Predictive value of the renal resistive index in the immediate postoperative period after kidney transplantation on short- and long-term graft and patient outcomes.

INTRODUCTION: During the postoperative stay in the intensive care unit after kidney transplantation, the renal resistive index (RI) is routinely measured. An increased RI, measured months posttransplant, is associated with a higher mortality. We wanted to investigate the value of the RI immediately posttransplant in predicting both short- and long-term outcome. METHODS: We performed a retrospective single-center study. The RI was collected <48 h posttransplant in patients undergoing kidney transplantations between 2005 and 2014. Short-term outcome was evaluated by delayed graft function (DGF). The long-term endpoints were kidney function and mortality at 30 days, 1 year and 5 years. RESULTS: We included 478 recipients, 91.4% of whom reached the end of the 5-year follow-up. A higher RI < 48 h posttransplant was significantly associated with DGF. This association was particularly strong in patients receiving grafts from donors after brain death and expanded criteria donors. A higher RI also correlated with mortality and death with functioning graft but not with graft failure. After adjustment for confounders, we found an association between increased RI and DGF, but not with long-term kidney function or mortality. CONCLUSION: The RI routinely measured <48 h posttransplant is an independent predictor of short-term kidney function.

Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis.

BACKGROUND: Soft-tissue sarcomas (STSs) are rare malignancies, accounting for approximately 1% of adult cancer. Metastatic disease carries a poor prognosis, and various efforts have been made to improve the prognosis of advanced STS, to date with little success. Immune checkpoint inhibitors (ICPIs) have substantially improved prognosis for many cancer types. Their role in the treatment of STS, however, remains unravelled. OBJECTIVE: The objective of the study is to assess the activity of ICPIs in the treatment of STS. METHODS: We performed a systematic review using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Furthermore, abstracts from European Society of Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and Connective Tissue Society Oncology (CTOS) congress were searched from 2017 until 2020. Prospective clinical trials investigating ICPIs, either monotherapy or combination therapy, in STS were available for inclusion. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and major toxicity. Cut-off for clinical activity was defined as an ORR of ≥0.15. Subgroup analysis was carried out as per treatment category, disease setting and histologic subtype, using a random effects model. RESULTS: We identified 27 studies, including a total of 1012 patients (range 6-85) with more than 25 histologic subtypes. The pooled ORR was 0.14 (95% confidence interval [CI] 0.09-0.18), DCR was 0.55 (95% CI 0.43-0.66), mean PFS range was 1.8-11.5 months and mean OS was 6.1-34.7 months. The pooled ORR as per treatment category was 0.14 for anti-programmed cell death 1 (anti-PD1) monotherapy (95% CI 0.07-0.23), 0.16 for anti-PD1 + anti-cytotoxic T-lymphocyte-associated protein 4 (95% CI 0.06-0.29), 0.20 for anti-PD1 + tyrosine kinase inhibitor (95% CI 0.06-0.38), 0.20 for anti-PD1 + chemo (95% CI 0.06-0.38) and 0.08 for anti-PD1 + immunomodulator (95% CI 0.01-0.19). The pooled ORR as per disease setting was as follows: neoadjuvant treatment, 0.09 (0.00-0.25); advanced disease first line, 0.23 (0.15-0.32) and advanced pretreated, 0.13 (0.09-0.19). High response rates were seen in classic Kaposi sarcoma (CKS), alveolar soft part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (UPS) with ORR of 0.69 (95% CI 0.51-0.82), 0.35 (95% CI 0.27-0.44) and 0.20 (95% CI 0.15-0.27), respectively. Activity was limited in gastrointestinal stromal tumour (ORR 0.01 [95% CI 0.0-0.08]), uterine leiomyosarcoma (ORR 0.06 [95% CI 0.02-0.18]), leiomyosarcoma (ORR 0.10 [95% CI 0.06-0.17]) and liposarcoma (ORR 0.11 [95% CI 0.07-0.17]). CONCLUSION: Clinical activity of ICPIs in STS is highly variable and depends on histologic subtype, disease setting and concomitant treatment strategy. Activity was high in CKS, ASPS and UPS. Early incorporation of ICPIs in combination with chemotherapy seems a promising strategy that warrants further interest. Translational research integrating molecular profile, biological behaviour and response to ICPIs should determine their role in treatment of STS.

WITHDRAWN: Impact on Delayed Graft Function of the Renal Resistive Index in the Immediate Postoperative Period After Kidney Transplantation: A Cohort Analysis.

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Epidemiology, causes, evolution and outcome in a single-center cohort of 1116 critically ill patients with hypoxic hepatitis.

BACKGROUND: Hypoxic hepatitis (HH) is a type of acute hepatic injury that is histologically characterized by centrilobular liver cell necrosis and that is caused by insufficient oxygen delivery to the hepatocytes. Typical for HH is the sudden and significant increase of aspartate aminotransferase (AST) in response to cardiac, circulatory or respiratory failure. The aim of this study is to investigate its epidemiology, causes, evolution and outcome. METHODS: The screened population consisted of all adults admitted to the intensive care unit (ICU) at the Ghent University Hospital between January 1, 2007 and September 21, 2015. HH was defined as peak AST > 5 times the upper limit of normal (ULN) after exclusion of other causes of liver injury. Thirty-five variables were retrospectively collected and used in descriptive analysis, time series plots and Kaplan-Meier survival curves with multi-group log-rank tests. RESULTS: HH was observed in 4.0% of the ICU admissions at our center. The study cohort comprised 1116 patients. Causes of HH were cardiac failure (49.1%), septic shock (29.8%), hypovolemic shock (9.4%), acute respiratory failure (6.4%), acute on chronic respiratory failure (3.3%), pulmonary embolism (1.4%) and hyperthermia (0.5%). The 28-day mortality associated with HH was 45.0%. Mortality rates differed significantly (P = 0.007) among the causes, ranging from 33.3% in the hyperthermia subgroup to 52.9 and 56.2% in the septic shock and pulmonary embolism subgroups, respectively. The magnitude of AST increase was also significantly correlated (P < 0.001) with mortality: 33.2, 44.4 and 55.4% for peak AST 5-10× ULN, 10-20× ULN and > 20× ULN, respectively. CONCLUSION: This study surpasses by far the largest cohort of critically ill patients with HH. HH is more common than previously thought with an ICU incidence of 4.0%, and it is associated with a high all-cause mortality of 45.0% at 28 days. The main causes of HH are cardiac failure and septic shock, which include more than 3/4 of all episodes. Clinicians should search actively for any underlying hemodynamic or respiratory instability even in patients with moderately increased AST levels.

A Single-Center Comparison of 22 Competing Definitions of Delayed Graft Function After Kidney Transplantation.

BACKGROUND: This study compared 22 different definitions of delayed graft function (DGF) following kidney transplantation. MATERIAL AND METHODS: Our study included 497 kidney transplantations from deceased donors at our center between 2005 and 2011. Graft survival analysis including log-rank tests and Cox proportional hazards model was performed. Sensitivity and specificity were calculated in relation to graft failure. RESULTS: Mean follow-up time was 5.1 years. All dialysis-based definitions were associated with graft failure and characterized by high specificity (88-97%), but low sensitivity (25-29%). Hazard ratios ranged from 2.87 to 13.73, with increased risk when dialysis was required earlier and more frequently. The urine output-based definition performed similarly, with an association with graft failure and high specificity (96%), but low sensitivity (21%). Serum creatinine-based definitions were more heterogeneous. Higher sensitivity (4-67%) was found in some of these definitions, but was often associated with lower specificity (47-96%), losing the association with graft failure. Definitions combining different criteria varied in sensitivity (17-62%) and specificity (60-96%). However, some were able to achieve higher sensitivity without compromising too much on specificity, while keeping the association with graft failure. CONCLUSIONS: Our results indicate a potential advantage of combined definitions, because they are able to detect a larger group of recipients with increased risk of graft failure.

Validation in a Single-Center Cohort of Existing Predictive Models for Delayed Graft Function After Kidney Transplantation.

BACKGROUND Kidney transplantation is the preferred treatment for patients with end-stage renal disease. Delayed graft function (DGF) is a common complication and is associated with short- and long-term outcomes. Several predictive models for DGF have been developed. MATERIAL AND METHODS 497 kidney transplantations from deceased donors at our center between 2005-2011 are included. Firstly, the predictive accuracy of the existing models proposed by Irish et al. (M1), Jeldres et al. (M2), Chapal et al. (M3), and Zaza et al. (M4) was assessed. Secondly, the existing models were aggregated into a meta-model (MM) using stacked regressions. Finally, the association between 47 risk factors and DGF was studied in our -cohort-fitted model (CFM) using logistic regression. The accuracy of all models was assessed by area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test. RESULTS M1, M2, M3, M4, MM, and CFM have AUROCs of 0.78, 0.65, 0.59, 0.67, 0.78, and 0.82, respectively. M1 (P=0.018), M2 (P<0.001), M3 (P<0.001), and M4 (P<0.001) overestimate the risk. MM (P=0.255) and CFM (P=0.836) are well calibrated. Donor subtype (P<0.001), recipient cardiac function (P<0.001), donor serum creatinine (P<0.001), donor age (P=0.006), duration of dialysis (P=0.02), recipient BMI (P=0.008), donor BMI (P=0.041), and recipient preoperative diastolic blood pressure (P=0.049) are associated with DGF in our CFM. CONCLUSIONS Four existing predictive models for DGF overestimate the risk in a cohort with a low incidence of DGF. We have identified 2 recipient parameters that are not included in previous models: cardiac function and preoperative diastolic blood pressure.