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Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. 118 patients (median age 31·0 years; IQR 18·0–61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31–53%]) for everolimus and 0% (0 of 39 [0–9%]) for placebo (response rate difference 42% [24–58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. Novartis Pharmaceuticals.

Background Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Many gaps remain in the understanding of TSC because of the complexity in clinical presentation. The T uber O us SC lerosis registry to increase disease A wareness (TOSCA) is an international disease registry designed to address knowledge gaps in the natural history and management of TSC. Here, we present the baseline data of TOSCA cohort. Methods Patients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals were included. The registry includes a “core” section designed to record detailed background information on each patient including disease manifestations, interventions, and outcomes collected at baseline and updated annually. “Subsections” of the registry recorded additional data related to specific features of TSC. Results Baseline “core” data from 2093 patients enrolled from 170 sites across 31 countries were available at the cut-off date September 30, 2014. Median age of patients at enrollment was 13 years (range, 0–71) and at diagnosis of TSC was 1 year (range, 0–69). The occurrence rates of major manifestations of TSC included – cortical tubers (82.2%), subependymal nodules (78.2%), subependymal giant cell astrocytomas (24.4%), renal angiomyolipomas (47.2%), lymphangioleiomyomatosis (6.9%), cardiac rhabdomyomas (34.3%), facial angiofibromas (57.3%), forehead plaque (14.1%), ≥ 3 hypomelanotic macules (66.8%), and shagreen patches (27.4%). Epilepsy was reported in 1748 (83.5%) patients, of which 1372 were diagnosed at ≤ 2 years (78%). Intellectual disability was identified in 451 (54.9%) patients of those assessed. TSC-associated neuropsychiatric disorders (TAND) were diagnosed late, and not evaluated in 30–50% of patients. Conclusion TOSCA is the largest clinical case series of TSC to date. It provided a detailed description of the disease trajectory with increased awareness of various TSC manifestations. The rates of different features of TSC reported here reflect the age range and referral patterns of clinics contributing patients to the cohort. Documentation of TAND and LAM was poor. A widespread adoption of the international TSC assessment and treatment guidelines, including use of the TAND Checklist, could improve surveillance. The registry provides valuable insights into the necessity for monitoring, timing, and indications for the treatment of TSC.

Objectives(1) To assess the methodological quality of radiomics studies investigating histological subtypes, therapy response, and survival in patients with renal cell carcinoma (RCC) and (2) to determine the risk of bias in these radiomics studies.MethodsIn this systematic review, literature published since 2000 on radiomics in RCC was included and assessed for methodological quality using the Radiomics Quality Score. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool and a meta-analysis of radiomics studies focusing on differentiating between angiomyolipoma without visible fat and RCC was performed.ResultsFifty-seven studies investigating the use of radiomics in renal cancer were identified, including 4590 patients in total. The average Radiomics Quality Score was 3.41 (9.4% of total) with good inter-rater agreement (ICC 0.96, 95% CI 0.93–0.98). Three studies validated results with an independent dataset, one used a publically available validation dataset. None of the studies shared the code, images, or regions of interest. The meta-analysis showed moderate heterogeneity among the included studies and an odds ratio of 6.24 (95% CI 4.27–9.12; p < 0.001) for the differentiation of angiomyolipoma without visible fat from RCC.ConclusionsRadiomics algorithms show promise for answering clinical questions where subjective interpretation is challenging or not established. However, the generalizability of findings to prospective cohorts needs to be demonstrated in future trials for progression towards clinical translation. Improved sharing of methods including code and images could facilitate independent validation of radiomics signatures.Key Points• Studies achieved an average Radiomics Quality Score of 10.8%. Common reasons for low Radiomics Quality Scores were unvalidated results, retrospective study design, absence of open science, and insufficient control for multiple comparisons.• A previous training phase allowed reaching almost perfect inter-rater agreement in the application of the Radiomics Quality Score.• Meta-analysis of radiomics studies distinguishing angiomyolipoma without visible fat from renal cell carcinoma show moderate diagnostic odds ratios of 6.24 and moderate methodological diversity.

ObjectiveTo evaluate the diagnostic performance of machine-learning based quantitative texture analysis of CT images to differentiate small (≤ 4 cm) angiomyolipoma without visible fat (AMLwvf) from renal cell carcinoma (RCC).MethodsThis single-institutional retrospective study included 58 patients with pathologically proven small renal mass (17 in AMLwvf and 41 in RCC groups). Texture features were extracted from the largest possible tumorous regions of interest (ROIs) by manual segmentation in preoperative three-phase CT images. Interobserver reliability and the Mann-Whitney U test were applied to select features preliminarily. Then support vector machine with recursive feature elimination (SVM-RFE) and synthetic minority oversampling technique (SMOTE) were adopted to establish discriminative classifiers, and the performance of classifiers was assessed.ResultsOf the 42 extracted features, 16 candidate features showed significant intergroup differences (P < 0.05) and had good interobserver agreement. An optimal feature subset including 11 features was further selected by the SVM-RFE method. The SVM-RFE+SMOTE classifier achieved the best performance in discriminating between small AMLwvf and RCC, with the highest accuracy, sensitivity, specificity and AUC of 93.9 %, 87.8 %, 100 % and 0.955, respectively.ConclusionMachine learning analysis of CT texture features can facilitate the accurate differentiation of small AMLwvf from RCC.Key Points• Although conventional CT is useful for diagnosis of SRMs, it has limitations.• Machine-learning based CT texture analysis facilitate differentiation of small AMLwvf from RCC.• The highest accuracy of SVM-RFE+SMOTE classifier reached 93.9 %.• Texture analysis combined with machine-learning methods might spare unnecessary surgery for AMLwvf.

Background We aimed to launched new staging criteria to predict mTOR inhibitors treatment effect of renal angiomyolipomas (r-AMLs) in TSC patients. Methods 40 TSC patients with 69 r-AMLs were divided into two groups based on the efficacy of 6-month mTOR inhibitor treatment. Epidemiological data, therapeutic response, and predictive factors of enrolled patients were collected and analyzed. Age, sex, maximum diameter, maximum cross-sectional area (CSAmax), unenhanced mean CT value, enhanced mean CT value, and added value of enhanced CT of largest r-AML at baseline were assessed as potential influencing factors. Receiver operating characteristic (ROC) curve analysis and the area under the ROC curve (AUC) was used to estimate prediction power. Results After 6 months of mTOR inhibitor treatment, the tumor reduction rates in the two groups were 55.87% and 16.44% ( P  < 0.001). At the start of treatment, the maximum diameters, CSAmax, added value of enhanced CT of the target lesion in two groups were 7.70 ± 0.73 cm vs. 13.18 ± 1.23 cm( P  = 0.028), 57.40 ± 10.76cm2 vs. 167.29 ± 33.09cm2 ( P  = 0.015), and 62.32 ± 5.03HU vs. 33.06 ± 3.13HU ( P  = 0.009), respectively. AUCs of CSAmax, added value of enhanced CT, and combination of both were 0.8024, 0.7672, and 0.8116, respectively ( P  < 0.001). Cut-off values of CSAmax combined with the added value of enhanced CT were 40cm2 and 46HU. AUCs of maximum diameters, combination of maximum diameters and added value of enhanced CT were 0.7600 and 0.8100, respectively ( P  < 0.001), with cut-off values of 6.6 cm and 46 HU. Conclusion New staging criteria, based on CSAmax and added value of enhanced CT, can predict the treatment efficiency of m-TOR inhibitors for r-AMLs in TSC patients. A simplified version based on maximum diameter and added value of enhanced CT of lesion has also been proposed.

The 2004 World Health Organization classification of tumors defines epithelioid angiomyolipoma of kidney as a potentially malignant mesenchymal neoplasm with reported metastasis in approximately one-third of the cases. However, this conclusion was based primarily on individual case reports and small retrospective series. More recently reported larger series have shown varying results. We reviewed 437 consecutive renal angiomyolipomas with primary resection at three tertiary-care institutions with high nephrectomy volumes. Only tumors showing >80% epithelioid histology were included in this study. Tumors resected elsewhere and reviewed in consultation were not included. Twenty of these 437 (4.6%) were classified as epithelioid angiomyolipoma. The female to male ratio was 11:9, mean age 49.7 (range, 30–80) years, and mean tumor size 8.7 (range, 1–25) cm. Microscopic tumor necrosis was present in 10 (50%) tumors and mitotic activity (range, <1–5/10 high power fields) in 8 (40%); atypical mitoses were seen in only 1 (5%) tumor. Pleomorphic ganglion-like or multinucleated giant cells were seen in 18 (90%) tumors. With a mean follow-up of 82.5 (range, 1–356) months, seventeen patients were alive with no-evidence-of-disease at the time of last follow-up; two patients died of unrelated causes with no-evidence-of-disease, and one patient (5%) developed distant metastases. Our data, based on consecutively resected angiomyolipomas with long clinical follow-up, suggests that epithelioid angiomyolipomas constitute a small proportion of all angiomyolipomas, and the rate of aggressive behavior among epithelioid angiomyolipomas, even when showing morphologic features previously reported to portend aggressive clinical behavior, is very low.

Background The response to everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC-RAML) varies among individuals. This study aims to identify potential factors associated with the response to everolimus. Method We retrospectively examined data encompassing age, gender, tumor size, computed tomography attenuation value (CT value), CT enhancement, and tumor reduction rate in patients with TSC-RAML undergoing everolimus in two previously registered clinical trials. Result A total of 33 participants (29.33 ± 6.63 years old, 20 females) were included. The correlation analysis conducted separately for tumors located in the left and right kidneys revealed significant negative correlations ( P  < 0.05) between tumor reduction rate and age, as well as tumor size. While significant positive correlations ( P  < 0.05) were observed between tumor reduction rate and unenhanced CT value as well as CT enhancement. Nonetheless, based on multiple linear regression analysis, unenhanced CT value emerged as the sole-independent predictor of tumor reduction rate among age, gender, tumor size, unenhanced CT value and CT enhancement for both left (coefficient = 0.00319, P  < 0.0001) and right kidneys (coefficient = 0.00315, P  = 0.0104). Notable reductions were observed in unenhanced CT value (− 3.81 vs − 24.70HU, P  < 0.0001) and CT enhancement (48.16 vs 33.56HU, P  < 0.0001) following a 3-month administration of everolimus. The decline in both unenhanced CT value and tumor size predominantly occurred within the initial 3 months, subsequently maintaining a relatively stable level throughout the treatment. Conclusion The unenhanced CT value of TSC-RAML showed an independent correlation with the response to everolimus, suggesting its potential as a predictor of everolimus efficacy in patients with TSC-RAML.

Renal angiomyolipoma (AML) is a rare benign renal tumor with notable clinical implications, including potential compression of adjacent organs and a heightened risk of spontaneous hemorrhage, particularly when the tumor grows large. We present a complex case involving renal AML in a 52-year-old male patient who exhibited persistent left flank pain. Radiological imaging revealed a bilateral AML, with the most significant lesion on the left measuring approximately 13.5 × 19.3 × 15.6 cm. This lesion was associated with multiple renal stones, fluid accumulation, and atrophy of the left kidney. Surgical intervention was necessary, leading to open nephrectomy and removal of the left renal mass. Histopathological examination confirmed the diagnosis of renal angiomyolipoma and left renal atrophy. This case report provides critical insights into the multifaceted nature of renal AML, covering its pathogenesis, clinical presentation, diagnosis, and treatment, and thus enhances the understanding and management of this condition in clinical practice.

Abstract Objectives Epithelioid angiomyolipoma (EAML, perivascular epithelioid cell tumor) is an uncommon primary renal tumor that may recur or metastasize, although there remain limited data for prediction of these outcomes. Here, we report two cases of renal EAML with molecular testing, adding to the existing literature of potential alterations associated with malignant behavior. Methods Tumors diagnosed as malignant renal EAML were identified, and clinical data, radiology, histology, immunohistochemistry, and molecular testing results were reviewed. Results Two cases of malignant renal EAML were identified, both of which demonstrated TSC2 and TP53 mutations. In ATRX, one had a mutation and the other had a variant of uncertain significance. In addition, one patient had a synchronous classic angiomyolipoma that lacked TP53 and ATRX alterations. Conclusions These findings highlight the molecular landscape of malignant renal EAML and expand on the existing literature suggesting a role for TP53 and ATRX alterations in malignant progression of these tumors. The presence of synchronous benign and malignant tumors within the same patient offers a unique opportunity to directly compare the molecular alterations, further supporting the association with aggressive behavior.