Sporadic Angiomyolipoma Research Articles

Natural History and Management of Ultrasound-detected Small Renal Angiomyolipoma.

Recent advances in imaging methods increased the incidental detection of small renal angiomyolipoma (AML). However, guidelines for managing small AML are lacking, and decisions about imaging frequency and timing of intervention are made on an individual basis. This study aims to investigate the clinical behavior of small sporadic AML and propose an optimal follow-up strategy. The study is a retrospective analysis of 168 individuals who had hyperechoic lesions, suggestive of AML detected during abdominal ultrasound as a part of their health checkup. The clinical information of the individuals, including tumor characteristics and renal function, was reviewed. Statistical analysis was performed to identify factors associated with tumor growth and renal function. Most AMLs were small (≤20 mm) and did not exhibit malignant characteristics. The tumors showed a slow growth rate, with a mean growth rate of 0.24 mm/year. Only a small proportion of cases (1.2%) required intervention due to significant enlargement. Factors such as tumor size and gender were not significantly associated with tumor growth rate or renal function. However, younger patients showed a higher tumor growth rate and a more pronounced decline in renal function. Small sporadic AMLs have a slow growth rate and little risk of malignancy. Neither tumor size nor gender was predictive factors for tumor growth or renal function. Nevertheless, close monitoring of tumor growth and renal function is advised, particularly in younger patients. This study highlights the need for further research and guidelines to establish an optimal surveillance protocol for small AMLs.

UPLC-MS based integrated plasma proteomic and metabolomic profiling of TSC-RAML and its relationship with everolimus treatment.

Aim: To profile the plasma proteomics and metabolomics of patients with renal cysts, sporadic angiomyolipoma (S-AML) and tuberous sclerosis complex related angiomyolipoma (TSC-RAML) before and after everolimus treatment, and to find potential diagnostic and prognostic biomarkers as well as reveal the underlying mechanism of TSC tumorigenesis. Materials and Methods: We retrospectively measured the plasma proteins and metabolites from November 2016 to November 2017 in a cohort of pre-treatment and post-treatment TSC-RAML patients and compared them with renal cyst and S-AML patients by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS). The tumor reduction rates of TSC-RAML were assessed and correlated with the plasma protein and metabolite levels. In addition, functional analysis based on differentially expressed molecules was performed to reveal the underlying mechanisms. Results: Eighty-five patients with one hundred and ten plasma samples were enrolled in our study. Multiple proteins and metabolites, such as pre-melanosome protein (PMEL) and S-adenosylmethionine (SAM), demonstrated both diagnostic and prognostic effects. Functional analysis revealed many dysregulated pathways, including angiogenesis synthesis, smooth muscle proliferation and migration, amino acid metabolism and glycerophospholipid metabolism. Conclusion: The plasma proteomics and metabolomics pattern of TSC-RAML was clearly different from that of other renal tumors, and the differentially expressed plasma molecules could be used as prognostic and diagnostic biomarkers. The dysregulated pathways, such as angiogenesis and amino acid metabolism, may shed new light on the treatment of TSC-RAML.

A multi‑omics study of diagnostic markers and the unique inflammatory tumor micro‑environment involved in tuberous sclerosis complex‑related renal angiomyolipoma.

Tuberous sclerosis complex (TSC) is a rare disease that threatens multiple organs in the human body. TSC-associated renal angiomyolipoma (TSC-RAML) has potentially life-threatening complications and a generally poor prognosis. The present study aimed to find plasma proteomic diagnostics and disease-associated markers, and explore the tumor microenvironment using multi-omics. To achieve this goal, the plasma proteomics as well as tissue proteomics, bulk and single-cell RNA transcriptome from patients with TSC-RAML were examined and analyzed. The results suggested that plasma proteins such as MMP9 and C-C motif chemokine ligand 5 were able to differentiate TSC-RAML from sporadic angiomyolipoma and renal cyst. A correlation analysis revealed that plasma proteomics were associated with lymphangioleiomyomatosis, TSC-RAML grading and whole-body disease burden. Tissue proteomics of participants with TSC-RAML revealed disturbed small molecule catabolic process, mitochondrial matrix component and actin binding function. Bulk and single-cell RNA sequencing suggested a greater number of tumor-like cells, fibroblasts and mono-nuclear macrophages within the tumor microenvironment. The above results indicated that TSC-RAML exhibited a characteristic and disease-associated plasma proteomic profile. The unique microenvironment, made up of fibroblasts and mono-macrophages, may promote tumorigenesis and TSC-RAML progression.

Complex Arterial Pathology of Angiomyolipomas of Tuberous Sclerosis.

Based on observations at angiography, it was hypothesized that angiomyolipomas (AMLs) associated with tuberous sclerosis complex (TSC) have a more robust parasitic blood supply and require more complex embolization involving lower order vessels compared with the non-TSC patients' AMLs. This was a retrospective review of 71 patients who underwent angiography and embolization for renal AML at multiple centers within a single health system. All of the patients with TSC (11/11) were found to have "complex" tumor vascular supply. Of the patients with sporadic AML, 51/60 (85%) had "simple" tumor vascular supply. Sporadic cases with a complex tumor blood supply were larger tumors, with an average size of 11.5 cm. This study supports our hypothesis that AMLs associated with TSC have more complex tumor vascularity compared with sporadic lesions, and aims to better prepare interventionalists to deal with the complex cases.

Tuberous sclerosis complex: a complex case.

Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms’ tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.

Superselective embolization of the branches of the renal artery, as a method of choice for surgical treatment of giant kidney angiomyolipoma

The case of surgical treatment of giant sporadic angiomyolipoma of the kidney is presented. By definition, an angiomyolipoma is a highly active vascular benign tumor consisting of endothelial cells, smooth muscles and adipose tissue. The diagnostic standard includes ultrasound diagnostics and computed tomography. The presented patient has in the lower segment of the left kidney, a giant subcapsular lipoma with a pronounced angiomatous component, 64×40×82 mm in size. The main method of treatment for this disease is surgical. In this case, the minimally invasive surgical intervention was chosen as the first stage: superselective embolization of the branches of the left renal artery. Selective angiography revealed a symptom of pathological neovascularization. Through the microcatheter, embolization of the branches of the left renal artery by embospheres was performed. In the postoperative period, the patient noted a decrease in the intensity of the pain syndrome, up to its complete disappearance. In the case of formations larger than 4-5 cm in diameter, embolization can be considered as the first stage of the surgical operation. Further reduction of the education in volume can allow the second stage of surgical treatment to be performed — laparoscopic kidney resection. Angiomyolipoma of the kidney of this size is a rather rare pathology. Similar formations make up approximately 0.3–3% in the population and the methods of their treatment are not always unambiguous. Therefore, we believe that each clinical case is very important and interesting in its own way and is also valuable in terms of accumulating experience in the treatment of such patients.

Transarterial Embolization for Sporadic Renal Angiomyolipoma: Patient Selection and Technical Considerations for Optimal Therapeutic Outcomes.

Although renal angiomyolipoma (AML) is a benign tumor, treatment may be necessary occasionally because it can cause potentially life-threatening retroperitoneal hemorrhage. Transarterial embolization (TAE) is a safe and effective treatment option to prevent the hemorrhagic rupture of AMLs and relieve the symptoms caused by enlarged lesions or active bleeding. However, there is no clear consensus regarding the indications for prophylactic TAE in patients with sporadic renal AMLs. In urgent TAE for bleeding AMLs, there is a likelihood of incomplete embolization when the focus is on stabilizing the clinical symptoms. This pictorial essay discusses the patient selection and technical considerations to achieve optimal therapeutic effects as well as the follow-up findings after TAE.

Robot-Assisted versus Laparoscopic Partial Nephrectomy for Giant Sporadic Renal Angiomyolipomas of ≥7 cm: A Propensity Score-Matched Analysis.

Background To compare the perioperative and functional outcomes between robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN) for giant sporadic renal angiomyolipomas (AMLs) of ≥7 cm. Materials and Methods Patients with sporadic renal AMLs of ≥7 cm who underwent RAPN or LPN in the First Affiliated Hospital of Nanchang University between 2015 and 2020 were retrospectively analyzed. Propensity score matching (1 : 1) was performed to adjust for potential baseline confounders. Perioperative and functional outcomes of the RAPN and LPN groups were collected and compared. Result After propensity score matching, no statistically significant differences in baseline characteristics were found between the groups (41 vs. 41). Within the matched cohort, the warm ischemia time (WIT) in the RAPN group was significantly shorter than that in the LPN group (21 vs. 27 min, p < 0.001). In addition, the RAPN group was associated with improved postoperative renal function (72.8 vs. 69.8 mL/min/1.73 m2, p=0.045). WIT and preoperative renal function are independent predictors of renal function at 6 months postoperatively, and renal score and operation method are independent predictors of WIT. Conclusion RAPN and LPN are safe and feasible minimally invasive treatments for sporadic giant renal AMLs, but RAPN is associated with shorter WIT and better postoperative renal functional preservation. WIT and preoperative renal function are independent predictors of renal function at 6 months postoperatively, while the RENAL score and surgical method are independent risk factors to WIT. For giant and complex renal AMLs, RAPN is the first choice when condition permits.

Use of microspheres in embolization for unruptured renal angiomyolipomas.

PurposeTo describe our initial experience with use of microspheres in transcatheter arterial embolization (TAE) for unruptured sporadic renal angiomyolipomas (AMLs).Materials and methodsSeven consecutive patients with seven unruptured sporadic renal AMLs, 6 females and 1 male, with a median age of 45 years (range, 30–69 years), underwent TAE using microspheres between November 2016 and February 2020. We evaluated the technical success rate, complications related to the procedure, clinical success rate, and the shrinkage rate of renal AML. Technical success was defined as the completion of TAE. Clinical success was defined as presence of shrinkage of the renal AML after TAE.ResultsIn all patients, TAE using microspheres was accomplished and technical success rate was 100% (7/7). Three patients exhibited slight pain, but it improved with only observation, and the minor complication rate was 43% (3/7) and major complication rate was 0% (0/7). After the TAE, shrinkage of renal AML was confirmed in 6 of 7 patients, and clinical success rate was 86% (6/7). The median of shrinkage rate was 47% (range, 26–83%) with a median follow-up period of 19 months (range, 4–30 months).ConclusionTAE using microspheres appears to be effective and safe for unruptured sporadic renal AMLs.

The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

Wunderlich‘s syndrome in patient with sporadic bilateral angiomyolipomas – case report

We present the case report of bilateral renal angiomyolipomas in a 70-year-old patient. Spontaneous bleeding into the retroperitoneum and hemodynamic instability required an acute surgical revision with a left-sided nephrectomy. The contralateral angiomyolipoma was selectively embolized in the second period and subsequently resected.

Canadian Urological Association best practice report: Diagnosis and management of sporadic angiomyolipomas.

Canadian Urological Association best practice report: Diagnosis and management of sporadic angiomyolipomas.

Résultats de la surveillance active des angiomyolipomes sporadiques du rein de plus de 4 cm : un plaidoyer en faveur de la surveillance active

Active surveillance (AS) of sporadic renal angiomyolipomas (AML) is under-utilised because of an old dogma fearing a life-threatening retroperitoneal hemorrhage when tumour size exceeds 4cm. The objective of this study was to report the outcome of AS in patients with sporadic AML greater than 4cm. The results of AS in 35 patients managed for sporadic renal AML greater than 4cm were analysed. During AS, tumour growth, occurrence of new symptoms and/or complications, discontinuation of AS protocol, reason for discontinuation as well as subsequent treatment options were reported. Within a median follow-up of 36months, 16 (46%) patients discontinued AS at the end of the study period (mean follow-up 55±66, median 36months). Patients who discontinued AS were more symptomatic at diagnosis but had similar age, mean tumour size and sex ratio. Active treatment-free survival was 66% at 5years. Retroperitoneal hemorrhage was reported in 3 (8.5%) patients. None of these bleedings required transfusion or monitoring in an intensive care unit. Other reasons for discontinuation were pain (37%), patient preference (19), changes in the radiological appearance of the tumour (19%), and hematuria (6%). This study showed that AS in AML bearing patients was feasible even in the setting of tumours larger than 4cm. More than 50% of the patients were still on AS at 5 years. Discontinuation of AS was not related to bleeding complications in most cases. 3.

Natural growth pattern of sporadic renal angiomyolipoma.

Surveillance of sporadic renal angiomyolipomas is a growing issue for physicians and radiologists. Current treatment recommendations favor active surveillance. However, the evidence underlying these is based on small case series, which also typically include angiomyolipomas associated with tuberous sclerosis. To evaluate the natural growth pattern of sporadic renal angiomyolipomas in patients without tuberous sclerosis. A retrospective review was performed in three separate tertiary referral centers. A keyword search of each institutions PACS history was performed. Inclusion criteria were angiomyolipomas > 1 cm in size, three years of follow-up, and lesions requiring treatment before reaching three years of follow-up. Exclusion criteria included a diagnosis of tuberous sclerosis, pregnancy, prior treatment with embolization without any prior imaging, and lesions which were treated on presentation. Growth of the angiomyolipomas was evaluated on the basis of maximum dimension on initial and follow-up images. Sixty-three patients were identified in total, with 64 lesions eligible for inclusion. The majority of patients were women (55/63). The mean age at which the angiomyolipomas discovered was 56.4 years. Mean total growth was 0.085 mm and mean follow-up was 65.5 months. At initial measurement, the mean maximum dimension of the lesions in our cohort was 2.08 cm. After follow-up, this was 2.16 cm. The average rate of growth was 0.015 cm per year. Sporadic angiomyolipomas exhibit minimal, if any, natural growth. Current surveillance strategies could be relaxed.

SUN-446 RENAL ANGIOMYOLYPOMAS IN SPORADIC LYMPHANGIOLEIOMYOMATOSIS

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease that mostly afflicts young women. The average age at presentation is typically between the mid-thirties and mid-forties but can extend to eighties. Sporadic LAM is used for patients with LAM not associated with tuberous sclerosis complex (TSC). A 46 year old female initial presentation with shortness of breath at age of 43. Part of her evaluation for dyspnea included CT Chest which showed multiple thin-walled cysts and some reticular changes, which were compatible with Lymphangioleiomyomatosis and chronic interstitial lung disease, pulmonary function test revealed an obstructive pattern. CT and MRI abdomen done for surveillance showed multiple hepatic hemangiomas with bilateral renal masses represents angiomyolipoma. She had no other pulmonary complications. Patient denied personal of family history of seizure disorders, no skin lesions apart from the chronic idiopathic urticaria. There is no family history of Tuberos sclerosis. Her renal function was normal through out her follow up period. started initially on tamoxifen but she was shifted to sirolimus due to side effects. Follow up imaging showed stable renal masses. Clinical presentation: Pulmonary manifestations include fatigue, progressive dyspnea, spontaneous pneumothorax, pleural effusion which is most likely due to chylothorax and occurs in 10-30 % of patients in LAM. Exertional dyspnea is the most common presenting symptom and 1/3 of women with LAM have reversible airflow obstruction, which is confused with other obstructive lung diseases. Non pulmonary manifestations include Renal angiomyolipomas (AMLs) which are benign masses that contain blood vessels, muscle tissue, and fat. They occur in approximately 30% of patients with sporadic LAM & usually asymptomatic unless lesions are >4 cm it may present with abdominal pain due to hemorrhage specially if the mass contains aneurysm. Tuberous sclerosis is suspected if lesions are large, bilateral and multiple or if there is renal impairment. usually it is incidentally discovered on CT abdomen but Ct chest should be considered in case of large, bilateral lesions are present,11 % of patients with sporadic AMLs have cystic changes in the lung consistent with LAM. Renal AMLs are typically diagnosed by the presence of fat within a renal tumor on non contrast-enhanced CT. Fat-free or fat-poor AMLs can also occur, and must be distinguished from renal cell carcinomas, oncocytomas, or other more aggressive neoplasms, which can rarely complicate TSC and sporadic LAM.MRI can be more sensitive for detecting fat density. Vascular endothelial growth factor-D, VEGF-D levels are measured in the serum of patients with suspected LAM, in whom typical thin-walled cysts are found on chest CT and it is diagnostic for LAM if the level is greater than or equal to 800 pg/mL. The primary histopathologic abnormality is the proliferation of atypical smooth muscle like cells (LAM cells). Sirolimus, mTOR inhibitor, is a supportive but not curative medication. Lung function goes back to pretreatment function upon discontinuation of the medication,. Most renal angiomyolipomas do not require specific treatment unless big or hemorrhagic. Big tumors can be treated with embolization, radiofrequency ablation or partial nephrectomy if not responding to mTOR therapy.

Renal angiomyolipoma-patient characteristics and treatment with focus on active surveillance

Objectives: To present a patient material of renal angiomyolipoma (AML) with focus on the risk of bleeding during active surveillance (AS).Methods: Medical records, 1999–2014, were studied and 98 patients (80 female, 18 men) with renal AML were identified. Eleven patients had tuberous sclerosis complex (TSC). Mean age was 54 (13–89) years.Results: Sixty patients (61%) were asymptomatic at presentation, 33 (34%) presented with flank pain and five (5%) with hematuria. Retroperitoneal bleeding or hematuria was diagnosed in 20 patients with a mean AML size of 74 mm (25–200 mm). Twenty-one patients were treated with angioembolization at time of diagnosis and 25 had surgery. Forty-five patients with sporadic AML (mean size 34 mm) and six with TSC (mean size 120 mm) were selected for AS. Only one patient with sporadic AML (46 mm) had a bleeding, whereas two of the six TSC patients had bleedings from three kidneys (AML 70–300 mm). In 25 patients (49%), the AML-size increased with 2.7 mm/year in sporadic and 5.4 mm/year in TSC-associated AML. Thirteen patients were treated with AE (including all six TSC-patients) and five with surgery in 22 kidneys due to AML-size in 16, bleeding in four and suspicion of cancer in two.Conclusion: Bleeding occurred in 20% of AML at presentation. In patients selected for AS, we found a very low risk of bleeding in sporadic AML justifying our cut off size of 50 mm to trigger intervention. In TSC-associated AML individually tailored follow-up is needed due to a higher intervention rate.

How many surgically-treated angiomyolipomas are related to tuberous sclerosis complex? Insights from a retrospective multicenter study.

Patients with TSC - related renal angiomyolipoma (AML) are eligible for targeted therapy with mTOR inhibitors, avoiding the morbidity of interventional management. Despite clinical criteria for TSC diagnosis have been defined, their use in routine clinical practice is likely suboptimal, leading to potential misclassification of TSC-related AML. The study aims to assess the proportion and characteristics of surgically-treated patients with putative sporadic AML that would have been re-classified as TSC-related. We retrospectively reviewed a prospectively collected multi-institutional database to select patients with suspected TSC-related AML among those undergoing surgery at three referral Centers over 11-years (2005-2015). Possible diagnosis of TSC was defined according to the 2012 International Tuberous Sclerosis Complex Consensus (ITSCC) criteria. The proportion and characteristics of patients with possible TSC-related AML (as compared to those of patients with sporadic AML) were considered the main study endpoints. Overall, 132 patients were included. Of these, 10 (7.6%) were considered TSC-related. Most patients (84%) were female. Patients with TSC-related AML were likely to be younger (median age 53 vs. 56 years, P=0.29), symptomatic at diagnosis (70% vs. 21%, P=0.002), with slightly worse preoperative physical status (median ASA score 2 vs. 1, P=0.001) and bilateral disease (30% vs. 7.4%, P=0.04) as compared to patients with sporadic AML. Anatomic complexity and tumor size were also higher among TSC-related AMLs. A non-negligible proportion of surgically-treated, putative sporadic AMLs were reclassified as potentially hereditary (TSC-related). As TSC patients may be treated with targeted therapies, our findings may increase urologists' awareness of TSC-related AML and prompt the design of future studies evaluating targeted diagnostic pathways for these patients.

Renal function, complications, and outcomes of a reduction in tumor size after transarterial embolization for renal angiomyolipomas: a meta-analysis.

ObjectiveThe present study aimed to evaluate renal function, complications, and changes in tumor size after transarterial embolization for patients with renal angiomyolipomas.MethodsWe performed a meta-analysis of transarterial embolization in patients with renal angiomyolipomas from January 1994 to April 2018. Endpoints of interest were the estimated glomerular filtration rate, serum creatinine levels, blood urea nitrogen levels, complications, and reduction of tumors.ResultsA total of 30 studies comprising 653 patients were included. A total of 32.0% of patients were treated by urgent transarterial embolization for spontaneous ruptured renal angiomyolipomas. Other patients sought to relieve symptoms or received embolism prophylactically. The estimated glomerular filtration rate showed no significant difference between before and after embolization. In 363 patients with data on complications, post-embolization syndrome occurred most frequently (54.0%). Only 16 (4.4%) patients had major complications. The diameter of sporadic angiomyolipomas was reduced by a mean of 2.09 cm (95% confidence interval [CI], 0.73–3.45 cm; I2 = 29.3%) and they were reduced in size by 30.0% (95% CI, 16.0%–44.0%; I2 = 27.9%).ConclusionsTransarterial embolization of renal angiomyolipomas affects renal function preservation, with a low complication rate. Transarterial embolization is useful for sporadic and tuberous sclerosis complex-related angiomyolipomas.

Sporadic angiomyolipomas (AMLs) growth kinetics while on everolimus (SAGE).

560 Background: Level I evidence exists demonstrating the efficacy of the mTOR inhibitor everolimus (EVE) in decreasing tumor volume of syndromic angiomyolipomas (AMLs) among patients with Tuberous Sclerosis. No prospective data are available regarding the effect of mTOR inhibition on growth kinetics in patients with sporadic AMLs. Methods: We conducted a multi-institutional, prospective, phase 2 trial with an optimal two-stage Simon design in patients presenting with &gt; 3cm sporadic AMLs who were candidates for surgical or percutaneous intervention. Response was defined as ≥25% volumetric reduction of the AML. Planned enrollment was 43 patients to test the null hypothesis at a 5% level of significance with 80% power. Baseline, 4- and 6-month volumetric analysis was performed by dynamic contrast-enhanced MRI (DCE-MRI). Patients received EVE 10mg for four 28-day cycles, at which point EVE was discontinued in those with &lt; 25% volumetric reduction. Those with ≥ 25% volumetric reduction received two additional cycles of EVE. Dose reductions and interruptions were allowed to 5 mg QOD. Conservative stopping rules were established for toxicity, given the benign nature of AMLs. Results: The early stopping rules for both efficacy and toxicity were invoked. We enrolled 20 patients (median age = 68) from 5 centers with 21 sporadic AMLs. 11/20 (55%) patients completed 4 cycles of EVE, while 7/20 (35%) completed 6 cycles. Median days on treatment was 88 (2 cycles). 4/20 (20%) patients were withdrawn due to toxicity, while 8/20 (40%) withdrew due to personal preference. Dose reductions were required in 6/20 (30%) patients, and 5/20 (25%) patients had grade 3 toxicities which resolved upon discontinuation or dose reduction of EVE. At 4-month MRI, 10/16 (62.5%) patients had a ≥25% reduction in volume (mean = 54.1% decrease). At 6-month MRI, 8/12 (66.6%) patients had a ≥25% reduction in volume (mean = 51.5% decrease). Conclusions: EVE was effective in reducing tumor volume in patients with sporadic AMLs but was associated with a high rate of treatment termination due to patient preference or prespecified AEs. Neoadjuvant EVE may be useful in potentiating surgical resection of large or anatomically complex AMLs. Clinical trial information: NCT02539459.

Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis

Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway. Our recent work provided a new molecular link between these two syndromes by identifying FLCN and Tsc2 as clients of the molecular chaperone Hsp90. Folliculin interacting proteins FNIP1/2 and Tsc1 are important for FLCN and Tsc2 stability as new Hsp90 co-chaperones. Here we present a case of sporadic AML as a result of somatic Tsc1/2 loss in a patient with BHD. We further demonstrate that FNIP1 and Tsc1 are capable of compensating for each other in the chaperoning of mutated FLCN tumor suppressor. Our findings demonstrate interconnectivity and compensatory mechanisms between the BHD and TSC pathways.