Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2.

BACKGROUND: A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. METHODS: The long-term effects of EVE on renal function (∼4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5 mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10 mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3 months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88 mL/min/1.73 m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. CONCLUSIONS: The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients.ClinicalTrials.gov identifiers NCT00789828 and NCT00790400.

Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are recommended as first-line treatment of renal angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sporadic LAM), but follow-up is limited. Longer term efficacy and tolerability data from a Phase 3, double-blind, placebo-controlled trial are presented. METHODS: Following favorable results from the primary analysis (data cutoff 30 June 2011) of the EXIST-2 trial, patients still receiving study treatment were allowed to enter an open-label extension. Everolimus was initiated at 10 mg once daily and titrated based on tolerability. The primary outcome was angiomyolipoma response rate (≥ 50% reduction from baseline in target lesion volumes). Safety was a secondary endpoint. RESULTS: As of the cutoff date (1 May 2013), 112 patients had received everolimus, and the response rate in 107 patients with angiomyolipoma (median duration of medication exposure of 28.9 months) was 54%. The proportion of patients achieving angiomyolipoma reductions of ≥ 30% and ≥ 50% increased over time, reaching 81.6% (62/76) and 64.5% (49/76), respectively, by Week 96. No everolimus-treated patients experienced renal bleeding. The long-term safety profile was consistent with previous reports; adverse events (AEs) were mostly Grade 1/2, and there were no new safety issues. The frequency of emerging AEs and severe AEs lessened over time. CONCLUSIONS: Longer term everolimus treatment appeared safe and effective in patients with TSC- or sporadic LAM-associated renal angiomyolipoma not requiring surgical intervention. Continued reduction in angiomyolipoma volume was demonstrated, and there was no angiomyolipoma-related bleeding; AEs were predictable and generally manageable. TRIAL REGISTRATION: clinicaltrialsgov identifier: NCT00790400 (http://clinicaltrials.gov/ct2/show/NCT00790400).

Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis.

AIMS: The purpose was to determine the exposure-response relationship of everolimus in patients with angiomyolipoma from the EXIST-2 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients. METHODS: One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2 : 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus. CONCLUSIONS: These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 118 patients (median age 31·0 years; IQR 18·0­61·0) 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 31­53%]) for everolimus and 0% (0 of 39 [0­9%]) for placebo (response rate difference 42% [24­58%]; 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]). INTERPRETATION: Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. FUNDING: Novartis Pharmaceuticals.

(99m)Tc-MAA overestimates the absorbed dose to the lungs in radioembolization: a quantitative evaluation in patients treated with ¹66Ho-microspheres.

PURPOSE: Radiation pneumonitis is a rare but serious complication of radioembolic therapy of liver tumours. Estimation of the mean absorbed dose to the lungs based on pretreatment diagnostic (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) imaging should prevent this, with administered activities adjusted accordingly. The accuracy of (99m)Tc-MAA-based lung absorbed dose estimates was evaluated and compared to absorbed dose estimates based on pretreatment diagnostic (166)Ho-microsphere imaging and to the actual lung absorbed doses after (166)Ho radioembolization. METHODS: This prospective clinical study included 14 patients with chemorefractory, unresectable liver metastases treated with (166)Ho radioembolization. (99m)Tc-MAA-based and (166)Ho-microsphere-based estimation of lung absorbed doses was performed on pretreatment diagnostic planar scintigraphic and SPECT/CT images. The clinical analysis was preceded by an anthropomorphic torso phantom study with simulated lung shunt fractions of 0 to 30 % to determine the accuracy of the image-based lung absorbed dose estimates after (166)Ho radioembolization. RESULTS: In the phantom study, (166)Ho SPECT/CT-based lung absorbed dose estimates were more accurate (absolute error range 0.1 to -4.4 Gy) than (166)Ho planar scintigraphy-based lung absorbed dose estimates (absolute error range 9.5 to 12.1 Gy). Clinically, the actual median lung absorbed dose was 0.02 Gy (range 0.0 to 0.7 Gy) based on posttreatment (166)Ho-microsphere SPECT/CT imaging. Lung absorbed doses estimated on the basis of pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging (median 0.02 Gy, range 0.0 to 0.4 Gy) were significantly better predictors of the actual lung absorbed doses than doses estimated on the basis of (166)Ho-microsphere planar scintigraphy (median 10.4 Gy, range 4.0 to 17.3 Gy; p < 0.001), (99m)Tc-MAA SPECT/CT imaging (median 2.5 Gy, range 1.2 to 12.3 Gy; p < 0.001), and (99m)Tc-MAA planar scintigraphy (median 5.5 Gy, range 2.3 to 18.2 Gy; p < 0.001). CONCLUSION: In clinical practice, lung absorbed doses are significantly overestimated by pretreatment diagnostic (99m)Tc-MAA imaging. Pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging accurately predicts lung absorbed doses after (166)Ho radioembolization.

Radiation emission from patients treated with holmium-166 radioembolization.

PURPOSE: To assess the radiation exposure to individuals coming from patients after treatment with holmium-166 ((166)Ho) microspheres. MATERIALS AND METHODS: Holmium-166 radioembolization (RE) with escalating whole-liver doses of 20 Gy, 40 Gy, 60 Gy, and 80 Gy was administered to 15 patients. Exposure rates (µSv/h) from patients were measured at 1.0 m distance from a lateral and frontal position at 0, 3, 6, 24, and 48 hours after infusion. The total effective dose equivalent (TEDE) to a maximally exposed contact was calculated in accordance with guidelines of the U.S. Nuclear Regulatory Commission (NRC). Results were extrapolated to a whole-liver dose of 60 Gy used in future treatments. RESULTS: The median exposure rate at discharge, 48 hours after infusion, measured from a lateral position was 26 µSv/h (range, 7-45 µSv/h). Extrapolated to a whole-liver dose of 60 Gy, none of the exposure rates for the NRC contact scenario, at any time, frontal or lateral, would lead to a TEDE > 5 mSv; all patients may be released directly after treatment. Release after 6 hours is possible without contact restrictions for patients who received up to 7 GBq. CONCLUSIONS: The TEDE to a contact of patients treated with (166)Ho RE would not exceed the NRC limit of 5 mSv. Contact restrictions 6 hours after treatment are unnecessary for infused activities < 7 GBq.

MRI-based biodistribution assessment of holmium-166 poly(L-lactic acid) microspheres after radioembolisation.

OBJECTIVES: To demonstrate the feasibility of MRI-based assessment of the intrahepatic Ho-PLLA-MS biodistribution after radioembolisation in order to estimate the absorbed radiation dose. METHODS: Fifteen patients were treated with holmium-166 ((166)Ho) poly(L-lactic acid)-loaded microspheres (Ho-PLLA-MS, mean 484 mg; range 408-593 mg) in a phase I study. Multi-echo gradient-echo MR images were acquired from which R (2) maps were constructed. The amount of Ho-PLLA-MS in the liver was determined by using the relaxivity r (2) of the Ho-PLLA-MS and compared with the administered amount. Quantitative single photon emission computed tomography (SPECT) was used for comparison with MRI regarding the whole liver absorbed radiation dose. RESULTS: R (2) maps visualised the deposition of Ho-PLLA-MS with great detail. The mean total amount of Ho-PLLA-MS detected in the liver based on MRI was 431 mg (range 236-666 mg) or 89 ± 19 % of the delivered amount (correlation coefficient r = 0.7; P < 0.01). A good correlation was found between the whole liver mean absorbed radiation dose as assessed by MRI and SPECT (correlation coefficient r = 0.927; P < 0.001). CONCLUSION: MRI-based dosimetry for holmium-166 radioembolisation is feasible. Biodistribution is visualised with great detail and quantitative measurements are possible.

Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study.

BACKGROUND: The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases. METHODS: Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784. FINDINGS: 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity. INTERPRETATION: (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy.

Compliance with periodic surveillance for Von-Hippel-Lindau disease.

PURPOSE: To assess compliance with a periodic surveillance regimen for Von Hippel-Lindau disease. METHODS: In this nationwide study, Von Hippel-Lindau disease mutation carriers and those at 50% risk were invited to complete a questionnaire assessing (compliance with) advice given for periodic surveillance. Medical record data on compliance with recommended radiologic surveillance examinations were also collected. RESULTS: Of the 84 (77%) participants, 78 indicated having received advice to undergo periodic surveillance. Of these, 71 reported being fully compliant with that advice. In 64% of the cases, this advice was only partially consistent with published guidelines. Based on medical record data, between one quarter and one third of individuals did not undergo surveillance as recommended in the guidelines for central nervous system lesions and one half for visceral lesions. Screening delay for central nervous system lesions was significantly higher in one hospital and in those cases where "the advice given" deviated from the guidelines. CONCLUSIONS: The majority of those with or at risk of Von Hippel-Lindau disease reported having received and being fully compliant with screening advice. However, in many cases, the advice given was only partially consistent with published guidelines, and screening delays were observed. Efforts should be undertaken to stimulate guideline-based surveillance advice and to minimize screening delay.

A new concept for non-invasive renal tumour ablation using real-time MRI-guided radiation therapy.

OBJECTIVE To present a new concept for non-invasive renal tumour ablation using real-time magnetic resonance imaging (MRI)-guided radiation therapy. All currently available treatment techniques for localized renal cell carcinoma (RCC) have to be performed in a laparoscopic or percutaneous way. MATERIALS AND METHODS A technical prototype MRI-accelerator which performs real-time 1.5 T MRI imaging during the irradiation has been constructed. We performed a technical feasibility study on real-time MRI-guided arc therapy using repeated breath-holds for renal tumour ablation by (i) investigating renal mobility during breath-holding, (ii) performing dose calculation and (iii) measuring the radiation delivery time on a phantom. The renal mobility during free breathing and end-expiration breath-holding during 15 s was investigated for three patients with renal tumour appearance. Conventional MRI screening data of four patients was used for arc therapy dose calculation. Tumour and normal tissues were delineated and a tumour margin of 3 mm was applied. The radiation delivery time of a 25-Gy arc therapy plan was measured on a phantom. RESULTS Renal mobility during free breathing varied from 10 to 25 mm, whereas breath-holding resulted in nearly non-moving kidneys (0 to 2 mm) for all patients. Arc therapy dose calculation resulted in an adequate tumour coverage. The radiation delivery time of the arc therapy plan was about 10 min. This means that 20 to 40 repeated breath-holds of 15 to 30 s will be needed for a single session treatment. A higher maximum dose rate would reduce the number of breath-holds needed and improve patient comfort. A phase I study will be started to proof the clinical feasibility. CONCLUSION Real-time MRI-guided radiation therapy using an MRI-accelerator might become a valuable non-invasive alternative to the current RCC treatment options.

Trans-arterial (90)yttrium radioembolization for patients with unresectable tumors originating from the biliary tree.

Patients with malignant tumors originating from the biliary tree have a poor prognosis, since only a minority of tumors can be resected and most palliative regimens have shown only limited success. We present two patients with unresectable tumors, who were treated with trans-arterial (90)yttrium radioembolization: a patient with an infiltrating gallbladder carcinoma and a patient with an extensive intrahepatic cholangiocarcinoma. In both cases the treatment was technically feasible, effective in controlling tumor growth, and without significant side effects. In conclusion, the presented cases demonstrate the potential of (90)yttrium radioembolization as a palliative treatment option for malignant tumors of the biliary tree.

Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial.

OBJECTIVES: To report the final analysis of a Phase II trial, which investigated the safety and efficacy of the specific endothelin A receptor antagonist zibotentan (AstraZeneca, Macclesfield, UK) in patients with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain were randomized to receive once-daily oral tablets of zibotentan 10 mg, 15 mg or placebo. The primary endpoint was the time to progression and secondary endpoints included overall survival, change in the number of bone metastases, and safety. RESULTS: In total, 312 patients were randomized (placebo, n= 107; zibotentan 10 mg, n= 107; zibotentan 15 mg, n= 98). The median duration of study treatment and median follow-up time were 4 and 22 months, respectively. At the final analysis, there were no statistical differences of the primary outcome of time to progression between treatment groups, although an improvement in overall survival was observed in the zibotentan groups compared to placebo. Consistent with the previous analyses for overall survival, hazard ratios (HRs) of less than one were sustained for both zibotentan 15 mg (HR, 0.76; 80% CI, 0.61-0.94; P= 0.103) and 10 mg (HR, 0.83; 80% CI, 0.67-1.02; P= 0.254). The most commonly reported adverse events considered to be related to zibotentan treatment were peripheral oedema, headache and nasal congestion. CONCLUSIONS: The results obtained in the present study support endothelin A receptor antagonism as an approach for treating patients with CRPC. To confirm the survival signal observed in the present study, zibotentan is being investigated further in the ENdoTHelin A USE (ENTHUSE) Phase III clinical trial programme.

Fatty foci in the myocardium in patients with tuberous sclerosis complex: common finding at CT.

PURPOSE: To examine the morphologic characteristics of focal fatty foci in the myocardium of patients with tuberous sclerosis complex (TSC) at computed tomography (CT). MATERIALS AND METHODS: Institutional review board approval was obtained, and patient informed consent was waived. Fifty-five patients with TSC (mean age, 37 years; range, 16-67 years; 22 male patients) who had CT results available that included at least the basal portions of the heart were included. Fifty-five age- and sex-matched control subjects without TSC were selected from a CT database. Images were reviewed for the presence of areas of fat attenuation in the depicted portions of the myocardium. Descriptive statistics and the McNemar test for case-control comparisons were used. RESULTS: CT results demonstrated foci of fat attenuation within the myocardium in 35 (64%) of 55 patients with TSC. Foci were well circumscribed and focal and located in the interventricular septum, left ventricle wall, right ventricle wall, and papillary muscles. Size varied between 3 x 1 mm and 62 x 31 mm. Multiple lesions were seen in 19 patients. In the control group, only one (2%) lesion with fat attenuation was found (P < .001). Its linear shape and subendocardial location in the left ventricular wall differed from the morphology of fatty foci seen in patients with TSC. CONCLUSION: Despite incomplete depiction of the heart with CT, the majority of patients with TSC demonstrated well-circumscribed foci of fat attenuation in the myocardium that were not present in age- and sex-matched control subjects. This suggests that such fatty foci may be another characteristic of TSC.

(188)Re-HEDP combined with capecitabine in hormone-refractory prostate cancer patients with bone metastases: a phase I safety and toxicity study.

PURPOSE: (188)Re-HEDP is indicated for the treatment of pain in patients with painful osteoblastic bone metastases, including hormone-refractory prostate cancer patients. Efficacy may be improved by adding chemotherapy to the treatment regimen as a radiation sensitizer. The combination of (188)Re-HEDP and capecitabine (Xeloda(R)) was tested in a clinical phase I study. METHODS: Patients with hormone-refractory prostate cancer were treated with capecitabine for 14 days (oral twice daily in a dose escalation regimen with steps of 1/3 of 2,500 mg/m(2) per day in cohorts of three to six patients, depending on toxicity). Two days later patients were treated with 37 MBq/kg (188)Re-HEDP as an intravenous injection. Six hours after treatment post-therapy scintigraphy was performed. Urine was collected for 8 h post-injection. Follow-up was at least 8 weeks. The primary end-point was to establish the maximum tolerable dose (MTD) of capecitabine when combined with (188)Re-HEDP. Secondary end-points included the effect of capecitabine on the biodistribution and pharmacokinetics of (188)Re-HEDP. RESULTS: Three patients were treated in the first and second cohorts, each without unacceptable toxicity. One of six patients in the highest cohort experienced unacceptable toxicity (grade 4 thrombopaenia). The MTD proved to be the maximum dose of 2,500 mg/m(2) per day capecitabine. No unexpected toxicity occurred. Capecitabine had no effect on uptake or excretion of (188)Re-HEDP. CONCLUSION: Capecitabine may be safely used in combination with (188)Re-HEDP in a dose of 2,500 mg/m(2) per day and 37 MBq/kg, respectively. Efficacy will be further studied in a phase II study using these dosages.

Blood and urine analyses after radioembolization of liver malignancies with [166Ho]Ho-acetylacetonate-poly(l-lactic acid) microspheres.

BACKGROUND: [166Ho]Ho-acetylacetonate-poly(L-lactic acid) microspheres were used in radioembolization of liver malignancies by intra-arterial administration. The primary aim of this study was to assess the stability and biodistribution of these microspheres. MATERIALS AND METHODS: Peripheral blood and urine samples were obtained from two clinical studies. Patient and in vitro experiment samples were analyzed using inductively coupled plasma mass spectrometry (ICP-MS), gamma-ray spectroscopy, light microscopy, Coulter particle counting, and high performance liquid chromatography (HPLC). RESULTS: The median percentage holmium compared to the total amount injected into the hepatic artery was 0.19% (range 0.08-2.8%) and 0.32% (range 0.03-1.8%) in the 1 h blood plasma and 24 h urine, respectively. Both the blood plasma and urine were correlated with the neutron irradiation exposure required for [166Ho]Ho-AcAc-PLLA microsphere production (ρ = 0.616, p = 0.002). After a temporary interruption of the phase 2 clinical study, the resuspension medium was replaced to precipitate [166Ho]Ho3+ pre-administration using phosphate. The in vitro near-maximum neutron irradiation experiments showed significant [166Ho]Ho-AcAc-PLLA microsphere damage. CONCLUSION: The amount of holmium in the peripheral blood and urine samples after [166Ho]Ho-AcAc-PLLA microsphere intrahepatic infusion was low. A further decrease was observed after reformulation of the resuspension solution but minimization of production damage is necessary.

Epilepsy, impaired functioning, and quality of life in patients with tuberous sclerosis complex.

OBJECTIVE: To estimate health-related quality of life (HRQoL) in patients with tuberous sclerosis complex (TSC) and associated manifestations and to identify potential factors associated with HRQoL in this population of patients. METHODS: We performed a retrospective chart review of adults with TSC who attended the outpatient clinic of the University Medical Center Utrecht in the Netherlands from 1990 to 2015 (N = 363; on average 33.6 years of follow-up). HRQoL data were assessed in 2012 using the Health Utility Index version 3 (HUI-3) questionnaire completed by patients or caregivers (N = 214 with HUI score and ≥1 TSC manifestation, including renal angiomyolipomas [rAMLs], subependymal giant cell astrocytoma [SEGA], or epilepsy). RESULTS: Of 214 patients in the study sample, 171 had TSC-associated epilepsy (with or without rAML/SEGA), 37 had TSC and rAML (without epilepsy or SEGA), and 6 had other combinations of manifestations. The median HUI score for the 214 patients with ≥1 TSC manifestation was 0.51 (-0.371 to 1 scale, 1 = perfect health, 0 = death, <0 = worse than death). Among all components used to build the overall HUI score, the cognition component had the lowest score (mean = 0.47; 0-1 scale). Patients with TSC-epilepsy had significantly lower overall HUI than patients with TSC and rAML only (median HUI = 0.31 vs 0.95, P < .05), especially those who were in refractory state for prolonged periods of time (median HUI = -0.11 among patients with seizures during the entire duration of their follow-up time). In multivariate analyses, severe impairment of daily functioning was the strongest predictor of HRQoL decrement (adjusted HUI difference between patients with severe vs. no impairment = -0.55, P < .05). SIGNIFICANCE: This study showed that TSC-related epilepsy is associated with lower HUI, especially for patients who have refractory seizures for prolonged periods of time. Early and effective interventions to control or reduce seizures and preserve patients' cognitive functions may help to improve patients' quality of life.

Observational study of characteristics and clinical outcomes of Dutch patients with tuberous sclerosis complex and renal angiomyolipoma treated with everolimus.

OBJECTIVE: To compare kidney size (used as proxy for total renal angiomyolipoma [rAML] size) and kidney function outcomes between patients with tuberous sclerosis complex (TSC) and rAML treated and not treated with everolimus. METHODS: Medical charts of adults with TSC-associated rAML followed at a specialty medical center in the Netherlands (1990-2015). Included patients treated with everolimus (n = 33, of which 27 were included in the kidney size analyses and 27 in the kidney function analyses [21 patients in both]; index date = everolimus initiation) and non-treated patients (n = 39, of which 29 were included in the kidney size analyses and 33 in the kidney function analyses [23 patients in both]; index date = one date among all dates with outcome measurement).Percent change in kidney size and kidney function from the index date to the best measurement in the two years post-index date (best response) compared between patients treated and not treated with everolimus. RESULTS: Compared with non-treated patients, significantly more everolimus-treated patients experienced a reduction in the size of their largest kidney in the two years post-index date (85.2% vs. 37.9%, p < 0.01). Also, there was a tendency towards more improvement in the estimated glomerular filtration rate (eGFR) among the everolimus-treated patients (55.6% vs. 33.3%, p = 0.08). CONCLUSIONS: The study results suggest that everolimus is effective in controlling and even reversing the growth of the kidneys, used as a proxy for rAML size, as well as preserving or improving kidney function in patients with TSC and rAML treated in a real-world, observational setting.

Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.

INTRODUCTION: The EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase. METHODS: For patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015). RESULTS: Of the 112 patients who received ≥1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm3) from baseline was -70.56 (-88.30; -49.64) at time of everolimus discontinuation (n = 11), and -50.55 (-79.40; -23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage. CONCLUSIONS: Angiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth. TRIAL REGISTRATION: ClinicalTrials.gov NCT00790400.

Factors associated with the number and size of renal angiomyolipomas in sporadic angiomyolipoma (sAML): a study of adult patients with sAML managed in a Dutch tertiary referral center.

PURPOSE: To describe the patient characteristics, treatments, disease monitoring, and kidney function of patients with sporadic angiomyolipoma (sAML), stratified by the number and size of renal angiomyolipomas (AMLs). METHODS: Single-center retrospective analysis of patients with sAML treated from 1990 to 2015 in a dedicated clinic for inheritable tumor syndromes in a tertiary referral center from the Netherlands. Patients' first AML assessment at the clinic was defined as the index date. Patient characteristics were measured at the index date. Treatments, disease monitoring, and kidney function were measured post-index date. RESULTS: The study sample included 53 patients followed for a total of 184.6 patient-years. At the index date, the largest AML was ≥ 3.5 cm for 26 patients and < 3.5 cm for 27 patients (including six patients with five or more AMLs of < 3.5 cm). As compared to patients with AMLs < 3.5 cm, patients with largest AML ≥ 3.5 cm had higher frequency of pre-index bleeding episodes (31 vs. 4%), pre-index hypertension (35 vs. 15%), post-index nephrectomy (19 vs. 4%), post-index embolization (8 vs. 0%), and post-index renal scans (1.14 vs. 0.74 scans/year). Kidney impairment was especially pronounced in young adults with AML ≥ 3.5 cm. On average, patients with sAML developed chronic kidney disease stage two earlier than the general Dutch population (age 42 vs. 55 years), but later than the patients with tuberous sclerosis complex (35 years). CONCLUSIONS: Patients with sAML, especially those with larger AMLs, have high disease burden.