238 research outputs found
Multimodality treatment in hormone-refractory prostate cancer patients with bone metastases
We agree with the interesting points made by Koutsikos et
al. They confirm the feasibility of the combined use of
bone-seeking radiopharmaceuticals and bisphosphonates
and highlight the potential benefit of this combined
treatment. We would like to stress the importance to study
multimodality treatment strategies in well-designed clinical
trials. These trials should evaluate the multidimensional
character of pain, as well as survival, and they should
incorporate imaging modalities for response stratification ..
Four-year update of the EXIST-2 study
Objectives We examined the long-term effects of everolimus in patients with
renal angiomyolipoma associated with tuberous sclerosis complex or sporadic
lymphangioleiomyomatosis. Methods Following favorable results from the double-
blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive
open-label everolimus (extension phase). Patients initially randomly assigned
to everolimus continued on the same dose; those who were receiving placebo
crossed over to everolimus 10 mg/day. Dose modifications were based on
tolerability. The primary end point was angiomyolipoma response rate, defined
as a ≥50% reduction from baseline in the sum volume of target renal
angiomyolipomas in the absence of new target angiomyolipomas, kidney volume
increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The
key secondary end point was safety. Results Of the 112 patients who received
≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma
response. Almost all patients (97%) experienced reduction in renal lesion
volumes at some point during the study period. Median duration of everolimus
exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma
progression at some point in the study. No angiomyolipoma-related bleeding or
nephrectomies were reported. One patient on everolimus underwent embolization
for worsening right flank pain. Subependymal giant cell astrocytoma lesion
response was achieved in 48% of patients and skin lesion response in 68% of
patients. The most common adverse events suspected to be treatment-related
were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous
stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew
because of an adverse event. Renal function remained stable, and the frequency
of emergent adverse events generally decreased over time. Conclusions
Everolimus treatment remained safe and effective over approximately 4 years.
The overall risk/benefit assessment supports the use of everolimus as a viable
treatment option for angiomyolipoma associated with tuberous sclerosis complex
or sporadic lymphangioleiomyomatosis. Trial registration ClinicalTrials.gov
NCT0079040
Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases
Purpose: 153Sm-ethylenediaminetetramethylenephosphonic
acid (EDTMP; Quadramet®) is indicated for the treatment of
painful bone metastases, whereas zoledronic acid (Zometa®)
is indicated for the prevention of skeletal complications.
Because of the different therapeutic effects, combining the
treatments may be beneficial. Both, however, accumulate in
areas with increased osteoblastic activity. Possible drug
interactions were investigated.
Methods: Patients with hormone-refractory prostate cancer
were treated with 18.5 MBq/kg 153Sm-EDTMP in weeks 1
and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg
zoledronic acid began in week 3 and continued every
4 weeks through week 23. In weeks 3 and 15, zoledronic
acid was administered 2 days before 153Sm-EDTMP
treatment. Urine was collected 48 h after injection of
153Sm-EDTMP, and whole-body images were obtained 6,
24 and 48 h post-injection. The effect of zoledronic acid on
total bone uptake of 153Sm-EDTMP was measured indirectly
by the cumulative activity excreted in the urine in weeks 1, 3
and 15. Biodistribution, safety, tolerability and effect on
prostate-specific antigen level were also studied.
Results: The urinary excretion in week 3 divided by the
urinary excretion in week 1 (baseline) times 100% was
mean 98.4±11.6% (median 96.2%). From week 1 to 15,
after four zoledronic acid treatments, the mean ratio was
101.9±10.7% (median 101.8%). Bioequivalence could be
concluded by using a two-sample t test for both perprotocol
(n=13) and full-analysis sets (n=18). Toxicity was
comparable to of monotherapy with 153Sm-EDTMP.
Conclusion: Zoledronic acid treatment does not influence
153Sm-EDTMP skeletal uptake. Combined treatment is
feasible and safe
The TOSCA Registry for Tuberous Sclerosis-Lessons Learnt for Future Registry Development in Rare and Complex Diseases.
Introduction: The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to provide insights into the clinical characteristics of patients with Tuberous Sclerosis Complex (TSC). The aims of this study were to identify issues that arose during the design, execution, and publication phases of TOSCA, and to reflect on lessons learnt that may guide future registries in rare and complex diseases. Methods: A questionnaire was designed to identify the strengths, weaknesses, and issues that arose at any stage of development and implementation of the TOSCA registry. The questionnaire contained 225 questions distributed in 7 sections (identification of issues during registry planning, during the operation of the registry, during data analysis, during the publication of the results, other issues, assessment of lessons learnt, and additional comments), and was sent by e-mail to 511 people involved in the registry, including 28 members of the Scientific Advisory Board (SAB), 162 principal investigators (PIs), and 321 employees of the sponsor belonging to the medical department or that were clinical research associate (CRA). Questionnaires received within the 2 months from the initial mailing were included in the analysis. Results: A total of 53 (10.4%) questionnaires were received (64.3% for SAB members, 12.3% for PIs and 4.7% for employees of the sponsor), and the overall completeness rate for closed questions was 87.6%. The most common issues identified were the limited duration of the registry (38%) and issues related to handling of missing data (32%). In addition, 25% of the respondents commented that biases might have compromised the validity of the results. More than 80% of the respondents reported that the registry improved the knowledge on the natural history and manifestations of TSC, increased disease awareness and helped to identify relevant information for clinical research in TSC. Conclusions: This analysis shows the importance of registries as a powerful tool to increase disease awareness, to produce real-world evidence, and to generate questions for future research. However, there is a need to implement strategies to ensure patient retention and long-term sustainability of patient registries, to improve data quality, and to reduce biases
MR Spectroscopy Shows Long Propylene Glycol Half-Life in Neonatal Brain
Introduction: Neonatal propylene glycol (PG) clearance is low with long plasma half-life. We hypothesized that neonatal brain PG clearance is diminished and may be related to perinatal asphyxia, infection, or stroke, via different blood-brain barrier permeability. This study aimed to estimate cerebral PG half-life with a clearance model including PG measured with MR spectroscopy (MRS) in neonates that received phenobarbital as the only PG source and to evaluate whether PG clearance was related to intracerebral pathology, for example, perinatal asphyxia, infection, or stroke. Methods: In this retrospective cohort study, 45 neonates receiving any dose of phenobarbital underwent MRS (short echo time single-voxel MRS at 1.5 T). Cumulative phenobarbital/PG doses were calculated. MRS indications were perinatal asphyxia (n = 22), infection (n = 4), stroke (n = 10), metabolic disease (n = 4), and others (n = 5). Results: Medians (interquartile range) included gestational age 39.4 (3.1) weeks, birth weight 3,146 (1,340) g, and cumulative PG dose 700 (1,120) mg/kg. First-order kinetics with mono-exponential decay showed cerebral PG half-life of 40.7 h and volume of distribution of 1.6 L/kg. Zero-order kinetics showed a rate constant of 0.048 mM/h and a volume of distribution of 2.3 L/kg, but the fit had larger residuals than the first-order model. There were no differences in ΔPG (i.e., PG estimated with clearance model minus PG observed with MRS) in infants with perinatal asphyxia, infection, or stroke. Discussion/Conclusion: This study showed a long cerebral PG half-life of 40.7 h in neonates, unrelated to perinatal asphyxia, infection, or stroke. These findings should increase awareness of possible toxic PG concentrations in neonatal brain due to intravenous PG-containing drugs
Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse
Background: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. Patients and methods: We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITI] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) ≥ 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naïve patients were treated with temozolomide 200 mg/m2/day2/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea- containing adjuvant chemotherapy received 150 mg/m2/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle. Results: The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43%;A and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. Conclusions: Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agent
Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial
<p>Abstract</p> <p>Background</p> <p>Intra-arterial radioembolization with yttrium-90 microspheres ( <sup>90</sup>Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( <sup>166</sup>Ho-PLLA-MS) have been developed as a possible alternative to <sup>90</sup>Y-RE. Next to high-energy beta-radiation, <sup>166</sup>Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of <sup>166</sup>Ho-PLLA-MS radioembolization ( <sup>166</sup>Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of <sup>166</sup>Ho-RE in patients with liver metastases.</p> <p>Methods</p> <p>The HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( <sup>99m</sup>Tc-MAA) dose, a low radioactive safety dose of 60-mg <sup>166</sup>Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of <sup>166</sup>Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the <sup>166</sup>Ho-PLLA-MS safety dose and the <sup>99m</sup>Tc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution.</p> <p>Discussion</p> <p>This will be the first clinical study on <sup>166</sup>Ho-RE. Based on preclinical studies, it is expected that <sup>166</sup>Ho-RE has a safety and toxicity profile comparable to that of <sup>90</sup>Y-RE. The biochemical and radionuclide characteristics of <sup>166</sup>Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT01031784</p
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