Intrafraction Motion Management of Renal Cell Carcinoma With Magnetic Resonance Imaging-Guided Stereotactic Body Radiation Therapy.

PURPOSE: One of the major challenges in stereotactic body radiation therapy (SBRT) of renal cell carcinoma is internal motion during treatment. Previous literature has aimed to mitigate the effects of motion by expanding the treatment margins or respiratory tracking. Online magnetic resonance imaging (MRI)-guided radiation therapy has the potential to further improve the treatment of renal cell carcinoma by direct visualization of the tumor during treatment. The efficacy of 2 motion management techniques were assessed: tumor trailing and respiratory tracking. The simulation of a single-fraction, MRI-based SBRT was performed to quantify intrafraction motion and assess the efficacy of the different motion management strategies. METHODS AND MATERIALS: Fifteen patients were included in the study. At the beginning and end of the scanning protocol, 2 cine-MRI scans were acquired to assess cyclic respiratory motion. In addition, 3-dimensional spoiled gradient echo scans were acquired at 4 different time points to assess the slow drifts over 25 minutes. The systematic and random errors owing to intrafraction drift were calculated, as well as the random error induced by respiratory motion. The motion margins were calculated for tumor trailing and respiratory tracking and compared with the margin when no motion compensation would be performed to assess the relative efficacy of each technique. RESULTS: The largest respiratory tumor motion was observed along the caudo-cranial direction with a median 95% maximum amplitude of approximately 12 mm. ΣDRIFT, σDRIFT, and σRESP were determined to be 1.0 mm 1.8 mm, and 3.8 mm, respectively. Without mechanical immobilization, intrafraction drift accounted for 75% of the total intrafraction motion margin for online midposition-based SBRT treatments. CONCLUSIONS: The contribution of intrafraction drift to the total internal motion margin is much larger than periodic respiratory motion. This makes tumor trailing a viable option to consider on the MRI linac because it allows for 3-dimensional MRI acquisitions during beam delivery, which simplifies the introduction of new techniques, such as dose accumulation and online intrafraction replanning.

Renal Cell Carcinoma: Alternative Nephron-Sparing Treatment Options for Small Renal Masses, a Systematic Review.

BACKGROUND: The standard treatment of T1 renal cell carcinoma (RCC) is (partial) nephrectomy. For patients where surgery is not the treatment of choice, for example in the elderly, in case of severe comorbidity, inoperability, or refusal of surgery, alternative treatment options are available. These treatment options include active surveillance (AS), radiofrequency ablation (RFA), cryoablation (CA), microwave ablation (MWA), or stereotactic body radiotherapy (SBRT). In the present overview, the efficacy, safety, and outcome of these different options are summarized, particularly focusing on recent developments. MATERIALS AND METHODS: Databases of MEDLINE (through PubMed), EMBASE, and the Cochrane Library were systematically searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The search was performed in December 2016, and included a search period from 2010 to 2016. The terms and synonyms used were renal cell carcinoma, active surveillance, radiofrequency ablation, microwave ablation, cryoablation and stereotactic body radiotherapy. RESULTS: The database search identified 2806 records, in total 73 articles were included to assess the rationale and clinical evidence of alternative treatment modalities for small renal masses. The methodological quality of the included articles varied between level 2b and level 4. CONCLUSION: Alternative treatment modalities, such as AS, RFA, CA, MWA, and SBRT, are treatment options especially for those patients who are unfit to undergo an invasive treatment. There are no randomized controlled trials available comparing surgery and less invasive modalities, leading to a low quality on the reported articles. A case-controlled registry might be an alternative to compare outcomes of noninvasive treatment modalities in the future.

Dosimetric feasibility of MRI-guided external beam radiotherapy of the kidney.

At our institution a treatment for kidney tumours with an MRI-Linac is under development. In order to set inclusion criteria for this treatment the anatomical eligibility criteria and the influence of the motion compensation strategy on the delivered dose should be known. Twenty patients with a renal lesion underwent an MR-scan to image the kidney. Static treatment plans were made and the doses to the organs at risk were evaluated. Furthermore, to calculate the influence of remnant motion in a gated treatment, a convolution of the static dose plan with the residual motion in a gating window was done. For ten patients (50%) a static plan within the dose constraints could be obtained. For all patients where the kidney constraint was obeyed in the static plan, the dose to the gross tumour volume (GTV) and the ipsilateral kidney remained within limits for residual motion in a gating window up to and including 12 mm. For four patients (20%) no static plan without violation of the constraint to the ipsilateral kidney could be made. One of these patients had a tumour of 73 mm in the upper pole and the other patients had a tumour of at least 30 mm in the mid pole. In 6 patients (30%), where the bowels were within the planning target volume, the maximum dose to the bowels was above the limit used. Patient specific assessment might degrade this violation. For tumours smaller than 30 mm a clinically acceptable plan could be created. For other patients the feasibility depends on the geometry of the GTV and kidney. Neither the GTV coverage nor the ipsilateral kidney dose is compromised by breathing motion for gating with a gating window up to and including 12 mm.

Kidney motion during free breathing and breath hold for MR-guided radiotherapy.

Current treatments for renal cell carcinoma have a high complication rate due to the invasiveness of the treatment. With the MRI-linac it may be possible to treat renal tumours non-invasively with high-precision radiotherapy. This is expected to reduce complications. To deliver a static dose distribution, radiation gating will be used. In this study the reproducibility and efficiency of free breathing gating and a breath hold treatment of the kidney was investigated. For 15 patients with a renal lesion the kidney motion during 2 min of free breathing and 10 consecutive expiration breath holds was studied with 2D cine MRI. The variability in kidney expiration position and treatment efficiency for gating windows of 1 to 20 mm was measured for both breathing patterns. Additionally the time trend in free breathing and the variation in expiration breath hold kidney position with baseline shift correction was determined. In 80% of the patients the variation in expiration position during free breathing is smaller than 2 mm. No clinically relevant time trends were detected. The variation in expiration breath hold is for all patients larger than the free breathing expiration variation. Gating on free breathing is, for gating windows of 1 to 5 mm more efficient than breath hold without baseline correction. When applying a baseline correction to the breath hold it increases the treatment efficiency. The kidney position is more reproducible in expiration free breathing than non-guided expiration breath hold. For small gating windows it is also more time efficient. Since free breathing also seems more comfortable for the patients it is the preferred breathing pattern for MRI-Linac treatments of the kidney.

Navigators for motion detection during real-time MRI-guided radiotherapy.

An MRI-linac system provides direct MRI feedback and with that the possibility of adapting radiation treatments to the actual tumour position. This paper addresses the use of fast 1D MRI, pencil-beam navigators, for this feedback. The accuracy of using navigators was determined on a moving phantom. The possibility of organ tracking and breath-hold monitoring based on navigator guidance was shown for the kidney. Navigators are accurate within 0.5 mm and the analysis has a minimal time lag smaller than 30 ms as shown for the phantom measurements. The correlation of 2D kidney images and navigators shows the possibility of complete organ tracking. Furthermore the breath-hold monitoring of the kidney is accurate within 1.5 mm, allowing gated radiotherapy based on navigator feedback. Navigators are a fast and precise method for monitoring and real-time tracking of anatomical landmarks. As such, they provide direct MRI feedback on anatomical changes for more precise radiation delivery.

The effect of bladder outlet obstruction on alpha1- and beta-adrenoceptor expression and function.

AIMS: To explore possible changes in expression and/or function of alpha(1)- and beta-adrenoceptor subtypes as a cause for bladder dysfunction in a rat model of bladder outlet obstruction (BOO). METHODS: BOO was induced in rats by partial urethral ligature. Contraction and relaxation experiments were performed with isolated bladder strips from BOO, sham-operated and non-operated (control) rats 7 days after BOO induction. mRNA expression of alpha(1)- and beta-adrenoceptor subtypes was assessed by quantitative real-time PCR. RESULTS: Receptor-independent contraction or relaxation did not differ between BOO and sham rats. The alpha(1)-agonists methoxamine and A-61,603 caused only weak contraction without major differences between groups. Against KCl-induced tone, the beta-adrenoceptor agonists noradrenaline and isoprenaline caused similar relaxation in BOO and sham rats, whereas relaxation in response to the beta(3)-selective BRL 37,344 was attenuated. Against passive tension, noradrenaline induced relaxation in sham and control rats; in contrast, noradrenaline induced contraction at low concentrations and relaxation at high concentrations in BOO rats. The contraction component was abolished by the alpha(1)-antagonist prazosin. The mRNA expression of alpha(1D)-adrenoceptors was increased in BOO, whereas none of the other receptor mRNAs were up-regulated. CONCLUSIONS: In a rat BOO model, weak contraction responses to alpha(1)-agonists and relaxation responses to beta-agonists are not altered to a major extent. Nevertheless, relaxation responses to the endogenous agonist noradrenaline are turned into alpha(1)-adrenoceptor-mediated contraction responses in BOO, possibly due to an up-regulation of alpha(1D)-adrenoceptors.

Physiological and pathological regulation of the autonomic control of urinary bladder contractility.

The urinary bladder stores urine for most of the day, a process facilitated by beta-adrenergic receptor-mediated detrusor relaxation and alpha(1)-adrenergic receptor-mediated contraction of the bladder neck. Physiological voiding is caused by detrusor contraction induced by muscarinic receptor stimulation. This manuscript reviews data on alterations of alpha(1)- and beta-adrenergic and of muscarinic responsiveness of the detrusor related to gender, developmental maturation, ageing and pathophysiological conditions such as diabetes, arterial hypertension and bladder outlet obstruction, all of which can be associated with alterations of bladder function such as bladder overactivity. The existing data show that none of the conditions associated with bladder overactivity exhibit increased muscarinic receptor responsiveness which could explain the clinical observations; while not being fully consistent, they if anything show a reduced responsiveness. On the other hand, more limited data demonstrate that alpha(1)-adrenergic responsiveness may be enhanced and beta-adrenergic responsiveness reduced in states associated with bladder overactivity. However, the existing data are too sparse and/or too inconsistent to allow definitive conclusions. Thus, alterations distinct from those of autonomic receptors may be better candidates to explain bladder dysfunction.

Do alpha1-adrenoceptor antagonists improve lower urinary tract symptoms by reducing bladder outlet resistance?

AIMS: To test the hypothesis that improvements of lower urinary tract symptoms (IPSS) upon treatment with an alpha-blocker are due to reduction of bladder outlet obstruction (assessed as the bladder outlet obstruction index, BOOI); relationships of either with free flow Q(max) were also explored. METHODS: The database of a large placebo-controlled, randomized, double-blind study with the alpha-blocker tamsulosin was analyzed retrospectively. Patients were stratified into lower and upper halves according to baseline IPSS, Q(max) or BOOI and treatment-associated alterations thereof. In these strata differences between values for the other two parameters were analyzed, for example, improvement of IPSS and Q(max) were compared in patients with below and above median improvement of BOOI. RESULTS: Patients with below and above median baseline for one parameter, for example, IPSS had rather similar values for the other two parameters, for example, Q(max) and BOOI. Likewise, patients based upon baseline strata for one parameter had rather similar improvements of the other two parameters. Most importantly, patients with below and above median treatment-associated improvements of one parameter, for example, BOOI exhibited only small if any difference for alterations of the other two parameters, for example, IPPS and Q(max). CONCLUSIONS: We conclude that IPSS, free flow Q(max) and BOOI are only loosely related at baseline. More importantly, treatment-induced improvements of these parameters are also only loosely related. These data do question the hypothesis that alpha-blockers largely improve lower urinary tract symptoms by reducing bladder outlet obstruction and suggest that they may also act independent of prostatic smooth muscle tone.

Role of transforming growth factor beta in rat bladder smooth muscle cell proliferation.

Conditions associated with hypertrophy of the urinary bladder have repeatedly been associated with an increased urinary excretion of transforming growth factor (TGF) beta in both rats and patients. Because TGFbeta can have both growth-promoting and -inhibiting effects, we have studied its effects on cell growth and death in primary cultures of rat bladder smooth muscle cells. TGFbeta1, TGFbeta2, or TGFbeta3 did not cause apoptosis, but all three isoforms inhibited DNA synthesis with similar potency (EC(50) of approximately 0.1 ng/ml) and efficacy. Such inhibition was antagonized by a specific TGFbeta receptor antagonist and independent of the presence of serum. Mitogen-activated protein kinases (MAPKs) are involved in the control of cell growth, and all three TGFbeta isoforms inhibited activation of the extracellular signal-regulated kinase, c-Jun NH(2)-terminal kinase, and p38 MAPK subfamilies. Nevertheless, the inhibitory effects of the TGFbeta isoforms on DNA synthesis were not affected by presence of inhibitors of the three MAPK pathways. TGFbeta did not alter cell size as measured by flow cytometry or mitochondrial activity, an integrated measure of cell size and number. We conclude that our data do not support the hypothesis that TGFbeta is a mediator of rat bladder hypertrophy.

Is the use of parasympathomimetics for treating an underactive urinary bladder evidence-based?

An underactive urinary bladder (UUB), often occurring after surgery, can lead to urinary retention even in otherwise healthy people. We systematically reviewed published reports to determine whether the use of parasympathomimetic agents is warranted in patients with a UUB. Agents allegedly useful in treating UUB were identified from urology and pharmacology textbooks. A systematic search for randomized clinical trials in patients with UUB using these agents revealed 10 such studies. Controls typically received placebo or no treatment. While three studies reported statistically significant improvements relative to the control group, six did not and one even reported a significant worsening of symptoms. There was no evidence for differences between individual drugs, specific uses of such drugs, or in outcome measures. We conclude that the available studies do not support the use of parasympathomimetics for treating UUB, specifically when frequent and/or serious possible side-effects are taken into account.

Susceptibility to cyclosporin A-induced autoimmunity: strain differences in relation to autoregulatory T cells.

Cyclosporin A-induced autoimmunity (CsA-AI), also called autoimmune syngeneic graft-vs-host disease, is a thymus dependent, T cell mediated rodent animal model of disease and is considered to be an experimental model for human scleroderma. Since adoptive transfer of CsA-AI by effector T cells can be prevented by autoregulatory T cells, there may also be a role for dominant tolerance in the resistance of certain rat strains to develop clinical manifest CsA-AI. LEW rats have been reported to be susceptible, whereas BN rats are resistant to CsA-AI. In the present study we first demonstrate that PVG, but not DA rats, are susceptible to CsA-AI and that disease characteristics in PVG rats are comparable to LEW rats in terms of pathogenesis and T cell kinetics, although of more rapid onset and greater severity. Next, we examined whether the relative presence of autoregulatory T-helper cells, i.e. CD25+ and/or CD45RClow CD4 T cells, is increased in resistant BN and DA rats. The results obtained reveal that the genetically determined CD45RChigh/CD45RClow ratio, but not the percentage CD25+ cells, within the CD4 T cell compartment of naïve rats is correlated with resistance to CsA-AI in these rat strains. We conclude that the relative presence of autoregulatory T cells with a CD45RClow T-helper cell phenotype may be a critical determinant in susceptibility to CsA-AI.