Overcoming inter-observer planning variability in target volume contouring and dose planning for high-risk neuroblastoma - a European multicenter effort of the SIOPEN radiotherapy committee.

BACKGROUND AND PURPOSE: To establish an international quality standard for contouring and planning for high-risk neuroblastoma within the prospective High-Risk Neuroblastoma Study 2 of SIOP-Europe-Neuroblastoma (SIOPEN HR-NBL2), which includes a randomized question on dose escalation for residual disease. MATERIALS AND METHODS: Data on four patients with high-risk neuroblastoma were selected and distributed to the radiotherapy committee of the HR-NBL2 study for independent contouring and planning. Differences in contouring were analyzed using apparent and kappa-corrected agreement. Plans were analyzed regarding the dose-volume histogram metrics. Results were discussed among experts and agreement was obtained. RESULTS: Substantial agreement was found for contouring of the heart (0.64), liver (0.70), left lung (0.74), and right lung (0.74). For contouring of the gastrointestinal tract (0.54), left kidney (0.60), and right kidney (0.59) moderate agreement was obtained. For target volume delineation, agreement for preoperative tumour extent was moderate (0.42), for CTV fair (0.35) and only low (0.06) for residual tumour, respectively. The dose planning strategies appeared to be relatively homogeneous among all experts. CONCLUSION: Considerable variability was found for the delineation of target volumes, particularly the boost volume, whereas the contouring of the organs at risk and the planning strategy were reasonably consistent. In order to obtain reliable results from the randomized HR-NBL2 trial, standardization of target volume delineation based on adequate imaging is crucial.

Is an Endorectal Balloon Beneficial for Rectal Sparing after Spacer Implantation in Prostate Cancer Patients Treated with Hypofractionated Intensity-Modulated Proton Beam Therapy? A Dosimetric and Radiobiological Comparison Study.

BACKGROUND: The aim of this study is to examine the dosimetric influence of endorectal balloons (ERB) on rectal sparing in prostate cancer patients with implanted hydrogel rectum spacers treated with dose-escalated or hypofractionated intensity-modulated proton beam therapy (IMPT). METHODS: Ten patients with localized prostate cancer included in the ProRegPros study and treated at our center were investigated. All patients underwent placement of hydrogel rectum spacers before planning. Two planning CTs (with and without 120 cm3 fluid-filled ERB) were applied for each patient. Dose prescription was set according to the h strategy, with 72 Gray (Gy)/2.4 Gy/5× weekly to prostate + 1 cm of the seminal vesicle, and 60 Gy/2 Gy/5× weekly to prostate + 2 cm of the seminal vesicle. Planning with two laterally opposed IMPT beams was performed in both CTs. Rectal dosimetry values including dose-volume statistics and normal tissue complication probability (NTCP) were compared for both plans (non-ERB plans vs. ERB plans). RESULTS: For ERB plans compared with non-ERB, the reductions were 8.51 ± 5.25 Gy (RBE) (p = 0.000) and 15.76 ± 11.11 Gy (p = 0.001) for the mean and the median rectal doses, respectively. No significant reductions in rectal volumes were found after high dose levels. The use of ERB resulted in significant reduction in rectal volume after receiving 50 Gy (RBE), 40 Gy (RBE), 30 Gy (RBE), 20 Gy (RBE), and 10 Gy (RBE) with p values of 0.034, 0.008, 0.003, 0.001, and 0.001, respectively. No differences between ERB and non-ERB plans for the anterior rectum were observed. ERB reduced posterior rectal volumes in patients who received 30 Gy (RBE), 20 Gy (RBE), or 10 Gy (RBE), with p values of 0.019, 0.003, and 0.001, respectively. According to the NTCP models, no significant reductions were observed in mean or median rectal toxicity (late rectal bleeding ≥ 2, necrosis or stenosis, and late rectal toxicity ≥ 3) when using the ERB. CONCLUSION: ERB reduced rectal volumes exposed to intermediate or low dose levels. However, no significant reduction in rectal volume was observed in patients receiving high or intermediate doses. There was no benefit and also no disadvantage associated with the use of ERB for late rectal toxicity, according to available NTCP models.

Dopamine D2 receptor overexpression alters behavior and physiology in Drd2-EGFP mice.

Bacteria artificial chromosome (BAC) transgenic mice expressing the reporter protein enhanced green fluorescent protein (EGFP) under the control of the D1 and D2 dopamine receptor promoters (Drd1-EGFP and Drd2-EGFP) have been widely used to study striatal function and have contributed to our understanding of the physiological and pathological functions of the basal ganglia. These tools were produced and promptly made available to address questions in a cell-specific manner that has transformed the way we frame hypotheses in neuroscience. However, these mice have not been fully characterized until now. We found that Drd2-EGFP mice display an ∼40% increase in membrane expression of the dopamine D2 receptor (D2R) and a twofold increase in D2R mRNA levels in the striatum when compared with wild-type and Drd1-EGFP mice. D2R overexpression was accompanied by behavioral hypersensitivity to D2R-like agonists, as well as enhanced electrophysiological responses to D2R activation in midbrain dopaminergic neurons. Dopamine (DA) transients evoked by stimulation in the nucleus accumbens showed slower clearance in Drd2-EGFP mice, and cocaine actions on DA clearance were impaired in these mice. Thus, it was not surprising to find that Drd2-EGFP mice were hyperactive when exposed to a novel environment and locomotion was suppressed by acute cocaine administration. All together, this study demonstrates that Drd2-EGFP mice overexpress D2R and have altered dopaminergic signaling that fundamentally differentiates them from wild-type and Drd1-EGFP mice.

Localized delivery of chemotherapy to the cervix for radiosensitization.

OBJECTIVE: Chemoradiation is the mainstay of therapy for advanced cervical cancer, with the most effective treatment regimens involving combinations of radiosensitizing agents. However, administration of radiosensitizing chemotherapeutics concurrently with pelvic radiation is not without side effects. The aim of this study was to examine the utility of localized drug delivery as a means of improving drug targeting of radiosensitizing chemotherapeutics to the cervix while limiting systemic toxicities. METHODS: An initial proof-of-concept study was performed in 14 healthy women following local administration of diazepam utilizing a novel cervical delivery device (CerviPrep™). Uterine vein and peripheral blood samples were collected and diazepam was measured using a GC-MS method. In the follow-up study, gemcitabine was applied to the cervix in 17 women undergoing hysterectomy for various gynecological malignancies. Cervical tissue, uterine vein blood samples, and peripheral plasma were collected, and gemcitabine and its deaminated metabolite 2',2'-difluorodeoxyuridine (dFdU) were measured using HPLC-UV and LC/MS methods. RESULTS: Targeted delivery of diazepam to the cervix was consistent with parent drug detectable in the uterine vein of 13 of 14 women. In the second study, pharmacologically relevant concentrations of gemcitabine (0.01-6.6 nmol/g tissue) were detected in the cervical tissue of 11 of 16 available specimens with dFdU measureable in 15 samples (0.04-8.8 nmol/g tissue). Neither gemcitabine nor its metabolites were detected in the peripheral plasma of any subject. CONCLUSIONS: Localized drug delivery to the cervix is possible and may be useful in limiting toxicity associated with intravenous administration of chemotherapeutics for radiosensitization.

A Mobile Health Application to Enhance Self-Management Skills of Patients with Shoulder Impingement Syndrome During Rehabilitation.

Especially in chronic diseases, such as shoulder impingement syndrome (SIS), good self-management is important for patients to take personal responsibility for their treatment and make informed decisions in rehabilitation processes. Mobile apps integrating game design elements have great potential to increase patients self-management skills. A total of 21 functionalities for a self-management app were derived from semi-structured interviews with six patients and three therapists. Thereby, welcome messages, a personalized home-screen, and training plans are rated as particular useful. Ten of these functionalities could be implemented in a first prototype of SISco: your shoulder impingement syndrome companion. SISco provides possibilities for creating and executing training programs, learning about SIS, checking daily challenges, and making diary entries. Thereby, SISco motivates patients via progress bars, collecting XP, unlocking content and Dr. SISco the virtual therapist. Future work includes the implementation of further functionalities and the evaluation of SISco for usability and user acceptance.

An action potential initiation mechanism in distal axons for the control of dopamine release.

Information flow in neurons proceeds by integrating inputs in dendrites, generating action potentials near the soma, and releasing neurotransmitters from nerve terminals in the axon. We found that in the striatum, acetylcholine-releasing neurons induce action potential firing in distal dopamine axons. Spontaneous activity of cholinergic neurons produced dopamine release that extended beyond acetylcholine-signaling domains, and traveling action potentials were readily recorded from dopamine axons in response to cholinergic activation. In freely moving mice, dopamine and acetylcholine covaried with movement direction. Local inhibition of nicotinic acetylcholine receptors impaired dopamine dynamics and affected movement. Our findings uncover an endogenous mechanism for action potential initiation independent of somatodendritic integration and establish that this mechanism segregates the control of dopamine signaling between axons and somata.

Evaluation of dose, volume, and outcome in children with localized, intracranial ependymoma treated with proton therapy within the prospective KiProReg Study.

BACKGROUND: Radiotherapy (RT) of ependymoma in children is an important part of the interdisciplinary treatment concept. However, feasibility and dose concepts are still under investigation, particularly in very young children. The aim of this study was to evaluate the standard dose and volume of proton therapy (PT) in children with ependymoma. METHODS: In this analysis, 105 patients with localized, intracranial ependymoma under the age of 18 years treated with PT between 2013 and 2018 were included. Patient characteristics, treatment, outcome, and follow-up data were analyzed using descriptive statistics, Kaplan-Meier, and Cox regression analysis. RESULTS: The median age of patients at PT was 2.8 years (0.9-17.0 years). The molecular subgroup analysis was performed in a subset of 50 patients (37 EP-PFA, 2 EP-PFB, 7 EP-RELA, 2 EP-YAP, 2 NEC [not elsewhere classified]). The median total dose was 59.4 Gy (54.0-62.0 Gy). The median follow-up time was 1.9 years. The estimated 3-year overall survival (OS), local control (LC), and progression-free survival (PFS) rates were 93.7%, 74.1%, and 55.6%, respectively. Within univariable analysis, female gender and lower dose had a positive impact on OS, whereas age ≥4 years had a negative impact on OS and PT given after progression had a negative impact on PFS. In the multivariable analysis, multiple tumor surgeries were associated with lower PFS. New ≥3° late toxicities occurred in 11 patients. CONCLUSION: For children with localized ependymoma, PT was effective and well tolerable. Multiple surgeries showed a negative impact on PFS.

Dosimetric feasibility of moderately hypofractionated/dose escalated radiation therapy for localised prostate cancer with intensity-modulated proton beam therapy using simultaneous integrated boost (SIB-IMPT) and impact of hydrogel prostate-rectum spacer.

PURPOSE: To examine the dosimetric feasibility of hypofractionated/dose escalated radiation therapy in patients with localized prostate carcinoma using simultaneous integrated boost intensity-modulated proton beam therapy (SIB-IMPT) in absence or presence of prostate-rectum spacer. METHODS: IMPT technique was implemented in 23 patients with intermediate- and high-risk prostate cancer treated at West German Proton Therapy Centre from March 2016 till June 2018, using SIB technique prescribing 60 GyRBE and 72 GyRBE in 30 fractions to PTV1 (prostate and seminal vesicle) and PTV2 boost (prostate and proximal seminal vesicle), respectively. In 15 patients, a transperineal injection of hydrogel was applied prior to radiotherapy to increase the distance between prostate and rectum. Planning and all treatments were performed with a 120 ml fluid-filled endorectal balloon customised daily for each patient. For each patient, 2 lateral IMPT beams were implemented taking a field-specific range uncertainty (RU) into account. Dose volume histograms (DVH) were analyzed for PTV2, PTV2 with range uncertainty margin (PTV2RU), rectum, bladder, right/left femoral heads, and penile bulb. For late rectal toxicities, the normal tissue complication probabilities (NTCP) were calculated using different biological models. A DVH- and NTCP-based dosimetric comparison was carried out between non-spacer and spacer groups. RESULTS: For the 23 patients, high-quality plans could be achieved for target volume and for other organs at risk (OARs). For PTV2, the V107% was 0% and the Dmax did not exceed 106.2% of the prescribed dose. The volume PTV2RU covered by 95% of the dose ranged from 96.16 to 99.95%. The conformality index for PTV2RU was 1.12 ± 0.057 and the homogeneity index (HI) was 1.04 ± 0.014. Rectum Dmax and rectal volume receiving 73-50 Gy could be further reduced for the spacer-group. Significant reductions in mean and median rectal NTCPs (stenosis/necrosis, late rectal bleeding ≥ 2, and late rectal toxicities ≥ 3) were predicted for the spacer group in comparison to the non-spacer group. CONCLUSION: Hypofractionated/dose escalated radiotherapy with SIB-IMPT is dosimetrically feasible. Further reduction of the rectal volumes receiving high and medium dose levels (73-50 Gy) and rectal NTCP could be achieved through injection of spacers between rectum and prostate.

Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers.

Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear. We examined axo-axonal transmission from CINs onto dopaminergic axons using perforated-patch recordings, which revealed rapid spontaneous EPSPs with properties characteristic of fast synapses. Pharmacology showed that axonal EPSPs (axEPSPs) were mediated primarily by high-affinity α6-containing receptors. Remarkably, axEPSPs triggered spontaneous action potentials, suggesting that these axons perform integration to convert synaptic input into spiking, a function associated with somatodendritic compartments. We investigated the cross-species validity of cholinergic axo-axonal transmission by recording dopaminergic axons in macaque putamen and found similar axEPSPs. Thus, we reveal that synaptic-like neurotransmission underlies cholinergic signaling onto dopaminergic axons, supporting the idea that striatal dopamine release can occur independently of somatic firing to provide distinct signaling.

Clinical Implementation of Proton Therapy Using Pencil-Beam Scanning Delivery Combined With Static Apertures.

Proton therapy makes use of the favorable depth-dose distribution with its characteristic Bragg peak to spare normal tissue distal of the target volume. A steep dose gradient would be desired in lateral dimensions, too. The widespread spot scanning delivery technique is based, however, on pencil-beams with in-air spot full-widths-at-half-maximum of typically 1 cm or more. This hampers the sparing of organs-at-risk if small-scale structures adjacent to the target volume are concerned. The trimming of spot scanning fields with collimating apertures constitutes a simple measure to increase the transversal dose gradient. The current study describes the clinical implementation of brass apertures in conjunction with the pencil-beam scanning delivery mode at a horizontal, clinical treatment head based on commercial hardware and software components. Furthermore, clinical cases, which comprised craniopharyngiomas, re-irradiations and ocular tumors, were evaluated. The dosimetric benefits of 31 treatment plans using apertures were compared to the corresponding plans without aperture. Furthermore, an overview of the radiation protection aspects is given. Regarding the results, robust optimization considering range and setup uncertainties was combined with apertures. The treatment plan optimizations followed a single-field uniform dose or a restricted multi-field optimization approach. Robustness evaluation was expanded to account for possible deviations of the center of the pencil-beam delivery and the mechanical center of the aperture holder. Supplementary apertures improved the conformity index on average by 15.3%. The volume of the dose gradient surrounding the PTV (evaluated between 80 and 20% dose levels) was decreased on average by 17.6%. The mean dose of the hippocampi could be reduced on average by 2.9 GyRBE. In particular cases the apertures facilitated a sparing of an organ-at-risk, e.g. the eye lens or the brainstem. For six craniopharyngioma cases the inclusion of apertures led to a reduction of the mean dose of 1.5 GyRBE (13%) for the brain and 3.1 GyRBE (16%) for the hippocampi.

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release.

Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic axons and directly inhibited release, but also likely acts by reducing excitation from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insights into the actions of benzodiazepines within the striatum.

iCoapsys mitral valve repair system: Percutaneous implantation in an animal model.

OBJECTIVE: Determine if the iCoapsys device could be accurately and safely implanted using a novel transcatheter system. BACKGROUND: Functional mitral regurgitation is a ventricular disease characterized by mitral insufficiency in the absence of structural valve abnormalities. It occurs in the presence of ischemic or non-ischemic cardiomyopathy. The Coapsys (surgical) transventricular device, currently undergoing randomized evaluation, offers a more integrated treatment strategy. METHODS: The iCoapsys transcatheter mitral valve repair system was developed for percutaneous delivery of an implant designed to emulate the surgical (i.e. Coapsys) device. Nine operators tested the ability of this novel catheter system to successfully deliver and position the iCoapsys implant in 12 adult sheep. RESULTS: Post mortem evaluation in this acute model demonstrated precise percutaneous delivery and implantation in all 12 animals using fluoroscopic, coronary angiographic, and epicardial echo guidance. There was no excessive bleeding, hemodynamic compromise or sustained arrhythmias. CONCLUSIONS: A novel transcatheter methodology was developed to consistently deliver and accurately position the iCoapsys implant. The percutaneous iCoapsys system was successfully implanted without complication in this acute animal model series.

Self-test device for cytology and HPV testing in rural Appalachian women: an evaluation.

OBJECTIVE: To determine the efficacy of a self-test device for obtaining vaginal/cervical samples for HPV DNA and cytologic testing. STUDY DESIGN: We recruited 878 Appalachian women; 775 were able to submit a self-test sample and a provider-collected sample. Each specimen was assessed for cytologic abnormalities and for high-risk HPV infection. RESULTS: Specimen adequacy: 869 of 878 (99%) women had sufficient material for cytologic analysis in provider-collected samples compared to 771 of 775 (99%) self-collected specimens (p = NS). There was sufficient cellular material (DNA) for HPV testing in 724 of 834 (87%) provider-collected samples compared to 690 of 736 (94%) self-collected specimens (p <0.04). In the provider-collected samples, 654 of 869 (75%) women had endocervical cells compared to 103 of 771 (13%) self-collected specimens (p <0.001). HPV assessment: 142 (19%) had high-risk HPV DNA detected. Of those women, 28 (20%) had HPV infection detected on the provider-collected specimen only, 51 (36%) on the self-collected specimen only, and 63 (44%) had HPV DNA on both specimens. CONCLUSION: Our device is sufficient to obtain an adequate number of epithelial cells for cytologic and HPV testing.

Chronic uterine inversion at 14 weeks postpartum.

BACKGROUND: Uterine inversion is a rare complication of vaginal delivery. When chronic inversion is encountered it is often associated with benign or malignant tumors of the uterus. Management of chronic uterine inversion may require several standard techniques before reversion is accomplished. CASE: A woman presented with chronic vaginal bleeding 14 weeks after vaginal delivery complicated by a fourth-degree laceration. Chronic uterine inversion was diagnosed. This diagnosis was unique due to the length of time from delivery to diagnosis and therapeutic modalities implemented. CONCLUSION: Uterine inversion can occur in the acute (less than 24 hours) or chronic (greater than 1 month) phases. The clinician's clue to chronic uterine inversion, as in this case, may be persistent vaginal bleeding.

Two-color, one-photon uncaging of glutamate and GABA.

Neuronal cells receive a variety of excitatory and inhibitory signals which they process to generate an output signal. In order to study the interaction between excitatory and inhibitory receptors with exogenously applied transmitters in the same preparation, two caging chromophores attached to glutamate and GABA were developed that were selectively photolyzed by different wavelengths of light. This technique has the advantage that the biologically inactive caged compound can be applied at equilibrium prior to the near instantaneous release of the transmitters. This method therefore mimics the kinetics of endogenously released transmitters that is otherwise not possible in brain slice preparations. Repeated photolysis with either of the two wavelengths resulted in GABA- or glutamate-induced activation of both ionotropic and metabotropic receptors to evoke reproducible currents. With these compounds, the interaction between inhibitory and excitatory receptors was examined using whole field photolysis.

Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation: results from the international multi-center feasibility trials.

OBJECTIVES: These studies were conducted to evaluate the feasibility of percutaneous left atrial appendage (LAA) occlusion using the PLAATO system (ev3 Inc., Plymouth, Minnesota). BACKGROUND: Patients with atrial fibrillation (AF) have a five-fold increased risk for stroke. Other studies have shown that more than 90% of atrial thrombi in patients with non-rheumatic AF originate in the LAA. Transvenous closure of the LAA is a new approach in preventing embolism in these patients. METHODS: Within two prospective, multi-center trials, LAA occlusion was attempted in 111 patients (age 71 +/- 9 years). All patients had a contraindication for anticoagulation therapy and at least one additional risk factor for stroke. The primary end point was incidence of major adverse events (MAEs), a composite of stroke, cardiac or neurological death, myocardial infarction, and requirement for procedure-related cardiovascular surgery within the first month. RESULTS: Implantation was successful in 108 of 111 patients (97.3%, 95% confidence interval [CI] 92.3% to 99.4%) who underwent 113 procedures. One patient (0.9%, 95% CI 0.02% to 4.9%) experienced two MAEs within the first 30 days: need for cardiovascular surgery and in-hospital neurological death. Three other patients underwent in-hospital pericardiocentesis due to a hemopericardium. Average follow-up was 9.8 months. Two patients experienced stroke. No migration or mobile thrombus was noted on transesophageal echocardiogram at one and six months after device implantation. CONCLUSIONS: Closing the LAA using the PLAATO system is feasible and can be performed at acceptable risk. It may become an alternative in patients with AF and a contraindication for lifelong anticoagulation treatment.

Calcium Release from Stores Inhibits GIRK.

Synaptic transmission is mediated by ionotropic and metabotropic receptors that together regulate the rate and pattern of action potential firing. Metabotropic receptors can activate ion channels and modulate other receptors and channels. The present paper examines the interaction between group 1 mGluR-mediated calcium release from stores and GABAB/D2-mediated GIRK currents in rat dopamine neurons of the Substantia Nigra. Transient activation of mGluRs decreased the GIRK current evoked by GABAB and D2 receptors, although less efficaciously for D2. The mGluR-induced inhibition of GIRK current peaked in 1 s and recovered to baseline after 5 s. The inhibition was dependent on release of calcium from stores, was larger for transient than for tonic currents, and was unaffected by inhibitors of PLC, PKC, PLA2, or calmodulin. This inhibition of GABAB IPSCs through release of calcium from stores is a postsynaptic mechanism that may broadly reduce GIRK-dependent inhibition of many central neurons.

Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation: early clinical experience.

BACKGROUND: Thromboembolism due to atrial fibrillation (AF) is a frequent cause of stroke. More than 90% of thrombi in AF form in the left atrial appendage (LAA). Obliteration of the appendage may prevent embolic complications. METHODS AND RESULTS: We evaluated the feasibility and safety of implanting a novel device for percutaneous left atrial appendage transcatheter occlusion (PLAATO). LAA occlusion using the PLAATO system was attempted in 15 patients with chronic AF at high risk for stroke, who are poor candidates for long-term warfarin therapy. The implant consists of a self-expanding nitinol cage covered with a polymeric membrane (ePTFE). The LAA was successfully occluded in 15/15 patients (100%). Angiography and transesophageal echocardiography (TEE) during the procedure showed that the device was well-seated in all patients and that there was no evidence of perforation, device embolization, or interference with surrounding structures. In 1 patient, the first procedure was complicated by a hemopericardium, which occurred during LAA access. A second attempt 30 days later was successful with no untoward sequela. No other complications occurred. At 1-month follow-up, chest fluoroscopy and TEE revealed continued stable implant position with smooth atrial-facing surface and no evidence of thrombus. CONCLUSIONS: Thus, transcatheter closure of the LAA is feasible in humans. This novel implant technology may be appropriate for patients with AF who are not suitable candidates for anticoagulation therapy. Further trials are needed to show the long-term safety and its efficacy in reducing stroke.

Phase I drug and light dose-escalation trial of motexafin lutetium and far red light activation (phototherapy) in subjects with coronary artery disease undergoing percutaneous coronary intervention and stent deployment: procedural and long-term results.

BACKGROUND: Motexafin lutetium (MLu; Antrin) is a photosensitizer that is taken up by atherosclerotic plaque and concentrated within macrophages and vascular smooth muscle cells. After photoactivation with far red light, MLu facilitates production of cytotoxic oxygen radicals that mediate apoptosis. We assessed the safety and tolerability of phototherapy (PT) with MLu in patients undergoing percutaneous coronary intervention with stent deployment. METHODS AND RESULTS: An open-label, phase I, drug and light dose-escalation clinical trial of MLu PT enrolled 80 patients undergoing de novo coronary stent deployment. MLu was administered to 79 patients by intravenous infusion 18 to 24 hours before procedure, and photoactivation was performed after balloon predilatation and before stent deployment. Clinical evaluation, serial quantitative angiography, and intravascular ultrasound were performed periprocedurally and at 6 months follow-up. MLu PT was well tolerated without serious dose-limiting toxicities, and side effects (paresthesia and rash) were minor. No adverse angiographic outcomes were attributed to phototherapy. CONCLUSIONS: This study demonstrates that coronary MLu PT seems safe, and the maximum well-tolerated MLu dose and range of tolerated light doses were identified. These data can be used in phase II efficacy trials of MLu PT for the treatment of coronary atherosclerosis or vulnerable plaque.