Dosimetric evaluation of a novel modular cell irradiation platform for multi-modality in vitro studies including high dose rate brachytherapy.

PURPOSE: High dose-rate (HDR) brachytherapy is integral for the treatment of numerous cancers. Preclinical studies involving HDR brachytherapy are limited. We aimed to describe a novel platform allowing multi-modality studies with clinical HDR brachytherapy and external beam irradiators, establish baseline dosimetry standard of a preclinical orthovoltage irradiator, to determine accurate dosimetric methods. METHODS: A dosimetric assessment of a commercial preclinical irradiator was performed establishing the baseline dosimetry goals for clinical irradiators. A 3D printed platform was then constructed with 14 brachytherapy channels at 1cm spacing to accommodate a standard tissue culture plate at a source-to-cell distance (SCD) of 1 cm or 0.4 cm. 4-Gy CT-based treatment plans were created in clinical treatment planning software and delivered to 96-well tissue culture plates using an Ir192 source or a clinical linear accelerator. Standard calculation models for HDR brachytherapy and external beam were compared to corresponding deterministic model-based dose calculation algorithms (MBDCAs). Agreement between predicted and measured dose was assessed with 2D-gamma passing rates to determine the best planning methodology. RESULTS: Mean (±standard deviation) and median dose measured across the plate for the preclinical irradiator was 423.7 ± 8.5 cGy and 430.0 cGy. Mean percentage differences between standard and MBDCA dose calculations were 9.4% (HDR, 1 cm SCD), 0.43% (HDR, 0.4 cm SCD), and 2.4% (EBRT). Predicted and measured dose agreement was highest for MBDCAs for all modalities. CONCLUSION: A 3D-printed tissue culture platform can be used for multi-modality irradiation studies with great accuracy. This tool will facilitate preclinical studies to reveal biologic differences between clinically relevant radiation modalities.

Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections.

Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead 1, we describe efforts to identify an improved compound with a lower human dose projection, minimal P-glycoprotein (P-gp) efflux, and acceptable pregnane X receptor (PXR) profile through fluorine substitution. Our strategy involved the use of predicted volume ligand efficiency to advance compounds with greater potential for low human doses down our screening funnel. We also applied minimized electrostatic potentials (Vmin) calculations for hydrogen bond acceptor sites to rationalize P-gp SAR. Together, our strategies enabled the alignment of a lower human dose with reduced P-gp efflux, and favorable PXR selectivity for the discovery of compound 12.

Dosimetric evaluation of dose shaping by adaptive aperture and its impact on plan quality.

Mevion's single-room HYPERSCAN proton therapy system employs a proton multileaf collimator called the adaptive aperture (AA), which collimates individual spots in the proton delivery as determined by the Treatment Planning System (TPS). The purpose of this study is to assess the dosimetric benefits of the AA, specifically in the dynamic aperture (DA) mode, and evaluate its impact on proton treatment plan quality as compared to a traditional pencil beam scanning (PBS) system (Varian ProBeam). The spot dose distributions with dynamic collimation (DA), a unique AA shape for each energy layer, and with static collimation (SA), a single AA collimation shape shared by all energy layers per field, were calculated and compared with the spot dose distribution of the Varian ProBeam proton therapy system. The lateral and distal dose falloff gradients and their dependence on air gap were evaluated quantitatively. Treatment plans for ten arbitrarily selected intracranial target image sets were created, and the HYPERSCAN and ProBeam beam models were compared. The spot sizes of the HYPERSCAN system are significantly larger than ProBeam system, especially at low energy. With the help of DA, the lateral dose penumbra of the HYPERSCAN is dramatically improved at lower energy and comparable at higher to ProBeam PBS beams. While the ProBeam spot size does not change with the air gap, beam penumbra of the HYPERSCAN with DA increases with the air gap. The distal dose falloff gradient for the HYPERSCAN with or without DA remains consistently around 4.8 mm through all energies due to the beamline design, not substantially varying with energy or air gap. Treatment plans of ten randomly selected intracranial cases demonstrated favorable OAR sparing but unfavorable dose uniformity for the HYPERSCAN with DA compared to ProBeam. Dose shaping by adaptive aperture substantially improves the lateral penumbra without a significant change in the distal dose gradient. The dose gradients of the multiple beam DA plans with layer-by-layer blocking are improved compared with SA plans and are close to the ProBeam plans for the ten randomly selected brain cases. With layer-by-layer DA blocking, the HYPERSCAN plans have similar plan conformality indices as the ProBeam plans, but the overall plan quality indices are lower than ProBeam plans, largely due to the lower dose homogeneity. In some cases, DA blocking was found to be superior in sparing OAR surrounding the target.

Phenotypic heterogeneity of the mitochondrial DNA A8344G variant presenting with dorsal midbrain syndrome.

Purpose: To describe a neuro-ophthalmic presentation of a phenotypically heterogeneous mitochondrial DNA variant. Observations: A 10-year-old female with gross motor developmental delay, absence seizures and ataxia subacutely developed poor near acuity and asthenopia. She was found to have accommodative insufficiency, impaired supraduction and convergence retraction nystagmus leading to a diagnosis of dorsal midbrain syndrome. Brain MRI showed highly symmetrical lesions involving the dorsal pons. Genetic testing revealed a previously undiagnosed mitochondrial DNA (mtDNA) pathogenic variant, adenine to guanine at nucleopeptide pair 8344 (A8344G). Conclusion and importance: The authors describe a unique, neuro-ophthalmic manifestation of mitochondrial disease in a pediatric patient. This report discusses the phenotypic heterogeneity of the mtDNA A8344G variant, which may include 'stroke-like episodes' involving the brainstem, thus presenting with ophthalmic manifestations.

Temporal coherence envelope function of field emission in electron microscopy.

Imaging in electron microscopy is adversely affected by partial electron spatial and temporal coherence. Temporal coherence has been treated theoretically in the past using the method pioneered fifty years ago by Hanßen and Trepte, who assumed a Gaussian energy distribution. However, state-of-the-art instruments employ field emission (FE) sources that emit electrons with a non-Gaussian energy distribution. We have updated the treatment of temporal coherence to describe the effects of an arbitrary energy distribution on image formation. The updated approach is implemented in Fourier optics simulations to explore the effect of FE on image formation in conventional, non-aberration-corrected (NAC) and aberration-corrected (AC) low energy electron microscopy. It is found that the resolution that can be achieved for the FE distribution is only slightly degraded compared to a Gaussian distribution with the same energy spread. FE also produces a focus offset. These two effects are weaker for AC than for NAC microscopy. These and other insights may be relevant to the selection of the aperture size that optimizes resolution and to analyses that make use of focal image series. The approach developed here is also applicable to transmission electron microscopy.

Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.

Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with in vivo activity in mouse models and ex vivo activity in iPSC neuronal models of synucleinopathy and lysosomal dysfunction. This was accomplished through the judicious use of parallel medicinal chemistry, direct-to-biology screening, physics-based rationalization of transporter profiles, pharmacophore modeling, and use a novel metric: volume ligand efficiency.

Design and synthesis of unprecedented 9- and 10-membered cyclonucleosides with PRMT5 inhibitory activity.

Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5'-cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5.

Single-crystal two-dimensional material epitaxy on tailored non-single-crystal substrates.

The use of single-crystal substrates as templates for the epitaxial growth of single-crystal overlayers has been a primary principle of materials epitaxy for more than 70 years. Here we report our finding that, though counterintuitive, single-crystal 2D materials can be epitaxially grown on twinned crystals. By establishing a geometric principle to describe 2D materials alignment on high-index surfaces, we show that 2D material islands grown on the two sides of a twin boundary can be well aligned. To validate this prediction, wafer-scale Cu foils with abundant twin boundaries were synthesized, and on the surfaces of these polycrystalline Cu foils, we have successfully grown wafer-scale single-crystal graphene and hexagonal boron nitride films. In addition, to greatly increasing the availability of large area high-quality 2D single crystals, our discovery also extends the fundamental understanding of materials epitaxy.

Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer.

Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity. Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy.

A kinase-cGAS cascade to synthesize a therapeutic STING activator.

The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence1-3. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents4,5. Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic6,7 (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.

Discovery of MK-4688: an Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction.

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.

Discovery and characterization of novel peptide inhibitors of the NRF2/MAFG/DNA ternary complex for the treatment of cancer.

Pathway activating mutations of the transcription factor NRF2 and its negative regulator KEAP1 are strongly correlative with poor clinical outcome with pemetrexed/carbo(cis)platin/pembrolizumab (PCP) chemo-immunotherapy in lung cancer. Despite the strong genetic support and therapeutic potential for a NRF2 transcriptional inhibitor, currently there are no known direct inhibitors of the NRF2 protein or its complexes with MAF and/or DNA. Herein we describe the design of a novel and high-confidence homology model to guide a medicinal chemistry effort that resulted in the discovery of a series of peptides that demonstrate high affinity, selective binding to the Antioxidant Response Element (ARE) DNA and thereby displace NRF2-MAFG from its promoter, which is an inhibitory mechanism that to our knowledge has not been previously described. In addition to their activity in electrophoretic mobility shift (EMSA) and TR-FRET-based assays, we show significant dose-dependent ternary complex disruption of NRF2-MAFG binding to DNA by SPR, as well as cellular target engagement by thermal destabilization of HiBiT-tagged NRF2 in the NCI-H1944 NSCLC cell line upon digitonin permeabilization, and SAR studies leading to improved cellular stability. We report the characterization and unique profile of lead peptide 18, which we believe to be a useful in vitro tool to probe NRF2 biology in cancer cell lines and models, while also serving as an excellent starting point for additional in vivo optimization toward inhibition of NRF2-driven transcription to address a significant unmet medical need in non-small cell lung cancer (NSCLC).

Does the sequence of high-dose rate brachytherapy boost and IMRT for prostate cancer impact early toxicity outcomes? Results from a single institution analysis.

BACKGROUND: We present the first report comparing early toxicity outcomes with high-dose rate brachytherapy (HDR-BT) boost upfront versus intensity modulated RT (IMRT) upfront combined with androgen deprivation therapy (ADT) as definitive management for intermediate risk or higher prostate cancer. METHODS AND MATERIALS: We reviewed all non-metastatic prostate cancer patients who received HDR-BT boost from 2014 to 2019. HDR-BT boost was offered to patients with intermediate-risk disease or higher. ADT use and IMRT target volume was based on NCCN risk group. IMRT dose was typically 45 Gy in 25 fractions to the prostate and seminal vesicles ± pelvic lymph nodes. HDR-BT dose was 15 Gy in 1 fraction, delivered approximately 3 weeks before or after IMRT. The sequence was based on physician preference. Biochemical recurrence was defined per ASTRO definition. Gastrointestinal (GI) and Genitourinary (GU) toxicity was graded per CTCAE v5.0. Pearson Chi-squared test and Wilcoxon tests were used to compare toxicity rates. P-value < 0.05 was significant. RESULTS: Fifty-eight received HDR-BT upfront (majority 2014-2016) and 57 IMRT upfront (majority 2017-2018). Median follow-up was 26.0 months. The two cohorts were well-balanced for baseline patient/disease characteristics and treatment factors. There were differences in treatment sequence based on the year in which patients received treatment. Overall, rates of grade 3 or higher GI or GU toxicity were <1%. There was no significant difference in acute or late GI or GU toxicity between the two groups. CONCLUSION: We found no significant difference in GI/GU toxicity in intermediate-risk or higher prostate cancer patients receiving HDR-BT boost upfront versus IMRT upfront combined with ADT. These findings suggest that either approach may be reasonable. Longer follow-up is needed to evaluate late toxicity and long-term disease control.

Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators.

The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.

Discovery of a new series of PI3K-δ inhibitors from Virtual Screening.

PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.

High order phase contrast and source divergence in low energy electron microscopy.

We present experimental observations of high order phase contrast in aberration corrected low energy electron microscopy (AC-LEEM). Phase contrast produced by atomic steps on a Ag (111) surface exhibits prominent high order interference fringes, which have not been reported before. These phase contrast features depend upon defocus and incident electron energy, similar to the prominent first order fringes observed previously and in agreement with Fourier optics (FO) model predictions. The comparison of experimental results and FO model simulations demonstrates that fringe amplitudes are strongly affected at large defocus by the source divergence. This effect is exploited to quantitatively determine the divergence, 0.055 ± 0.005 mrad, of the field emission source in AC-LEEM under the imaging conditions used. Although the divergence determines the spatial coherence of the illumination in microscopy, it has not been possible to characterize this key instrumental parameter in LEEM before.

Targetability of cervical cancer by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated hyperthermia (HT) for patients receiving radiation therapy.

PURPOSE: To evaluate the targetability of late-stage cervical cancer by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-induced hyperthermia (HT) as an adjuvant to radiation therapy (RT). METHODS: Seventy-nine cervical cancer patients (stage IIIB-IVA) who received RT with lesions visible on positron emission tomography-computed tomography (PET-CT) were retrospectively analyzed for targetability using a commercially-available HT-capable MRgHIFU system. Targetability was assessed for both primary targets and/or any metastatic lymph nodes using both posterior (supine) and anterior (prone) patient setups relative to the transducer. Thirty-four different angles of rotation along subjects' longitudinal axis were analyzed. Targetability was categorized as: (1) Targetable with/without minimal intervention; (2) Not targetable. To determine if any factors could be used for prospective screening of patients, potential associations between demographic/anatomical factors and targetability were analyzed. RESULTS: 72.15% primary tumors and 33.96% metastatic lymph nodes were targetable from at least one angle. 49.37% and 39.24% of primary tumors could be targeted with patient laying in supine and prone positions, respectively. 25°-30° rotation and 0° rotation had the highest rate of the posterior and anterior targetability, respectively. The ventral depth of the tumor and its distance to the coccyx were statistically correlated with the anterior and posterior targetability, respectively. CONCLUSION: Most late-stage cervical cancer primaries were targetable by MRgHIFU HT requiring either no/minimal intervention. A rotation of 0° or 25°-30° relative to the transducer might benefit anterior and posterior targetability, respectively. Certain demographic/anatomic parameters might be useful in screening patients for treatability.

Characterization of Dosimetric Differences in Strut-Adjusted Volume Implant Treatment Plans Calculated With TG-43 Formalism and a Model-Based Dose Calculation Algorithm.

PURPOSE: To comprehensively characterize dosimetric differences between calculations with a commercial model-based dose calculation algorithm (MBDCA) and the TG-43 formalism in application to accelerated partial breast irradiation (APBI) with the strut-adjusted volume implant (SAVI) applicator. METHODS: Dose for 100 patients treated with the SAVI applicator was recalculated with an MBDCA for comparison to dose calculated via TG-43. For every pair of dose calculations, dose-volume histogram (DVH) metrics including V90%, V95%, V100%, V150%, and V200% for the PTV_EVAL were compared. Features were defined for each case including (1) applicator size, (2) ratio between PTV_EVAL contour and 1-cm rind surrounding SAVI applicator, (3) ratio between dwell time in central catheter and total dwell time, and (4) mean computed tomography (CT) number within the lumpectomy cavity. Wilcoxon rank sum tests were performed to test whether treatment plans could be stratified according to feature values into groups with statistically significant dosimetry differences between MBDCA and TG-43. RESULTS: For all DVH metrics, differences between TG-43 and MBDCA calculations were statistically significant (P < .05). Minimum (maximum) relative percent differences between the MBDCA and TG-43 for V90%, V95%, and V100% were -2.1% (0.1%), -3.1% (-0.1%), and -5.0% (-0.5%), respectively. The median relative percent difference in mean PTV_EVAL dose between the MBDCA and TG-43 was -3.9%, with minimum (maximum) difference of -6.5% (-1.8%). For V90%, V95%, and V100%, plan quality worsened beyond defined thresholds in 26, 23, and 31 cases with no instances of coverage improvement. Features 1, 2, and 4 were shown to be able to stratify treatment plans into groups with statistically significant differences in dosimetry metrics between MBDCA and TG-43. CONCLUSIONS: Investigated dose metrics for SAVI treatments were found to be systematically lower with MBDCA calculation in comparison to TG-43. Plans could be stratified according to several features by the magnitude of dosimetric differences between these calculations.

High-Quality Hexagonal Boron Nitride from 2D Distillation.

The production of high-quality two-dimensional (2D) materials is essential for the ultimate performance of single layers and their hybrids. Hexagonal boron nitride (h-BN) is foreseen to become the key 2D hybrid and packaging material since it is insulating, impermeable, flat, transparent, and chemically inert, though it is difficult to attain in ultimate quality. Here, a scheme is reported for producing single layer h-BN that shows higher quality in view of mosaicity and strain variations than material from chemical vapor deposition (CVD). We delaminate CVD h-BN from Rh(111) and transfer it to a clean metal surface. The twisting angle between BN and the second substrate yields metastable moiré structures. Annealing above 1000 K leads to 2D distillation, i.e., catalyst-assisted BN sublimation from the edges of the transferred layer and subsequent condensation into superior quality h-BN. This provides a way for 2D material production remote from CVD instrumentation.

Initial experience and lessons learned with implementing Lutetium-177-dotatate radiopharmaceutical therapy in a radiation oncology-based program.

PURPOSE: To assist radiation oncology centers in implementing Lutetium-177-dotatate (177Lu) radiopharmaceutical therapy for midgut neuroendocrine tumors. Here we describe our workflow and how it was revised based on our initial experience on an expanded access protocol (EAP). METHODS: A treatment team/area was identified. An IV-pump-based infusion technique was implemented. Exposure-based techniques were implemented to determine completion of administration, administered activity, and patient releasability. Acute toxicities were assessed at each fraction. A workflow failure modes and effects analysis (FMEA) was performed. RESULTS: A total of 22 patients were treated: 11 patients during EAP (36 administrations) and 11 patients after EAP (44 administrations). Mean 177Lu infusion time was 37 min (range 26-65 min). Mean administered activity was 97% (range 90-99%). Mean patient exposures at 1 m were 1.9 mR/h (range 1.0-4.1 mR/h) post-177Lu and 0.9 mR/h (range 0.4-1.8 mR/h) at discharge, rendering patients releasable with instructions. Treatment area was decontaminated and released same day. All patients in the EAP experienced nausea, and nearly half experienced emesis despite premedication with antiemetics. Peripheral IV-line complications occurred in six treatments (16.7%), halting administration in 2 cases (5.6%). We transitioned to peripherally inserted central catheter (PICC)-lines and revised amino acid formulary after the EAP. The second cohort of 11 patients after EAP were analyzed for PICC-line complications and acute toxicity. Nausea and emesis rates decreased (nausea G1+ 61%-27%; emesis G1+ 23%-7%), and no PICC complications were observed. FMEA revealed that a failure in amino acid preparation was the highest risk. CONCLUSION: 177Lu-dotatate can be administered safely in an outpatient radiation oncology department.