Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Selumetinib in Children with Inoperable Plexiform Neurofibromas.

BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).

Retrospective Cohort Analysis of the Impact of Puberty on Plexiform Neurofibroma Growth in Patients with Neurofibromatosis Type 1.

OBJECTIVE: To assess the hypothesis that plexiform neurofibroma (PN) growth rates increase during puberty. STUDY DESIGN: PN growth rates before and during puberty were compared in a retrospective cohort of children with neurofibromatosis type 1 with puberty defined by Tanner staging. Of 33 potentially eligible patients, 25 had adequate quality magnetic resonance imaging for volumetric analysis and were included in ≥1 anchor cohort. Volumetric analysis was performed for all available imaging studies within the 4 years before and after puberty, and before and after 9- and 11-year-old anchor scans. Linear regression was performed to estimate the slope of change (PN growth rate); growth rates were compared with paired t test or Wilcoxon matched-pairs signed rank test. RESULTS: There were no significant difference in rates of PN growth in milliliters per month or milliliters per kilogram per month in the prepubertal vs pubertal periods (mean, 1.33 ± 1.67 vs 1.15 ± 1.38 [P = .139] and -0.003 ± 0.015 vs -0.002 ± 0.02 [P = .568]). Percent increases of PN volumes from baseline per month were significantly higher prepubertally (1.8% vs 0.84%; P = .041) and seemed to be related inversely to advancing age. CONCLUSIONS: Puberty and its associated hormonal changes do not seem to influence PN growth rate. These findings support those previously reported, but from a typical population of children with neurofibromatosis type 1 with puberty confirmed by Tanner staging.

B-cell acute lymphoblastic leukemia and juvenile xanthogranuloma in a patient with ETV6 thrombocytopenia and leukemia predisposition syndrome: novel clinical presentation and perspective.

Not available.

Research productivity of radiation therapy physics faculty in the United States.

PURPOSE: Research productivity metrics are important for decisions regarding hiring, retention, and promotion in academic medicine, and these metrics can vary widely among different disciplines. This article examines productivity metrics for radiation therapy physicists (RTP) in the United States. METHODS AND MATERIALS: Database searches were performed for RTP faculty at US institutions that have RTP residencies accredited by the Commission on Accreditation of Medical Physics Education Programs (CAMPEP). Demographics, academic rank, number of publications, academic career length, Hirsch index (h-index), m-quotient, and history of National Institutes of Health (NIH) funding as a principal investigator (PI) were collected for each RTP. Logistic regression was performed to determine the probability of academic rank as a function of h-index and m-quotient. Statistical tests used included the Wilcoxon ranked sum test and the Pearson χ2 test. RESULTS: A total of 1038 faculty and staff were identified at 78 institutions with CAMPEP-accredited residencies. The average RTP academic career duration is 13.5 years, with 46.7 total publications, h-index of 10.7, and m-quotient of 0.66. Additionally, 10.5% of RTP have a history of NIH funding as a PI. Large disparities were found in academic productivity of doctoral-prepared physicists compared to those with a terminal master's degree. For differences in junior and senior faculty, statistical tests yielded significance in career duration, number of publications, h-index, and m-quotient. Gender disparities were identified in the overall distribution of RTP consistent with the membership of the American Association of Physicists in Medicine. Further gender disparities were found in the number of doctoral-prepared RTP and physicists in senior faculty roles. CONCLUSIONS: This manuscript provides objective benchmark data regarding research productivity of academic RTP. These data may be of interest to faculty preparing for promotion, and also to institutional leadership.

Variability in commercially available deformable image registration: A multi-institution analysis using virtual head and neck phantoms.

PURPOSE: The purpose of this study was to evaluate the performance of three common deformable image registration (DIR) packages across algorithms and institutions. METHODS AND MATERIALS: The Deformable Image Registration Evaluation Project (DIREP) provides ten virtual phantoms derived from computed tomography (CT) datasets of head-and-neck cancer patients over a single treatment course. Using the DIREP phantoms, DIR results from 35 institutions were submitted using either Velocity, MIM, or Eclipse. Submitted deformation vector fields (DVFs) were compared to ground-truth DVFs to calculate target registration error (TRE) for six regions of interest (ROIs). Statistical analysis was performed to determine the variability between each DIR software package and the variability of users within each algorithm. RESULTS: Overall mean TRE was 2.04 ± 0.35 mm for Velocity, 1.10 ± 0.29 mm for MIM, and 2.35 ± 0.15 mm for Eclipse. The MIM mean TRE was significantly different than both Velocity and Eclipse for all ROIs. Velocity and Eclipse mean TREs were not significantly different except for when evaluating the registration of the cord or mandible. Significant differences between institutions were found for the MIM and Velocity platforms. However, these differences could be explained by variations in Velocity DIR parameters and MIM software versions. CONCLUSIONS: Average TRE was shown to be <3 mm for all three software platforms. However, maximum errors could be larger than 2 cm indicating that care should be exercised when using DIR. While MIM performed statistically better than the other packages, all evaluated algorithms had an average TRE better than the largest voxel dimension. For the phantoms studied here, significant differences between algorithm users were minimal suggesting that the algorithm used may have more impact on DIR accuracy than the particular registration technique employed. A significant difference in TRE was discovered between MIM versions showing that DIR QA should be performed after software upgrades as recommended by TG-132.

Evaluation of cine imaging during multileaf collimator and gantry motion for real-time magnetic resonance guided radiation therapy.

PURPOSE: Real-time magnetic resonance guided radiation therapy (MRgRT) uses 2D cine imaging for target tracking. This work evaluates the percent image uniformity (PIU) and spatial integrity of cine images in the presence of multileaf collimator (MLC) and gantry motion in order to simulate sliding window and volumetric modulated arc therapy (VMAT) conditions. METHODS: Percent image uniformity and spatial integrity of cine images were measured (1) during MLC motion, (2) as a function of static gantry position, and (3) during gantry rotation. PIU was calculated according to the ACR MRI Quality Control Manual. Spatial integrity was evaluated by measuring the geometric distortion of 16 measured marker positions (10 cm or 15.225 cm from isocenter). RESULTS: The PIU of cine images did not vary by more than 1% from static linac conditions during MLC motion and did not vary by more than 3% during gantry rotation. Banding artifacts were present during gantry rotation. The geometric distortion in the cine images was less than 0.88 mm for all points measured throughout MLC motion. For all static gantry positions, the geometric distortion was less than 0.88 mm at 10 cm from isocenter and less than 1.4 mm at 15.225 cm from isocenter. During gantry rotation, the geometric distortion remained less than 0.92 mm at 10 cm from isocenter and less than 1.60 mm at 15.225 cm from isocenter. CONCLUSION: During MLC motion, cine images maintained adequate PIU, and the geometric distortion of points within 15.225 cm from isocenter was less than the 1 mm threshold necessary for real-time target tracking and gating. During gantry rotation, PIU was negatively affected by banding artifacts, and spatial integrity was only maintained within 10 cm from isocenter. Future work should investigate the effects imaging artifacts have on real-time target tracking during MRgRT.

Commissioning an in-room mobile CT for adaptive proton therapy with a compact proton system.

PURPOSE: To describe the commissioning of AIRO mobile CT system (AIRO) for adaptive proton therapy on a compact double scattering proton therapy system. METHODS: A Gammex phantom was scanned with varying plug patterns, table heights, and mAs on a CT simulator (CT Sim) and on the AIRO. AIRO-specific CT-stopping power ratio (SPR) curves were created with a commonly used stoichiometric method using the Gammex phantom. A RANDO anthropomorphic thorax, pelvis, and head phantom, and a CIRS thorax and head phantom were scanned on the CT Sim and AIRO. Clinically realistic treatment plans and nonclinical plans were generated on the CT Sim images and subsequently copied onto the AIRO CT scans for dose recalculation and comparison for various AIRO SPR curves. Gamma analysis was used to evaluate dosimetric deviation between both plans. RESULTS: AIRO CT values skewed toward solid water when plugs were scanned surrounded by other plugs in phantom. Low-density materials demonstrated largest differences. Dose calculated on AIRO CT scans with stoichiometric-based SPR curves produced over-ranged proton beams when large volumes of low-density material were in the path of the beam. To create equivalent dose distributions on both data sets, the AIRO SPR curve's low-density data points were iteratively adjusted to yield better proton beam range agreement based on isodose lines. Comparison of the stoichiometric-based AIRO SPR curve and the "dose-adjusted" SPR curve showed slight improvement on gamma analysis between the treatment plan and the AIRO plan for single-field plans at the 1%, 1 mm level, but did not affect clinical plans indicating that HU number differences between the CT Sim and AIRO did not affect dose calculations for robust clinical beam arrangements. CONCLUSION: Based on this study, we believe the AIRO can be used offline for adaptive proton therapy on a compact double scattering proton therapy system.

The Mobius AIRO mobile CT for image-guided proton therapy: Characterization & commissioning.

PURPOSE: The purpose of this study was to characterize the Mobius AIRO Mobile CT System for localization and image-guided proton therapy. This is the first known application of the AIRO for proton therapy. METHODS: Five CT images of a Catphan® 504 phantom were acquired on the AIRO Mobile CT System, Varian EDGE radiosurgery system cone beam CT (CBCT), Philips Brilliance Big Bore 16 slice CT simulator, and Siemens SOMATOM Definition AS 20 slice CT simulator. DoseLAB software v.6.6 was utilized for image quality analysis. Modulation transfer function, scaling discrepancy, geometric distortion, spatial resolution, overall uniformity, minimum uniformity, contrast, high CNR, and maximum HU deviation were acquired. Low CNR was acquired manually using the CTP515 module. Localization accuracy and CT Dose Index were measured and compared to reported values on each imaging device. For treatment delivery systems (Edge and Mevion), the localization accuracy of the 3D imaging systems were compared to 2D imaging systems on each system. RESULTS: The AIRO spatial resolution was 0.21 lp mm-1 compared with 0.40 lp mm-1 for the Philips CT Simulator, 0.37 lp mm-1 for the Edge CBCT, and 0.35 lp mm-1 for the Siemens CT Simulator. AIRO/Siemens and AIRO/Philips differences exceeded 100% for scaling discrepancy (191.2% and 145.8%). The AIRO exhibited higher dose (>27 mGy) than the Philips CT Simulator. Localization accuracy (based on the MIMI phantom) was 0.6° and 0.5 mm. Localization accuracy (based on Stereophan) demonstrated maximum AIRO-kV/kV shift differences of 0.1 mm in the x-direction, 0.1 mm in the y-direction, and 0.2 mm in the z-direction. CONCLUSIONS: The localization accuracy of AIRO was determined to be within 0.6° and 0.5 mm despite its slightly lower image quality overall compared to other CT imaging systems at our institution. Based on our study, the Mobile AIRO CT system can be utilized accurately and reliably for image-guided proton therapy.

Carboplatin Rechallenge After Hypersensitivity Reactions in Pediatric Patients With Low-Grade Glioma.

BACKGROUND: The high prevalence of carboplatin hypersensitivity reactions (HSR) significantly affects the treatment of pediatric patients with low-grade glioma (LGG). Rechallenging patients is an option that must balance the risks of repeat allergic reaction to the benefits of retaining an effective anti-tumor regimen. PROCEDURE: We performed a retrospective review of children with LGG treated with carboplatin and vincristine between October 2000 and April 2013, who had a documented HSR to carboplatin. Patients were re-exposed to carboplatin using either precautionary measures (prolonged infusion time and premedication with H1 antagonists, H2 antagonists, and corticosteroids), a desensitization protocol, or both. RESULTS: We report the results of our institutional experience of carboplatin re-exposure using both premedication with a prolonged infusion time and a desensitization protocol. Overall, 40 of 55 (73%) patients were successfully rechallenged with carboplatin, including 19 of 25 (76%) patients who underwent desensitization. CONCLUSION: Our results demonstrate re-exposure to be a safe alternative to abandoning carboplatin for patients with a hypersensitivity reaction. We propose a clinical algorithm for treatment.

Benchmarking of five commercial deformable image registration algorithms for head and neck patients.

Benchmarking is a process in which standardized tests are used to assess system performance. The data produced in the process are important for comparative purposes, particularly when considering the implementation and quality assurance of DIR algorithms. In this work, five commercial DIR algorithms (MIM, Velocity, RayStation, Pinnacle, and Eclipse) were benchmarked using a set of 10 virtual phantoms. The phantoms were previously developed based on CT data collected from real head and neck patients. Each phantom includes a start of treatment CT dataset, an end of treatment CT dataset, and the ground-truth deformation vector field (DVF) which links them together. These virtual phantoms were imported into the commercial systems and registered through a deformable process. The resulting DVFs were compared to the ground-truth DVF to determine the target registration error (TRE) at every voxel within the image set. Real treatment plans were also recalculated on each end of treatment CT dataset and the dose transferred according to both the ground-truth and test DVFs. Dosimetric changes were assessed, and TRE was correlated with changes in the DVH of individual structures. In the first part of the study, results show mean TRE on the order of 0.5 mm to 3 mm for all phan-toms and ROIs. In certain instances, however, misregistrations were encountered which produced mean and max errors up to 6.8 mm and 22 mm, respectively. In the second part of the study, dosimetric error was found to be strongly correlated with TRE in the brainstem, but weakly correlated with TRE in the spinal cord. Several interesting cases were assessed which highlight the interplay between the direction and magnitude of TRE and the dose distribution, including the slope of dosimetric gradients and the distance to critical structures. This information can be used to help clinicians better implement and test their algorithms, and also understand the strengths and weaknesses of a dose adaptive approach.

Enhanced oxidation of nanoparticles through strain-mediated ionic transport.

Geometry and confinement effects at the nanoscale can result in substantial modifications to a material's properties with significant consequences in terms of chemical reactivity, biocompatibility and toxicity. Although benefiting applications across a diverse array of environmental and technological settings, the long-term effects of these changes, for example in the reaction of metallic nanoparticles under atmospheric conditions, are not well understood. Here, we use the unprecedented resolution attainable with aberration-corrected scanning transmission electron microscopy to study the oxidation of cuboid Fe nanoparticles. Performing strain analysis at the atomic level, we reveal that strain gradients induced in the confined oxide shell by the nanoparticle geometry enhance the transport of diffusing species, ultimately driving oxide domain formation and the shape evolution of the particle. We conjecture that such a strain-gradient-enhanced mass transport mechanism may prove essential for understanding the reaction of nanoparticles with gases in general, and for providing deeper insight into ionic conductivity in strained nanostructures.

Sonographic inferior vena cava measurements to assess hydration status in college football players during preseason camp.

OBJECTIVES: The purpose of this study was to determine whether sonographic measurement of the inferior vena cava (IVC) in college football players during preseason camp is a reliable way to detect and monitor dehydration. Our primary hypothesis was that IVC diameter measurements, the postpractice caval index, and expiratory diameter were significantly related to percent weight loss after a preseason football practice. METHODS: A prospective cohort sample of Division I intercollegiate football players in preseason training camp was recruited before practice. All football players on the active roster who were at least 18 years of age were eligible to participate in the study. Sonographic IVC measurements were obtained in the long axis using either the subcostal or subxiphoid approach during inspiration and expiration both before and after an approximately 3-hour practice with moderate to high levels of exertion at high ambient temperatures. Player weights were recorded in the locker room before and after practice. RESULTS: A total of 27 prepractice and postpractice sonographic measurements were obtained. The postpractice expiratory IVC diameter was significantly related to percent weight loss after practice (R(2) = 0.153; P = .042), with the IVC diameter being significantly inversely correlated with percent weight loss; the regression coefficient was -1.07 (95% confidence interval, -2.09 to -0.04). There was no statistically significant relationship between percent weight loss and the postpractice caval index; the regression coefficient was 0.245 (95% confidence interval, -0.10 to 0.59; R(2) = 0.078; P = .16). CONCLUSIONS: The postpractice expiratory IVC diameter was significantly related to percent weight loss after practice, whereas the caval index was not found to correlate with weight loss.

Prognostic use of lactate to predict inpatient mortality in acute gastrointestinal hemorrhage.

BACKGROUND: Gastrointestinal hemorrhage (GIH) is a common complaint seen in the emergency department (ED) and carries a small but significant mortality rate. The principal purpose of this investigation was to determine whether an ED venous lactate as part of initial laboratory studies is predictive of mortality in patients admitted to the hospital for GIH. METHODS: Retrospective cohort study for 6 years at an urban tertiary referral hospital included all ED patients with the charted diagnosis of acute GIH. Serum lactate was drawn at the bedside as part of patient care after arrival to the ED at the discretion of the clinical team. Clinical parameters and inpatient mortality were collected from the medical record. Optimal cut points for lactate were derived using receiver operating characteristics curves and imputed into a multivariable logistic regression model. RESULTS: Of the 2834 medical records that had GIH diagnoses, 1644 had an ED lactate recorded. A lactate greater than 4 mmol/L conferred a 6.4-fold increased odds of in-hospital mortality (94% specificity, P < .001). Controlling for age, initial hematocrit, and heart rate, every 1-point increase in lactate conferred a 1.4-fold increase in the odds of mortality. CONCLUSIONS: Elevated initial lactate drawn in the ED can be associated with in-hospital mortality for ED patients with acute GIH. Prospective validation studies are warranted.

High-index facets in gold nanocrystals elucidated by coherent electron diffraction.

Characterization of high-index facets in noble metal nanocrystals for plasmonics and catalysis has been a challenge due to their small sizes and complex shapes. Here, we present an approach to determine the high-index facets of nanocrystals using streaked Bragg reflections in coherent electron diffraction patterns, and provide a comparison of high-index facets on unusual nanostructures such as trisoctahedra. We report new high-index facets in trisoctahedra and previous unappreciated diversity in facet sharpness.

Defining the role of intensity modulation in electron conformal therapy for the treatment of head and neck cancer.

Bolus electron conformal therapy (BECT) in the treatment of cancers of the head and neck is often limited by an inability to reduce dosimetric hot spots resulting from surface irregularity or tissue heterogeneity. We examined the potential benefits of using intensity modulation for electron therapy (IM-BECT) to reduce hotspots in patients undergoing electron beam therapy for superficial cancers of the head and neck (HN). Twenty patients with HN cancer previously treated with BECT were identified. Each case included the treatment targets and a primary organ at risk (OAR) that were defined by the radiation oncologist. A target +2 cm rind structure was created for analysis of the dose deposition in areas surrounding the target volume as a measure of conformality. Each patient plan was transferred into the novel IM-BECT planning software and each case was recomputed as per the original parameters. Next, each case was replanned with the inclusion of intensity modulation, as well as a new custom conformal bolus that was redesigned for optimized range compensation when paired with an intensity modulator. The plans were then normalized to prescription dose and compared for target coverage/dose and OAR dose. For patients who had a hotspot of 125% or greater, the hotspot was on average reduced by 13.1% with IM-BECT. For IM-BECT, the average primary OAR means dose and target+2cm rind mean dose increased slightly by 10.6% and 6.4%, respectively (primary OAR mean [p = 0.0001], and Target+2cm rind mean [p = 0.0001], paired t-test). IM-BECT is an effective method of reducing hotspots in patients with superficial HN cancer. Improvements came at the expense of slight increases in dose to the underlying tissues. This retrospective planning study represents the first example of IM-BECT to actual HN patient cases. Expanding the role of IM-BECT in other disease sites could potentially compared to conventional BECT.

Targeting GPC2 on intraocular and CNS metastatic retinoblastomas with local and systemic delivery of CAR T-cells.

PURPOSE: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T-cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy. EXPERIMENTAL DESIGN: GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T-cells with different co-stimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T-cells were evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models. RESULTS: Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2 and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB co-stimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence that led to significant tumor regression compared to either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T-cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T-cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival. CONCLUSIONS: GPC2-directed CAR T-cells are effective against intraocular and CNS metastatic retinoblastomas.

Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study.

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.