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High-temperature superconducting REBa{2} Cu{3}O{7-x} (rebco) conductors have the potential to generate a high magnetic field over a broad temperature range. The corresponding accelerator magnet technology, still in its infancy, can be attractive for future energy-frontier particle colliders such as a multi-TeV muon collider. To help develop the technology, we explore the requirements and potential characteristics of a rebco magnet, operating at 4.2 or 20 K, with a dipole field of 8-10 T in a clear aperture of 150 mm. We use the canted \cos \theta magnet configuration to reduce the electromagnetic stresses on the conductors. We present the resulting dipole fields, field gradients for combined-function cases, conductor stresses, magnet dimensions and conductor lengths. We also discuss the conductor performance that is required to achieve the target dipole field at 4.2 and 20 K. The information can provide useful input to the development of rebco magnet and conductor technology for collider-ring magnets in a muon collider.

Although the high-temperature superconducting (HTS) REBa2Cu3O x (REBCO, RE-rare earth elements) material has a strong potential to enable dipole magnetic fields above 20 T in future circular particle colliders, the magnet and conductor technology needs to be developed. As part of an ongoing development to address this need, here we report on our CORC® canted cosθ magnet called C2 with a target dipole field of 3 T in a 65 mm aperture. The magnet was wound with 70 m of 3.8 mm diameter CORC® wire on machined metal mandrels. The wire had 30 commercial REBCO tapes from SuperPower Inc. each 2 mm wide with a 30 µm thick substrate. The magnet generated a peak dipole field of 2.91 T at 6.290 kA, 4.2 K. The magnet could be consistently driven into the flux-flow regime with reproducible voltage rise at an engineering current density between 400-550 A mm-2, allowing reliable quench detection and magnet protection. The C2 magnet represents another successful step towards the development of high-field accelerator magnet and CORC® conductor technologies. The test results highlighted two development needs: continue improving the performance and flexibility of CORC® wires and develop the capability to identify locations of first onset of flux-flow voltage.

The U.S. Magnet Development Program (MDP) collaboration is designing a utility mechanical structure for testing various high-field superconducting dipole coils. The design uses a shell-based structure concept, which allows applying preload in two steps: During a room temperature assembly and during a cool down to a cryogenic temperature. The structure is designed to accommodate various coil designs - including Nb3Sn Cosine Theta (CT) and Canted CT magnets as well as hybrid magnets with high temperature superconductor cables. Superconducting coils, enclosed by bolted pads to form an octagonal coil pack, will be inserted into a reusable yoke-shell subassembly and precisely preloaded during the assembly using a bladder-and-key technology. Due to a differential thermal contraction between an external aluminum shell and the magnet core, the coil preload increases during the cool down up to level required for 17-T excitation. Such a reusable structure will serve as a testing fixture supporting goals of the MDP program, decreasing cost and simplifying coil performance testing at different preload levels. We present a finite-element analysis of the structure preloading various coil designs and examine the predicted coil stress at each step of the magnet assembly and excitation.

The U.S. Magnet Development Program (MDP) is exploring the possibility of combining low-and higherature superconductor technologies, using cosine-theta and canted-cosine-theta (CCT) Nb3Sn dipole magnets together with Bi-2212 CCT inserts, with the ultimate goal of constructing a 20-T dipole. The MDP short-term goal is a Bi-2212 CCT insert capable of reaching 5 T in the bore when operating as a stand-alone and 3 T when operating under a background field of 15 T. This paper reports on the fabrication of our BIN4 dipole magnet and our BIN5a and BIN5b coils, designed and built at the Lawrence Berkeley National Laboratory to address potential fabrication issues of Bi-2212 coils and verify the design of our 18-20-T dipole magnet. BIN4 is a two-layer 50-cm-long CCT magnet that uses a nine-strand Rutherford cable made with 0.8-mm-diameter Bi-2212 strands. Its goal is to investigate critical current, insulation integrity, manufacturing challenges, and quench protection issues after heat treating both layers together under oxygen at standard atmosphere (1 bar). BIN5a and BIN5b are two identical coils, similar to the outer layer of BIN4, with the difference that the length is 39 cm, and they will undergo 50-bar overpressure processing heat treatment. BIN5 coils are made from the state-of-the-art strand with an engineering critical current density of 1150 A/mm2 at 4.2 K and 5 T.

A future circular collider (FCC) with a center-of-mass energy of 100 TeV and a circumference of around 100 km, or an energy upgrade of the LHC (HE-LHC) to 27 TeV require bending magnets providing 16 T in a 50-mm aperture. Several development programs for these magnets, based on Nb3Sn technology, are being pursued in Europe and in the U.S. In these programs, cos-theta, block-type, common-coil, and canted-cos-theta magnets are explored; first model magnets are under manufacture; limits on conductor stress levels are studied; and a conductor with enhanced characteristics is developed. This paper summarizes and discusses the status, plans, and preliminary results of these programs.

The critical current density of Bi-2212 round wires has seen significant improvement over the past two years. We present the magnetic design and stress analysis of two Bi-2212 dipoles based on Canted-Cosine-Theta (CCT) technology using the state-of-the-art wires. The first design, based on a 19-strand Rutherford cable of θ0.8mm strands, is a two-layer dipole with a bore diameter of 40 mm and an outer diameter of 98.4 mm; it generates 5.4Twhen operating in stand-alone configuration and 18.9T in 15 T background field. The second design, based on a 13-strand Rutherford cable of θ0.8mm strands, is also a two-layer dipole with a bore diameter of 40 mm and an outer diameter of 81 mm; it generates 4.0 T when operating in stand-alone configuration and 17.8 T in 15 T background field. Normal stresses on the conductor in these magnets do not exceed 35 MPa when working under background field.Moreover, we propose a novel approach for increasing the efficiency of CCT magnets using keystoned Rutherford cable while removing the midplane ribs. with this method, it is possible to increase the efficiency of small radius CCT coils by 20%. We conclude that Bi-2212 can be used to increase the limit of accelerator magnet dipole fields beyond 15 T while managing stresses in the coils to acceptable levels.

© 2017 EU. Canted-cosine-theta (CCT) technology has been studied for its suitability for a future-circular-collider (FCC) main dipole in terms of magnetic and mechanical performance, elec-trothermal protectability, as well as efficiency. In this paper, we present lessons learnt from our search for efficient CCT solutions by means of two-dimensional (2-D) magnetic and mechanical simulations, discuss the 3-D periodic mechanical model, as well as 3-D electromagnetic analysis of the end regions. Temperature and voltage distributions during a quench under simplifying assumptions are discussed, and the magnet’s efficiency is compared to that of other contenders in the FCC design study. The results qualify the CCT design as a contender for the FCC main dipole.

The Canted–Cosine–Theta is a design option for the next generation of high field superconducting dipoles being pursued within the US Magnet Development Program. This paper presents new modeling techniques developed for design and analysis of CCT magnets. For mechanical modeling in ANSYS, three approaches with increasing accuracy are compared: 2-D symmetry models; 3-D periodic symmetry models; and full 3-D models. Methods for the static and transient magnetic simulation using ANSYS are presented with a focus on circuit-coupled models for predicting magnet behavior following quench. Where applicable, simulation results are compared to data from CCT magnet tests at Berkeley.

The Canted-Cosine-Theta (CCT) technology has the potential, by its intrinsic stress-management, to lower coil stresses in high-field accelerator magnets. This is especially relevant for Nb3Sn magnets, which may be subject to irreversible degradation if the coil stresses exceed critical values. The internal structure of CCT coils, however, dilutes the engineering current density. For an efficient design, the internal structure, therefore, needs to be reduced to the limit given by the computer-numerical-control machining capabilities. In that case, however, additional mechanical stiffness must be provided by an external mechanical structure. The mechanical structure for the Paul Scherrer Institut (PSI) CCT program, which is described in this paper, is based on the bladder and key concept. The CCT-specific deviations from the prevalent bladder and key implementations are discussed. In addition, a two-dimensional and three-dimensional analysis in all stages of loading, cooling, and powering of the first PSI magnet prototype, as well as a tolerance analysis, is reported.

A next step of energy increase of hadron colliders beyond the LHC requires high-field superconducting magnets capable of providing a dipolar field in the range of 16 T in a 50-mm aperture with accelerator quality. These characteristics could meet the requirements for an upgrade of the LHC to twice the present beam energy or for a 100-TeV center of mass energy future circular collider. This paper summarizes the activities and plans for the development of these magnets, in particular within the 16 T Magnet Technology Program, the WP5 of the EuroCirCol, and the U.S. Magnet Development Program.

REBCO coated conductors maintain a high engineering current density above 16 T at 4.2 K. That fact will significantly impact markets of various magnet applications including high-field magnets for high-energy physics and fusion reactors. One of the main challenges for the high-field accelerator magnet is the use of multi-tape REBCO cables with high engineering current density in magnet development. Several approaches developing high-field accelerator magnets using REBCO cables are demonstrated. In this paper, we introduce an alternative concept based on the canted cos θ (CCT) magnet design using conductor on round core (CORC®) wires that are wound from multiple REBCO tapes with a Cu core. We report the development and test of double-layer three-turn CCT dipole magnets using CORC® wires at 77 and 4.2 K. The scalability of the CCT design allowed us to effectively develop and demonstrate important magnet technology features such as coil design, winding, joints and testing with minimum conductor lengths. The test results showed that the CCT dipole magnet using CORC® wires was a viable option in developing a REBCO accelerator magnet. One of the critical development needs is to increase the engineering current density of the 3.7 mm diameter CORC® wire to 540 A mm-2 at 21 T, 4.2 K and to reduce the bending radius to 15 mm. This would enable a compact REBCO dipole insert magnet to generate a 5 T field in a background field of 16 T at 4.2 K.

Cable and magnet applications require bending REBa2 Cu3O 7-δ (REBCO, RE = rare earth) tapes around a former to carry high current or generate specific magnetic fields. With a high aspect ratio, REBCO tapes favor the bending along their broad surfaces (easy way) than their thin edges (hard way). The easy-way bending forms can be effectively determined by the constant-perimeter method that was developed in the 1970s to fabricate accelerator magnets with flat thin conductors. The method, however, does not consider the strain distribution in the REBCO layer that can result from bending. Therefore, the REBCO layer can be overstrained and damaged even if it is bent in an easy way as determined by the constant-perimeter method. To address this issue, we developed a numerical approach to determine the strain in the REBCO layer using the local curvatures of the tape neutral plane. Two orthogonal strain components are determined: the axial component along the tape length and the transverse component along the tape width. These two components can be used to determine the conductor critical current after bending. The approach is demonstrated with four examples relevant for applications: a helical form for cables, forms for canted cos θ dipole and quadrupole magnets, and a form for the coil end design. The approach allows us to optimize the design of REBCO cables and magnets based on the constant-perimeter geometry and to reduce the strain-induced critical current degradation.

Recent studies have shown that strong, alternating focusing magnets can be used to greatly increase the momentum acceptance of hadron therapy gantries. With the high gradients achievable with superconducting magnets a level of momentum acceptance can be reached which may have significant implications to medical gantries and to the introduction of superconducting technology in this area. The design of such a superconducting magnet system for a proton therapy gantry will be presented. The Canted-Cosine-Theta concept is extended to a curved magnet system generating the desired bending and alternating focusing fields for the achromatic optics. Magnetic, structural, and thermal analysis of this design is presented along with preliminary efforts towards fabrication and assembly of the curved magnet.

A four-layer canted-cosine-theta 16-T dipole has been designed as a possible candidate for future hadron colliders. The design maintains part of the future-circular-collider magnet requirements, i.e., a 50 mm clear bore and 16 T operating at 1.9 K. The magnet intercepts Lorentz forces with an internal structure of ribs and spars, minimizes conductor, and reduces the number of layers and magnet size by using wide cables. The role of iron and its impact on field and magnet size is discussed. A three-dimensional magnetic analysis was carried out for 1-in-1 and 2-in-1 designs including a structural analysis for the 1-in-1 case. Thoughts on future improvements during winding are also discussed.

We present a design of superconducting magnets, optimized for application in a gantry for proton therapy. We have introduced a new magnet design concept, called an alternating-gradient canted cosine theta (AG-CCT) concept, which is compatible with an achromatic layout. This layout allows a large momentum acceptance. The 15 cm radius of the bore aperture enables the application of pencil beam scanning in front of the SC-magnet. The optical and dynamic performance of a gantry based on these magnets has been analyzed using the fields derived (via Biot-Savart law) from the actual windings of the AG-CCT combined with the full equations of motion. The results show that with appropriate higher order correction, a large 3D volume can be rapidly scanned with little beam shape distortion. A very big advantage is that all this can be done while keeping the AG-CCT fields fixed. This reduces the need for fast field ramping of the superconducting magnets between the successive beam energies used for the scanning in depth and it is important for medical application since this reduces the technical risk (e.g., a quench) associated with fast field changes in superconducting magnets. For proton gantries the corresponding superconducting magnet system holds promise of dramatic reduction in weight. For heavier ion gantries there may furthermore be a significant reduction in size.

A multilayer high field dipole magnet has been designed for future particle accelerators. The magnet has eight layers of a Nb3Sn outsert coil and four layers of a Bi-2212 insert coil (see Figs. 1 and 2). The layers are graded, delivering a short-sample field of 17.7 T in a 40-mm bore. The coil layers are of a canted cosine-theta design - with ribs and spars that guide and support the coil windings, shape the field, intercept Lorentz forces, and minimize conductor prestress. We present a general overview of the concept and report on the magnetic and mechanical design including an initial cost estimate and construction plan.

The first MICE Coupling Coil has been tested in a conduction-cooled environment in the new Solenoid Test Facility at Fermilab. We present an overview of the power and quench protection scheme, and report on the electrical and quench performance results obtained during cold power tests of the magnet.

The ECR source magnet of the FRIB facility has been designed by the Superconducting Magnet Program at the Lawrence Berkeley National Laboratory (LBNL). The magnetic parameters are close to the VENUS magnet (sextupole-in-solenoids) operated at LBNL. The mechanical assembly concept, however, is different and uses a shell-based support structure. The main advantage of this structure is the ability to finely tune the sextupole prestress both azimuthally (by way of bladder and key technology, and axially by means of end plates. This method of structural pre-loading applies the desired compression on the sextupole coils while maintaining acceptable peak stresses. Also, bladder and key technology is a reversible assembly process allowing fast and easy coil replacement, when necessary. This paper also describes the mechanical analysis required to estimate the sextupole and solenoids preloads. The stress distribution in the windings and structural components are presented during assembly, cool-down, and magnet excitation.

The Superconducting Magnet Program at the Lawrence Berkeley National Laboratory (LBNL) is completing the design of a 28 GHz NbTi ion source magnet for the Facility for Rare Isotope Beams (FRIB). The design parameters are based on the parameters of the ECR ion source VENUS in operation at LBNL since 2002 featuring a sextupole-in-solenoids configuration. Whereas most of the magnet components (such as conductor, magnetic design, protection scheme) remain very similar to the VENUS magnet components, the support structure of the FRIB ion source uses a different concept. A shell-based support structure using bladders and keys is implemented in the design allowing fine tuning of the sextupole preload and reversibility of the magnet assembly process. As part of the design work, conductor insulation scheme, coil fabrication processes and assembly procedures are also explored to optimize performance. We present the main features of the design emphasizing the integrated design approach used at LBNL to achieve this result.

A two-layer Canted-Cosine-Theta (CCT) superconducting dipole magnet was built and tested. The magnet's unique mandrel design uses machined channels and spars to guide the windings, intercept Lorentz forces, and circumvent tangential stress accumulation. The CCT magnet design provides a "near-perfect" current density distribution and requires minimal coil prestress. The CCT magnet design, with these inherent features, makes it a desirable option for a high field accelerator magnet. A two layer dipole (CCT1) using NbTi cable and a 50.8-mm clear bore was built and tested generating a 2.4 T dipole field. We report on the winding experience, measured field quality and quench history.

Correlated oxides are known to have remarkable properties, with a range of electronic, magnetic, optoelectronic, and photonic functionalities. A key ingredient in realizing these properties into practical technology is the effective and scalable integration of oxides with conventional semiconductors. Unlocking the full spectrum of functionality requires atomically abrupt oxide-semiconductor interfaces and intimate knowledge of their potential landscape and charge transport. In this study, we investigated the electrical properties of epitaxial SrTiO 3 /GaAs heterostructures by examining the band alignment and transport behavior at the interface. We employ X-ray photoelectron spectroscopy (XPS) to measure the barriers for electrons and holes across the interface and, through them, explain the transport behavior for junctions with n- and p-type GaAs. We further show qualitative evidence of the strong photoresponse of these structures, illustrating the potential of these structures in optoelectronic devices. These results establish the fundamental groundwork for utilizing these interfaces toward new devices and define their design space., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background and Purpose: Multiple studies demonstrated hypothalamic-pituitary dysfunction in survivors of pediatric brain tumors. However, few studies investigated the trajectories of pituitary height in these patients and their associations with pituitary function. We aimed to evaluate longitudinal changes of pituitary height in children and adolescents with brain tumors, and their association with endocrine deficiencies., Materials and Methods: We conducted a retrospective analysis of 193 pediatric patients (54.9% male) diagnosed with brain tumors from 2002 to 2018, with a minimum of two years of radiological follow-up. Pituitary height was measured using MRI scans at diagnosis and at 2, 5, and 10 years post-diagnosis, with clinical data sourced from patient charts., Results: Average age at diagnosis was 7.6 ± 4.5 years, with a follow-up of 6.1 ± 3.4 years. 52.8% underwent radiotherapy and 37.8% experienced pituitary hormone deficiency. Radiation treatment was a significant predictor of decreased pituitary height at all observed time points (p = 0.016, p < 0.001, p = 0.008, respectively). Additionally, chemotherapy (p = 0.004) or radiotherapy (p = 0.022) history and pituitary height at 10 years (p = 0.047) were predictors of endocrine deficiencies. ANOVA revealed an expected increase in pituitary height over time in pediatric patients, but this growth was significantly impacted by radiation treatment and gender (p for interaction = 0.005 and 0.025, respectively)., Conclusion: Cranial irradiation in pediatric patients is associated with impairment of the physiologic increase in pituitary size; in turn, decreased pituitary height is associated with endocrine dysfunction. We suggest that pituitary gland should be evaluated on surveillance imaging of pediatric brain tumor survivors, and if small for age, clinical endocrine evaluation should be pursued., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of interests ALa reports payment from Alexion, support from Servier and stock from Gilead, outside of the submitted work. AV is co-lead role of the Consortium for Childhood Cancer Predisposition, outside of the submitted work. BH reports payment and stock from Invitae, outside of the submitted work. BC reports participation as data safety and monitoring board member in ReRad Study, participation in the chapter advisory board for Make a Wish Canada Nova Scotia, and participation in the medical advisory committee for Make a Wish Canada, outside of the submitted work. CCP reports grants from St Baldrick's Foundation, outside of the submitted work. DSZ reports consulting fees for Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Alexion, Amgen, and Norgine, outside of the submitted work. DTB reports grants from MSD and Novocure, consulting fees from Nanocarry Therapeutics and Servier, and payment from Servier, outside of the submitted work. EO reports payment and support from Alexion for educational event, outside of the submitted work. EB reports grants from Roche and board participation for Novartis, Alexion and Gilead, outside of the submitted work. FC reports grants from Hall Hunter Foundation (UK), outside of the submitted work. HBF reports payments from Illumina and Sanofi Genzyme, support from Illumina, participation as scientific advisory committee for Sanofi Genzyme, International Gaucher Alliance and Igentify, stock from Igentify, and receipt of materials from Illumina, outside of the submitted work. IW reports grants from Chimerix and payment from COG Partners, outside of the submitted work. IS reports grants from Fondation Saint-Luc and FNRS-CDR, outside of the submitted work. JK reports other financial interests at Servier and PRA Health Sciences, outside of the submitted work. JRG-S reports participation on the board of the Philippine Society of Pediatric Oncology and Philippine Board of Pediatric Oncology, and stock in Macrogenics, Moderna, Mirati Therapeutics, CRISPR Therapeutics, Repligen, Quidelortho, and Shockwave Medical, outside of the submitted work. KJB reports consulting fees from US WorldMeds, Springworks Therapeutics, Alexion, and YmAbs, and payment from Alexion, outside of the submitted work. MS reports grants and support from the Swedish Childhood Cancer Fund, participation as a data safety and monitoring board member for clinical trial NCT05230758, and participation in the Swedish Pediatric CNS tumour group, outside of the submitted work. MAC reports financial support from SUNY Upstate Department of Pediatrics and board participation for Paige's Butterfly Run, outside of the submitted work. MO reports payment from Aptitude Health and participation on a data safety monitoring board or advisory board for Ultragenyx and Abeona, outside of the submitted works. MZ reports payment and support from and board participation for AstraZeneca. NW reports grants from CANSEARCH Foundation, Childhood Cancer Research Switzerland, and the Foundation for Children and Adolescents with Cancer; payment, support, and advisory board participation for Swedish Orphan Biovitrum; and board participation for Childhood Cancer Switzerland, outside of the submitted work. NH reports grants from the National Institutes of Health (NIH) and board participation for Incyte and Pfizer, outside of the submitted work. PCN reports grants from the Canadian Institutes for Health Research (CIHR) Foundation, US Department of Defense, and Garron Family Cancer Centre, outside of the submitted work. RP reports participation in the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer, outside of the submitted work. RT reports consulting fees from Fennec Pharmaceuticals and Day One Biopharmaceuticals and payment from Fennec Pharmaceuticals, outside of the submitted work. SS reports payments from Sanofi Pharmaceuticals and Mylan Pharmaceutical, and board participation for Sanofi Pharmaceuticals, outside of the submitted work. SB reports consulting fees from Hoffmann-La Roche, YmAbs, MAP Biopharma and SERB SAS, and payment from Zschimmer & Schwarz Mohsdorf, outside of the submitted work. UI reports board participation in Pakistan Society of Pediatric Oncology, outside of the submitted work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Endocrine deficiencies, including hypothalamic-pituitary-gonadal axis (HPGA) impairment, are common in survivors of childhood and adolescent medulloblastoma. Still, data regarding pubertal development and fecundity are limited, and few studies assessed HPGA function in males. We aimed to describe HPGA function in a large cohort of patients with medulloblastoma., Methods: A retrospective study comprising all 62 medulloblastoma patients treated in our center between 1987 and 2021, who were at least 2 years from completion of therapy. HPGA function was assessed based on clinical data, biochemical markers, and questionnaires., Results: Overall, 76% of female patients had clinical or biochemical evidence of HPGA dysfunction. Biochemical evidence of diminished ovarian reserve was seen in all prepubertal girls (n = 4). Among the males, 34% had clinical or biochemical evidence of gonadal dysfunction, 34% had normal function, and 29% were age-appropriately clinically and biochemically prepubertal. The difference between males and females was significant (P = .003). Cyclophosphamide-equivalent dose was significantly associated with HPGA function in females, but not in males. There was no association between HPGA dysfunction and other endocrine deficiencies, length of follow-up, weight status, and radiation treatment protocol. Two female and 2 male patients achieved successful pregnancies, resulting in 6 live births., Conclusions: HPGA dysfunction is common after treatment for childhood medulloblastoma. This is seen more in females, likely due to damage to the ovaries from spinal radiotherapy. Our findings may assist in counseling patients and their families regarding risk to future fertility and need for fertility preservation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Vaccine hesitancy is increasing. We assessed attitudes toward influenza and COVID-19 vaccines and the relation between hesitancy to influenza vaccine and hesitancy towards COVID-19 vaccines., Methods: A structured questionnaire administered during September 2020 to a representative sample of the Jewish Israeli population assessed attitudes and acceptance of influenza and COVID-19 vaccines. Factors for vaccine hesitancy were determined using logistic regression. Questionnaires were administered prior to the release of clinical data regarding efficacy and safety of COVID-19 vaccines and prior to vaccine rollout., Results: We approached 10,625 people, of these 2,080 responded (19%), and 2,024 completed the questionnaire (97.3%), 64.9% aged 15-64 years and 35.1% aged ≥65 years. 37% had co-morbidities. 43.5% experienced financial deterioration due to the pandemic. 65.9% received influenza vaccine ≥1 time in the past. Influenza vaccination rates were higher in the elderly (81.8%). Reasons for influenza vaccine hesitancy were opinions that the vaccine is ineffective (27.1%), and fear of side effects (29.3%). 8.2% of people aged 16-64 and 13.8% of people aged≥65 refused to be vaccinated at least once over the course of one's lifetime. Percent of responders willing to receive a COVID-19 vaccine were higher than percent of responders willing to receive the influenza vaccine both in people aged 16-64 years (942 (72.3%) vs. 38.4%, respectively) and in people 65 years and older (84.0% vs. 76.8%, respectively). Hesitancy towards COVID-19 vaccine was associated with hesitancy towards other vaccines. Only 26.8% would participate in a COVID-19 vaccine trial., Conclusions: Willingness to receive COVID-19 vaccine was higher than willingness to receive influenza vaccine. The results point to areas of fear from influenza vaccines side effects and lack of knowledge regarding influenza vaccines effectiveness that can be addressed to increase acceptance. Hesitancy towards other vaccines was associated with hesitancy towards COVID-19 vaccination., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: YM receiving grant funding and lecture fees from Pfizer, and lecture fees from MSD. There are no patents, products in development or marketing products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. SC has no competing interests.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., (© 2022. The Author(s).)

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals., Patients and Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation., Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years., Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD., Competing Interests: Hagit N. BarisConsulting or Advisory Role: Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics, Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & Development, MerckStock and Other Ownership Interests: Johnson & Johnson, MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. NicholsStock and Other Ownership Interests: IncyteResearch Funding: Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers SquibbNo other potential conflicts of interest were reported.

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment., Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication., Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy., Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK ( n = 31), NTRK1/2/3 ( n = 21), ROS1 ( n = 9), and MET ( n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1 , or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related commentary by Szulzewsky and Cimino, p. 904 . This article is highlighted in the In This Issue feature, p. 890 ., (©2020 American Association for Cancer Research.)