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Within the past decade, incremental integration of molecular characteristics into the classification of central nervous system neoplasms increasingly facilitated precise diagnosis and advanced stratification, beyond potentially providing the foundation for advanced targeted therapies. We report a series of three cases of infant-type hemispheric glioma (IHG) involving three infants diagnosed with neuroepithelial tumors of the cerebral hemispheres harboring a novel, recurrent TRIM24::MET fusion. Histopathology showed glial tumors with either low-grade or high-grade characteristics, while molecular characterization found an additional homozygous CDKN2A/B deletion in two cases. Two patients showed leptomeningeal dissemination, while multiple supra- and infratentorial tumor manifestations were found in one case. Following subtotal resection (two cases) and biopsy (one case), treatment intensity of adjuvant chemotherapy regimens did not reflect in the progression patterns within the reported cases. Two patients showed progression after first-line treatment, of which one patient died not responding to tyrosine kinase inhibitor cabozantinib. As the detection of a recurrent TRIM24::MET fusion expands the spectrum of renowned driving fusion genes in IHG, this comparative illustration may indicate a distinct clinico-pathological heterogeneity of tumors bearing this driver alteration. Upfront clinical trials of IHG promoting further characterization and the implementation of individualized therapies involving receptor tyrosine kinase inhibition are required., (© 2024. The Author(s).)

Background: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality., Methods: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy., Results: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair., Conclusions: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials., (© 2024. The Author(s).)

The use of central nervous system (CNS) prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) remains controversial. Although uncommon, CNS relapses are invariably fatal in this otherwise curable disease. Accurate identification of patients at risk and the optimal approach to CNS prophylaxis therefore remains an area of unmet need. The existing literature, largely retrospective in nature, provides mixed conclusions regarding the efficacy of CNS prophylaxis. The utility of CNS prophylaxis has itself been challenged. In this review, we dissect the issues which render the value of CNS prophylaxis uncertain. We first compare international clinical guidelines for CNS prophylaxis. We then interrogate the factors that should be used to identify high-risk patients accurately. We also explore how clinical patterns of CNS relapse have changed in the pre-rituximab and rituximab era. We then discuss the efficacy of CNS-directed approaches, intensification of systemic treatment and other novel approaches in CNS prophylaxis. Improved diagnostics for early detection of CNS relapses and newer therapeutics for CNS prophylaxis are areas of active investigation. In an area where prospective, randomized studies are impracticable and lacking, guidance for the use of CNS prophylaxis will depend on rigorous statistical review of retrospective data., (© 2023. The Author(s).)

Background: Although Singapore is one of the highest vaccinated countries in the world, vaccine hesitancy remains in a subpopulation, including individuals with cancer predisposition syndromes. At the Cancer Genetics Service National Cancer Centre Singapore, we see patients with germline genetic alterations, most being BRCA1/2 pathogenic/likely pathogenic variant (PV/LPV) carriers. While reported safe for cancer patients, there are limited studies addressing the safety profile and outcomes of COVID-19 vaccination among individuals with germline PV/LPV in cancer predisposition genes such as BRCA1/2. This study aims to evaluate the outcomes of COVID-19 vaccination among germline PV/LPV carriers in BRCA1/2., Methods: We conducted a phone call survey of COVID-19 vaccination uptake and toxicity in a prospective cohort of 189 participants with germline BRCA1/2 PV/LPV between 1st Sept 2021 and 30th Sept 2021. We collected demographics data including gender, race, age, history of cancer, types of cancer, and number of cancers. Statistical difference in baseline demographics between responders with history of cancer and those without were assessed using Chi-square, Fisher's exact and independent t-test analysis. Logistic regression was used to evaluate effect of demographics on the occurrence of post-vaccination side effects., Results: Among 189 BRCA1/2 PV/LPV carriers responded, 97 carried PV/LPV in BRCA1 and 92 in BRCA2. Majority were vaccinated (89.5%) and had completed the two-dose vaccine schedule, with 7 (4.1%) received only one dose. The most common post-vaccination side effects was myalgia (56.5%) followed by fever (40.2%), headache (16.3%) and fatigue (11.2%). There were no major severe side events. Evaluation by logistic regression showed that the occurrence of side effects was not affected by PV/LPV gene (BRCA1 or BRCA2), gender, race, age or history of cancer., Conclusion: The post-vaccination side effects profile among individuals with germline PV/LPV in BRCA1/2 is consistent with the Singaporean general population, hence recommendations for COVID-19 vaccination for these individuals should not differ from non-carriers and should be encouraged by their healthcare providers., (© 2023. The Author(s).)

Background: With increasing numbers of people living with dementia relying on family to care for them at home, there is an urgent need for practical and evidence-based programs to support carers in maintaining their mental health and well-being. The objective of this study was to evaluate the acceptability and feasibility of a modified STrAtegies for RelaTives (START) program delivered online (START-online)., Method: A mixed-methods non-blinded evaluation of START-online (using Zoom as videoconferencing platform) for acceptability and feasibility (completion rates and qualitative feedback through surveys and focus groups) and quantitative evaluation. This occurred at the National Ageing Research Institute, in metropolitan Victoria, Australia., Results: Twenty-nine eligible carers were referred, 20 (70%) consented to the study. Of these, 16 (80%) completed all 8 sessions, 2 completed only 3 sessions, and 2 withdrew. Carers' qualitative feedback indicated that the therapist interaction was valued, content and online delivery of the program was acceptable. Feedback was mixed on the appropriate stage of caring., Conclusion: START-online was feasible and acceptable for carers, including those living outside of metropolitan areas who might otherwise be unable to access face-to-face programs. With the recent COVID-19 pandemic necessitating social distancing to avoid infection, interventions such as this one have increasing relevance in the provision of flexible services., (© 2022. The Author(s).)

Background: Lower gastrointestinal bleeding (LGIB) is a common presentation of surgical admissions, imposing a significant burden on healthcare costs and resources. There is a paucity of standardised clinical predictive tools available for the initial assessment and risk stratification of patients with LGIB. We propose a simple clinical scoring model to prognosticate patients at risk of severe LGIB and an algorithm to guide management of such patients., Methods: A retrospective cohort study was conducted, identifying consecutive patients admitted to our institution for LGIB over a 1-year period. Baseline demographics, clinical parameters at initial presentation and treatment interventions were recorded. Multivariate logistic regression was performed to identify factors predictive of severe LGIB. A clinical management algorithm was developed to discriminate between patients requiring admission, and to guide endoscopic, angiographic and/or surgical intervention., Results: 226/649 (34.8%) patients had severe LGIB. Six variables were entered into a clinical predictive model for risk stratification of LGIB: Tachycardia (HR ≥ 100), hypotension (SBP < 90 mmHg), anaemia (Hb < 9 g/dL), metabolic acidosis, use of antiplatelet/anticoagulants, and active per-rectal bleeding. The optimum cut-off score of ≥ 1 had a sensitivity of 91.9%, specificity of 39.8%, and positive and negative predictive Values of 45% and 90.2%, respectively, for predicting severe LGIB. The area under curve (AUC) was 0.77., Conclusion: Early diagnosis and management of severe LGIB remains a challenge for the acute care surgeon. The predictive model described comprises objective clinical parameters routinely obtained at initial triage to guide risk stratification, disposition and inpatient management of patients., (© 2021. The Author(s).)

Although CDKN2A is well-known as a susceptibility gene for melanoma and pancreatic cancer, germline variants have also been anecdotally associated with a broader range of neoplasms including neural system tumors, head and neck squamous cell carcinomas, breast carcinomas, as well as sarcomas. The CDKN2A gene encodes for two distinct tumor suppressor proteins, p16 INK4A and p14 ARF , however, the independent association of germline alterations affecting these two proteins with cancer is under-appreciated. Here, we reviewed CDKN2A germline alterations reported among individuals and families with cancer in the literature, specifically addressing the cancer phenotypes in relation to the molecular consequence on p16 INK4A and p14 ARF . While melanoma is observed to associate with variants affecting both p16 INK4A and p14 ARF transcripts, it is noted that variants affecting p14 ARF are more frequently observed with a heterogenous range of cancers. Finally, we reflected on the implications of this inferred genotype-phenotype association in clinical practice and proposed that clinical management of CDKN2A germline variant carriers should involve dedicated cancer genetics services, with multidisciplinary input from various healthcare professionals.

Introduction: Identification of one's status as a BRCA1/2 pathogenic variant carrier often marks the start of navigating challenging decisions related to cancer risk management and result disclosure. Carriers report unmet informational needs, but studies have yet to explore the specific aspects of and how best to fulfill these needs. This study aims to explore the informational needs of BRCA1/2 pathogenic variant carriers in Asia to inform for the design of educational materials to support risk management decision-making., Methods: Semi-structured in-depth interviews were conducted with two male and 22 female English-speaking BRCA1/2 pathogenic variant carriers, aged 29-66 years, identified through the Cancer Genetics Service at the National Cancer Centre Singapore. A grounded theory approach with thematic analysis was undertaken to extract dominant themes., Results: Four themes were identified: (i) proactive online information seeking behaviors (ii) personalized informational needs; (iii) challenges in sharing the results; and (iv) lack of genetic awareness., Discussion: Participants highlight challenges with sharing their result arising from significant post-result informational needs, which have manifested into proactive online information-seeking behaviors. They desire for an online source of information, where content is personalized, reliable and local. Participants foresee the potential of an online resource to raise genetic awareness. This suggests the use of a culturally tailored online-based genetics resource, to promote result disclosure, empower risk-management decisions and raise genetic literacy rates., Supplementary Information: Supplementary information accompanies this paper at 10.1186/s13053-020-00154-x., Competing Interests: Competing interestsAll other authors declare no conflicts of interest., (© The Author(s) 2020.)

Background: In this paper, the authors review the safety and practicality of elastomeric respirators for protecting themselves and others from the novel coronavirus or COVID-19. They also describe the safe donning and doffing procedures for this protective gear., Main Text: Due to the shortage of personal protective equipment (PPE), the CDC has recommended ways to conserve disposable N95 masks, including re-use and extended use, and reserving N95 masks for aerosol-generating procedures. However, these were never made to be re-used. Although the modes of transmission of COVID-19 are not fully understood, based on what we know about severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), droplets and aerosolized droplets contribute to the spread of this virus. More evidence from Wuhan, China, has demonstrated that COVID-19 viral particles are aerosolized and found in higher concentrations in rooms where PPE is being removed. Thus, it is best for all healthcare providers to have full aerosol protection., Conclusion: Given the shortage of PPE for aerosols, it is logical to utilize reusable elastomeric respirators with filter efficiency of 95% or higher. A single elastomeric respirator may replace hundreds to thousands of new disposable N95 masks.

Diffuse intrinsic pontine glioma (DIPG) is most commonly diagnosed based on imaging criteria, with biopsy often reserved for pontine tumors with imaging features not typical for DIPG (atypical DIPG, 'aDIPG'). The histopathologic and molecular spectra of the clinical entity aDIPG remain to be studied systematically. In this study, thirty-three patients with newly diagnosed pontine-centered tumors with imaging inconsistent with DIPG for whom a pathologic diagnosis was subsequently obtained were included. Neoplasms were characterized by routine histology, immunohistochemistry, interphase fluorescence in situ hybridization, Sanger and next-generation DNA/RNA sequencing, and genome-wide DNA methylome profiling. Clinicopathologic features and survival outcomes were analyzed and compared to those of a contemporary cohort with imaging features consistent with DIPG (typical DIPG, 'tDIPG'). Blinded retrospective neuroimaging review assessed the consistency of the initial imaging-based diagnosis and correlation with histopathology. WHO grade II-IV infiltrating gliomas were observed in 54.6% of the cases; the remaining were low-grade gliomas/glioneuronal tumors or CNS embryonal tumors. Histone H3 K27M mutation, identified in 36% of the cases, was the major prognostic determinant. H3 K27M-mutant aDIPG and H3 K27M-mutant tDIPG had similar methylome profiles but clustered separately from diffuse midline gliomas of the diencephalon and spinal cord. In the aDIPG cohort, clinicoradiographic features did not differ by H3 status, yet significant differences in clinical and imaging features were observed between aDIPG without H3 K27M mutation and tDIPG. Neuroimaging review revealed discordance between the classification of aDIPG and tDIPG and did not correlate with the histology of glial/glioneuronal tumors or tumor grade. One patient (3.1%) developed persistent neurologic deficits after surgery; there were no surgery-related deaths. Our study demonstrates that surgical sampling of aDIPG is well-tolerated and provides significant diagnostic, therapeutic, and prognostic implications, and that neuroimaging alone is insufficient to distinguish aDIPG from tDIPG. H3 K27M-mutant aDIPG is epigenetically and clinically similar to H3 K27M-mutant tDIPG.

Background: General Practice Optimising Structured Monitoring to Improve Clinical Outcomes in Type 2 Diabetes (GP-OSMOTIC) is a multicentre, individually randomised controlled trial aiming to compare the use of intermittent retrospective continuous glucose monitoring (r-CGM) to usual care in patients with type 2 diabetes attending general practice. The study protocol was published in the British Medical Journal Open and described the principal features of the statistical methods that will be used to analyse the trial data. This paper provides greater detail on the statistical analysis plan, including background and justification for the statistical methods chosen, in accordance with SPIRIT guidelines., Objective: To describe in detail the data management process and statistical methods that will be used to analyse the trial data., Methods: An overview of the trial design and primary and secondary research questions are provided. Sample size assumptions and calculations are explained, and randomisation and data management processes are described in detail. The planned statistical analyses for primary and secondary outcomes and sub-group analyses are specified along with the intended table layouts for presentation of the results., Conclusion: In accordance with best practice, all analyses outlined in the document are based on the aims of the study and have been pre-specified prior to the completion of data collection and outcome analyses., Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001372471 . Registered on 3 August 2016.

Tectal glioma (TG) is a rare low-grade tumor occurring predominantly in the pediatric population. There has been no detailed analysis of molecular alterations in TG. Risk factors associated with inferior outcome and long-term sequelae of TG have not been well-documented. We retrospectively studied TGs treated or referred for review at St. Jude Children's Research Hospital (SJCRH) between 1986 and 2013. Longitudinal clinical data were summarized, imaging and pathology specimen centrally reviewed, and tumor material analyzed with targeted molecular testing and genome-wide DNA methylation profiling. Forty-five patients with TG were included. Twenty-six (57.8%) were male. Median age at diagnosis was 9.9 years (range, 0.01-20.5). Median follow-up was 7.6 years (range, 0.5-17.0). The most common presenting symptoms were related to increased intracranial pressure. Of the 22 patients treated at SJCRH, 19 (86%) required cerebrospinal fluid diversion and seven (32%) underwent tumor-directed surgery. Five patients (23%) received radiation therapy and four (18%) systemic therapy. Ten-year overall and progression-free survival were 83.9 ± 10.4% and 48.7 ± 14.2%, respectively. Long-term morbidities included chronic headaches, visual symptoms and neurocognitive impairment. Lesion ≥3cm 2 , contrast enhancement and cystic changes at presentation were risk factors for progression. Among those with tumor tissue available, 83% showed growth patterns similar to pilocytic astrocytoma and 17% aligned best with diffuse astrocytoma. BRAF duplication (a marker of KIAA1549-BRAF fusion) and BRAF V600E mutation were detected in 25% and 7.7%, respectively. No case had histone H3 K27M mutation. DNA methylation profile of TG was distinct from other brain tumors. In summary, TG is an indolent, chronic disease with unique clinical and molecular profiles and associated with long term morbidities. Large size, contrast enhancement and cystic changes are risk factors for progression.

Background: Retinal dystrophies constitute a group of diseases characterized by clinical variability and pronounced genetic heterogeneity. Retinitis pigmentosa is the most common subtype of hereditary retinal dystrophy and is characterized by a progressive loss of peripheral field vision (Tunnel Vision), eventual loss of central vision, and progressive night blindness. The characteristics of the fundus changes include bone-spicule formations, attenuated blood vessels, reduced and/or abnormal electroretinograms, changes in structure imaged by optical coherence tomography, and subjective changes in visual function. The different syndromic and nonsyndromic forms of retinal dystrophies can be attributed to mutations in more than 250 genes. Molecular diagnosis for patients with retinitis pigmentosa has been hampered by extreme genetic and clinical heterogeneity between retinitis pigmentosa and other forms of retinal dystrophies. Next generation sequencing (NGS) technologies are among the most promising techniques to identify pathogenic variations in retinal dystrophies., Purpose: The purpose of this study was to discover the molecular diagnosis for Brazilian patients clinically diagnosed with a retinitis pigmentosa pattern of inheritance by using NGS technologies., Materials and Methods: Sixteen patients with the clinical diagnosis of retinitis pigmentosa were included in the study. Their DNA was sequenced in a panel with 132 genes related to retinal dystrophies using the Illumina ® platform. Sequence analysis and variation calling was performed using Soft Genetics ® , NextGene, and Geneticist Assistant software. The criteria for pathogenicity analysis were established according to the results of prediction programs (Polyphen 2, Mutation taster and MetaCore™) and comparison of pathogenic variations found with databases., Results: The identified potentially pathogenic variations were all confirmed by Sanger sequencing. There were 89 variations predicted as pathogenic, but only 10 of them supported the conclusion of the molecular diagnosis. Five of the nine patients were autosomal dominant RP (56%), two (22%) were autosomal recessive RP, and two (22%) were X-linked RP. Nine of the 16 patients (56%) had probably positive or positive results., Conclusion: The Next Generation Sequencing used in this study allowed the molecular diagnosis to be confirmed in 56% of the patients and clarified the inheritance pattern of the patient's retinal dystrophies.

Background: This single-arm study evaluated feasibility, safety, and initial efficacy of electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy (PN) in cancer patients with multiple myeloma., Methods: Patients with neuropathy ≥ grade 2 received 20 acupuncture treatments over 9 weeks., Results: For the 19 evaluable patients, Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity (FACT/GOG/NTX) mean (SD) scores improved significantly between baseline and week 13 (20.8 [9.6] vs 13.2 [8.5], p = 0.0002). Moderate effect size differences began on week 4, with the largest effect size differences found at week 9 for FACT/GOG/NTX scores, worst pain in the last 24 hours, and pain severity (Cohen's d = 1.43, 1.19, and 1.08, respectively) and continuing through week 13 (Cohen's d = 0.86, 0.88, and 0.90, respectively). From baseline to week 13, additional significant improvements were seen as follows: postural stability (1.0 [0.6] vs 0.8 [0.4], p = 0.02); coin test (10.0 [7.4] vs 5.6 [1.9], p < 0.0001); button test (96.1 [144.4] vs 54.9 [47.3], p < 0.0001); and walking test (21.6 [10.0] vs 17.2 [7.7], p = 0.0003). No significant changes were seen with NCS., Conclusions: Acupuncture may help patients experiencing thalidomide- or bortezomib-induced PN. Larger, randomized, clinical trials are needed., Trial Registration: ClinicalTrials.gov Identifier: NCT00891618.

Background: Cerebrospinal fluid (CSF) sodium concentration increases during migraine attacks, and both CSF and vitreous humor sodium increase in the rat migraine model. The Na,K-ATPase is a probable source of these sodium fluxes. Since Na,K-ATPase isoforms have different locations and physiological roles, our objective was to establish which alpha isoforms are present at sites where sodium homeostasis is disrupted., Methods: Specific Na,K-ATPase alpha isoforms were identified in rat tissues by immunohistochemistry at the blood-CSF barrier at the choroid plexus, at the blood-CSF-trigeminal barrier at the meninges, at the blood-retina barrier, and at the blood-aqueous barrier at the ciliary body. Calcitonin gene-related peptide (CGRP), occludin, or von Willibrand factor (vWF) were co-localized with Na,K-ATPase to identify trigeminal nociceptor fibers, tight junctions, and capillary endothelial cells respectively., Results: The Na,K-ATPase alpha-2 isoform is located on capillaries and intensely at nociceptive trigeminal nerve fibers at the meningeal blood-CSF-trigeminal barrier. Alpha-1 and -3 are lightly expressed on the trigeminal nerve fibers but not at capillaries. Alpha-2 is expressed at the blood-retina barriers and, with alpha-1, at the ciliary body blood aqueous barrier. Intense apical membrane alpha-1 was associated with moderate cytoplasmic alpha-2 expression at the choroid plexus blood-CSF barrier., Conclusion: Na,K-ATPase alpha isoforms are present at the meningeal, choroid plexus, and retinal barriers. Alpha-2 predominates at the capillary endothelial cells in the meninges and retinal ganglion cell layer.

Objective. To characterize the pediatric endocrinologists' evaluation and followup of short-statured patients. Study Design. Observational study of 21,548 short-statured children (April 1996 to December 1999). Baseline demographics, laboratory testing, height standard deviation score (SDS), target height, and height relative to target height were analyzed at initial and return visits with the specialist. Patients were scheduled for at least one return visit and no recombinant human growth hormone therapy was administered. Results. Mean patient age was 8.6 years with a mean height SDS of -2.1. Patients were predominantly male (69%), prepubertal (73%), and white (76%). Few screening tests were obtained during initial evaluation. Nearly 40% of children did not return for their second scheduled visit. The follow-up rate was unrelated to demographics or degree of short stature. Conclusions. Low return rates limit specialists' ability to monitor growth or obtain laboratory testing over time. Further studies are needed to determine which tests should be obtained at the initial clinic visit as well as the basis for the low return rate in this group of children.