Brain Tumor Imaging in Adolescents and Young Adults: 2021 WHO Updates for Molecular-based Tumor Types.

Published in 2021, the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) introduced new molecular criteria for tumor types that commonly occur in either pediatric or adult age groups. Adolescents and young adults (AYAs) are at the intersection of adult and pediatric care, and both pediatric-type and adult-type CNS tumors occur at that age. Mortality rates for AYAs with CNS tumors have increased by 0.6% per year for males and 1% per year for females from 2007 to 2016. To best serve patients, it is crucial that both pediatric and adult radiologists who interpret neuroimages are familiar with the various pediatric- and adult-type brain tumors and their typical imaging morphologic characteristics. Gliomas account for approximately 80% of all malignant CNS tumors in the AYA age group, with the most common types observed being diffuse astrocytic and glioneuronal tumors. Ependymomas and medulloblastomas also occur in the AYA population but are seen less frequently. Importantly, biologic behavior and progression of distinct molecular subgroups of brain tumors differ across ages. This review discusses newly added or revised gliomas in the fifth edition of the CNS WHO classification, as well as other CNS tumor types common in the AYA population.

Pediatric-type low-grade gliomas in adolescents and young adults-challenges and emerging paradigms.

Pediatric-type low-grade glioma (PLGG) encompasses a heterogeneous group of WHO grade 1 or 2 tumors and is the most common central nervous system tumor found in children. PLGG extends beyond pediatrics, into adolescents and young adults (AYA, ages 15-40). PLGG represents 25% of all gliomas diagnosed in AYA with differences in tumor location and molecular alterations compared to children, resulting in improved outcome for AYAs. Long-term outcome is excellent, though patients may suffer significant morbidity depending on tumor location. There are differences in treatment practices with radiation used to treat PLGG in AYAs more often than in children. Most PLGG in AYA harbor an alteration in the RAS/MAPK pathway, with limited insight into response to targeted therapy in this age group. This review discusses the epidemiology, current therapeutic approaches, and challenges in the management of PLGG in AYA.

Understanding diffuse leptomeningeal glioneuronal tumors.

INTODUCTION: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances. METHODS: This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted. RESULTS: DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts. CONCLUSION: Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms.

Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.

Review of the Impact of Housing Quality on Inequalities in Health and Well-Being.

Housing quality is essential for population health and broader well-being. The World Health Organization Housing and health guidelines highlight interventions that protect occupants from cold and hot temperatures, injuries, and other hazards. The COVID-19 pandemic has emphasized the importance of ventilation standards. Housing standards are unevenly developed, implemented, and monitored globally, despite robust research demonstrating that retrofitting existing houses and constructing high-quality new ones can reduce respiratory, cardiovascular, and infectious diseases. Indigenous peoples, ethnic minorities, and people with low incomes face cumulative disadvantages that are exacerbated by poor-quality housing. These can be partially ameliorated by community-based programs to improve housing quality, particularly for children and older people, who are hospitalized more often for housing-related illnesses. There is renewed interest among policy makers and researchers in the health and well-being of people in public and subsidized housing, who are disproportionately disadvantaged by avoidable housing-related diseases and injuries. Improving the overall quality of new and existing housing and neighborhoods has multiple cobenefits, including reducing carbon emissions.

Brain Tumors in Adolescents and Young Adults: A Review.

Brain tumors account for the majority of cancer-related deaths in adolescents and young adults (AYAs), defined as individuals aged 15 to 39. AYAs constitute a distinct population in which both pediatric- and adult-type central nervous system (CNS) tumors can be observed. Clinical manifestations vary depending on tumor location and often include headaches, seizures, focal neurological deficits, and signs of increased intracranial pressure. With the publication of the updated World Health Organization CNS tumor classification in 2021, diagnoses have been redefined to emphasize key molecular alterations. Gliomas represent the majority of malignant brain tumors in this age group. Glioneuronal and neuronal tumors are associated with longstanding refractory epilepsy. The classification of ependymomas and medulloblastomas has been refined, enabling better identification of low-risk tumors that could benefit from treatment de-escalation strategies. Owing to their midline location, germ cell tumors often present with oculomotor and visual alterations as well as endocrinopathies. The management of CNS tumors in AYA is often extrapolated from pediatric and adult guidelines, and generally consists of a combination of surgical resection, radiation therapy, and systemic therapy. Ongoing research is investigating multiple agents targeting molecular alterations, including isocitrate dehydrogenase inhibitors, SHH pathway inhibitors, and BRAF inhibitors. AYA patients with CNS tumors should be managed by multidisciplinary teams and counselled regarding fertility preservation, psychosocial comorbidities, and risks of long-term comorbidities. There is a need for further efforts to design clinical trials targeting CNS tumors in the AYA population.

Shouldn't We Know This Already? UK Women's Views About Communicating the Link Between Alcohol Consumption and Risk of Breast Cancer.

Alcohol is a causal factor in about 10% of breast cancer (BCa) cases, but awareness of this link is low. This study explored how to raise awareness and inform the development of an intervention using the COM-B model (capability, opportunity, motivation, behavior) framework. Eight online focus groups were conducted with 36 participants (6 expert stakeholders,and 30 women aged 40-65). Participants reflected on a package of information about alcohol and BCa and discussed how to impart this information and encourage women to reduce drinking. Thematic analysis of focus group transcripts was undertaken. Three themes were identified: understanding ineffective messaging; transitions and challenges; and message acceptability. Current health information about alcohol was perceived as judgmental and BCa was put down to chance. Mid-life consisted of many challenges that could lead to increased consumption, but menopause transition may be a key moment for alcohol reduction. Barriers and enablers to communicating risk information and encouraging alcohol reduction were mapped onto the COM-B model. Psychological capability (relating to knowledge), social opportunity (in the form of social pressure) and automatic motivation (relating to drinking to cope) were barriers to behavior change.  These will be targeted in an alcohol reduction intervention. It is important to tailor information to women's experiences, taking into account the social benefits of drinking, and encourage the development of healthy coping strategies. Acceptable intervention messages may include personal stories, clear statistics, and suggest healthy alternatives to drinking. It is vital that messaging does not appear judgmental or patronizing.

Increased Breadth of Group A Streptococcus Antibody Responses in Children With Acute Rheumatic Fever Compared to Precursor Pharyngitis and Skin Infections.

BACKGROUND: Group A Streptococcus (GAS) causes superficial pharyngitis and skin infections as well as serious autoimmune sequelae such as acute rheumatic fever (ARF) and subsequent rheumatic heart disease. ARF pathogenesis remains poorly understood. Immune priming by repeated GAS infections is thought to trigger ARF, and there is growing evidence for the role of skin infections in this process. METHODS: We utilized our recently developed 8-plex immunoassay, comprising antigens used in clinical serology for diagnosis of ARF (SLO, DNase B, SpnA), and 5 conserved putative GAS vaccine antigens (Spy0843, SCPA, SpyCEP, SpyAD, Group A carbohydrate), to characterize antibody responses in sera from New Zealand children with a range of clinically diagnosed GAS disease: ARF (n = 79), GAS-positive pharyngitis (n = 94), GAS-positive skin infection (n = 51), and matched healthy controls (n = 90). RESULTS: The magnitude and breadth of antibodies in ARF was very high, giving rise to a distinct serological profile. An average of 6.5 antigen-specific reactivities per individual was observed in ARF, compared to 4.2 in skin infections and 3.3 in pharyngitis. CONCLUSIONS: ARF patients have a unique serological profile, which may be the result of repeated precursor pharyngitis and skin infections that progressively boost antibody breadth and magnitude.

Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma.

BACKGROUND: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. METHODS: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. RESULTS: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. CONCLUSIONS: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

Medical Treatment for Rheumatic Heart Disease: A Narrative Review.

BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are rare in high-income countries; however, in Aotearoa New Zealand ARF and RHD disproportionately affect Indigenous Maori and Pacific Peoples. This narrative review explores the evidence regarding non-surgical management of patients with clinically significant valve disease or heart failure due to RHD. METHODS: Medline, EMBASE and Scopus databases were searched, and additional publications were identified through cross-referencing. Included were 28 publications from 1980 onwards. RESULTS: Of the available interventions, improved anticoagulation management and a national RHD register could improve RHD outcomes in New Zealand. Where community pharmacy anticoagulant management services (CPAMS) are available good anticoagulation control can be achieved with a time in the therapeutic range (TTR) of more than 70%, which is above the internationally recommended level of 60%. The use of pharmacists in anticoagulation control is cost-effective, acceptable to patients, pharmacists, and primary care practitioners. There is a lack of local data available to fully assess other interventions; including optimal therapy for heart failure, equitable access to specialist RHD care, prevention, and management of endocarditis. CONCLUSION: As RHD continues to disproportionately affect Indigenous and minority groups, pro-equity tertiary prevention interventions should be fully evaluated to ensure they are reducing disease burden and improving outcomes in patients with RHD.

Rising Ethnic Inequalities in Acute Rheumatic Fever and Rheumatic Heart Disease, New Zealand, 2000-2018.

We describe trends in acute rheumatic fever (ARF), rheumatic heart disease (RHD), and RHD deaths among population groups in New Zealand. We analyzed initial primary ARF and RHD hospitalizations during 2000-2018 and RHD mortality rates during 2000-2016. We found elevated rates of initial ARF hospitalizations for persons of Maori (adjusted rate ratio [aRR] 11.8, 95% CI 10.0-14.0) and Pacific Islander (aRR 23.6, 95% CI 19.9-27.9) ethnicity compared with persons of European/other ethnicity. We also noted higher rates of initial RHD hospitalization for Maori (aRR 3.2, 95% CI 2.9-3.5) and Pacific Islander (aRR 4.6, 95% CI 4.2-5.1) groups and RHD deaths among these groups (Maori aRR 12.3, 95% CI 10.3-14.6, and Pacific Islanders aRR 11.2, 95% CI 9.1-13.8). Rates also were higher in socioeconomically disadvantaged neighborhoods. To curb high rates of ARF and RHD, New Zealand must address increasing social and ethnic inequalities.

Ethnically Disparate Disease Progression and Outcomes among Acute Rheumatic Fever Patients in New Zealand, 1989-2015.

We investigated outcomes for patients born after 1983 and hospitalized with initial acute rheumatic fever (ARF) in New Zealand during 1989-2012. We linked ARF progression outcome data (recurrent hospitalization for ARF, hospitalization for rheumatic heart disease [RHD], and death from circulatory causes) for 1989-2015. Retrospective analysis identified initial RHD patients <40 years of age who were hospitalized during 2010-2015 and previously hospitalized for ARF. Most (86.4%) of the 2,182 initial ARF patients did not experience disease progression by the end of 2015. Progression probability after 26.8 years of theoretical follow-up was 24.0%; probability of death, 1.0%. Progression was more rapid and ≈2 times more likely for indigenous Maori or Pacific Islander patients. Of 435 initial RHD patients, 82.2% had not been previously hospitalized for ARF. This young cohort demonstrated low mortality rates but considerable illness, especially among underserved populations. A national patient register could help monitor, prevent, and reduce ARF progression.

Early diagnosis of acute rheumatic fever and rheumatic heart disease as part of a secondary prevention strategy: Narrative review.

Acute rheumatic fever (ARF) and its sequela rheumatic heart disease (RHD) remain significant causes of morbidity and mortality. In New Zealand, ARF almost exclusively affects Indigenous Maori and Pacific children. This narrative review aims to present secondary interventions to improve early and accurate diagnosis of ARF and RHD, in order to minimise disease progression in New Zealand. Medline, EMBASE and Scopus databases were searched as well as other electronic publications. Included were 56 publications from 1980 onwards. Diagnosing ARF and RHD as early as possible is central to reducing disease progression. Recent identification of specific ARF biomarkers offer the opportunity to aid initial diagnosis and portable echocardiography has the potential to detect undiagnosed RHD in high-risk areas. However, further research into the benefits and risks to children with subclinical RHD is necessary, as well as an economic evaluation.

Structured review of primary interventions to reduce group A streptococcal infections, acute rheumatic fever and rheumatic heart disease.

Rheumatic heart disease (RHD) is a large, preventable, global public health burden. In New Zealand (NZ), acute rheumatic fever (ARF) and RHD rates are highest for Maori and Pacific children. This structured review explores the evidence for primary prevention interventions to diagnose and effectively treat group A Streptococcus (GAS) pharyngitis and skin infections to reduce rates of ARF and RHD. Medline, EMBASE and Scopus databases were searched as well as other electronic publications. Included were 50 publications from 1980 onwards. This review has identified that there is little available evidence for effective primary prevention strategies to reduce ARF rates in NZ. However, two primary intervention strategies that should be considered by communities at high-risk of ARF are: the use of school-based clinics to identify and treat GAS pharyngitis and GAS skin infections; and intramuscular benzathine penicillin G with lignocaine analgesia in children who present with a GAS positive throat.

Understanding group A streptococcal pharyngitis and skin infections as causes of rheumatic fever: protocol for a prospective disease incidence study.

BACKGROUND: Group A Streptococcal (GAS) infections cause the autoimmune disease acute rheumatic fever (ARF), which can progress to chronic rheumatic heart disease (RHD). Treating pharyngitis caused by GAS with antibiotics is important in preventing ARF. However, it is difficult to distinguish these infections from GAS carriers. There is growing evidence for GAS skin infections as a cause of ARF. This study will identify the incidence of true GAS pharyngitis and serological responses to GAS skin infections. The effectiveness of antibiotics for these conditions will be explored, and modifiable risk factors. Serum antibody titres indicating the upper limits of normal (ULN for ASO/ADB antibodies) will be established alongside carriage rates in asymptomatic children. METHODS: This is a prospective disease incidence study, with an associated case-control study. The study population includes 1000 children (5-14 years) from Auckland, New Zealand, 800 of whom have visited their healthcare professional, resulting in a throat or skin swab for GAS, and 200 who are asymptomatic. The conditions of interest are GAS throat swab positive pharyngitis (n = 200); GAS carriage (n = 200); GAS negative throat swab (n = 200); GAS skin infections (n = 200); and asymptomatic controls (n = 200). All participants, except asymptomatic controls, will have acute and convalescent serological testing for ASO/ADB titres (collected < 9 days, and 2-4 weeks following symptom onset, respectively), alongside viral PCR from throat swabs. Asymptomatic controls will have ASO/ADB titres measured in one blood specimen and a throat swab for microbial culture. Caregivers of children will be interviewed using a questionnaire and any GAS isolates identified will be emm typed. The persistence of GAS antibodies will also be investigated. DISCUSSION: Findings from this study will fill critical gaps in scientific knowledge to better understand the pathophysiology of ARF, improve clinical management of GAS infections, and design more effective ARF prevention programmes. In particular it will measure the incidence of true, serologically confirmed GAS pharyngitis; assess the immune response to GAS skin infections and its role as a cause of ARF; examine the effectiveness of oral antibiotics for treating GAS pharyngitis and carriage; and identify whether risk factors for GAS infections might provide intervention points for reducing ARF.

Hepatoblastoma in a Child With Early-onset Cirrhosis.

Hepatoblastoma is the most common hepatic malignancy of childhood with known genetic predispositions and perinatal risk factors, with rare case reports occurring in the setting of cirrhosis. This case describes a young patient with cirrhosis attributed to early-onset hereditary hemochromatosis who was diagnosed with hepatoblastoma with uncommon histologic findings, evidence of chemotherapy resistance who ultimately succumbed to her disease. It is important to consider diagnoses beyond hepatocellular carcinoma in this scenario and consider early biopsy. With atypical histology, the tumor may respond poorly to conventional treatment and aggressive surgery or intensive therapy should be contemplated.

Evaluation of a Passive Sampling Method for Long-Term Continuous Monitoring of Volatile Organic Compounds in Urban Environments.

Environmental Protection Agency Method 325 was developed for continuous passive monitoring of volatile organic compounds (VOCs), particularly benzene, at petroleum refinery fencelines. In this work, a modified version of the method was evaluated at an Ontario near-road research station in winter to assess its suitability for urban air quality monitoring. Samples were collected at 24 hour and 14 day resolution to investigate accuracy for different exposure times. Tubes were analyzed by thermal desorption-gas chromatography-mass spectrometry, and 11 VOCs were quantified, including aromatic air toxics. The same VOCs were simultaneously monitored using traditional canister sampling for comparison, and a subset of four were also monitored using a novel miniature gas chromatograph. Good agreement (within 10%) was observed between the 14 day passive tube samples and the canister samples for benzene. However, field-calibrated uptake rates were required to correct passive tube concentrations for less volatile aromatics. Passive tube deployment and analysis is inexpensive; sampling does not require power, and accurate measurements of benzene are demonstrated here for an urban environment. The method is expected to be advantageous for the generation of long-term continuous benzene datasets suitable for epidemiological research with greater spatial coverage than is currently available using traditional monitoring techniques.

Spatial structuring of soil microbial communities in commercial apple orchards.

Characterising spatial microbial community structure is important to understand and explain the consequences of continuous plantation of one crop species on the performance of subsequent crops, especially where this leads to reduced growth vigour and crop yield. We investigated the spatial structure, specifically distance-decay of similarity, of soil bacterial and fungal communities in two long-established orchards with contrasting agronomic characteristics. A spatially explicit sampling strategy was used to collect soil from under recently grubbed rows of apple trees and under the grassed aisles. Amplicon-based metabarcoding technology was used to characterise the soil microbial communities. The results suggested that (1) most of the differences in soil microbial community structure were due to large-scale differences (i.e. between orchards), (2) within-orchard, small-scale (1-5 m) spatial variability was also present, but spatial relationships in microbial community structure differed between orchards and were not predictable, and (3) vegetation type (i.e. trees or grass and their associated management) can significantly alter the structure of soil microbial communities, affecting a large proportion of microbial groups. The discontinuous nature of soil microbial community structure in the tree stations and neighbouring grass aisles within an orchard illustrate the importance of vegetation type and allied weed and nutrient management on soil microbial community structure.

The clinical significance of equivocal findings on spinal MRI in children with medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor of childhood, with cerebrospinal fluid spread the most common site of metastasis. Currently, children diagnosed with MB and evidence of spinal metastasis are treated with an increased dose of craniospinal radiation (CSI). This report reviewed equivocal abnormalities including nerve root clumping, linear vascular enhancement, nerve root enhancement and/or other vague findings on spinal magnetic resonance imaging (MRI) to elucidate their prognostic significance and aid in risk stratification. METHODS: This retrospective cohort study identified children (≥3 years) diagnosed with MB between 1988 and 2012. Children treated with upfront CSI were included, and staging spine MRI must have been done preoperatively or within 72 hr of primary tumor resection. Initial MRI of the spine was assessed by two independent reviewers blinded to outcome to evaluate for equivocal findings. Survival analysis was done to determine impact on prognosis. RESULTS: One hundred of 157 patients were eligible for the analysis. Equivocal findings were identified in 48 (48%) patients, with MRI done preoperatively in 45 (94%) patients. Analysis by subgroup identified a higher proportion of equivocal findings in the sonic hedgehog (SHH) subgroup (P = 0.007). Five-year overall survival (OS) in children with equivocal findings compared to those with normal MRI was not different, 80 vs. 84.8% respectively, while OS in M3 patients was worse at 54.7% (P = 0.02). CONCLUSION: A higher proportion of equivocal findings was identified in the SHH subgroup. This institutional retrospective review demonstrates equivocal findings are common, not associated with decreased OS and should not prompt increased dose of CSI.