Diffuse intrinsic pontine glioma (DIPG) has proven to be one of the most challenging of all pediatric cancers. Owing to a historical reticence to obtain tumor tissue for study, and based on an ...erroneous assumption that the biology of DIPG would mirror that of supratentorial high-grade astrocytomas, innumerable studies have been undertaken-all of which have had a negligible impact on the natural history of this disease. More recently, improvements in neurosurgical techniques have allowed for the safe upfront biopsy of DIPG, which, together with a wider use of autopsy tissue, has led to an evolving understanding of the biology of this tumor. The discovery of a recurrent somatic gain-of-function mutation leading to lysine 27 to methionine (p.Lys27Met, K27M) substitution in histone 3 variants characterizes more than 85% of DIPG, suggesting for the first time the role of the epigenome and histones in the pathogenesis of this disease, and more unified diagnostic criteria. Along with further molecular insights into the pathogenesis of DIPG, rational targets are being identified and studied in the hopes of improving the otherwise dismal outcome for children with DIPG.
What is indigenous science? Cohen, Kenneth S.
Explore (New York, N.Y.),
July-August 2023, 2023 Jul-Aug, 2023-07-00, 20230701, Letnik:
19, Številka:
4
Journal Article
Purpose
Therapy for medulloblastoma in patients < 4 years old omits radiotherapy due to anticipated neurocognitive deficits. The German Pediatric Brain Tumor Study Group described a chemotherapy ...regimen (HIT-SKK’ 92 and HIT-SKK 2000) without radiation which yielded a 5-year progression-free survival (PFS) rate of 85% in children with nodular/desmoplastic medulloblastoma (NDMB) and medulloblastoma with extensive nodularity (MBEN). We modified the HIT-SKK regimen to reduce the total number of intrathecal methotrexate (IT MTX) doses from 12 to 2 doses/cycle and obviate Ommaya reservoir implantation through the use of lumbar administration. We report the outcomes of five patients treated with our approach.
Methods
IT MTX was eliminated altogether on weeks when high-dose intravenous methotrexate was administered. On weeks when no systemic methotrexate was administered, a single dose of lumbar-administered IT MTX was substituted in place of multiple intra-Ommaya doses. Cumulative dosing of MTX was 16–24 mg/cycle (age-based) compared to 24 mg/cycle in the HIT-SKK regimen. Following chemotherapy, patients were monitored with interval imaging, observation for acute and late effects, and survival.
Results
Four children remained in remission 3, 5, 9, and 10 years post-treatment respectively, without observed learning difficulties. One child had recurrent tumor and metastasis 6 months post-treatment. She failed the attempted salvage regimen and continued to deteriorate, dying of disease at 3 years old.
Conclusions
Review of existing literature supported our modifications well. While this report is limited by the small number of children treated, we believe there is encouraging evidence that our approach warrants further evaluation in a larger population of young children with NDMB and MBEN.
Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with
V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, ...open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients.
Patients ages 1 to <18 years who had
V600-mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2.
Overall, 32 patients with pLGG were enrolled (part 1,
= 15; part 2,
= 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% 95% confidence interval (CI), 26-62 by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64-94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%).
Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with
V600-mutant pLGG.
Real-world analysis of the incidence of SARS-CoV-2 infection post vaccination is important in determining the comparative effectiveness of the available vaccines. In this retrospective cohort study ...using deidentified administrative claims for Medicare Advantage and commercially insured individuals in a research database we examine over 3.5 million fully vaccinated individuals, including 8,848 individuals with SARS-CoV-2 infection, with a follow-up period between 14 and 151 days after their second dose. Our primary outcome was the rate of Covid-19 infection occurring at 30, 60, and 90 days at least 14 days after the second dose of either the mRNA-1273 vaccine or the BNT162b2 vaccine. Sub-analyses included the incidence of hospitalization, ICU admission, and death/hospice transfer. Separate analysis was conducted for individuals above and below age 65 and those without a prior diagnosis of Covid-19. We show that immunization with mRNA-1273, compared to BNT162b2, provides slightly more protection against SARS-CoV-2 infection that reaches statistical significance at 90 days with a number needed to vaccinate of >290. There are no differences in vaccine effectiveness for protection against hospitalization, ICU admission, or death/hospice transfer (aOR 1.23, 95% CI (0.67, 2.25)).
InThey Will Have Their Game, Kenneth Cohen explores how sports, drinking, gambling, and theater produced a sense of democracy while also reinforcing racial, gender, and class divisions in early ...America. Pairing previously unexplored financial records with a wide range of published reports, unpublished correspondence, and material and visual evidence, Cohen demonstrates how investors, participants, and professional managers and performers from all sorts of backgrounds saw these "sporting" activities as stages for securing economic and political advantage over others.
They Will Have Their Gametracks the evolution of this fight for power from 1760 to 1860, showing how its roots in masculine competition and risk-taking gradually developed gendered and racial limits and then spread from leisure activities to the consideration of elections as "races" and business as a "game." Compelling narratives about individual participants illustrate the processes by which challenge and conflict across class, race, and gender lines produced a sporting culture that continued to grant unique freedoms to a wide range of society even as it also provided a basis for the normalization of systematic inequality. The result reorients the standard narrative about the rise of commercial popular culture to question the influence of ideas such as "gentility" and "respectability," and to put men like P. T. Barnum at the end instead of the beginning of the process, unveiling a new take on the creation of the white male republic of the early nineteenth century in which sporting activities lie at the center and not the margins of economic and political history.
Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ...pandemic.
In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.
A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval CI, 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine.
None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).
Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in ...Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent ...glioblastoma.
Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points.
Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival.
Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
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