Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these ...young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure.
In this multicentre, phase 2 trial, we enrolled children younger than 3 years with newly diagnosed medulloblastoma at six centres in the USA and Australia. Children aged 3–5 years with newly diagnosed, non-metastatic medulloblastoma without any high-risk features were also eligible. Eligible patients were required to start therapy within 31 days from definitive surgery, had a Lansky performance score of at least 30, and did not receive previous radiotherapy or chemotherapy. Patients were stratified postoperatively by clinical and histological criteria into low-risk, intermediate-risk, and high-risk treatment groups. All patients received identical induction chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide), with high-risk patients also receiving an additional five doses of vinblastine. Induction was followed by risk-adapted consolidation therapy: low-risk patients received cyclophosphamide (1500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2), and carboplatin (area under the curve 5 mg/mL per min on day 2) for two 4-week cycles; intermediate-risk patients received focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks) to the tumour bed; and high-risk patients received chemotherapy with targeted intravenous topotecan (area under the curve 120–160 ng-h/mL intravenously on days 1–5) and cyclophosphamide (600 mg/m2 intravenously on days 1–5). After consolidation, all patients received maintenance chemotherapy with cyclophosphamide, topotecan, and erlotinib. The coprimary endpoints were event-free survival and patterns of methylation profiling associated with progression-free survival. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy); biological analyses included all patients with tissue available for methylation profiling. This trial is registered with ClinicalTrials.gov, number NCT00602667, and was closed to accrual on April 19, 2017.
Between Nov 27, 2007, and April 19, 2017, we enrolled 81 patients with histologically confirmed medulloblastoma. Accrual to the low-risk group was suspended after an interim analysis on Dec 2, 2015, when the 1-year event-free survival was estimated to be below the stopping rule boundary. After a median follow-up of 5·5 years (IQR 2·7–7·3), 5-year event-free survival was 31·3% (95% CI 19·3–43·3) for the whole cohort, 55·3% (95% CI 33·3–77·3) in the low-risk cohort (n=23) versus 24·6% (3·6–45·6) in the intermediate-risk cohort (n=32; hazard ratio 2·50, 95% CI 1·19–5·27; p=0·016) and 16·7% (3·4–30·0) in the high-risk cohort (n=26; 3·55, 1·66–7·59; p=0·0011; overall p=0·0021). 5-year progression-free survival by methylation subgroup was 51·1% (95% CI 34·6–67·6) in the sonic hedgehog (SHH) subgroup (n=42), 8·3% (95% CI 0·0–24·0%) in the group 3 subgroup (n=24), and 13·3% (95% CI 0·0–37·6%) in the group 4 subgroup (n=10). Within the SHH subgroup, two distinct methylation subtypes were identified and named iSHH-I and iSHH-II. 5-year progression-free survival was 27·8% (95% CI 9·0–46·6; n=21) for iSHH-I and 75·4% (55·0–95·8; n=21) for iSHH-II. The most common adverse events were grade 3–4 febrile neutropenia (48 patients 59%), neutropenia (21 26%), infection with neutropenia (20 25%), leucopenia (15 19%), vomiting (15 19%), and anorexia (13 16%). No treatment-related deaths occurred.
The risk-adapted approach did not improve event-free survival in young children with medulloblastoma. However, the methylation subgroup analyses showed that the SHH subgroup had improved progression-free survival compared with the group 3 subgroup. Moreover, within the SHH subgroup, the iSHH-II subtype had improved progression-free survival in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy compared with the iSHH-I subtype. These findings support the development of a molecularly driven, risk-adapted, treatment approach in future trials in young children with medulloblastoma.
American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.
Obesity, a chronic inflammatory disease, is the most prevalent modifiable risk factor for cardiovascular disease. The mechanisms underlying inflammation in obesity are incompletely understood. Recent ...developments have challenged the dogma of immunological memory occurring exclusively in the adaptive immune system and show that the innate immune system has potential to be reprogrammed. This innate immune memory (trained immunity) is characterized by epigenetic and metabolic reprogramming of myeloid cells following endogenous or exogenous stimulation, resulting in enhanced inflammation to subsequent stimuli. Trained immunity phenotypes have now been reported for other immune and non-immune cells. Here, we provide a novel perspective on the putative role of trained immunity in mediating the adverse cardiovascular effects of obesity and highlight potential translational pathways.
Obesity, a chronic inflammatory disorder, is the most prevalent modifiable risk factor for cardiovascular disease throughout the life-course; long-term outcomes following lifestyle interventions have generally been disappointing.Inhibition of inflammation has been shown to decrease cardiovascular risk in patients with a residual inflammatory risk.Recent studies have demonstrated that the innate immune system can adopt a long-term memory (trained immunity) after a previous encounter with a stimulus, resulting in an increased response upon secondary stimulation. Monocytes from patients with atherosclerosis have a trained immune phenotype.In obesity, a state of dyslipidemia, endotoxemia, and increased plasma cytokines and adipokines is likely to induce trained immunity.Non-immune cells can also be trained, indicating a possible role for adipocyte memory in chronic inflammation.
To examine how overweight and obesity at specific ages and overall BMI growth patterns throughout childhood predict cardiometabolic phenotypes at 11 to 12 years.
In a population-based sample of 5107 ...infants, BMI was measured every 2 years between ages 2 to 3 and 10 to 11 years. We identified 5 BMI trajectories using growth curve models. At ages 11 to 12 years, 1811 children completed assessments for metabolic syndrome risk scores, carotid-femoral pulse wave velocity, and carotid intima-media thickness. Multivariable regression models were used to estimate associations, adjusted for potential confounders (eg, age, sex, smoking exposure, and small for gestational age).
Overweight and obesity from early childhood onward were strongly associated with higher cardiometabolic risk at 11 to 12 years of age. At age 6 to 7 years, compared with those with a healthy weight, children with overweight had higher metabolic syndrome risk scores by 0.23 SD units (95% confidence interval 0.05 to 0.41) and with obesity by 0.76 SD units (0.51-1.01), with associations almost doubling by age 10 to 11 years. Obese (but not overweight) children had higher outcome pulse wave velocity (0.64-0.73 SD units) from ages 6 to 7 years and slightly higher outcome carotid intima-media thickness (0.20-0.30 SD units) at all ages. Cumulative exposure to high BMI from 2 to 3 years of age carried the greatest cardiometabolic risk, with a gradient of risk across trajectories.
High early-childhood BMI is already silently associated with the development of cardiometabolic risk by 11 to 12 years, highlighting the urgent need for effective action to reduce overweight and obesity in early childhood.
Loss of efficacy of diagnostic tests may lead to untreated or mistreated malaria cases, compromising case management and control. There is an increasing reliance on rapid diagnostic tests (RDTs) for ...malaria diagnosis, with the most widely used of these targeting the Plasmodium falciparum histidine-rich protein 2 (PfHRP2). There are numerous reports of the deletion of this gene in P. falciparum parasites in some populations, rendering them undetectable by PfHRP2 RDTs. The aim of this study was to identify P. falciparum parasites lacking the P. falciparum histidine rich protein 2 and 3 genes (pfhrp2/3) isolated from asymptomatic and symptomatic school-age children in Kinshasa, Democratic Republic of Congo.
The performance of PfHRP2-based RDTs in comparison to microscopy and PCR was assessed using blood samples collected and spotted on Whatman 903™ filter papers between October and November 2019 from school-age children aged 6-14 years. PCR was then used to identify parasite isolates lacking pfhrp2/3 genes.
Among asymptomatic malaria carriers (N = 266), 49%, 65%, and 70% were microscopy, PfHRP2_RDT, and pfldh-qPCR positive, respectively. The sensitivity and specificity of RDTs compared to PCR were 80% and 70% while the sensitivity and specificity of RDTs compared to microscopy were 92% and 60%, respectively. Among symptomatic malaria carriers (N = 196), 62%, 67%, and 87% were microscopy, PfHRP2-based RDT, pfldh-qPCR and positive, respectively. The sensitivity and specificity of RDTs compared to PCR were 75% and 88%, whereas the sensitivity and specificity of RDTs compared to microscopy were 93% and 77%, respectively. Of 173 samples with sufficient DNA for PCR amplification of pfhrp2/3, deletions of pfhrp2 and pfhrp3 were identified in 2% and 1%, respectively. Three (4%) of samples harboured deletions of the pfhrp2 gene in asymptomatic parasite carriers and one (1%) isolate lacked the pfhrp3 gene among symptomatic parasite carriers in the RDT positive subgroup. No parasites lacking the pfhrp2/3 genes were found in the RDT negative subgroup.
Plasmodium falciparum histidine-rich protein 2/3 gene deletions are uncommon in the surveyed population, and do not result in diagnostic failure. The use of rigorous PCR methods to identify pfhrp2/3 gene deletions is encouraged in order to minimize the overestimation of their prevalence.
As the population of women with HIV ages, an increasing proportion are experiencing the menopause, with potential associated pain. Among 844 participants in the Positive Transitions Through the ...Menopause (PRIME) study (72.3% black African; median age 49 (interquartile-range 47-53) years; 20.9%, 44.0% and 35.1% pre-, peri- and post-menopausal), 376 (44.6%) and 73 (8.7%) reported moderate or extreme pain. Women had been diagnosed with HIV for 14 (9-18) years, 97.7% were receiving antiretroviral therapy and 88.4% had a suppressed viral load. In adjusted ordinal logistic regression, peri-menopausal status (adjusted odds ratio (1.80) 95% confidence interval 1.22-2.67), current smoking (1.85 1.11-3.09), number of comorbid conditions (1.95 1.64-2.33 /condition) and longer duration of HIV (1.12 1.00-1.24/5 years) were independently associated with increased reported pain, whereas being in full-time work (0.61 0.45-0.83) and having enough money for basic needs (0.47 0.34-0.64) were associated with decreased pain reporting. Increasing pain was independently related to insomnia symptoms (moderate: 2.76 1.96-3.90; extreme: 8.09 4.03-16.24) and severe depressive symptoms (PHQ4 ≥ 6; moderate: 3.96 2.50-6.28; extreme: 9.13 4.45-18.72). Whilst our analyses cannot determine the direction of any associations, our findings point to the importance of eliciting a history of pain and addressing symptoms in order to improve wellbeing.
We describe the prevalence of pain and its associations with healthcare resource utilization and quality-of-life.
The POPPY Study recruited three cohorts: older people living with HIV (PLWH; ≥50 ...years, n = 699), younger demographically/lifestyle similar PLWH (less than 50 years, n = 374) and older demographically/lifestyle similar HIV-negative (≥50 years, n = 304) people from April 2013 to February 2016.
Current pain and pain-related healthcare use was collected via a self-reported questionnaire. Logistic regression assessed between-group differences in the prevalence of pain in the past month and current pain after controlling for potential confounders. Associations between current pain and healthcare resource use, reported joint problems, depressive symptoms, quality-of-life and functional status were assessed in PLWH using Mann-Whitney U and chi-squared tests.
Pain in the past month was reported by 473 out of 676 (70.0%) older PLWH, 224 out of 357 (62.7%) younger PLWH and 188 out of 295 (63.7%) older HIV-negative controls (P = 0.03), with current pain reported in 330 (48.8%), 134 (37.5%) and 116 (39.3%), respectively (P = 0.0007). Older PLWH were more likely to experience current pain, even after adjustment for confounders. Of those with pain in the past month, 56 out of 412 (13.6%) had missed days of work or study due to pain, and 520 (59%) had seen a doctor about their pain. PLWH experiencing current pain had more depressive symptoms, poorer quality-of-life on all domains and greater functional impairment, regardless of age group.
Even in the effective antiretroviral therapy era, pain remains common in PLWH and has a major impact on quality-of-life and associated healthcare and societal costs. Interventions are required to assist clinicians and PLWH to proactively manage pain.
Using data from the PRIME Study, an observational study of the menopause in women living with HIV in England, we explored the association between menopausal symptoms and: (i) antiretroviral therapy ...(ART) adherence and (ii) HIV clinic attendance.
We measured menopausal symptom severity with the Menopause Rating Scale (MRS, score ≥17 indicating severe symptoms), adherence with the CPCRA Antiretroviral Medication Adherence Self-Report Form, and ascertained HIV clinic attendance via self-report. Odds ratios were obtained using logistic regression.
Women who reported severe menopausal symptoms had greater odds of suboptimal ART adherence (adjusted odds ratio (AOR) 2.22; 95% CI 1.13, 4.35) and suboptimal clinic attendance (AOR 1.52; 95% CI 1.01, 2.29). When psychological, somatic and urogenital domains of the MRS were analysed individually there was no association between adherence and severe symptoms (all p > 0.1), however there was an association between suboptimal HIV clinic attendance and severe somatic (AOR 1.98; 95% CI 1.24, 3.16) and psychological (AOR 1.76; 95% CI 1.17, 2.65) symptoms.
Severe menopausal symptoms were significantly associated with sub-optimal ART adherence and HIV clinic attendance, however we cannot infer causality, highlighting the need for longitudinal data.
Objectives To estimate life expectancy for people with HIV undergoing treatment compared with life expectancy in the general population and to assess the impact on life expectancy of late treatment, ...defined as CD4 count <200 cells/mm3 at start of antiretroviral therapy.Design Cohort study.Setting Outpatient HIV clinics throughout the United Kingdom.Population Adult patients from the UK Collaborative HIV Cohort (UK CHIC) Study with CD4 count ≤350 cells/mm3 at start of antiretroviral therapy in 1996-2008.Main outcome measures Life expectancy at the exact age of 20 (the average additional years that will be lived by a person after age 20), according to the cross sectional age specific mortality rates during the study period.Results 1248 of 17 661 eligible patients died during 91 203 person years’ follow-up. Life expectancy (standard error) at exact age 20 increased from 30.0 (1.2) to 45.8 (1.7) years from 1996-9 to 2006-8. Life expectancy was 39.5 (0.45) for male patients and 50.2 (0.45) years for female patients compared with 57.8 and 61.6 years for men and women in the general population (1996-2006). Starting antiretroviral therapy later than guidelines suggest resulted in up to 15 years’ loss of life: at age 20, life expectancy was 37.9 (1.3), 41.0 (2.2), and 53.4 (1.2) years in those starting antiretroviral therapy with CD4 count <100, 100-199, and 200-350 cells/mm3, respectively.Conclusions Life expectancy in people treated for HIV infection has increased by over 15 years during 1996-2008, but is still about 13 years less than that of the UK population. The higher life expectancy in women is magnified in those with HIV. Earlier diagnosis and subsequent timely treatment with antiretroviral therapy might increase life expectancy.
Background. Cellular insulin resistance is the hallmark of type 2 diabetes and predominantly affects adipose and muscle cells. The saturated free fatty acid palmitate is elevated in insulin-resistant ...states and may directly contribute to cellular insulin resistance. A spectrum of renal disease is associated with increased markers of insulin resistance, although direct causal mechanisms are not known. In the kidney, glomerular podocytes are novel insulin-sensitive cells that have the ability to rapidly transport glucose. In this study, we tested the hypothesis that palmitate would induce insulin resistance in podocytes. Methods. Conditionally immortalized human podocytes were cultured for up to 24 h with 375–750 μM palmitate. Functional effects on glucose uptake and ceramide production were measured. Gene expression was investigated using a focused gene array, and protein signalling and trafficking were studied with Western blotting and immunofluorescence. Results. We found that palmitate blocked insulin-stimulated glucose uptake in human podocytes. This was associated with increased ceramide production, and use of the ceramide inhibitors myriocin and fumonisin B1 partially recovered the insulin sensitivity. At the level of transcription, palmitate downregulated genes associated with several pathways involved in insulin signalling. At the protein level, phosphorylation of the insulin receptor, IRS1 and PKB was reduced and there was impaired translocation of GLUT4 to the cell surface. Conclusion. This is the first study to demonstrate a direct effect of saturated fatty acids on podocyte function. These findings may represent a novel link between systemic insulin resistance and the development of nephropathy.
Lipid antigens in immunity Dowds, C. Marie; Kornell, Sabin-Christin; Blumberg, Richard S. ...
Biological chemistry,
01/2014, Letnik:
395, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Lipids are not only a central part of human metabolism but also play diverse and critical roles in the immune system. As such, they can act as ligands of lipid-activated nuclear receptors, control ...inflammatory signaling through bioactive lipids such as prostaglandins, leukotrienes, lipoxins, resolvins, and protectins, and modulate immunity as intracellular phospholipid- or sphingolipid-derived signaling mediators. In addition, lipids can serve as antigens and regulate immunity through the activation of lipid-reactive T cells, which is the topic of this review. We will provide an overview of the mechanisms of lipid antigen presentation, the biology of lipid-reactive T cells, and their contribution to immunity.
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