Serial MR diffusion to predict treatment response in high-grade pediatric brain tumors: a comparison of regional and voxel-based diffusion change metrics

Background Assessment of treatment response by measuring tumor size is known to be a late and potentially confounded response index. Serial diffusion MRI has shown potential for allowing earlier and possibly more reliable response assessment in adult patients, with limited experience in clinical settings and in pediatric brain cancer. We present a retrospective study of clinical MRI data in children with high-grade brain tumors to assess and compare the values of several diffusion change metrics to predict treatment response. Methods Eighteen patients (age range, 1.9–20.6 years) with high-grade brain tumors and serial diffusion MRI (pre- and posttreatment interval range, 1–16 weeks posttreatment) were identified after obtaining parental consent. The following diffusion change metrics were compared with the clinical response status assessed at 6 months: (1) regional change in absolute and normalized apparent diffusivity coefficient (ADC), (2) voxel-based fractional volume of increased (fiADC) and decreased ADC (fdADC), and (3) a new metric based on the slope of the first principal component of functional diffusion maps (fDM). Results Responders (n = 12) differed significantly from nonresponders (n = 6) in all 3 diffusional change metrics demonstrating higher regional ADC increase, larger fiADC, and steeper slopes (P < .05). The slope method allowed the best response prediction (P < .01, η2 = 0.78) with a classification accuracy of 83% for a slope of 58° using receiver operating characteristic (ROC) analysis. Conclusions We demonstrate that diffusion change metrics are suitable response predictors for high-grade pediatric tumors, even in the presence of variable clinical diffusion imaging protocols

QuantiFERON®-TB gold in-tube performance for diagnosing active tuberculosis in children and adults in a high burden setting.

To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania. Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-γ levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB. Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-γ were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline. QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting

SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study

BACKGROUND: SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3 to 21 years treated with a staged management strategy. A further aim was to assess the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide and cyclophosphamide (VEC). We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers. METHODS: 74 participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation, 1q, hTERT, ReLA, Tenascin-C, H3K27me3 and pAKT status were evaluated. RESULTS: Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.003, HR=2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (p=0.005, HR=2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (p=0.003, HR=2.70, 95%CI 1.49-6.10 and p=0.014, HR=5.8, 95%CI 1.2-28) and H3K27me3 loss with worse OS (p=0.003, HR=4.6, 95%CI 1.5-13.2). Methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, best chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding the prespecified 45%. CONCLUSIONS: Participants with totally resected ependymoma had the best outcomes. RR of STR to VEC exceeded the pre-specified efficacy criterion. However, cases of inaccurate stratification highlighted the need for rapid central review. 1q gain, H3K27me3 loss and hTERT expression were all associated with poorer survival outcomes

Development of a pre-operative scoring system for predicting risk of post-operative paediatric cerebellar mutism syndrome

BACKGROUND: Despite previous identification of pre-operative clinical and radiological predictors of post-operative paediatric cerebellar mutism syndrome (CMS), a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aim of the project is to develop a simple imaging-based pre-operative risk scoring scheme to stratify patients in terms of post-operative CMS risk. METHODS: Pre-operative radiological features were recorded for a retrospectively assembled cohort of 89 posterior fossa tumour patients from two major UK treatment centers (age 2-23yrs; gender 28 M, 61 F; diagnosis: 38 pilocytic astrocytoma, 32 medulloblastoma, 12 ependymoma, 1 high grade glioma, 1 pilomyxoid astrocytoma, 1 atypical teratoid rhabdoid tumour, 1 hemangioma, 1 neurilemmoma, 2 oligodendroglioma). Twenty-six (29%) developed post-operative CMS. Based upon results from univariate analysis and C4.5 decision tree, stepwise logistic regression was used to develop the optimal model and generate risk scores. RESULTS: Univariate analysis identified five significant risk factors and C4.5 decision tree analysis identified six predictors. Variables included in the final model are MRI primary location, bilateral middle cerebellar peduncle involvement (invasion and/or compression), dentate nucleus invasion and age at imaging >12.4 years. This model has an accuracy of 88.8% (79/89). Using risk score cut-off of 203 and 238, respectively, allowed discrimination into low (38/89, predicted CMS probability <3%), intermediate (17/89, predicted CMS probability 3-52%) and high-risk (34/89, predicted CMS probability ≥52%). CONCLUSIONS: A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process

Magnetic resonance imaging protocols for paediatric neuroradiology

Increasingly, radiologists are encouraged to have protocols for all imaging studies and to include imaging guidelines in care pathways set up by the referring clinicians. This is particularly advantageous in MRI where magnet time is limited and a radiologist’s review of each patient’s images often results in additional sequences and longer scanning times without the advantage of improvement in diagnostic ability. The difficulties of imaging small children and the challenges presented to the radiologist as the brain develops are discussed. We present our protocols for imaging the brain and spine of children based on 20 years experience of paediatric neurological MRI. The protocols are adapted to suit children under the age of 2 years, small body parts and paediatric clinical scenarios

Bacterial Disease and Antimicrobial Susceptibility Patterns in HIV-Infected, Hospitalized Children: A Retrospective Cohort Study

The orginal version is available at www.plosone.orgBackground: Serious bacterial infections are a major source of morbidity and mortality in HIV-infected children. The spectrum of disease is wide, and responsible organisms vary according to setting. The use of antibiotic prophylaxis and the emergence of multi-drug resistant bacteria necessitate examination of responsible organisms and their antibiotic susceptibility. Methodology/Principal Findings: A retrospective cohort study of all HIV-positive pediatric admissions at an urban public sector hospital in Cape Town between January 2002 and June 2006 was conducted. Children between the ages of one month and nine years with laboratory confirmed HIV status, serious bacterial infection, and a hospital length of stay of 5 days or more, were eligible for inclusion. Organisms isolated from blood, urine, and cerebral spinal fluid cultures and their antimicrobial susceptibility were examined, and compared according to timing of isolation to distinguish nosocomial versus community-acquired. One hundred and forty-one children were identified (median age 1.2 years), 39% of whom were on antiretrovirals started before or during this hospitalization. Bacterial infections involved all organ systems, however pneumonia was most common (67%). S. pneumoniae and S. aureus were the most common gram positive and K. pneumoniae was the most common gram negative organism. K pneumoniae isolates were resistant to many first and second line antibiotics, and were all considered nosocomial. All S. aureus isolates were methicillin resistant, some of which were community-acquired. Conclusions/Significance: Bacterial infections are an important source of co-morbidity in HIV-infected children in resourcelimited settings. Clinicians should have a low threshold to initiate antibiotics in children requiring hospitalization. Broadspectrum antibiotics should be used judiciously. Clinicians caring for HIV-infected children should be cognizant of the most common organisms affecting such children, and of their local antimicrobial susceptibilities, when treating empirically for serious bacterial infections.Publisher's versio

The role of polyclonal intravenous immunoglobulin in treating HIV-infected children with severe bacterial infections: A retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Mortality among HIV-infected children in developing countries remains high after serious bacterial infections despite the use of antibiotics. Intravenous immunoglobulin (IVIG) has been used as an adjuvant therapy to treat these infections, but little data exists regarding its efficacy, and previous studies have focused on IVIG as a prophylactic agent. We examined the impact of IVIG as an adjuvant therapy in reducing mortality and length of hospital stay in HIV-infected children with serious bacterial infections.</p> <p>Methods</p> <p>This retrospective study focused on pediatric admissions at a large urban hospital between 2002 and 2006. Children between the ages of one month and nine years of age with laboratory confirmed HIV-status, serious bacterial infection, no prior exposure to IVIG, and a hospital length of stay of 5 days or more, were eligible for inclusion.</p> <p>Results</p> <p>A total of 140 children (median age 1.2 years) met inclusion criteria; lower respiratory tract infection was diagnosed in 94 (67%) of the children, while 74 (53%) had bacterial sepsis. Fifty-four (39%) children were receiving antiretroviral therapy and 39 (28%) were receiving tuberculosis treatment. Overall 73 (52%) were treated with IVIG, with the majority (74%) of children receiving a single dose. Thirteen (9%) died during their hospital admission. In crude analysis IVIG was significantly associated with increased mortality was (Odds Ratio (OR): 5.8; 95% Confidence Interval (CI): 1.2–27.1) and this association was weakened by adjustment for other predictors of mortality (OR 4.3, 95% CI 0.7–27.9, p = 0.123). IVIG use was also associated with longer hospital stays.</p> <p>Conclusion</p> <p>Administration of one to three doses of IVIG during the acute phase of illness does not appear to reduce mortality or the length of hospital stays in HIV-infected children with serious bacterial infections. However, the retrospective nature of this study makes confounding by indication difficult to control and further studies regarding the timing, dosing, and method of administration are required. Nonetheless the routine use of IVIG in resource-limited settings should be carefully considered given its high cost.</p

SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study

BackgroundSIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3 to 21 years treated with a staged management strategy. A further aim was to assess the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide and cyclophosphamide (VEC). We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers.Methods74 participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation, 1q, hTERT ,ReLA, Tenascin-C, H3K27me3 and pAKT status were evaluated.ResultsFive- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.003, HR=2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (p=0.005, HR=2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (p=0.003, HR=2.70, 95%CI 1.49-6.10 and p=0.014, HR=5.8, 95%CI 1.2-28) and H3K27me3 loss with worse OS (p=0.003, HR=4.6, 95%CI 1.5-13.2). Methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, best chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding the prespecified 45%.ConclusionsParticipants with totally resected ependymoma had the best outcomes. RR of STR to VEC exceeded the pre-specified efficacy criterion. However, cases of inaccurate stratification highlighted the need for rapid central review. 1q gain, H3K27me3 loss and hTERT expression were all associated with poorer survival outcomes

Changes to the law on consent in South Africa: implications for school-based adolescent sexual and reproductive health research

BACKGROUND:The National Health Act, No 61, 2003 in South Africa is the first effort made by the government to protect health-related research participants under law. Implemented on March 1, 2012, the law mandates active consent from a parent or legal guardian for all research conducted with research participants under the age of 18 years. This paper focuses on the Act's implications for school-based adolescent sexual and reproductive health research.DISCUSSION:Although well intentioned, the added legal protections in the National Health Act may have the unintended consequence of reducing participation rates in school-based adolescent sexual and reproductive health research, thereby excluding the most at-risk students. The Act may also compromise adolescents' right to dignity and privacy, especially considering the personal nature of research on sex and sexuality. Devolved, discretionary decision-making, which empowers local human research ethics committees to permit a wider range of protective measures, including passive consent, independent adolescent consent or community consultation ought to be considered. The continued and direct involvement of young people in their sexual and reproductive health and well-being is an important principle to uphold.SUMMARY:This paper calls for a re-examination of section 71's ethical guidelines relating to informed consent in the National Health Act, No 61, 2003 in South Africa in order to better serve the interests of South African adolescents in sexual and reproductive health research