Treatment of children with favorable histology Wilms tumor with extrapulmonary metastases: A report from the COG studies AREN0533 and AREN03B2 and NWTSG study NWTS-5.

BACKGROUND: Patients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children's Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD-4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS-5, were reviewed. METHODS: Combined outcomes for patients with EPM from NWTS-5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS-5. Prognostic factors were explored in the pooled cohort. RESULTS: Forty-seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS-5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4-year event-free survival (EFS) of 77.3% (95% CI, 70.8-84.4) and 4-year overall survival of 88.9% (95% CI, 83.9-94.2). Four-year EFS of patients with EPM treated on AREN0533 was 76.0% (95% CI, 64.6-89.4) vs 64.9% (95% CI, 51.7-82.2) on NWTS-5; hazard ratio, 0.64, p = .26; no difference in overall survival was observed. Increasing linear age and slow incomplete lung response were associated with worse EFS in a pooled cohort. CONCLUSIONS: Outcomes for patients with EPM are among the lowest for children with FHWT. Further trials with standardized surgical and radiation treatment to metastatic sites, and prospectively collected biologic and treatment details are needed. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifiers: NCT00379340, NCT00898365, and NCT00002611.

Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2.

BACKGROUND: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. METHODS: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. RESULTS: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. CONCLUSIONS: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).

A prospective study of shared decision-making in brain tumor surgery.

PURPOSE: Shared decision-making (SDM) is a key tenet of personalized care and is becoming an essential component of informed consent in an increasing number of countries. The aim of this study is to analyze patient and healthcare staff satisfaction with the SDM process before and after SDM was officially introduced as the standard of care. Decision grids are important tools in the SDM process, and we developed them for three different types of intracranial tumors. METHODS: This prospective study was conducted in a high-volume neuro-oncological center on all consecutive eligible patients undergoing consideration of treatment for intracranial glioma and metastases. Twenty-two patients participated before and 74 after the introduction of SDM. Six and 5 staff members respectively participated in the analysis before and after team training and the introduction of SDM. The main outcome was patient and healthcare staff satisfaction with the SDM process. RESULTS: Patients reported high satisfaction with the SDM process before (mean CollaboRATE score 26 of 27 points) and after (mean CollaboRATE score 26.3 of 27 points, p = 0.23) the introduction of SDM. Interestingly, staff attitude toward SDM improved significantly from 61.68 before to 90.95% after the introduction of SDM (p-value < 0.001). Decision grids that were developed for three different types of intracranial tumors are presented. CONCLUSIONS: Team training in SDM and the introduction of techniques into daily practice can increase staff satisfaction with the SDM process. High levels of patient satisfaction were observed before, with a non-significant increase after the introduction of SDM. Decision grids are an important tool to facilitate the conveyance and understanding of complex information and to achieve SDM in daily clinical practice.

Animal products in neurosurgery - navigating informed consent.

Informed consent is an ethical and legal requirement integral to modern surgical practice. Clinicians have a duty to consider, disclose and discuss risks and concerns relevant to an individual patient. With medical advances there are now a significant number of animal-derived products and adjuncts available for use in modern neurosurgical practice, which may be relevant when consenting patients for specific procedures if such products are used. This paper highlights commonly used products in neurosurgery that contain animal-derived constituents with the aim of facilitating an informed discussion between the neurosurgeon and patient. We have reviewed the commonly used products in the centres of the authors and their commercial equivalents. The product information is taken from the manufacturer's instructions or the Federal Drug Administration documents regarding the product. Animal products commonly available to neurosurgeons can be broadly categorised into haemostatic agents, dural substitutes, dural sealants and bone cements. Many products contain a variety of animal (or human) derived products. In order to ensure informed consent and shared decision making, it is important to establish any relevant patient beliefs or views regarding the use of animal-derived products. Given the wide availability and use of neurosurgical adjuncts containing human or animal derived products, coupled with the heterogeneity within ethnic, religious, and social groups, each patient must be approached individually to ensure patient-specific concerns are identified and alternatives offered when appropriate.

Outcomes based on histopathologic response to preoperative chemotherapy in children with bilateral Wilms tumor: A prospective study (COG AREN0534).

BACKGROUND: An objective of the Children's Oncology Group AREN0534 Study was to improve the survival of patients with bilateral Wilms tumors (BWT) by using preoperative chemotherapy of limited duration and tailoring postoperative therapy based on histopathologic response. The authors report outcomes based on postoperative histopathologic responses. METHODS: Patients with BWT received treatment with vincristine, dactinomycin, and doxorubicin for 6 or 12 weeks followed by surgery. Postoperative therapy was prescribed based on the highest risk tumor according to the International Society of Pediatric Oncology classification and the Children's Oncology Group staging system. RESULTS: Analyses were performed on data from 180 evaluable children. The 4-year event-free survival (EFS) and overall survival (OS) rates were 81% (95% CI, 74%-87%) and 95% (95% CI, 91%-99%), respectively. Seven patients who had completely necrotic tumors had a 4-year EFS rate of 100%. Of 118 patients who had tumors with intermediate-risk histopathology, the 4-year EFS and OS rates were 82% (95% CI, 74%-90%) and 97% (95% CI, 94%-100%), respectively. Fourteen patients who had blastemal-type tumors had 4-year EFS and OS rates of 79% (95% CI, 56%-100%) and 93% (95% CI, 79%-100%), respectively. Eighteen patients who had diffuse anaplasia had 4-year EFS and OS rates of 61% (95% CI, 35%-88%) and 72% (95% CI, 47%-97%), respectively; and the 4-year EFS and OS rates of 7 patients who had focal anaplasia were 71% (95% CI, 38%-100%) and 100%, respectively. There was no difference in the outcomes of patients who had different histopathologic subtypes within the intermediate-risk group (P = .54). CONCLUSIONS: A risk-adapted treatment approach for BWT results in excellent outcomes. This approach was not successful in improving the outcome of patients who had diffuse anaplasia.

Impact of the First Generation of Children's Oncology Group Clinical Trials on Clinical Practice for Wilms Tumor.

Refinements in surgery, radiation therapy, and chemotherapy since the mid-20th century have resulted in a survival rate exceeding 90% for patients with Wilms tumor (WT). Although this figure is remarkable, a significant proportion of patients continue to have event-free survival (EFS) estimates of <75%, and nearly 25% of survivors experience severe chronic medical conditions. The first-generation Children's Oncology Group (COG) renal tumor trials (AREN '0'), which opened to enrollment in 2006, focused on augmenting treatment regimens for WT subgroups with predicted EFS <75% to 80%, including those with the adverse prognostic marker of combined loss of heterozygosity (LOH) at chromosomes 1p/16q, pulmonary metastasis with incomplete lung nodule response after 6 weeks of chemotherapy, bilateral disease, and anaplastic histology. Conversely, therapy was reduced for patient subgroups with good outcomes and potential for long-term toxicity, such as those with lung metastasis with complete lung nodule response after 6 weeks of chemotherapy. This article summarizes the key findings of the first-generation COG renal tumor studies and their implications for clinical practice.

Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons.

The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

Neurosurgery activity levels in the United Kingdom and republic of Ireland during the first wave of the covid-19 pandemic - a retrospective cross-sectional cohort study.

The impact of Covid-19 on surgical patients worldwide has been substantial. In the United Kingdom (UK) and the Republic of Ireland (RoI), the first wave of the pandemic occurred in March 2020. The aims of this study were to: (1) evaluate the volume of neurosurgical operative activity levels, Covid-19 infection rate and mortality rate in April 2020 with a retrospective cross-sectional cohort study conducted across 16 UK and RoI neurosurgical centres, and (2) compare patient outcomes in a single institution in April-June 2020 with a comparative cohort in 2019. Across the UK and RoI, 818 patients were included. There were 594 emergency and 224 elective operations. The incidence rate of Covid-19 infection was 2.6% (21/818). The overall mortality rate in patients with a Covid-19 infection was 28.6% (6/21). In the single centre cohort analysis, an overall reduction in neurosurgical operative activity by 65% was observed between 2020 (n = 304) and 2019 (n = 868). The current and future impact on UK neurosurgical operative activity has implications for service delivery and neurosurgical training.

Results of Treatment for Patients With Multicentric or Bilaterally Predisposed Unilateral Wilms Tumor (AREN0534): A report from the Children's Oncology Group.

BACKGROUND: A primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to facilitate partial nephrectomy in 25% of children with bilaterally predisposed unilateral tumors (Wilms tumor/aniridia/genitourinary anomalies/range of developmental delays [WAGR] syndrome; and multifocal and overgrowth syndromes). The purpose of this prospective study was to achieve excellent event-free survival (EFS) and overall survival (OS) while preserving renal tissue through preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response. METHODS: The treating institution identified whether a predisposition syndrome existed. Patients underwent a central review of imaging studies through the biology and classification study AREN03B2 and then were eligible to enroll on AREN0534. Patients were treated with induction chemotherapy determined by localized or metastatic disease on imaging (and histology if a biopsy had been undertaken). Surgery was based on radiographic response at 6 or 12 weeks. Further chemotherapy was determined by histology. Patients who had stage III or IV disease with favorable histology received radiotherapy as well as those who had stage I through IV anaplasia. RESULTS: In total, 34 patients were evaluable, including 13 males and 21 females with a mean age at diagnosis of 2.79 years (range, 0.49-8.78 years). The median follow-up was 4.49 years (range, 1.67-8.01 years). The underlying diagnosis included Beckwith-Wiedemann syndrome in 9 patients, hemihypertrophy in 9 patients, multicentric tumors in 10 patients, WAGR syndrome in 2 patients, a solitary kidney in 2 patients, Denys-Drash syndrome in 1 patient, and Simpson-Golabi-Behmel syndrome in 1 patient. The 4-year EFS and OS rates were 94% (95% CI, 85.2%-100%) and 100%, respectively. Two patients relapsed (1 tumor bed, 1 abdomen), and none had disease progression during induction. According to Response Evaluation Criteria in Solid Tumor 1.1 criteria, radiographic responses included a complete response in 2 patients, a partial response in 21 patients, stable disease in 11 patients, and progressive disease in 0 patients. Posttherapy histologic classification was low-risk in 13 patients (including the 2 complete responders), intermediate-risk in 15 patients, and high-risk in 6 patients (1 focal anaplasia and 5 blastemal subtype). Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%). CONCLUSIONS: A standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology-based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.

Imaging Characteristics of Nephrogenic Rests Versus Small Wilms Tumors: A Report From the Children's Oncology Group Study AREN03B2.

OBJECTIVE. Distinguishing nephrogenic rests from small Wilms tumors can be challenging. This retrospective study was performed to determine if imaging characteristics can be used to distinguish nephrogenic rests from Wilms tumors. MATERIALS AND METHODS. All cases of pathologically confirmed nephrogenic rests and Wilms tumors smaller than 5 cm in maximum dimension on imaging in patients younger than 5 years old were identified from the Children's Oncology Group AREN03B2 study (July 2006-August 2016). Exclusion criteria were chemotherapy before pathologic evaluation or more than 30 days between imaging and surgery; in addition, patients with nephrogenic rests occurring within or juxtaposed to a Wilms tumor and patients with diffuse hyperplastic perilobar nephroblastomatosis were excluded. Two radiologists who were blinded to pathology results assessed all lesions. The two-sample t test was used for continuous variables, and the Fisher exact test was used for categoric variables. ROC analysis was performed to determine the optimal size cutoff for distinguishing between nephrogenic rests and Wilms tumors. RESULTS. Thirty-one pathologically confirmed rests (20 perilobar, 11 intralobar) and 26 Wilms tumors smaller than 5 cm met the eligibility criteria for study inclusion. The median diameter of the nephrogenic rests was 1.3 cm (range, 0.7-3.4 cm) and the median diameter of the Wilms tumor was 3.2 cm (range, 1.8-4.9 cm) (p < 0.001). Imaging findings supportive of Wilms tumors were spherical (p < 0.001) and exophytic (p < 0.001) lesions. Perilobar rests (17/20) were more likely to be homogeneous than intralobar rests (3/11) or Wilms tumor (3/26) (p < 0.001). ROC analysis showed that the optimal size cutoff for distinguishing between nephrogenic rests and Wilms tumors was 1.75 cm. CONCLUSION. In children younger than 5 years old, the diagnosis of a Wilms tumor should be favored over a nephrogenic rest when a renal mass is spherical, exophytic, or larger than 1.75 cm. Homogeneity favors the diagnosis of perilobar nephrogenic rests, whereas intralobar rests and Wilms tumors are more likely to be inhomogeneous.

Impact of cyclophosphamide and etoposide on outcome of clear cell sarcoma of the kidney treated on the National Wilms Tumor Study-5 (NWTS-5).

PURPOSE: To improve the event-free survival (EFS) and overall survival (OS) for patients with clear cell sarcoma of the kidney (CCSK) by incorporating cyclophosphamide and etoposide into treatment on National Wilms Tumor Study (NWTS)-5. PATIENTS AND METHODS: Patients less than 16 years of age with a centrally confirmed pathological diagnosis of CCSK were eligible for treatment on this prospective single-arm study conducted between August 1995 and June 2002. Staging consisted of CT scans of chest, abdomen, pelvis, bone scan, skeletal survey, and CT or MRI of the head. Treatment consisted of vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide for 24 weeks and radiation to sites of disease. RESULTS: One hundred eight eligible patients were enrolled on study (69% males, 63% Caucasian), with a median age of 22 months. Stage distribution was as follows: stage I, 12; II, 44; III, 45; IV, 7. Median follow-up was 9.7 years. Five-year EFS and OS were 79% (95% CI: 71%-88%) and 90% (95% CI: 84%-96%). Five-year EFS for stage I-IV was 100%, 88%, 73%, and 29%, respectively. Twenty of the 23 disease-related events occurred within three years of initial treatment. The most common site of recurrence was brain (12/23). CONCLUSION: The outcome for patients with CCSK treated on NWTS-5 was similar to NWTS-4 and accomplished over a shorter treatment duration. Stage was highly predictive of outcome. Brain metastases occurred more frequently than on NWTS-4. Regimen I showed more benefit for patients with stage I and II disease as compared with higher stages of disease where new therapies are needed.

SVM Optimization for Brain Tumor Identification Using Infrared Spectroscopic Samples.

The work presented in this paper is focused on the use of spectroscopy to identify the type of tissue of human brain samples employing support vector machine classifiers. Two different spectrometers were used to acquire infrared spectroscopic signatures in the wavenumber range between 1200⁻3500 cm-1. An extensive analysis was performed to find the optimal configuration for a support vector machine classifier and determine the most relevant regions of the spectra for this particular application. The results demonstrate that the developed algorithm is robust enough to classify the infrared spectroscopic data of human brain tissue at three different discrimination levels.

Results of the First Prospective Multi-institutional Treatment Study in Children With Bilateral Wilms Tumor (AREN0534): A Report From the Children's Oncology Group.

OBJECTIVE: The Children's Oncology Group study AREN0534 aimed to improve event-free survival (EFS) and overall survival (OS) while preserving renal tissue by intensifying preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response. BACKGROUND: No prospective therapeutic clinic trials in children with bilateral Wilms tumors (BWT) exist. Historical outcomes for this group were poor and often involved prolonged chemotherapy; on NWTS-5, 4-year EFS for all children with BWT was 56%. METHODS: Patients were enrolled and imaging studies were centrally reviewed to assess for bilateral renal lesions. They were treated with 3-drug induction chemotherapy (vincristine, dactinomycin, and doxorubicin) for 6 or 12 weeks based on radiographic response followed by surgery and further chemotherapy determined by histology. Radiation therapy was provided for postchemotherapy stage III and IV disease. RESULTS: One hundred eighty-nine of 208 patients were evaluable. Four-year EFS and OS were 82.1% (95% CI: 73.5%-90.8%) and 94.9% (95% CI: 90.1%-99.7%. Twenty-three patients relapsed and 7 had disease progression. After induction chemotherapy 163 of 189 (84.0%) underwent definitive surgical treatment in at least 1 kidney by 12 weeks and 39% retained parts of both kidneys. Surgical approaches included: unilateral total nephrectomy with contralateral partial nephrectomy (48%), bilateral partial nephrectomy (35%), unilateral total nephrectomy (10.5%), unilateral partial nephrectomy (4%), and bilateral total nephrectomies (2.5%). CONCLUSION: This treatment approach including standardized 3-drug preoperative chemotherapy, surgical resection within 12 weeks of diagnosis and response and histology-based postoperative therapy improved EFS and OS and preservation of renal parenchyma compared with historical outcomes for children with BWT.

Clinical Outcome and Biological Predictors of Relapse After Nephrectomy Only for Very Low-risk Wilms Tumor: A Report From Children's Oncology Group AREN0532.

OBJECTIVE: To determine if observation alone after nephrectomy in very low-risk Wilms tumor (defined as stage I favorable histology Wilms tumors with nephrectomy weight <550g and age at diagnosis <2 years) results in satisfactory event-free survival and overall survival, and to correlate relapse with biomarkers. PATIENTS AND METHODS: The AREN0532 study enrolled patients with very low-risk Wilms tumor confirmed by central review of pathology, diagnostic imaging, and surgical reports. After nephrectomy, patients were followed without adjuvant chemotherapy. Evaluable tumors were analyzed for WT1mutation, 1p and 16q copy loss, 1q copy gain, and 11p15 imprinting. The study was powered to detect a reduction in 4-year EFS from 87% to 75% and overall survival from 95% to 88%. RESULTS: A total of 116 eligible patients enrolled with a median follow up of 80 months (range: 5-97 months). Twelve patients relapsed. Estimated 4-year event-free survival was 89.7% (95% confidence interval 84.1-95.2%) and overall survival was 100%. First sites of relapse were lung (n = 5), tumor bed (n = 4), and abdomen (n = 2), with one metachronous tumor in the contralateral kidney (n = 1) at a median time of 4.3 months for those who relapsed (range 2.3-44 months). The presence of intralobar (P = 0.46) or perilobar rests (P = 1.0) were not associated with relapse (P = 0.16). 1q gain, 1p and 16q loss, and WT1 mutation status were not associated with relapse. 11p15 methylation status was associated relapse (20% relapse with loss of heterozygosity, 25% with loss of imprinting, and 3.3% relapse with retention of the normal imprinting (P = 0.011)). CONCLUSIONS: Most patients meeting very low-risk criteria can be safely managed by nephrectomy alone with resultant reduced exposure to chemotherapy. Expansion of an observation alone strategy for low-risk Wilms tumor incorporating both clinical features and biomarkers should be considered.

Outcome of patients with Stage II/favorable histology Wilms tumor with and without local tumor spill: a report from the National Wilms Tumor Study Group.

BACKGROUND: Intra-operative tumor spill increases the risk of local recurrence of Wilms tumor, and adversely impacts relapse-free (RFS) and overall survival (OS) rates. METHODS: Surgical checklists, operative notes, institutional pathology reports, central pathology review and flow sheets of 602 patients registered between August 1986 and September 1994 on National Wilms Tumor Study-4 as randomized, followed or switched and coded as Final Stage II, favorable histology (FH) were reviewed. RFS and OS were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated using the Cox model and tested for statistical significance by the log-rank test. RESULTS: Four hundred ninety-nine patients were found after review to have Stage II, FH Wilms tumor. The 8-year RFS percentages were 85.0% (95% confidence interval (CI): 81.1%, 88.1%) for those with no spill compared to 75.7% (65.8%, 83.2%) for those with spill. The 8-year OS percentages were 95.6% (93.1%, 97.3%) for those with no spill compared to 90.3% (82.2%, 94.9%) for those with spill. The HR for relapse among those with spill was 1.55 ((95%CI: 0.97,2.51), P = 0.067) and the HR for death was 1.94 ((0.92,4.09), P = 0.077). CONCLUSIONS: RFS and OS were lower for patients who had intra-operative tumor spill. The majority of NWTS Stage II, FH patients with intra-operative tumor spill have an overall excellent outcome when treated with two drug chemotherapy (vincristine and actinomycin D) and no abdominal irradiation.

Delayed post-operative haemorrhage after carmustine wafer implantation: a case series from two UK centres.

OBJECT: Significant haemorrhage following intracranial tumour resection may occur in 1-2% of cases and the majority occur within the first few hours post-operatively. Implantation of carmustine wafers has been associated with increased operative site complications in some series, but post-operative haematoma is not routinely reported. We analyzed the characteristics of post-operative haemorrhage after carmustine wafer insertion. METHODS: We performed a retrospective audit of surgical site haematoma after tumour resection and insertion of carmustine wafers in two neurosurgical units in the UK (University Hospital of North Staffordshire, Stoke-on-Trent, March 2003 - July 2012; Wessex Neurological Centre, Southampton, October 2005 - January 2013). RESULTS: During the specified time periods, carmustine wafers were inserted in 181 operations in 177 patients. We identified acute operative site haematomas after carmustine wafer insertion in 8 (4.4%) patients. All presented in a delayed fashion on or after Day 2 post-operatively. In contrast, acute operative site haematoma was present in 4/491 (0.81%) of patients who underwent resection without gliadel wafer insertion. CONCLUSIONS: In contrast to the expected timing of bleeding following intracranial tumour resection, all carmustine wafer patients who experienced haemorrhage presented in a delayed fashion on or after Day 2 post-operatively. The causative factors for universally delayed post-operative haematoma after carmustine wafer insertion are unclear and further studies are required to characterize this phenomenon.

New policies to address the global burden of childhood cancers.

Childhood cancer is a major global health issue. Every year, almost 100 000 children die from cancer before the age of 15 years, more than 90% of them in resource-limited countries. Here, we review the key policy issues for the delivery of better care, research, and education of professionals and patients. We present a key list of time-limited proposals focusing on change to health systems and research and development. These include sector and system reforms to make care affordable to all, policies to promote growth of civil society around both cancer and Millennium Development Goals, major improvements to public health services (particularly the introduction of national cancer plans), improved career development, and increased remuneration of specialist health-care workers and government support for childhood cancer registries. Research and development proposals focus on sustainable funding, the establishment of more research networks, and clinical research specifically targeted at the needs of low-income and middle-income countries. Finally, we present proposals to address the need for clinical trial innovation, the complex dichotomy of regulations, and the threats to the availability of data for childhood cancers.

Hallmark discoveries in the biology of Wilms tumour.

The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions.