A phase 2 study of valproic acid and radiation, followed by maintenance valproic acid and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma.

PURPOSE: To study the efficacy and tolerability of valproic acid (VPA) and radiation, followed by VPA and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG). METHODS: Children 3 to 21 years of age received radiation therapy and VPA at 15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 µg/mL. VPA was continued post-radiation, and bevacizumab was started at 10 mg/kg intravenously biweekly, four weeks after completing radiation therapy. RESULTS: From September 2009 through August 2015, 20 DIPG and 18 HGG patients were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher toxicities requiring discontinuation or modification of VPA dosing included grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis (1). During VPA and bevacizumab, the most common grade 3 or higher toxicities were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3), and grade 3 hypertension (4). Two patients discontinued protocol therapy prior to disease progression (one grade 4 thrombosis and one grade 1 intratumoral hemorrhage). Median event-free survival (EFS) and overall survival (OS) for DIPG were 7.8 (95% CI 5.6-8.2) and 10.3 (7.4-13.4) months, and estimated one-year EFS was 12% (2%-31%). Median EFS and OS for HGG were 9.1 (6.4-11) and 12.1 (10-22.1) months, and estimated one-year EFS was 24% (7%-45%). Four patients with glioblastoma and mismatch-repair deficiency syndrome had EFS of 28.5, 16.7, 10.4, and 9 months. CONCLUSION: Addition of VPA and bevacizumab to radiation was well tolerated but did not appear to improve EFS or OS in children with DIPG or HGG.

A cohort study on blood coagulation in childhood cancer survivors.

Cancer survivors are at an increased risk of thromboembolism compared to the general pediatric population. Anticoagulant therapy decreases the risk of thromboembolism in cancer patients. We hypothesized that pediatric cancer survivors are in a chronically hypercoagulable state compared to healthy controls. Children who survived for more than five years from cancer diagnosis at the UT Health Science Center at San Antonio Cancer Survivorship Clinic were compared to healthy controls. The exclusion criteria were recent NSAID use or a history of coagulopathy. Coagulation analysis included platelet count, thrombin-antithrombin complexes (TAT), plasminogen activator inhibitor (PAI), routine coagulation assays, and thrombin generation with and without thrombomodulin. We enrolled 47 pediatric cancer survivors and 37 healthy controls. Platelet count was significantly lower in cancer survivors at a mean of 254 × 109/L (95%CI: 234-273 × 109/L) compared at 307 × 109/L (283-331 × 109/L) in healthy controls (p < 0.001), although not outside the normal range. Routine coagulation assays showed no differences, except for a significantly lower prothrombin time (PT) in cancer survivors (p < 0.004). Cancer survivors has significantly elevated biomarkers of the procoagulant state, such as TAT and PAI, compared to healthy controls (p < 0.001). A multiple logistic regression model controlling for age, BMI, gender, and race/ethnicity documented that a low platelet count, short prothrombin clot time, and higher procoagulant biomarkers (TAT and PAI) were significantly associated with past cancer therapy. Survivors of childhood cancer have a persistent procoagulant imbalance for more than five years after diagnosis. Further studies are needed to establish whether procoagulant imbalance increases the risk of thromboembolism in childhood cancer survivors.

Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer.

Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.

Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study.

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

Metastatic medulloblastoma in an adolescent with Simpson-Golabi-Behmel syndrome.

We describe the case of a 12-year-old Hispanic male with a clinical and molecular diagnosis of Simpson-Golabi-Behmel Syndrome (SGBS) who subsequently developed metastatic medulloblastoma. While individuals with SGBS have been documented to have increased risk for intra-abdominal tumors such as Wilms tumor and neuroblastoma, medulloblastomas, or CNS tumors in general, have not been reported in patients with this syndrome. Our patient was clinically diagnosed with SGBS as an infant. He presented with many of the common features of the syndrome, such as cleft palate, macroglossia, post-axial polydactyly, "coarse" facial features, and ventricular septal defects (VSDs). Molecular testing performed in April 2009 confirmed the SGBS diagnosis. This testing detected a large intragenic deletion in the GPC3 gene (more than 500 kb, 8 exons) extending from intron 2, 37 kb downstream of exon 2, to the 5' end of the gene, deleting exons 1 and 2. However, subsequent testing by gene-centric high-density array comparative genomic hybridization (aCGH) detected a deletion encompassing only exon 2. Therefore, the exact 5' boundary of the deletion cannot currently be determined, due to an apparent complex rearrangement upstream of exon 1. We present this case of metastatic medulloblastoma as a unique malignancy in a patient with SGBS.

First American College of Surgeons National Surgical Quality Improvement Program Report from a Low-Middle-Income Country: A 1-Year Outcome Analysis of Neurosurgical Cases.

BACKGROUND: Low-middle-income countries (LMICs) share a substantial proportion of global surgical complications. This is compounded by the seemingly deficient documentation of postsurgical complications and the lack of a national average for comparison. In this context, the implementation of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) that compares hospital performance based on postsurgical complication data provided by a wide array of centers, could be a major initiative in a resource-challenged setting. Implementation of the NSQIP has provenly mitigated postoperative morbidity and mortality across many centers all over the world. To our knowledge, this report is the first from an LMIC to report its postoperative neurosurgical complications in comparison with international benchmarks. METHODS: Our hospital joined the NSQIP in 2019. Through a standardized ACS protocol, ACS-trained surgical clinical reviewers (SCRs) reviewed and extracted data from randomly assigned neurosurgical patients' medical records from preoperative to postoperative (30-day) data using validated, standardized data definitions. SCRs entered deidentified data in an online Health Insurance Portability and Accountability Act web-based secure platform. The validated data were then consigned to the ACS NSQIP head office in the United States where the data were analyzed and compared with similar data from other centers registered with the NSQIP. In this way, our hospital was rated for each of the variables related to postsurgical complications after both spinal and cranial procedures, and the results were sent back to us in the form of text, tables, and graphs. RESULTS: Our initial report suggested a relatively higher odds ratio for sepsis and readmissions after spinal procedures at our hospital, and a similarly higher odds ratio for morbidity, sepsis, urinary tract infection, and surgical site infection for cranial procedures. For these variables, our hospital fell in the needs improvement category of the NSQIP. For the rest of the variables studied for both spinal and cranial procedures, the hospital fell in the as expected category of the NSQIP. CONCLUSIONS: Implementation of the NSQIP is an important first step in creating a culture of transparency, safety, and quality. This is the first report of NSQIP implementation in an LMIC, and we have shown comparable results to developed countries.

Patterns of ocular trauma.

OBJECTIVE: To describe the patterns of ocular trauma, cause of injury and its effects on eye. DESIGN: A retrospective case series. PLACE AND DURATION OF STUDY: Khyber Institute of Ophthalmic Medical Sciences, Hayatabad Medical Complex, Peshawar, from January 1999 to June 2004. PATIENTS AND METHODS: Medical records of 1105 patients admitted with ocular trauma were reviewed. The details of patients regarding age, gender, literacy, cause of injury and its effects on eye were entered into specially-designed performa. Sample selection consisted of all patients with history of ocular trauma and who were admitted to hospital. Population details consisted patients who were referred to the hospital from all parts of N.W.F.P. Thus, the frequency of trauma in the hospital admissions was analysed. RESULTS: Ophthalmic trauma comprised 6.78% of the hospital admission. One thousand one hundred and five patients presented with eye injuries. Out of them, 21 patients suffered from trauma to both eyes. Almost 80% patients were male and 69% patients were below 30 years of age. Delayed presentation was more common and 63.61% patients presented after one week. Open globe injuries were more common [520 eyes (46.18%)] than closed globe injuries [484 eyes (42.98%)]. 23.26% of open globe injuries were associated with intraocular and intra-orbital foreign bodies. Superficial non-perforating, eyelid and adnexal and burns were seen in 122 eyes (10.83%). Among the complications, lens damage and hyphema was seen in more than 50% of the patients, 16.60% eyes were infected at the time of admission and 4.88% of eyes needed enucleation or evisceration. The common causes of injury were violence in 37.37%, occupational in 24.43% and domestic accidents in 19.18%. CONCLUSION: Ophthalmic trauma is a major public health problem. Majority of the involved are male and under 30 years of age. Delayed presentation is more common. Open globe injuries are more frequent. Violence and occupational injuries are the major causes.

Frequency and causes of bilateral occular trauma.

OBJECTIVE: To determine the frequency and causes of bilateral ocular trauma. DESIGN: A descriptive case series. PLACE AND DURATION OF STUDY: Khyber Institute of Ophthalmic Medical Sciences, Hayatabad Medical Complex, Peshawar from October 1999 to September 2006. PATIENTS AND METHODS: All patients coming to the hospital with bilateral eye trauma and requiring admission were recruited into the study. The details of patients' demographics, risk factors, ocular examination, treatment offered and final visual acuity were noted and described as frequency and percentages. RESULTS: Out of a total of 1551 patients of hospitalized ocular trauma, 46 (2.9%, 92 eyes) had bilateral ocular trauma. The majority (54.3%) were due to landmine blast injuries followed by dynamite blast in 10.8%, coalmine blast and firearm injury in 6.5% each. Pressure cooker explosion and road traffic accident was the cause in 4.3% each. Gas cylinder and automobile battery explosion, alkali and acid burn, assault and incidental trauma occurred in 2.1%. Sixty three percent were between 16 and 40 years of age. Males were affected in 93.4%. Corneal and / or scleral repair was done in 58.6%, conjunctival and or corneal foreign body removal in 26% and extracapular cataract extraction with intraocular lens implantation in 16.3%. The visual acuity was in the range of 6/60 and perception of light in 54.3%, while in 21.7%, there was no perception of light at the time of admission. Due to severity of injury, the final visual acuity was poor and only 28.2% regained vision between 6/18 and 6/60. CONCLUSION: In this series, landmine, dynamite and coalmine blasts were the major causes of bilateral ocular trauma. Victims were usually young males. Due to severity of ocular trauma, majority had poor visual outcome.

Comparison of Anaesthetic Efficacy of 4% Articaine Primary Buccal Infiltration Versus 2% Lidocaine Inferior Alveolar Nerve Block in Symptomatic Mandibular First Molar Teeth.

OBJECTIVE: To evaluate success of pulpal anaesthesia of mandibular 1st molar by using 4% articaine in buccal infiltration versus 2% lidocaine in inferior alveolar nerve block. STUDY DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: Department of Operative Dentistry, Sardar Begum Dental College, Gandhara University, Peshawar, from March to August 2014. METHODOLOGY: One hundred and fifty-six emergency patients, who had 1st molar diagnosed with irreversible pulpitis, participated in the study. Subjects were divided into two groups by random allocation. One group received 4% articaine buccal infiltration and the other group received inferior alveolar nerve block of 2% lidocaine. Subjects’self-reported pain response was recorded on Heft Parker Visual Analogue Scale after local anaesthetic administration during access cavity preparation and pulp extirpation. RESULTS: Mean age of subjects was 31.46 ±10.994 years. The success rate of 4% buccal infiltration was 76.9%; whereas the success rate of 2% lidocaine inferior alveolar nerve block was 62.8%. There was no statistically significant difference between the two groups. CONCLUSION: 4% articaine buccal infiltration can be considered a viable alternative to 2% lidocaine inferior alveolar nerve block in securing successful pulpal anaesthesia for endodontic therapy.

Primary CNS lymphoma in children and adolescents: a descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG).

PURPOSE: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). EXPERIMENTAL DESIGN: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. RESULTS: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤ 14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. CONCLUSION: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival.