Haroon Hasan

Long-Term Outcomes and Complications in Patients With Craniopharyngioma: The British Columbia Cancer Agency Experience

PURPOSE We report long-term outcomes and complications of craniopharyngioma patients referred to our institution. METHODS AND MATERIALS Between 1971 and 2010, 123 consecutive patients received primary treatment for craniopharyngioma in British Columbia and were referred to our institution. The median age was 30 years (range, 2-80 years). Thirty-nine percent of patients were treated primarily with subtotal resection (STR) and radiation therapy (RT), 28% with STR alone, 15% with gross total resection, 11% with cyst drainage (CD) alone, 5% with CD+RT, and 2% with RT alone. Eight percent of patients received intracystic bleomycin (ICB) therapy. RESULTS Median follow-up was 8.9 years, and study endpoints were reported at 10 years. Ten-year Kaplan-Meier progression-free survival (PFS) was 46%. Patients treated with STR+RT or CD+RT had the highest PFS (82% and 83%, respectively). There were no significant differences between PFS after adjuvant versus salvage RT (84% vs 74%, respectively; P=.6). Disease-specific survival (DSS) was 88%, and overall survival (OS) was 80%. Primary treatment modality did not affect DSS or OS, while older age was a negative prognostic factor for OS but not DSS. Kaplan-Meier rates for visual deterioration, anterior pituitary hormone deficiency, diabetes insipidus, seizure disorder, and cerebrovascular events (CVE) due to treatment, not tumor progression, were 27%, 76%, 45%, 16%, and 11%, respectively. The CVE rate was 29% in patients who received ICB compared to 10% in those who did not (P=.07). CONCLUSIONS We report favorable PFS in patients with craniopharyngioma, especially in those who received RT after surgery. DSS and OS rates were excellent regardless of primary treatment modality. We observed a high incidence of hypopituitarism, visual deterioration, and seizure disorder. Eleven percent of patients experienced CVEs after treatment. There was a suggestion of increased CVE risk in patients treated with ICB.

Long-term Outcomes and Complications in Pediatric Ewing Sarcoma.

Objectives: The objective of this study was to determine treatment outcomes and long-term complications in pediatric patients with Ewing Sarcoma treated at the British Columbia Cancer Agency (BCCA). Methods: A retrospective chart review of 101 pediatric patients (<19 y old) with Ewing Sarcoma diagnosed between 1960 and 2005 was performed. The Kaplan-Meier survival analysis and Cox regression multivariate analysis were used to assess prognostic factors for overall survival (OS) and event-free survival (EFS). Results: The median age at diagnosis was 11 years and the median follow-up for nondeceased patients was 13.5 years. The most common primary tumor locations were lower extremity (33%), pelvis (24%), and thorax (18%). Fifty percent of patients received surgery, 79% radiotherapy and 94% chemotherapy. The 5-year OS and EFS for patients with localized disease was 85% and 73% and for metastatic disease was 27% (P<0.0001) and 28% (P<0.0001), respectively. Metastatic disease was an independent predictor of lower OS (hazard ratio [HR], 9.5; 95% confidence interval [CI],4.7-19.4; P<0.0001) and EFS (HR, 4.9; 95% CI, 2.7-8.8; P<0.0001). Extremity tumor location was an independent predictor for improved OS (HR, 0.4; 95% CI, 0.2-0.9; P=0.03). The majority (77%) of long-term survivors (≥5 y) had long-term complications; the most common were musculoskeletal abnormalities (50%) and cardiac toxicity (28%). The actuarial second neoplasm risk was 5% at 10 years. Conclusions: Ewing sarcoma patients with localized disease had excellent treatment outcomes at the BCCA. However, the majority of patients had chronic complications from treatment. This study validates the need for long-term follow-up of Ewing Sarcoma survivors for management of late effects.

A Cross-Sectional Cohort Study of Cerebrovascular Disease and Late Effects After Radiation Therapy for Craniopharyngioma.

The study objective was to describe radiation‐induced vascular abnormalities, stroke prevalence, and stroke risk factors in survivors of childhood craniopharyngioma.

Comparison of hypersensitivity rates to intravenous and intramuscular PEG-asparaginase in children with acute lymphoblastic leukemia: A meta-analysis and systematic review

Pegylated‐asparaginase (PEG‐ASP) is a critical treatment for pediatric acute lymphoblastic leukemia (ALL) and has traditionally been delivered via intramuscular (IM) injection. In an attempt to reduce pain and anxiety, PEG‐ASP has increasingly been delivered via intravenous (IV) administration. The study objective was to perform a meta‐analysis and systematic review to compare and generate pooled hypersensitivity rates for IM and IV PEG‐ASP.

The quality of systematic reviews in hand surgery: an analysis using AMSTAR.

1. Jazayeri L, Klausner JQ, Chang J. Distal digital replantation. Plast Reconstr Surg. 2013;132:1207–1217. 2. Koshima I, Soeda S, Moriguchi T, Higaki H, Miyakawa S, Yamasaki M. The use of arteriovenous anastomosis for replantation of the distal phalanx of the fingers. Plast Reconstr Surg. 1992;89:710–714. 3. Kamei K, Sinokawa Y, Kishibe M. The venocutaneous fistula: A new technique for reducing venous congestion in replanted fingertips. Plast Reconstr Surg. 1997;99: 1771–1774. 4. Koshima I, Yamashita S, Sugiyama N, Ushio S, Tsutsui T, Nanba Y. Successful delayed venous drainage in 16 consecutive distal phalangeal replantations. Plast Reconstr Surg. 2005;115:149–154. 5. Baek SM, Kim SS. Successful digital replantation after 42 hours of warm ischemia. J Reconstr Microsurg. 1992;8:455–458; discussion 459.

“Assessing the methodological quality of systematic reviews in radiation oncology: A systematic review”

OBJECTIVE The objective of our study was to evaluate the methodological quality of systematic reviews and meta-analyses in Radiation Oncology. METHODS A systematic literature search was conducted for all eligible systematic reviews and meta-analyses in Radiation Oncology from 1966 to 2015. Methodological characteristics were abstracted from all works that satisfied the inclusion criteria and quality was assessed using the critical appraisal tool, AMSTAR. Regression analyses were performed to determine factors associated with a higher score of quality. RESULTS Following exclusion based on a priori criteria, 410 studies (157 systematic reviews and 253 meta-analyses) satisfied the inclusion criteria. Meta-analyses were found to be of fair to good quality while systematic reviews were found to be of less than fair quality. Factors associated with higher scores of quality in the multivariable analysis were including primary studies consisting of randomized control trials, performing a meta-analysis, and applying a recommended guideline related to establishing a systematic review protocol and/or reporting. CONCLUSIONS Systematic reviews and meta-analyses may introduce a high risk of bias if applied to inform decision-making based on AMSTAR. We recommend that decision-makers in Radiation Oncology scrutinize the methodological quality of systematic reviews and meta-analyses prior to assessing their utility to inform evidence-based medicine and researchers adhere to methodological standards outlined in validated guidelines when embarking on a systematic review.

PEComa of the terminal ileum mesentery as a secondary tumour in an adult survivor of embryonal rhabdomyosarcoma.

Perivascular epithelioid cell tumours (pecomas) are rare mesenchymal tumours that are characterized by perivascular epithelioid cell differentiation and immunoreactivity to myogenic and melanocytic markers. These tumours can be classified as benign, uncertain malignant potential, or malignant. Because of the rarity of pecomas, their cause and clinical prognosis remain unclear. To the best of our knowledge, no reports in the literature describe a pecoma of the terminal ileum mesentery as a secondary tumour in an adult survivor of childhood embryonal rhabdomyosarcoma, let alone any childhood cancer. Here, we present the case of a 27-year-old man with a pecoma involving the mesentery of the terminal ileum. At the age of 5, he had been treated with a combination of chemotherapy and high-dose pelvic radiation therapy for embryonal rhabdomyosarcoma, most likely arising from the posterior bladder wall. During routine follow-up 22 years after this patients initial treatment, computed tomography imaging revealed a mass within the terminal ileum mesentery. The tumour was successfully treated with surgical resection, and pathology examination determined the mass to be a pecoma with uncertain malignant potential. This first case of a pecoma of the terminal ileum mesentery arising within a high-dose radiation therapy field as a secondary tumour in an adult survivor of childhood cancer highlights the importance of screening and surveillance in high-risk childhood cancer survivors treated with high-dose radiation therapy. Further research to build a better understanding of this remarkably rare tumour is warranted.

Clinical significance in pediatric oncology randomized controlled treatment trials: a systematic review

BackgroundClinical significance in a randomized controlled trial (RCT) can be determined using the minimal clinically important difference (MCID), which should inform the delta value used to determine sample size. The primary objective was to assess clinical significance in the pediatric oncology randomized controlled trial (RCT) treatment literature by evaluating: (1) the relationship between the treatment effect and the delta value as reported in the sample size calculation, and (2) the concordance between statistical and clinical significance. The secondary objective was to evaluate the reporting of methodological attributes related to clinical significance.MethodsRCTs of pediatric cancer treatments, where a sample size calculation with a delta value was reported or could be calculated, were systematically reviewed. MEDLINE, EMBASE, and the Cochrane Childhood Cancer Group Specialized Register through CENTRAL were searched from inception to July 2016.ResultsRCTs (77 overall; 11 and 66), representing 95 (13 and 82) randomized questions were included for non-inferiority and superiority RCTs (herein, respectively). The minority (22.1% overall; 76.9 and 13.4%) of randomized questions reported conclusions based on clinical significance, and only 4.2% (15.4 and 2.4%) explicitly based the delta value on the MCID. Over half (67.4% overall; 92.3 and 63.4%) reported a confidence interval or standard error for the primary outcome experimental and control values and 12.6% (46.2 and 7.3%) reported the treatment effect, respectively. Of the 47 randomized questions in superiority trials that reported statistically non-significant findings, 25.5% were possibly clinically significant. Of the 24 randomized questions in superiority trials that were statistically significant, only 8.3% were definitely clinically significant.ConclusionsA minority of RCTs in the pediatric oncology literature reported methodological attributes related to clinical significance and a notable portion of statistically insignificant studies were possibly clinically significance.

Reply to: Comment on: Comparison of hypersensitivity rates to intravenous and intramuscular PEG-asparaginase in children with acute lymphoblastic leukemia: A meta-analysis and systematic review

To the editor We thank Dholaria and colleagues for their letter1 in response to our manuscript titled, “Comparison of Hypersensitivity Rates to Intravenous and Intramuscular PEG-Asparaginase in Children with Acute Lymphoblastic Leukemia: A meta-analysis and systematic review.”2 Dholaria and colleagues conducted a retrospective cohort study inclusive of children treated for acute lymphoblastic leukemia in a single Australian institution, and participating in a Childrens Oncology Group trial from 2004 to 2014. They found that hypersensitivity rates were not significantly different (P = 0.53) between patients treated with pegylated asparaginase delivered by intravenous (IV) and intramuscular (IM) routes (27.1% [95% CI 16.4–37.8%; N = 70] vs. 22.8% [95% CI 14.0–31.6%; N = 92], respectively). This is in contrast to our findings where we found pooled hypersensitivity rates of 23.5% (95% CI 14.7–33.7%) and 8.7% (95% CI 5.4–12.8%) for IV (N = 261) and IM (N = 491) administration, respectively. Of note, our pooled rates were calculated separately for eachgroupand, therefore, each studywasnot assigned equivalentweights given thediffering sample size between IV and IM groups. Based on the sample size in the Dholaria study, they are able to detect an absolute risk difference greater than 0.22, assuming an alpha of 0.05 and a power of 0.80 based on the chi-squared test. Thus, their study was not sufficiently powered to detect a minimal clinical important difference of 0.10, a value we consider appropriate. Additionally, the authors do not present the clinical, treatment, or demographic characteristics of theparticipants included in the IVand IMgroups and, thus, we are unable to assess the degree to which their estimates are affected by confounding variables. In the light of the evidence presented by Dholaria and colleagues, we performed an update of our meta-analysis using the same methods outlined in our manuscript.2 We identified six additional reports, two of which were referenced by Dholaria and colleagues,3,4 all of which were deemed unfit for inclusion in our meta-analysis for the following reasons: Data was already included in our meta-analysis from an abstract which is now formally published,5 inclusion of relapsed patients6 or young adults,4,7 insufficient data reported to conduct meta-analysis (i.e., only grades 3–4 hypersensitivity reactions reported)4,7,8 and both study arms did not use pegylated asparaginase.3 We, therefore, performed a meta-analysis without5,9–11 and with1,5,9–11 the data reported by Dholaria and colleagues, which is presented in Figure 1, to calculate the absolute risk difference of IV versus IM. Our analysis reveals that inclusion of the findingsbyDholaria and colleaguesmarginally shifted the absolute risk difference from 0.12 (95% CI 0.06–0.18) to 0.11 (95% CI 0.06–0.16) and remained significant. However, as Dholaria and colleagues, along with others, have demonstrated, the rate of hypersensitivity is confounded by risk type among other factors. This has been detailed in our manuscript2 and in other reviews.12,13 Thequality of ourmeta-analysis findings aredependenton thequality of the observational studies included and, thus, the evidence we present should be interpreted accordingly. With the aforementioned in mind, our meta-analysis is a synthesis of the evidence available, and additional studies are needed to better understand the differences in hypersensitivity between pegylated asparaginase delivered via IVe and IM.

Assessing the accuracy of death records and pre-mortem clinical diagnoses in children diagnosed with brain tumors: A retrospective chart review of children in British Columbia, Canada.

The advantages of autopsy have been demonstrated in pediatric oncology; however, it is unknown to what extent the utility of autopsy is in deceased children diagnosed with a pediatric brain tumor (PBT). The purpose of this study was to describe the frequency of autopsy, prevalence of clinical discrepancies, and accuracy of cancer registry death records for deceased children diagnosed with a PBT in British Columbia, Canada. A retrospective chart review was performed of medical records and autopsy reports of pediatric patients diagnosed with a PBT that died between 1982 and 2012 in British Columbia. Clinical discrepancies between pre- and post-mortem findings were classified based on a modified classification system of the Goldman Criteria. The overall autopsy rate was 15.5% (32 of 206) during 1982-2012, with a significant (P=0.001) decrease of 22.4% observed between decade 1 (32.8%) and decade 2 (10.4%) and a further slight decrease (4.5%) between decade 2 (10.4%) and decade 3 (5.9%) (P=0.379). A third of patients had discrepancies between pre-mortem and post-mortem clinical diagnoses, with slightly over 10% of these cases revealing information that would have altered the probability of survival had it been known prior to death. More than half (59.3%) of cases had discordant cause of death as recorded in the cancer registry when compared to autopsy findings. Autopsy for children diagnosed with a PBT can provide health care professionals with important information about the accuracy of their diagnoses and evaluate the efficacy of therapy.