Brian Cameron

Absolute vs relative improvements in congenital diaphragmatic hernia survival: what happened to “hidden mortality”

PURPOSE The aim of this study is to determine if there has been a true, absolute, or apparent relative increase in congenital diaphragmatic hernia (CDH) survival for the last 2 decades. METHOD All neonatal Bochdalek CDH patients admitted to an Ontario pediatric surgical hospital during the period when significant improvements in CDH survival was reported (from January 1, 1992, to December 31, 1999) were analyzed. Patient characteristics were assessed for CDH population homogeneity and differences between institutional and vital statistics-based population survival outcomes. SAS 9.1 (SAS Institute, Cary, NC) was used for analysis. RESULT Of 198 cohorts, demographic parameters including birth weight, gestational age, Apgar scores, sex, and associated congenital anomalies did not change significantly. Preoperative survival was 149 (75.2%) of 198, whereas postoperative survival was 133 (89.3%) of 149, and overall institutional survival was 133 (67.2%) of 198. Comparison of institution and population-based mortality (n = 65 vs 96) during the period yielded 32% of CDH deaths unaccounted for by institutions. Yearly analysis of hidden mortality consistently showed a significantly lower mortality in institution-based reporting than population. CONCLUSION A hidden mortality exists for institutionally reported CDH survival rates. Careful interpretation of research findings and more comprehensive population-based tools are needed for reliable counseling and evaluation of current and future treatments.

The HLA A*0201–restricted hTERT540–548 peptide is not detected on tumor cells by a CTL clone or a high-affinity T-cell receptor

Tumor-associated human telomerase reverse transcriptase (hTERT) is expressed in >85% of human tumors but not in most normal cells. As a result, this antigen has received considerable attention from those interested in cancer immunotherapy. Specifically, there has been strong interest in MHC class I–associated peptides derived from hTERT because these are expressed on the cell surface and thus may enable the targeting of tumor cells. Much of this interest has focused on peptide 540–548, ILAKFLHWL, which was predicted to exhibit the strongest binding to the common HLA A*0201 presenting molecule. The hTERT540–548 peptide is currently being assessed in therapeutic vaccination trials; however, there is controversy surrounding whether it is naturally processed and presented on the surface of neoplastic cells. Here, we generate two highly sensitive reagents to assess the presentation of hTERT540–548 on tumor cells: (a) a CD8+ CTL clone, and (b) a recombinant T-cell receptor (TCR) that binds with picomolar affinity and a half-life exceeding 14 h. This TCR enables the identification of individual HLA A2-hTERT540–548 complexes on the cell surface. The use of both this TCR and the highly antigen-sensitive CTL clone shows that the hTERT540–548 peptide cannot be detected on the surface of tumor cells, indicating that this peptide is not a naturally presented epitope. We propose that, in future, rigorous methods must be applied for the validation of peptide epitopes used for clinical applications. [Mol Cancer Ther 2007;6(7):2081–91]

The uncut Collis-Nissen fundoplication: Results for 79 consecutively treated high-risk children

PURPOSE The Nissen fundoplication fails to control gastroesophageal reflux (GER) in up to 25% of children with neurological impairment or chronic lung disease. The uncut Collis modification lengthens the intraabdominal esophagus, improving the antireflux function without opening the stomach. This study reviews the results of the uncut Collis-Nissen fundoplication in a pediatric series. METHODS Seventy-nine children had an uncut Collis-Nissen fundoplication performed over a 5-year period. The median age was 1.4 years. Associated problems included neurological impairment (77%), chronic lung disease (38%), and esophageal atresia (3%). Surgery was undertaken only in children with objective documentation of pathological GER, who had GER complications unresponsive to medical treatment. The usual complications that led to surgery were pulmonary (73%), esophagitis (67%), or failure to thrive (35%). Liquid gastric emptying was assessed routinely preoperatively, and was delayed in 42% patients who then had concomitant pyloroplasty. RESULTS GER was controlled in 97% of patients after a median follow-up of 1.8 years. All children with recurrent symptoms were restudied, and only two children had documented recurrent GER. One of these required a repeat fundoplication. Thirty-three percent were on promotility medication for feeding difficulties, gagging, or retching. There were postoperative complications in 26% (minor 23%, major 3%) and one postoperative mortality. Eleven late deaths were unrelated to surgery or GER. CONCLUSION The uncut Collis-Nissen fundoplication provides excellent control of GER in children and is associated with acceptable morbidity and low mortality. It should be particularly considered in children with neurological impairment or chronic lung disease.

Evaluating the long-term impact of the Trauma Team Training course in Guyana: an explanatory mixed-methods approach

BACKGROUND We evaluated the retention of trauma knowledge and skills after an interprofessional Trauma Team Training (TTT) course in Guyana and explored the course impact on participants. METHODS A mixed-methods design evaluated knowledge using a multiple-choice quiz test, skills and trauma moulage simulation with checklists, and course impact with qualitative interviews. Participants were evaluated at 3 time points; before, after, and 4 months after TTT. RESULTS Forty-seven course participants included 20 physicians, 17 nurses, and 10 paramedical providers. All participants had improved multiple-choice quiz test scores after the course and retained knowledge after 4 months, with nonphysicians showing the most improved scores. Trauma skill and moulage scores declined slightly after 4 months, with the greatest decline observed in complex skills. Qualitatively, course participants self-reported impact of the TTT course included improved empowerment, knowledge, teamwork, and patient care. CONCLUSIONS Interprofessional team-based training led to the retention of trauma knowledge and skills as well as the empowerment of nonphysicians. The decline in performance of some trauma skills indicates the need for a regular trauma update course.

The burden of waiting: DALYs accrued from delayed access to pediatric surgery in Kenya and Canada

BACKGROUND Disability-adjusted life years (DALYs) have become the standard metric for estimating burden of disease (BoD), but have not yet been applied to delayed access to surgical procedures. This study estimates the DALYs accrued from delayed access to surgical care in two pediatric surgical units in Kenya and Canada. METHODS Records of operations for 13 congenital health states in a Kenyan and a Canadian hospital were prospectively collected for 2012. DALYs caused by delayed presentation were estimated using disability weights and ideal and actual age at surgery. RESULTS 1208 first-time procedures in general surgery, neurosurgery, plastic surgery, and urology were included. Delays were longest in general surgery and longer in Kenya than in Canada in all specialties. The longest delays in Kenya were for orchidopexy (72 months) and anorectoplasty (PSARP) (74 months), and in Canada for orchidopexy (40 months). Corresponding total delayed BoD was highest in general surgery and neurosurgery and higher again in Kenya than in Canada (484 cf. 84 DALYs). CONCLUSIONS Estimating BoD resulting from delayed surgery is feasible and reflects both late presentation and limited access to care. Further exploration of these factors can make delayed DALYs a useful measure of health care coverage and waitlist prioritization.

Establishing disability weights for congenital paediatric surgical disease: a cross-sectional, multi-modal study

Abstract Background Quantifying burden of disease using disability-adjusted life-years (DALYs) is a recognised method of establishing priorities for health-care resource allocation. Disabilities weights (DWs)—needed to calculate DALYs for surgical conditions—are currently underdeveloped or non-existent in paediatric surgery. The objective of this study is to establish DWs for a subset of paediatric congenital anomalies prevalent in Kenya and Canada. Methods We provided 15 expert-panel-derived health states using six disability domain descriptions adapted from the EuroQol-5D to health professionals (physicians, nurses, social workers, and therapists) and community caregivers. Participants rated each health state using four health valuation exercises including two psychometric (preference ranking, visual analogue scale) and two economic (paired comparison and time trade-off). Mean DWs from each exercise were calculated and combined to yield overall DWs for each health state on a scale from 0 (perfect health) to 1 (death). We examined country data and statistically analysed any differences in DWs between the two countries. Findings In total, 154 participants, matched by profession, were recruited from Kijabe, Kenya (n=78) and Hamilton, ON, Canada (n=76). Overall DWs for 15 health states ranged from 0·15 to 0·98 (SD 0·0–0·17), with little difference between countries. However, DWs generated in Kenya for severe hypospadias and undescended testes were higher (0·52, SD 0·20) than Canadian-derived DWs (0·27, SD 0·15; both p Interpretation We established novel DWs for paediatric congenital anomalies using a low-cost multi-method approach. DWs do not appear to differ significantly across cultural contexts and can be used to calculate burden of global paediatric surgical disease. Funding This study was funded by a clinical research grant from the McMaster Surgical Associates in the Department of Surgery at McMaster University.

Outcomes following neonatal patent ductus arteriosus ligation done by pediatric surgeons: A retrospective cohort analysis

PURPOSE Patent Ductus Arteriosus (PDA) ligation in premature infants is an urgent procedure performed by some but not all pediatric surgeons. Proficiency in PDA ligation is not a requirement of Canadian pediatric surgery training. Our purpose was to determine the outcomes of neonatal PDA ligation done by pediatric surgeons. METHODS We performed a retrospective review of premature infants who underwent PDA ligation by pediatric surgeons in 3 Canadian centers from 2005 to 2009. Outcomes were compared to published controls. RESULTS The review identified 98 patients with a mean corrected GA and weight at repair of 29 weeks and 1122 g, respectively. There were no intraoperative deaths. The 30-day and inhospital mortality rates were 1% and 5%. Mortality and morbidity were comparable to the published outcomes. CONCLUSIONS This study documents that a significant number of preterm infant PDA ligations are safely done by pediatric surgeons. To meet the Canadian needs for this service by pediatric surgeons, proficiency in PDA ligation should be considered important in pediatric surgery training programs.

Abstract 2900: IMCgp100: A novel bi-specific biologic for the treatment of malignant melanoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Despite significant advances in the treatment of metastatic melanoma, long-term remission for the majority of patients remains elusive. Kinase inhibitors provide potent but short-term responses for a significant proportion of patients and immunotherapy elicits long-term responses with the prospect of cure, but only in a minority. IMCgp100 is a novel bi-specific immunotherapy comprising a soluble, affinity enhanced, T cell receptor (TCR) specific for the melanoma-associated antigen gp100, fused to an anti-CD3 specific antibody fragment (scFv). The engineered TCR portion of the drug targets and binds the gp100 peptide 280-288 antigen, which is over-expressed and presented by HLA-A2 on the surface of melanoma cells. The anti-CD3 scFv portion captures and redirects T cells to kill the melanoma cells, while normal antigen negative tissues are unaffected. Here, we present data which provides the foundation for the clinical observations. In vitro, IMCgp100 is demonstrated to potently redirect T cells from late stage cancer patients to target melanoma tumors exhibiting HLA-down regulation, even in the presence of high numbers of regulatory T cells. Target cell killing is observed within hours and is specific for gp100. In addition killing is associated with the release of various pro-inflammatory cytokines and chemokines as well as cross-presentation of gp100 and other melanoma-associated antigens by dendritic cells. Thus, IMCgp100 demonstrates the potential to elicit potent short-term responses and trigger longer-term anti melanoma activity in vivo. IMCgp100 is undergoing Phase I clinical testing in patients with advanced malignant melanoma; with the maximum tolerated dose having been established. The drug is well tolerated with evidence of tumor shrinkage. Analyses of serum samples obtained from patients on the trial demonstrate T cell mobilisation and transient drug mediated increases in various cytokines and chemokines, some of which are reported to play a key role in anti-melanoma responses. These data support the potential of IMCgp100 as an effective treatment for malignant melanoma. Citation Format: Namir J. Hassan, Giovanna Bossi, Debbie Baker, Katherine Adams, Jane Harper, Joseph Dukes, Nathaniel Liddy, Samantha Paston, Yvonne McGrath, Tara Mahon, Peter Molloy, Malkit Sami, Emma Baston, Brian Cameron, Andrew Johnson, Annelise Vuidepot, Gerry Linette, Michael Kalos, Carl June, Bent Jakobsen. IMCgp100: A novel bi-specific biologic for the treatment of malignant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2900. doi:10.1158/1538-7445.AM2014-2900

Variability of diagnostic approach, surgical technique, and medical management for children with biliary atresia in Canada — Is it time for standardization?

BACKGROUND The Canadian 4-year native liver survival rate for biliary atresia (BA) after Kasai Portoenterostomy (KP) is 39%. The Canadian Biliary Atresia Registry (CBAR) was used to examine variability of surgical and medical management of BA. METHODS Gastroenterologists and surgeons in all 14 Canadian pediatric tertiary centers were invited to complete an online survey of their BA management practices. RESULTS Of gastroenterologists, diagnostic procedures included liver biopsy (92%), HIDA scan (58%), and percutaneous cholangiogram (46%). Surgeons reported Roux-en-Y lengths of 20-50cm with 78% avoiding diathermy at the portal plate; 16% performed laparoscopic exploration, but none laparoscopic KP. Postoperative corticosteroids and antibiotics were used by 24% and 85% of gastroenterologists, respectively, with similar rates for surgeons. At discharge, gastroenterologists prescribed oral antibiotics (80%), and ursodeoxycholic acid (95%), while surgeons reported lower rates (62% and 55%). Considerable variation existed in follow-up monitoring. No center had a standard protocol for evaluating suspected cholangitis. There was a lack of consensus for defining failed KP and referral criteria for transplant evaluation. CONCLUSION In Canada, treatment of BA is not centralized, and there is variability in diagnostic approaches and management. Collaboration through CBAR will allow for implementation and evaluation of standardized surgical and medical management with a goal to improve outcomes. LEVEL OF EVIDENCE Survey study. Level IV evidence.

Perinephric abscesses in the pediatric population: case presentation and review of the literature

BackgroundPerinephric abscesses in children are rare. Infection can come from various areas, and clinical signs overlap with more common etiologies, such as pyelonephritis. Imaging modalities and laboratory investigations help lead to a definitive diagnosis.Case-diagnosis/treatmentWe present a case of a 5-month-old infant presenting with a febrile illness and eventual diagnosis of a perinephric abscess causing abdominal compartment syndrome. The infant had no known risk factors, i.e., congenital genitourinal abnormalities or immunosuppression, and was treated successfully following initial resuscitation, appropriate antibiotics, and open surgical drainage. Cultures obtained from the abscess and peritoneal fluid were positive for S. aureus, while blood and urine cultures were negative.ConclusionsA literature review found 13 studies looking at diagnosis and/or treatment of idiopathic perinephric abscess. With non-specific clinical signs and symptoms, diagnosis can be delayed and rests heavily on clinical suspicion and appropriate imaging. Treatment includes antibiotics alone, or in conjunction with percutaneous or open surgical drainage. In summarizing these studies, a suggestion for diagnosis and basic treatment approach is outlined.