Gordon A. MacKinlay

Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group.

PURPOSE To improve survival and reduce operative morbidity and mortality in children with primary epithelial liver tumors by using preoperative chemotherapy, as well as to collect information on the epidemiology, natural history, and prognostic factors. PATIENTS AND METHODS Forty children with hepatocellular carcinoma (HCC) were registered onto the Group for Epithelial Liver Tumors International Society of Pediatric Oncologys first study from January 1990 to February 1994. The outcome could be analyzed in 39 of those patients. Disease was often advanced at the time of diagnosis; metastases were identified in 31% of the children and extrahepatic tumor extension, vascular invasion, or both in 39%. Multifocal tumors were common (56%). Thirty-three percent of tumors were associated with hepatic cirrhosis. All but two patients received preoperative chemotherapy (cisplatin and doxorubicin). RESULTS Partial response was observed in 18 (49%) of 37 patients; there was no response or progression in the remainder. Complete tumor resection was achieved in 14 patients (36%). Twenty patients (51%) never became operable. Overall survival at 5 years was 28%, and event-free survival was 17%. Most deaths resulted from tumor progression (26 of 28). Presence of metastases and pretreatment extent of disease system grouping at diagnosis had an adverse influence on overall survival in multivariate analysis. CONCLUSION Survival for pediatric HCC patients is significantly inferior to that for children with hepatoblastoma. Complete tumor excision remains the only realistic chance of cure, although it is often prevented by advanced disease. The presence of metastases is the most potent predictor of poor prognosis. A prospective worldwide cooperation in the field of pediatric HCC should be encouraged to look for novel therapeutic concepts.

Successful Treatment of Childhood High-Risk Hepatoblastoma With Dose-Intensive Multiagent Chemotherapy and Surgery: Final Results of the SIOPEL-3HR Study

PURPOSE The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma. PATIENTS AND METHODS High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or alpha-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection. RESULTS Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis. CONCLUSION The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.

Cisplatin versus Cisplatin plus Doxorubicin for Standard-Risk Hepatoblastoma

BACKGROUND Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we randomly assigned patients to receive cisplatin (every 14 days) or cisplatin plus doxorubicin administered in three preoperative cycles and two postoperative cycles. The primary outcome was the rate of complete resection, and the trial was powered to test the noninferiority of cisplatin alone (<10% difference in the rate of complete resection). RESULTS Between June 1998 and December 2006, 126 patients were randomly assigned to receive cisplatin and 129 were randomly assigned to receive cisplatin plus doxorubicin. The rate of complete resection was 95% in the cisplatin-alone group and 93% in the cisplatin-doxorubicin group in the intention-to-treat analysis (difference, 1.4%; 95% confidence interval [CI], -4.1 to 7.0); these rates were 99% and 95%, respectively, in the per-protocol analysis. Three-year event-free survival and overall survival were, respectively, 83% (95% CI, 77 to 90) and 95% (95% CI, 91 to 99) in the cisplatin group, and 85% (95% CI, 79 to 92) and 93% (95% CI, 88 to 98) in the cisplatin-doxorubicin group (median follow-up, 46 months). Acute grade 3 or 4 adverse events were more frequent with combination therapy (74.4% vs. 20.6%). CONCLUSIONS As compared with cisplatin plus doxorubicin, cisplatin monotherapy achieved similar rates of complete resection and survival among children with standard-risk hepatoblastoma. Doxorubicin can be safely omitted from the treatment of standard-risk hepatoblastoma. (ClinicalTrials.gov number, NCT00003912.)

Totally implantable central venous access devices for paediatric oncology patients

BACKGROUND Totally implantable central venous access devices (ports) have been available for over 10 years but have not achieved widespread use in paediatric oncology patients. We reviewed our experience with these devices over 9 years to assess their safety and acceptability. PROCEDURE We conducted a retrospective review of insertion technique and reasons for removal of all ports placed in paediatric oncology patients in this hospital between 1989 and 1996, with follow-up until 1998. Acceptability of both ports and external catheters was assessed by a questionnaire in a subgroup of families attending the oncology clinic. RESULTS One hundred forty-nine ports were inserted during the study period. The median catheter life was 399 days (4-1,406), with a total of 69,342 catheter days. Sixty-nine percent of ports were removed electively at the end of treatment; 8% required removal because of infection and 5% because of blockage. No ports were accidentally dislodged or damaged. Children experienced significantly less restriction of activity with a port compared to an external catheter and greatly preferred the cosmetic appearance. The need for needle insertion to access the port was not seen as a disadvantage by most families. CONCLUSIONS Ports can provide satisfactory central venous access for the majority of paediatric oncology patients, with a low risk of line-related complications and a high degree of acceptability to children and their parents.

Esophageal atresia surgery in the 21st century

The results of thoracoscopic repair of oesophageal atresia with or without tracheo-oesophageal fistula are presented. Twenty-six children had the repair performed thoracoscopically (22 in Edinburgh and 4 by Edinburgh surgeons in other institutions). Twenty infants had oesophageal atresia with tracheo-oesophageal fistula and 6 had isolated oesophageal atresia without fistula. Details of the technique are presented. Birth weights ranged from 1.4 to 3.9 kg and children were operated between 1 day and three months of age. There were 7 minor anastomotic leaks all managed conservatively, 1 recurrent fistula managed thoracoscopically and 9 anastomotic strictures. One child had a tracheo-bronchial fistula not seen at original thoracoscopy. There were 3 deaths (one child with Edwards syndrome, one with associated congenital diaphragmatic hernia and one late death with severe cardiac disease). Thoracoscopic repair of oesophageal atresia is feasible and the long term outcome appears favorable.

Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy.

BACKGROUND Despite randomized controlled trials and meta-analyses, it remains unclear whether laparoscopic pyloromyotomy (LP) carries a higher risk of incomplete pyloromyotomy and mucosal perforation compared with open pyloromyotomy (OP). METHODS Multicenter study of all pyloromyotomies (May 2007-December 2010) at nine high-volume institutions. The effect of laparoscopy on the procedure-related complications of incomplete pyloromyotomy and mucosal perforation was determined using binomial logistic regression adjusting for differences among centers. RESULTS Data relating to 2830 pyloromyotomies (1802 [64%] LP) were analyzed. There were 24 cases of incomplete pyloromyotomy; 3 in the open group (0.29%) and 21 in the laparoscopic group (1.16%). There were 18 cases of mucosal perforation; 3 in the open group (0.29%) and 15 in the laparoscopic group (0.83%). The regression model demonstrated that LP was a marginally significant predictor of incomplete pyloromyotomy (adjusted difference 0.87% [95% CI 0.006-4.083]; P=0.046) but not of mucosal perforation (adjusted difference 0.56% [95% CI -0.096 to 3.365]; P=0.153). Trainees performed a similar proportion of each procedure (laparoscopic 82.6% vs. open 80.3%; P=0.2) and grade of primary operator did not affect the rate of either complication. CONCLUSIONS This is one of the largest series of pyloromyotomy ever reported. Although laparoscopy is associated with a statistically significant increase in the risk of incomplete pyloromyotomy, the effect size is small and of questionable clinical relevance. Both OP and LP are associated with low rates of mucosal perforation and incomplete pyloromyotomy in specialist centers, whether trainee or consultant surgeons perform the procedure.

A common language for childhood liver tumours

As a follow-up to the recommendations of the liver turnout workshc9 held in Berne in February 1990 [1], the CELTIC (Childhood Epithelial Liver Turnouts International Criteria) greup was convened at St. Bartholomews Hospital, London, in September 1990. Representatives from the Intematioral Society of Paediatfic Oncology (SIOP), the German Paediatric Oncology Group (GPOG), the Japanese Liver St~.tdy, and Canada were present 1. In order to compare oulcomes across studies using differing treatment philosophies, common definitions are mandatory. The aim of the meeting was, therefore, to achieve a consensus on (a) histopatt:ologic definitions of childhood hepatocellular tumors, (b) criteria for assigning pre-treatment extent of disease, ~.nd (c) definitions of response to treatment.

Oesophageal atresia: paralysis and ventilation in management of the wide gap

The position of the upper pouch in oesophageal atresia is greatly influenced by flexion and extension of the neck and that of the lower pouch by diaphragmatic excursion. Successful repair was achieved in five infants with a wide gap without leak or significant stricture by paralysing, ventilating, and maintaining neck flexion for 6–7 days. Improvement in morbidity and mortality using this method over a 2-year period is shown in comparison with the previous 2 years. The technique was also used successfully in 2 cases of oesophageal atresia without fistula.

Effect of Patient Weight and Anesthetic Technique on CO2 Excretion During Thoracoscopy in Children Assessed by End-Tidal CO2

AIM The aim of this study was to review the changes in CO(2) excretion and anesthetic management during thoracoscopy in children. METHODS We analyzed end-tidal carbon dioxide concentration (EtCO(2); kPa) during CO(2) pneumothorax. EtCO(2) was measured on a continuous basis by using a positive sampling system and recorded every 10 minutes. Baseline and highest EtCO(2) were used to derive the maximum change in the intraoperative period. EtCO(2) was also analyzed in three time periods: (1) preinsufflation, (2) during insufflation of CO(2) into the chest, and (3) after desufflation. Core temperature was also recorded as an index of thermoregulation. Data are presented as the mean +/- standard error of the mean. Differences within time periods were compared by using paired t tests or repeated measures analysis of variance. Correlation between changes in EtCO(2) and patient demographics was performed by using linear regression. The pattern of change was compared to children undergoing laparoscopy. RESULTS Median age was 1.9 years (range, 1 day to 15 years). EtCO(2) increased significantly from preinsufflation 5.1 +/- 0.2 to 6.4 +/- 0.3 during insufflation (P < 0.01); values were still significantly elevated after desufflation 6.4 +/- 0.4 (P < 0.01). Single-lung ventilation was associated with higher EtCO(2) levels during insufflation than with two-lung ventilation (P = 0.02). Maximum change in the EtCO(2) in the group undergoing one-lung ventilation negatively correlated to patient weight (r(2) = 0.25, P = 0.02); this correlation was not present with two-lung ventilation (r(2) = 0.02, P = 0.84). Laparoscopy increased EtCO(2) from 4.7 +/- 0.2 preinsufflation to 5.3 +/- 0.2 (P < 0.001) during and decreased to 4.8 +/- 0.2 postdesufflation (P = 0.60). There was a significant increase in core temperature from 35.9 +/- 0.3 to 36.9 +/- 0.2 postoperatively (P = 0.007). CONCLUSIONS There is a significant increase in EtCO(2) in children undergoing thoracoscopy, which is higher than during laparoscopy. Changes in EtCO(2) are larger in smaller children undergoing single-lung ventilation. Thoracoscopy may preserve intraoperative thermoregulation.

Multiple Gastric Stromal Tumors in a Child without Syndromic Association Lacks Common KIT or PDGFRα Mutations

A diagnosis of multiple gastric stromal tumors that were nonmetastatic at presentation was made in an 11-year-old girl who presented with hematemesis. Gastrointestinal stromal tumor (GIST) is a rare diagnosis in childhood and reported multiple lesions are generally seen in the context of familial disease, occasionally with syndromic associations. Although there are no reports of genetic mutation in cases of pediatric GIST, very many cases of multiple GISTs investigated on a molecular level have shown germline KIT or platelet-derived growth factor receptor-α mutation; these were familial cases. Despite the negative family history in our patient, the multiplicity of lesions in such a young patient raised concern for a genetic predisposition and prompted extensive molecular workup. Repeat evaluation of distinct aliquots of tumor tissue by polymerase chain amplification followed by sequence analysis of selected coding sequences of KIT and platelet-derived growth factor receptor-α previously shown to harbor mutations in GIST, yielded no evidence of even a somatic mutation. This clinically unique case is discussed in the context of a literature review.