Outcomes of Wilms tumor therapy in Lilongwe, Malawi, 2016-2021: Successes and ongoing research priorities.

INTRODUCTION: Wilms tumor therapy in low- and middle-income countries (LMICs) relies on treatment protocols adapted to resource limitations, but these protocols have rarely been evaluated in real-world settings. Such evaluations are necessary to identify high-impact research priorities for clinical and implementation trials in LMICs. The purpose of this study was to identify highest priority targets for future clinical and implementation trials in sub-Saharan Africa by assessing outcomes of a resource-adapted treatment protocol in Malawi. METHODS: We conducted a retrospective cohort study of children treated for Wilms tumor with an adapted SIOP-backbone protocol in Lilongwe, Malawi between 2016 and 2021. Survival analysis assessed variables associated with poor outcome with high potential for future research and intervention. RESULTS: We identified 136 patients, most commonly with stage III (n = 35; 25.7%) or IV disease (n = 35; 25.7%). Two-year event-free survival (EFS) was 54% for stage I/II, 51% for stage III, and 13% for stage IV. A single patient with stage V disease survived to 1 year. Treatment abandonment occurred in 36 (26.5%) patients. Radiotherapy was indicated for 55 (40.4%), among whom three received it. Of these 55 patients, 2-year EFS was 31%. Of 14 patients with persistent metastatic pulmonary disease at the time of nephrectomy, none survived to 2 years. Notable variables independently associated with survival were severe acute malnutrition (hazard ratio [HR]: 1.9), increasing tumor stage (HR: 1.5), and vena cava involvement (HR: 3.1). CONCLUSION: High-impact targets for clinical and implementation trials in low-resource settings include treatment abandonment, late presentation, and approaches optimized for healthcare systems with persistently unavailable radiotherapy.

A Novel Standard for Systematic Reporting of Neuroblastoma Surgery: The International Neuroblastoma Surgical Report Form (INSRF): A Joint Initiative by the Pediatric Oncological Cooperative Groups SIOPEN∗, COG∗∗, and GPOH∗∗∗.

OBJECTIVE: To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes. SUMMARY OF BACKGROUND DATA: NBL, the most common extracranial solid malignant tumor in children, covers a wide spectrum of tumors with significant differences in anatomical localization, organ or vessel involvement, and tumor biology. Complete surgical resection of the primary tumor is an important part of NBL treatment, but maybe hazardous, prone to complications and its role in high-risk disease remains debated. Various surgical guidelines exist within the protocols of the different cooperative groups, although there is no standardized operative report form to document the surgical treatment of NBL. METHODS: After analyzing the treatment protocols of the SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology pediatric cooperative groups, important variables were defined to completely describe surgical biopsy and resection of NBL and their outcomes. All variables were discussed within the Surgical Committees of SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology. Thereafter, joint meetings were organized to obtain intercontinental consensus. RESULTS: The "International Neuroblastoma Surgical Report Form" provides a structured reporting tool for all NBL surgery, in every anatomical region, documenting all Image Defined Risk Factors and structures involved, with obligatory reporting of intraoperative and 30 day-postoperative complications. CONCLUSION: The International Neuroblastoma Surgical Report Form is the first universal form for the structured and uniform reporting of NBL-related surgical procedures and their outcomes, aiming to facilitate the postoperative communication, treatment planning and analysis of surgical treatment of NBL.

Angiosarcoma of the Pancreas in a Pediatric Patient With an Activating KDR-Internal Tandem Duplication: A Case Report and Review of the Literature.

Pancreatic angiosarcoma is an exceedingly rare malignancy accounting for <1% of pancreatic neoplasms. A very limited number of pancreatic angiosarcomas have been reported in the literature without any cases described in children. We present the case of a 17-year-old female diagnosed with angiosarcoma of the pancreas following pancreaticoduodenectomy for a pancreatic mass, initially presumed to be a solid pseudopapillary neoplasm of the pancreas. The angiosarcoma was found to have a novel activating internal tandem duplication in the KDR gene (KDR-internal tandem duplication). We discuss the current literature on this disease process. This is the first reported case of pancreatic angiosarcoma in a pediatric patient and the first with an activating KDR-internal tandem duplication.

Global Disparities in Wilms Tumor.

BACKGROUND: Wilms tumor accounts for more than 90% of all malignant kidney neoplasms in children. Survival after diagnosis and treatment is excellent in most high-income countries. Low- and middle-income countries (LMICs) continue to struggle with Wilms tumor detection and treatment. The purpose of this study was to compare the global incidence and outcomes of Wilms tumor. MATERIAL AND METHODS: Wilms tumor incidence data from the World Health Organization (WHO), International Incidence of Childhood Cancer, Volume III, was analyzed according to world region and country socioeconomic status using descriptive statistics and independent-sample Kruskal-Wallis Test. A literature review was also performed to assess outcomes and identify common themes. RESULTS: Wilms tumor was most common in children aged 0-4 y (median incidence 15.1 [IQR 11.8-18.7] ASR/million). High-income countries reported significantly higher median incidence than middle-income countries (8.6 [7.4-9.3] versus 6.1 [4.9-8.7] ASR/million; P < 0.01), although low-income countries reported the highest median incidence overall (9.8 [6.2-16.4] ASR/million). Low-income countries had the fewest countries with registries (n = 6). Overall survival ranged from 70% to 97% in high-income countries, 61%-94% in upper-middle-income countries, 0%-85% in lower-middle-income countries, and 25%-53% in low-income countries. Delay in diagnosis, lack of available treatment, and inadequate follow up contributed to the large variations in outcomes. CONCLUSIONS: Reported Wilms tumor incidence is highest in low-income countries, and these are also the countries that have the lowest survival. Lack of significance may reflect incomplete and absent data reporting from lower income countries. Accurate and comprehensive registries are the first steps to appropriate resource allocation in order to improve outcomes for this highly curable childhood malignancy.

Is high-risk neuroblastoma induction chemotherapy possible without G-CSF? A pilot study of safety and treatment delays in the absence of primary prophylactic hematopoietic growth factors.

BACKGROUND/OBJECTIVES: Standard supportive care during induction therapy for high-risk neuroblastoma (HR-NBL) includes primary prophylactic granulocyte colony-stimulating factor (G-CSF) aimed at limiting duration of neutropenia, reducing infection risk, and minimizing treatment delays. Preclinical models suggest that G-CSF promotes maintenance of neuroblastoma cancer stem cells and may reduce the efficacy of chemotherapy. This study's objective was to determine the safety and feasibility of administering induction chemotherapy without routine use of prophylactic G-CSF. DESIGN/METHODS: Children with newly diagnosed HR-NBL received six-cycle induction chemotherapy regimen without prophylactic G-CSF in four cycles. G-CSF was administered for stem cell mobilization after cycle 3 and granulocyte-monocyte colony-stimulating factor after cycle 5 prior to surgical resection of primary disease. The primary outcome measure was the incidence of grade 3 or higher infection. We hypothesized that the per patient infection rate would be comparable to our institutional baseline rate of 58% in patients with HR-NBL receiving induction chemotherapy with prophylactic growth factor support. The trial used an A'Hern single-stage design. RESULTS: Twelve patients with HR-NBL received 58 cycles of chemotherapy on study. Three patients completed the entire six-cycle regimen with no infections. Nine patients experienced grade 3 infections (bacteremia four, urinary tract infection two, skin/soft tissue infection three). No patients experienced grade 4 infections or required intensive care treatment for infection. CONCLUSION: A greater than expected number of serious bacterial infections were observed during administration of induction chemotherapy for HR-NBL without primary prophylactic G-CSF. These results support continued prophylactic administration growth factor during induction chemotherapy.

Do Ventriculoperitoneal Shunts Increase Complications After Laparoscopic Gastrostomy in Children?

BACKGROUND: In patients requiring gastrostomies, ventriculoperitoneal (VP) shunts are a frequently encountered comorbidity. The objective of this study is to evaluate the postoperative management of children with VP shunts that undergo laparoscopic gastrostomy placement and determine their incidence of complications. MATERIALS AND METHODS: Children 18 y old or younger who underwent laparoscopic gastrostomy placement at a freestanding academic children's hospital between January 2014 and October 2016 were reviewed. Data collected included demographics, management, and outcomes. Patients were compared based on their presence of a VP shunt before laparoscopic gastrostomy. Statistical analysis was performed using chi square, Fisher's exact, and Wilcoxon rank-sum tests. RESULTS: We reviewed the medical records of 270 children that underwent laparoscopic gastrostomy placement by 15 pediatric surgeons. Of these, 9% (25) had a previously placed VP shunt. In comparing patients with a VP shunt with those without a VP shunt, there was no significant difference in median age (4 versus 3 y, P = 0.92), gender (48% versus 51% males, P = 0.80), body mass index (15 versus 16, P = 0.69), preoperative diet (48% versus 47% nasogastric tube dependent, P = 0.60), or procedure time (43 versus 42 min, P = 0.37). The postoperative management of these children was similar: day of initiation of postoperative feeds (84% versus 73% on postoperative day #1, P = 0.70), method of initiation of feeds (60% versus 55% continuous, P = 0.25), and type of initial feeds (83% versus 71% Pedialyte, P = 0.24). Similarly, there was no difference in hospital length of stay, return to the emergency department, or postoperative complications within 90 d (P > 0.05). CONCLUSIONS: Children with ventriculoperitoneal shunts do not have a higher rate of immediate complications after laparoscopic gastrostomy placement and may be managed similar to other children in the postoperative period.

Disparities in fertility-sparing surgery in adolescent and young women with stage I ovarian dysgerminoma.

BACKGROUND: In many cancers, racial and socioeconomic disparities exist regarding the extent of surgery. For ovarian dysgerminoma, fertility-sparing (FS) surgery is recommended whenever possible. The aim of this study was to investigate rates of FS versus non-fertility-sparing (NFS) procedures for stage I ovarian dysgerminoma in adolescents and young adults (AYAs) by ethnicity/race and socioeconomic status. MATERIALS AND METHODS: The National Cancer Data Base was queried for patients with ovarian dysgerminoma from 1998 to 2012. After selecting patients aged 15-39 y with stage I disease, a multivariate regression analysis was performed, and rates of FS and NFS procedures were compared, first according to ethnicity/race, and then by socioeconomic surrogate variables. RESULTS: Among the 687 AYAs with stage I ovarian dysgerminoma, there was no significant difference in rates of FS and NFS procedures based on ethnicity/race alone (P = 0.17), but there was a significant difference in procedure type for all three socioeconomic surrogates. The uninsured had higher NFS rates (30%) than those with government (21%) or private (19%) insurance (P = 0.036). Those in the poorest ZIP codes had almost twice the rate of NFS procedures (31%) compared with those in the most affluent ZIP codes (17%). For those in the least-educated regions, 24% underwent NFS procedures compared to 14% in the most-educated areas (P = 0.027). CONCLUSIONS: AYAs with stage I ovarian dysgerminoma in lower socioeconomic groups were more likely to undergo NFS procedures than those in higher socioeconomic groups, but there was no difference in rates of FS versus NFS procedures by ethnicity/race. Approaches aimed at reducing socioeconomic disparities require further examination.

Socioeconomic disparities affect survival in malignant ovarian germ cell tumors in AYA population.

BACKGROUND: Malignant ovarian germ cell tumors (MOGCTs) are a rare form of ovarian malignancy. Socioeconomic status (SES) has been shown to affect survival in several gynecologic cancers. We examined whether SES impacted survival in adolescent and young adults (AYAs) with MOGCT. MATERIALS AND METHODS: The National Cancer Data Base was used to identify AYAs (aged 15-39 years) with MOGCT from 1998 to 2012. Three SES surrogate variables identified were as follows: insurance type, income quartile, and education quartile. Pooled variance t-tests and chi-square tests were used to compare tumor characteristics, the time from diagnosis to staging/treatment, and clinical outcome variables for each SES surrogate variable, while controlling for age and race/ethnicity in a multivariate model. Kaplan-Meier survival estimates were calculated using the log-rank test. RESULTS: A total of 3125 AYAs with MOGCT were identified. Subjects with lower SES measures had higher overall stage and T-stage MOGCTs at presentation. There was no significant difference in the time to staging/treatment, extent of surgery, or use of chemotherapy by SES. Subjects from a lower education background, from a lower income quartile, and without insurance had decreased survival (P ≤ 0.02 for all). Controlling for overall stage and T-stage, the difference in survival was no longer significant. CONCLUSIONS: AYAs with MOGCT from lower SES backgrounds presented with more advanced stage disease. Further studies that focus on the underlying reasons for this difference are needed to address these disparities.

Local therapy to distant metastatic sites in stage IV rhabdomyosarcoma.

PURPOSE: To determine the impact of surgery and/or radiation therapy on distant metastatic sites (DMS) in children with stage IV rhabdomyosarcoma (RMS). METHODS: A retrospective chart review was conducted on all patients with stage IV RMS at Texas Children's Hospital from 1992 to 2012. Data analyzed included age, gender, primary site, histologic subtype, number and sites of metastases, treatment including local therapy to DMS, and Oberlin score. RESULTS: The 5-year progression-free survival (PFS) and overall survival (OS) rates were 20% and 25%. The 5-year PFS in patients receiving local therapy to all DMS (n = 16) and to less than all DMS (n = 19) was 31.3% versus 0% (P = 0.002), whereas the 5-year OS was 37.3% versus 0% (P < 0.001), respectively. The 5-year PFS in patients with isolated lung metastasis versus other types of metastasis was 29% versus 7% (P = n.s.), whereas the 5-year OS was 43% versus 10% (P = 0.01). The 5-year pulmonary local control was improved by the use of whole lung irradiation (WLI; 56% vs. 10%, P = 0.03). CONCLUSIONS: Local treatment to all metastatic sites was associated with improved PFS and OS at 5 years. The use of WLI improved pulmonary control in patients with lung metastasis. We recommend an aggressive approach including local therapy to DMS in children with stage IV RMS.

Breast Malignancies in Children: Presentation, Management, and Survival.

PURPOSE: Pediatric breast malignancies are rare, and descriptions in the literature are limited. The purpose of our study was to compare pediatric and adult breast malignancy. METHODS: We performed a retrospective cohort study using the National Cancer Data Base comparing patients ≤21 years to those >21 years at diagnosis (1998-2012). Generalized linear models estimated differences in demographic, tumor, and treatment characteristics. Cox regression was used to compare overall survival. RESULTS: Of 1,999,181 cases of invasive breast malignancies, 477 (0.02%) occurred in patients ≤21 years. Ninety-nine percent of adult patients had invasive carcinoma compared with 64.8% of pediatric patients with the remaining patients having sarcoma, malignant phyllodes, or malignancy not otherwise specified (p < 0.001). Pediatric patients were twice as likely to have an undifferentiated malignancy [relative risk (RR) 2.19; 95% confidence interval (CI) 1.72-3.79]. Half of adults presented with Stage I disease compared with only 22.7% of pediatric patients (p < 0.001). Pediatric patients were 40% more likely to have positive axillary nodes (RR 1.42; 95% CI 1.10-1.84). Among patients with invasive carcinoma, pediatric patients were more than four times as likely to receive a bilateral than a unilateral mastectomy compared with adults (RR 4.56; 95% CI 3.19-6.53). There was no difference in overall survival between children and adults. CONCLUSIONS: Pediatric breast malignancies are more advanced at presentation, and there is variability in treatment practices. Adult and pediatric patients with invasive carcinoma have similar overall survival.

Characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver: A report from the National Cancer Database.

OBJECTIVE: To examine patient characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver (UESL) using a multi-institutional database. SUMMARY BACKGROUND DATA: UESL is a rare disease (incidence is one per million). Therefore, the current literature is mostly limited to small case series. METHODS: The National Cancer Database was queried for primary UESL diagnosed between 1998 and 2012. RESULTS: A total of 103 patients (<18 years) were identified. The 5-year overall survival of the entire group was 86%. The best outcomes were seen in children who had tumors smaller than 15 cm and were able to undergo surgical resection with or without chemotherapy. Margin status did not appear to significantly affect survival. The most common type of resection was hemihepatectomy (37%), followed by sectionectomy (10%) and trisectionectomy (10%). Orthotopic liver transplant was performed in 10 children, all of whom survived to 5 years. CONCLUSION: Surgical resection with or without chemotherapy should be the mainstay of treatment in children with UESL, and is associated with very favorable outcomes. Negative surgical margins were not associated with improved survival. Orthotopic liver transplantation may be a viable method of attaining local control in tumors, which would otherwise be unresectable.

Neuroendocrine Tumor of the Appendix in Children.

Neuroendocrine tumor (NET) of the appendix is the most common gastrointestinal epithelial tumor in children. The utility of serum markers or the indication for hemicolectomy has not been established in children. In 45 children diagnosed with appendiceal NET, 89% NETs were incidentally found following appendectomy performed for suspected acute appendicitis. The median age was 12 years, and 56% patients were female. Postoperative somatostatin scan (n=5), serum chromogranin A (n=4), and urine 5-HIAA (n=9) were all within normal limits. Pathology slides of 35 patients showed mesoappendiceal invasion in 29% patients, and vascular invasion in 6% patients. Seven patients (16%) underwent hemicolectomy for invasion of mesoappendix (n=5), tumor near the resection margin (n=1), and tumor size 1.5 cm with vascular invasion (n=1). Only 2 hemicolectomy specimens showed disease: one in the appendiceal stump and the other as a micrometastasis in a mesenteric lymph node. There were no recurrences and all patients were alive and without evidence of disease at last follow-up. Pediatric appendiceal NET tends to have a benign clinical course with excellent prognosis. In the absence of carcinoid syndrome, postoperative scans and serum biomarkers do not seem to be useful. With completely resected tumors, the indication for hemicolectomy is unclear.

Mucoepidermoid Carcinoma in Children: A Single Institutional Experience.

PURPOSE AND OBJECTIVE: To determine the clinicopathologic and molecular features and outcome of children with mucoepidermoid carcinoma (MEC). METHODS: A retrospective analysis of clinical and histopathologic findings was performed in patients with MEC diagnosed at Texas Children's Cancer Center between 2000 and 2014. RESULTS: Ten female and four male patients with median age 12 years (range 7-19 years) were included in the study. Tumors involved major salivary glands, minor salivary glands of the palate, and the tracheobronchial tree. Nine of 11 patients with salivary MEC underwent more than one surgical resection at the time of initial diagnosis to achieve a gross total resection. Three patients with tracheobronchial tumors underwent pulmonary lobectomy. Three patients received postoperative radiation therapy. No patient was treated with chemotherapy. Histopathologic grades were classified as low (n = 2), intermediate (n = 9), and high (n = 3). All 12 patients with tumor tissue available for testing were positive for MECT1/MAML2 fusion transcripts. There were no deaths, metastases, or recurrences in this series, with a median follow-up of 24 months (range 5-96 months). CONCLUSIONS: Low to intermediate histopathologic grade MECs are more common than high grade MEC in children. In contrast to adults, MECT1/MAML2 fusion transcripts occur with a frequency of 100% in our pediatric MEC series. Complete excision is the treatment of choice and is associated with excellent outcome. The role of radiotherapy is unclear, but may be indicated in patients with high grade tumors with positive surgical margins.

Childhood and adolescent tracheobronchial mucoepidermoid carcinoma (MEC): a case-series and review of the literature.

Tracheobronchial mucoepidermoid carcinomas (MEC) are rare in the pediatric population with literature limited primarily to case reports. Here we present our institutional experience treating MEC in three patients and review the literature of 142 pediatric cases previously published from 1968 to 2013. Although rare, tracheobronchial MEC should be included in the differential diagnosis in a child with recurrent respiratory symptoms. Conservative surgical management is often sufficient to achieve complete resection and good outcomes.

mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling.

High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.

Intraoperative ultrasound for liver tumor resection in children.

BACKGROUND: Primary hepatic neoplasms in children are rare tumors. All malignant and medically refractive benign primary pediatric liver tumors ultimately require surgical resection for cure. Accurate preoperative imaging including multidetector helical computerized tomography or magnetic resonance imaging (MRI) is necessary to determine resectability. In the literature intraoperative ultrasound (IOUS) has proven to be a vital adjunct to liver surgery in adults, but this is not well established in children. MATERIALS AND METHODS: Between April 2003 and November 2014, children (<18-y-old) with a primary liver neoplasm, preoperatively evaluated with multidetector helical computerized tomography or MRI, who had IOUS used at the time of surgery were retrospectively reviewed. RESULTS: Preoperative evaluation with high-resolution MRI and IOUS were discordant in 4 of 19 patients (21%). In one case, right hepatic vein involvement was not accurately assessed with MRI. Two cases showed tumor involvement in segment IV by MRI; however, IOUS revealed no medial segment involvement. The final patient had a large (>5 cm), solitary hepatic adenoma on MRI, but IOUS in this case revealed diffuse adenomatosis. The operative management was altered in three of these cases. CONCLUSIONS: Although MRI can provide a detailed view of the hepatic anatomy and is an invaluable tool for preoperative planning for the pediatric patient with a primary liver neoplasm, IOUS may provide further and more up to date delineation of tumor extent and should be considered a crucial element in operative planning for hepatectomy in children.

Management of appendiceal carcinoid tumors in children.

BACKGROUND: Appendiceal carcinoid tumors, also know as well-differentiated neuroendocrine neoplasms, are rare lesions detected incidentally after appendectomy in children. There are limited data about the natural history of these tumors, and guidelines regarding family counseling and need for additional surgery or follow-up imaging are not established in the pediatric age group. The purpose of this study was to review our institutional experience with appendiceal carcinoid tumors to provide data that might improve management. METHODS: After institutional review board approval, the charts of all patients treated at our institution for an appendiceal carcinoid tumor between 2002 and 2014 were reviewed. Data collected included patient demographics, pathologic details, postoperative management, and follow-up information. Descriptive analyses were performed. RESULTS: Twenty-eight patients were identified, which represents an incidence of 0.2% of children undergoing appendectomy during that time interval. The mean age at surgery was 13.8 ± 2.1 y; 54% were females. Two patients had symptoms suspicious for carcinoid syndrome at presentation, though none had evidence of metastatic disease. The mean tumor size was 0.73 ± 0.4 cm. Five patients (18%) underwent subsequent ileocecectomy or right hemicolectomy because of pathologic findings of invasion of the mesoappendix (n = 4) or lymphovascular invasion and subserosal extension (n = 1), two of whom had residual disease in the resected specimen (one in a lymph node). No recurrences have been detected at mean follow-up of 1.8 y. CONCLUSIONS: Appendiceal carcinoid tumors are discovered incidentally in about 0.2% of children undergoing appendectomy. Based on findings from a large contemporary series, we can conclude that these tumors are generally small and demonstrate lymphovascular invasion or mesenteric extension in fewer than 20% of cases. Prospective, multicenter studies are necessary to better define the indication for ileocecectomy and follow-up imaging protocols.

Identifying and reducing early complications of surgical central lines in infants and toddlers.

BACKGROUND: Hospitalized infants>1 y old often require central venous catheters (CVC) for prolonged therapy. There are limited data describing the complication profile for this young population. The purpose of this study was to review outcomes associated with CVC insertion in this high-risk group and compare them to those in older children to develop directed quality improvement projects. MATERIALS AND METHODS: Patients receiving their first CVC, a tunneled central line or port-a-cath, from 2007-2010 were included. Femoral, non-tunneled, and hemodialysis catheters were excluded. Patients aged 0-12.0 mo (infants) were compared with those 12.1-36 mo (toddlers). Complications (<30 d) included infection, malposition, malfunction, intraoperative, and the need for operative exchange. Statistical analysis included Student t-test, chi-square, and a Kaplan-Meier survival analysis. RESULTS: We identified 115 infants and 129 toddlers who underwent CVC insertion during the study period. Complication rates were higher in the infant group than in the toddler group, as was the operative exchange rate. Higher infection rates in the infant group appeared to contribute to the difference in early complications and exchange rates. A survival analysis indicated improved catheter duration in toddlers (P=0.001). CONCLUSIONS: In this cohort study, infants had a higher early complication rate, mostly attributable to infection, than their older counterparts. This difference could be explained by increased use of a tunneled central line for daily total parented nutrition in infants with gastrointestinal anomalies, as opposed to port-a-cath for chemotherapy infusion in older children. These data have prompted a number of targeted quality improvement initiatives to address relevant complications in this infant population.

Relapse surveillance in AFP-positive hepatoblastoma: re-evaluating the role of imaging.

BACKGROUND: Children with hepatoblastoma routinely undergo repetitive surveillance imaging, with CT scans for several years after therapy, increasing the risk of radiation-induced cancer. OBJECTIVE: The purpose of this study was to determine the utility of surveillance CT scans compared to serum alpha-fetoprotein (AFP) levels for the detection of hepatoblastoma relapse. MATERIALS AND METHODS: This was a retrospective study of all children diagnosed with AFP-positive hepatoblastoma from 2001 to 2011 at a single institution. RESULTS: Twenty-six children with hepatoblastoma were identified, with a mean age at diagnosis of 2 years 4 months (range 3 months to 11 years). Mean AFP level at diagnosis was 132,732 ng/ml (range 172.8-572,613 ng/ml). Five of the 26 children had hepatoblastoma relapse. A total of 105 imaging exams were performed following completion of therapy; 88 (84%) CT, 8 (8%) MRI, 5 (5%) US and 4 (4%) FDG PET/CT exams. A total of 288 alpha-fetoprotein levels were drawn, with a mean of 11 per child. The AFP level was elevated in all recurrences and no relapses were detected by imaging before AFP elevation. Two false-positive AFP levels and 15 false-positive imaging exams were detected. AFP elevation was found to be significantly more specific than PET/CT and CT imaging at detecting relapse. CONCLUSION: We recommend using serial serum AFP levels as the preferred method of surveillance in children with AFP-positive hepatoblastoma, reserving imaging for the early postoperative period, for children at high risk of relapse, and for determination of the anatomical site of clinically suspected recurrence. Given the small size of this preliminary study, validation in a larger patient population is warranted.

TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.

Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-κB activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy-induced cell-death. TAK1 is an essential component in genotoxic stresses-induced NF-κB activation; however, the role of TAK1 in the development of chemoresistance in neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox- and VP16-induced NF-κB activation and enhanced Dox- and VP16-induced apoptosis. Moreover, 5Z-7-oxozeaenol was able to overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, our results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk diseases.