Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT).

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p < .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Central Nervous System Involvement of Rhabdomyosarcoma: A Single Institution Experience.

The incidence of central nervous system (CNS) involvement in patients with rhabdomyosarcoma (RMS) is low, and the outcome is dismal. We present a single institution analysis of CNS involvement of pediatric RMS. In 59 patients, the prevalence of CNS involvement was 11.9% (7 patients), higher than prior reports. Of the 6 deaths from disease, all had rapid progression, with a median survival of 14 days. The higher incidence could be secondary to treatment modifications or more sensitive detection. These findings are useful for decisions at the time of CNS involvement and could lead to modifications for future RMS clinical trials.

Reliability of intraoperative frozen section for the diagnosis of renal tumors suspicious for malignancy in children and adolescents.

BACKGROUND: The ability of intraoperative frozen section (IFS) to reliably diagnose renal tumors in children and adolescents is largely unknown. The objective of our study is to evaluate the ability of IFS to establish a histologic diagnosis for renal tumors in this population. METHODS: We reviewed our experience with patients who underwent IFS at the time of surgery for a renal tumor suspicious for malignancy from 2005 to 2015. The IFS was compared to the final pathology (FP). Data on concordance and reliability were analyzed. RESULTS: One hundred thirty patients underwent surgical interventions for a renal tumor suspicious for malignancy, and 32 (25%) patients underwent IFS. Median turnaround time for IFS was 20 min (range 13-44). The histologic IFS diagnosis correlated with FP in 26 (81.2%) cases was discrepant in three (9.4%) cases, and IFS was deferred to FP in three (9.4%) cases (kappa 0.71, 95% confidence interval [CI]: 0.52-0.899, P < 0.001). The IFS correctly distinguished between Wilms tumor and non-Wilms tumor in 30 (94%) cases (kappa 0.874, 95% CI: 0.705-1, P < 0.001). A total of 17 of 19 (89.5%) Wilms tumors were correctly diagnosed by IFS, yielding a sensitivity of 0.89 (95% CI: 0.67-0.99) and a specificity of 1 (95% CI: 0.75-1). CONCLUSION: IFS is a reliable tool to establish a histologic diagnosis and to differentiate between Wilms and non-Wilms tumors in children and adolescents with renal tumors. The use of IFS should be encouraged in cases in which obtaining a diagnosis will provide guidance for important "real-time" medical decision making, specifically additional adjunctive surgical procedures.

Development of a Primary Care-Based Clinic to Support Adults With a History of Childhood Cancer: The Tactic Clinic.

PURPOSE: Describe the development and evolution of a primary-care-based, multidisciplinary clinic to support the ongoing care of adult survivors of childhood cancer. METHODS: A consultative clinic for adult survivors of childhood cancer has been developed that is located in an adult, academic internal medicine setting and is based on a long-term follow-up clinic model available at Children's Hospital Colorado. RESULTS: The clinic opened in July 2008. One hundred thirty-five patients have been seen as of April 2014. Referrals and clinic capacity have gradually increased over time, and a template has been developed in the electronic medical record to help facilitate completion of individualized care plan letters. CONCLUSIONS: A primary care-based, multidisciplinary consultative clinic for adults with a history of childhood cancer survivor is feasible and actively engages adult primary care resources to provide risk-based care for long-term pediatric cancer survivors. This model of care planning can help support adult survivors of pediatric cancer and their primary care providers in non-academic, community settings as well.

Acute tumor lysis syndrome in a 7-month-old with hepatoblastoma.

Acute tumor lysis syndrome (TLS) is characterized by the triad of hyperuricemia, hyperkalemia, and hyperphosphatemia and is caused by the death of tumor cells and release of intracellular contents into the circulation. This syndrome is most frequently associated with hematopoietic malignancies with a high growth fraction, including acute leukemias and lymphomas, but can be encountered in patients with nonhematopoietic solid tumors. Acute tumor lysis is typically precipitated by chemotherapy leading to rapid cell death, but may also occur spontaneously prior to treatment. In severe cases, the metabolic abnormalities of TLS can cause renal failure, cardiac arrhythmias, and death. Standard therapies include intravenous hydration, alkalinization of the urine to increase the solubility of uric acid, and administration of allopurinol to block production of uric acid. Recombinant urate oxidase (rasburicase) is a newer agent that directly cleaves uric acid. It is important for the clinician to maintain a high level of clinical suspicion for TLS when initiating therapy in children newly diagnosed with cancer, including those with solid tumors, and to know how to prevent and treat this potentially deadly metabolic complication.

Timing of Radiation Therapy in Pediatric Wilms Tumor: A Report From the National Cancer Database.

PURPOSE: To determine, using the National Cancer Database (NCDB), the impact of the surgery to radiation therapy interval (SRI) on survival in contemporary patients with Wilms tumor (WT). METHODS AND MATERIALS: The NCDB was queried for patients aged ≤25 years diagnosed from 2004 to 2013 with unilateral WT who underwent definitive surgery and radiation therapy. The SRI was calculated for each patient. A stratified analysis was performed based on presence of metastasis using logistic regression to calculate risk factors for prolonged SRI, with a focus on the recommended SRI according to recent Children's Oncology Group trials (by day 14) and National Wilms Tumor Study-5 (by day 9). Cox regression was performed to assess the association of SRI with overall survival. RESULTS: A total of 1488 patients were included; 32.1% had metastasis at diagnosis. Among both metastatic and nonmetastatic groups, older patients were more likely to have prolonged SRI. For those without metastasis, SRI > 14 days was associated with increased risk of mortality (hazard ratio 2.13, P = .013). Analyzing SRI as a continuous variable also demonstrated an increased risk of death with longer SRI (hazard ratio 1.04 per day, P = .006) in this group. In contrast, among patients with metastasis, no significant association between SRI and mortality was found. CONCLUSION: Early initiation of radiation therapy remains a critical component of multimodal treatment for patients with nonmetastatic WT. For nonmetastatic patients, SRI ≤ 14 days correlates with improved overall survival. However, no such association was noted for patients with metastases. These results may inform the development of future WT trials.

Patterns of care and survival outcomes for adolescent and young adult patients with testicular seminoma in the United States: A National Cancer Database analysis.

INTRODUCTION: Testicular germ cell tumors (GCTs) are the most common solid tumor among adolescent and young adult (AYA) males. AYA patients with GCTs most typically have non-seminoma compared with seminoma, and accordingly there are fewer data reported on the AYA experience with testicular seminoma. OBJECTIVE: To evaluate national trends in postoperative treatment and overall survival (OS) outcomes in testicular seminoma by age group, specifically comparing AYAs with older adults. STUDY DESIGN: The National Cancer Data Base (NCDB) was queried for patients with testicular seminoma diagnosed between 2004 and 2012, who underwent orchiectomy followed by observation or adjuvant therapy (chemotherapy, radiation (RT), or both). Patients were grouped by age: AYA (15-39 years), adults between 40 and 55 years, and adults >55 years. Overall survival (OS) was presented using Kaplan-Meier curves and groups compared via a log-rank test. Univariate (UVA) and multivariate (MVA) analyses were performed using Cox proportional hazards regression models. Binary multiple logistic regression identified differences in variables by age category. RESULTS: Of the total 22,361 patients the majority were AYAs (12,880, 57.6%), followed by adults 40-55 years (8,022, 35.9%), and >55 years (1,459, 6.5%). Unadjusted 5-year OS was significantly better for AYAs versus adults 40-55 years and >55 years (98.0%, 96.4%, 87.7%; p < 0.001), as was 10-year OS (96.1%, 91.8%, 71.3% respectively; p < 0.001). The Table shows that on a MVA, OS was significantly better for AYAs versus adults 40-55 years and adults >55 years. AYA patients were also more commonly treated at centers with greater clinical volume. Additionally, AYA patients were less likely to present with metastatic disease. Accordingly, AYA patients were less likely to undergo retroperitoneal lymph node dissection (OR 0.81; p = 0.001) and were less often managed with adjuvant therapy including chemotherapy (OR 0.91; p = 0.027), RT (OR 0.93; p = 0.025), or both (OR 0.68; p = 0.020). DISCUSSION: AYA patients with testicular seminoma present with earlier stage disease and in the clinical Stage I setting are more often are managed with active surveillance following orchiectomy when compared with older adults in this population-based analysis. Among AYA patients, OS was modestly better when compared with adults 40-55 years and significantly better when compared with adults >55 years. CONCLUSION: Our objective to describe the patterns of care and survival outcomes for AYA patients with testicular seminoma in the USA was met by reviewing this large national dataset. These results may inform future guidelines for management of AYA seminoma.

Cardiac Mortality in Children and Adolescents with Hodgkin's Lymphoma: A Surveillance, Epidemiology and End Results Analysis.

PURPOSE: The purpose of this study was to evaluate the risk of cardiac death in pediatric Hodgkin's lymphoma (HL) survivors and identify high-risk groups that may need additional surveillance. METHODS: The Surveillance, Epidemiology and End Results program database was queried to analyze the rates of radiation therapy (RT) use and cardiac-specific mortality (CSM) in HL patients, aged 0-21 years, treated from 1973 to 2007. Primary endpoint was cardiac mortality. RESULTS: A total of 6552 patients were included. Median follow-up was 12 years (range, 0-40). Median age at diagnosis was 17 years (range, 0-21). The majority were white (85.5%), from western states (41.2%), had nodular sclerosis HL (73.2%), presented with stage I or II disease (51.5%), and received RT (56.1%). Death from cardiac disease occurred in 114 patients (9.2% of all deaths). CSM for the entire cohort at 10-, 20-, and 30-year time points was 0.3%, 1.6%, and 5.0%, respectively. Median age at the time of cardiac death was 39 years (range, 18-58 years). Under multivariate analysis (MVA), adolescent patients (ages 13-21) had higher rates of CSM (hazard ratio [HR], 3.05; p = 0.005). Female gender (HR, 0.43; p < 0.001), patients treated from 1998 to 2007 (HR, 0.19; p = 0.018), and those with lymphocyte-rich histology (HR, 0.14; p = 0.047) had significantly lower rates of CSM. Use of RT was not associated with CSM under MVA (HR, 1.18, p = 0.452). CONCLUSION: The cumulative incidence of CSM in this population analysis of pediatric HL was 9.2%, with a steady decline over the past several decades. Adolescent patients at diagnosis and males were more likely to die of cardiac-related causes.

Survival outcomes of adolescent and adult patients with non-seminomatous testicular germ-cell tumors: A population-based study.

BACKGROUND: In adolescents, approximately 90% of testicular germ cell tumors (T-GCTs) are non-seminomas (NS T-GCTs). Few studies have evaluated the impact of age, specifically in adolescence, on outcomes of NS T-GCTs. OBJECTIVE: The purpose of this study was to review all patients diagnosed with NS T-GCTs in the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the association between age (adolescents vs. adults) and survival outcomes. METHOD: The SEER database was queried for individuals ≥13 years old diagnosed with NS T-GCTs from 1995 to 2012. Patients were categorized into adolescent (13-19 years) and adult (≥20 years) cohorts. A Cox proportional hazards model was used for multivariate analysis (MVA). RESULTS: A total of 13,963 patients (1496 adolescents, 12,467 adults) was included. Median follow-up was 71 months (range 1-215). Five-year overall survival (OS) for adolescent and adult patients was 94% and 92%, respectively (p = 0.007); 5-year cancer-specific survival (CSS) was 95% and 94%, respectively (p = 0.139). Under MVA, adolescent patients had improved OS (HR 0.61; 95% CI 0.50-0.75; p < 0.001) and CSS (HR 0.65; 95% CI 0.51-0.82; p < 0.001), when compared with adults (Table). In a logistic regression analysis adjusting for demographics, adolescent patients were more likely to present with regional or distant metastatic disease (OR 1.16; 95% CI 1.01-1.35; p = 0.039), undergo an orchiectomy (OR 2.44; 95% CI 1.50-4.00; p < 0.001) or tumor excision (OR 2.43; 95% CI 1.57-3.77; p < 0.001), and receive other adjuvant surgery (OR 5.87; 95% CI 2.25-15.30; p < 0.001). CONCLUSIONS: To our knowledge, this is the largest population-based comparative analysis in NS T-GCTs comparing outcomes between these two age groups. Adolescent patients with NS T-GCTs had slightly improved survival compared with adults, despite presenting with more advanced disease. While adolescent patients present at more advanced stage, they achieve excellent survival outcomes possibly at the cost of a greater therapeutic burden.

Non-Rhabdomyosarcoma Soft Tissue Sarcomas in Children: A Surveillance, Epidemiology, and End Results Analysis Validating COG Risk Stratifications.

PURPOSE: Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group of sarcomas that encompass over 35 histologies. With an incidence of ∼500 cases per year in the United States in those <20 years of age, NRSTS are rare and therefore difficult to study in pediatric populations. We used the large Surveillance, Epidemiology, and End Results (SEER) database to validate the prognostic ability of the Children's Oncology Group (COG) risk classification system and to define patient, tumor, and treatment characteristics. METHODS AND MATERIALS: From SEER data from 1988 to 2007, we identified patients ≤18 years of age with NRSTS. Data for age, sex, year of diagnosis, race, registry, histology, grade, primary size, primary site, stage, radiation therapy, and survival outcomes were analyzed. Patients with nonmetastatic grossly resected low-grade tumors of any size or high-grade tumors ≤5 cm were considered low risk. Cases of nonmetastatic tumors that were high grade, >5 cm, or unresectable were considered intermediate risk. Patients with nodal or distant metastases were considered high risk. RESULTS: A total of 941 patients met the review criteria. On univariate analysis, black race, malignant peripheral nerve sheath (MPNST) histology, tumors >5 cm, nonextremity primary, lymph node involvement, radiation therapy, and higher risk group were associated with significantly worse overall survival (OS) and cancer-specific survival (CSS). On multivariate analysis, MPNST histology, chemotherapy-resistant histology, and higher risk group were significantly poor prognostic factors for OS and CSS. Compared to low-risk patients, intermediate patients showed poorer OS (hazard ratio [HR]: 6.08, 95% confidence interval [CI]: 3.53-10.47, P<.001) and CSS (HR: 6.27; 95% CI: 3.44-11.43, P<.001), and high-risk patients had the worst OS (HR: 13.35, 95% CI: 8.18-21.76, P<.001) and CSS (HR: 14.65, 95% CI: 8.49-25.28, P<.001). CONCLUSIONS: The current COG risk group stratification for children with NRSTS has been validated with a large number of children in the SEER database.

Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

PURPOSE: To determine the risk of subsequent carcinomas other than breast, thyroid, and skin, and to identify factors that influence the risk among survivors of childhood cancer. PATIENTS AND METHODS: Subsequent malignant neoplasm history was determined in 13,136 participants (surviving > or = 5 years postmalignancy, diagnosed from 1970 to 1986 at age < 21 years) of the Childhood Cancer Survivor Study to calculate standardized incidence ratios (SIRs), using Surveillance, Epidemiology, and End Results data. RESULTS: In 71 individuals, 71 carcinomas were diagnosed at a median age of 27 years and a median elapsed time of 15 years in the genitourinary system (35%), head and neck area (32%), gastrointestinal tract (23%), and other sites (10%). Fifty-nine patients (83%) had received radiotherapy, and 42 (59%) developed a second malignant neoplasm in a previous radiotherapy field. Risk was significantly elevated following all childhood diagnoses except CNS neoplasms, and was highest following neuroblastoma (SIR = 24.2) and soft tissue sarcoma (SIR = 6.2). Survivors of neuroblastoma had a 329-fold increased risk of renal cell carcinomas; survivors of Hodgkin's lymphoma had a 4.5-fold increased risk of gastrointestinal carcinomas. Significantly elevated risk of head and neck carcinoma occurred in survivors of soft tissue sarcoma (SIR = 22.6), neuroblastoma (SIR = 20.9), and leukemia (SIR = 20.9). CONCLUSION: Young survivors of childhood cancers are at increased risk of developing subsequent carcinomas typical of later adulthood, underscoring the importance of long-term follow-up and risk-based screening. Follow-up of the cohort is ongoing to determine lifetime risk and delineate individual characteristics that contribute to risk.

Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome.

PURPOSE: To determine if rituximab, an anti-CD20 monoclonal antibody, reduces cerebrospinal fluid (CSF) B-cell expansion in opsoclonus-myoclonus syndrome (OMS) and results in clinical improvement. METHODS: Sixteen children with OMS and increased % CD20 B-cells in CSF received 4 rituximab infusions (375 mg/m IV) as add-on therapy to corticotropin (ACTH), intravenous immunoglobulins, or both, and were reevaluated 6 months later. Outcome measures were clinical (motor function, behavior, sleep) and immunologic (CSF and blood immunophenotype and Ig levels). Controls were 16 age-matched and sex-matched children, who did not have OMS. RESULTS: After rituximab, 81% of OMS had a lower motor severity score, and 44% improved one severity category. Mean total score decreased by 44% (P = 0.0005). Rituximab reduced rage score, nighttime awakenings, and the number of children with opsoclonus, action myoclonus, drooling, gait ataxia, and rage. Despite a 51% reduction in ACTH dose, 9 of 11 children on ACTH did not relapse. The percentage of CSF CD19 (and CD20) B-cells was lowered in all children (undetectable in 6), with a 90% reduction in the group mean (P = 0.00003). CSF B-cells were no longer expanded compared with controls. In blood, CD19 B-cells decreased (-90%, P = 0.0003), as did the CSF:blood CD19 B-cell ratio (P = 0.00003). Serum IgM fell by 69% (below reference range), with no statistically significant change in IgG or IgA. CONCLUSIONS: Rituximab seems efficacious and safe as adjunctive therapy for OMS. Selective targeting of CSF B lymphocytes represents a novel and valuable paradigm shift in the therapy for centrally mediated paraneoplastic disorders.

Recurrent inflammatory pseudotumors in children.

BACKGROUND/PURPOSE: pulmonary (PPT) and extrapulmonary pseudotumors (EPPT) are uncommon benign tumors, which, in general, do not recur after complete resection. Recurrence rates for both types of pseudotumors are undocumented in a large population of children, and the salient features of potential recurrences are unspecified. METHODS: This is a report of 15 children with PPT and EPPT; 3 children had a recurrence. These pseudotumors recurred despite adequate primary resection of all gross disease at first presentation. The literature was reviewed to determine rate of recurrence for PPT and EPPT and also to document features common to recurrent pseudotumors. RESULTS: Overall recurrence rate for pseudotumors was 14%. PPT and EPPT, which were not confined to a single organ, had a high chance of recurrence (46% and 30%, respectively) compared with PPT and EPPT, which were confined to a single organ (1.5% and 8%, respectively). Recurrences have appeared between 3 months and 7 years. Intraabdominal EPPT accounts for more than 75% of the EPPT recurrences. CONCLUSIONS: PPT and EPPT recur more frequently than anticipated. All pseudotumors, which on initial presentation extend beyond the confines of a single organ, have a high chance of recurrence despite what appears to be adequate resection. Children with pseudotumors that extend beyond a single organ, require frequent postoperative evaluation for recurrence and may be candidates for chemotherapy or radiotherapy at the time of initial resection.