Brian S. Greffe

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 Hodgkins 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/m2 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.

Pulmonary veno-occlusive disease after autologous bone marrow transplant in a child with stage IV neuroblastoma: case report and literature review.

Pulmonary veno-occlusive disease (PVOD) is a rare, almost universally fatal complication of chemotherapy and bone marrow transplantation with few treatment options. A 19-month-old boy with stage 4 neuroblastoma with fatal PVOD following high-dose chemotherapy with autologous peripheral blood stem cell rescue is described here. A comprehensive literature review revealed 40 case reports of PVOD in oncology patients. Various therapeutic modalities were attempted, with four survivors. PVOD should be considered in patients with dyspnea and cardiomegaly. Less invasive diagnostic methods and more effective therapies are needed.

Cessation of antibiotics regardless of ANC is safe in children with febrile neutropenia: A preliminary prospective trial

Purpose This study was designed to evaluate the safety and efficacy of stopping antibiotic treatment regardless of absolute neutrophil count (ANC) or signs of impending neutrophil recovery in children with febrile neutropenia (FN) and no identifiable infectious source. Patients and Methods Thirty-two consecutive cases of FN without identifiable source were prospectively evaluated. Patients were examined, cultured, and initially treated with ceftazidime ± vancomycin. Antibiotics were discontinued and patients discharged regardless of ANC (WBC/μl X [% segs + bands]) once all the following criteria were met: afebrile × 24 h; cultures negative at 48 h; thermometer and telephone available at home. Prompt notification of fever (T > 38.3°C) and readmission were required. Results Median ANC was 60/μl on admission and 160/μl at discharge. Median length of treatment was 3 days. Four patients were readmitted for FN, and two patients were readmitted afebrile for cultures which became positive after discharge. None of the 32 cases suffered apparent complications from early discharge. Conclusion Results of this preliminary trial suggest that cessation of antibiotics regardless of ANC is safe in cases of FN without identifiable source, provided that marrow is not infiltrated and that recurrent fever receives prompt antibiotic retreatment.

NEW PERSPECTIVES ON THERAPY FOR VAGINAL ENDODERMAL SINUS TUMORS

PURPOSE Malignant germ cell tumors account for 3% of childhood cancers. Endodermal sinus tumor, the most common malignant germ cell tumor, requires treatment primarily with chemotherapy and surgery is reserved as a last resort. It is rare for the vagina to be the primary site of endodermal sinus tumor, and we report on our experiences with this phenomenon at a single institution. MATERIALS AND METHODS We retrospectively reviewed the clinical features, treatment and outcomes of 3 children with vaginal endodermal sinus tumor. RESULTS Initial treatment was combination chemotherapy, in 2 patients. alpha-fetoprotein decreased rapidly and returned to normal in both. One patient is disease-free 7 years after chemotherapy and the other patient is currently disease-free with a normal alpha-fetoprotein 3 months after induction chemotherapy. In the remaining case progressive disease developed following initial chemotherapy and subsequent salvage surgery combined with radiation, chemotherapy and ultimately autologous bone marrow transplant was performed. The patient has remained disease-free for 6.5 years since completing this extensive therapy. CONCLUSIONS Endodermal sinus tumor of the vagina is rare. All of our patients presented with painless bleeding of no obvious source. In such cases one must maintain a high index of suspicion for possible underlying pathological conditions even if ultrasound is negative. Evaluation must include endoscopic examination of the lower genitourinary tract. Bone marrow transplant should be considered as a last therapeutic resort in salvage cases of unresponsive vaginal endodermal sinus tumor.

Local control of metastatic sites with radiation therapy in metastatic Ewing sarcoma and rhabdomyosarcoma

Approximately 20% of children with Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS) present with metastatic disease at initial diagnosis. Overall, the outcome is poor, with an event‐free survival of <20%. Local control at metastatic sites has not been previously reported. We reviewed control of metastatic sites in children with EWS and RMS that received curative intent radiation therapy to each metastatic site. In 13 children, at a median follow‐up of 18 months, a single local failure was seen. Toxicity was minimal. Our data suggest that radiation therapy is effective and tolerable in children with metastatic EWS and RMS. Pediatr Blood Cancer 2011;57:169–171.

Dual ALK and MYC rearrangements leading to an aggressive variant of anaplastic large cell lymphoma.

Anaplastic lymphoma kinase (ALK) and MYC are oncogenes often dysregulated in pediatric lymphomas. NPM-ALK/t(2;5)(p23;q35) is a genetic hallmark of ALK+ anaplastic large cell lymphoma (ALCL). MYC gene translocations are frequently detected in high-grade B-cell lymphomas. ALK+ALCL cases with concurrent MYC translocation are exceedingly rare and are more aggressive and chemoresistent compared with other ALK+ALCL. We report a patient who presented with ALK+ALCL possessing coexistent MYC rearrangement, massive tumor dissemination, and early widespread relapse. This case underscores the importance of recognition of close correlation between dual ALK and MYC rearrangements and the characteristic clinical features in this unusual ALCL variant.

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 Childrens 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.

Precursor natural killer cell leukemia

Natural killer (NK) cell tumors are a rare and heterogeneous group of disorders. Immature NK cell tumors are less common, and are less recognized and defined than mature NK cell tumors. There is insufficient experience of diagnosis and treatment with immature NK cell tumors, especially in pediatric patients. Here we describe a pediatric patient with precursor NK cell leukemia and review the literature of the previously reported cases in children to further help characterize the diagnosis, treatment, and outcome. Pediatr Blood Cancer 2008;50:876–878.