Fredric A. Hoffer

Diagnostic relevance of clonal cytogenetic aberrations in malignant soft tissue tumors

BACKGROUND Malignant soft-tissue tumors often present substantial diagnostic challenges. Chromosome aberrations that might be diagnostic have been identified in some types of soft-tissue tumors, but the overall frequency and diagnostic relevance of these aberrations have not been established. METHODS We attempted to determine the karyotypes of a series of 62 consecutive, unselected malignant spindle-cell or small round-cell soft-tissue tumors (from 46 adults and 16 children) after direct harvesting of cells or short-term culture. All tumors were examined independently by immunohistochemical staining in addition to routine light-microscopical evaluation, and all but two tumors were examined by electron microscopy. RESULTS Metaphases were obtained from 61 of the 62 tumors, and clonal chromosome aberrations were identified in 55 (89 percent). In the six tumors that yielded metaphases but lacked apparent clonal aberrations, the normal metaphases were found to originate from non-neoplastic stromal elements within the tumor specimens. Thus, all tumors in which karyotyping was successful contained clonal chromosome aberrations. Forty of 62 tumors (65 percent) contained clonal chromosome aberrations that either suggested or confirmed a specific diagnosis; in 15 of these tumors (24 percent of all tumors), the aberrations were important in establishing the final diagnosis. Cytogenetic analyses were particularly informative about small round-cell tumors from children: 8 of 14 round-cell tumors contained diagnostically important chromosome aberrations. Using the combined approaches of light and electron microscopy, immunohistochemistry, and cytogenetics, we established an unambiguous diagnosis for 60 of 62 tumors. CONCLUSIONS Cytogenetic analyses reveal clonal chromosome aberrations in virtually all malignant soft-tissue tumors. These clonal chromosome aberrations, particularly in small round-cell tumors in children, often have diagnostic relevance.

R2* magnetic resonance imaging of the liver in patients with iron overload

R2* magnetic resonance imaging (R2*-MRI) can quantify hepatic iron content (HIC) by noninvasive means but is not fully investigated. Patients with iron overload completed 1.5T R2*-MRI examination and liver biopsy within 30 days. Forty-three patients (sickle cell anemia, n = 32; beta-thalassemia major, n = 6; and bone marrow failure, n = 5) were analyzed: median age, 14 years, median transfusion duration, 15 months, average (+/-SD) serum ferritin 2718 plus or minus 1994 ng/mL, and average HIC 10.9 plus or minus 6.8 mg Fe/g dry weight liver. Regions of interest were drawn and analyzed by 3 independent reviewers with excellent agreement of their measurements (intraclass correlation coefficient = 0.98). Ferritin and R2*-MRI were weakly but significantly associated (range of correlation coefficients among the 3 reviewers, 0.41-0.48; all P < .01). R2*-MRI was strongly associated with HIC for all 3 reviewers (correlation coefficients, 0.96-0.98; all P < .001). This high correlation confirms prior reports, calibrates R2*-MRI measurements, and suggests its clinical utility for predicting HIC using R2*-MRI. This study was registered at www.clinicaltrials.gov as #NCT00675038.

Vinblastine and Methotrexate for Desmoid Fibromatosis in Children: Results of a Pediatric Oncology Group Phase II Trial

PURPOSE To determine the efficacy and safety of using vinblastine (Vbl) and methotrexate (Mtx) in children with desmoid-type fibromatosis that is recurrent or not amenable to treatment with radiation or surgery. PATIENTS AND METHODS A phase II study was conducted within the Pediatric Oncology Group. Patients were treated using Vbl (5 mg/m2/dose) and Mtx (30 mg/m2/dose), both administered by intravenous injection weekly for 26 weeks and every other week for an additional 26 weeks. Response was assessed by bidimensional measurements of tumor on axial imaging (magnetic resonance imaging or computed tomography). RESULTS Over 35 months, 28 patients were enrolled; 27 were eligible, and 26 were assessable for response. A measurable response was documented in eight patients (31%), and 10 patients had stable disease documented as the best response to treatment. Eighteen patients had disease progression at a median time of 9.1 months. Eight patients remain free of disease progression at a median of 43.4 months from study entry. Nine patients reported no to moderate toxicity. Neutropenia was the most common toxicity (n = 22) and the most common grade 4 toxicity (n = 5). Anemia, nausea, vomiting, and elevations in hepatic transaminases were also common and were reversible with interruption of chemotherapy. CONCLUSION Vbl and Mtx are well tolerated in children with desmoid-type fibromatosis. Furthermore, this combination can promote tumor regression or block tumor growth in most children.

Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children.

PURPOSE We report the treatment of 10 children for progressive desmoid tumor not amenable to standard surgical or radiation therapy with the use of vinblastine (VBL) and methotrexate (MTX). PATIENTS AND METHODS Ten patients aged 6.4 to 18 years with primary (two patients) or recurrent (eight patients) desmoid tumor were treated with VBL and MTX for 2 to 35 months. Patients with recurrent tumors had been previously treated with surgical resection with (two patients) or without (five patients) radiation therapy or with radiation therapy alone (one patient). No patient had previously received cytotoxic chemotherapy. The tumor response was assessed at routine intervals by physical examination and magnetic resonance imaging (MRI). RESULTS Five patients had clinical evidence of response to therapy with complete resolution (three patients) or partial resolution (two patients) of physical examination and radiographic abnormalities. Three patients had stable disease during 10 to 35 months of treatment. Two of these patients had progressive disease 9 and 37 months after treatment stopped; one patient had no progression 16 months after therapy. Two additional patients with stable disease had chemotherapy discontinued after 2 and 3 months. Common side effects included mild alopecia and myelosuppression and moderate nausea and vomiting. In patients with responding tumors, MRI showed decreased tumor size and, in two patients, changes consistent with fibrosis and decreased cellularity of the tumor. CONCLUSION Combination chemotherapy with VBL and MTX appears to control desmoid tumor without significant acute or long-term morbidity in most children. This may allow for further growth and development in these patients, which may decrease the morbidity of subsequent definitive therapy.

The feasibility and outcome of nephron-sparing surgery for children with bilateral Wilms tumor. The St Jude Children's Research Hospital experience: 1999-2006.

Approximately 5% of children with Wilms tumor present with bilateral disease. The treatment challenge is to achieve a high cure rate while maintaining adequate long‐term renal function. The authors of this report assessed the feasibility and outcome of nephron‐sparing surgery in patients with bilateral Wilms tumor who were treated at a single institution.

Improved Response in High-Risk Neuroblastoma With Protracted Topotecan Administration Using a Pharmacokinetically Guided Dosing Approach

PURPOSE To estimate the response rate and toxicity associated with intravenous topotecan when it is administered on a protracted schedule according to a pharmacokinetically guided dosing approach to treat childhood high-risk neuroblastoma. PATIENTS AND METHODS In this prospective phase II trial, topotecan was administered intravenously daily for 5 days for each of 2 consecutive weeks for two cycles. On the basis of topotecan systemic clearance, doses were individualized to attain a single-day topotecan lactone area under the plasma concentration-time curve (AUC) of 80 to 120 ng/mL . h. Patients subsequently received standard treatment. RESULTS Both cycles were administered to 28 (93%) of the 30 enrolled patients (median age, 3.1 years). Target topotecan AUCs were achieved in 92 (72%) of the 127 measurements conducted after pharmacokinetically guided adjustment; the median dosage required to achieve target AUCs was 2.7 mg/m(2) (range, 0.95 to 3.8 mg/m(2)). The response rate was 60% (95% CI, 41% to 77%); there were one complete and 17 partial responses. No patient experienced disease progression during initial topotecan therapy. Primary tumor volumes decreased (median decrease, -58.2%; range, -95.1% to -4.9%) in the 26 patients with available size data. Homovanillic acid levels in 16 (89%) of 18 patients and vanillylmandelic acid levels in 14 (78%) of 18 patients were lower (P = .002 and P = .018, respectively) after topotecan therapy. Reversible grade 4 myelosuppression occurred in all patients, but no deaths occurred as a result of infection or toxicity. CONCLUSION Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.

Accuracy of percutaneous lung biopsy for invasive pulmonary aspergillosis

Background. Invasive pulmonary aspergillosis is fulminant and often fatal in immunosuppressed patients. Percutaneous biopsy may select patients who could benefit from surgical resection. Objective. We sought to determine the accuracy of percutaneous biopsy for pediatric invasive pulmonary aspergillosis. Materials and methods. We retrospectively reviewed 28 imaging-guided percutaneous biopsies of the lungs of 24 children with suspected pulmonary aspergillosis. Twenty-two were being treated for malignancy and two for congenital immunodeficiency; 15 had received bone-marrow transplants. The accuracy of the percutaneous lung biopsy was determined by subsequent surgical resection, autopsy, or clinical course. Results. Histopathological studies showed ten biopsy specimens with septate hyphae, indicating a mold, and seven with Aspergillus flavus colonies in culture. The remaining 18 biopsies revealed no fungi. No patient had progressive aspergillosis after negative biopsy. Invasive pulmonary mold was detected by percutaneous biopsy with 100 % (10/10) sensitivity and 100 % (18/18) specificity. Percutaneous biopsy results influenced the surgical decision in 86 % (24 of 28) of the cases. Bleeding complicated the biopsy in 46 % (13/28) and hastened one death. Conclusion. Percutaneous biopsy of the lung is an accurate technique for the diagnosis of invasive pulmonary aspergillosis and correctly determines which immunosuppressed pediatric patients would benefit from therapeutic pulmonary resection.

Accuracy of MR imaging for detecting epiphyseal extension of osteosarcoma

Background. Too few patients are receiving epiphyseal-sparing limb salvage procedures for osteosarcoma. Objective. To determine how magnetic resonance (MR) imaging can best predict the epiphyseal extension of osteosarcoma. Materials and methods. Forty children underwent complete pretreatment static and dynamic contrast-enhanced MR imaging (DEMRI). Static MR images [T1-weighted and short tau inversion recovery (STIR)] of the epiphyses were read in three ways: (1) for suspicion of any abnormality (tumor or edema), (2) for suspicion of tumor, excluding suspected edema, and (3) validating the second method by using a scale to rate the likelihood of tumor. Presentation imaging was compared to histopathologic findings after chemotherapy and resection. The receiver operating characteristic (ROC) method was used to analyze the scaled ratings of static MR and DEMRI values. Results. At delayed resection, 20 of 40 children with osteosarcoma had confirmed epiphyseal tumor; however, 32 epiphyses were abnormal on STIR and 28 abnormal on T1. Differentiating suspected tumor from edema increased the accuracy to an Az (area under the ROC curve) of 0.94 for both T1-weighted and STIR static sequences. T1-weighted MR had better specificity and STIR better sensitivity at any given rating. DEMRI was slightly less accurate (Az = 0.90). Conclusion. Static MR imaging most accurately detected epiphyseal extension of osteosarcoma when readers distinguished suspected tumor from edematous or normal tissue.

Liver biopsy methods for pediatric oncology patients

Background. Liver biopsy is a high-risk procedure in oncology patients, and optimal methods for children have not been established.¶Objective. To assess the effectiveness and safety of two methods of performing liver biopsy in pediatric oncology patients.¶Materials and methods. Between May 1997 and July 1999, 51 liver biopsies (22 percutaneous and 29 transjugular) were performed. The 22 percutaneous biopsies (13 focal hepatic lesions and 9 general liver biopsies) were performed under sonographic guidance; 21 used a spring-loaded needle (usually 18 G). In 21 patients, a coaxial sheath was used to inject a slurry of microfibrillar collagen into the needle track. The 29 transjugular general liver biopsies were performed with a 19-G spring-loaded needle, under sonographic and fluoroscopic guidance. The transjugular technique was used for children with thrombocytopenia, coagulopathy, ascites, or recent bone-marrow transplantation.¶Results. All biopsies yielded sufficient tissue for diagnostic studies. Bleeding occurred after 3 of 21 percutaneous biopsies, despite coaxial track embolization. No bleeding or other major complication occurred after transjugular biopsy.¶Conclusion. Coaxial percutaneous biopsy with track embolization was effective, but was not complication-free; it should be reserved for focal lesions or for patients at low risk of bleeding. Transjugular liver biopsy is safe and effective for use in high-risk pediatric oncology patients.

Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: Results of a Children's Oncology Group (COG) Phase II Study

Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non‐cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Childrens Oncology Group.