Biomedical subjects

A S Pappo

Publications and source records attributed to A S Pappo.

At least 73 records · Page 4Linked to original sources

PubMed1995

Rhabdomyosarcoma and other soft tissue sarcomas of childhood.

This review of the past year's literature summarizes the most relevant advances in the biology and therapy of rhabdomyosarcoma and other pediatric soft tissue sarcomas. The results of the third Intergroup Rhabdomyosarcoma Study clearly show that therapy based on specific risk factors offers the best chance of cure for children with rhabdomyosarcoma. The recent identification of nonrandom chromosomal translocations within distinct histologic subtypes of rhabdomyosarcoma and nonrhabdomyosarcoma soft tissue sarcomas offers a unique opportunity to improve our ability to diagnose, stage, and monitor these patients. Finally, identification of the genetic features that characterize these tumors will help us better understand the mechanisms involved in tumorigenesis and will facilitate the development of novel specific therapies.

Antineoplastic Agents, Alkylating↗

PubMed1995

Ewing's sarcoma as a second malignant neoplasm in a child previously treated for Wilms' tumor.

PURPOSE: Second malignant neoplasms (SMNs) are a rare occurrence after the successful treatment of childhood cancer. For survivors of Wilms' tumor, the 10-year cumulative risk of developing an SMN has been estimated to be 1%. Bone sarcomas arising within the radiation field are a common occurrence, yet Ewing's sarcoma has been rarely reported as an SMN. PATIENTS AND METHODS: A 10-year-old girl presented with dyspnea 5 years after the diagnosis of stage III favorable histology Wilms' tumor and was found to have a right intrathoracic mass arising from the eighth and ninth ribs. The mass was located at the edge of the previous radiation field. RESULTS: Tumor cytogenetics and immunocytochemistry were helpful in establishing the diagnosis of Ewing's sarcoma. Treatment included combination chemotherapy, with hematopoietic growth factor support, and excluded anthracyclines and radiotherapy. More than 1 year after the diagnosis of Ewing's sarcoma, the patient has completed therapy with no evidence of disease. CONCLUSIONS: This is the first report to our knowledge of Ewing's sarcoma arising in the irradiation field of a patient treated previously for Wilms' tumor.

Child↗

PubMed1995

Biology and therapy of pediatric rhabdomyosarcoma.

PURPOSE: To review key developments in biology and therapy of rhabdomyosarcoma (RMS) since the early 1970s. PATIENTS AND METHODS: The literature regarding biology, therapy, and late effects of therapy through March 1995 was reviewed. RESULTS: The two major histiotypes, embryonal and alveolar, are characterized by specific genetic abnormalities that provide clues to mechanisms of tumor induction. Alveolar tumors, for example, often possess a chromosomal translocation [t(2;13)(q35;q14)] that fuses the PAX3 gene in band 2q35 with the FKHR gene in band 13q14, creating a novel chimeric protein that could inappropriately activate normal targets of the PAX3 gene product, thereby contributing to tumorigenesis. Recognition of prognostically important patient groups primarily identified by tumor extent, site, and histology, and development of effective risk-based multimodal therapy in randomized trials, have increased long-term survival in RMS from 25% in 1970 to more than 70% in current studies. The most significant recent gain in therapeutic results was realized in patients with gross residual tumor after biopsy. CONCLUSION: Contemporary risk-based therapy cures more than two thirds of children with RMS while minimizing acute and late effects. Increased dose-intensity of known effective agents with hematopoietic growth factor support, new agents, and hyperfractionated irradiation are being evaluated in hopes of further improving therapy. Recent discovery of novel genetic features in this tumor should lead to better methods of diagnosis and risk assessment, and ultimately to identification of molecular targets for specific treatment.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Multiplex RT-PCR assay for the differential diagnosis of alveolar rhabdomyosarcoma and Ewing's sarcoma.

Cytogenetic analysis has defined specific translocations associated with two of the most common small round cell tumors of childhood, t(11;22) in Ewing's sarcoma and t(2;13) in alveolar rhabdomyosarcoma. We and others have previously demonstrated the diagnostic utility of a reverse transcriptase polymerase chain reaction (RT-PCR) assay for the detection of the t(11;22) encoded EWS/FLI-1 chimeric message in Ewing's sarcoma. More recently, we have cloned the t(2;13)(q35;q14) translocation and have shown that it results in the fusion of the PAX3 gene on chromosome 2 to FKHR, a novel member of the fork-head family of transcription factors on chromosome 13. To define the morphological spectrum of childhood sarcomas that express the t(2;13) encoded PAX3/FKHR chimeric message, we have performed RT-PCR analysis on samples from 44 primary pediatric sarcomas and 8 sarcoma cell lines. PAX3/FKHR chimeric messages were detected in 24 of 27 alveolar, 2 of 12 embryonal, and 0 of 1 pleomorphic rhabdomyosarcoma and in 1 of 2 ectomesenchymomas. In contrast, none of 8 Ewing's sarcomas or 2 undifferentiated sarcomas expressed this message. Chimeric transcripts were detected in all cases with cytogenetic evidence of the (2;13) translocation, and in each case the chimeric PAX3/FKHR message had the identical junction sequence, suggesting that genomic chromosome breaks were clustered in a single intron in both genes. By combining the PAX3/FKHR RT-PCR assay with primers for detection of the Ewing's sarcoma t(11;22) encoded EWS/FLI-1 chimeric transcript, we have developed a multiplex RT-PCR reaction that allows the rapid and accurate identification of either translocation in a biopsy sample.

Base Sequence↗

PubMed1994

Breast malignancy in children.

In 25 years, 18 patients with breast cancer were treated at St Jude Children's Research Hospital, 16 were female and 2 were male. The patients presented with primary malignancy (2), metastatic disease (13), or secondary malignancy (3). One of the females with primary breast malignancy had alveolar rhabdomyosarcoma. She was treated with wide excision and is currently receiving chemotherapy. The other patient presented with non-Hodgkin's lymphoma of the right breast. After biopsy, she was treated with chemotherapy. Of 13 patients with metastatic disease, the primary lesion was rhabdomyosarcoma in nine. One patient each had non-Hodgkin's lymphoma, Hodgkin's lymphoma, neuroblastoma, and signet-cell adenocarcinoma. All patients with metastatic disease to the breast died of the disease. Three females presented with invasive ductal carcinoma of the breast after treatment for Hodgkin's disease. Two underwent mastectomy and are alive without evidence of disease. One patient refused therapy and died of the second malignancy. We conclude that (1) breast malignancies had three distinctly different presentations in our patients, (2) the breasts of pediatric oncology patients should be carefully and routinely examined for metastatic disease, and (3) metastatic disease in the breast of a child is a manifestation of disseminated disease and is associated with an extremely poor prognosis.

Adolescent↗

PubMed1994

Rhabdomyosarcoma and other soft tissue sarcomas of childhood.

The past year has seen the publication of several important findings regarding the epidemiology, molecular biology, and treatment of pediatric rhabdomyosarcoma and other childhood soft tissue sarcomas. These research advances will help us better understand the mechanisms involved in tumor development and progression, tailor therapy according to specific pretreatment tumor biologic characteristics, and develop novel treatments for rhabdomyosarcoma.

Adolescent↗

PubMed1994

Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience.

PURPOSE AND METHODS: We reviewed the clinical records and pathologic findings of 37 children and adolescents with synovial sarcoma treated at our institution over a 30-year period to evaluate the prognostic significance of tumor size, invasiveness, histology, and other features. RESULTS: The 20 male and 17 female patients with synovial sarcoma had a median age of 13.7 years at diagnosis. Primary tumor sites were the extremities (n = 27), trunk (n = 8), and head and neck (n = 2). Disease stage (clinical group) was as follows: group I, n = 21; group II, n = 7; group III, n = 4; and group IV, n = 5. Nineteen patients had invasive (T2) lesions, 20 had tumors more than 5 cm in diameter, and 14 had histologic grade 3 lesions. The estimated 5-year survival rate (+/- SE) for patients with group I or II disease was 80% +/- 9%, compared with 17% +/- 15% for those with group III or IV tumors (P = .0003). An exact log-rank test, adjusted for clinical group, showed that tumor invasiveness and grade independently predicted overall and progression-free survival (P < .05); tumor size was significantly correlated with progression-free survival. A borderline significant relationship with overall survival was found for both tumor size and histologic subtype (P = .09). CONCLUSION: A controlled trial of adjuvant chemotherapy is merited in children with resected synovial sarcoma (clinical group I or II) who present with unfavorable clinicopathologic features such as large, invasive, or grade 3 lesions. Children with unresected or metastatic disease fare poorly despite multimodality therapy and require novel treatment approaches.

Adolescent↗

PubMed1993

A phase II trial of ifosfamide in previously untreated children and adolescents with unresectable rhabdomyosarcoma.

BACKGROUND: Children and adolescents with unresectable rhabdomyosarcoma fare poorly when treated with contemporary chemotherapeutic regimens. Evaluation of newly developed agents in these patients is important to improve their outcome. Based on a preclinical rhabdomyosarcoma xenograft model that accurately predicted the activity of new agents, the safety and efficacy of ifosfamide was evaluated as part of a Phase II clinical trial in previously untreated children with unresectable rhabdomyosarcoma. METHODS: Twenty-two children and adolescents (median age, 9 years) with newly diagnosed unresectable rhabdomyosarcoma (Intergroup Rhabdomyosarcoma Study Group III [n = 15] or IV [n = 7]) received two courses of ifosfamide at a dose of 1.6 g/m2 intravenously for 5 days over a 6-week period. Then the patients were evaluated for response, and additional treatment with surgery, radiation therapy, and multiagent chemotherapy (vincristine, cyclophosphamide, dactinomycin, and doxorubicin) was administered. RESULTS: Nineteen of 22 patients (86%) had a partial response to ifosfamide given as a single agent. No complete responses to this agent alone were observed. After administration of additional chemotherapy and local control measures (radiation therapy and surgery), the estimated proportion of patients surviving progression-free at 2 years was 63% (95% confidence interval, 37-80%). Ifosfamide was tolerated well; the most frequent toxicity was nondose-limiting myelosuppression. Transient mild renal toxicity infrequently was observed, and no central nervous system toxicity occurred in this group of patients. CONCLUSIONS: Ifosfamide appears to have significant clinical activity in untreated patients with unresectable rhabdomyosarcomas. These findings provide an accurate estimate of the response rate to single-agent ifosfamide in this group of previously untreated patients and thus provide a foundation for its rational incorporation into multiagent clinical trials. In addition, the potential benefits of this type of new drug development were demonstrated.

Adolescent↗

PubMed1993

Phase I trial of trimetrexate in pediatric solid tumors: a Pediatric Oncology Group study.

Trimetrexate (TMTX), a lipophilic antifol, was evaluated in a Pediatric Oncology Group (POG) Phase I trial in children with refractory solid tumors. TMTX was administered intravenously daily x 5 every three weeks. Starting dose was 6.4 mg/m2/day. Dose was escalated by 20% until the maximal tolerated dose was reached. A total of 75 courses were administered to 26 children. The major toxicity was myelosuppression, of which neutropenia and thrombocytopenia were most prominent. Rash, mucositis, and transient liver enzyme elevations were infrequently seen. Responses were observed in children with brainstem glioma, neuroblastoma, and renal cell carcinoma. The recommended Phase II dose using this schedule is 9.2-11 mg/m2/day depending on how heavily the patient has been treated prior to initiating this therapy.

Adolescent↗

PubMed1993

Use of HBA 71 and anti-beta 2-microglobulin to distinguish peripheral neuroepithelioma from neuroblastoma.

Peripheral neuroepithelioma (PN) can be difficult to distinguish from undifferentiated neuroblastoma (NBL) in the absence of molecular and cytogenetic studies. These primitive neural tumors of childhood are similar in morphology and immunocytochemistry, despite their distinct biochemical and behavioral characteristics. The recently developed monoclonal antibody HBA 71 is specific for the product MIC2, a marker of peripheral primitive neuroectodermal tumors. Because beta 2-microglobulin also is selectively expressed by most tumors in this subset, we examined whether a combination of the antibodies HBA 71 and anti-beta 2-microglobulin could facilitate the differentiation of the two malignancies. We histologically confirmed the diagnoses of 45 paraffin-embedded tumors of presumed neuroectodermal origin (19 PNs and 26 NBLs) from the pathology files of St Jude Children's Research Hospital. Samples were immunohistochemically stained using HBA 71 and anti-beta 2-microglobulin. Molecular and cytogenetic data were correlated with the results in a subset of eight patients. Sixteen (84%) of the 19 PNs reacted with HBA 71 and 13 (76%) of 17 PNs reacted with anti-beta 2-microglobulin. None of the NBLs reacted with either antibody. Three PNs were identified by HBA 71 alone and one was identified by anti-beta 2-microglobulin alone. Cellular genetic findings were consistent with the results. HBA 71 and anti-beta 2-microglobulin, when used in combination, can facilitate the differential diagnosis of PN and NBL.

12E7 Antigen↗

PubMed1993

Tumor-cell DNA content predicts outcome in children and adolescents with clinical group III embryonal rhabdomyosarcoma. The Intergroup Rhabdomyosarcoma Study Committee of the Children's Cancer Group and the Pediatric Oncology Group.

PURPOSE: The prognostic value of tumor-cell DNA content (ploidy) was evaluated in children with unresectable, nonmetastic rhabdomyosarcoma of embryonal histology. PATIENTS AND METHODS: Flow-cytometric techniques were used to estimate the ploidy of tumor specimens from 34 patients with embryonal rhabdomyosarcoma who were enrolled in the intergroup rhabdomyosarcoma study III (IRS III) from 1985 to 1991. Tumors were classified as diploid or hyperdiploid (DNA content, 1.1 to 1.8 times that of normal diploid cells). The influence of ploidy on clinical outcome was assessed by the Kaplan-Meier technique and Cox regression analysis with stepwise selection. RESULTS: Twelve of the tumor specimens were diploid and 22 were hyperdiploid. The patient groups defined by diploid or hyperdiploid tumors had similar presenting characteristics (eg, age, tumor size, and anatomic site). Significantly more children with hyperdiploid tumors achieved a complete response than did children with diploid tumors (85% v 42%; P = .01). The probability of progression-free survival at 5 years (+/- SE) was 91% +/- 6% for the hyperdiploid group, compared with 17% +/- 11% for the diploid group (P < .001). Hyperdiploidy was also associated with a significantly higher overall survival rate at 5 years: 96% +/- 4% versus 50% +/- 14% (P = .004). Ploidy retained its prognostic significance after adjustment for tumor site in the Cox regression model. CONCLUSION: Tumor-cell ploidy strongly correlates with outcome in children with nonmetastic, unresectable embryonal rhabdomyosarcoma. The two biologically distinct groups identified by this measure would benefit from further refinements in risk-directed therapy.

Adolescent↗

PubMed1992

Etiology of red blood cell macrocytosis during childhood: impact of new diseases and therapies.

Although an elevated erythrocyte mean corpuscular volume has been noted in many conditions, the relative frequency of various causes of macrocytosis in the pediatric population has not been defined. Therefore, the different medical conditions associated with red cell macrocytosis were retrospectively reviewed. One hundred forty-six children between 6 months and 12 years of age with a mean corpuscular volume greater than or equal to 90 fL were identified during a 13-month period. The most common association with macrocytosis was drug ingestion (anticonvulsants, zidovudine, immunosuppressive agents), observed in 51 (35%) of the cases. Other conditions associated with macrocytosis were congenital heart disease (20), Down syndrome (12), reticulocytosis (11), and marrow failure/myelodysplasia (6). Miscellaneous diseases were identified in 21 children. Twenty-four cases had no apparent cause of their macrocytosis; 21 of them had just a slight elevation of the mean corpuscular volume (91 or 92 fL), suggesting that these values probably represent the upper limit of normal. No cases of vitamin B12 or folate deficiency were observed. The use of relatively new drugs such as valproate, zidovudine, and immunosuppressants (for the treatment of diverse medical conditions) accounted for more than half of the cases of drug administration and 24% of the children with macrocytosis. Three children with bone marrow failure had macrocytosis and pancytopenia, suggesting that this finding might be the first manifestation of serious but treatable disorders such as aplastic anemia.

Child↗

PubMed1989

Disseminated primitive neuroectodermal tumor: diagnosis using immunocytochemistry, electron microscopy, and molecular probes.

A patient with a disseminated small cell tumor presented with hyperuricemia, gingival hypertrophy, lymphadenopathy, and bone marrow replacement with tumor cells. Initial histologic examination and clinical presentation were consistent with presumed marker silent lymphoma/leukemia. Despite initial treatment with and response to lymphoma/leukemia therapy the patient relapsed in the testis, bone marrow, pancreas, and skin whereupon subsequent and retrospective immunocytochemical, ultrastructural, cytogenetic, and molecular analysis led to the diagnosis of primitive neuroectodermal tumor (PNET). Despite extensive investigation and autopsy no primary site of tumor could be found demonstrating that PNET should be considered in the differential diagnosis of disseminated small cell tumors without an apparent primary.

Adolescent↗

PubMed1989

Septic arthritis in children with hemophilia.

Four of the 139 children with hemophilia followed up at our center have developed septic arthritis during the past 6 years (2.9% incidence). Two infections were caused by Streptococcus pneumoniae and one each by Staphylococcus aureus and Haemophilus influenzae type B. Common features at time of presentation included fever and a 2- to 7-day history of joint pain and swelling unresponsive to factor replacement infusions. Since three of the patients were human immunodeficiency virus seropositive, we propose that human immunodeficiency virus infection may be responsible for the disproportionately high number of cases of septic arthritis observed in our patient population.

Adolescent↗

PubMedDate not supplied

Clear cell sarcoma of soft tissues in children and young adults: the St. Jude Children's Research Hospital experience.

Clear cell sarcoma is a rare soft tissue neoplasm whose clinical behavior and outcome has not been previously characterized. This study reviewed the clinical characteristics and outcome of all children with clear cell sarcoma of the soft tissues who were treated at St. Jude Children's Research Hospital from March 1962 through August 1998. Of 225 children with nonrhabdomyosarcomatous soft tissue sarcomas, 5 (2.2%) were diagnosed with clear cell sarcoma. Median age at diagnosis was 15 years 3 months. Primary sites included the extremities (n = 3), chest wall (n = 1), and abdomen (n = 1). At diagnosis 3 patients had localized disease. Following surgical resection (n = 3), radiotherapy (n = 2), and chemotherapy (n = 1) all three survive disease-free 10, 11, and 90 months after diagnosis, respectively. The remaining two patients with metastatic disease at diagnosis died 21 days and 9 months after diagnosis. Clear cell sarcoma of the soft tissues is rare in pediatrics. Complete surgical resection with negative margins is the most effective treatment for this disease. Patients with metastatic disease are candidates for multiinstitutional chemotherapy trials.

Adolescent↗

PubMedDate not supplied

Disseminated intrathoracic desmoplastic small round-cell tumor: a case report.

PURPOSE: Recently recognized as a distinct clinicopathologic entity, desmoplastic small round-cell tumors typically affect young men. These aggressive tumors usually arise in the abdomen; other sites of primary disease have been described only rarely. We report the case of an extraabdominal primary tumor with widespread dissemination, including the subcutaneous tissue, a previously unrecognized metastatic site. PATIENT AND METHODS: We describe the case of a 16-year-old boy with a primary extraabdominal metastatic desmoplastic small round-cell tumor. RESULTS: Our patient had a primary intrathoracic desmoplastic small round-cell tumor and widespread dissemination involving the subcutaneous tissue, kidney, liver, bone, and lymph nodes. Histopathologic analysis found intense desmoplasia and polyphenotypic expression of neural, muscle, and epithelial markers. Reverse transcriptase-polymerase chain reaction analysis of fresh tumor tissue confirmed the characteristic EWS-WT1 transcript. CONCLUSIONS: Broader than originally anticipated, the clinical spectrum of desmoplastic small round-cell tumors continues to evolve. Primary intrathoracic tumors with soft-tissue dissemination and polyphenotypic expression should prompt suspicion of this malignancy. Molecular analysis of fresh tumor tissue is an important adjunct to diagnosing this rare neoplasm.

Adolescent↗

PubMedDate not supplied

A phase II trial of high-dose methotrexate in previously untreated children and adolescents with high-risk unresectable or metastatic rhabdomyosarcoma.

PURPOSE: The outcome for children with advanced-stage rhabdomyosarcoma remains poor with contemporary treatment regimens. Evaluation of new drugs is important to improve clinical outcome. Because methotrexate has shown promising activity in the treatment of patients with recurrent rhabdomyosarcoma, we conducted a phase II trial in untreated children with advanced-stage disease to evaluate the efficacy and safety of this agent. PATIENTS AND METHODS: Fifteen patients received 1 to 4 courses of high-dose methotrexate (HDMTX, 12 g/m2). Patients then received standard multiagent chemotherapy (vincristine, dactinomycin, cyclophosphamide, ifosfamide, mesna) with cytokine support and local radiotherapy. Patients who responded to HDMTX received four additional courses of this drug during continuation therapy. RESULTS: Twelve patients were evaluable for response after 2 or more courses of HDMTX; 4 achieved a partial response (33.3%). After administration of standard chemotherapy and radiation, the estimated 2-year progression-free survival for all patients was 56% (SD 15%). The drug was well-tolerated and the most common side effects included mucositis, transient elevation of transaminases, and neutropenia. The four patients who received additional courses of HDMTX during continuation therapy had limited toxicity which included mucositis, anemia, and thrombocytopenia. CONCLUSIONS: About one-third of children with previously untreated advanced-stage rhabdomyosarcoma responded to HDMTX. Its different mechanism of action and non-overlapping toxicity with other agents make HDMTX an attractive candidate for incorporation into front-line treatment regimens for rhabdomyosarcoma.

Adolescent↗

PubMedDate not supplied

Primitive neuroectodermal tumor of bone as a second malignant neoplasm in a child previously treated for acute lymphoblastic leukemia.

PURPOSE: Although rare, second malignant neoplasms (SMNs) are a devastating consequence of successful treatment of childhood cancer. The 15-year estimated risk of developing a second malignant neoplasm after treatment of childhood acute lymphoblastic leukemia (ALL) is 2.5%. Most of these neoplasms are central nervous system tumors. The risk of secondary acute myeloid leukemia has been negligible in most treatment regimens. Here, we report the first case of a primitive neuroectodermal tumor (PNET) in a patient treated for ALL. PATIENTS AND METHODS: A 15.7-year-old girl developed pain in her left leg 7 years after diagnosis of low-risk ALL. Imaging studies revealed lytic lesions in her left proximal tibia and several vertebra as well as metastatic nodules in both lungs. RESULTS: Immunocytochemical and molecular analyses led to the diagnosis of PNET. The treatment of this SMN was composed of combination chemotherapy with hematopoietic growth factor support and radiotherapy to the primary lesion and affected spine. The tumor recurred 5 months after the completion of treatment, and the patient is now undergoing salvage therapy composed of chemotherapy and radiotherapy. CONCLUSIONS: To our knowledge, this is the first report of PNET as an SMN after successful treatment of ALL.

Adolescent↗