Biomedical subjects
Publications and source records attributed to N Jaffe.
A case of cystic retroperitoneal lymphangioma complicated by hemorrhage is reported in a 7-year-old boy who presented with an abdominal mass. The mass which was partially obstructing the ureter was successfully resected. The imaging findings with emphasis on MR features are described.
As the cure rate for childhood malignancies increases, the number of patients at risk for development of second malignancies also increases. Due to the potentially long remaining life span, long-term follow-up is difficult and patients are often at risk after presumptive cures. Some authors believe that cure rates for second malignancies are similar to cure rates for primary malignancies. We reviewed the records of 162 patients seen at our institution who had developed a second malignancy after treatment for childhood cancer. Presentation, age at diagnosis, tumor histology, extent of tumor, treatment (including radiotherapy with dosage when available, and chemotherapy) plus outcome were recorded. Mean age at diagnosis of the primary malignancy was 10.3 years. The most common primary malignancy was Hodgkin's disease (33) followed by soft tissue sarcoma (28), retinoblastoma (20), bone tumor (17), central nervous system (CNS) tumor (13), leukemia (8), Wilms' tumor (7), non-Hodgkin's lymphoma (6), neuroblastoma (5), thyroid neoplasm (5), and others (20). The average interval between diagnosis of the first and second malignancy was 10.8 years. These second tumors carried a high mortality. Only 56 patients have no evidence of disease. Five patients are known to be alive with disease and 92 patients have expired due to their second malignancy. Disease status in 8 patients is unknown. The most common second malignancy was osteosarcoma (35) followed by soft tissue sarcoma (24), breast cancer (15), leukemia (14), thyroid carcinoma (14), CNS tumors (12), melanoma (8), nonmelanomatous skin cancer (8), lymphoma (5), and others (27).(ABSTRACT TRUNCATED AT 250 WORDS)
Studies in which high-dose methotrexate (HDMTX) is used for the treatment of osteosarcoma have utilized commercial formulations of d,l-leucovorin (leucovorin calcium) for rescue from potential methotrexate (MTX) toxicity. These formulations are racemic mixtures containing equal amounts of d and l isomers of leucovorin. All of the available data indicate that the l isomer is the pharmacologically active diastereomer. A clinical study was conducted to determine if l-leucovorin was as safe and efficacious as d,l-leucovorin in the rescue of patients with osteosarcoma who were treated with HDMTX (12.5 g/m2 over 6 h). Because d,l-leucovorin consists of equal proportions of d and l isomers, l-leucovorin was administered at half the usual dose of d,l-leucovorin. In patients with delayed methotrexate excretion, l-leucovorin doses were escalated from 7.5 to 50 mg every 3 h until the MTX level was 0.3 mumol/l or less. Due to the low incidence of osteosarcoma, a control group of patients previously treated with d,l-leucovorin was utilized for comparison. Efficacy of l-leucovorin was determined by its ability to prevent HDMTX-associated toxicity. Demographic and clinical toxicity data from three patients who received 22 courses of MTX rescued with l-leucovorin were compared with data from six patients who had received 42 MTX courses rescued with d,l-leucovorin. Some liver function abnormalities and leukocyte elevations were found in both groups and were attributed to MTX administration. No clinical toxicity attributable to l-leucovorin was observed. l-Leucovorin in half the d,l-leucovorin dose was (equally) effective as a rescue treatment.
Acute nonlymphocytic leukemia (ANLL) developed in 2 of 142 pediatric patients with osteosarcoma treated with a cis-diamminedichloroplatinum-II (CDP)-based regimen: acute monomyelogenous leukemia (M4) with a normal female karyotype in one and acute myelogenous leukemia (M2) with t (8,21) in the other. The ANLLs occurred, respectively, in each patient 3 and 4 years after the initial diagnosis of osteosarcoma. In contrast to most of the adult experience and consistent with the majority of reported ANLL in children, the disease was characterized by an absence of the smoldering phase and cytogenetic findings similar to those seen in de novo ANLL.
We have recently begun a phase II trial in patients with osteosarcoma who developed pulmonary metastases during adjuvant chemotherapy or who presented with pulmonary metastases that persisted despite chemotherapy. Eligible patients were rendered free of visible disease by surgery. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (MTP-PE, CGP 19835A lipid) (2 mg/m2) was infused twice weekly for 3 months. In five patients, a single tumor nodule recurred within 6 weeks after completion of therapy. These lesions were resected and submitted for pathological examination. Tissue specimens obtained after therapy were compared to those obtained before therapy. All the patients showed a histological change in the characteristics of the pulmonary tumors. In three patients, peripheral fibrosis surrounded the tumor and inflammatory cell infiltration and neovascularization were present. This is in contrast to central necrosis, with viable peripheral tumor cells and no inflammatory response observed in lesions resected following chemotherapy. In a fourth case, evidence of early fibrotic changes was found. This and the fifth case showed a change in malignant characteristics, from high grade before liposomal therapy to low grade after therapy. The present study provides evidence for a biological effect of liposomal MTP-PE.
PURPOSE: A phase II trial that uses liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in patients with relapsed osteosarcoma is underway. To determine if in vivo cytokine induction plays a role in the mechanism of action of L-MTP-PE, we investigated the circulating cytokine levels of 16 patients who were undergoing therapy. PATIENTS AND METHODS: Patients had histologically proven osteosarcoma and pulmonary metastases that developed either during adjuvant chemotherapy or that were present at diagnosis and persisted despite chemotherapy. Patients were rendered disease-free by surgery. The major goal of the study was to improve the disease-free interval in this high-risk group. L-MTP-PE 2 mg/m2 was infused during a 1-hour period twice a week for 12 weeks, then once a week for 12 weeks. Serial blood samples were collected after L-MTP-PE administration and were assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha] interleukin-1 alpha [IL-1 alpha], IL-1 beta, IL-6, interferon-gamma [IFN-gamma], neopterin, C-reactive protein). RESULTS: After the infusion of L-MTP-PE, there was rapid induction of circulating TNF alpha and IL-6. TNF alpha levels peaked 1 to 2 hours after infusion in 10 of 16 patients, whereas peak IL-6 levels were detected at 2 to 3 hours in all patients. Induction of circulating TNF alpha and IL-6 was evident only after the first dose of L-MTP-PE. Neither IL-1 alpha nor IL-1 beta was detected in the plasma. Neopterin levels increased at 24 hours postinfusion, which indicated macrophage activation, and were not related to the induction of circulating IFN-gamma. C-reactive protein was elevated in all patients at 24 hours and decreased by 72 hours. Unlike circulating TNF alpha and IL-6, elevations in C-reactive protein and neopterin could be detected throughout the treatment course. CONCLUSION: It is concluded that L-MTP-PE has specific biologic effects in patients with osteosarcoma that may be important to the drug's immunostimulatory capacity and its effectiveness as an antitumor agent.
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The purpose of these studies was to determine whether chemotherapy interfered with the ability of peripheral blood monocytes from patients with osteosarcoma to respond to the liposome-encapsulated activating agent muramyl tripeptide phosphatidylethanolamine (L-MTP-PE). This was done in preparation of designing an adjuvant therapy protocol that includes L-MTP-PE combined with chemotherapy postoperatively for the treatment of primary osteosarcoma. The majority of patients who fail current adjuvant chemotherapy do so while on chemotherapy. Therefore, we believe it is important to combine L-MTP-PE with chemotherapy early in the treatment course rather than waiting until all chemotherapy cycles are completed. The tumoricidal properties of monocytes from patients with osteosarcoma could be activated by L-MTP-PE to levels equal to or greater than those expressed by normal control monocytes. No intrinsic monocyte defect could be demonstrated. Single-agent chemotherapy consisting of cisplatin (CPD), high-dose methotrexate (MTX), Cytoxan (CTX, cyclophosphamide; Bristol-Myers Co, Evansville, IN), or Adriamycin (ADR, doxorubicin; Adria Laboratories, Columbus, OH) did not interfere with this activation process. There was even a suggestion of enhanced activation potential following the administration of ADR. However, when both ADR and CTX were administered together on the same day, profound suppression in monocyte activation was observed. This suppressed function returned to normal by 3 weeks postcombination therapy. We therefore conclude that L-MTP-PE can be combined with ADR, CPD, MTX, or CTX as single agents but recommend that ADR plus L-MTP-PE is the most effective combination. By contrast, we discourage the use of L-MTP-PE when ADR and CTX are given together.
Sixty patients with extremity osteosarcoma were treated with intraarterial cisplatin. This was followed by surgical resection (amputation or limb salvage) and postoperative adjuvant chemotherapy utilizing two different protocols. Seventy-five percent of patients achieved an initial response. Overall disease-free survival was 58%. The number of patients treated with limb-salvage surgery gradually increased to the extent that 80% of newly-registered patients achieved a response and were subjected to limb salvage. Disease-free survival was 48% in amputation and 68% in limb salvage. The only factors found to have prognostic significance in determining disease-free survival were extent of tumor destruction induced by preoperative chemotherapy and tumor size.
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Osteosarcoma is principally a disease of the pre-teenager and teenage individual. Pain and swelling of an extremity are the usual initial symptoms. A number of neoplastic and nonneoplastic conditions must be considered in the differential diagnosis. Good quality radiographs complement pathologic material in establishing the diagnosis. Major advances as a consequence of chemotherapy have been achieved during the past decade. Disease-free survival following surgical ablation of the primary tumor and postoperative adjuvant chemotherapy is approximately 60%. The majority of patients undergoing modern forms of treatment are also candidates for limb salvage.
Six patients with extremity osteosarcoma initially underwent successful treatment of the primary tumor with four to seven courses of intraarterial cis-diamminedichloroplatin-II (IA-CDP; 100 to 150 mg/m2/course). The primary tumors in two patients were then extirpated by limb salvage. However, a local soft tissue recurrence occurred in both patients several months later. The other four patients refused surgical intervention and later also developed local bony recurrences. Reinstatement of three to five courses of IA-CDP in all six patients induced a complete response in five. The local recurrences (bony and soft tissue) in all six patients were excised. This included limb-salvage procedures in three patients. Additional postoperative chemotherapy was administered. Four patients remain alive and continuously free of disease 3.5+ to 4.5+ years after retreatment with IA-CDP.
Two new cases of malignant rhabdoid tumor of the kidney (RTK) in childhood are reported. Both presented with large abdominal masses and developed hypertension and one became hypercalcemic during the course of the disease. In each case disseminated disease and death occurred within three months of diagnosis. The findings on imaging consisted of large renal masses with a central site of origin, distant metastases at the time of presentation, and a subcapsular fluid collection in one of the two patients. The clinical and imaging features of RTK may suggest this diagnosis when faced with a primary renal neoplasm in childhood.
The records of 50 selected pediatric patients who were treated and followed at M. D. Anderson Cancer Center were reviewed to study the late effects of nonsurgical treatment of cancer in children. There were 26 girls and 24 boys ranging in age between 2 months and 16 years. Patients with head and neck cancer received chemotherapy and radiotherapy for rhabdomyosarcoma (n = 27), retinoblastoma (n = 8), or nasopharynx cancer (n = 2). Median follow-up was 13 years. The most severe side effects were noted in the fields of radiation and included hypoplasia of the jaw, orbit, or hemi-face with varying degrees of atrophy of the overlying soft tissues. A wide range of endocrine, dental, and psychologic abnormalities was also documented. Since 1 in every 1,000 adults older than 20 years today is likely to be a survivor of childhood cancer, recommendations are made for this "new" class of patients whom the head and neck surgeon will be seeing in the future.
The authors reviewed 76 magnetic resonance (MR) images of 38 patients with osteosarcoma treated with preoperative chemotherapy (intraarterial cisplatin with or without systemic chemotherapy). Histologic maps of the surgical tumor specimens in 33 cases were correlated with either late-chemotherapy or postchemotherapy MR images. There were four MR patterns--dark, mottled or speckled, homogeneous, and cystic--that corresponded to different amounts of tumor matrix, granulation tissue, hemosiderin deposits, fluid-filled cysts, and residual viable tumor. Nested foci of residual viable tumor could not be specifically identified, although tumor progression or skip metastases were accurately depicted in four patients. Other findings included (a) peritumoral edema in the soft tissues and intramedullary space that shrank with chemotherapy, (b) chemotherapy effect in the surrounding soft tissues, (c) a dark rim around the extramedullary component of the tumors corresponding to a collagenous capsule continuous with the periosteum, (d) development of metaphyseal hemorrhages and bone marrow infarcts, and (e) intramedullary vascular channels.
Ninety-eight pediatric patients were treated with three separate protocols (Treatment and investigation of Osteosarcoma [TIOS] I, II, and III) and 47 developed recurrent disease (metastases and/or local recurrence). Actuarial overall disease-free survival (hereafter designated survival) was 43%. Over 90% of the patients were treated initially with preoperative intraarterial cisplatin (CDP). Postoperative chemotherapeutic regimens comprised high-dose methotrexate with leucovorin rescue (MTX-CF), Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH), and cyclophosphamide. Primary definitive treatment comprised amputation or limb salvage (TIOS I and TIOS III). Patients treated with preoperative CDP and surgery (TIOS I and III) had a 62% survival. Patients in TIOS II refused surgical extirpation; they were treated exclusively with chemotherapy and had a 23% survival. Survival in patients treated with amputation was 55% and limb salvage 58%. Prognostic factors considered significant in relation to development of pulmonary metastases comprised tumor burden (P = .04) and the percentage of tumor necrosis induced by preoperative chemotherapy (P = .01). Histopathologic subtype was marginally significant: chondroblastic was more favorable as opposed to osteoblastic (P = .05). These findings are compared with results and prognostic factors published in the literature.
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We report a study of 27 patients with small cell osteosarcoma (SCO), 17 from the M. D. Anderson Cancer Center (MDAH) and ten from the Pediatric Oncology Group (POG). There were 12 male patients and 15 female patients; 19 were white, five were black, and three were Hispanic. They ranged from 6 to 28 years of age with a median of 14 years. Histologically there were three patterns: Ewing's-like, lymphoma-like, and spindle cell. All cases showed osteoid formation and a few had chondroid areas. There was cytoplasmic glycogen in ten cases. Initial treatment for MDAH patients included intraarterial infusion of cisplatin in ten, amputation in four, partial mandibulectomies in two, and biopsy with local radiotherapy and systemic chemotherapy in one. All POG patients had resection or amputation followed by adjuvant chemotherapy. Twelve patients are alive, of whom nine have had significant follow-ups for 25 to 90 months. Fourteen patients are dead of lung, spine, and brain metastases from 1 to 23 months after initial diagnosis. One patient is alive with lung relapse at 4 months. In summary, SCO is a high-grade variant of osteosarcoma, with an incidence of up to 4% of all osteosarcomas, that affects patients of the same age group and has the same anatomic location as conventional osteosarcoma. Currently, SCO appears to have a prognosis that is the same as or slightly worse than that of conventional osteosarcoma. Furthermore, although intraarterial infusion is effective for the primary tumors in the bone, distant metastases are difficult to control.