Relationship of urinary excretion of modified nucleosides to disease status in childhood acute lymphoblastic leukemia.

The levels of urinary excretion of five modified nucleosides were quantitated by high-performance liquid chromatography for 15 normal children and 24 children with acute lymphoblastic leukemia (ALL). Excretion of each nucleoside decreased linearly with age when quantitation was based on urine creatinine content. Patients with childhood ALL at initial diagnosis or in relapse had significantly higher concentrations of 1-methylinosine, N2,N2-dimethylguanosine, 1-methylguanosine, and pseudouridine in their urine when compared to the concentrations in either patients in remission (P less than 0.001, P less than 0.001, P less than 0.01, and P less than 0.05, respectively) or normal controls (P less than 0.001, P less than 0.02, P less than 0.01, and P less than 0.001, respectively). Excretion of 2-pyridone-5-carboxamide-N'-ribofuranoside did not show significant differences. Urinary excretion of 1-methylinosine demonstrated a positive linear relationship with the percentage of blast cells in the bone marrow [correlation coefficient (r) = 0.90]; the other nucleosides had lower degrees of correlation. In comparison, the absolute blast cell count in the peripheral blood showed less correlation to the percentage of blast cells in the bone marrow (r = 0.47) than did four of the five nucleosides. The data demonstrate that excretion of modified nucleosides reflects disease activity in childhood ALL and that the urinary nucleosides could be useful clinical markers for this disease.

Indistinguishable patterns of protooncogene expression in two distinct but closely related tumors: Ewing's sarcoma and neuroepithelioma.

Genetic characterization of human tumors promises new insights of biological importance and clinical relevance. We have found that two solid tumors, peripheral neuroepithelioma and Ewing's sarcoma of bone, which share a common cytogenetic rearrangement, are characterized by an indistinguishable and highly reproducible pattern of protooncogene expression. c-myc, N-myc, c-myb, and c-mil/raf-1 are all expressed at similar levels in these tumors. c-fes and c-sis expression was not detected in any specimens of either tumor. In contrast, the protooncogene c-ets-1, located near the breakpoint of the chromosomal translocation in these tumors, is variable in its expression. We also detected high levels of choline acetyltransferase in these tumors, which suggests a common neural origin. Since it is likely that the clinical behavior and therapeutic responsiveness of tumors relate closely to their biological and genetic features, the pattern of protooncogene expression of individual tumors may provide a novel basis for their characterization.

The efficacy of mesna (2-mercaptoethane sodium sulfonate) as a uroprotectant in patients with hemorrhagic cystitis receiving further oxazaphosphorine chemotherapy.

We examined the possibility of continuing oxazaphosphorine therapy in patients with previously documented cyclophosphamide- or ifosfamide-induced hematuria by concomitant use of the uroprotective agent, mesna. Twenty-six patients with oxazaphosphorine-induced hematuria received additional cyclophosphamide or ifosfamide with mesna. Twelve, who had previously experienced hematuria with ifosfamide, received a median of 3.5 more cycles of ifosfamide/mesna. One patient developed further hematuria (grade 1). Of seven patients who experienced acute hematuria with cyclophosphamide, one experienced further hematuria after an additional course of cyclophosphamide with mesna, but none of the other six patients developed further hematuria when administered either cyclophosphamide/mesna (two) or ifosfamide/mesna (four). Seven patients who had chronic cyclophosphamide-induced hematuria had further oxazaphosphorine with mesna without worsening of their hematuria. Mesna is an effective uroprotective agent that prevents recurrent acute hemorrhagic cystitis, or worsening of chronic hemorrhagic cystitis, in patients receiving further oxazaphosphorine after previous ifosfamide- or cyclophosphamide-induced hematuria.

Preliminary results of treatment of Ewing's sarcoma of bone in children and young adults: six months of intensive combined modality therapy without maintenance.

Thirty-one previously untreated patients with Ewing's sarcoma were treated with an intensive chemotherapy program of vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclosphosphamide (VADRIAC) in combination with radiation therapy to the primary site (greater than 50 Gy) and bone metastases (45 to 50 Gy). An intensified regimen with one further cycle of chemotherapy (VADRIAC), total body irradiation (TBI), and autologous bone marrow transplantation was given to patients with primary tumors of the pelvis, humerus, femur, and chest wall without metastases and to all patients with metastases at diagnosis. Patients with primary tumors of the distal extremity and other sites without metastases at diagnosis were treated on a less intensive chemotherapy regimen of VADRIAC without the intensification. Therapy was completed within 6 to 7 months in all patients. Thirteen patients had metastatic disease at diagnosis; only two of these had the lung as the sole site of metastatic disease. Eighteen patients had no evidence of metastatic disease at diagnosis: ten of these patients had tumors that arose in central axis and proximal extremity sites, and eight had tumors that arose in distal extremity and other sites. Thirty of the 31 patients achieved a complete remission, although two patients underwent amputation: one before chemotherapy and radiation and one after chemotherapy and radiation because of persistent local disease. Seventeen remain in their first complete remission at a median time on study of 30 months and a median time after completion of therapy of 24 months. Fourteen patients have relapsed (13) or progressed (1): ten in metastatic sites and four in the primary site. One patient had persistent local disease after radiation requiring amputation. Nine of the 13 patients with metastatic disease at diagnosis have relapsed compared with five of the 18 patients without metastatic disease. For the entire group, the actuarial survival is 78% (65% to 87%) at 30 months, and the actuarial disease-free survival is 58% (46% to 69%) at 30 months.

Treatment of peripheral neuroepithelioma in children and young adults.

Seventeen patients with peripheral neuroepithelioma were treated with an intensive chemotherapy regimen of vincristine, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (VADRIAC) in combination with radiation therapy. Fifteen patients with stage III (seven) or stage IV (eight) at presentation were treated on a more intensive regimen including total body irradiation (TBI) (8 Gy). Two patients with stage I (one) or II (one) disease received a less intensive chemotherapy regimen of VADRIAC. Therapy was completed within 6 to 7 months in all patients. The disease arose in the chest wall in 12 patients, pelvis in three patients, and extremity in two patients. Sixteen of the 17 (94%) patients achieved a complete remission. With a median follow-up of 18 months, ten patients remain in complete remission with an actuarial survival of 68% and an actuarial relapse-free survival of 56% at 12 months. On the basis of our initial experience with this tumor, we believe that peripheral neuroepithelioma is a chemoresponsive and radioresponsive tumor.

Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults.

One hundred twenty-four children and young adults with recurrent tumors, predominantly sarcomas, were treated with the combination of ifosfamide, etoposide, and the uroprotector, mesna (2-mercaptoethane sulphonate), in a phase II trial. The treatment regimen consisted of 12 cycles of therapy administered every 3 weeks. After evaluation of the tumor response to chemotherapy alone, radiation or surgery was used to eradicate residual sites of metastatic disease where possible. At the present time, 77 patients are evaluable for response to the chemotherapy; 43 of the patients have experienced a significant reduction in the tumor size in response to the chemotherapy alone (39 partial responses [PR] and four complete responses [CR]). Sixteen of 17 patients with Ewing's sarcoma, nine of 13 with rhabdomyosarcoma, four of eight with peripheral neuroepithelioma, three of eight with osteosarcoma, and 11 of 31 with other tumors have responded with a PR or CR. The toxicity of the regimen was acceptable. Moderate or severe toxicity evaluated on a per cycle basis included: neutropenia, 97%; thrombocytopenia, 32%; nephrotoxicity, less than 1%; mucositis, 1%; neurologic toxicity, 2%; nausea and vomiting, 13%; hemorrhagic cystitis, less than 1%. Fever was present after 33% of cycles and sepsis following 7%. One patient died due to sepsis and pancytopenia. At the present time, only seven of the 43 patients who responded to the chemotherapy regimen have relapsed, with a median follow-up of 10 weeks after the response. This drug combination is highly active in the treatment of recurrent sarcomas and other tumors in children and young adults.

Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group.

PURPOSE: The specific aims of this study were to improve event-free survival (EFS) in patients with newly diagnosed nonmetastatic osteosarcoma of an extremity using the histologic response to neoadjuvant chemotherapy to determine postoperative chemotherapy; to evaluate a uniform histologic grading system that measures tumor response; and to identify patient characteristics that might influence EFS and survival. PATIENTS AND METHODS: Two hundred sixty-eight patients with nonmetastatic osteosarcoma of the extremity were entered between August 1983 and October 1986. Preoperative chemotherapy consisted of four courses of high-dose methotrexate (MTX) and one course of bleomycin, cyclophosphamide, and dactinomycin (BCD). Histologic response to preoperative chemotherapy was determined by morphometric analysis. Good histologic responders (< 5% residual viable tumor) were treated postoperatively with MTX, BCD, and doxorubicin (DOX); poor histologic responders were treated with BCD, DOX, and cisplatin (CDDP). RESULTS: The 8-year EFS and survival rates were 53% and 60%, respectively. Two hundred six patients had their tumors assessed for histologic response: 28% displayed a good histologic response to preoperative chemotherapy. Good histologic responders had an 8-year postoperative EFS rate of 81% and survival rate of 87%; those with a poor histologic response had an 8-year postoperative EFS rate of 46% and survival rate of 52%. A primary tumor site in the proximal humerus or proximal femur and an elevated serum alkaline phosphatase level were associated with an increased risk of an adverse event, whereas the type of surgical procedure was not. CONCLUSION: EFS and survival appear to be directly related to histologic response to neoadjuvant chemotherapy.

Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing's sarcomas and soft tissue sarcomas in children.

71 children with sarcomas were treated in a prospective pilot study to determine whether granulocyte colony stimulating factor (G-CSF) permits compression of the interval between chemotherapy cycles. Patients had Ewing's sarcoma/primitive neuroectodermal tumour (PNET), rhabdomyosarcoma, non-rhabdo soft tissue sarcomas or other advanced soft tissue tumours. The chemotherapy alternated vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide, with G-CSF between courses. Therapy had two phases: induction (six cycles) and continuation (six cycles), which included primary tumour treatment with surgery and/or radiation. Chemotherapy cycles began every 14 days, or upon absolute neutrophil count (ANC) and platelet count recovery. The median chemotherapy cycle interval was 16 (11-48) days in the induction phase, with a median average relative dose intensification (ARDI) of 1.27 compared with every-21-day therapy. In the continuation phase, the median cycle interval was 21 days, with a median ARDI of 1.10. Radiation therapy prolonged chemotherapy intervals, whilst erythropoietin shortened them. Toxicity was modest for such chemotherapy. Event-free survival is comparable with or superior to that in recent large studies. G-CSF permits intensification of this regimen through interval compression. The impact of this approach on efficacy remains to be determined in a randomised trial.

Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide.

Over 50% of patients with newly diagnosed rhabdomyosarcoma (RMS) are in the 'intermediate risk' group with a 3-year progression-free survival of approximately 65%. This group consists of stage 1, group III, non-orbit tumours; stage 2, group II and III; and all stage 3 patients utilising the Intergroup Rhabdomyosarcoma Study (IRS) staging system. The role of doxorubicin in the treatment of RMS has been controversial. Ifosfamide, both alone and in combination with etoposide, has significant activity in patients with RMS. The aim of this pilot study was to examine the efficacy and toxicity of a chemotherapy regimen of alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for intermediate risk RMS. 30 patients with intermediate risk RMS or undifferentiated sarcoma (US) were treated with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and etoposide/ifosfamide (EI) at planned intervals of 3 weeks. Local treatment of the tumour in most cases was performed after four cycles of chemotherapy, followed by an additional 10 cycles of chemotherapy. At a median follow-up of 37.5 months, the Kaplan-Meier estimate of 3-year event-free survival was 85% (95% confidence interval 72-99%). The overall survival at 3 years was 91% (95% confidence interval 80-100%). No patient died from toxicity. The most common toxicity was febrile neutropenia in 35% of VDC and 26% of EI cycles. No nephrotoxicity or cardiac toxicity was seen. No patient progressed prior to week 12 local therapy. Alternating cycles of VDC and EI are an effective treatment for patients with intermediate risk RMS and US. Toxicity is tolerable. Delaying local treatment until week 12 does not compromise outcome.

Is neuro-ectodermal differentiation of Ewing's sarcoma of bone associated with an unfavourable prognosis?

Among Ewing's sarcoma (ES) of bone and related entities are tumours with neuro-ectodermal features that could represent a biologically distinct type. In order to assess the prognostic significance of the various forms of ES, a retrospective joint study involving three cancer centres in Europe and the U.S.A. was initiated. The material from 315 primary ES was reviewed by a panel of five pathologists and classified as typical ES (220 cases), atypical ES (48 cases) or ES with neuro-ectodermal features (47 cases). Prognostic factor analysis on treatment failure-free survival was performed using the Cox model. It included histopathological classification, initial patient characteristics, clinical presentation and treatment type. After multivariate analysis, in addition to treatment type (P < 0.001), metastases (P = 0.003) and proximal tumour location (P = 0.006), two histopathological parameters correlated with poor treatment failure-free survival, the presence of filigree pattern (P = 0.044) and dark cells (P = 0.043). We conclude that ES with neuro-ectodermal features does not appear to have a different outcome to the other subtypes.

Treatment of pelvic sarcomas in adolescents and young adults with intensive combined modality therapy.

Adolescent and young adult patients with pelvic sarcomas continue to have a poor prognosis with standard combination chemotherapy and local irradiation. In addition to a significant risk of local failure, these patients are at high risk for systemic relapse. Twenty-three consecutive patients with Ewing's sarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or malignant peripheral neuroepithelioma originating in the pelvis were treated with short, intensive combined modality therapy. This approach integrates 5 cycles of VADRIAC chemotherapy (Vincristine, Adriamycin, Cyclophosphamide) with high dose irradiation to the primary lesion (55-60 Gy) and sites of gross metastatic disease (45-50 Gy). Following achievement of a complete response, intensification therapy consisting of total body irradiation (TBI) (8.0 Gy), high dose VADRIAC chemotherapy, and autologous bone marow transplantation is given. All therapy is completed within 6-7 months. No maintenance chemotherapy is given; no surgery is intended. Of the twenty-three patients with pelvic sarcomas treated on this combined modality protocol, 22 achieved a complete remission. Local control was achieved and maintained in all twenty-three patients. With a median follow-up of 21 months since initiation of treatment, there have been nine relapses (all systemic). Seven relapses occurred among the thirteen patients who presented with overt metastatic disease and the other two relapses were among the ten patients with localized disease at presentation. All seven metastatic patients who relapsed have died, whereas both of the relapsed localized patients remain alive. Acute and late toxicities have been acceptable using this aggressive combined modality approach. Induction chemotherapy had a significant impact on reduction of the typically large (greater than 10 cm diameter) soft tissue mass associated with these pelvic tumors, thus facilitating achievement of local control by high dose irradiation. Of 18 patients with measureable soft tissue tumor, all experienced a partial response (greater than 50% reduction in size) following the initial two cycles of chemotherapy given prior to local irradiation. In conclusion, this short, intensive chemoradiotherapeutic regimen is highly effective in controlling the primary lesion (100% local control) and inducing a complete response in a high proportion (96%) of these high risk pediatric and young adult patients with pelvic sarcomas. The role of TBI as "systemic" adjuvant therapy to control micrometastatic disease is discussed as still under investigation.

Long-term follow-up of Ewing's sarcoma of bone treated with combined modality therapy.

Between 1968 and 1980, 107 consecutive patients with Ewing's sarcoma of bone were entered on three sequential combined modality treatment protocols (S2, S3, S4) at the National Cancer Institute (NCI). Protocol treatment involved 4 cycles of two drug [cyclophosphamide (CTX) and vincristine (VCR)] or three drug [CTX and VCR with either actinomycin-D (ACT-D) or doxorubicin (ADR)] regimens and local irradiation (50 Gy) to the involved bone. Eighty patients presented with localized disease and 27 patients had metastatic disease at presentation, including 11 patients with multiple metastatic sites. With a median potential follow-up of greater than 15 yrs (range 8-20 yrs), 28 pts (27%) remain alive. Disease-free (DFS) and overall survival (OS) decreased most rapidly during the initial 5 yrs of follow-up with 5-yr DFS of 29% and 5-yr OS of 39%. Only two patients with metastases at presentation are long term (greater than 5 yr) survivors. For localized disease patients, the 2, 5, 10, and 15 yr DFS and OS are 52%, 37%, 35%, and 33% DFS and 68%, 51%, 39%, and 34% OS, respectively. Eleven patients relapsed locally as the first site of failure. Using the Cox proportional hazards model, four significant variables for both DFS and OS were recognized, including metastatic disease at presentation, age greater than 25 yrs, high LDH in localized disease patients, and central primary tumor in localized disease patients in decreasing order of significance. We conclude that a majority of these patients with Ewing's sarcoma of bone relapsed within 5 yrs of presentation although late relapse (5-15 yrs) did occur. Local failure occurred in 20% of patients using these combined modality treatments but had no impact on overall survival.

Treatment of sarcomas of the chest wall using intensive combined modality therapy.

As part of two sequential protocols using intensive combined modality treatment in pediatric and adolescent sarcomas, 31 consecutive patients with primary chest wall tumors were treated between November 1977 and March 1986. This group included 13 patients with peripheral neuroepithelioma (Askin's tumor), 11 patients with Ewing's sarcoma, 3 patients with rhabdomyosarcoma, and 4 patients with undifferentiated sarcomas. Following complete work-up, 17 patients presented with localized disease and 14 patients presented with metastases. Patients received intensive combined modality treatment with combination chemotherapy (vincristine, cyclophosphamide, Adriamycin, +/- actinomycin-D and DTIC) and high-dose conventionally fractionated radiation therapy to the primary (55-60 Gy) and non-pulmonary metastases (45-50 Gy). Radiation techniques used for the primary chest wall tumor varied with the clinical presentation. Patients achieving a complete response received either low-dose fractionated TBI (1.5 Gy/0.15 Gy fx/5 weeks) or high-dose TBI (8 Gy/4 Gy fx/2 days) and an intensive cycle of chemotherapy followed by autologous bone marrow transplantation. Twenty-five of 31 patients were judged to have a complete response (including 1 patient with complete resection). With minimum follow-up of 6 months and median follow-up of 36 months from completion of treatment, 14 patients remain disease-free with 2 additional patients alive in second remission after relapse. Patients with localized disease at presentation have improved disease-free survival and overall survival compared to patients with metastases at presentation. All 17 localized patients achieved a CR and 11 are NED compared to 8 of 14 metastatic patients achieving a CR and only 3 are NED. There have been 5 loco-regional recurrences with 3 "in-field" failures and 2 failures in the regional pleura. There were no treatment-related deaths and no clinically significant cases of pneumonitis. To date, 2 patients have significant treatment related morbidity, including 1 patient with scoliosis requiring surgery and 1 patient with acute leukemia developing 42 months after the start of therapy (presently in remission). We conclude that this intensive combined modality therapy results in a high CR rate and good local control with acceptable morbidity. Patients with metastatic disease at presentation remain a therapeutic challenge.

Intensive combined modality therapy of small round cell and undifferentiated sarcomas in children and young adults: local control and patterns of failure.

Seventy-five patients (ages 4-35 years) with the following small round cell tumors and undifferentiated sarcoma were treated at the National Cancer Institute: Ewing's sarcoma (n = 32), peripheral neuroepithelioma (n = 14), rhabdomyosarcoma (n = 24), undifferentiated sarcoma (n = 5). Most patients had poor prognostic features including 36 (48%) with metastatic disease, and 42 (56%) with central (truncal) tumors (22 in the pelvis). Treatment included 5 cycles of intensive induction chemotherapy with vincristine, cyclophosphamide and adriamycin, plus aggressive local radiation therapy using simulation and computerized treatment planning for all patients. Thereafter, complete clinical responses were consolidated with intensive chemotherapy, total body irradiation and autologous bone marrow transplantation. There were three local only failures, 10 local plus distant failures, 36 distant only failures, 3 treatment-related deaths, and one intercurrent death. Overall actuarial survival and event-free survival at 4 years are 49 and 29%, respectively. Actuarial freedom from local progression was seen in 74% of patients at 4 years, quite remarkable considering the bulk and location of most of these tumors. Without aggressive surgery, many of these high risk patients had satisfactory outcomes, but better systemic treatments are still needed.

Ewing's sarcoma--routine diagnostic utilization of MIC2 analysis: a Pediatric Oncology Group/Children's Cancer Group Intergroup Study.

Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) are small blue cell tumors with no reliable positive diagnostic markers. However, Ewing's sarcoma and PNET recently have been shown to strongly express an antigen determined by the MIC2 gene, whereas other blue cell tumors of childhood for the most part do not. MIC2 analysis therefore offers a distinctive addition to the panel of immunohistochemical stains used to differentiate among small blue cell tumors of childhood, since it represents the first positive marker for Ewing's sarcoma and PNET. This study addresses the reliability of MIC2 analysis using the monoclonal antibody 12E7 on tumors registered in the current Intergroup Ewing's Sarcoma protocol. Of 244 tumors, 221 (91%) showed a diffuse strong membranous pattern. The antibody appears to withstand all the fixation variables inherent in a multi-institutional study. We conclude that MIC2 expression is highly reliable as a positive marker for the Ewing's sarcoma/PNET family of tumors when the results are interpreted in the total context with clinical and pathologic parameters.

The role of resection in the treatment of pulmonary metastases from Ewing's sarcoma.

We have investigated the role of resection in the treatment of patients with isolated pulmonary metastases from Ewing's sarcoma. In a retrospective review, 19 patients with the diagnosis of Ewing's sarcoma treated at the National Cancer Institute from 1965 to 1985 who underwent chest exploration for resection of pulmonary nodules were evaluated. Ten patients (53%) were made disease free by resection of pulmonary metastases, six patients (32%) were found to have unresectable disease, and three patients (16%) were found to have benign pulmonary disease. The actuarial 5 year survival rate of the 10 patients successfully made disease free by resection was 15%, and the median survival of this group was 28 months. In contrast, the median survival of the six patients not made disease free was 12 months, and no patient with residual disease was alive 22 months after thoracotomy (p2 = 0.0047). There were no postoperative deaths and only three minor postoperative complications for 25 operative procedures. Various prognostic variables were analyzed to determine their influence on postmetastasectomy survival. There was no difference in postmetastasectomy survival between patients who underwent resection of synchronous versus metachronous pulmonary metastases (p2 = 0.90). Patients who underwent resection of fewer than four malignant nodules had a significantly longer postmetastasectomy disease-free survival (p2 = 0.0019) and overall survival (p2 = 0.06) than those undergoing resection of four or more nodules. Patients who underwent resection of metastases that developed during chemotherapy had a significantly shorter postmetastasectomy survival that those who underwent resection of metastases that developed after chemotherapy (p2 = 0.0295). Our data show that selected patients with Ewing's sarcoma metastatic to the lungs may benefit from an aggressive surgical approach. Also, a significant proportion of these patients will have benign pulmonary disease and can thus avoid additional intensive systemic therapy.

Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection.

OBJECTIVE: We sought to establish the outcome and optimal therapeutic sequence for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the chest wall. METHODS: Patients 30 years of age or younger with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the bone were randomly assigned to receive vincristine, doxorubicin, cyclophosphamide, and dactinomycin or those drugs alternating with ifosfamide and etoposide. Local control was obtained with an operation, radiotherapy, or both. RESULTS: Fifty-three (13.4%) of 393 patients had primary tumors of the chest wall (all rib). Event-free survival at 5 years was 57% for the chest wall compared with 61% for other sites (P >.2). Ifosfamide and etoposide improved outcome in the overall group (5-year event-free survival, 68% vs 54%; P =.002), and a similar trend occurred in chest wall lesions (5-year event-free survival, 64% vs 51%). Patients with chest wall lesions had more attempts at initial surgical resection (30%) than those with other primary tumor sites (8%, P <.01). The attempt at initial resection for chest wall lesions did not correlate with size. Initial resections at other sites were restricted to smaller tumors. Initial resection resulted in negative pathologic margins in 6 of 16 patients, whereas the delayed resection resulted in negative margins in 17 of 24 patients (P =.05). Although there was no difference in survival by timing of the operation in rib lesions, a higher percentage of patients with initial surgical resection received radiation than those with resection after initial chemotherapy (P =. 13). CONCLUSIONS: Although rib primary tumors are significantly larger than tumors found in other sites, their outcome is similar. We favor delayed resection whenever possible to minimize the number of patients requiring radiation therapy.

Pharmacokinetic study of indicine N-oxide in pediatric cancer patients.

Pharmacokinetics of the experimental antitumor agent indicine N-oxide were investigated in a group of 23 pediatric cancer patients. Plasma elimination of indicine N-oxide was best described by a two-compartment open model. The mean plasma distribution phase half-life, plasma elimination phase half-life, and plasma clearance were 8 min, 84 min, and 62 ml/min/m2 (2.1 ml/min/kg), respectively. One patient with renal impairment had an abnormally long plasma elimination phase half-life (275 min) and reduced plasma clearance (17 ml/min/m2). Plasma elimination phase half-life values increased and plasma clearance values decreased with increasing age of the pediatric patients. Plasma elimination of indicine N-oxide was more rapid in this group of children than in adults who had previously received the drug.

The management of relapsed Wilms tumor.

Relapsed Wilms tumor is often very responsive to re-treatment, and cures are possible in many cases. Recurrent Wilms tumor forms a heterogeneous group because initial therapies vary widely. Given the complexity of the problem, there is a great need for an organized clinical investigative approach. Ideally, the treatment of initial relapse should be specified by the primary treatment protocol in order to better evaluate overall survival as an end-point for new primary therapy strategies. This is especially appropriate for Wilms tumor, because the investigations of this tumor over the last 20 years have attempted to determine the minimal therapy necessary for cure. Thus, survival rather than relapse-free survival is the most appropriate criterion for the success of a primary retreatment regimen. This investigative approach would also allow evaluation of treatment strategies tailored to a specific patient population. Important questions remain for those who treat recurrent Wilms tumor. Defining the role of high-dose therapy, defining the role of total body irradiation in high-dose therapy regimens, and defining the benefit and toxicity of cyclophosphamide compared with ifosfamide are three current questions under investigation. Developing new agents and regimens effective against Wilms tumor, especially against anaplastic tumors, RTK, and CCSK, is extremely important if progress is to be made in treating these tumors after relapse. Finally, there is a strong need to develop biologic information about tumors that recur, so not only will we better understand why patients relapse but also we can develop therapy tailored specifically to the biology of the recurrent tumor.

Sweet syndrome in a patient with osteosarcoma.

Neutrophilic dermatosis (Sweet syndrome) is a rare condition characterized by painful indurated cutaneous plaques infiltrated with mature neutrophils and may be accompanied by fever, granulocytosis, arthritis, and conjunctivitis. It is associated with various malignant and preneoplastic states, the most common being leukemia and myeloproliferative disorders. Its association with solid tumors is infrequent. The case described here represents, to our knowledge, the first report of Sweet syndrome in a patient with osteogenic sarcoma, a primary tumor of bone arising from mesenchymal cells.