Search

Clinicopathologic variables associated with a good histological response to primary chemotherapy in Ewing's sarcoma are identified. The histological response to preoperative chemotherapy in 243 cases of Ewing's sarcoma treated with neoadjuvant chemotherapy was analyzed in relation to different clinicopathological features (sex and age of the patients, tumor size, serum lactate dehydrogenase (LDH) levels, tumor site) and to the type and schedule of anticancer drugs delivered preoperatively according to three consecutive chemotherapy regimens. A higher rate of good responses was achieved with the use of ifosfamide and dactinomycin in addition to a conventional three-drug VAC regimen, suggesting that these drugs should be included from the beginning in neoadjuvant regimens for the treatment of Ewing's sarcoma. The analysis of event-free survival in 158 patients with a 4-year minimum follow-up confirmed that histological response to preoperative chemotherapy is a reliable predictor of outcome in Ewing's sarcoma.

Based upon phase I and II studies of deferoxamine alone and in combination with cytotoxic agents cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT), we initiated a single arm multicentre trial in 1992 for advanced neuroblastoma. 57 of 65 patients who entered the trial were evaluable. Following 4 courses of the DCECaT, almost all the patients underwent surgery. Toxicity was moderate and mainly reversible myelosuppression. The post-surgically defined responses in stage 3 high risk, stage 4 moderate risk and stage 4 high risk patients included 24 complete responses, 26 partial responses, and 3 minor responses, and 4 patients had progressive disease. These patients are being followed to determine the impact of this programme on their overall survival.

The study evaluated 139 patients diagnosed with Langerhans' cell histiocytosis (LCH) and enrolled in any protocol of the Italian Association of Pediatric Hematology/Oncology since 1982. Treatment was etoposide (VP-16) only in 50 patients, VP-16 and other drugs with an already established leukemogenic effect in 17 patients, only drugs with leukemogenic effect in 6 patients, other drugs in 35 patients, and surgery only in 31 patients. Median length of follow-up after diagnosis was 65 months (range, 1 to 126 months) for a total of 742.5 person-years at risk (PYRs). Three cases of acute myelogenous leukemia (AML) were reported; only 0.0044 case was expected. The standard incidence ratio (SIR) of AML in this cohort was 680.5 [95% confidence interval (CI), 140.2-1988.5], and the incidence rate per 1000 PYRs was 4.0 (95% CI, 0.8-11.8). For the subgroup treated with single-agent VP-16, the SIR after treatment was 2270.0 (95% CI, 275-8199), and the incidence rate after treatment was 14.7 (95% CI, 1.8-42.8). The study confirms a higher risk of leukemia after LCH and supports the hypothesis of an association between treatment-related acute nonlymphocytic leukemia and single-agent treatment with VP-16.

The results of two sequential studies of neoadjuvant chemotherapy for osteosarcoma of the extremities performed at Rizzoli Institute between 1986 and 1991 in 228 patients are presented. In both studies preoperative chemotherapy consisted of two cycles of high dose methotrexate (HDMTX), cisplatinum (CDP) and adriamycin (ADM). Postoperatively the good responder patients were treated with the same drugs used before surgery while in the poor responder patients ifosfamide was added to these three drugs. The preoperative treatment was the same in both studies while after surgery in the second protocol either the cumulative dose of ADM (270 mg/m2 instead of 360 mg/m2) or the single dose per cycle of this drug (60 mg/m2 instead of 90 mg/m2) was reduced. These changes in the last protocol were done to reduce the cardiotoxicity of ADM that was high in the first study (2 deaths and 1 heart transplantation). Since in the last protocol--in comparison with the first protocol--after surgery chemotherapy was restarted earlier and ADM was administered not as a single drug but in combination with the CDP the dose intensity of ADM was unchanged while the dose intensity of MTX, CDP and ifosfamide was higher than in the first study. The preliminary results of the 84 patients treated in the second study show a 2-year disease free survival significantly lower than that achieved in the 144 patients treated in the first study (37/51--73% vs 123/144--85%: P0.008). In addition, even if in the last study there were no cases of clinical cardiotoxicity due to ADM, there was a significantly higher percentage of severe myelodepression that led to two deaths for infectious complications. These results suggest that in neoadjuvant treatment of osteosarcoma the total dose of ADM and/or the single dose per cycle of the same drug are an important determinant of outcome and that increasing the dose-intensity of less toxic but less active agents, MTX, CDP and ifosfamide, at the expense of the more active and more toxic agent, ADM, can lead to a poorer outcome without reducing toxicity.

A total of 2192 children with acute lymphoblastic leukaemia who had reached cessation of therapy in complete remission were followed for a median time of 52 months after treatment suspension. Of the 485 relapses observed, 62.3% occurred in the first year off therapy and 68.9% involved the bone marrow. Eight relapses were reported more than 5 years (62–143 months) after treatment withdrawal. Males fared worse than females consistently, experiencing 1.5 times more relapses ( P 20 years) were married and 16 have had 21 healthy children. Twenty-four per cent of patients experienced an unfavourable event. Relapses accounted for 93% of failures. Central nervous system late effects and second malignancies were the major causes of non-leukaemic morbidity and mortality.

Ninety patients with biopsy-proven Langerhans cell histiocytosis (LCH) were enrolled from June, 1983, to December, 1988, in the multicenter AIEOP-CNR-H.X. '83 study. They were divided into two groups: poor prognosis (PP), comprising 11 children with organ dysfunction (OD), and good prognosis (GP), made up of 79 patients without OD. Eighty-four patients were evaluable for treatment results. Among GP patients, 16 with a single lesion received only local treatment, while 59 entered a clinical trial of immunotherapy and/or monochemotherapy with vinblastine (VBL). Nonresponders, sequentially received doxorubicin (ADM) and then etoposide (VP16). PP patients were treated with 4 week cycles of vincristine, ADM, cyclophosphamide, and prednisone for nine courses. The overall survival was 92.8% (100% for GP patients and 45.5% for PP patients) at 48 months. The complete response (CR) rates for immunotherapy, VBL, ADM, and VP16 were 10%, 62.9%, 42.8%, and 88.2%, respectively. Two of the 11 PP patients had a CR (18.2%), while six died and three are still alive with recurrent disease. The overall incidence of disease-related disabilities was 47.7%, while that of diabetes insipidus was 20%. Monochemotherapy is probably adequate in GP patients, while more effective treatments are needed for PP patients.

Background. Infants (age 0–11 months) with disseminated neuroblastoma are known to have a better prognosis than older children with the disease, but there is little information regarding factors that influence the outcome of the disease in these patients. Methods. The authors report a series of 110 infants with disseminated neuroblastoma with disease diagnosed between March 1976 and February 1991 in 21 institutions participating in the Italian Cooperative Group on Neuroblastoma (ICGNB). Of the 110 infants, 34 had Stage IV disease, and 76 had Stage IV-S disease. Results. The 5-year survival probability was 77% for all patients, 71% for those with Stage IV disease, and 81% for those with Stage IV-S disease. Of the 34 infants with Stage IV disease, the 9 who were 5 months or younger at the time of disease diagnosis are all alive (1 with active disease) at 7–143 months after diagnosis, whereas of the 25 infants who were 6–11 months of age at the time of disease diagnosis, 10 have died. Of the 76 infants with Stage IV-S disease, 12/64 who were 5 months of age or younger at the time of disease diagnosis died (mostly of massive hepatomegaly); 9 of these deaths occurred in infants with disease diagnosed before they were 2 months old, whereas 1 death occurred in the 12 infants with disease diagnosed when they were 6–11 months old. Four infants with Stage IV-S disease achieved complete disease remission and subsequently had relapse of disease. High levels of serum LDH and low urinary excretion of vanillylmandelic acid were associated with worse prognosis. Conclusions. The authors suggest that infants older than 6 months of age who have Stage IV disease require aggressive therapy. For infants with disease diagnosed before they are 2 months old, Stage IV-S disease may have a worse prognosis than Stage IV disease.

Between March 1983 and June 1986 127 patients with localized osteosarcoma of the extremity were treated with neoadjuvant chemotherapy. Preoperative chemotherapy consisted of two cycles of methotrexate (MTX) (high or moderate doses) followed by 6 days by cisplatin (CDP). Surgery was an amputation or a rotation plasty, or a limb salvage. Necrosis was good in 52% of cases, fair in 36%, and poor in 12%. Postoperative chemotherapy consisted of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor responders; and ADM, MTX, and CDP for fair responders. Good responders were treated as fair responders or with only MTX and CDP. At a 47-month follow-up, 66 patients remained continuously disease free and 61 patients developed metastases. Six of these patients had also a local recurrence. According to the grade of necrosis, the cumulative disease-free probability at 5 years was 67% for good responders, 42% for fair responders, and for poor responders 10% at 45 months. According to the doses of MTX, survival at 5 years was 58% for patients who received high doses and 42% for patients treated with moderate doses. No differences in the rate of survivors were observed between amputated patients and patients treated with limb salvage. The authors conclude that (1) a limb salvage procedure is possible in about 70% of cases and as safe as demolitive surgery, if adequate surgical margins are achieved; (2) good responders have a better prognosis than fair and poor responders if postoperative chemotherapy is sufficiently prolonged and also includes ADM; (3) a different postoperative chemotherapy for poor responders did not improve their prognosis; and (4) a multidrug regimen using high doses of MTX is probably more effective than moderate doses.

Purpose: To identify the prognostic factors, treatment, and outcome of children affected by renal cell carcinoma (RCC). Patients and Methods: The series included 41 patients (18 males and 23 females) with a median age of 124 months observed at the 11 Italian Association for Pediatric Hematology and Oncology centers from January 1973 to January 2001. Clinical data, surgical notes, pathologic findings, and summaries of therapy were taken from the charts. Results: Seven (17%) of the 41 patients had a papillary histology, and 34 (82.4%) had nonpapillary histology. Eighteen patients (43.9%) had stage I, one patient (2.4%) had stage II, two patients (4.8%) had stage IIIA, 10 patients (24.3%) had stage IIIB, and nine patients (21.9%) had stage IV disease. One patient had a bilateral involvement at diagnosis. Seven patients experienced disease recurrence. Lung and liver were the most common distant lesions and usually were fatal. In this study, the major factor influencing the prognosis was the stage. Event-free survival at 20 years was 53.5% for all patients. Overall survival at 20 years was 54.9% for all patients. Conclusion: RCC is a rare disease in children and adolescents. This neoplasm has a different clinical presentation in children compared with adults but the same outcome. In our experience, patients with localized disease could be cured by nephrectomy alone. Prospective studies in a larger number of patients are needed to confirm radiation therapy and biologic response modifiers as effective adjunct therapy in RCC stage III. The alternative therapy seems warranted in patients with advanced disease.

Aims and Background From 1986 to 1989, a study for the treatment of nonmetastatic osteosarcoma of the extremity (IOR/OS-2) was carried out at the Rizzoli Institute. The cumulative dose of doxorubicin delivered was 480 mg/m2, and severe heart failure developed in 5 (3%) of the 164 treated patients. The specific aim of the subsequent study was to assess the efficacy of a protocol, similar to IOR/OS-2, but with a reduced cumulative dose of doxorubicin (390 mg/m2). Additional aims were to assess the role of the route of infusion (intraarterial or intravenous) of cisplatin on histologic response of the primary tumor and the use of ifosfamide as salvage chemotherapy in poor responders. Methods The new chemotherapy regimen (IOR/OS-3) was comprised of a preoperative phase with methotrexate (10 g/m2), cisplatin (120 mg/m2 intraarterially or intravenously), and doxorubicin (60 mg/m2). After surgery, the same drugs were administered, with the addition of ifosfamide (10 g/m2) in patients who had a poor histologic response to primary chemotherapy. Results Ninety-five patients entered the study. The rate of good histologic response was 64% with intraarterial cisplatin and 43% with intravenous cisplatin (P = 0.05). The 8-year event-free survival and overall survival were 54% and 61%, respectively, with no significant difference according to the histologic response. No cases of clinical doxorubicin-induced cardiopathy were recorded. Event-free and overall survival did not significantly differ from those achieved with IOR/OS-2 (8-year disease-free and overall survival, respectively 63% and 72%). Conclusions The reduction in the doxorubicin cumulative dose avoided episodes of cardiotoxicity, without consequences on the efficacy of treatment. The addition of ifosfamide was an effective “salvage” therapy for poor responders. A better histologic response with intraarterial cisplatin was observed, but owing to the availability of an effective salvage therapy for poor responders, the advantages in terms of histologic response did not compensate for the cost and discomfort for the patients of this modality of infusion of cisplatin.

In 1989 we started an accelerated hyperfractionated schedule of radiotherapy (two 1.6 Gy daily fractions) in standard risk localized Ewing's sarcoma of bone, with the aim at reducing late effects in young patients and at improving disease control through a better integration of treatment modalities. From 1991, the same schedule was used in preoperative radiotherapy of adult soft tissue sarcomas of the extremities: the main purpose was to reduce the time to surgery and to evaluate surgical complications in comparison with a previous experience of hypofractionated radiotherapy (one 3 Gy daily fraction). From 1991 to 1997, 76 patients with Ewing's sarcoma and 24 patients with soft tissue sarcoma were treated at our Institution. Results and complication rates are analyzed in comparison with historical data. In Ewing's sarcoma, a correct evaluation of improvement in local control was difficult because of changing treatment policy (bulky disease was not included in the present series). Late effects, as evaluated in patients with a minimum follow-up of 3 years, occurred with similar incidence, but at higher total dose levels in patients treated with accelerated hyperfractionation. In patients with soft tissue sarcomas, incidence of surgical complications is reduced as compared to historical experience. Major problems of wound healing were seen in association with intraoperative brachitherapy boost.

The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etoposide. Between November 1991 and November 1994, 61 patients with non metastatic Ewing's sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing's sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing's sarcoma of the extremity.

The outlook for disseminated neuroblastoma (NB) continues to be dismal. NB is a radiosensitive tumour. Owing to its high concentration in NB lesions, [ 131 I]meta-iodobenzylguanidine [ 131 I]MIBG has the potential for specifically delivering very large radiation doses to the malignant cells. Encouraging results have been reported with [ 131 I]MIBG used alone in patients resistant to conventional therapy and at diagnosis. We report the first attempt to explore the integration of this new treatment modality with chemotherapy. Among the drugs effective in NB, cisplatin was chosen because of its high degree of activity against NB, its mild haematological toxicity and the known synergism between cisplatin and radiation. 4 patients, 3 with relapsed, heavily pre-treated, progressive stage IV NB, and 1 with stage IV NB at diagnosis, all with a good [ 131 I]MIBG uptake, were investigated with combined therapy (CO-TH). Two complete remissions and one partial remission were observed in these patients 4–6 weeks following only a single course of both cisplatin and [ 131 I]MIBG at "standard" dosage. The only toxicity was haematological, which was significant and relatively long-lasting, but was not associated with any serious infections or bleeding tendency. The general condition of these patients during the entire study period was excellent. The fourth patient, investigated at diagnosis with a modified less intensive treatment, obtained a partial remission with mild haematological toxicity. During the subsequent courses of intensive multidrug chemotherapy, this patient showed haematological toxicity comparable with that experienced by patients treated with an identical drug combination, but without previous treatment with CO-TH. The provisional conclusion of this ongoing study is that this new form of CO-TH appears most effective in obtaining a rapid and excellent response in heavily pretreated relapsed patients with progressive disease, and should be further investigated in earlier stages of the disease.

To evaluate the incidence of second malignant tumors in a cohort of subjects previously treated for childhood cancer, we analyzed data from the Off-Therapy Registry (OTR) of the Italian Association of Pediatric Hematology/Oncology, which collects information on children treated for Hodgkin's disease, non-Hodgkin's lymphoma, Wilms' tumor, acute lymphoblastic leukemia (ALL) and acute non-lymphatic leukemia and who had been removed from treatment in the absence of clinical signs of disease, i.e. the off-therapy stage. Second malignant tumors (SMT), diagnosed before December 31, 1988, were identified through a special enquiry to the 36 institutions cooperating in the registry. Observed cases were compared to expected numbers estimated from age- and sex-specific incidence rates derived from the Cancer Registry of the Province of Varese. In a total of 3,310 study subjects, 27 SMTs have been registered. The Cumulative Risk (CR) of SMT was 2.9% 15 years after the end of treatment and the Standard Incidence Ratio (SIR) was 10.8. The ALL sub-cohort had the highest risk of SMT (SIR 13.6) and 9 cases of CNS tumor occurred in this group (SIR 58.9). All 9 had received prophylactic cranial radiotherapy (CRT) and 5 had been treated on one protocol, characterized by low-dose intrathecal methotrexate (IT MTX) given monthly for 2 years after CRT. The Off-Therapy Registry has unique criteria for inclusion; direct comparisons with similar studies are therefore somewhat problematic. However, our data suggest that the risk of SMT in childhood ALL cancer survivors may be greater than previously reported, and that CNS tumors are the most common SMT in this group. The administration schedule of IT MTX may be an important risk factor.

Transient bullous dermolysis of the new-born consists of congenital skin defects and a tendency for blistering of the skin and mucous membranes during the neonatal period. A case of transient bullous dermolysis of the newborn associated with Wilms' tumor is reported. Transient bullous dermolysis of the newborn does not represent an obstacle to administering appropriate chemotherapy when simple precautions are taken.

Sixteen children, aged 16 days to 13 years with hepatoblastoma (HB) (13 patients) or hepatocellular carcinoma (HCC) (3 patients), were given a total of 89 courses of cisplatin and doxorubicin (PLADO) as IV continuous infusion. All tumors were confined to the liver except for 1 hepatoblastoma patient with pulmonary metastases at presentation. Tumor response to PLADO was evaluable in 10 children (8 HB, 2 HCC) treated with preoperative chemotherapy and in another 2 HB patients treated when they developed pulmonary metastases after initial treatment with surgery alone. There were 2 complete responses (2 HB with pulmonary recurrences), 7 very good partial responses (6 HB and 1 HCC), 2 partial responses (1 HB, 1 HCC), and 1 stable disease (HB). The last patient underwent orthotopic liver transplantation whereas all the other patients had their tumor completely excised at delayed surgery. Documented toxicity was BM depression (16 patients), infection (11), vomitting (11), mucositis (3), hearing loss (1), and cardiotoxicity (1). These data indicate that PLADO in continuous infusion is effective in the treatment of malignant epithelial liver tumors with acceptable toxicity.

From 1979 to 1986, 182 patients with biopsy proven diagnosis of Ewing's sarcoma of bone were observed. One hundred of the 182 patients (72 males, 28 females, median age 15.8 years) with localized disease and no previous treatment were treated with chemotherapy (VCR, ADM, CTX, D-ACT) for 15-18 months. Local treatment was radiotherapy (42 patients), surgery (31 patients), or a combination of both (27 pts). Radiation doses ranged from 45 to 64 Gy given with conventional fractionation. Median follow-up was 51.2 months (24-106). Overall and disease-free survival were, respectively, 58.7 and 42.6%. Resected patients tended to have a better local control (Surgery 93.6%, Surgery + Radiation therapy 92.6%, Radiation therapy 69.1%). Disease-free survival was significantly related to the volume of the primary tumor (bulky: 33.2%, not-bulky: 57.7%), to site (extremities 54.6%, central sites 16.6%, other sites 40.9%), and to local treatment (Radiation therapy 30.3%, Surgery + Radiation therapy 47.9%, Surgery 59.1%). These results are, however, biased because resected patients tended to have smaller tumors in favorable sites.

Zusammenfassung18 Sauglinge wurde in der Italienischen Kooperativstudie RMS-79 registriert und behandelt. 10 Patienten hatten ein Rhabdomyosarkom (7 ein «embryonales», 3 ein «alveo-lares», 8 andere We

The prognosis of localized osteosarcoma of the extremities (LOE) treated by surgery alone is very poor. In our experience, in spite of amputation, the disease-free survival rate for these patients is only 10%. This percentage seems unchanged in the last 20 years, at least at the Rizzoli Institute (Table 1).

• Objective. —To determine the effects of 18-Gy cranial irradiation on growth, growth hormone (GH) secretion, and pituitary magnetic resonance imaging in children who underwent previous irradiation for treatment of acute lymphoblastic leukemia. Design. —Clinical survey. Setting. —Department of Pediatrics of the University of Bologna (Italy). Patients. —Ten boys and 18 girls who were treated for acute lymphoblastic leukemia; median age at diagnosis was 3.1 years and at the end of follow-up was 11.5 years. Measurements and Results. —Height was periodically measured from diagnosis until the end of follow-up, when GH secretion study and magnetic resonance imaging were performed. The mean height SD score was significantly lower than at diagnosis only at the end of treatment. Nocturnal mean GH concentration and GH response to pharmacological tests (arginine and levodopa [L-dopa]) were pathological in 22 cases (81.5%) and 18 cases (64.3%), respectively. Sixteen cases (59.2%) had a blunted GH release to the three tests. Mean pituitary anterior lobe height was reduced and seven subjects (25%) showed an empty sella. Conclusions. —Cranial irradiation with 18 Gy does not seem to influence the growth pattern of most children who are treated for acute lymphoblastic leukemia, despite severe impairment of GH secretion and morphological abnormalities of the sellar area. However, a follow-up until final height is necessary. ( AJDC . 1992;146:1343-1348)

Information was obtained on the living status or cause of death of 2223 close relatives of 195 children with soft-tissue sarcomas (STS) diagnosed under age 15. Three-hundred nine relatives had died, from all causes, before STS diagnosis in the index child. The expected figure estimated from age- and sex-specific mortality rates in Italy was 293.3. Cancer was reported as cause of death in 76 relatives (75.1 expected). Seven grandmothers, 2 aunts, 1 uncle and 0 mothers died from breast cancer vs. 4.6, 0.9, 0.0 and 0.2 expected. Three siblings died from cancer (0.2 expected, P less than 0.01), i.e. STS, ependymoma and non-Hodgkin lymphoma. These results confirm and expand previous observations that STS in children are associated with other cancers, particularly childhood and breast cancer, in members of the same family.

Eighteen evaluable children with recurrent Langerhans' cell histiocytosis (LCH) which was resistant to standard therapy, were treated with etoposide (VP 16-213), 200 mg/m2/day for 3 days every 3 weeks, to study the efficacy and toxicity of this drug. Complete and partial responses were demonstrated in 15 patients (83.3%). Only one of the 12 children achieving a complete remission has relapsed. No dose-limiting major toxicities were registered. Although etoposide might be an effective treatment in recurrent LCH which needs a chemotherapeutic approach, it is emphasized that this drug must be used carefully.

Ninety-one children with cancer (thirty-seven with leukemia and fifty-four with solid tumors)--school aged (elementary and middle school), residing in Emilia-Romagna Region (Italy), and receiving treatment at the Department of Pediatrics (III), University of Bologna, from August 1973 to April 1987--took part in a study of school behavior as perceived by the teacher. The research was carried out through a 29-item forced-choice questionnaire based on the questionnaire proposed by Deasy-Spinetta for a similar study in the U.S.A. Results revealed that children with cancer have a school behavior scoring at levels significantly lower than controls. There are more difficulties for children attending middle than elementary school, for children on therapy than off therapy, and for children with leukemia than with solid tumors. In conclusion, the main obstacle to school performance seems to be lower attendance, which is mainly due to treatment and clinic visits and probably in part to an overprotection and an excessive concern on the part of physicians and parents.

A total of 290 children off therapy after acute lymphoblastic leukemia, in continuous complete remission for at least 2 years, were evaluated for height at the onset of the disease and at the most recent clinical visit (median time after suspension of treatment 4 years 4 months, range 2 years-11 years 3 months). All patients had been treated with multidrug schedules; intrathecal drugs had been given to 84% of the patients for prevention of CNS involvement, associated with radiotherapy. The height percentiles at the most recent examination were shifted downward significantly compared with the expected pattern (p less than 0.001). The effect on stature was much more marked in girls, with a reduction of height percentiles at most recent examination from expected and from diagnosis; in males there was a reduction from diagnosis to latest follow-up, but the values were within the limits of normal. The short stature was mostly observed in pubertal girls and in patients who had undergone radiotherapy.

The results obtained in the treatment by multimodal therapy (surgery, radiation therapy and chemotherapy) of 124 cases of Ewing's sarcoma are presented. At a medium follow-up of 65 months 48% of the patients are disease-free. One patient died of leukemia and two patients developed an irradiation-induced sarcoma. Analysing the data, three factors seem to be correlated to prognosis: location of the initial lesion outside the pelvis and sacrum, a four-drug chemotherapy protocol and the use of surgery in the treatment of the initial lesion seem to give better results.

Four cases of infantile sarcomatous renal tumors are reported. Rhabdomyoblastic differentiation was investigated in these tumors by the immunoperoxidase method using antimyoglobin sera. Rhabdomyoblastic cells were found in 2 cases and in a metastasis of one case in which the primary tumor was composed by undifferentiated cells negative for myoglobin stain. The histogenesis of these neoplasias is discussed, and it is suggested that they are a sarcomatous variant of Wilms’ tumor.

A case of cystic nephroma is described in a 20-month-old female. The diagnosis of this rare renal pathologic lesion is essentially based on its pathologic features. The treatment consisted of nephrectomy followed by a brief course of chemotherapy. The literature is reviewed with regard to the pathologic features and treatment of this lesion, which has a favorable prognosis.

Summary Serum samples were examined from 125 children (1–12 years) entering a paediatric unit for haematological disorders (74: acute lymphoblastic leukaemia; 11: Hodgkin's disease; 17: solid tumors; 23: non neoplastic disorders). Fifty healthy children were also studied. The sera were tested for class specific IgG and IgM antibodies to EB viral capsid antigen (VCA) and early antigen (EA), and for heterophil antibody. Serological findings consistent with a recent EBV primary infection, not related to the onset of the diseases, were found in six per cent of the patients. Antibodies against EBV-VCA were found in a significantly ( P

From June 1983 to December 1985, thirty-eight paients with localized Ewing's sarcoma of the extremities were treated with a protocol that consisted of an initial nine week period of polychemotherapy (vincristine, adriamycin and cyclophosphamide) followed by local therapy and additional chemotherapy (vincristine, adriamycin, cyclophosphamide and dactino-mycln) for one year. As local treatment all patients were offered surgery; thirty-two accepted and six refused. These six patients were locally treated with radiotherapy alone (50 Gy). In the remaining patients an amputation was performed in one case and a resection in thirty-one. In resected patients when a wide margin was achieved (24 cases) no further local treatment was performed; when it was marginal (5 cases) or intralesional (2 cases) radiotherapy at lower doses (40 Gy) followed. At mean follow-up of thirty-seven months the percentage of continuously disease-free patients was 50 % for those treated with radiotherapy, 76 % with surgery, and 85 % with surgery and radiotherapy. Eight patients developed metastatic disease and two patients had local recurrence and metastases. The local recurrences were seen in one patient locally treated with surgery and in one locally treated with radiotherapy. Nine major local complications were observed: three in patients treated with radiotherapy, five in patients treated with surgery, and one in a patient treated with surgery and radiotherapy. These results indicate that after induction chemotherapy conservative surgery is possible in almost all cases of Ewing's sarcoma of the extremities and that such treatment is better than radiotherapy alone as local therapy.

Of 255 cases of Ewing's sarcoma recorded at the Bone Tumor Center of the Rizzoli Orthopaedic Institute, 78 patients (irradiated and with a follow-up of longer than 3 years) were considered « at risk » for the development of a second radio-induced sarcoma (RIS). Three of the 78 patients developed an RIS in the irradiated field. Theoretical and statistical analyses were carried out considering different modalities of local treatment. Statistically, the only significant factor was related to the irradiation dose. Surgical resection seems to prevent RIS.

Smooth-muscle antibodies (SMA) were detected in 16 of 18 (89%) children with neuroblastoma and in 43 of 172 (25%) pediatric hospital patients without malignancies. The SMA were mainly of the IgG class. The most common immunofluorescence pattern was SMA-V (vessel) and titers did not exceed 1:160. Absorption and immunodiffusion tests with action (from rabbit skeletal muscle) showed that the SMA associated with neuroblastoma are mainly directed against actin, although different antigen specificities (myosin, meromyosin) are probably involved in some cases. In both chronic active hepatitis and neuroblastoma, SMA would represent a specific response to intracellular contractile proteins (mainly actin) induced by tissue damage. A feedback role in controlling cellular proliferation has been postulated for experimentally raised SMA. This would be relevant in cases of malignancy.

From June 1976 to May 1980, 25 previously untreated children with non-Hodgkin's lymphoma (NHL) were studied and treated with a protocol modified from the one (LSA2L2) proposed by Wollner [8]. Stage III and IV had, in addition, prophylactic treatment of the central nervous system (CNS) with cranial irradiation (2,400 rad plus intrathecal metho-trexate). The complete remission rate is 96%. Of these patients, 76% are disease free surviving after a median observation time of nearly two years. The disease-free actuarial survival is 100% for 6 children with Stage I-II disease and 68% for 19 Stage III-IV children after median observation times respectively of 25 + and 19 + months. None of the 19 high-risk patients developed CNS disease after prophylactic treatment. Mediastinal involvement and leukemic conversion at diagnosis were not unfavorable prognostic factors, but primary skeletal or subcutaneous disease and Burkitt-type histology were ominous features in patients treated by this regimen. It is concluded that good results are obtained when an aggressive multimodal and multiple drug regimen like the LSA2-L2 is coupled with CNS prophylaxis and is used assiduously to maintain complete remission during the first 12 months of treatment.

PTC, a mixture of oligopeptides of m-L-sarcholysin, acting primarily as an alkylating agent, was utilized as initial therapy following diagnosis in 80 children with nonlocalized neuroblastoma. Of the 67 evaluable patients (21 Stage III,41 Stage IV and five Stage IV-S), 51 had measurable lesions allowing to evaluate PTC activity; objective tumor responses to the drug were recorded in 45 of these 51 cases (88.2%): 5/5 Stage 111, 37/41 Stage IV, 3/5 Stage IV-S. Complete responses were obtained in seven patients (13.7%), partial responses in 32 (62.7%), objective improvement in six (1 1.8%). Four patients (7.8%) had either no tumor change, or tumor progression. There have been two early drug-related deaths (3.9%). Stage I11 and IV patients responding to PTC were then treated by irradiation + VCR, followed by cycles of a combination of Adriamycin, vincristine, and cyclophosphamide. Stage IV-S patients received no further therapy. Thirteen of 21 Stage 111 (61.9%), five of 41 Stage IV (12.2%) and four of five Stage IV-S (80%) are presently alive from 19-48 months (median, 27 months). PTC is an effective agent in advanced neuroblastoma. However, the results of this report do not indicate that its addition to a “standard” treatment, at least in the schedule adopted in this protocol, has improved the final outcome of children with nonlocalized disease. Cancer 5O:lO-17, 1982.

The previously reported high prevalence of smooth muscle antibodies in neuroblastoma has been found to be associated with a similarly elevated prevalence of anti-cytoskeleton antibodies. The most relevant finding is related to anti-microfilaments (anti-actin) and anti-microtubules antibodies, which were detected with highly significantly different prevalences when compared with a disease control group (p < 0.001 and p < 0.000001, respectively). The correspondence between smooth muscle antibodies and anti-cytoskeleton antibodies is incomplete, and it is more relevant for anti-microfilaments. It is concluded that antigen specificities of smooth muscle antibodies in neuroblastoma are as complex as documented in other diseases. Possible pathogenetic and clinical implications emerging from these data are discussed.

Rhabdomyosarcoma of the diaphragm is a very rare entity, especially in childhood. A case of a 4-year-old girl is reported. The mass extended completely into the abdominal cavity, causing problems in differential diagnosis with other abdominal masses. Dimensions, structure and limits of the mass had been outlined by several examinations (IVP, sonography, CT, angiography), but its actual nature could not be shown, so that a surgical exploration was needed. A pedunculated, well-capsulated mass, arising from the left diaphragmatic portion, was found. A complete excision could be performed and histologic findings were compatible with rhabdomyosarcoma of the diaphragm.

The clinical features of 30 children with IV-S neuroblastoma have been reviewed. They were treated at 11 Italian pediatric institutions in the period 1970-1981. Patients with IV-S neuroblastoma comprise 6.1% of all the neuroblastoma cases observed during that period. The age at diagnosis ranged from birth to 11 months (mean, 3 months). The distribution of "primary" lesions was of interest. The adrenal gland was affected most often (57% of patients), but tumors of the chest and neck were also encountered. No specific "primary" lesion was identified in ten children. The most frequent site of widespread disease was the liver (87%). Neither the size of the "primary" tumor, nor the number or size of subcutaneous nodules was of prognostic significance. Unfavorable features were age less than 2 months and clinical signs of pulmonary, renal, or hepatic embarrassment. These data confirm the need for prompt intervention in the infant who is suffering from compression of these vital structures by the enlarged liver. Radiation therapy is to be preferred for this purpose, because of the often severe toxicity that is associated with chemotherapy in infants. One, and possibly two babies in this series died of chemotherapy-related complications.

Hereditary neuroblastoma in a pair of identical twins is reported. In one of the twins the tumor occurred in fetal life and caused death of the twin before birth; in the other one, the tumor occurred at two months of life as IV-S neuroblastoma in the liver with primary tumor undetected. The unusual clinical course of the latter case is described: twice there was tumor regression, but in spite of treatment, fatal uncontrolled growth occurred. The family history, characterized by neoplasms of dissimilar cell types but without additional cases of neuroblastoma, is also detailed.

From June 1976 to December 1984, 48 previously untreated children with non-Hodgkin's lymphoma (NHL) were treated according to the LSA2-L2 protocol, modified by inclusion of cranial irradiation for patients in stage III and stage IV disease. According to the staging system proposed by Wollner, 4 patients were in stage I, 8 in stage II, 11 in stage III, 8 in stage IVA (less than or equal to 25% blasts in the bone marrow), 15 in stage IVB (greater than 25% blasts in the bone marrow), and 2 in stage IV central nervous system disease. The complete remission rate was 95.8%. The relapse-free survival (RFS) rate of 46 complete responders was 76% after a median observation time of 47+ months. Only 1 of 35 high-risk responder patients developed CNS relapse after prophylactic treatment. Clinical stages were related to the RFS: 100% in stage I-II vs. 69% in stage III-IV. All 8 patients in stage IV were alive without evidence of disease with a median observation time of 59+ months. Fifteen patients in stage IVB who had leukemia-lymphoma syndrome attained 59% RFS with a median observation time of 39+ months. After a median observation time of 38+ months, 29 of 37 patients are off therapy. The results emphasize the value of both the histologic and immunologic features and the stage of disease in predicting the outcome of NHL in children. The LSA2-L2 regimen appears to be a very effective protocol for children with lymphoblastic lymphoma, although it may be less efficacious for patients with large bone marrow involvement.

The clinical features and the treatment of undifferentiated (embryonal) sarcoma of the liver in 8 patients younger than 19 years old were analyzed. AH these cases were registered in the retrospective multicentric study on childhood malignant tumors of the liver, conducted between 1983 and 1985 by the Italian Association of Pediatric Hematology Oncology. The age of the patients ranged from 94 to 190 months (median = 113.5 months); all children were males. An abdominal mass was the common presenting features. Abnormalities in hemogram and common liver tests were rarely reported. Angiography revealed various degrees of vascularization in these tumors. Two patients achieved a surgical complete remission (CR) at diagnosis; one patient achieved surgical CR after primary chemotherapy with vincristine, adriamycin, cyclophosphamide and 5-fluorouracil, which reduced the tumor volume and permitted surgical resection. Two of these patients are still in CR at 14 and 60 months after diagnosis; the third patient died of liver failure without evidence of recurrence 6 months after diagnosis. All of the other patients, who never achieved CR, died of disease. One was lost to follow-up, and one surgical death occurred. Reports of childhood undifferentiated sarcoma are reviewed.

PURPOSE This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma. PATIENTS AND METHODS The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.

In Wilm's tumour, there is frequent spontaneous deletion of chromosome 11 and insulin and growth factor genes are located close to the deletion area. We studied growth and glycemia situation in 42 Wilms tumour cases in complete remission and off therapy for at least 2 years. We also studied adrenal, thyroid and gonad efficiency, as regards adrenalectomy, and irradiation (local, abdominal and abdominal-thoracic). Growth: initial height was normal; non-irradiated subjects' final height resembled chronological, while lower in irradiated subjects (-0.24 SDS±0.95). Differences between standing and sitting height at the latest examination indicate probable spinal column growth deficiency in irradiated subjects. 64.5% responded normally to arginine (like normals). Glycemia situation: in glucose oral load glycemia area is normal, insulin lower (p < 0.05), peptide C higher (p < 0.01 at 90 mins.). ACTH test: adrenalectomy cases'cortisol response was lower, n.s. compared to others. Thyroid: irradiated prepubertals' fT4 is significantly lower, irradiated pubertals' TSH is lower. Gonads: totally irradiated impubertal males' testosterone is lower; irradiated pubertal females' estradiol is lower. In conclusion an abnormality of chromosome 11 does not seem to be responsible for the alterations observed in our patients; on contrary irradiation and chemioterapy seem to have a real significance