bluuebunny/crossref_metadata_2025 huggingface dataset:
Concept of maximum tolerated systemic exposure and its application to phase I‐II studies of anticancer drugs
Authors: Evans William E. , Rodman John H. , Relling Mary V. , Crom William R. , Rivera Gaston K. , Pratt Charles B. , Crist William M.
Published: February 2007

The traditional approach to conducting Phase I studies of anticancer drugs is to select a starting dosage for humans based on preclinical data (e.g., mg equivalent of 1/10 LD10 in mice), then empirically escalate dosages in cohorts of patients until the maximum tolerated dosage (MTD) is established. More recently, NCI and EORTC investigators have advocated the use of pharmacokinetic data from preclinical studies to facilitate more rapid dose escalation (e.g., double the dose until the area under the concentration‐time curve [AUC] in humans equals the AUC in mice at the LD10). The present paper describes a strategy which builds on the above approach, by extending the application of pharmacokinetic principles to systematically escalate systemic exposure (AUC) instead of dosage in Phase I trials. Human trials are initiated at whatever patient‐specific dosage is required to achieve an AUC equal to 1/10 the AUC in mice at the LD10, such that three patients at the first treatment level might receive three different dosages. If no dose‐limiting toxicity is observed, the next cohort of patients receives whatever dosage is required to achieve 2x AUC of the first dosage level, with AUC escalation continuing until the maximum tolerate systemic exposure (MTSE) is reached. By escalating systemic exposure instead of dosage, one adjusts for interpatient pharmacokinetic variability. This strategy will permit more rapid and precise dosage escalations and, more importantly, it should more precisely establish the maximum level of treatment intensity for future Phase II trials.
Natural killer cell function in children with malignant solid neoplasias
Authors: Gallego‐Melcón Soledad , Boren Teresa Español , de Toledo Jose Sanchez , Viñas Jorge Prats
Published: February 2007

Natural killer (NK) cell numbers and lytic activity were determined in 40 children with various types of solid malignant neoplasias and in 25 control children by NKH‐1 monoclonal antibody and cytotoxicity against K562 target cells, respectively. Patients were analyzed at the time of diagnosis before initiation of therapy and followed over a median time of 15.8 months. Mean NK cell numbers and lytic activity were similar among different types of tumor analyzed. Patients with localized disease (stages I, II; n = 25) also showed values not statistically different from those of patients in advanced disease (stages III, IV; n = 15). According to their response to therapy, patients were divided into three groups: group 1 (complete remission; n = 28), group 2 (partial remission; n = 5), and group 3 (progression of disease; n = 6). Patients in group 3 showed at the time of diagnosis a mean NK activity significantly lower than that of patients in groups 1 and 2 and control children (P = 0.007). The defect in NK cell lytic capacity in vitro observed in patients with progressive disease suggests that NK cells play a role in the control of neoplasic growth in vivo and may imply that some children with refractory progressive disease can benefit from immu‐nomodulation destined to improve the lytic potential of NK cells.
The conduct of phase I‐II clinical trials in children with cancer
Authors: Pratt Charles B.
Published: February 2007

Phase 1 Clinical Trials in children with cancer are carried out with therapeutic intent, so as to define antileukemic/antitumor activity, dose‐limiting toxicity, maximum tolerated dosage, and pharmacokinetics. These studies define a dosage of an agent or combination that may be used in a larger study of pediatric patients with leukemias or malignant solid tumors. The content of phase I and II protocols is outlined, with a brief discussion of the ethics of performance of phase 1 trials in children.
Reproduction following treatment for childhood leukemia: A population‐based prospective cohort study of fertility and offspring
Authors: Nygaard Randi , Clausen Niels , Siimes Martti A. , Márky Ildikó , Skjeldestad Finn Egil , Kristinsson Jon R. , Vuoristo Aira , Wegelius Ruth , Moe Peter Johan
Published: February 2007

Of all children diagnosed with leukemia in Denmark, Finland, Iceland, Norway, and Sweden, 981 had discontinued therapy before 1985 and had been followed up annually after cessation of therapy. Progeny was registered and fertility evaluated among survivors who passed age 18 years without a relapse (n = 299).

By April 1989, 48 offspring were registered, one of whom had congenital anomalies. This was no more than expected from the incidence of birth defects in the general population. No childhood malignancies or genetic diseases have so far been diagnosed in the progeny, in the study group, none of the 19 female and 8 male survivors of myeloid leukemias had become parents, and only 4 fathers were reported among the 131 male survivors of acute lymphoblastic leukemia (ALL). However, 23 of the 149 females treated for ALL had delivered 41 children. Fertility was measured as cumulative rates of first birth by maternal age. In a Cox regression analysis, cases who had received prophylactic radiation of the central nervous system (CNS) had a lower first birth rate than those without radiation (rate ratio 0.39, 95% CI 0.15–1.00), indicating that doses of 18–24 Gy to the brain may possibly be a risk factor. By using the Norwegian birth cohort of 1966 as a control group, matching the median year of birth for the study subjects, the group of female ALL survivors as a whole was as likely as the general female population to have given birth up to the age of 23.

The first generation of females successfully treated for childhood ALL seems to have a nearly normal reproductive pattern during young adulthood, without increased risk of congenital anomalies in the offspring. However, cranial radiation as CNS prophy laxis may possibly impair subsequent reproduction.
Intraoperative radiotherapy in the multidisciplinary treatment of bone sarcomas in children and adolescents
Authors: Calvo Felipe A. , de Urbina David Ortiz , Sierrasesúmaga Luis , Abuchaibe Oscar , Azinovic Ignacio , Antillon Federico , Santos Manuel , Canadell José
Published: February 2007

From September 1984 to December 1989, 38 patients of pediatric age with localized bone sarcomas received intraoperative radiotherapy (IORT) as part of a multidisci plinary treatment program. The age ranged from 6 to 21 years. The tumor histologies were 22 osteosarcomas and 16 Ewing's sarcomas.

Thirty‐four had initial primary disease (90%) and 4 were treated for local recurrence (10%). IORT was used on 32 untreated patients and in 6 previously treated with external beam radiotherapy (EBR). The IORT field included the surgically exposed tumor bed area. Single radiation doses ranging from 10 to 20 Gy were delivered, using 6–20 MeV electron beams. The median follow‐up time for the entire group is 25 months (2–65+ months). The projected 5‐year disease‐free and overall survival rates are 65% and 69%, respectively. One patient developed a local recurrence in each histological group: one chondroblastic osteosarcoma and one cervical Ewing's sarcoma. Six patients died from metastatic progression: 3 initially recurrent tumors and three primary disease cases. Severe neuropathy and soft tissue necrosis were seen in some patients as IORT related complications.

IORT is a feasible technique to be integrated in multidisciplinary programs that may promote local control in pediatric and adolescent patients with bone sarcomas. Peripheral nerves are dose‐limiting tissue structures for IORT.
Late effects of therapy in adult survivors of osteosarcoma and Ewing's sarcoma
Authors: Nicholson H. Stacy , Mulvihill John J. , Byrne Julianne
Published: February 2007

To study the late consequences of primary bone cancer, we interviewed 82 osteosarcoma and 29 Ewing's sarcoma survivors regarding their health, fertility and offspring, employment, annual income, and activities of daily living. All subjects had been diagnosed before age 20 (mean age, 14.6 years), had survived at least 5 years from diagnosis, and were at least 21 years of age. On average, they were 32.5 years of age at interview. As controls, 151 siblings were interviewed.

During the follow‐up period, eight survivors had died, and eight survivors had been diagnosed with a second malignancy (7.2%;P= .002). No other health condition distinguished survivors from controls. Although the survivors were more likely than controls to have some difficulty climbing stairs and to have had employment disability, employment status and annual income at follow‐up were similar. Deficits in marriage and fertility were not significant.

Adult survivors of primary bone tumors diagnosed during childhood or adolescence are at high risk for second malignancies and premature death, making continued medical follow‐up of utmost importance. Despite the physical impairment following limb amputation for many, the majority of outcomes we measured did not differ from controls, suggesting few adverse psychosocial outcomes in this group of cancer survivors.
Surgical complications in acute leukemia in childhood: A 20 year experience
Authors: Rice Michael S. , Cord‐Udy Catherine , Little Kenneth E. T. , Toogood Ian R. G.
Published: February 2007

A retrospective study of all patients presenting with acute leukemia to a single institution during the period 1968–1988 was undertaken to determine the type and incidence of surgical complications. One hundred twenty‐eight of 296 patients were identified as requiring a surgical consultation for complications occurring during the course of the disease and many surgical disciplines were involved. Operative intervention was often required for these complications. Pediatric surgical specialists need to be aware of the range of surgical complications that can occur in children with acute leukemia and they must work in close co‐operation with pediatric medical oncologists to ensure optimal treatment for all patients.
Humoral hypercalcemia in seminomas
Authors: da Silva Marco A. P. , Edmondson James W. , Eby Charles , Loehrer Patrick J.
Published: February 2007

Seminomas are germ cell tumors that are rarely associated with hypercalcemia. In this report, four cases of seminoma with concomitant hypercalcemia are presented and another three from the literature are reviewed. All seven patients exhibited hypercalcemia with a normal serum concentration of inorganic phosphorus and no evidence of skeletal metastases. The peripheral venous level of parathyroid hormone (PTH) was normal in four of the five patients in whom it was measured. The serum concentration of calcitriol was elevated in the two patients in whom it was measured. After systemic chemotherapy, the serum “corrected” total calcium concentration returned to normal and remained normal; the decrease in the levels temporally paralleled the decrease in tumor volume. Both patients with elevated calcitriol levels remained eucalcemic after treatment of the malignancy, suggesting that the increased serum calcitriol level was linked to the development of hypercalcemia as this humoral agent was inappropriately elevated by patients with this syndrome. In contrast to many forms of malignancy, the development of hypercalcemia did not adversely affect the prognosis of the patients with seminoma, since all seven patients entered complete remission. Hypercalcemia appears to be a heretofore unrecognized paraneoplastic syndrome associated with seminoma.
The pediatric patient with suspected adrenal neoplasm: Which radiological test to use?
Authors: Petrus Leonard V. , Hall Theodore R. , Boechat M. Ines , Westra Sjirk J. , Curran John G. , Steckel Richard J. , Kangarloo Hooshang
Published: February 2007

To establish which radiological test to use in a pediatric patient with suspected neoplasm, we retrospectively studied 19 children with proven adrenal neoplasm who had a combination of ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). The results show that US should remain the initial imaging modality for evaluating abdominal masses in children but that MRI is more accurate than CT and US in detecting the organ of origin and the extent of an adrenal lesion and should, therefore, be the modality of choice for the definitive evaluation of adrenal neoplasm in children.
Results of the LMT81 protocol, a modified LSA2L2 protocol with high dose methotrexate, on 84 children with non‐B‐cell (lymphoblastic) lymphoma
Authors: Patte Catherine , Kalifa Chantal , Flamant Francoise , Hartmann Olivier , Brugières Laurence , Valteau‐Couanet Dominique , Bayle Chantal , Caillaud Jean‐Michel , Lemerle Jean
Published: February 2007

From May 1981 to June 1989, 84 children with non‐B‐cell lymphoma (82 lymphoblastic, 1 T‐cell immunoblastic, 1 unclassified diffuse lymphoma) were treated in the pediatric department of the Institut Gustave Roussy according to a protocol called LMT81, which was derived from the LSA2L2 protocol of Wollner and modified by the adjunction of 10 courses of high dose methotrexate to improve the CNS prophylaxis. No planned irradiation was performed except in cases of initial testis (2 patients) or CNS (5 patients) involvement and residual mass (2 patients). Sixty patients had mediastinal involvement; for the others, primaries were in the head and neck (7), nodes (2), (sub)cutaneous (4), bone (7), and elsewhere (2). According to Murphy's staging system, there were 2 stage I, 6 stage II, 33 stage III, and 43 stage IV. Among the stage IV patients, 41 had bone marrow involvement, 24 of them with more than 25% blast cells in bone marrow and 19 with blast cells in blood; 7 hadCNS involvement. Three patients did not achieve complete remission, 4 died in remission (two measles, one post‐transfusion AIDS, one unexplained definitive aplasia) and 13 relapsed at 2 to 29 months (median‐13 months). Among the 77 patients without initial CNS involvement, there was only one isolated CNS relapse. With a median follow‐up of 57 months (10‐106 months), the event‐free survival is 75% (SE 2.5) for the 84 patients with a plateau at 29 months, 73% (SE 8) for stage I and II patients, 79% (SE 4) for stage III, and 72% (SE 4) for stage IV patients. Survival was similar in each stage group. Reasons for failure of treatment, however, were different, being toxic deaths in stage II; initial therapy resistance, early relapses, and toxic deaths in stage III; and tumor failures in stage IV. In conclusion, this protocol is efficacious on T and non‐T, non‐B childhood lymphoma with a low incidence of CNS relapse. A future study will seek to diminish toxicity and long‐term sequellae while at least maintaining the same cure rate of patients.
Soft‐tissue sarcomas other than rhabdomyosarcoma in children
Authors: Hayani Ammar , Mahoney Donald H. , Hawkins Hal K. , Steuber C. Philip , Hurwitz Richard , Fernbach Donald J.
Published: February 2007

Forty‐seven children with nonrhabdomyosarcomatous soft‐tissue sarcomas (NRSTS) were treated by the Hematology‐Oncology Service at Texas Children's Hospital, Houston, Texas, between 1958 and 1990. The male: female ratio was 1:1, and the median age was 11 years (3 weeks‐16 years). A preexisting condition was found in 9/47 (19%) patients including neurofibromatosis (3), Down's syndrome (1), spina bifida (1), congenital facial asymmetry (1), giant pigmented nevus (1), juvenile onset diabetes mellitus (1), and acquired immune deficiency syndrome (1). The site of primary tumor was head and neck (3), trunk (33), and extremities (11). Twenty‐four patients (51%) have survived free of disease with a median follow‐up of 5 years (4 months‐22 years). No patient whose disease recurred achieved a second remission. Of the 19 patients with group I disease, 16 (84%) survived free of disease. Wide excision of the primary tumor, with no microscopic residual disease, was associated with the greatest chance of disease‐freesurvival.
Value of cytogenetics in the differential diagnosis of the small round cell tumors of childhood
Authors: Sainati Laura , Stella Mario , Montaldi Anna , Bolcato Sonia , Guercini Nicola , Bonan Franca , Ninfo Vito , Zanesco Luigi , Basso Giuseppe
Published: February 2007

Small round cell tumors are among the most common problems in the differential diagnosis of cancer, even when more sophisticated histological techniques are utilized (Ezinger and Weiss: In Soft Tissue Tumors. St. Louis: CV Mosby, 1988, pp 668–683). Six cases of small round cell tumors are described the diagnosis of which was particularly difficult.

Cytogenetic analysis provided useful information in all of them in making the definitive diagnosis. The reported cases stress the value of cytogenetic methods in approaching difficult diagnostic problems.
Inflammatory pseudotumor of the liver masquerading as a metastasis in a child treated for nephroblastoma
Authors: Newbould Melanie J. , Kelsey Anna , Lendon Mehrou , Gururangan Sridharan
Published: February 2007

A 31/2‐year‐old boy presented with a palpable hepatic tumor thought on clinical and radiological grounds to be a metastasis but which was found to be an inflammatory pseudotumor on histological examination. Eighteen months previously he had received chemotherapy and radiotherapy for a stage IV Wilms' tumor, which had been surgically excised 4 months after commencing treatment. This case illustrates the importance of obtaining a histological diagnosis in the management of patients with malignant tumors.
The usefulness of serum thyroglobulin in the follow‐up of differentiated thyroid carcinoma in children
Authors: Kirk Jeremy M. W. , Mort Catherine , Grant David B. , Touzel Richard J. , Plowman Nicholas
Published: February 2007

Serum thyroglobulin has been measured serially in ten children aged 5–17 years presenting with differentiated thyroid carcinoma. At presentation 4 had intra‐thyroidal disease, 3 had lymph node metastases, and 3 had lung metastases. During follow‐up for a median of 37.0 months (range 21–108) 3 patients have been disease‐free, 4 have had a local relapse, and 3 have had persistent disease. Seventy‐seven separate serum thyroglobulin measurements have been performed; 36 on and 41 off thyroid replacement therapy. A level of thyroglobulin of <5 ng/ml was taken as indicative of absence of disease, and compared against combined clinical examination and 131 I scanning. Over‐all sensitivity of thyroglobulin measurement was 36/37 (97%), and although specificity was 30/40 (75%), this rose to 30/32 (94%) if raised thyroglobulin levels noted within 3 months of 131 I therapy in otherwise asymptomatic patients (n = 4) or in subjects with intact thyroid tissue (n = 4) were excluded. Concordance with clinical status was 30/31 (97%) in measurements taken on, and 31/32 (94%) in those taken off, thyroid replacement. These data indicate that thyroglobulin measurement is a sensitive and specific means of detecting residual, recurrent, and metastatic thyroid carcinoma in children. © 1992 Wiley‐Liss, Inc.
T‐cell acute lymphoblastic leukemia following therapy of rhabdomyosarcoma
Authors: Kaplinsky Chaim , Frisch Amos , Cohen Ian J. , Goshen Yacov , Jaber Lutfi , Yaniv Isaar , Stark Batia , Tamary Hanah , Zaizov Rina
Published: February 2007

Multiple studies have documented an increased risk of secondary malignancies in patients receiving alkylating agents. Secondary leukemia following chemotherapy accounts for about 20% of all secondary neoplasms; most are acute nonlymphocytic. Secondary acute lymphoblastic leukemia has rarely been reported in either adult or childhood cancer. We report the development of acute T‐cell lymphoblastic leukemia in a child following successful treatment of a paravertebral embryonal rhabdomyosarcoma (ERS). Southern blot analysis of DNA extracted from the T‐cell lymphoblasts, using probes homologous to loci on the short arm of chromosome 11; P‐calcitonin, P40.1 and H‐ras, did not demonstrate the chromosomal loss of heterozygosity (LOH), a common feature of embryonal rhabdomyosarcoma. The data presented support the assumption that de novo leukemia emerged following treatment of the primary malignancy. © 1992 Wiley‐Liss, Inc.
A unique case of retinoblastoma masked by retinal detachment diagnosis and management
Authors: Cangir Ayten , Lee Ya Yen , Salmonsen Paul
Published: February 2007

A 4‐year‐old Latin American boy presented with a history of loss of vision of his left eye for 7 months. He was followed by different ophthalmologists and diagnosed with a retinal detachment. Computerized tomograms and magnetic resonance imaging demonstrated a large calcified left eye and markedly enlarged optic nerve. Based on these radiologic findings diagnosis of retinoblastoma was strongly suspected. Initially enucleation was not done because it was thought that cutting through the involved optic nerve would cause dissemination. The patient was treated with chemotherapy which resulted in marked response. Following normalization of optic nerve and after irradiation the eye was enucleated. The diagnosis of retinoblastoma was confirmed. No tumor was found in the optic nerve. The importance of imaging studies in diagnosis of retinoblastoma and the role of chemotherapy in the treatment of primary retinoblastoma are emphasized. © 1992 Wiley‐Liss, Inc.
13‐cis‐retinoic acid (NSC 122758) in the treatment of children with metastatic neuroblastoma unresponsive to conventional chemotherapy: Report from the childrens cancer study group
Authors: Finklestein Jerry Z. , Krailo Mark D. , Lenarsky Carl , Ladisch Stephen , Blair Geoffrey K. , Reynolds C. Patrick , Sitarz Anneliese L. , Hammond G. Denman
Published: February 2007

The Childrens Cancer Study Group evaluated daily oral 13‐cis‐retinoic acid to determine its therapeutic efficacy in 28 children with advanced neuroblastoma refractory to conventional therapy. Cheilitis and fissured lips were the most common side effects; however, fewer than 50% of the patients experienced any toxicity. Two of twenty‐two evaluable children demonstrated positive response to therapy. In one case, a child received the drug for 11 months. Seventeen patients demonstrated progressive disease within 28 days of the start of treatment. Three other patients with stable disease, or removed from study at day 28, were considered nonresponsive. Our data demonstrate that, when given as a single daily oral dose of 100 mg/m2, 13‐cis‐retinoic acid does not have significant activity in children with advanced neuroblastoma. © 1992 Wiley‐Liss, Inc.
Treatment of malignant scala posterior brain tumors in children: The chemotherapy of relapsed medulloblastoma with a dibromdulcitol containing drug regime and pharmacokinetic studies of dibromdulcitol in children
Authors: Schuler Dezsõ , Somló Pál , Koós Rozólia , Kálmánchey Rozália , Paraicz Ervin
Published: February 2007

Dibromdulcitol (Elobromol) has favorable pharmacokinetic parameters for the treatment of brain tumors: high spinal fluid/plasma ratio and long half‐life in spinal fluid. Oral application makes its administration easy. The drug combination vincristine, procarbazine, and dibromdulcitol proved to be effective in a pilot trial on relapsed medulloblastomas: 8 complete and 4 partial remissions were achieved from 16 cases. The main side effect was granulocytopenia, which was in some cases severe. However, in the doseschedule we used it did not delay the treatment longer than 1 week. © 1992 Wiley‐Liss, Inc.
Simultaneously occurring alopecia areata and Hodgkin's lymphoma: Complete remission of both diseases with MOPP/ABV chemotherapy
Authors: Chan Paul D. , Berk M. Allan , Kucuk Omer , Singh Satinder
Published: February 2007

A 43‐year‐old man presented with simultaneously occurring alopecia areata and stage IIIB nodular sclerosing Hodgkin's disease. Systemic symptoms of Hodgkin's disease were present for 6 months, and rapidly developing patchy hair loss of the scalp was present for 2 weeks prior to presentation. The patient was treated with eight cycles of MOPP‐ABV chemotherapy that resulted in complete remission of Hodgkin's disease. Four months after the completion of chemotherapy, the patient had normal hair regrowth with no evidence of alopecia areata. Alopecia areata may be an autoimmune disease and may respond to chemotherapy. © 1992 Wiley‐Liss, Inc.
Detection of Epstein‐Barr virus in Reed‐Sternberg cells of Hodgkin's disease arising in children
Authors: Coates Philip J. , d'Ardenne A. Jane , Slavin Gerard , Kingston Judith E. , Malpas James S.
Published: February 2007

Nonisotopic in situ hybridization has been used to investigate the role of Epstein‐Barr virus (EBV) in the aetiology of pediatric Hodgkin's disease. Sections from 24 cases arising in children under the age of 15 years were hybridised with digoxigenin‐labelled probes for both EBV and cytomegalovirus, and reactive sites were identified by a sensitive three‐layer immunoperoxidase technique.

EBV was identified in Reed‐Sternberg and mononuclear Hodgkin's cells in five samples (21%). No samples were positive when the cytomegalovirus probe was employed. The specific identification of EBV in the malignant cells of Hodgkin's disease arising in children lends further support for a role of EBV in the aetiology of this disorder. © 1993 Wiley‐Liss, Inc.
Evaluation of bone marrow metastasis of neuroblastoma and changes after chemotherapy by MRI
Authors: Tanabe Masahiro , Takahashi Hideyo , Ohnuma Naomi , Iwai Jun , Yoshida Hideo
Published: February 2007

To evaluate the usefulness of MRI for diagnosing bone marrow metastasis of neuroblastoma, we compared MRI findings with histological findings. MRI was performed 26 times in 20 patients with neuroblastoma to detect metastasis to the bone marrow of the femur and tibia. Abnormal areas observed by MRI were histologically examined. The lesion visualized by MRI as a low‐intensity area on T1‐weighted images and as a high‐intensity area on T2‐weighted images was histologically confirmed to be neuroblastoma in 81% (17/21). The percentage varied according to the treatment state: 89% (8/9) by MRI imaging performed before the initiation of chemotherapy, 67% (6/9) within 3 weeks after cessation of chemotherapy (during chemotherapy), and 100% (3/3) in recurrent cases 1 year or more after chemotherapy. During the follow‐up period after chemotherapy, tissue with signal intensities similar to that of bone marrow was observed in a speckled pattern in the intramedullary space on T1‐ and T2‐weighted images. This tissue was histologically demonstrated to be normal bone marrow and was considered to be bone marrow remaining after chemotherapy.

In this small series, histological findings supported the results of MRI, confirming the usefulness of MRI for diagnosing bone marrow metastasis of neuroblastoma. However, bone marrow metastasis after chemotherapy was difficult to evaluate by comparing signal intensities alone. © 1993 Wiley‐Liss, Inc.
Local failure in childhood rhabdomyosarcoma and undifferentiated sarcoma: Prognostic factors and implications for curative therapy
Authors: Mameghan Hedy , Fisher Richard , Tobias Vivienne , Kern Ian B. , O′Gorman‐Hughes Darcy , Vowels Marcus , Mameghan Jill
Published: February 2007

In this retrospective review, the risk factors for local failure in childhood rhabdomy‐osarcoma and undifferentiated sarcoma were assessed in 49 patients managed by a multi‐disciplinary team at the Prince of Wales Children′s Hospital, Sydney, between 1970 and 1988. Average follow‐up time was 6.1 years. Sixteen of 49 patients experienced local failure defined as local recurrence after complete excision (5/20) or progressive local disease following incomplete resection (11/29). Fourteen of 16 patients who experienced local failure have died. Using logrank analysis of time to local failure, we found significantly increased risk with “non‐embryonal” histology (P= 0.032), residual tumour (P= 0.052, higher IRS group (P= 0.088), “inadequate radiotherapy” for residual tumour (P= 0.001), delay in definitive local treatment (P= 0.038) and Adriamycin‐containing chemotherapy (P= 0.017). When these factors were examined by multivariate analysis (Cox regression), only the presence of residual tumour after resection, “inadequate radiotherapy” for residual tumour (P< 0.001), and delay in definitive local therapy (P= 0.037) were shown to have independent significant association with local failure. We conclude that local failure may be avoided by prompt local treatment by either complete surgical resection or adequate radiotherapy. © 1993 Wiley‐Liss, Inc.
Neuroblastoma: A 32‐year population‐based study—implications for screening
Authors: Huddart Simon N. , Muir Kenneth R. , Parkes Sheila , Mann Jillian R. , Stevens Michael C. G. , Raafat Faro
Published: February 2007

This paper describes a retrospective population‐based study of neuroblastoma in the West Midlands Health Authority Region—childhood population 1.12 million (OPCS, census 1981)—in which 239 cases were diagnosed between 1st January 1957 and 31st December 1988. The age standardised rate of tumour incidence has remained constant at 7.2 cases per million children per year. The median age at diagnosis was 2 years with 18% of children presenting before the age of 6 months. Fifty children (21%) presented before the age of one year, and for this group of children, the prognosis has improved significantly over the 32‐year period (10 year survival increasing from 63% in 1957–67 to 87% in 1978–88), whereas for the 189 (79%) children who presented after one year of age, the prognosis has remained very poor during the study period (10 year survival 1957–67 = 9.5%, 1978–88 = 8.5%). This study supports the need for a prospective study of mass screening at several intervals rather than only at 6 months of age. © 1993 Wiley‐Liss, Inc.
Cancer associated haemolytic uraemic syndrome developing prior to treatment with cytotoxic agents
Authors: Milford David V. , Goldstein Amanda , Barrett Martin , Mann Jillian R. , Raafat Faro
Published: February 2007

The haemolytic uraemic syndrome has been reported in children and adults with neoplasias treated with mitomycin C and occasionally in adults prior to chemotherapeutic treatment, but it has not been reported in a child prior to the use of cytotoxic drugs. This case report concerns the development of the haemolytic uraemic syndrome in a 7‐year‐old male child with a metastatic hepatocellular carcinoma. The child had persisting haemolysis and renal imparment, and died three weeks after presentation. Though our exprerience with similar tumours suggested the outlook would be poor, we had hoped to provide palliative chemotherapy. This proved impossible as optimal chemotherapy could not be used because of the renal impairment.
Cutaneous squamous cell carcinoma following treatment for acute lymphoblastic leukaemia
Authors: Morland Bruce J. , Radford Martin
Published: February 2007

The importance of second malignant neoplasms following successful treatment of childhood malignancy is of concern to all professionals involved with the care of these patients. We present an 18 year old patient with a squamous cell carcinoma of his lower lip following prolonged treatment for acute lymphoblastic leukaemia in childhood. The rarity of this tumor in this age group and the aetiological factors involved in developing the second malignancy are discussed. © 1993 Wiley‐Liss, Inc.
Precursor lesions of Wilms tumor: Clinical and biological implications
Authors: Beckwith J. Bruce
Published: February 2007

Nephrogenic rests (NR) are persistent embryonal remnants in the kidney that are apparent precursors of Wilms tumor (WT). Nephroblastomatosis (Nbl) denotes multiple or diffuse NR. Two major categories of NR have been recognized to date, perilobar (PLNR) and intralobar (ILNR). A dynamic classification of NR according to their recognized developmental fates is presented. Dormancy, maturation, involution, hyperplastic overgrowth, and neoplastic induction are the common fates of NR. Hyperplastic NR are far more common than formerly recognized, and are frequently confused with WT, especially in cases of multicentric and bilateral tumors. Biopsy is of limited value in distinguishing hyperplastic NR from WT, and the use of surgery in cases of Nbl requires careful consideration, as its role can in many cases be reduced or supplanted due to the effectiveness of modern imaging techniques and chemotherapy. An understanding of the natural history of NR and Nbl is essential for rational patient care decisions, and is important for understanding the molecular biology of WT. © 1993 Wiley‐Liss, Inc.
Epidemiology of Wilms tumor
Authors: Breslow Norman , Olshan Andrew , Beckwith J. Bruce , Green Daniel M.
Published: February 2007

Wilms tumor affects approximately one child per 10,000 worldwide before the age of 15 years. Incidence rates appear to be slightly elevated for U.S. and African Blacks in comparison to Whites, but are only half as great among Asians. Several case‐control studies have suggested that paternal occupational or maternal hormonal exposures during pregnancy may increase the risk of Wilms tumor, but small numbers of subjects and inconsistencies in the patterns of exposures do not permit firm conclusions to be drawn. It is unlikely that such environmental exposures play a major role in the etiology of Wilms tumor. The median age‐at‐onset of Wilms tumor is 38 months in the U.S. National Wilms Tumor Study series, with cases in girls occurring on average 6 months later than in boys. Patients with bilateral tumors, aniridia, cryptorchism/hypospadias, Beck‐with‐Wiedemann syndrome, or intralobar nephrogenic rests tend to be diagnosed much younger than average (median 17–27 months). Those with familial disease or multicentric tumors have intermediate age‐at‐onset distributions, while those with perilo‐bar nephrogenic rests are diagnosed at older ages. The epidemiologic features suggest that somatic mosaicism, rather than a germ‐line mutation, may be responsible for some of the bilateral and multicentric cases. © 1993 Wiley‐Liss, Inc.
Screening of children with hemihypertrophy, aniridia, and Beckwith‐Wiedemann syndrome in patients with wilms tumor: A report from the national Wilms tumor study
Authors: Green Daniel M. , Breslow Norman E. , Beckwith J. Bruce , Norkool Patricia
Published: February 2007

To evaluate the usefulness of regular radiographic screening to detect an asymptomatic intraabdominal tumor in patients with an increased risk of developing Wilms tumor, we reviewed the files of patients with hemihypertrophy, aniridia, or Beckwith‐Wiedemann syndrome who were registered on the National Wilms Tumor Studies. Screening was employed infrequently in the management of children with hemihypertrophy, with only 25% (6/24) of those whose hemihypertrophy was identified more than 30 days prior to the diagnosis of Wilms tumor undergoing such examinations. Most patients with aniridia were evaluated regularly for the occcurrence of Wilms tumor. There were more stage 1 tumors identified in patients whose tumor was detected only through radiographic evaluation. The role of routine radiographic screening needs to be carefully evaluated in a homogeneous group of patients such as those with aniridia using a prospective study design to determine if such screening improves the survival rate of children with this rapidly growing, but readily treatable form of childhood cancer. © 1993 Wiley‐Liss, Inc.
Position paper: Imaging methods for primary renal tumors of childhood: Costs versus benefits
Authors: D'Angio Giulio J. , Rosenberg Henrietta , Sharples Katrina , Kelalis Panos , Breslow Norman , Green Daniel M.
Published: February 2007

The patterns of disease distribution at diagnosis and during follow‐up were cataloged for the primary renal tumors of childhood. These data, derived from more than 1,500 patients, were used to define the most rewarding and cost‐effective imaging methods required for patient management. The basic information needed prior to surgery includes whether there is a functioning kidney on the opposite side, and whether there are lung metastases or inferior vena cava thrombi. Simple X‐ray examinations and ultrasonography (US) will provide the necessary data. Postoperatively, when the histology is known, examination of the brain (MRI or CT scan) is needed for patients with the rhabdoid tumor and clear cell sarcoma of the kidney (CCSK) who are prone to develop brain lesions; and the skeletal system (bone scan, X‐ray skeletal survey) for CCSK and for renal cell carcinoma patients who tend to develop bone metastases. Continuing examination of the lung (chest films) is required for all histologies except perhaps for mesoblastic nephroma, which seldom metastasizes. The opposite kidney needs follow‐up (US) for 5 or more years to exclude metachronous involvement if nephrogenic rests are present in either kidney. Sophisticated imaging studies, which cost five times or more than simple X‐ray examinations or US, are not warranted routinely, and should be reserved for those cases where simpler, less expensive studies do not suffice for reaching patient management decisions. © 1993 Wiley‐Liss, Inc.
The use of nuclear morphometry to predict prognosis in pediatric urologic malignancies: A review
Authors: Partin Alan W. , Gearhart John P. , Leonard Michael P. , Leventhal Brigid G. , Yoo John K. , Crooks David , Epstein Jonathan I. , Beckwith J. Bruce
Published: February 2007

Wilms tumor, the most common pediatric urologic malignancy, and genitourinary rhabdomyosarcoma, the most common soft tissue sarcoma of childhood, respresent two of the most commonly diagnosed pediatric urologic malignancies. The introduction and use of multimodal therapy (surgery, radiation, and chemotherapy) by the National Wilms Tumor Study (NWTS) and the Inter‐group Rhabdomyosarcoma Study (IRS) groups have greatly improved the survival among children with these malignancies. Present survival rates for Wilms tumor exceed 85% and for rhabdomyosarcoma survival rates are approaching 80% as well. For Wilms tumor, current treatment trends suggest less intense therapy for those children with favorable histology tumors who are considered at relatively low risk for tumor recurrence. Likewise, the significant morbidity associated with the present therapy regimens for rhabdomyosarcomas has prompted investigators to search for individualized management schemes for children with a high probability of responding. The need for accurate criteria to separate these high and low risk groups becomes imperative. In this review we present our work using nuclear morphometry, as a prognostic indicator, to retrospectively predict response to therapy for children with Wilms tumors and genitourinary rhabdomyosarcomas. © 1993 Wiley‐Liss, Inc.
Langerhans cell histiocytosis and acute leukemia: Unusual association in two cases
Authors: Aricò Maurizio , Comelli Adele , Bossi Grazia , Raiteri Emanuela , Piombo Margherita , Egeler R. Maarten
Published: February 2007

Langerhans cell histiocytosis (LCH) is a non‐malignant disorder, whether localized or disseminated, and usually has a favourable prognosis. A possible relationship between LCH and neoplastic diseases has not been assessed up to now even if a few cases have been recorded.

We report two new cases of acute leukemia in children with LCH. The first child had acute lymphoblastic leukemia after untreated LCH; the second developed acute promyelocytic leukemia after LCH treated with vinblastine and etoposide. To our knowledge, this is the first case of secondary leukemia after exposure to an epipodophyllotoxin derivative in a child with benign disease.

Cooperative studies of large numbers of LCH patients are needed to evaluate a possible association between LCH and acute leukemia, and to identify common risk factors or predisposing agents if such be present. © 1993 Wiley‐Liss, Inc.
Phase I trial of trimetrexate in pediatric solid tumors: A pediatric oncology group study
Authors: Pappo Alberto S. , Vats Tribhawan , Williams Thomas E. , Bernstein Mark , Kamen Barton A.
Published: February 2007

Trimetrexate (TMTX), a lipophilic antifol, was evaluated in a Pediatric Oncology Group (POG) Phase I trial in children with refractory solid tumors. TMTX was administered intravenously daily × 5 every three weeks. Starting dose was 6.4 mg/m2/day. Dose was escalated by 20% until the maximal tolerated dose was reached. A total of 75 courses were administered to 26 children. The major toxicity was myelosuppression, of which neutropenia and thrombocytopenia were most prominent. Rash, mucositis, and transient liver enzyme elevations were infrequently seen. Responses were observed in children with brainstem glioma, neuroblastoma, and renal cell carcinoma. The recommended Phase II dose using this schedule is 9.2–11 mg/m2/day depending on how heavily the patient has been treated prior to initiating this therapy. © 1993 Wiley‐Liss, Inc.
Cytogenetic abnormalities in a disseminated medulloblastoma
Authors: Stuart A. Graham , Pearson Andrew D. J. , Emslie John , Lennard Anne , Davison E. Valerie , Perry Robert H. , Crawford Peter J.
Published: February 2007

A 3‐year‐old girl developed central nervous system, bone and bone marrow metastases, and hypercalcaemia shortly after presentation with medulloblastoma. Cytogenetic studies of the involved bone marrow showed multiple abnormalities including iso(17q). This chromosome rearrangement has been reported in other cases of recurrent or disseminated medulloblastoma. More studies are required relating the karyotypes of medulloblastomas to long‐term outcome to determine if the presence of iso(17q) is a prognostic factor in this malignancy. © 1993 Wiley‐Liss, Inc.
Neuropeptide Y in neuroblastoma: Increased concentration in metastasis, release during surgery, and characterization of plasma and tumor extracts
Authors: Kogner Per , Björk Olle , Theodorsson Elvar
Published: February 2007

Five children with neural crest tumors (two ganglioneuromas, one ganglioneuroblastoma, and two neuroblastomas) were investigated regarding neuropeptide Y‐like immunoreactivity (NPY‐Ll) in tumor tissue and plasma at diagnosis and during surgery. Radioimmunoassay of extracted plasma revealed higher NPY‐Ll at diagnosis of neuroblastoma (640 and 230 pmol/L resp) than ganglioneuroblastoma or ganglioneuroma (74, 45, and 26 pmol/L resp). During surgery of neuroblastoma plasma NPY‐L2 increased two‐ to four‐fold while no peroperative increase was seen in the other children. NPY‐Ll was considerably higher in neuroblastoma tissue (220 pmol/g and 144 pmol/g) than in ganglioneuroblastoma (40.2 pmol/g), ganglioneuroma (0.6 and 4.4 pmol/g), or healthy adrenal tissue (5.5 pmol/g). The highest NPY‐Ll concentration was found in neuroblastoma metastasis, 3,091 pmol/g. Gel‐permeation chromatography of a neuro‐blastoma tumor showed that a majority of NPY‐Ll was representing intact NPY (NPY 1–36) while metastasis and plasma from the same child mainly contained smaller immunoreactive fragments. High concentrations of systemic NPY in neuroblastoma patients are of tumoral origin. Plasma levels of NPY and its fragments can be useful in diagnosing and monitoring neuroblastoma, and for early detection of relapse or metastatic disease. A possible involvement of NPY in neuroblastoma tumor growth and spread deserves further investigation. © 1993 Wiley‐Liss, Inc.
T‐Lymphocytes bearing the γδ T‐cell receptor in cutaneous lesions of langerhans' cell histiocytosis
Authors: Alaibac Mauro , Chu Anthony C.
Published: February 2007

The aim of this study was to investigate the regional importance of γδ T cells in cutaneous lesions of Langerhans' cell histiocytosis. Six cases of Langerhans' cell histiocytosis were investigated by immunohistochemical techniques (alkaline phosphatase‐antialkaline phosphatase complex and indirect immunoperoxidase). Increase of γδ T cells was observed in 3 cases of Langerhans' cell histiocytosis. In these cases up to 30% of CD3+ cells stained with an anti‐TCR γδ monoclonal antibodies and in two of them γδ T cells showed a marked epidermotropism. In the specimens of the remaining three cases γδ T cells were found in an overall percentage of 5% of CD3+ cells, but in two cases a significant increase of epidermal γδ T cells was observed. The finding of numerous γδ T cells in Langerhans' cell histiocytosis is provocative and supports the suggestion of a functional relationship between γδ T cells and LCH cells. © 1993 Wiley‐Liss, Inc.
Comparison of carboplatin pharmacokinetics between an anephric child and two children with normal renal function
Authors: Koren Gideon , Weitzman Sheila , Klein Julia , Moselhy Galina
Published: February 2007

Carboplatin, a promising second generation platinum compound, is an effective antitumor drug and appears to be less nephrotoxic than cisplatin. We report comparative pharmacokinetics of carboplatin in an anephric child and two children with normal renal function. All three children were infused with carboplatin over 4 hours, the anephric child receiving 100 mg/m2 (25% of the dose received by the other two children). This dose was well tolerated and 18 days later the anephric patient received a second course of carboplatin at 50% of the regular dose received by the control patients. Following this dose the girl experienced severe pancytopenia and recovered with the use of GM‐CSF, blood, and platelet transfusion. Blood samples were obtained at timed intervals for 24 hours in the control subjects and for 40 hours in the anephric patient. Plasma and plasma ultrafiltrates were analyzed for total and free platinum. The results show that elimination half‐life of total platinum was 13 hours in the children with normal renal function and 42 hours in the anephric child following the 100 mg/m2 dose. The elimination T1/2 of free platinum was 8 hours in a child with normal GFR and 32 hours in the anephric child. In the anephric child the clearance of ultrafiltrable platinum was 10% of the normal total body clearance. We suggest that, in children with renal insufficiency, the dose of platinum derivatives should be carefully chosen, proportionally to the degree of renal impairment. © 1993 Wiley‐Liss, Inc.
Anaplastic large cell lymphoma (Ki‐1+/CD30+) in childhood
Authors: Vecchi Vico , Burnelli Roberta , Pileri Stefano , Rosito Pasquale , Sabattini Elena , Civino Adele , Pericoli Roberta , Paolucci Guido
Published: February 2007

In 1985, Stein et al. (Blood 66:848–858) described a large cell lymphoma consisting of activated lymphoid elements, expressing the Reed‐Sternberg cell‐associated antigen Ki‐1 (CD30); this tumor has recently been included in the updated Kiel classification and has been termed anaplastic large cell lymphoma (ALCL).

This report concerns 13 patients with previously untreated ALCL who were admitted to the Pediatric Hematology and Oncology Department of Bologna University between January 1983 and December 1989. Ten cases were diagnosed as common type ALCL, 1 as Hodgkin's‐related ALCL and the remaining 2 as histiocyte‐rich ALCL/lymphohistiocytic T‐cell lymphoma. T‐cell markers were present in 85% of the cases, and B pheno‐type in the remaining 15%. About one‐half of the patients presented systemic symptoms; all but one showed more than one involved site, mostly an association of nodal and extranodal sites. All patients (1 in stage 1,7 in stage II, and 5 in stage III) were treated with a modified version of the LSA2‐L2 protocol. Survival and event‐free survival at 4 years were 100% and 62.9%, respectively. Two out of 3 relapsed patients presented a recurrence of disease when they were off‐therapy 24 and 36 months after first complete remission. Good response to salvage chemotherapy of all the relapsed patients and the long duration of the second complete remission were a distinctive characteristic of this neoplasm when compared to other histological subtypes. The clinical presentation, the tendency to develop late relapses and to achieve and maintain second remission easily suggest that ALCL is a high grade non‐Hodgkin's lymphoma, from the histological point of view, but is similar to Hodgkin's disease from the clinical point of view. This would confirm the hypothesis that Hodgkin's disease and ALCL represent a continuous spectrum of the same disease. © 1993 Wiley‐Liss, Inc.