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In this article the difficulties that face survivors of childhood cancer therapy are presented, and the late effects of such therapy, separated into nonmalignant and malignant late effects, are discussed according to organ system. Recommendations for monitoring the late effects are set forth. A table listing radiation-therapy site and chemotherapeutic agents and selected late effects that result from their use is provided. Finally, a brief recommendation regarding the establishment of a late-effects clinic is also presented. [ABSTRACT FROM AUTHOR]

Noonan Syndrome (NS) is a common genetic disease with multiple organ defects including bleeding disorders, which was last reviewed in 1997. Since then significant information has been acquired regarding bleeding problems in NS, specifically on the underlying genetics. Associations between mutated genes and bleeding disorders are reviewed along with prevalence and underlying etiologies. Between 50-89% of NS patients will have a bleeding disorder and since a significant number will require surgery it is important to identify which ones are at risk prior to their procedure. Recommendations regarding screening for bleeding disorders and their treatment are discussed., (Copyright © 2011 Wiley Periodicals, Inc.)

Thrombophilia can be defined as a predisposition to form clots inappropriately. Thrombotic events during infancy and childhood are increasingly recognized as a significant source of mortality and morbidity. The predisposition to form clots can arise from genetic factors, acquired changes in the clotting mechanism, or, more commonly, an interaction between genetic and acquired factors. Since the turn of the last century, there has been extensive research focusing on both the genetic and acquired causes of thrombophilia, with particular focus on clotting events in the venous circulation. This review describes clinically relevant aspects of genetic venous thrombophilia, which include well-established, lesser known, and suggested causes of inherited thrombophilias.

The potential mechanism underlying the rapid response to vitamin K replacement in acquired deficiency states is incompletely understood. To examine vitamin K metabolism, a 10-year-old boy with autoimmune enteropathy on oral vitamin K supplementation, who presented with profuse nosebleeds and calf tenderness, was evaluated. Laboratory analyses were consistent with severe vitamin K deficiency: vitamin K dependent protein (VKDP) levels < 5%, normal vitamin K epoxide level and depressed total prothrombin antigen (carboxylated and undercarboxyated forms). Intramuscular vitamin K (10 mg) was administered. Nine hours following therapy, VKDP levels corrected completely. Total prothrombin antigen increased indicating new prothrombin synthesis. However, the increase in the prothrombin-clotting assay far exceeded the increase in total prothrombin, supporting storage of undercarboxylated prothrombin in vitamin K deficiency states, with carboxylation and secretion after vitamin K replacement. Although this mechanism is known to occur in rodents, it has not been reported in humans. Our findings suggest a new potential mechanism of prothrombin metabolism in humans.

Wilms' tumor is the most common malignancy of the genitourinary tract in children but the occurrence of extrarenal Wilms' tumor is extremely rare. Extrarenal Wilms' tumor, which by definition excludes a primary tumor in the kidney, has been reported less than fifty times. The ultrastructural appearance of renal Wilms' tumor has been well documented, but the present report is believed to be the first description of the ultrastructural appearance of extrarenal Wilms' tumor. The authors report, for the first time, localization of intermediate filament proteins (vimentin and cytokeratin) and epithelial membrane antigen (EMA) by immunoelectron microscopy in this neoplasm. Demonstration of the coexpression of vimentin and cytokeratin within the same blastemal cell, as well as the identification of desmosomes in a cell with vimentin intermediate filaments, suggests a relationship between stroma, blastema, and epithelia similar to that proposed in renal Wilms' tumor.

Purpose: The combination of ifosfamide (I) and etoposide (E) was useful in salvaging patients with recurrent/resistant malignant solid tumors of childhood. Carboplatin (C), active against a number of pediatric cancers, was added to I and E to form a three-drug combination called ICE to improve the response rate., Patients and Methods: ICE, consisting of I 1.5 g/m2 plus E 100 mg/m2 i.v.q.d. x 3 plus C i.v. on day 3 only, was given in 21-28-day intervals. C was started at 300 mg/m2, and the dose was escalated in 25% increments, with three evaluable patients treated at each level., Results: Ninety-two patients were enrolled in this phase I/II study between July 1990 and April 1993. A total of 331 courses of ICE was administered. Median courses of ICE received were three (range, 1-16). The maximum tolerated dose (MTD) for C when used in combination was found to be 635 mg/m2. The response rate for ICE at the MTD for C was complete response (CR) 26% and CR + partial response (PR) 53%. The response was even better in those who received C at the MTD: 32% achieving a CR and 63% a CR + PR. Pancytopenia was the dose-limiting toxicity. Thirteen episodes of bacterial infection were reported, none fatal. Only one patient developed a Fanconi-like syndrome., Conclusion: The MTD of C when used with I and E was found to be 635 mg/m2. The overall CR + PR rate for all patients treated at all C dose levels was 53%. Best responses were seen in non-Hodgkin's lymphoma, neuroblastoma, soft tissue sarcomas, and Wilms' tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

A 13-year-old boy presented with cardiac tamponade. Echocardiography revealed a large mass extending from the right and left ventricles into a large pericardial effusion. Pathology confirmed the first reported case of a primary cardiac extraskeletal Ewing's sarcoma.

Rebound thymic hyperplasia following chemotherapy is well documented, usually occurring within the first year. A delayed presentation makes distinction from an anterior mediastinal mass problematic in view of the increased risk of a second primary malignancy in pediatric cancer survivors. An unusual case of rebound thymic hyperplasia is described, presenting five years after completion of chemotherapy for Wilms' tumors.

The clinical course of a two-year-old girl with acute lymphocytic leukemia (ALL) who inadvertently received intrathecal vincristine is presented. Despite aggressive treatment with parenteral folinic acid and extensive central nervous system washout, the outcome was fatal. The pharmacologic aspects of vincristine and folinic acid that may explain why treatment was unsuccessful, are reviewed.

In experiment 1, splenectomized mice exposed to 1 X 10(9) colony-forming units (cfu) of type 3 Streptococcus pneumoniae experienced no mortality when given 40,000 or 4,000 units of procaine penicillin IM starting 2 days before exposure and continuing for 4 days. On day 5, Bicillin was given once in the same dosages. In experiment 2, splenectomized mice exposed to 2.2 X 10(9) cfu were significantly protected by 400 but not 40 units of penicillin when compared to controls (P less than 0.005). In experiment 3, splenectomized mice exposed to 2.7 X 10(9) cfu were significantly protected when compared to controls if 4,000 units of procaine penicillin were given either 2 days postexposure for 2 days followed by 1 day of Bicillin in the same dosage or 4 days postexposure with the same schedule and dosage (P less than 0.005 and 0.01, respectively) but not 6 days postexposure.

A person with acute lymphocytic leukemia who developed Hodgkin disease is described. His family had an excessive number of members with cancer. This paper describes various laboratory investigations, which were done in an attempt to elucidate certain host factors that might have been responsible for the increased incidence of cancer in this family.

The risk of bacterial sepsis in the surgically or functionally asplenic host is reviewed. The lowest morbidity occurs in patients splenectomized because of trauma to the spleen; the highest morbidity occurs in patients splenectomized for thalassemia. There is approximately a 50% mortality associated with sepsis secondary to asplenia and the pneumococcus is responsible for over 50% of the cases. Normal spleen function and alteration in host defense occurring as a consequence of asplenia is discussed. Finally, alternatives to and indications for splenectomy as well as prophylactic measures are considered. It is concluded that, at the present time, antibiotic coverage for an indefinite period of time may be indicated for surgically or functionally asplenic patients.

CT-2 mouse monoclonal antibody to the E-rosette receptor was used with complement to deplete bone marrow of E-rosette-positive cells (T cells). Depletion of E-rosette-positive cells was complete and nontoxic to hematopoietic progenitor cells. Depletion of E-rosette-positive cells with CT-2 may decrease the severity of graft-versus-host disease following bone marrow transplantation and extend the application of bone marrow transplantation to those without HLA-identical donors.

HLA-matched bone marrow transplantation is an effective form of treatment for some patients with malignant osteopetrosis, a defect of osteoclast function. Following transplant, normal osteoclasts differentiate from donor-derived marrow stem cells and can function normally in some of these patients. For patients without an HLA-matched marrow donor, pharmacologic treatments have not yet proved effective. This article demonstrates that normal osteoclast function can be obtained following the transplantation of HLA-nonidentical marrow that has been purged of T lymphocytes in vitro.

The problem of postsplenectomy sepsis in adults with traumatic asplenia was reviewed and discussed. Alternatives to splenectomy should be considered when feasible, and pnemococcal vaccination and prophylactic antibiotics are necessary when splenectomy is unavoidable.

The clinical, hematologic, and cytogenetic features of ACML in children appear to be identical to Ph1-positive CML seen in adults. From our review of the literature, one could anticipate that a child with this condition would have a response to therapy and an anticipated survival similar to that seen in adults. This situation is quite different when one compares adults with ALL to children with the same disease. It has been suggested that Ph1-positive CML is an acquired, postzygotic abnormality induced by environmental agents. It is difficult to reconcile this hypothesis with the fact that this condition can be seen in infants as young as 5 months of age and the general belief that environmental carcinogens take many years to produce malignant changes in cells. Ph1-positive CML has been associated with atomic bomb exposure and it is of interest to note that two patients in the present series had received radiation. For both children and adults, bone marrow transplantation during the chronic phase is the most successful therapy if a suitable donor is available. Recently, successful marrow transplantation during the accelerated phase has also been reported. For patients without a suitable donor, control of the disease with either busulfan or hydroxyurea and attempts to induce a remission with chemotherapy during the accelerated or blast phase is the best current alternative. For patients whose blasts have lymphoid characteristics such as TdT activity, vincristine and prednisone may be successful. For those patients with a myeloid or mixed lymphoid-myeloid transformation, no chemotherapy regimen has been successful. An aggressive approach such as that described by Weinstein et al. for the treatment of acute nonlymphocytic leukemia might prove beneficial.

A patient with Burkitt's lymphoma is described who, on presentation, had a bone marrow aspirate which did not show abnormal cells. Cells from the bone marrow were cultured and an 8;14 chromosome translocation was identified. This finding allowed us to upgrade the stage of disease from III to IV with therapeutic as well as prognostic implications.

The problem of postsplenectomy sepsis in children who have had splenectomy secondary to trauma is reviewed. Alternatives to splenectomy should be considered when appropriate. Pneumococcal vaccination and the use of prophylactic antibiotics are necessary if splenectomy is unavoidable.

Most reported experimental studies concerning the effect of splenectomy in animals have shown enhanced mortality from pneumococci injected either intravenously or intraperitoneally. We have developed a laboratory model in which mice are exposed to type III Streptococcus pneumoniae via an aerosolized atmosphere, thus closely approximating the route of human infection with this organism. Ninety-one male Swiss mice (mean weight 26 g) were divided into three approximately equal groups of control, sham-operated, and splenectomized animals. Two weeks later they were exposed for 30 min in individualized compartments within a confined chamber to an aerosolized atmosphere producing a uniform challenge of 5.9 X 10(9) colony-forming units per ml of pneumococci. A statistically significant increase (P less than 0.01) in mortality was demonstrated in the splenectomized group over the pooled sham-operated and control groups. The animal model used in these investigations can be applied to the study of infections acquired by the respiratory route in numerous experimental designs.

A 7-year-old child developed slipped capital femoral epiphysis (SCFE) 3 years following pelvic irradiation for rhabdomyosarcoma. The reasons for this occurrence are discussed. This is the second report of radiation-induced SCFE and it is anticipated that more such cases are likely to occur.

We report a 15-month-old boy with acute myelomonocytic leukemia [French-American-British classification M4 (FAB-M4)] whose leukemic cells demonstrated a translocation 46,XY, t(9;11)(p24;q12) that has not been described previously.

In an infant with unexplained hyperbilirubinemia, abdominal mass and a fall in hematocrit, an IVP with total body opacification should be considered so that the diagnosis of adrenal hemorrhage, which is almost always a benign conditions, may be made. Follow-up abdominal films at 3 months of age may further substantiate the etiology by revealing calcifications in the involved areas.

Giant cell pneumonia associated with parainfluenza virus type 3 infection and chronic poliovirus type 2 meningoencephalomyelitis are documented in an infant with combined immunologic deficiency (Swiss type). Caution should be exercised in attributing cases of giant cell pneumonia to measles virus without serologic or virologic evidence.

Hemoglobin studies are presented on two children in whom electrophoretic analysis of hemolysates at alkaline pH initially suggested the diagnosis of hemoglobin SC disease. In both patients the course of the disease was unusually severe, blood smears contained irreversibly sickled cells, and crystal formation did not occur when red cells were incubated in 3 per cent sodium chloride solution. Each of these findings is inconsistent with the interpretation of the electrophoretic patterns. Family studies demonstrated that one of the patients had sickle cell anemia and was also a carrier of an alpha chain variant; citrate agar electrophoresis at pH 6.2 of the second child's hemolysate revealed that the "C-like" hemoglobin was not hemoglobin C. Tryptic peptide analyses of the nonhemoglobin S fractions showed that the first child has SS/GPhiladelphia disease and that the second child has SOArab disease. These observations emphasize the importance of integrating the clinical and hematologic data with the results of electrophoretic procedures in order to define precisely the hemoglobin abnormality in patients with sickling disorders.

The capillary microhematocrit test is widely used to screen pediatric patients for anemia. Recently, it has been suggested that this method produces spuriously elevated values compared with venous hematocrits measured by a Coulter electronic counter and might consequently fail to detect children who are truly anemic. To address this issue we studied 66 white children 9 months to 14 years of age whose capillary hematocrits were either below, equal to, or one or two points above the lower limit of normal for age. Venous specimens were obtained simultaneously with the capillary sample; hemoglobin, hematocrit, and mean corpuscular volume results were obtained using a Coulter electronic counter. Using published standards of venous hemoglobin, we determined the sensitivity, specificity, and predictive values of the capillary microhematocrit in this population of patients with low or borderline values. Twenty of the 66 patients had venous hemoglobin values less than the lower limit of normal. The sensitivity of the microhematocrit was 90.0%; the specificity was 43.5%. The predictive values for a normal (negative) hematocrit was 90.1%; the predictive value for a low (positive) hematocrit was 40.9%. We conclude that the microhematocrit method using capillary blood will miss very few patients with significantly low venous hemoglobin values and is thus an acceptable screening test for anemia. Because it does not require expensive equipment or special skill to obtain the specimen or perform the test, it is ideal for physicians' offices or nonhospital-based clinics.

Translocation between chromosomes 4 and 11 has been associated with an aggressive subtype of acute lymphoblastic leukemia. To date, 32 cases have been reported, 12 of which have been in infants. We report the 13th infantile case and the first associated with a somatic abnormality (septate uterus with double cervix and double vagina).

The efficacy of pneumococcal vaccine given after splenectomy lacks experimental validation. Adult CD-1 male mice that received type III pneumococcal capsular polysaccharide vaccine 1 microgram IP, 48 hours postsplenectomy and 7 days before challenge with aerosolized type III Streptococcus pneumoniae had a significantly higher mortality (96%) compared to immunized controls (64%) (p less than 0.002). The vaccine protected immunized sham-operated mice compared to unimmunized controls (p less than 0.015). Mice immunized 7 days before splenectomy were equally protected when compared to immunized sham-operated mice (p = NS). All deaths were secondary to culture-proven pneumococcal infection. These findings corroborate previous experimental and clinical studies demonstrating an impaired immunologic response and increased susceptibility to infection in asplenic individuals. Pneumococcal vaccines should be given before nonemergent splenectomy. Alternatives to splenectomy should be considered for patients with traumatized spleens where possible.

Fragile X [Fra(X)] syndrome is an example of a heritable fragility syndrome associated with mental retardation. It is characterized by a fragile site on the X chromosome at Xq27-28. There have recently been three reports of malignant solid tumors associated with Fra(X) syndrome. We describe the first case of a hematologic malignancy [T-cell acute lymphocytic leukemia (ALL)] in a patient with Fra(X) syndrome. The possibility of a predisposition to malignancy in Fra(X) is discussed.

A patient was diagnosed with gastric outlet obstruction (GOO) 17 months after the neonatal diagnosis of chronic granulomatous disease (CGD). Gastric outlet obstruction was the first clinical manifestation of CGD in this patient. Twenty-three percent of the 17 patients with GOO complicating CGD described in the literature were found to present with GOO before any other clinical manifestations of CGD. The diagnosis of GOO can be established by ultrasound and, if necessary, upper gastrointestinal roentgenogram or gastroscopy. A nonsurgical approach to management is suggested. The diagnosis of CGD should be considered in an infant or child who has GOO.

A national survey was conducted to determine the number of children with acute lymphocytic leukemia who have survived 5 years or longer in their second or subsequent remission. Seventy-two such patients were identified. The clinical and laboratory characteristics of these patients as well as their therapy are described. It is concluded that long-term second or subsequent remission may occur more frequently than previously appreciated.

A case of infectious mononucleosis initially seen as cold-induced acrocyanosis is discussed. Serological evaluation of the patient showed the presence of auto-anti-M and anti-I antibodies. Both the M and I antigens are normally found on RBCs. It is postulated that one or both of these antibodies were responsible for the acrocyanosis.