Hemolytic disease of the newborn caused by a new deletion of the entire beta-globin cluster.

We describe a new type of gamma delta beta-thalassemia in four generations of a family of Scotch-Irish descent. The proposita presented with hemolytic disease of the newborn, which was characterized by a microcytic anemia. Initial restriction endonuclease analysis of the DNA showed no grossly abnormal patterns, but studies of polymorphic restriction sites and gene dosage revealed an extensive deletion that removed all the beta- and beta-like globin genes from the affected chromosome. In situ hybridization of chromosome preparations with radioactive beta-globin gene probes showed that only one 11p homolog contained the beta-globin gene cluster in the affected family members.

Competitive polymerase chain reaction quantitation of c-erbA beta 1, c-erbA alpha 1, and c-erbA alpha 2 messenger ribonucleic acid levels in normal, heterozygous, and homozygous fibroblasts of kindred S with thyroid hormone resistance.

Mutations in the T3-binding domain of the thyroid hormone receptor gene c-erbA beta result in dominant negative proteins and thyroid hormone resistance syndromes. Variable clinical manifestations of resistance to thyroid hormones have been reported, including short stature and neuropsychological abnormalities. The molecular bases for heterogeneity of phenotype among and within kindreds have not been fully elucidated. Recent investigations have considered differential expression of mutant and wild-type beta 1-receptor alleles and the regulation thereof as a mechanism to explain differential sensitivity to thyroid hormones. We used reverse transcription-competitive polymerase chain reaction (PCR) to measure c-erbA beta 1, c-erbA alpha 1, and c-erbA alpha 2 mRNAs in skin fibroblasts cultured from normal subjects, heterozygotes, and a severely affected homozygous mutant of kindred S. The homozygous mutant of kindred S had severe growth and mental retardation. After reverse transcription with primers specific for each of the c-erbA mRNAs, first strand cDNAs were amplified by PCR using subtype-specific amplimers. Primer design allowed simultaneous detection of wild-type and mutant messages in heterozygous fibroblasts and showed an approximately 1:1 ratio of these mRNAs in three patients. Inclusion of competitive standard cDNAs of known concentration in the PCR reactions allowed quantitation of the absolute levels of the beta 1-, alpha 1-, and alpha 2 mRNAs by comparison of products on ethidium bromide-stained agarose gels. These studies showed no effect of the presence of the mutant beta 1-allele, as fibroblast RNA from normal subjects, heterozygotes, and the homozygote gave values of 56-184, 2.8-12, and 23-40 attomol/5 micrograms total RNA for beta 1-, alpha 1-, and alpha 2 mRNAs, respectively. We conclude that these sensitive methods allow the detection of molecular species present at levels as low as 10 molecules/cell, and that this potent dominant negative receptor does not disrupt c-erbA expression at the level of mRNA. The neuropsychological sequelae of the kindred S mutation are not due to relative overexpression of the mutant allele.

Systematization of primary histopathologic and fine-needle aspiration cytologic features and description of unusual histopathologic features of neuroblastic tumors: a report from the Pediatric Oncology Group.

On the basis of a detailed review of the primary histopathologic features of 239 cases and the fine-needle aspiration cytologic features of seven cases, a systematized schema of differentiation, progressive maturation and organization, and biologic behavior in neuroblastic tumors (NTs) is presented. The differentiation is of the gangliocytic and schwannian lineages. Maturation occurs in differentiating neuroblasts, leading to the formation of various stages of ganglion cells and Schwann cells. Organization is characterized by nesting pattern, rosette formation, parallel arrangement of neuropil, and alignment of Schwann cells along the neurites. According to this schema the NTs can be arranged in the following order: undifferentiated, poorly differentiated, and differentiating neuroblastoma; nodular, intermixed, and borderline ganglioneuroblastoma; and ganglioneuroma. Formulation of such a schema is helpful in gaining a better understanding of the complex pathologic features and in defining the criteria for various types of NTs. Therefore, the schema also would be helpful in achieving uniformity and reproducibility of the diagnosis of various types of NTs. Previously unreported features related to shape, size, nucleus, and cytoplasm of neuroblasts; secondary changes and patterns; changes in the fibrovascular septa; and other morphologic aspects of NTs and features (such as large tumor cells, karyorrhectic cells in fine-needle aspiration biopsy, tumor giant cells, anaplasia, and nesting pattern of tumor cells that have not been sufficiently emphasized) also are described. The importance of these previously unreported and insufficiently emphasized features relates to the histologic and cytologic diagnosis of NTs. For example, some of the features, such as starry sky appearance and spindle-shaped neuroblasts, may be misleading if seen in a small biopsy specimen. Others, such as tumor giant cells resembling ganglion cells and nesting pattern, will provide clues to the correct diagnosis. Some of the features, such as sclerosing pattern, hyalinization, and dense lymphoplasmacytic infiltration, may be related to the phenomenon of regression exhibited by neuroblastomas.

Pediatric fine-needle aspiration biopsy.

A total of 135 fine-needle aspiration (FNA) biopsies from varying sites were performed in 123 children (mean, 10.5 years; range, one day to 18 years) over a five-year period. One hundred thirty (96.3%) biopsy specimens were satisfactory for evaluation. Seventy-nine cases were nonneoplastic (60.8%); among these cases, a specific diagnosis of infectious disease was made in 17 (13.1%). A diagnosis of neoplastic disease was made in 50 (38.5%) cases, of which 14 (10.8%) were benign, 28 (21.5%) were malignant, and 8 (6.2%) were neoplasms of uncertain biologic potential. The sensitivity of pediatric FNA biopsies was 90.6%, specificity 100%, positive predictive value 100%, negative predictive value 94.7%, and efficiency of the test 96.5%. There were no false-positive diagnoses and there were four false-negative diagnoses, three of which involved aspirates of the central nervous system (CNS). Ancillary studies, including immunocytochemistry (20 cases), electron microscopic examination (18 cases), microbiologic culture (8 cases), cytogenetic studies (7 cases), and flow cytometry (3 cases), were performed on the aspirated material, enabling a more specific diagnosis or supplying additional information in many cases. Definitive diagnosis by FNA biopsy enabled radiation therapy and/or chemotherapy to be administered for unresectable malignant neoplasms, provided material for culture of infectious lesions, identified benign lesions not needing surgery, and aided the surgeon in planning the extent of surgery in resectable malignant neoplasms. These results support the greater use of FNA biopsy in the pediatric population.

Enhanced levels of wild-type versus mutant thyroid hormone receptor beta 1 messenger RNA in fibroblasts from heterozygotes of kindred S with thyroid hormone resistance.

Thyroid hormone resistance syndromes, which result from heterozygous mutations in the beta 1 thyroid hormone receptor gene, are sometimes associated with adult short stature, but more frequently with delayed bone age (BA). Primary fibroblasts from young children with both delayed BA and short stature from a kindred A have been reported to overexpress the mutant allele. However, in fibroblasts from affected members of two different kindreds with thyroid hormone resistance, S and Mf, there were equal levels of mutant and wild-type beta 1 mRNA. We investigated the ontogeny of differential allelic expression using competitive reverse transcription with PCR (RT-PCR) to measure relative mRNA levels for beta 1 and S receptor in very young affected children of kindred S. Total RNA was prepared from fibroblasts of two patients (ages 3-0.5/12 and 1-4/12 years) with delayed BA but normal growth curves. Using PCR amplimers that create an Mlu-1 site in wild-type but not mutant cDNA products from the competitive RT, we quantitated mRNA levels. Normal beta 1 mRNA was present at nearly twice the level of the mutant mRNA in cells from these patients. Relative expression of the c-erbA beta alleles thus appeared to be increased during this period of somatic growth. The relative overexpression of the normal allele potentially counteracted the potent dominant negative effect of the S receptor during early childhood ameliorating a deleterious effect on linear growth.

Fine needle aspiration biopsy cytology as an adjunct in the diagnosis of childhood sarcoidosis.

Fine needle aspiration biopsy cytology performed in three children with sarcoidosis expedited clinical investigation and diagnosis of their disease. Each patient had a different clinical presentation; in two of them lymphoma was part of the initial differential diagnosis. Aspiration cytology in all cases revealed collections of epithelioid histiocytes, and multinucleate foreign body-type giant cells, without accompanying necrosis or acute inflammation. A diagnosis of non-caseating granulomas consistent with sarcoidosis was made in all aspirates. Special stains for identification of organisms performed on the smears of one case, and culture of aspirate material from one case were negative. Subsequent serum angiotensin converting enzyme levels in all patients were elevated. Chest x-ray films in all patients showed mediastinal and hilar lymphadenopathy. One patient had an interstitial pulmonary infiltrate. All patients responded to steroid therapy. Fine needle aspiration biopsy can be a useful diagnostic tool in the evaluation of children with suspected sarcoidosis.

Chemotherapy of murine colorectal carcinoma with cisplatin and cisplatin plus 3'-deoxy-3'-azidothymidine.

In light of the discouraging results obtained with conventional chemotherapy of human colon cancer using 5-fluorouracil, we examined the effects of cis-diamminedichloroplatinum (cisplatin) alone and combined with 3'-deoxy-3'-azidothymidine (AZT) on chemotherapy of colorectal adenocarcinomas induced by dimethyldrazine in CD-1 mice. Thirteen weeks after a 20 week tumor induction period (15 mg/kg dimethylhydrazine weekly) groups of 19 mice were given either no therapy, or weekly cisplatin (6 mg/kg for 4 wks), AZT (400 mg/kg, wks 3 and 4), or cisplatin and AZT. Animals were autospied at death or after euthanasia on day 99 post initiation of therapy, their colons excised, fixed in buffered formalin and the number and volume of tumors measured. Cisplatin alone or with AZT decreased tumor size by 47-52%, and enhanced survival, leaving 55% of the mice alive at day 99 compared to 18% in controls. These therapeutic effects were amplified when animals were given chemotherapy during recovery from the effects of short-term dietary provision of the anti-carcinogenic steroid, dehydroepiandrosterone (DHEA). Our results suggest cisplatin is an effective chemotherapeutic agent against colon cancer in this murine model, and warrant further studies of its interaction with AZT and DHEA in enhancing this effect.

Chronic renal failure presenting as proximal muscle weakness in a child.

A 13-year old boy presented with a three-year history of slowly progressive proximal muscle weakness, particularly involving the lower extremities. Chronic renal failure was uncovered in the course of his evaluation. Urologic investigation showed small and poorly functioning kidneys with a BUN of 118 mg/dL and a creatinine of 10.7 mg/dL. There were no anomalies of the proximal or distal collecting systems or history suggestive of recurrent urinary tract infection. The neurologic examination revealed proximal muscle weakness primarily of the lower extremities and especially of the proximal musculature of the pelvic girdle. Nerve conduction studies were normal. The electromyogram (EMG) showed high-voltage polyphasic potentials consistent with neurogenic muscle disease. A biopsy of the right quadriceps muscle demonstrated type II muscle fiber atrophy with histochemical staining. The patient's clinical findings, EMG studies, and muscle biopsy were not specific for either neurogenic or myopathic disease. Following a period of home peritoneal dialysis and renal transplantation, there was significant clinical improvement of the muscle weakness.

Conventional versus modified morphologic criteria for ganglioneuroblastoma. A review of cases from the Pediatric Oncology Group.

BACKGROUND: Conventional criteria for ganglioneuroblastoma (GNB) do not require the presence of ganglioneuromatous component for pathologic diagnosis. This leads to inclusion of a mixed variety of neuroblastic tumors in the category of GNB. Therefore, GNB diagnosed by conventional criteria includes tumors showing more than 5% ganglion cells but no predominant ganglioneuromatous component, as well as tumors containing predominant ganglioneuromatous component. By previously described modified criteria, the former would be considered differentiating neuroblastoma (NB), and only the latter would be considered GNB. Data on Pediatric Oncology Group cases were analyzed to compare the prognostic subgroups of GNB diagnosed by conventional and modified criteria. The two prognostic subgroups (low risk and high risk) were defined on the basis of previously described prognostic differences between histologic grades of differentiating NBs and subtypes of GNB. METHODS: Pathologic data from cases of neuroblastic tumors registered on Pediatric Oncology Group NB protocols 8104 and 8441 were reviewed. The GNBs diagnosed by conventional and modified criteria were divided into low-risk and high-risk histology subgroups as follows: (1) GNB by conventional criteria: low-risk group, differentiating NB of histologic grades 1 and 2 and GNB of intermixed and borderline subtypes; high-risk group, differentiating NB of histologic grade 3 and GNB of nodular subtype; (2) GNB by modified criteria: low-risk group, GNB of intermixed and borderline subtypes; high-risk group, GNB of nodular subtype. RESULTS: The low- and high-risk subgroups of GNBs diagnosed by conventional (69 cases) and modified (36 cases) criteria showed statistically significant differences in survival (P = .03 and .01, respectively). However, from the histologic point of view, GNBs diagnosed by modified criteria form a more uniform morphologic group, which can be divided into low- and high-risk subgroups by a single set of morphologic criteria. In contrast, GNBs diagnosed by conventional criteria form a heterogeneous group, which requires two sets of criteria (ie, histologic grade and subtypes of GNB) for its classification into low- and high-risk subgroups. CONCLUSIONS: The modified criteria for GNB define a morphologically uniform group of neuroblastic tumors to which a single set of prognostic criteria can be applied. It is recommended that the term GNB should be used both clinically and pathologically to designate a distinctive subgroup of neuroblastic tumors, in contrast to the current use, which designates both NB and GNB.

Fine-needle aspiration cytology of Langerhans' cell histiocytosis (eosinophilic granuloma) of bone in children.

Fine-needle aspiration (FNA) cytology of three cases of Langerhans' cell histiocytosis (eosinophilic granuloma [EG]) of bone in children (mean age--8.3 yr; range 5-11 yr) is presented. Two patients presented with vertebral lesions and the third had a femoral mass. Cytomorphologic features of EG were seen in all cases including Langerhans' cell histiocytes having oval to reniform shape nuclei with nuclear grooving and abundant pale cytoplasm. The background showed a polymorphic population of cells including neutrophils, lymphocytes, foamy histiocytes, and osteoclasts. Moderate numbers of eosinophils were seen in two cases, while eosinophils were sparse in the third case. Ancillary immunocytochemical (ICC) studies performed on the aspirated material demonstrated positive staining for S-100 protein (all three cases) and T-6 antigen (one case). Ultrastructural examination (EM) performed in one case demonstrated characteristic Birbeck granules in the histiocytes. A specific cytologic diagnosis was made in all cases, enabling proper chemotherapy in one case, surgical excision in another and spontaneous resolution in the third case. Our experience demonstrates that FNA cytology can make a definitive diagnosis of EG, especially when coupled with ancillary studies such as ICC and EM on the aspirated material.

Cytomorphology of familial hemophagocytic syndrome.

Familial hemophagocytic syndrome (FHS) is a rare, fatal disorder of childhood demonstrating failure to thrive, fever, hepatosplenomegaly (HSM), recurrent infections, pancytopenia, and histologically, the infiltration of reticuloendothelial organs by benign-appearing histiocytes demonstrating hemophagocytosis. We report two fatal cases of FHS including a 3 year-old female who underwent fine-needle aspiration (FNA) biopsy of the liver in the initial workup of the disease (case 1) and an 8 month-old boy with ascites and HSM having peritoneal fluid cytology submitted as the first specimen for morphologic examination (case 2). In case 1, the FNA cytologic findings included benign hepatocytes and scattered mature and reactive lymphocytes and histiocytes. The histiocytes demonstrated fine to coarse cytoplasmic vacuoles and erythrophagocytosis. The diagnosis was confirmed at autopsy which revealed extensive lymphohistiocytic infiltrates in various organs including the central nervous system. In case 2, the peritoneal fluid cytology specimen contained numerous atypical and degenerating mononuclear lymphoreticular cells which were dispersed as a single cell suspension admixed with infrequent mesothelial elements; hemophagocytosis was not appreciated. Subsequent liver biopsy revealed portal tracts and sinusoids infiltrated by benign but atypical histiocytes with hemophagocytosis. Bone marrow examination and then autopsy confirmed the diagnosis of FHS. A panel of immunocytochemical studies was performed in the first case which was an aid in confirming the diagnosis of FHS and ultrastructural examination of the second case revealed well-developed erythrophagocytosis. Both patients had siblings who died of FHS. Although not diagnostic, cytomorphology may suggest FHS.

The utility of ancillary studies in pediatric FNA cytology.

We evaluated the diagnostic contribution of adjunct studies performed on aspirated material in the work-up of pediatric fine-needle aspiration (FNA) biopsies. Ancillary studies were performed on 54 of 136 (39.7%) pediatric FNA biopsies during a 5-year period. In 23 (16.9%) cases, immunocytochemical (ICC) studies, consisting of immunoperoxidase staining of direct smears and/or cell blocks or flow cytometric immunophenotyping, were performed. The studies were adequate in 14 cases (60.9%), suboptimal in five cases (21.7%), and inadequate in four cases (17.4%). Of the adequate and suboptimal cases, the ICC data helped to narrow the differential diagnosis or classify the disease process in eight cases (42.1%), confirmed cytologic impression in nine cases (47.4%), and gave contradictory results in two cases (10.5%). Adequate material for electron microscopy (EM) was obtained in 14/19 cases (73.7%). Ultrastructural studies were diagnostic, or helped classify the disease process in five cases (35.7%), confirmed the cytologic impression in four cases (28.6%), helped exclude diagnostic considerations in three cases (21.4%), and were judged to be non-contributory in two cases (14.3%). Cytogenetic studies revealed six of seven cases (all neoplasms) to have abnormal karyotypes. Special stains for organisms performed on smears from 25 cases including Ziehl-Neelsen, Gomori methenamine silver (GMS), Gram, and Warthin-Starry (WS) were negative except for 1/16 GMS and 4/9 Gram stains. In summary, we found that with appropriate case selection, ancillary studies performed on aspirated material can provide useful information in pediatric FNA cytology.

Role of immunocytochemistry, electron microscopy, and DNA analysis in fine-needle aspiration biopsy diagnosis of Wilms' tumor.

We reviewed the cytologic features and results of ancillary studies in eight fine-needle aspiration biopsies (FNAB) performed by posterior approach in 8 patients with unresectable Wilms' tumor (WT). Chemotherapy was given following the FNAB diagnosis of WT, which was confirmed subsequently by histologic examination of surgically resected specimens. Indications for FNAB included: unresectable tumor, bilateral disease, initial presentation with metastatic disease, uncertainty regarding tumor site, and documentation of recurrence. Cytologic examination revealed blastemal cells (8/8 aspirates), spindle cells (3/8 aspirates), and epithelial differentiation or tubules (3/8 aspirates). There was no cytologic evidence of anaplasia in any of the cases. Immunocytochemical studies on cell blocks and/or smears showed cytokeratin positivity in 5/8 and vimentin positivity in 5/5 of the aspirates in which these studies were performed. Focal positivity for neuron-specific enolase (NSE) was seen in 3/3 aspirates. Stains for actin and leukocyte-common antigen were negative (0/3 and 0/2 aspirates, respectively). DNA ploidy analysis of the aspiration material by flow cytometry revealed near-diploid populations in three aspirates. Electron microscopic findings helpful for diagnosis included: cell junctions, microvilli, flocculent basement membrane-like material, cilia, autophagolysosomes, and lack of neuroectodermal differentiation. Diagnostic morphologic pitfalls for an incorrect diagnosis of neuroblastoma included nuclear molding (all aspirates), pseudorosette formation (one aspirate), and focal NSE positivity (3/3 aspirates). None of the tumors showed anaplasia on histologic examination. Cytologic recognition of the triphasic cellular components of WT (blastemal cells, spindle cells, and epithelial cells) can be helpful for a correct diagnosis; however, in 5/8 aspirates in this study, only the blastemal component was present. In these cases, immunocytochemical stains and electron microscopy proved useful in arriving at a correct FNAB diagnosis of WT. However, NSE positivity can be a pitfall for a diagnosis of neuroblastoma if the radiologic, clinical, and other cytologic features are not clearly delineated. Presence of cytokeratin and vimentin positivity would be helpful in the diagnosis of WT in such instances.

Fine needle aspiration cytology of pancreatoblastoma with immunocytochemical and ultrastructural studies.

The cytologic features of a pancreatoblastoma (infantile adenocarcinoma), a rare pancreatic neoplasm of childhood, are described. Fine needle aspiration (FNA) under ultrasound guidance produced a hypercellular specimen consisting of numerous oval-to-cuboidal cells that had a moderate amount of granular cytoplasm. Spindle-shaped, elongated and triangular-shaped epithelial cells were also seen, along with smaller cells that had a higher nuclear/cytoplasmic ratio and a denser cytoplasm. In addition, there were abundant fragments of stroma present, including some surrounded by epithelial cells. Immunoperoxidase studies performed on the aspirated material revealed positive staining of the epithelial cells for cytokeratin (AE1/3), including high and low molecular weight cytokeratin, carcinoembryonic antigen, neuron-specific enolase and alpha-1-antitrypsin. Ultrastructural examination demonstrated epithelial cells containing either large electron-dense zymogen granules in the range of 400 nm to 600 nm or small dense neuroendocrine granules measuring from 100 nm to 200 nm. This finding, in concert with the immunocytochemical studies, supported a "blastemal" cell origin with bidirectional differentiation for this unusual pancreatic neoplasm and enabled a specific preoperative diagnosis of pancreatoblastoma to be made. The differential diagnosis of pancreatoblastoma from other pediatric neoplasms involving the pancreas, including neuroendocrine tumors and neoplasms of acinar cell derivation, is presented. We believe that the FNA cytologic findings can lead to a correct diagnosis of pancreatoblastoma, especially when coupled with immunocytochemical and ultrastructural studies performed on the aspirated material.

Fine needle aspiration cytology of neuroblastoma, including peripheral neuroectodermal tumor, with immunocytochemical and ultrastructural confirmation.

Eleven fine needle aspiration (FNA) biopsies were performed on seven children with neuroblastoma, including one patient with a congenital neuroblastoma and another with a peripheral neuroblastoma of the thoracopulmonary region. FNA cytology made the primary diagnosis of neuroblastoma in four of the seven cases. The other biopsies documented local recurrences and metastases to liver, lymph nodes, orbit and breast. The cytologic features included varying numbers of small primitive cells with scanty cytoplasm, poorly to well-formed pseudorosettes, cell processes, a fibrillary matrix and multinucleated ganglion cells. Five of the seven patients had electron microscopic (EM) examination of the FNA specimen, which in all cases confirmed the diagnosis. Batteries of immunoperoxidase stains were performed on all 11 aspirates with variable results. Staining for neuron-specific enolase was positive in four of the five neoplasms tested, although strongly positive in only three of the cases. Staining for neurofilament markers was positive in only two of five tumors. Studies for cytokeratin markers (AE1/3), low-molecular-weight cytokeratin (35BH11), hematopoietic markers (T29/33), immunoglobulin light chains and myoglobin were negative. One case was positive for vimentin. This study attests to the value of FNA cytology in suggesting a correct diagnosis of either primary, recurrent or metastatic neuroblastoma in children. Selective use of immunoperoxidase stains and EM on the aspirates may be of value.

Fine needle aspiration cytology of primitive neuroectodermal tumors. A report of these cases.

Primitive neuroectodermal tumor (PNET) is a small round cell malignancy arising in soft tissue and bone, predominantly in older children and adolescents. We report the cytomorphologic features and findings of ancillary studies of eight fine needle aspiration (FNA) biopsies from three patients (7-year-old male, 12-year-old female, 9-year-old female). Two of the biopsies suggested the initial diagnosis of PNET of the chest wall, while the remaining six documented recurrent or metastatic disease. In one of these cases the primary diagnosis made by FNA biopsy enabled the pediatric oncologists to give specific therapy for the unresectable tumor and achieve remission. Local recurrences included the chest wall (two cases), pleura (one case) and pericardium (one case), while metastatic disease involved the supraclavicular lymph node and breast. All the cases consisted of small malignant cells with a high nuclear/cytoplasmic ratio and hyperchromatic nuclei without prominent nucleoli. Homer Wright rosettes were seen in only two of the aspirates, and neuropil and ganglion cells were not present. Ancillary studies, including electron microscopy (two cases), immunocytochemistry (four aspirates from two cases) and cytogenetics (11/22 translocation, one case) performed on the aspirated material were aids in making a specific diagnosis and excluded other small round cell tumors of childhood, such as malignant lymphoma, rhabdomyosarcoma and Ewing's sarcoma. The differential diagnosis between PNET and neuroblastoma can be difficult on the basis of an FNA biopsy alone, although light microscopic morphologic differences exist. Clinical features (e.g., age, primary site, metastatic patterns), catecholamine levels, electron microscopy and cytogenetics are necessary in establishing the correct diagnosis.

Patient-controlled analgesia pain management for children with sickle cell disease.

Painful episodes account for approximately 60% of all hospitalizations of children and adults with sickle cell disease. Limited information is available on managing pain in these individuals. Increasing attention is being focused on new ways to promote pain control. A new, safe, and effective way to achieve pain relief and control is through patient-controlled analgesia (PCA). This report describes our experiences using PCA in children with sickle cell disease. Over an 18-month period, 61 children considered to have severe or intolerable pain (unassociated with infection or organ-related disease) were treated with PCA. The records of 10 children selected randomly from the 61 were examined and compared with those of 10 children also randomly selected who had been treated using a conventional, fixed-schedule approach. Time in the hospital, time until tapering of narcotic, time until pain relief, and duration of parenteral narcotic therapy were similar between the two groups. Total dose of intravenous narcotic therapy (meperidine equivalent in mg/kg) was greater in the PCA group. Five of 10 children using PCA, however, experienced relief within 6 hours compared with 1 of 10 children in the non-PCA group (P = .052). Patients, families, and hospital staff expressed satisfaction and preferred PCA to conventional management when offered a choice.

Biochemical modulation of 5-fluoropyrimidine toxicity by dehydroepiandrosterone in human colonic adenocarcinoma cells.

Exposure to dehydroepiandrosterone caused a concentration-dependent accumulation of HT-29 human colonic adenocarcinoma cells in S-phase and sensitization toward the cytotoxic effects of fluorouracil deoxyriboside but not 5-fluorouracil. These effects were synergistic at all tested concentrations of dehydroepiandrosterone (25-100 microM) and fluorouracil deoxyriboside (0.1-10 microM). Sterilization of cultures occurred at a fluorouracil deoxyriboside concentration of 1.0 microM in the presence of 50 microM dehydroepiandrosterone, while sterilization in the absence of dehydroepiandrosterone required nearly a 10-fold higher concentration of drug. Even in HT-29 cells selected for the ability to grow in 50 microM dehydroepiandrosterone, a synergistic response with fluorouracil deoxyriboside was observed. Double label experiments to examine the relative rates of incorporation of [14C]thymidine and [3H]uracil into DNA thymidine indicated that dehydroepiandrosterone exposure preferentially enhanced the de novo pathway for thymidylate synthesis, suggesting that this shift may have contributed to the observed synergism with fluorouracil deoxyriboside. Compared to controls, however, the salvage pathway for thymidylate biosynthesis was also stimulated following exposure to dehydroepiandrosterone. These results and the non-toxic nature of this naturally occurring steroid suggest that dehydroepiandrosterone may be useful as a biochemical modulator of fluorouracil deoxyriboside and, perhaps, other nucleoside analogs in cancer treatment.

Successful chemotherapy for childhood metastatic embryonal cell carcinoma of the testicle: a preliminary report.

A child with widespread metastases successfully treated with chemotherapy alone is described. One course of combination chemotherapy using cis-platinum, vinblastine, and bleomycin produced disappearance of multiple pulmonary metastatic lesions. Four courses of therapy produced shrinkage and tumor sterilization of an abdominal mass. Twenty-six months after initiation of chemotherapy the patient is well, off of all therapy for fourteen months, and free of disease or drug related complication with normal creatinine clearance and alphafetoprotein determinations. The published adult experience demonstrates that this therapy is extremely effective for the treatment of metastatic embryonal cell carcinoma of the testis in young adults, and our case report extends this favorable experience into childhood. Toxicity is substantial, but justifiable considering the poor outlook associated with widespread metastatic disease. Collectively, the reviewed data suggest that further trials of this type of therapy are indicated in children.

Bilateral Wilms tumor presenting with acute renal failure and clinical findings mimicking cardiac failure.

A six-year-old girl presented with clinical signs and symptoms of right-sided heart failure. Cardiac catheterization demonstrated filling defects in both pulmonary arteries felt to represent metastatic lesions or thromboemboli. Intravenous pyelogram revealed bilateral renal masses and intrarenal obstruction. Acute renal failure was unresponsive to standard therapy. An open renal biopsy revealed Wilms tumor with favorable histology. Aggressive chemotherapy and irradiation were undertaken and renal function returned. This case adds to the heterogeneity of presentations described for Wilms tumor, and review of the literature reveals no other cases with similar presenting signs.