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Biomedical subjects

W A Smithson

Publications and source records attributed to W A Smithson.

At least 19 recordsLinked to original sources
PubMed2002

Prognostic variables in newly diagnosed children and adolescents with acute myeloid leukemia: Children's Cancer Group Study 213.

The objective of this study was to identify biologic parameters that were associated with either exceptionally good or poor outcome in childhood acute myeloid leukemia (AML). Among the children with AML who entered Children's Cancer Group trial 213, 498 patients without Down syndrome or acute promyelocytic leukemia (APL) comprise the basis for this report. Univariate comparisons of the proportion of patients attaining complete remission after induction (CR) indicate that, at diagnosis, male gender, low platelet count (< or =20 000/microl), hepatomegaly, myelodysplastic syndrome (MDS), French-American- British (FAB) category M5, high (>15%) bone marrow (BM) blasts on day 14 of the first course of induction, and +8 are associated with lower CR rates, while abnormal 16 is associated with a higher CR rate. Multivariate analysis suggests high platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 are independent prognostic factors associated with better CR. Univariate analysis demonstrated a significant favorable relationship between platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, low percentage of BM blasts (< or =15%), and abnormal 16 with overall survival. Absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 were determined to be independent prognostic factors associated with better survival.

Acute Disease↗
PubMed2001

Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study.

PURPOSE: Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a retrospective cohort of 20,227 5-year survivors. PATIENTS AND METHODS: Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources and coded and categorized as recurrent disease, sequelae of cancer treatment, or non-cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data. RESULTS: The cohort, including 208,947 person-years of follow-up, demonstrated a 10.8-fold excess in overall mortality (95% confidence interval, 10.3 to 11.3). Risk of death was statistically significantly higher in females (SMR = 18.2), individuals diagnosed with cancer before the age of 5 years (SMR = 14.0), and those with an initial diagnosis of leukemia (SMR = 15.5) or CNS tumor (SMR = 15.7). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 67% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 19.4), along with cardiac (SMR = 8.2), pulmonary (SMR = 9.2), and other causes (SMR = 3.3). Treatment-related associations were present for subsequent cancer mortality (radiation, alkylating agents, epipodophyllotoxins), cardiac mortality (chest irradiation, bleomycin), and other deaths (radiation, anthracyclines). No excess mortality was observed for external causes (SMR = 0.8). CONCLUSION: While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.

Adolescent↗
PubMed1999

Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL, Saccharomyces cerevisiae SGS1 and Schizosaccharomyces pombe rqh1. We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.

Adenosine Triphosphatases↗
PubMed1999

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

Adolescent↗
PubMed1999

Aerosol granulocyte macrophage-colony stimulating factor: a low toxicity, lung-specific biological therapy in patients with lung metastases.

The objective was to study the feasibility of granulocyte macrophage-colony stimulating factor (GM-CSF) delivery to the lung using an aerosol in humans. A Phase I dose escalation study provided GM-CSF at three dose levels as a twice-a-day (BID) x 7 days schedule. Pulmonary functions were monitored using a remote spirometry device. Blood counts were checked at the beginning and end of each week of GM-CSF nebulization. If no toxicity was encountered, patients rested for 7 days and then were treated at the next dose level. Six of seven patients were successfully dose escalated from 60 microg/dose BID x 7 days, to 120 microg/dose BID x 7 days, then 240 microg/dose BID x 7 days. No toxicity was seen. Comparison of day 0 and day 7 blood leukocyte counts showed no significant increases in either leukocyte numbers or percentage of neutrophils. Pulmonary functions test changes were minor. No significant change in forced vital capacity, FEV1, peak flow, or FEF 25-75 related to either time or dose level was observed. One patient's lung metastases progressed. The other five patients received an additional 2-6 months of intermittent aerosol GM-CSF at dose level 3 without side effects. One patient with Ewing's sarcoma has a complete response, and a patient with melanoma had a partial response; the other three had stabilization of pulmonary metastases for 2-6 months. Aerosol delivery of GM-CSF is feasible, safe, and possibly effective. Aerosol cytokine delivery may achieve effective immunological activation against cancer in the lung and is worthy of further study.

Administration, Inhalation↗
PubMed1997

Intraoperative electron irradiation in the management of pediatric malignancies.

BACKGROUND: External beam irradiation (PBRT), especially in children, is limited by the radiosensitivity of normal tissues. Local control remains a problem in abdominopelvic childhood malignancies. Intraoperative electron irradiation (IOERT) has the potential to increase the dose to the tumor, thereby improving local control, without increasing treatment morbidity. METHODS: Between February 1983 and October 1990, 11 children received IOERT as part of a multidisciplinary treatment program for locally advanced primary or recurrent abdominopelvic malignancies. The 7 boys and 4 girls ranged in age from 2-18 years. Tumor histologies included four neuroblastomas, two desmoid tumors, and one each of the following: embryonal rhabdomyosarcoma, synovial cell sarcoma, neurofibrosarcoma, malignant fibrous histiocytoma, and paraganglioma. Single radiation doses of 10-25 grays were delivered using 6-15-megaelectron volt electron beams to 1-5 IOERT fields. All patients also underwent EBRT and six received chemotherapy. RESULTS: Eight patients (73%) were alive and disease free at a median follow-up of 99 months (range, 37-126 months). All eight patients who underwent gross total resection were locally controlled. Three patients required surgical intervention for IOERT-related complications and two patients developed neuropathies. CONCLUSIONS: IOERT as part of a multidisciplinary treatment approach in patients with locally advanced pediatric malignancies appears to enhance local control in those patients in whom a gross total resection is possible. The long term survival rate was encouraging. Further study, with a larger number of patients, appears warranted to more carefully delineate the efficacy and tolerance of IOERT in the pediatric population.

Abdominal Neoplasms↗
PubMed1996

A family inheriting different subtypes of acute myelogenous leukemia.

Rare inherited cancer syndromes have proven invaluable for the identification of genes involved in the more frequent corresponding noninherited cases. We report on a family with an adult onset, incompletely penetrant, autosomal dominant syndrome of myelodysplasia and acute myelogenous leukemia, affecting at least eight, and probably ten, individuals from three generations. The patients have developed leukemias differing in morphologic subtype, tumor cytogenetics, and abruptness of presentation. Some have presented with acute onset and others with protracted myelodysplasia. This family does not have an unusual incidence of other malignancies; however, one person at 50% risk of inheriting this gene developed atypical mycobacterium infection in the absence of leukemia, but also without appreciable risk factors for acquired deficiencies in cellular immunity. Features common to affected family members, including the individual with mycobacterium infection, are the early presence in the bone marrow of red cell and platelet maturation defects. A search for mutations in diseased marrows fails to detect abnormalities of p53 or N-ras. Two of the affected family members, third degree relatives, have co-inherited a constitutional chromosomal banding variation of 9p21-22, potentially suggesting linkage to this locus. The variable penetrance and expressivity of this syndrome support a multistep model of leukemia evolution, in which the gene defined by this family's syndrome is the signal step.

Adolescent↗
PubMed1996

Rothmund-Thomson syndrome in siblings: evidence for acquired in vivo mosaicism.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by skin abnormalities that appear in infancy, skeletal abnormalities, juvenile cataracts and other manifestations of premature aging, and a predisposition to malignancy. The diagnosis is made on clinical grounds as no consistent laboratory test has been identified. Chromosome studies have been reported for only three patients with RTS and in two of these three, trisomy 8 mosaicism was found. We performed a variety of cytogenetic and molecular genetic studies on two siblings with RTS and on their phenotypically normal parents. Two chromosomally abnormal clones involving either trisomy 8 or i(8q) were found in both patients with RTS. These clones were present in vivo, as they were seen in interphase buccal smears and lymphocytes from unstimulated preparations using both conventional cytogenetic studies and fluorescence in situ hybridization (FISH) with a centromere probe for chromosome 8. These results suggest that RTS is associated with in vivo clonal chromosomal rearrangements causing an acquired somatic mosaicism.

Adolescent↗
PubMed1996

Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2.

Prompt and appropriate management measures are critical in order to achieve a favorable outcome after a major overdose of intrathecally (IT) administered methotrexate (MTX). Published information available to guide clinicians in the immediate management of this medical emergency is scant. Herein we describe a 6-year-old boy with acute lymphoblastic leukemia who received an inadvertent overdose of 600 mg of IT administered MTX instead of the intended dose of 12 mg. Severe acute neurotoxicity developed rapidly. Lumbar puncture and drainage of 15 mL of cerebrospinal fluid 2 hours after administration resulted in removal of 32% of the administered drug. Ventriculolumbar perfusion with 240 mL of warmed isotonic saline through ventricular and lumbar catheters for 3 hours resulted in removal of a total of 90% of the drug within 8 1/2 hours after administration. IT administration of 2,000 U of carboxypeptidase G2 (CPDG2), an enzyme that inactivates MTX, resulted in a further 150-fold reduction in cerebrospinal fluid MTX concentration. The patient experienced complete recovery. To our knowledge, this is the first reported case of the use of IT instillation of CPDG2 for the treatment of an overdose of IT administered MTX in a human, and it is only the second reported favorable outcome after an IT overdose of more than 500 mg of MTX. Minor IT overdoses of MTX can be managed by immediate lumbar drainage alone. Major overdoses may also necessitate prompt ventriculolumbar perfusion, IT instillation of CPDG2, and further supportive measures for a successful outcome after this infrequent but potentially catastrophic event.

Antimetabolites, Antineoplastic↗
PubMed1996

Ewing's sarcoma of the proximal femur.

The cases of 16 patients with Ewing's sarcoma of the proximal femur treated in the era of multiagent chemotherapy were reviewed, with emphasis on the mechanical problem of tumor involvement in this structurally demanding site. Fourteen patients received chemotherapy and local radiotherapy as the initial primary treatment. One patient had chemotherapy and radiotherapy, followed by wide local resection. One patient had amputation, followed by chemotherapy, for pathologic fracture and extensive soft tissue involvement at presentation. Two local recurrences occurred. Excluding the 2 patients whose femurs were fixed prophylactically, the pathologic fracture rate was 79%. In addition, by excluding the 2 patients who died before fracture, the pathologic fracture rate was 92%. Nonunion occurred in 5 (71%) of the 7 pathologic fractures not treated by resection and required as many as 5 additional surgical procedures to obtain union. At latest followup evaluation (average, 6.3 years), 10 patients had no evidence of disease, 1 was alive with disease, and 5 had died of their disease. Options for management should include primary resection and reconstruction or prophylactic internal fixation after completion of chemotherapy plus or minus radiotherapy.

Adolescent↗
PubMed1995

Asplenia in two father-son pairs.

We report on two father-son pairs with isolated nonsyndromal asplenia. This may represent autosomal dominant inheritance of a mutation in a gene involved with spleen development and determination of laterality. The incidence of hereditary isolated asplenia is unknown; therefore, screening for asplenia in first degree relatives of individuals with (poly)asplenia should be considered.

Child↗
PubMed1994

Metastatic testicular choriocarcinoma and secondary hyperthyroidism: case report and review of the literature.

We report on a 16-year-old boy with metastatic testicular choriocarcinoma, increased levels of human chorionic gonadotropin and profound hyperthyroidism bordering on thyroid storm. Hyperthyroidism was secondary to elevated human chorionic gonadotropin, with a thyroid-stimulating hormone effect. Management consisted of suppressive therapy for the symptoms of thyrotoxicosis until chemotherapy achieved control of the primary tumor and elevated levels of human chorionic gonadotropin. Review of the urological literature demonstrated a lack of recognition of this potentially serious paraneoplastic syndrome and its management.

Adolescent↗
PubMed1994

Vancouver hybrid: preliminary experience in the treatment of Hodgkin's disease in childhood and adolescence.

OBJECTIVE: To describe our preliminary experience with 19 young patients with newly diagnosed Hodgkin's disease who received the Vancouver hybrid chemotherapeutic regimen. DESIGN: We summarized the characteristics of our 19 study patients, the treatment administered (between June 1988 and June 1992), and the outcome. RESULTS: The Vancouver hybrid, which consists of mechlorethamine, vincristine sulfate (Oncovin), procarbazine hydrochloride, prednisone, doxorubicin hydrochloride (Adriamycin), bleomycin, and vinblastine sulfate (MOPP/ABV), was based on the hypothesis of preventing drug resistance by early introduction and alternation of all active agents and was aimed at decreasing the severity and frequency of treatment-related complications. Of our 19 patients with Hodgkin's disease (age range, 6 to 20 years) treated with this regimen, 2 had clinical stage I disease, 10 had stage II, 6 had stage III, and 1 had stage IV. Only two patients had systemic symptoms, and nodular sclerosis was the most common histologic feature. Patients were given four to eight cycles of chemotherapy, depending on the clinical stage of disease. In addition, 10 patients received irradiation, including 6 of 9 patients with bulky disease. In all patients, complete remission was achieved. After a median follow-up of 3.3 years, only two patients had had a relapse; both underwent autologous bone marrow transplantation and were alive and well with no evidence of disease at last follow-up. The treatment was well tolerated, and delivery of treatment was excellent. The only severe toxicity was myelosuppression; 8 patients experienced a total of 15 episodes of fever and neutropenia that necessitated hospitalization and antibiotic therapy, but no systemic infections were confirmed during 104 cycles of therapy. CONCLUSION: The MOPP/ABV hybrid is an effective and well-tolerated therapy in most young patients with Hodgkin's disease. Long-term monitoring is needed to evaluate late effects.

Adolescent↗
PubMed1992

Cisplatin-based chemotherapy in primary central nervous system germ cell tumors.

We report a retrospective review of our experience with cisplatin-based chemotherapy in eight patients (ages 9-44 years) with histologically confirmed primary central nervous system germ cell tumors. Five patients received chemotherapy as the primary treatment, radiation therapy being administered either at completion of chemotherapy or between chemotherapy courses. Three patients received cisplatin-based chemotherapy for recurrent disease after prior radiation therapy and/or surgery. Four of five patients treated with chemotherapy at diagnosis are in complete remission at 11-14 months from diagnosis. The remaining patient twice achieved complete remission prior to dying of progressive disease 16 months after diagnosis. Two of three patients treated with chemotherapy for recurrent disease are in complete remission at 20 and 26 months; the remaining patient deteriorated after the first cycle of chemotherapy and expired six months thereafter. Overall, of seven patients evaluable for response, five achieved complete remission with chemotherapy alone, and two with chemotherapy and radiation therapy. Our results confirm previous reports of high complete remission rates utilizing cisplatin-based chemotherapy in conjunction with radiation therapy. Prospective evaluation of cisplatin-based chemotherapy followed by radiation therapy is warranted.

Adolescent↗
PubMed1992

Phase II trial of indicine N-oxide in relapsed acute leukemia of childhood. A report from the Childrens Cancer Study Group.

We treated 31 children with acute lymphoblastic leukemia (ALL), 14 children with acute nonlymphoblastic leukemia (ANLL) in relapse, and 1 child with chronic myelogenous leukemia (CML) in blast crisis (CALLA negative) with indicine N-oxide in a Phase II study. The efficacy and toxicity of the drug were assessed at two dose levels: 2,000 mg/m2/day for 5 consecutive days (14 patients) and 2,500 mg/m2/day for 5 consecutive days (17 patients). One patient with ALL at each dose level achieved a complete response (CR) lasting 6 months and 1 month, respectively. The patient with CML achieved a partial response lasting 4 months. None of the patients with ANLL achieved a CR. Hepatotoxicity was mild (grade 1 or 2) in 63% and moderate (grade 3) in 9% of mild (grade 1 or 2) in 63% and moderate (grade 3) in 9% of patients; 3 patients (9%) experienced severe hepatotoxicity. Although indicine N-oxide has some antileukemic activity in ALL and is safe at the doses used in this study, the antileukemic activity is significantly less at these two doses than at greater than or equal to 3,000 mg/m2/days for 5 consecutive days. Unfortunately, when the higher doses are administered to children, they are associated with an unacceptably high incidence of severe, irreversible hepatotoxicity.

Acute Disease↗
PubMed1992

Medulloblastoma: I. Clinical, diagnostic, and therapeutic overview.

Medulloblastoma, the most common embryonal tumor of the central nervous system, affects both children and adults. It poses a significant therapeutic challenge in that age-dependent differences exist, not only in their pathobiology, but in the efficacy of chemotherapy and radiotherapy. This is particularly the case in very young children, whose still developing nervous system exhibits a low tolerance to radiotherapy. We review the epidemiology, clinical presentation, radiologic features, and current therapeutic concepts relative to this unique neoplasm. Efforts are made to highlight clinical controversies.

Adolescent↗
PubMed1991

Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia.

Using birth-registration data, a case-control study was done to investigate the possible associations of childhood acute lymphoblastic leukemia (ALL) with birth characteristics and maternal reproductive history. The data included cases born and diagnosed in Minnesota since 1969. Matched analyses were conducted using 337 cases and 1336 birth year-matched controls. There was a statistically significant increased odds of ALL for birth to older (greater than 35 years) mothers (odds ratio (OR) = 2.14, 95% confidence interval (CI) = 1.28, 3.58), older fathers (OR = 1.62, 95% CI = 1.14, 2.30), mothers with at least a high school education (OR = 1.61, 95% CI = 1.05, 2.48), and larger intervals (greater than 5 years) between the birth of the proband and the preceding sibling (OR = 1.86, 95% CI = 1.12, 3.09). The increased odds of ALL for birth by Caesarean section approached significance (OR = 1.42, P = 0.06). No overall association was found for: gender, race, paternal education, fetal-loss history, birth order, prenatal care history, pregnancy complications, inducement of labor, multiple birth, gestational age, or birth weight. Age at diagnosis was an important effect modifier of some analyses. For cases diagnosed before age 2 years, there was a 2.7-fold increased odds of ALL if the last pregnancy had resulted in a fetal loss (P = 0.03). For cases diagnosed before age 4 years, birth weight greater than 3800 g was associated with a significant 2.05-fold increased odds of ALL. These data strengthen the hypothesis that prenatal events may play a causative role in childhood ALL, particularly in those cases diagnosed at a younger age.

Abortion, Spontaneous↗