An erythematous plaque on the face.
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Child↗
Biomedical subjects
C E Herzog
Publications and source records attributed to C E Herzog.
Concurrent ifosfamide-based chemotherapy and irradiation. Analysis of treatment-related toxicity in 43 patients with sarcoma.
BACKGROUND: The current study was performed to evaluate the toxicity profile of therapeutic doses of ifosfamide (IFX) given concurrently with full-dose external beam radiotherapy (EBRT) in patients with soft tissue and bone sarcomas. METHODS: The medical records of 43 consecutive patients with soft tissue or bone sarcomas who were treated with concurrent IFX and EBRT were reviewed. RESULTS: The median patient age was 20 years. Histologies were rhabdomyosarcoma (n = 16 patients), Ewing sarcoma (n = 10 patients), malignant fibrous histiocytoma (n = 9 patients), and other soft tissue sarcomas (n = 8 patients). Thirty-one patients (72%) had localized disease, and 12 patients (28%) had synchronous local and distant disease. Treatment consisted of EBRT (median dose, 50.4 gray [Gy]) with concomitant IFX (median dose per cycle, 10.2 g/m(2)). All patients with Ewing sarcoma or rhabdomyosarcoma received additional concurrent chemotherapy. Twenty-six patients (60%) received two or more cycles of IFX, and 17 patients (40%) were treated with one cycle of IFX and EBRT. The incidences of World Health Organization Grade 3 and Grade 4 toxicities were 29% (21 of 73 cycles) and 22% (16 of 73 cycles), respectively. Grade 4 systemic toxicities included leukopenia (n = 14 patients), neurotoxicity (suicidal ideation; n = 1 patient), and diarrhea (n = 1 patient). Confluent moist desquamation (Grade 3) occurred in nine patients in the treatment field; no patient experienced Grade 4 local toxicity. Among 14 patients who were treated preoperatively, 2 patients (14%) had a pathologic complete response, and 6 patients (43%) had a pathologic near-complete response (> or = 90% necrosis). CONCLUSIONS: Local and systemic toxicities after the administration of therapeutic doses of IFX with concomitant EBRT appear comparable to those observed with either treatment alone. These results support the design of prospective studies evaluating concurrent ifosfamide and radiation therapy for patients with sarcomas.
Adult↗
High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis.
PURPOSE: To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing's sarcoma (ES). PATIENTS AND METHODS: Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS: Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION: Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.
Adolescent↗
Drug-induced cytotoxicity in tissue culture.
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Agar↗
Childhood cancers: hepatoblastoma.
Hepatoblastoma is the most common primary liver tumor in children, accounting for just over 1% of pediatric cancers. The etiology is unknown, but it has been associated with Beckwith-Weidemann syndrome, familial adenomatosis polypi, and low birth weight. The primary treatment is surgical resection, however, chemotherapy plays an important role by increasing the number of tumors that are resectable. The prognosis for patients with resectable tumors is fairly good, however, the outcome for those with nonresectable or recurrent disease is poor.
Child↗
Congenital hepatoblastoma and schizencephaly in an infant with Beckwith-Wiedemann syndrome.
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Beckwith-Wiedemann Syndrome↗
Outcome and reproductive function after chemotherapy for ovarian dysgerminoma.
PURPOSE: To review the outcome for all patients with ovarian dysgerminoma treated at the M.D. Anderson Cancer Center who received bleomycin, etoposide, and cisplatin (BEP) and to assess the menstrual and reproductive function of those who received conservative treatment. PATIENTS AND METHODS: Clinical information was abstracted from the medical record. Patients completed a detailed questionnaire about menstrual and reproductive function; those who did not return the questionnaire were interviewed by telephone. RESULTS: Twenty-six patients were identified as having been treated with BEP chemotherapy for pure ovarian dysgerminoma from January 1984 to January 1998. Their median age was 19.5 years (range, 7 to 32 years). Sixteen patients underwent fertility-sparing surgery in the form of unilateral salpingo-oophorectomy. At a median follow-up time of 89 months, 25 (96%) of the 26 patients remained continuously disease-free. One patient apparently developed a second primary dysgerminoma in her remaining ovary after BEP and was clinically disease-free after further treatment. Of the 16 patients who underwent fertility-sparing surgery, one was lost to follow-up when she was pregnant, and one was still premenarchal. Of the remaining 14 patients, 10 (71%) maintained their normal menstrual function during and after chemotherapy, and 13 (93%) had returned to their prechemotherapy menstrual pattern at the time of the questionnaire. Five pregnancies have occurred thus far, and two patients have had difficulty conceiving. CONCLUSION: Most patients with metastatic dysgerminoma can expect cure with maintenance of normal reproductive function when treated with conservative surgery and BEP chemotherapy.
Adolescent↗
Absence of topoisomerase IIbeta in an amsacrine-resistant human leukemia cell line with mutant topoisomerase IIalpha.
Numerous chemotherapeutic agents act via stabilization of a topoisomerase (topo) II-DNA complex. HL-60/AMSA, a human leukemia cell line, is resistant to intercalator-mediated DNA complex formation and cytotoxicity. HL-60/AMSA contains a mutant form of topo IIalpha that was thought to explain this resistance. However, our present data show that expression of topo IIbeta RNA in HL-60/AMSA is only 10% of that in HL-60, and topo IIbeta protein levels are undetectable. Southern analysis of topo IIbeta shows no differences in gene dosage between the two cell lines but does show differences in the restriction patterns. These data suggest that decreased topo IIbeta expression may contribute to the intercalator resistance of HL-60/AMSA cells.
Amsacrine↗
Evaluation of a potential regulatory role for inverted CCAAT boxes in the human topoisomerase II alpha promoter.
Several chemotherapeutic agents act via inhibition of topoisomerase (topo) II activity. Topo II levels appear to correlate with drug sensitivity in vivo. The DNA immediately 5' to the topo II alpha coding region contains five potentially regulatory inverted CCAAT boxes (ICB). Electrophoretic mobility shift assays (EMSA) using oligomers containing the wild type forms of these ICBs show specific DNA-protein binding. Mutations in these ICBs result in loss of protein binding. EMSA competition studies indicate that the four most 3' ICBs (1-4) bind to the same protein(s), while the most 5' ICB (5) binds to a different protein(s). EMSA supershift assays with antibodies to two known CCAAT binding proteins, CBF and CEB/P, indicate that ICBs 1-4 are binding to CBF, but ICB 5 is not bound by either of these proteins.
Antigens, Neoplasm↗
Effect of transfection of a Drosophila topoisomerase II gene into a human brain tumour cell line intrinsically resistant to etoposide.
The human brain tumour cell line HBT20 is intrinsically resistant to etoposide and does not express mdr-1 mRNA. These studies were conducted to determine whether transfecting a Drosophila (D) topoisomerase II (topo II) gene into HBT20 cells could increase their sensitivity to etoposide. A D-topo II construct in a pMAMneo vector under the control of a mouse mammary tumour virus (MMTV) promoter was transfected into HBT20 cells. The gene is inducible by dexamethasone (Dex). The growth rate of the transfected cells and percentage of the cells in G1, S and G2M was no different than the parental cells. Survival after etoposide exposure (10 microM x 2 h) was measured by colony formation. Parental cells and cells transfected by pMAMneo vector alone showed no enhanced etoposide sensitivity after 24 h of Dex stimulation. By contrast, D-topo II transfected cells were sensitised 3-fold when etoposide treatment was preceded by 24 h Dex stimulation. Northern blotting and Western blotting confirmed that Dex had induced D-topo II expression in the sensitised cells. However, in D-topo II-transfected cells increasing the duration of Dex stimulation to 48 h eliminated the sensitisation to etoposide although increased MMTV promoter activity and expression of the D-topo II gene persisted. Measurement of endogenous human topo-II mRNA and protein revealed a decrease after Dex exposure of greater than 24 h. At these distal times, the total cellular topo II levels (endogenous + exogenous) may be decreased, which may explain why increased sensitivity to etoposide could no longer be demonstrated. This model suggests that D-topo II gene transfection can sensitise de novo resistant HBT20 cells to etoposide but that the time frame of that sensitisation is limited.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A half century of experience with carcinoid tumors in children.
PURPOSE: To investigate the frequency, presentation, clinical management, and prognosis of appendiceal carcinoid tumors in children. METHOD: A review of our institution's experience over 50 years. RESULTS: Twenty-two patients below the age of 20 presented with appendiceal carcinoid tumor. The mean age at presentation was 14.6 years. Twelve patients presented with symptoms of appendicitis. No tumor was > 2.0 cm in size. Only 2 patients underwent resection beyond appendectomy. No patient had recurrent or metastatic carcinoid tumor, and all but 1 patient (who died of ovarian choriocarcinoma) are alive without evidence of carcinoid tumors 1.5 to 30 years after diagnosis. CONCLUSIONS: Appendiceal carcinoid tumors in children are rarely life-threatening and the incidence of large tumors (> 2.0 cm) is very low. The role of right hemicolectomy in large (> 2.0 cm) tumors is questionable in this age group.
Adolescent↗
Intracranial hemangiopericytomas in children.
Hemangiopericytomas (HPs) are rare tumors, about 10% of which occur in children. Since 1988, 2 children with intracranial HP have been seen at the University of Texas M.D. Anderson Cancer Center. The patients presented at ages 2 weeks and 1 month. Both were treated with surgery alone. We also review 4 cases previously reported in the literature; at presentation, those patients were ages 2 days to 9 months. Infantile HPs have a better prognosis than do those that occur in adults, and an improved outcome is also evident for intracranial lesions. Tumors that occur in the neonatal period may be treated with surgery alone; however, those that occur after the neonatal period may be more likely to recur.
Brain↗
Expression of topoisomerase II, bcl-2, and p53 in three human brain tumor cell lines and their possible relationship to intrinsic resistance to etoposide.
We characterized three human brain tumor cell lines (D54, HBT-20, and HBT-28) with respect to resistance to etoposide (VP-16), a topoisomerase II-reactive drug. All three cell lines were inherently resistant to VP-16 when compared to other human cell lines, with D54 showing the greatest resistance using colony formation assays. Resistance to VP-16 has been attributed to decreased drug uptake and changes in topoisomerase II; however, drug uptake and topoisomerase II protein levels (immunoblot) were no lower in D54 than in HBT-20 and HBT-28, cell lines relatively more sensitive to VP-16. More to the point, measurement of topoisomerase II-mediated DNA cleavage of cellular DNA after treatment with VP-16 showed that the topoisomerase II in these cells was active. These data indicate mechanisms other than those attributable to decreased drug uptake or altered topoisomerase II exist for clinical resistance to VP-16. VP-16-induced DNA cleavage has been associated with apoptosis in some cell lines; however, neither DNA laddering nor morphological changes characteristic of apoptosis were detected in these cell lines after treatment with VP-16. Bcl-2 and mutant p53 were present in these cells. Either of these conditions can prevent apoptosis and could explain a dissociation between the proximal mediator of VP-16-induced cytotoxicity (topoisomerase II-DNA complex formation) and cellular death.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Molecular diagnosis of multidrug resistance.
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
Increased mdr-1/P-glycoprotein expression after treatment of human colon carcinoma cells with P-glycoprotein antagonists.
We observed increased levels of mdr-1 mRNA and its protein product P-glycoprotein (Pgp) in the human colon carcinoma cell line, LS 180, and its drug-resistant sublines, LS 180-Ad50 and LS 180-Vb2, after treatment with the Pgp antagonists, verapamil, nifedipine, and cyclosporin A. Increases in mdr-1 RNA were observed within 8 h of the addition of the Pgp antagonists and continued to rise over time. Peak levels were attained after several weeks and were sustained for the duration of treatment up to several months, with a rapid decline in mdr-1 mRNA levels after removal of the Pgp antagonist. Corresponding changes in Pgp were demonstrated with addition and removal of the Pgp antagonists. Increased mdr-1 mRNA was also seen with two other calcium channel blockers, nicardipine and diltiazem, but not with the Pgp antagonists, quinidine and chlorpromazine. Treatment with verapamil or nifedipine was associated with electron microscopic changes consistent with increased differentiation and resulted in increased carcinoembryonic antigen expression, suggesting that the increase in mdr-1 expression was associated with the process of differentiation. Nuclear runoff experiments and inhibition of new RNA synthesis with actinomycin D treatment failed to detect an increase in mdr-1 transcription or stabilization of the mdr-1 mRNA suggesting that the effect of these agents is mediated posttranscriptionally within the nucleus.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Various methods of analysis of mdr-1/P-glycoprotein in human colon cancer cell lines.
BACKGROUND: Multidrug resistance (MDR) mediated by high levels of mdr-1 (also known as PGY1)/P-glycoprotein (Pgp) has been studied in tissue culture systems; however, most tumor samples which express mdr-1/Pgp have much lower levels. PURPOSE: We wanted to determine if levels seen clinically could be detected by commonly used methods and to determine if these levels conferred MDR reversible by Pgp antagonists. METHODS: We studied multi-drug-resistant cell lines and sublines with levels of mdr-1/Pgp expression comparable to those seen clinically. We evaluated the expression of mdr-1 RNA by Northern blot analysis, slot blot analysis, polymerase chain reaction (PCR) analysis, and in situ hybridization. We evaluated protein expression by immunofluorescence, immunohistochemistry, fluorescence-activated cell sorting, and immunoblotting analyses. Drug resistance and reversibility were determined by cell growth during continuous drug exposure. RESULTS: In most cases, the low level of mdr-1/Pgp present in these cell lines could be detected by each method, but the assays were at the limit of sensitivity for all methods except the PCR method. These low levels of mdr-1/Pgp are capable of conferring MDR, which can be antagonized by verapamil. CONCLUSIONS: Levels of mdr-1/Pgp similar to those found in clinical samples can be detected by each of these methods, but the PCR method was the most sensitive and most reliably quantitative. IMPLICATIONS: In vitro sensitization by the addition of verapamil in cell lines with these low levels of mdr-1/Pgp suggests that clinically detected levels may confer drug resistance in vivo.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Use of the polymerase chain reaction in the quantitation of mdr-1 gene expression.
The ability of the polymerase chain reaction (PCR) to quantitate expression of mRNA was examined in the present study. The model chosen was expression of the multidrug resistance gene mdr-1/Pgp in two colon carcinoma cell lines which express mdr-1/Pgp at levels comparable to those found in many clinical samples. PCR was utilized to evaluate differences in mdr-1/Pgp expression in the two cell lines after modulation by sodium butyrate. Thus, comparisons were made across a range of mdr-1/Pgp expression as well as comparisons of small differences. The PCR was found to be both sensitive and quantitative. Accurate quantitation requires demonstration of an exponential range which varies among samples. The exponential range can be determined by carrying out the PCR for a fixed number of cycles on serial dilutions of the RNA reverse transcription product, or by performing the reaction with a varying number of cycles on a fixed quantity of cDNA. By quantitation of the difference in PCR product derived from a given amount of RNA from the sodium butyrate treated and untreated cells, the difference in mRNA expression between samples can be determined. Normalization of the results can be achieved by independent amplification of a control gene, such as beta 2-microglobulin, when the latter is also evaluated in the exponential range. Simultaneous amplification of the control and target genes results in lower levels of PCR products due to competition, which varies from sample to sample. The PCR is thus a labor-intensive but sensitive method of quantitating gene expression in small samples of RNA.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Localization of the L1Md family of repeated sequences in the mouse albumin-alpha-fetoprotein gene complex.
Studies on the beta-globin gene complex in the mouse have demonstrated the existence of repeated DNA sequences interspersed throughout the intergenic regions (1,2). These sequences are members of families of middle repetitive sequences and have been mapped to specific intergenic sites in the 60 kbp beta-globin complex. In this study we present evidence that members of this middle repetitive family of DNA sequences, the L1Md family, are interspersed throughout the mouse albumin and alpha-fetoprotein gene complex. Unlike those of the beta-globin complex, all of which are found in the intergenic regions, these sequences are localized within intron 12 of the albumin gene and intron 3 of the AFP gene as well as twice in the 13.5 kbp intergenic region that links the albumin gene to the AFP gene.
Animals↗