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Colorectal adenocarcinoma as a second malignant neoplasm following Wilms' tumor and rhabdomyosarcoma.

Colorectal carcinoma is one of the most common primary malignancies in adults and occurs in older patients after pelvic radiation. It is rare in children and young adults. We report two cases of colonic adenocarcinoma which were second malignant neoplasms following treatment for early childhood malignancies. One child had Wilms' tumor at 9 months of age treated with preoperative radiation and surgery. He developed radiation colitis and multifocal intestinal adenocarcinomas 42 years later and died with abdominal carcinomatosis. The second child had retroperitoneal embryonal rhabdomyosarcoma at age 1 year and was treated with preoperative radiation, surgery, and chemotherapy. At age 2 years he had radiation colitis; at age 11 years he had rectal adenocarcinoma associated with adenomatous polyps, focal adenomatous change and radiation colitis. Immunohistochemical studies revealed p53 positivity in both adenocarcinomas and in adenomas from the second patient, suggesting that p53 mutation was involved in carcinogenesis. The history of high-dose radiation in early childhood and the multifocal lesions suggest the adenocarcinomas in both patients were second malignant neoplasms, with associated reactive and benign neoplastic and premalignant lesions well documented in one case. These two cases document the phenomenon of early onset of adult type tumors in survivors of childhood cancer and emphasize the need for continued clinical evaluation of patients at risk for second malignant neoplasms.

Adenocarcinoma↗

Delayed-accelerated hyperfractionated radiation therapy for advanced-stage or high-risk rhabdomyosarcoma.

The treatment of six patients with advanced-stage or high-risk rhabdomyosarcoma (RMS) is described. These patients were treated with a delayed-accelerated hyperfractionated radiation therapy (DAHFRT) regimen which delivers 5200 cGy over 20 treatment days. Acceptable early toxicity was noted when radiation therapy was given after a full course of chemotherapy and major attempts at resection of the primary tumor. The DAHFRT regimen has inherent biological and time-intensity advantages compared to other fractionation schemes which may be exploited to improve local control. The DAHFRT regimen should be considered as an alternate fractionation scheme for RMS patients and a possible foundation from which dose-escalation of radiation therapy may be attempted using advanced treatment planning technology. Late effects of high-dose radiation therapy, although a major concern, should assume less priority given the high local failure rates of advanced-stage patients and the advent of conformed radiation therapy treatment planning and delivery which can be used to reduce treatment-related toxicity.

Adolescent↗

Organ-preserving management of rhabdomyosarcoma of the prostate and bladder in children.

Between November 1978 and July 1991, ten children between one and eight years of age with Group III pelvic rhabdomyosarcoma (IRS classification) and considered inoperable at diagnosis were treated primarily with intensive poly-chemotherapy. Complementary radiotherapy and conservative surgery were added as needed. Eight of the ten survive free of disease with functioning bladders for periods ranging from 5.7-18.4 years.

Antineoplastic Combined Chemotherapy Protocols↗

Chromosomal aberrations in a consecutive series of childhood rhabdomyosarcoma.

BACKGROUND AND PROCEDURE: During a 13-year period, 22 children were treated for rhabdomyosarcoma (RMS). In 18 of these patients chromosome analysis was attempted on material from tumor biopsies, fine needle aspiration biopsies and/or bone marrow samples. RESULTS: Clonal chromosome aberrations were detected in 14 cases; 7 of 9 embryonal RMS, 6 of 8 alveolar RMS and in the single case of pleomorphic RMS cytogenetic failures were more frequent in fine needle aspiration biopsies than in tumor biopsies. The characteristic t(2;13) translocation was seen in 2 alveolar RMS but not in any of the other subtypes. In 3 of the embryonal RMS hyperdiploid or hypertetraploid karyotypes with few or no structural rearrangements were seen. In all 3 cases the clinical course was relatively benign, suggesting that certain karyotypic patterns in RMS may be of prognostic significance. CONCLUSIONS: Our results add to the evidence that cytogenetic analysis should be an integral part of the diagnostic examinations of children with RMS.

Adolescent↗

Rhabdomyosarcoma of extrahepatic biliary tree: initial treatment with chemotherapy and conservative surgery.

BACKGROUND: The very low frequency of rhabdomyosarcoma (RMS) of the extrahepatic biliary tree has impeded the development of a standardized form of treatment. PROCEDURE: Based on the good response of embryonal RMS to chemotherapy, we used a multi-drug protocol as the initial treatment of a 3-year-old girl after obtaining adequate transparietohepatic biliary drainage. The treatment achieved complete remission. Later conservative laparoscopic surgery revealed only residual scar tissue. The patient is alive and well 1 year after remission. DISCUSSION AND CONCLUSIONS: Management of this difficult tumor using modern less invasive techniques for diagnosis and treatment, with the help of preoperative chemotherapy, prevented extensive damage to the biliary tree and allowed complete recovery.

Antineoplastic Combined Chemotherapy Protocols↗

Results of alternating chemotherapy and hyperfractionated radiation therapy in childhood rhabdomyosarcoma.

BACKGROUND: A regimen of multi-drug chemotherapy alternating with split course hyperfractionated radiation therapy (HFRT) was adopted for the treatment of patients with rhabdomyosarcoma (RMS). The purpose of this treatment regimen was to allow for the timely delivery of radiation and chemotherapy, reduce treatment-related toxicity, and improve compliance. PROCEDURE: Forty-four patients with stages II-IV RMS were treated with HFRT and received 5,400 cGy. The treatment was administered in two courses (3,000 and 2,400 cGy) and separated by a 4-week interval. HFRT consisted of 150 cGy delivered twice a day, 5 days a week with an interfraction interval of 4-6 hours. A limited comparison was made between the HFRT patients and 42 historical patients with comparable clinical characteristics who were treated with similar chemotherapy and conventionally fractionated radiation therapy (CFRT) (median 4,800 cGy, range 4,000-5,680 cGy). RESULTS: HFRT patients completed radiation therapy in 59.1 +/- 9.4 days (mean +/- SD) and CFRT patients completed treatment in 56.6 +/- 10.5 days compared to an expected 52 and 40 days, respectively. With a median follow-up of 55 months for the HFRT patients and 104 months for the CFRT patients, no differences in local control or survival were noted. Nine of 44 (21%) HFRT and 8/42 (19%) CFRT patients experienced local failure. The median time to local failure was 15 months for patients in the HFRT group and 11 months for patients in the CFRT group. CONCLUSIONS: The results of the HFRT regimen were acceptable in terms of toxicity and compliance. No improvement in local control was obtained by alternating radiation and chemotherapy. The lack of difference between patients treated with HFRT and CFRT may be related to the lengthened treatment time of the split course regimen, the small difference in total dose, and tumor repopulation.

Adolescent↗

Isolation of genes differentially expressed in human primary myoblasts and embryonal rhabdomyosarcoma.

Using a subtractive hybridization method, we have cloned 48 cDNAs which are expressed in human primary myoblasts but down-regulated in the embryonal-rhabdomyosarcoma (RMS) cell line RD. Twenty-nine sequences could be identified as coding for previously known gene products, while 19 encode unknown proteins. Twelve clones coding for known proteins that were highly down-regulated in the RD cells were chosen for further analysis on Northern blots containing additional normal and RMS cells. The expression pattern of TGF-beta-induced gene product-3 (beta(ig)H3), inhibitory G-protein alpha sub-unit (G(alpha)i2), osteoblast-specific factor-2 (OSF-2), 22-kDa smooth-muscle protein (SM22), clone A3351 (homologous to mouse talin), testican, thrombospondin-1 and thrombospondin-2 suggests involvement of these proteins in the genesis of the neoplastic phenotype. Among the clones with unknown sequence, several are identical or homologous to expressed sequence tags or known cDNAs, such as integrins or laminin. These results suggest that several isolated clones might have an important role in the determination or maintenance of the normal phenotype, and thus their loss is possibly involved in the progression of malignancy.

Base Sequence↗

Suppression of rhabdomyosarcoma growth by fumagillin analog TNP-470.

The purpose of our study was to investigate a novel therapeutic approach for rhabdomyosarcoma (RMS) in an animal model. The pursuit of new therapeutic modalities for RMS is critically important since this type of tumor is the most common soft tissue sarcoma in children and because patients with metastatic disease may not be cured with current therapeutic modalities. We studied whether RMS growth may be suppressed by TNP-470, an analog of fumagillin, which was found to inhibit neoangiogenesis. Our data had shown that animals treated with TNP-470 (60 mg/kg), over a specific period of time, had approximately 50% smaller tumors than controls. Consistent with previous observations, treatment with TNP-470 decreases the level of the cyclin D1. Tumors dissected from TNP-470-treated animals had also considerable necrotic areas. In addition, TNP-470 had a direct cytotoxic effect on RMS cells in vitro. Our study has shown, therefore, that RMS in an animal model and in vitro responds to treatment with TNP-470, which suggests that the inhibitors of angiogenesis may be useful in a novel therapeutic design for RMS.

Animals↗

Anti-alpha3 integrin antibody induces the activated form of matrix metalloprotease-2 (MMP-2) with concomitant stimulation of invasion through matrigel by human rhabdomyosarcoma cells.

Proteolytic enzymes, such as matrix metalloproteases (MMPs), play a pivotal role in cancer invasion and metastasis. Invasive human rhabdomyosarcoma cells (RD) secreted proMMP-2 (72-kDa progelatinase). We found that anti-alpha3 and -alpha2 integrin antibodies induced the activated form of MMP-2 and enhanced proMMP-2 secretion by RD cells. The effect of anti-alpha2 integrin antibody was less prominent than that seen with anti-alpha3 integrin antibody. Moreover, we have found that anti-alpha3 and -alpha2 integrin antibodies enhanced RD-cell invasion through matrigel (reconstituted basement membrane) by 2.6- and 2.0-fold respectively this process was abrogated by neutralizing antibody to MMP-2. These data suggest that signaling events induced by anti-alpha3 integrin antibody may be involved in RD-cell invasion as a result of modulation of matrix-metalloprotease expression.

Antibodies, Anti-Idiotypic↗

Therapeutic differentiation in a human rhabdomyosarcoma cell line selected for resistance to actinomycin D.

Classical cytotoxic treatment of rhabdomyosarcoma (RMS) is accompanied often by significant morbidity and poor response. The use of cytotoxic agents may induce a multidrug resistance phenotype, which plays an important role in the sensitivity of tumoral cells to drugs. Using actinomycin D, a drug of choice in the treatment of RMS, we induced resistance in the TE.32.7 human RMS cell line. The TE.32.7-DAC-resistant cell line exhibited cross-resistance to vincristine and doxorubicin and showed mdr1/P-glycoprotein over-expression, suggesting that this mechanism was involved in the reduction in intracellular drug concentration and may be responsible for the failure of treatment of RMS with classical cycles of cytotoxics. Furthermore, this resistant cell line showed increased expression of the muscle differentiation markers desmin and alpha-actinin and ultrastructural changes which clearly indicated myogenic differentiation. Our findings suggest that, although this tumor is probably arrested along the normal myogenic pathway to maturation, induction of cell differentiation with anti-neoplastic drugs may be an alternative therapeutic approach. However, the failure of TE.32.7-DAC cells to completely re-enter the program of myogenic differentiation supports the hypothesis that multidrug resistance is a major obstacle in differentiation therapy for RMS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R.

Previous results have shown that the insulin-like growth factor type I receptor (IGF-I-R) plays a critical role in the control of rhabdomyosarcoma (RMS) growth. The purpose of this study was to investigate whether a mutated IGF-I-R, when expressed in RMS cells, may interfere with the function of the endogenous wild-type IGF-I-R. We also examined whether the expression of a mutated IGF-I-R may induce phenotypic changes in RMS cells. We used here the mutated IGF-I-R with a lysine to arginine residue 1003 substitution, called IGF-I-KR, which carries a mutation in the ATP-binding domain of the intracellular beta subunit, while the extracellular, ligand binding alpha subunit remains unchanged. We observed that the expression of this mutated IGF-I-KR markedly decreased the response of RMS cells to stimulation with IGF-I. While stimulation with IGF-I increases the autophosphorylation of IGF-I-R in the parent cells, stimulation with IGF-I failed to produce a comparable increase in autophosphorylation in the cells expressing the mutated IGF-I-KR. We also observed a decreased plating efficiency of cells expressing the mutated IGF-I-KR. Consistently, a decrease of RMS growth in vivo was observed in an animal model. Our data suggest that the IGF/IGF-I-R signaling pathway may be inhibited by expressing a mutated IGF-I-KR and that such a mutant gene could be utilized in developing novel therapeutic strategies to suppress RMS growth. 1998.

Cell Division↗

New combined treatment of surgery, radiotherapy, and reconstruction in head and neck rhabdomyosarcoma in children: the AMORE protocol.

BACKGROUND: If no complete remission on chemotherapy is reached in head and neck rhabdomyosarcoma (RMS) in children, adjuvant radiotherapy and/or surgery are indicated. This often causes severe mutilation, and the prognosis is poor. Ablative surgery, moulage technique with afterloading brachytherapy, and reconstructive surgery, called the AMORE protocol, is developed for residual or recurrent disease after chemotherapy. METHODS: Ablative surgery with preservation of important structures is followed by the embedding of a gutta-percha mold in the created tissue defect. The wound bed is irradiated with Iridium192. Within 1 week, the defect is reconstructed with a muscle transplant. Fifteen children (mean age, 5.7 years) were treated accordingly. RESULTS: All patients were discharged within 4 weeks. Eleven patients are tumor-free, with a mean follow-up period of 2.8 years. No signs of radiation sequelae were observed. CONCLUSION: The preliminary results of this new, combined treatment are encouraging, if the advanced stage of disease is considered.

Brachytherapy↗

P53 mutation and MDM2 amplification frequency in pediatric rhabdomyosarcoma tumors and cell lines.

BACKGROUND: The p53 tumor suppressor gene is the most commonly mutated gene in human cancer, and mutations arise in a wide variety of tumor types. Wild-type p53 functions as a regulator of apoptosis, so mutations in the p53 gene are generally associated with aggressive tumors and a poor prognosis. PROCEDURE: We have investigated the p53 mutation and MDM2 amplification frequencies in biopsies from pediatric rhabdomyosarcoma (RMS) tumors and cell lines by SSCP and Southern analyses. RESULTS: A mutation was detected in only 1 of 20 tumor specimens (5%), whereas the frequency in established RMS cell lines was significantly higher (6/10, 60%). p53 Mutations were more common in cell lines derived from tumors previously exposed to chemotherapy compared to those derived from tumors at di-agnosis, and it is likely that these mutations enhanced the probability of successful long-term culture. The frequency of MDM2 gene amplification in patient biopsies was also low (2/20, 10%). Interestingly, complete responses to treatment were obtained in the two patients with tumors that demonstrated amplification of MDM2. The response to treatment of patients with tumors wild-type for p53 and without MDM2 amplification was quite varied, indicating that expression of a wild-type p53 gene at diagnosis cannot always facilitate a favorable outcome. CONCLUSIONS: p53 mutation and MDM2 gene amplification frequencies are extremely low in RMS tumors, but a wild-type p53 genotype is not always associated with a favorable prognosis.

Adolescent↗

Absent or reduced expression of the caspase 8 gene occurs frequently in neuroblastoma, but not commonly in Ewing sarcoma or rhabdomyosarcoma.

PROCEDURE: To clarify whether the caspase 8 gene is involved in the pathogenesis of neuroblastoma (NB), we examined alterations of the caspase 8 gene in 15 NB, seven Ewing sarcoma (ES), and eight rhabdomyosarcoma (RMS) cell lines, using reverse transcription-polymerase chain reaction (RT-PCR) and RT-PCR single-strand conformation polymorphism (SSCP) analyses. RESULTS: The caspase 8 gene was not expressed in 11 (73%) of 15 NB cell lines, it was absent in only one of seven ES cell lines, but was present in all eight RMS cell lines examined. No mutations were detected in any cell lines examined. CONCLUSIONS: Inactivation of the caspase 8 gene is considered to be involved in the pathogenesis of NB, but not ES or RMS.

Caspase 8↗

Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study.

BACKGROUND: Rhabdomyosarcomas are the most common type of pediatric soft tissue sarcoma. The cytogenetic literature on RMS is biased towards the less common alveolar subtype (ARMS), which is frequently associated with specific translocations and the PAX3/7-FKHR fusion genes. Relatively few karyotypes are reported for the embryonal subtype (ERMS). The aim of this study was to further cytogenetic knowledge of RMS subtypes. PROCEDURE: Representative examples of all karyotypes from UKCCG; member laboratories were reexamined and their histopathologies reviewed through the United Kingdom Children's Cancer Study (Group) (UKCCSG). Molecular evidence for the PAX3/7-FKHR fusion genes was available for five ERMS and seven ARMS cases and compiled with the karyotypes. RESULTS: Clonal chro mosome aberrations were characterized for 25 ERMS and 17 ARMS cases. Thirty-six percent of the ERMS cases involved translocation breakpoints in the 1p11-q11 region. Ten of the seventeen cases of ARMS showed cytogenetic evidence for the t(2;13)(q35;q14), consistent with molecular data available from four of these. Two further ARMS cases revealed a PAX3-FKHR and a variant PAX7-FKHR fusion gene product that were not detected cytogenetically. CONCLUSIONS: Many of the karyotypes from both subtypes were complex. The frequent involvement of the 1p11-1q11 region and gain of chromosomes 2, 8, 12, and 13 in ERMS may be functionally significant. There was no evidence for involvement of the PAX3/7-FKHR genes in ERMS, and cryptic involvement was found in some ARMS. There were no consistent chromosomal rearrangements associated with apparently translocation negative ARMS cases.

Adolescent↗

Trends in surgery for childhood rhabdomyosarcoma.

Total excision remains the aim of surgical management for rhabdomyosarcomas in children, but effective adjunctive treatment for the majority of these tumors permits preservation of function and appearance in situations where formerly these were sacrificed. Control of residual tumor in microscopic quantity can now be achieved by chemotherapy in the majority of cases. The coordination of surgery, irradiation, and chemotherapy has reduced the need for ultra-radical extirpative procedures. The following conservative trends have evolved: 1) Amputations are rarely indicated for tumors of the extremities. 2) Primary irradiation for orbital tumors may obviate exenteration and save the eye. 3) Multilating excisions for head and neck tumors can often be avoided. 4) Prophylactic regional lymph node dissections are usually not indicated. 5) Primary tumors of the bladder or prostate can usually be managed by anterior exenteration.

Adolescent↗

Multidisciplinary treatment of embryonal rhabdomyosarcoma in children.

Twenty-nine children under 15 years of age with embryonal rhabdomyosarcoma were treated according to a multidisciplinary protocol (T-2). The protocol consisted of surgical removal of the tumor if possible, followed by chemotherapy, and also with radiation therapy in patients with gross or microscopic residual disease. Radiation therapy was given in the 4500-7000 rads range. The chemotherapy consisted of cycles of sequential administration of dactinomycin, Adriamycin, vincristine, and cyclophosphamide, with obligatory periods of rest. The drug therapy was continued for 2 years. Following surgery, clinicopathologic staging of the disease revealed 10 patients with no residual disease (I-A), 5 with microscopic residual disease (I-B), 5 with unresectable tumors (II), 6 with unresectable tumors plus regional lymph node involvement (III), and 3 with disseminated tumors (IV). Twenty-four (82%) of the patients (20 Stages I-II, 4 Stage III) are alive with no evidence of disease for 4 plus to 42 plus months. These results are superior to those achieved between 1960-1970 among 108 children treated at Memorial Sloan-Kettering Cancer Center.

Adolescent↗

Combined therapy to prevent complete pelvic exenteration for rhabdomyosarcoma of the vagina or uterus.

Three children with rhabdomyosarcoma (sarcoma botryoides) of the vagina or uterus were managed by modified radical resection combined with pre- and/or postoperative chemotherapy and high-dose irradiation. This plan of therapy contrasts sharply with the conventional approach: i.e., pelvic exenteration consisting of cystectomy, hystovaginectomy, and oophorectomy, with urinary diversion by ureteroileostomy or ureterosigmoidostomy. Two patients had complete regressions of tumor following preoperative chemotherapy and irradiation. The third patient received no preoperative therapy, but was given postoperative radium implantation, irradiation, and chemotherapy. The surgical approach consisted of hystovaginectomy and oophorectomy without urinary diversion. These patients are free of tumor for 32, 44, and 54 months, respectively. There were no serious toxic reactions to the drugs, nor any significant postoperative urinary tract problems. The results reported here suggest that hystovaginectomy and oophorectomy coordinated with chemotherapy and irradiation is an acceptable alternative to pelvic exenteration in patients with sarcoma botryoides of the vagina or uterus.

Adolescent↗