RESUMEN
PHOX2B is a homeodomain-containing protein that is involved in the development of the peripheral nervous system and is the major disease gene for the rare congenital breathing disorder congenital central hypoventilation syndrome (CCHS). Germline PHOX2B alterations were also recently discovered in neuroblastoma cases with CCHS and/or Hirschsprung disease, but a comprehensive survey for mutational frequency and functional consequence has not been performed. We therefore studied a large panel of hereditary neuroblastomas to understand the frequency and functional effects of PHOX2B mutations. Three of 47 individuals with presumed genetic predisposition to neuroblastoma showed a germline PHOX2B mutation (6.4%). Mutations were also discovered in 2 of 30 human neuroblastoma-derived cell lines, but none of 86 primary tumors from patients with sporadically occurring neuroblastoma. The vast majority of primary tumors showed abundant PHOX2B mRNA expression relative to the remainder of the transcriptome. Consistent with its role as an important neurodevelopmental gene, forced overexpression of wild-type PHOX2B in neuroblastoma cell lines suppressed cell proliferation and synergized with all-trans retinoic acid to promote differentiation. Patient-derived mutant PHOX2B constructs retained the ability to suppress cellular proliferation, but were not able to promote differentiation or activate expression of a known PHOX2B target gene in vitro. These findings show that PHOX2B alterations are a rare cause of hereditary neuroblastoma, but disruption of this neurodevelopmental pathway can interfere with transcription-dependent terminal differentiation. These data also suggest that the genetics of neuroblastoma initiation are complex, and highlight genes involved in normal noradrenergic development as candidate predisposition genes.
Asunto(s)
Frecuencia de los Genes , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Mutación , Neuroblastoma/genética , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Secuencia de Aminoácidos , Secuencia de Bases , Diferenciación Celular/genética , Proliferación Celular , Células Cultivadas , Análisis Mutacional de ADN , Regulación de la Expresión Génica , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/genética , Humanos , Pérdida de Heterocigocidad , Neuroblastoma/complicaciones , Neuroblastoma/metabolismo , Linaje , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Apnea Central del Sueño/complicaciones , Apnea Central del Sueño/congénito , Apnea Central del Sueño/genética , TransfecciónRESUMEN
BACKGROUND: The N7 protocol for poor-risk neuroblastoma uses dose-intensive chemotherapy (as in N6 protocol [Kushner et al.: J Clin Oncol 12:2607-2613, 1994] but with lower dosing of vincristine) for induction, surgical resection and 2100 cGy hyperfractionated radiotherapy for local control, and for consolidation, targeted radioimmunotherapy with 131I-labeled anti-GD2 3F8 monoclonal antibody and immunotherapy with unlabeled/unmodified 3F8 (400 mg/m2). PROCEDURE: The chemotherapy consists of: cyclophosphamide 70 mg/kg/d x 2 and a 72-hr infusion of doxorubicin 75 mg/m2 plus vincristine 2 mg/m2, for courses 1, 2, 4, and 6; and cisplatin 50 mg/m2/d x 4 and etoposide 200 mg/m2/d x 3, for courses 3, 5, and 7. 131I-3F8 is dosed at 20 mCi/kg, which is myeloablative and therefore necessitates stem-cell support. RESULTS: Of the first 24 consecutive previously untreated patients more than 1 year old at diagnosis, 22 were stage 4 and two were unresectable stage 3 with MYCN amplification. Chemotherapy achieved CR/VGPR in 21 of 24 patients. Twenty patients to date have completed treatment with 131I-3F8, and 15 patients have completed all treatment. With a median follow-up of 19 months, 18 of 24 patients remain progression-free. CONCLUSIONS: Major toxicities were grade 4 myelosuppression and mucositis during chemotherapy, and self-limited pain and urticaria during antibody treatment. Late effects include hearing deficits and hypothyroidism.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoconjugados/uso terapéutico , Inmunoglobulina G/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Neuroblastoma/terapia , Radioinmunoterapia , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Enfermedades de la Médula Ósea/inducido químicamente , Quimioterapia Adyuvante , Niño , Preescolar , Aberraciones Cromosómicas , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Amplificación de Genes , Genes myc , Humanos , Hipotiroidismo/etiología , Inmunización Pasiva , Inmunoconjugados/efectos adversos , Radioisótopos de Yodo/efectos adversos , Proteínas de Neoplasias/sangre , Estadificación de Neoplasias , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/mortalidad , Neuroblastoma/radioterapia , Neuroblastoma/cirugía , Radioinmunoterapia/efectos adversos , Radioterapia Adyuvante , Inducción de Remisión , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
PURPOSE: To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery. PATIENTS AND METHODS: Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings. RESULTS: Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% +/- 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% +/- 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for > or = 36 months had short stature from decreased growth of irradiated vertebra. CONCLUSION: Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neuroblastoma/radioterapia , Preescolar , Fraccionamiento de la Dosis de Radiación , Femenino , Genes myc , Humanos , Lactante , Metástasis Linfática , Masculino , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/cirugía , Radioterapia Adyuvante , Factores de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid) is a new member of this class of compounds that is currently under development as an anticancer agent. We investigated the activity of pyroxamide as an inducer of differentiation and/or apoptosis in transformed cells. EXPERIMENTAL DESIGN AND RESULTS: Pyroxamide, at micromolar concentrations, induced terminal differentiation in murine erythroleukemia (MEL) cells and caused growth inhibition by cell cycle arrest and/or apoptosis in MEL, prostate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused little evident toxicity significantly suppressed the growth of s.c. CWR22 prostate cancer xenografts. Despite the potent growth-inhibitory effects of pyroxamide in this tumor model, serum prostate-specific antigen levels in control versus pyroxamide-treated mice were not significantly different. Pyroxamide is a potent inhibitor of affinity-purified HDAC1 (ID(50) = 100 nM) and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Human CWR22 prostate tumor xenografts from mice treated with pyroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetylation and increased expression of the cell cycle regulator p21/WAF1, compared with tumors from vehicle-treated control animals. CONCLUSIONS: The findings suggest that pyroxamide may be a useful agent for the treatment of malignancy and that induction of p21/WAF1 in transformed cells by pyroxamide may contribute to the antitumor effects of this agent.
Asunto(s)
Aminopiridinas/farmacología , Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/farmacología , Acetilación/efectos de los fármacos , Aminopiridinas/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , División Celular/efectos de los fármacos , Línea Celular Transformada , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/uso terapéutico , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Neuroblastoma is a common childhood cancer with a poor overall prognosis. Retinoic acids (RAs) have been studied as a potential therapy, showing promise in recurrent disease. The histone deacetylase inhibitor (HDACI) M-carboxycinnamic acid bishydroxamide (CBHA) is another potential therapy, which we recently described. Combinations of RAs and HDACIs currently under investigation display synergy in certain neoplasms. In this study, we evaluate the effect of combinations of RAs and HDACIs on human neuroblastoma cells. PROCEDURE: Established cell lines were cultured in increasing concentrations of HDACIs, RAs, and combinations thereof. Following exposure, viable cell number was quantified by trypan blue dye exclusion on a hemacytometer. Cell cycle analysis was performed by propidium iodide staining and FACS. RESULTS: All assayed HDACIs and RAs decreased viable cell number. Lower concentrations of each agent were effective when the two were combined. The primary reason for decreased cell number appears to be apoptosis following HDACI exposure and G1 arrest following RA exposure. Both effects are seen with cotreatment. Caspase inhibition abrogates the apoptotic response. CONCLUSIONS: CBHA causes apoptosis of human neuroblastoma in vitro, an effect that can add to the effects of RA. HDACIs and RAs inhibit neuroblastoma in significantly lower concentrations when used together than when used individually. Combination therapy may improve the ultimate efficacy while reducing the side effects of these agents in clinical use.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cinamatos/uso terapéutico , Inhibidores de Histona Desacetilasas , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Tretinoina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de Caspasas , División Celular/efectos de los fármacos , Cinamatos/farmacología , Fase G1/efectos de los fármacos , Humanos , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
Combination chemotherapy, often in conjunction with surgery and external radiotherapy, is utilized in most children with tumors of the genitourinary tract. These chemotherapeutic agents are capable of causing a variety of delayed toxicities. Common late complications include cardiotoxicity associated with prior exposure to an anthracycline, pulmonary dysfunction, infertility in males due to prior therapy with alkylating agents, and secondary leukemia in individuals treated with epipodophyllotoxins.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias Urogenitales/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Niño , Femenino , Humanos , Riñón/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Ovario/efectos de los fármacos , Testículo/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacosRESUMEN
OBJECTIVE: We sought to establish the outcome and optimal therapeutic sequence for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the chest wall. METHODS: Patients 30 years of age or younger with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the bone were randomly assigned to receive vincristine, doxorubicin, cyclophosphamide, and dactinomycin or those drugs alternating with ifosfamide and etoposide. Local control was obtained with an operation, radiotherapy, or both. RESULTS: Fifty-three (13.4%) of 393 patients had primary tumors of the chest wall (all rib). Event-free survival at 5 years was 57% for the chest wall compared with 61% for other sites (P >.2). Ifosfamide and etoposide improved outcome in the overall group (5-year event-free survival, 68% vs 54%; P =.002), and a similar trend occurred in chest wall lesions (5-year event-free survival, 64% vs 51%). Patients with chest wall lesions had more attempts at initial surgical resection (30%) than those with other primary tumor sites (8%, P <.01). The attempt at initial resection for chest wall lesions did not correlate with size. Initial resections at other sites were restricted to smaller tumors. Initial resection resulted in negative pathologic margins in 6 of 16 patients, whereas the delayed resection resulted in negative margins in 17 of 24 patients (P =.05). Although there was no difference in survival by timing of the operation in rib lesions, a higher percentage of patients with initial surgical resection received radiation than those with resection after initial chemotherapy (P =. 13). CONCLUSIONS: Although rib primary tumors are significantly larger than tumors found in other sites, their outcome is similar. We favor delayed resection whenever possible to minimize the number of patients requiring radiation therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/cirugía , Costillas , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/cirugía , Adolescente , Adulto , Neoplasias Óseas/mortalidad , Niño , Terapia Combinada , Supervivencia sin Enfermedad , Humanos , Sarcoma de Ewing/mortalidad , Resultado del TratamientoRESUMEN
BACKGROUND: Chest wall tumors of primitive neuroectodermal origin (PNET, Ewing's sarcoma [ES]) are rare and have a poor prognosis. Multimodality therapy has improved survival results, and long-term survival is possible. Whether adjuvant radiation therapy is uniformly beneficial remains unclear. METHODS: A retrospective analysis of the authors' institutional experience between 1979 and 1998 was performed. RESULTS: Twenty consecutive patients with PNET-ES of the chest wall were identified. The median age was 12 years (range, 2.5 to 21 years). Median follow-up was 3 years (range, 7 months to 19.4 years). Seven patients presented with a mass, 12 with pain, 1 with respiratory distress, and 1 with a neuropathy. Initial therapy consisted of biopsy and neoadjuvant chemotherapy followed by chest wall resection in 12 patients. Of the remaining 8 patients, 6 underwent biopsy, followed by chest wall resection and adjuvant chemotherapy, 1 underwent biopsy, chemotherapy, and resection of a lung nodule, and 1 underwent biopsy, chemotherapy, and a laminectomy and decompression procedure. All 20 patients were included in institutional-based trials using multiagent chemotherapy. Fifteen patients received radiation therapy with a median dose of 3,000 cGy. At last follow-up, 11 patients are alive and disease free, with a median survival of 7.5 years (range, 7 months to 19.4 years). Seven of 11 (64%) survivors had neoadjuvant therapy followed by chest wall resection. Seven of 11 (64%) survivors had radiation therapy. There was no surgical mortality. Twelve patients had treatment-related complications, 3 of which were related to surgical resection. There were no survivors among patients with recurrent disease. Three of the patients who died of disease had both local and distant recurrences, 4 patients had distant recurrence only, and one patient had local recurrence only. Only 4 of 9 (44%) patients who died were treated initially with chemotherapy followed by chest wall resection. All but 1 of those that died (89%) received initial radiation therapy. All 9 patients who did not survive received additional salvage radiotherapy as well. CONCLUSIONS: Long-term survival is possible with ES-PNET after complete chest wall resection. This may be facilitated by neoadjuvant chemotherapy. Long-term survival without radiation therapy is possible, and consideration of radiation therapy should be made on a case-by-case basis.
Asunto(s)
Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Neoplasias Torácicas/mortalidad , Neoplasias Torácicas/terapia , Adolescente , Adulto , Quimioterapia Adyuvante , Niño , Preescolar , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia , Pronóstico , Dosificación Radioterapéutica , Radioterapia Adyuvante , Estudios Retrospectivos , Sarcoma de Ewing/cirugía , Análisis de Supervivencia , Neoplasias Torácicas/cirugíaRESUMEN
PURPOSE: To evaluate the efficacy of 21 Gy hyperfractionated radiotherapy for local control in conjunction with surgery and intensive systemic therapy for patients with Stage 4 neuroblastoma. METHODS AND MATERIALS: After achieving a partial or complete remission, 47 children, ages 1-10 years, with Stage 4 neuroblastoma were treated on four consecutive institutional protocols (N4-N7) with dose-intensive multi-agent chemotherapy, maximal surgical debulking, and hyperfractionated radiotherapy (1.5 Gy twice a day to 21 Gy). Radiotherapy fields encompassed the initial tumor volume and regional lymph nodes plus a 3-cm margin. This was followed by consolidation with either autologous bone marrow transplantation (N4 and N5) or immunotherapy (N6 and N7). RESULTS: Forty-five of 47 patients had a complete response to surgery and chemotherapy prior to radiotherapy. Five-year actuarial rates of local control, progression-free survival, and overall survival were 84%, 40%, and 45%, respectively. Among 26 patients who relapsed, 1 failed only at the primary site, 22 developed distant metastases exclusively, and 3 had both local and distant failures. There were no acute complications of radiotherapy. CONCLUSION: Hyperfractionated radiotherapy to 21 Gy, in conjunction with dose-intensive systemic therapy and aggressive surgical resection, is well tolerated and is associated with durable local control for most patients with Stage 4 neuroblastoma.
Asunto(s)
Neuroblastoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Terapia Combinada , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasia Residual , Neuroblastoma/secundario , Neuroblastoma/cirugíaAsunto(s)
Neoplasias Colorrectales/genética , Repeticiones de Microsatélite/genética , Adolescente , Adulto , Niño , Humanos , Mutación , Linaje , FenotipoRESUMEN
Deletion of the short arm of chromosome 1 is frequently observed in neuroblastoma (NB). We performed loss of heterozygosity (LOH) analysis of 120 well characterized NB to better define specific regions of 1p loss and any association with clinical and biological prognostic features (DNA index, MYCN, age, and stage). All categories of disease were represented including 7 ganglioneuromas, 8 stage 4S, 33 local-regional (stages 1, 2, and 3), and 72 stage 4 NB according to the International Neuroblastoma Staging System. Patients were consistently treated with stage-appropriate protocols at a single institution. Sixteen highly informative, polymorphic loci mapping to chromosome 1 were evaluated using a sensitive, semi-automated, fluorescent detection system. Chromosome arm 1p deletions were detected in all categories of tumor except ganglioneuroma. Frequent LOH was detected at two separate regions of 1p and distinct patterns of losses were associated with individual clinical/biological categories. Clinically aggressive stage 4 tumors were predominantly diploid with extensive LOH frequently detected in the region of 1ptel to 1p35 (55%) and at 1p22 (56%). The shortest region of overlap for LOH at 1p36 was between D1S548 and D1S1592 and for 1p22 was between D1S1618 and D1S2766. Local-regional tumors were mostly hyperdiploid with short regions of loss primarily involving terminal regions of 1p36 (42%). Most spontaneously regressing stage 4S tumors (7/8) were hyperdiploid without loss of 1p36 or 1p22. These findings suggest that genes located on at least two separate regions of chromosome arm 1p play a significant role in the biology of NB and that distinct patterns of 1p LOH occur in individual clinical/biological categories.
Asunto(s)
Cromosomas Humanos Par 1/genética , Pérdida de Heterocigocidad , Neuroblastoma/genética , Alelos , Biomarcadores de Tumor/genética , Niño , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Standard cytogenetic techniques are time-consuming and often not informative with solid tumors. In contrast, the reverse transcriptase-polymerase chain reaction (RT-PCR) is a readily available technique that can rapidly detect tumor-specific chromosomal rearrangements, even in small biopsy specimens. We present cases depicting the importance of including molecular diagnostic studies in the routine evaluation of pediatric solid tumors. PROCEDURE: We used RT-PCR to detect chimeric transcripts specific for major pediatric solid tumors, including peripheral primitive neuroectodermal tumor (pPNET), alveolar rhabdomyosarcoma (ARMS), and desmoplastic small round-cell tumor (DSRCT). We reviewed six recent cases in which the initial diagnosis was changed by the results of RT-PCR. RESULTS: Highly unusual or nonspecific clinical and/or histopathologic findings led to the initial diagnoses of neuroblastoma in three patients and DSRCT, leukemia, and carcinoma in one patient each. The final diagnoses after RT-PCR studies were pPNET in three patients, ARMS in two patients, and DSRCT in one patient. RT-PCR results led to early corrections in the diagnosis in two patients, but four patients received treatment not considered optimal for the neoplasms ultimately diagnosed, including three who, despite presenting with localized tumors that have a >70% cure rate with standard therapy, have died or are dying of disease. CONCLUSIONS: Molecular genetic studies on solid tumors can clarify the diagnosis in seemingly straightforward as well as in overtly problematic cases. These diagnostic distinctions are now critical as disease-specific and risk-directed therapies have emerged.
Asunto(s)
Carcinoma/diagnóstico , Leucemia/diagnóstico , Tumores Neuroectodérmicos Primitivos/diagnóstico , Rabdomiosarcoma Alveolar/diagnóstico , Sarcoma de Células Pequeñas/diagnóstico , Translocación Genética/genética , Adolescente , Biomarcadores de Tumor/biosíntesis , Carcinoma/genética , Carcinoma/metabolismo , Niño , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Lactante , Leucemia/genética , Leucemia/metabolismo , Masculino , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/metabolismo , Valor Predictivo de las Pruebas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/metabolismo , Sarcoma de Células Pequeñas/genética , Sarcoma de Células Pequeñas/metabolismoRESUMEN
BACKGROUND: As an alternative to high-dose irradiation, limited surgery and low-dose irradiation have been investigated as a means to achieve local control. We retrospectively examined the clinical characteristics, treatment, and outcome for 25 patients with Ewing sarcoma treated with limited surgery and low-dose irradiation. PROCEDURE: The records of 25 patients (age 4-48 years) were reviewed who were treated between 1979 and 1996 at Memorial Sloan-Kettering Cancer Center. At the time of diagnosis, 21 of the 25 patients had prognostically unfavorable tumors including the presence of metastatic disease (n = 12), an axial primary (n = 17), and a tumor measuring greater than 8 cm (n = 18). The primary tumor was completely resected (wide local excision) in 13 patients, incompletely resected (marginal excision) in 7 patients, and biopsied only in the remaining 5 patients. The median dose of irradiation to the primary site was 30 Gy. RESULTS: With a median follow-up of 67 months (range 16-189 months) for the surviving patients, 28% failed distantly, and an additional 28% suffered from the progression of previously established metastatic disease. No patient failed locally. The median overall survival was 43 months. The actuarial overall survival at 5 years was 39% (+/-11%) for all patients and 60% (+/-14%) for patients with localized disease. CONCLUSIONS: Limited surgery and postoperative irradiation are one strategy that promises to balance the goal of achieving local control with the goal of diminishing late effects. Apart from the scenario in which radiation therapy is absolutely unnecessary, low-dose irradiation may be appropriate after considering the risk for local recurrence and overall prognosis.
Asunto(s)
Neoplasias Óseas/radioterapia , Sarcoma de Ewing/radioterapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Dosificación Radioterapéutica , Estudios Retrospectivos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/secundario , Sarcoma de Ewing/cirugía , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Melanoma in childhood is uncommon. Some believe that melanoma among children is associated with a better prognosis than among adults. METHODS: The authors reviewed their institutional experience with melanoma in 40 patients younger than 18 years treated between 1950 and 1984. All slides were reviewed by a single dermatopathologist who was blinded to clinical outcomes. Long term follow-up was available for all but three patients. RESULTS: There were 26 girls and 14 boys. The median age at diagnosis was 15 years (range, 3-17 years). Eleven patients (28%) were younger than 12 years. Fifteen patients (38%) had melanoma arise in a congenital nevus (2 had bathing trunk nevi. The most common site was the extremity (n = 23), followed by the trunk (n = 10) and the head and neck (n = 7). Seventeen patients (43%) initially were considered to have benign lesions, and 23 patients (57%) were diagnosed correctly with melanoma at initial presentation. Only 21 of 37 evaluable patients (57%) were alive at last follow-up with a median follow-up of 18 years (range, 2-48 years). Fifteen patients (41%) died of their disease, with a median survival of 12 months (range, 6-60 months). One patient died of breast carcinoma 14 years after treatment for melanoma. Disease free survival was 57% at 5 and 10 years. Of the 15 patients who died of disease, 12 were female (P = 0.09) and 10 had melanoma arising in a congenital nevus (P < 0.05). Five-year overall survival was 78% for patients who presented with localized disease (n = 23) and 30% for patients who presented with regional metastasis (n = 16, P < 0.001). There were no survivors among those who presented with systemic disease (n = 1). CONCLUSIONS: Children with melanoma are at significant risk of dying of their disease. Survival is similar to that seen among adults and depends on stage at presentation. The survival advantage observed for adult females is not seen among children.
Asunto(s)
Melanoma/mortalidad , Neoplasias Cutáneas/mortalidad , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/patología , Melanoma/cirugía , Estadificación de Neoplasias , Estudios Retrospectivos , Factores Sexuales , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
BACKGROUND: The identification of recently described nonrandom chromosomal defects specific for various small round-cell and spindle-cell sarcomas can eliminate diagnostic uncertainty arising from the clinical and histopathologic overlap of soft tissue neoplasms. METHODS: A 26-year-old man presented with bulky abdominal-pelvic disease. Immunohistochemical and molecular studies on tumor were performed. Treatment was instituted using cycles of high-dose cyclophosphamide (4,200 mg/m2) with doxorubicin (75 mg/m2). RESULTS: Clinical findings pointed to desmoplastic small round-cell tumor. The tumor was histologically undifferentiated and immunoreactive for vimentin but negative for other markers. Reverse transcriptase-polymerase chain reaction revealed the SYT/SSX2 fusion transcript of the synovial sarcoma t(X;18) chromosomal rearrangement. The high-dose chemotherapy, plus surgery, achieved a complete remission, but recurrent disease emerged 13 months from diagnosis. CONCLUSIONS: This clinically unique case of synovial sarcoma highlights how the use of now readily available molecular techniques will allow more accurate appraisals of the incidence and anatomic distribution of soft tissue neoplasms-information that bears upon pathogenesis and treatment. This case confirms the utility of high-dose alkylator-based therapy for synovial sarcoma. It also demonstrates that with nonlocalized solid tumors, the eradication of minimal residual disease remains an elusive goal. One alternative involves immunologic attack against markers derived from tumor-specific chromosomal defects such as those found in our patient.
Asunto(s)
Neoplasias Abdominales/diagnóstico , Sarcoma de Células Pequeñas/diagnóstico , Sarcoma Sinovial/diagnóstico , Neoplasias Abdominales/química , Neoplasias Abdominales/genética , Adulto , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Masculino , ARN Neoplásico/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma de Ewing/química , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Células Pequeñas/química , Sarcoma de Células Pequeñas/genética , Sarcoma Sinovial/química , Sarcoma Sinovial/genética , Translocación Genética/genética , Vimentina/análisisRESUMEN
The novel p73 gene is a structural and, in overexpression systems, functional p53 homologue. p73 resides on chromosome 1p36.33 within a commonly deleted region in neuroblastoma (NB) and other human tumors. To evaluate p73's candidacy for a NB suppressor, we analyzed 28 primary NB tumors, 14 NB cell lines, and 5 non-NB malignant pediatric tumors. We determined the level of p73 expression and its allelic origin and searched for mutations. Fifty-one different types of normal tissues all showed very low p73 expression. Although most NB tumors expressed p73 within the normal tissue range, wild-type p73 expression levels varied widely in NB and non-NB tumors and NB cell lines with increases up to 90-fold compared with normal tissues. Importantly, the p73 gene was biallelically expressed in five of six NB tumors and three of three normal tissues. Mutation analysis of the entire open reading frame of the gene in 16 tumors (including all 6 highly expressing tumors) revealed four polymorphic sites, but no mutations. Collectively, our data argue that p73 is unlikely to be a suppressor gene inactivated during neuroblastoma development.
Asunto(s)
Proteínas de Unión al ADN/genética , Neuroblastoma/genética , Proteínas Nucleares/genética , Alelos , Expresión Génica , Genes Supresores de Tumor , Humanos , Mutación , Células Tumorales Cultivadas , Proteína Tumoral p73 , Proteínas Supresoras de TumorRESUMEN
PURPOSE: Intense investigation has reshaped concepts about undifferentiated tumors occurring in young people (small round-cell tumors). Tumors associated with t(11;22)(p13;q12) and descriptively designated desmoplastic small round-cell tumor (DSRCT) are a distinctive, rare, poorly understood member of this family. We reviewed 109 cases of DSRCT to further characterize this entity better. METHODS: Clinical information and histology were reviewed. Immunohistochemistry and immunoblotting were performed using standard techniques. Chimeric EWS-WT1 RNA and DNA were detected by polymerase chain reaction (PCR) and genomic translocation breakpoints mapped in a subset of cases. RESULTS: There were 90 males and 19 females from 6 to 49 years of age (mean, 22 years). A total of 103 had tumor in the abdominal cavity, four in the thoracic region, one in the posterior cranial fossa, and one in the hand. Typical histologic and immunohistochemical features were usually evident in well-sampled tumors, but variations in cellularity, stromal components, cytology, architecture, and immunoreactivity occurred. Tumor cells were usually reactive with antibodies to keratin (67 of 78 cases, 86%), epithelial membrane antigen (50 of 54, 93%), vimentin (64 of 66, 97%), desmin (70 of 78, 90%), neuron-specific enolase (60 of 74, 81%), and the EWS-WT1 chimeric protein (25 of 27, 93%); typically nonreactive for muscle common actin (one of 58, 2%), myogenin (zero of eight, 0%), and chromogranin (one of 46, 2%); and variably reactive for MIC2 (nine of 47, 20%) and p53 (five of 17 with > 20% tumor cells reactive). Functional EWS-WT1 gene fusion was evident in 25 of 26 cases with genomic breakpoints in WT1 intron 7, and EWS introns 7, 8, and 9. Prognosis in general is poor, but tumors are responsive to aggressive therapy. CONCLUSION: This large review identifies a greater degree of clinical, pathologic, and molecular variation than originally appreciated for tumors associated with t(11;22)(p13;q12). Translocation and functional fusion of the EWS and WT1 genes appears to be a consistent feature of this unique tumor.
Asunto(s)
Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 22 , Translocación Genética , Neoplasias Abdominales/genética , Neoplasias Abdominales/metabolismo , Neoplasias Abdominales/patología , Adulto , Carcinoma de Células Pequeñas/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Femenino , Ribonucleoproteínas Nucleares Heterogéneas , Humanos , Masculino , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteína EWS de Unión a ARN , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Ribonucleoproteínas/biosíntesis , Ribonucleoproteínas/genética , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Proteínas WT1RESUMEN
PURPOSE: To improve response and survival rates in patients with high-risk rhabdomyosarcoma (RMS), extraosseous Ewing's sarcoma, and undifferentiated sarcoma, we used a short course of induction with multi-agent chemotherapy, hyperfractionated radiotherapy, and surgery when possible. Consolidation was with intensive chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Twenty-six patients (21 with RMS, three with undifferentiated sarcoma, and two with extraosseous Ewing's sarcoma) were entered onto the protocol between June 1990 and March 1994. Induction consisted of ifosfamide, etoposide, doxorubicin, dactinomycin, cyclophosphomide, and vincristine, and a split course of hyperfractionated radiotherapy. Patients who attained a complete response (CR) or good partial response (GPR) received consolidation with high-dose melphalan and etoposide followed by ABMT. RESULTS: Of 26 previously untreated patients 19 (73%) achieved a CR (n=13) or GPR (n=6) at the completion of induction and underwent ABMT. Two-year overall survival (OS) was 56% (95% confidence interval [CI], 36% to 76%) and progression-free survival (PFS) was 53% for the whole group (95% CI, 33% to 73%). CONCLUSION: Consolidation of response by myeloablative chemotherapy was well tolerated. Split-course hyperfractionated radiotherapy did not increase the rate of local control. The results of this short-course therapy were comparable to previous therapies of 1 to 2 years' duration. Induction and consolidation chemotherapy, as well as radiation dose, could be further intensified, since no death due to toxicity occurred among these patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Neoplasias de Células Germinales y Embrionarias/terapia , Rabdomiosarcoma/terapia , Sarcoma de Ewing/terapia , Adolescente , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Neoplasias de Células Germinales y Embrionarias/mortalidad , Dosificación Radioterapéutica , Rabdomiosarcoma/mortalidad , Sarcoma de Ewing/mortalidad , Tasa de Supervivencia , Trasplante AutólogoRESUMEN
PURPOSE: The results of laparoscopic procedures on patients with suspected or known lymphoma were analyzed to review the application and define the role of laparoscopy in lymphoma. PATIENTS AND METHODS: The hospital records of 94 patients who underwent 101 procedures between June 1993 and October 1996 were reviewed for demographic and clinicopathologic information. RESULTS: The procedure was diagnostic in 85 patients, either at primary presentation (48 patients), possible relapse (21 patients), in the course of treatment (eight patients), or of a liver lesion (eight patients). In the remaining 16 patients, it was used to stage possible intraabdominal disease. Twenty-seven patients had a previous unsuccessful diagnostic procedure. There were no operative deaths and eight postoperative complications (8%). The laparoscopy revealed non-Hodgkin's lymphoma (NHL) in 48 patients, Hodgkin's disease (HD) in 14 patients, other neoplastic conditions in six patients, and benign conditions in 33 patients. There was adequate information in all procedures in which lymphoma was diagnosed for treatment decisions. There was one false-negative and one nonresult for technical reasons. Ten patients commenced chemotherapy before discharge after a median delay of 3.5 days. In five of 24 patients (21%) with recurrent or persistent lymphoma, the precise diagnosis was significantly different from the original one. CONCLUSION: From our experience, laparoscopy can safely provide tissue samples of suspected lymphoma for full diagnostic analysis. It should be considered when percutaneous biopsy is not technically possible, when chromosomal or genetic analysis is needed for treatment decisions, or when the results of percutaneous biopsy are inadequate to make therapeutic decisions.