RESUMO
PURPOSE: Shared decision making (SDM) is ideally suited to abdominal wall surgery in older adults given the breadth of decision making required by the hernia surgeon and the impact on quality of life (QOL) by various treatment options. Given the paucity of literature surrounding SDM in hernia patients, the feasibility of a novel, formalized SDM aid/tool was evaluated in a pilot randomized trial. METHODS: Patients 60 years or older with a diagnosed ventral hernia were prospectively randomized at an academic hernia center. In the experimental arm, a novel SDM tool, based on the SHARE Approach, guided the consultation. Previously validated SDM assessments and patient's hernia knowledge retention was measured. RESULTS: Eighteen (18) patients were randomized (9 control and 9 experimental). Cohorts were well matched in age (p = 0.51), comorbidities (Charlson Comorbidity Score: p = 0.43) and frailty (mFI-11: p = 0.19; Risk Analysis Index: p = 0.33). Consultation time was 11 min longer in the experimental cohort (p < 0.01). There was a trend towards better Decisional Conflict Scores in the experimental group (p = 0.25) and the experimental cohort had improved post-visit retained hernia knowledge (p < 0.01). All patients in the experimental arm (100%) enjoyed working through the SDM aid/tool and felt it was a worthwhile exercise. CONCLUSION: Incorporating a formalized SDM tool into a busy hernia surgical practice is feasible and well received by patients. In addition, early results suggest it improves retention of basic hernia knowledge and may reduce patient's decisional conflict. Next steps include condensing the SDM tool to enhance efficiency within the clinic and beginning a large, randomized control trial.
Assuntos
Tomada de Decisão Compartilhada , Hérnia Ventral , Idoso , Tomada de Decisões , Avaliação Geriátrica , Hérnia Ventral/cirurgia , Herniorrafia , Humanos , Qualidade de VidaRESUMO
PURPOSE: Past techniques for the repair of complex incisional hernias have been met with unacceptably high recurrence rates and postoperative complications. The transversus abdominis release (TAR) is a versatile and durable solution gaining popularity amongst both abdominal wall specialists and general surgeons. However, several preoperative factors and specific intraoperative pitfalls can have a major impact on patient outcomes. METHODS: The authors review the current literature and draw upon their own practice experience to highlight key preoperative and perioperative steps for avoiding common pitfalls or "error traps" often performed by a surgeon new to this surgical technique. RESULTS: We discuss preoperative factors that influence the outcomes of patients undergoing incisional hernia repair. We show how a TAR that preserves the neurovascular bundles supplying the rectus complex and dissection in the correct plane prevents the formation of new, challenging unintended hernia defects and provides for wide prosthetic overlap offering the patient a sustainable repair. Lastly, we highlight key postoperative factors that affect a patient's recovery. CONCLUSIONS: Avoidance of surgical error traps combined with technique mastery can lead to the successful repair of challenging abdominal wall defects using the TAR approach.
Assuntos
Parede Abdominal , Hérnia Ventral , Hérnia Incisional , Músculos Abdominais/cirurgia , Parede Abdominal/cirurgia , Hérnia Ventral/cirurgia , Herniorrafia/métodos , Humanos , Hérnia Incisional/cirurgia , Erros Médicos , Recidiva , Telas CirúrgicasRESUMO
PURPOSE: Intraoperative drain placement during an open transversus abdominis release (TAR) is common practice. However, evidence detailing the optimal timing of drain removal is lacking. Surgical dogma teaches that drains should remain in place until output is minimal. This practice increases the risk of drain-associated complications (infection, pain, and skin irritation) and prolongs the burden of surgical drain maintenance. The objective of this study is to review infectious outcomes following TAR with early or late drain removal. METHODS: Patients who underwent an open bilateral TAR from 1/2018 to 1/2020 were eligible for the study. Prior to 2019, one of the two intraoperative drains was left in place at discharge. In 2019, clinical practice shifted to remove both drains at hospital discharge irrespective of output. The rate of infectious morbidity was compared between the two cohorts. RESULTS: A total of 184 patients were included: 89 late and 95 early drain removal. No differences in wound complications existed between the two cohorts: surgical site occurrence (SSO): 21.3% vs. 18.9% (p = 0.68); surgical site infection (SSI): 14.6% vs. 10.5% (p = 0.40); abscess: 8.9% vs. 4.2% (p = 0.20); seroma: 6.7% vs. 10.5% (p = 0.36); cellulitis: 14.6% vs. 8.4% (p = 0.19%); or SSO requiring procedural intervention (SSOPI): 5.6% vs. 5.2% (p = 0.92). Rates of antibiotic prescription and 30-day readmission were also similar (p = 0.69 and p = 0.89). CONCLUSIONS: Early removal of abdominal wall surgical drains at discharge irrespective of drain output does not increase the prevalence of infectious morbidity following TAR. It is likely safe to remove all drains at discharge regardless of drain output.
Assuntos
Parede Abdominal , Infecção da Ferida Cirúrgica , Músculos Abdominais/cirurgia , Parede Abdominal/cirurgia , Drenagem , Herniorrafia , Humanos , Seroma/epidemiologia , Seroma/etiologia , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologiaRESUMO
We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m2/day, x 4 days; thiotepa 300 mg/m2/day, x 3 days; and carboplatin approximately 500 mg/m2/day, x 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cis-retinoic acid, +/-oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.+/-8%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day +9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Nervoso Central/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neuroblastoma/terapia , Adolescente , Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Neoplasias do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , Terapia Combinada/métodos , Terapia Combinada/mortalidade , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/mortalidade , Neuroblastoma/mortalidade , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Falha de TratamentoRESUMO
Most studies of antibody-dependent cellular cytotoxicity (ADCC) by polymorphonuclear leukocytes (PMN) have supported oxidative lytic processes. This may be because the studies used nonhuman or nonneoplastic cells that were highly sensitive to reactive oxygen species or were small enough to be phagocytosed by PMN. We therefore investigated whether oxygen radicals participate in PMN cytotoxicity toward human neuroectodermal solid tumor cells sensitized by 3F8, which is an anti-ganglioside GD2 murine IgG3 monoclonal antibody with documented anticancer activity in humans. A 4-h 51Cr release assay was used to assess tumor cell lysis by hydrogen peroxide, superoxide, and hypochlorite. Nine of 11 GD2(+) human melanoma and neuroblastoma cell lines had equal or greater resistance to these oxidants as compared to a GD2(-) human carcinoma line (SKBr1-III) found by others (and confirmed by us) to be significantly more resistant to oxidative lysis than a murine cell line (P388D1) representative of those commonly used in cytotoxicity assays. To facilitate detection of oxidant-mediated lysis, subsequent studies of 3F8-mediated ADCC used GD2(+) targets that were relatively sensitive and others that were relatively resistant to oxygen radicals. Normal PMN and PMN obtained from children with chronic granulomatous disease, which do not generate reactive oxygen species, were equally effective in ADCC. Granulocyte-macrophage colony-stimulating factor, which primes oxidative responses of normal but not of chronic granulomatous disease PMN, enhanced ADCC by both kinds of PMN. During ADCC of 3F8-sensitized targets, with or without granulocyte-macrophage colony-stimulating factor, GD2(-) "innocent bystander" tumor cells (including P388D1) were not lysed, a finding consistent with unimportant extracellular release of cytotoxic mediators. Finally, antioxidant and antimyeloperoxidase moieties did not block ADCC. We conclude that oxidants are not key factors in 3F8-mediated lysis by PMN of human neuroectodermal tumor cells.
Assuntos
Anticorpos Monoclonais/farmacologia , Melanoma/imunologia , Neoplasias Embrionárias de Células Germinativas/imunologia , Neuroblastoma/imunologia , Neutrófilos/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Sobrevivência Celular , Radicais Livres , Gangliosídeos/metabolismo , Humanos , Imunoterapia , Melanoma/patologia , Melanoma/terapia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Neuroblastoma/patologia , Neuroblastoma/terapia , Oxigênio/metabolismo , Oxigênio/toxicidade , Células Tumorais CultivadasRESUMO
Clinical strategies which modulate the human anti-mouse antibody response (HAMA) in patients may have a profound influence on the idiotype network inducible by murine monoclonal antibodies (MoAb). Prior to myeloablative chemotherapy (ABMT), 9 patients with Stage IV neuroblastoma were imaged with 131I-3F8, a MoAb specific for the ganglioside GD2. Their serum HAMA, anti-idiotypic, anti-GD2, and anti-anti-idiotypic antibodies were assayed by enzyme-linked immunosorbent assay prior to, and at 3 and 6 months postimaging. HAMA and anti-idiotypic levels remained low, in contrast to the high levels in 10 patients imaged with 131I-3F8 without ABMT. Five of the 9 patients are long-term survivors; all had elevated anti-GD2 and anti-anti-idiotypic levels, significantly higher than those who died of disease. Although 131I-3F8 imaging prior to ABMT detected abnormal sites in 4 of 9 patients, 3 of the 4 patients have continued in remission for 24-63 months after ABMT, and all 3 mounted anti-GD2 and anti-anti-idiotypic antibody responses. We conclude that myeloablative therapy strongly suppressed the HAMA/anti-idiotypic response to murine MoAb and that the prognostic significance of host immune response to ganglioside GD2 MoAb deserves further investigation.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Anticorpos Monoclonais/imunologia , Gangliosídeos/imunologia , Neuroblastoma/imunologia , Neuroblastoma/terapia , Animais , Anticorpos Monoclonais/farmacologia , Formação de Anticorpos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Carmustina/administração & dosagem , Cisplatino/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Etoposídeo/administração & dosagem , Humanos , Melfalan/administração & dosagem , Camundongos/imunologia , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Prognóstico , Dosagem Radioterapêutica , Análise de Sobrevida , Taxa de Sobrevida , Tiotepa/administração & dosagemRESUMO
A rationally devised induction regimen of vincristine, Adriamycin (Adria Laboratories, Columbus, OH), and sequentially-escalated cyclophosphamide (CPM), followed by S-phase-specific agents (5-fluorouracil [5-FU]/cytosine arabinoside [ara-C]/hydroxyurea), was used in 100 patients with neuroblastoma. Of 17 patients under 1 year of age at diagnosis, complete (CR)/good partial (GPR) responses with long-term disease-free survival were achieved in 11 (85%) of 13 new patients and in two of four previously treated patients; six of the GPRs also received myeloablative therapy with autologous bone marrow rescue to consolidate remission status. The 83 patients over 1 year of age at diagnosis included three groups: (1) 36 new patients whose N4SE included maximal-dose CPM (ie, up to 140 to 160 mg/kg/course); (2) an earlier group of 18 new patients whose N4SE included moderate-dose CPM (ie, up to 80 mg/kg/course); and (3) 29 previously treated patients who all received the maximal-dose N4SE regimen. For new patients, CR/GPR rates were 72% in the maximal-dose group v 39% in the earlier moderate-dose group (P = .029). A CR/GPR rate of 41% and a partial response rate of 17% were observed for the 29 previously treated patients, all but two of whom had large tumor burdens after therapy that included moderate doses of CPM. Despite consolidation with myeloablative therapy, many responders in the three groups ultimately relapsed. The N4SE was strongly myelosuppressive, but only two patients died from associated infection. Extramedullary toxicity was limited to hemorrhagic cystitis in four of 33 CPM previously treated patients; this problem did not occur in the 67 new patients. The data indicate that the maximal-dose N4SE is an effective induction regimen for neuroblastoma, can achieve marked regressions of disease resistant to less intensive therapy, and is sparing of major body organs. This high rate of remission induction must be coupled with improvements in consolidation therapy to assure long-term disease-free survival of poor-risk patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Neuroblastoma/tratamento farmacológico , Fatores Etários , Transplante de Medula Óssea , Pré-Escolar , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Lactente , Masculino , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Fatores de Tempo , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
PURPOSE: Attempts to improve outcomes of patients with Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) metastatic to bone/bone marrow (BM) have focused on chemotherapy dose intensification strategies. We now present results achieved with that approach, as carried out at Memorial Sloan-Kettering Cancer Center (MSKCC) and as reported in the literature. PATIENTS AND METHODS: Twenty-one unselected MSKCC patients with newly diagnosed ES/PNET metastatic to bone/BM received the "P6" protocol which includes cycles of cyclophosphamide (4.2 g/m(2))/doxorubicin (75 mg/m(2))/vincristine and cycles of ifosfamide (9 g/m(2))/etoposide (500 mg/m(2)). Patients in complete/very good partial remission (CR/VGPR) after P6 received myeloablative therapy with either total-body irradiation (TBI) (hyperfractionated 15 Gy)/melphalan (180 mg/m(2)) or thiotepa (900 mg/m(2))/carboplatin (1,500 mg/m(2)). We reviewed the literature. RESULTS: Only one MSKCC patient became a long-term event-free survivor; all but one relapse was in a distant site. Initial responses to P6 were CR/VGPR in 19 patients, but eight of them plus two others developed PD while receiving or shortly after completing P6. Eight patients were treated with TBI/melphalan: four relapsed 2 to 7 months after transplantation; two died early of toxicity; one died of pulmonary failure 17 months after transplantation (no evidence of ES/PNET); and one remains in CR at more than 7 years. The three patients treated with thiotepa/carboplatin relapsed 3 to 4 months after transplantation. All reports on large series of unselected patients with ES/PNET metastatic to bone/BM showed similarly unsatisfactory results. Poor outcome was seen with use of active agents for ES/PNET-cyclophosphamide, ifosfamide, doxorubicin, dactinomycin, vincristine, etoposide - at standard dosages for prolonged periods of time and at higher dosages in intensive regimens for short or prolonged periods of time. No improvements in event-free survival rates occurred with successive cooperative group or large single-institutional studies that used increasingly aggressive chemotherapeutic approaches. Inclusion of ifosfamide with or without etoposide made no difference nor did consolidation of remission with myeloablative chemoradiotherapy. Secondary leukemia emerged as a major risk with dose-intensive regimens. CONCLUSION: The MSKCC experience and findings reported in the literature suggest that dose-intensive use of the chemotherapy agents with established activity against ES/PNET is reaching its efficacy and toxicity limits. A major impact on prognosis awaits the development of entirely novel therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Medula Óssea/tratamento farmacológico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Medula Óssea/radioterapia , Neoplasias da Medula Óssea/secundário , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Criança , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Masculino , Melfalan/administração & dosagem , Tumores Neuroectodérmicos Primitivos/radioterapia , Tumores Neuroectodérmicos Primitivos/secundário , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/secundário , Tiotepa/administração & dosagem , Vincristina/administração & dosagem , Irradiação Corporal TotalRESUMO
We report an unusual case of progressive disseminated neuroblastoma occurring in a child with a family history and stigmata of von Recklinghausen's disease. A review of the literature confirms the extreme rarity of finding these two neurocristopathies in a single individual and thus undermines the widely held notion of an association--genetic or otherwise--between these two entities. We propose that synchronous neuroblastoma and von Recklinghausen's disease is accounted for by chance alone and therefore represents a randomly occurring phenomenon.
Assuntos
Neuroblastoma/complicações , Neurofibromatose 1/complicações , Pré-Escolar , Humanos , Neuroblastoma/genética , Neurofibromatose 1/genéticaRESUMO
PURPOSE: To describe oncolytic effects of treatment with anti-G(D2) monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with neuroblastoma (NB). PATIENTS AND METHODS: Patients were eligible for 3F8/GM-CSF if intensive therapy had not eradicated potentially lethal NB. One cycle consisted of GM-CSF (subcutaneous bolus) on days 1 through 5, 11, and 12, and GM-CSF (2-hour intravenous [IV] infusion) followed after a 1-hour interval by 3F8 (1.5-hour IV infusion) on days 6 through 10 and 13 through 17. GM-CSF was dosed at 250 microg/m(2)/d on days 1 through 7 and at 500 microg/m(2)/d on days 8 through 17. 3F8 was dosed at 10 mg/m(2)/d (100 mg/m(2)/cycle). 3F8 was given with an opiate and an antihistamine. Patients without progressive disease (PD) or elevated human antimouse antibody titers could be treated again beginning 3 weeks after completion of a cycle. RESULTS: Among 19 patients treated for NB resistant to induction therapy, 12 of 15 had complete remission (CR) of bone marrow (BM) disease, and three others who had less than partial responses achieved prolonged progression-free survival (one remains on study at 21+ months, two had PD at 12 and 17 months). Among patients treated for recurrent NB resistant to retrieval therapy, five of 10 had CR in BM. The 15 patients treated for PD fared poorly, although two had scintigraphic findings suggestive of a short-term response. Side effects were limited to readily manageable pain and, less commonly, rash of short duration; hence, patients were treated as outpatients. CONCLUSION: 3F8/GM-CSF is well tolerated and shows promise for treatment of minimal residual NB in BM.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Medula Óssea/tratamento farmacológico , Neoplasias Ósseas/tratamento farmacológico , Gangliosídeos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Imunoglobulina G/uso terapêutico , Neuroblastoma/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais Murinos , Citotoxicidade Celular Dependente de Anticorpos , Criança , Pré-Escolar , Progressão da Doença , Quimioterapia Combinada , Feminino , Humanos , Infusões Intravenosas , MasculinoRESUMO
PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma. PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m(2) taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling. RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m(2) to 3,935 mg/m(2) (median, 2,300 mg/m(2)). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses. CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Medula Óssea/tratamento farmacológico , Etoposídeo/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Administração Oral , Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Medula Óssea/patologia , Criança , Pré-Escolar , Esquema de Medicação , Etoposídeo/efeitos adversos , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Neuroblastoma/patologia , Resultado do TratamentoRESUMO
PURPOSE: To assess treatment-related myelodysplasia/leukemia (t-AML) in neuroblastoma patients by a review of the Memorial Sloan-Kettering Cancer Center (MSKCC) data and the literature. PATIENTS AND METHODS: We studied 380 previously untreated and treated MSKCC patients. Low-risk patients received no cytotoxic therapy. High-risk patients received the N4, N5, or N6 regimens. Dosing per cycle and cumulative dosing of leukemogenic agents peaked with N6, which included four cycles of cyclophosphamide 4,200 mg/m2 and doxorubicin 75 mg/m2, plus three cycles of cisplatin 200 mg/m2 and etoposide 600 mg/m2. We reviewed the literature. RESULTS: t-AML occurred in six MSKCC patients, which included three of 53 patients in whom the only chemotherapy consisted of N6, and three patients treated for relapsed or refractory neuroblastoma; no case of leukemia emerged among the 50 low-risk patients. Four cases were found incidentally in routine follow-up bone marrow tests. The 36-month cumulative incidence of t-AML in the N6 cohort was 7% (95% confidence interval, 0 to 15). Published data parallel the MSKCC experience in that t-AML after neuroblastoma was once rare but has become less so since the mid-1980s, when the intensified use of topoisomerase-II inhibitors and alkylators first gained wide acceptance and produced better response rates and longer survival. CONCLUSION: Neuroblastoma itself is not associated with a host susceptibility to leukemia. However, current neuroblastoma treatment programs that use high-dose cyclophosphamide, cisplatin, and topoisomerase-II inhibitors may entail a considerable risk for t-AML. The incidence of t-AML in neuroblastoma patients may be underestimated because treatment and clinical factors can mask its presence. Efforts to devise effective but less leukemogenic treatment for neuroblastoma or to truncate leukemogenic therapy, eg, by exploiting molecular techniques for the early identification of complete remission, are warranted.
Assuntos
Antineoplásicos/efeitos adversos , Leucemia Mieloide/induzido quimicamente , Síndromes Mielodisplásicas/induzido quimicamente , Neuroblastoma/tratamento farmacológico , Institutos de Câncer , Humanos , New YorkRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neuroblastoma/radioterapia , Pré-Escolar , Fracionamento da Dose de Radiação , Feminino , Genes myc , Humanos , Lactente , Metástase Linfática , Masculino , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neuroblastoma/tratamento farmacológico , Neuroblastoma/cirurgia , Radioterapia Adjuvante , Fatores de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Although positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ((18)F-FDG) has a major impact on the treatment of adult cancer, the reported experience with extracranial tumors of childhood is limited. We describe a role for PET in patients with neuroblastoma (NB). PATIENTS AND METHODS: In 51 patients with high-risk NB, 92 PET scans were part of a staging evaluation that included iodine-123 or iodine-131 metaiodobenzylguanidine (MIBG) scan, bone scan, computed tomography (and/or magnetic resonance imaging), urine catecholamine measurements, and bone marrow (BM) examinations. The minimum number of tests sufficient to detect NB was determined. RESULTS: Of 40 patients who were not in complete remission, only 1 (2.5%) had NB that would have been missed had a staging evaluation been limited to PET and BM studies, and 13 (32.5%) had NB detected by PET but not by BM and urine tests. PET was equal or superior to MIBG scans for identifying NB in soft tissue and extracranial skeletal structures, for revealing small lesions, and for delineating the extent and localizing sites of disease. In 36 evaluations of 22 patients with NB in soft tissue, PET failed to identify only two long-standing MIBG-negative abdominal masses. PET and MIBG scans showed more skeletal lesions than bone scans, but the normally high physiologic brain uptake of FDG blocked PET visualization of cranial vault lesions. Similar to MIBG, FDG skeletal uptake was diffusely increased with extensive or progressing BM disease but faint or absent with minimal or nonprogressing BM disease. CONCLUSION: In the absence or after resolution of cranial vault lesions, and once the primary tumor is resected, PET and BM tests suffice for monitoring NB patients at high risk for progressive disease in soft tissue and bone/BM.
Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neuroblastoma/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem , Tomografia Computadorizada de Emissão , 3-Iodobenzilguanidina , Adolescente , Adulto , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/secundário , Compostos Radiofarmacêuticos , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/secundário , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: To measure the sensitivity of histologic examination in detecting metastatic solid tumor in bone marrow. PATIENTS AND METHODS: A total of 145 patients with stage 4 neuroblastoma underwent 840 marrow examinations, each consisting of six sites (four aspirates and two biopsies), from October 1990 to June 1996 at Memorial Sloan-Kettering Cancer Center. Metastasis was detected by either histology (aspirate by Wright-Giemse and biopsy by Hematoxylin-Eosin stains) or immunostaining of aspirates using anti-G(D2) monoclonal antibodies. RESULTS: The absence of tumor by histology at a single marrow site was a poor guarantee of the absence of disease. The number of false-negative sites increased as the percent of G(D2)-positive tumor cells in the marrow decreased: zero of six if tumor cell count was > or = 1%, and approximately six of six sites if < or = 0.003%. Sensitivity was comparable between marrow aspirate and biopsy. A lower bound (LB) for the probability of false-negative histology was calculated from the (1) discordance among the six marrow samplings and (2) comparison with immunofluorescence. When disease was extensive (eg, at diagnosis), the LB was 0.13 and 0.3, respectively. After treatment, it increased to 0.37 and 0.8. Examining multiple marrow sites can decrease the LB to 0.15. However, at least three sites have to be negative at relapse, six at diagnosis, and more than 50 during treatment or off-therapy follow-up. The marginal decrease in the LB by additional samplings rapidly diminished to less than 0.05 after two sites. CONCLUSION: Except at diagnosis and relapse when gross disease is present, marrow sampling by histology has limited sensitivity. Current practice grossly underestimates the true prevalence of marrow disease.
Assuntos
Neoplasias da Medula Óssea/diagnóstico , Neoplasias da Medula Óssea/secundário , Medula Óssea/patologia , Neuroblastoma/diagnóstico , Neuroblastoma/secundário , Biomarcadores Tumorais/análise , Biópsia por Agulha , Medula Óssea/metabolismo , Reações Falso-Negativas , Gangliosídeos/análise , Humanos , Imuno-Histoquímica , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
PURPOSE: To help fill the gap in knowledge about the risk of leukemia from repetitive high-dose use of alkylating agents and topoisomerase-II inhibitors in young patients with solid tumors. METHODS: Poor-risk solid tumors were treated with four courses of cyclophosphamide (4,200 mg/m2)/ doxorubicin (75 mg/m2), and three courses of ifosfamide (9,000 mg/m2)/etoposide (500 mg/m2). The cumulative incidence of treatment-related myelodysplasia/ leukemia (t-AML) was calculated using the method of competing risks. The expected number of leukemic events was calculated by applying national incidence rates to person-years classified by age and sex. RESULTS: Among 86 patients (median age, 17 years) monitored for 6 to 88 months (median, 24), five cases of t-AML were detected at 10 to 37 months (median, 17). The expected number of leukemic events in this cohort was .001. Clinical and cytogenetic findings implicated prior alkylator therapy in three cases and prior treatment with topoisomerase-II inhibitors in two. At 40 months, the cumulative incidence of t-AML was 8% (SE 7%). CONCLUSION: Repetitive high-dose use of alkylating agents given with topoisomerase-II inhibitors is strongly leukemogenic, even with modest cumulative doses of each drug. This finding is notable for the following reasons: (1) it undermines predictions that limited use of high-dose chemotherapy might be minimally leukemogenic, and (2) it contrasts strikingly with the previously reported low risk of t-AML following treatment of pediatric solid tumors with chemotherapy lacking the alkylator dose-intensity and prominence of etoposide that are hallmarks of current regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia/induzido quimicamente , Síndromes Mielodisplásicas/induzido quimicamente , Segunda Neoplasia Primária/induzido quimicamente , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Criança , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Masculino , Estudos Prospectivos , Fatores de Risco , Vincristina/administração & dosagemRESUMO
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.
Assuntos
Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 22 , Translocação Genética , Neoplasias Abdominais/genética , Neoplasias Abdominais/metabolismo , Neoplasias Abdominais/patologia , Adulto , Carcinoma de Células Pequenas/metabolismo , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Feminino , Ribonucleoproteínas Nucleares Heterogêneas , Humanos , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteína EWS de Ligação a RNA , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Ribonucleoproteínas/biossíntese , Ribonucleoproteínas/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Proteínas WT1RESUMO
PURPOSE: To eradicate minimal residual disease with anti-G(D2) monoclonal antibody 3F8 in stage 4 neuroblastoma (NB) diagnosed at more than 1 year of age. PATIENTS AND METHODS: Thirty-four patients were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (n=31) or distant bony metastases (n=29). Thirteen patients were treated at second or subsequent remission (group I) and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation (BMT); 21 patients were treated in first remission following N6 chemotherapy (group II). RESULTS: Before 3F8 treatment, 23 patients were in complete remission CR, eight in very good partial remission (VGPR), one in partial remission (PR), and two had microscopic foci in marrow. Twenty-five had evidence of NB by at least one measurement of occult/minimal tumor (iodine 131[(131)I]-3F8 imaging, marrow immunocytology, or marrow reverse-transcriptase polymerase chain reaction [RT-PCR]). Acute self-limited toxicities of 3F8 treatment were severe pain, fever, urticaria, and reversible decreases in blood counts and serum complement levels. There was evidence of response by immunocytology (six of nine), by GAGE RT-PCR (seven of 12), and by (131)I-3F8 scans (six of six). Fourteen patients are alive and 13 (age 1.8 to 7.4 years at diagnosis) are progression-free (40 to 130 months from the initiation of 3F8 treatment) without further systemic therapy, none with late neurologic complications. A transient anti-mouse response or the completion of four 3F8 cycles was associated with significantly better survival. CONCLUSION: Despite high-risk nature of stage 4 NB, long-term remission without autologous (A)BMT can be achieved with 3F8 treatment. Its side effects were short-lived and manageable. The potential benefits of 3F8 in consolidating remission warrant further investigations.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Gangliosídeos/imunologia , Neoplasia Residual/terapia , Neuroblastoma/terapia , Anticorpos Monoclonais/efeitos adversos , Antígenos de Neoplasias/biossíntese , Neoplasias da Medula Óssea/secundário , Neoplasias Ósseas/secundário , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Imunoterapia , Lactente , Masculino , Estadiamento de Neoplasias , Neuroblastoma/tratamento farmacológico , Neuroblastoma/radioterapia , Resultado do TratamentoRESUMO
PURPOSE: To test the efficacy of a protocol for poor-risk neuroblastoma that builds on the following: (1) our favorable previously reported results with dose-intensive use of cyclophosphamide; (2) our retrospective analysis of neuroblastoma chemotherapy reports, which supported the value of high-dose cisplatin and etoposide (VP-16); and (3) the Goldie-Coldman hypothesis that rapid cytoreduction plus the use of non-cross-resistant chemotherapy combinations will decrease the risk of drug resistance. PATIENTS AND METHODS: The N6 protocol included seven courses of high-dose chemotherapy plus surgical resection of bulk disease. Courses 1, 2, 4, and 6 consisted of 6-hour intravenous infusions of cyclophosphamide 70 mg/kg/d on days 1 and 2 (ie, 140 mg/kg per course), a 72-hour intravenous infusion of doxorubicin 75 mg/m2 and vincristine 0.1 mg/kg beginning day 1, and vincristine 1.5 mg/m2 intravenous bolus on day 9. Courses 3, 5, and 7 consisted of 2-hour intravenous infusions of VP-16 200 mg/m2/d on days 1 to 3 (ie, 600 mg/m2 per course), and 1-hour intravenous infusions of cisplatin 50 mg/m2/d on days 1 to 4 (ie, 200 mg/m2 per course). Courses were to start after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Response was defined by international criteria. RESULTS: Among 24 consecutive previously untreated patients diagnosed with stage 4 neuroblastoma at more than 1 year of age, 21 patients achieved a complete or very good partial remission; one patient had no evidence of disease except by iodine-131-metaiodobenzylguanidine (MIBG) scan, which was markedly improved; and one patient had resolution of extensive metastatic disease, but still had an incompletely resected primary tumor. The sole patient to have a poor response had clinical features at diagnosis that are atypical for neuroblastoma, namely, 8 years of age and an unknown primary tumor. Severe toxicities included myelosuppression, mucositis, and hearing deficits. CONCLUSION: The N6 approach reliably achieves significant cytoreduction against stage 4 neuroblastoma. This may eventuate in an improved cure rate, since consolidative treatments using myeloablative therapy, immunotherapy, or biologic response modifiers such as cis-retinoic acid are most likely to be effective against minimal residual disease.
Assuntos
Neoplasias Abdominais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neoplasias Torácicas/tratamento farmacológico , Neoplasias Abdominais/patologia , Neoplasias Abdominais/cirurgia , Antibacterianos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/terapia , Humanos , Infecções/induzido quimicamente , Infecções/terapia , Masculino , Estadiamento de Neoplasias , Neuroblastoma/secundário , Neuroblastoma/cirurgia , Transfusão de Plaquetas , Indução de Remissão/métodos , Estudos Retrospectivos , Neoplasias Torácicas/patologia , Neoplasias Torácicas/cirurgia , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Myeloablative treatment intensification in 25 patients diagnosed when older than 12 months of age with stage IV neuroblastoma included sequential delivery of cisplatin 120 mg/m2 x 1, hyperfractionated radiation (2,100 cGy) to the primary site and adjacent lymph nodes, carmustine (BCNU) 200 mg/m2 x 1, melphalan 60 mg/m2/d x 3 (n = 13) or thiotepa 300 mg/m2/d x 3. (n = 12), and etoposide (VP 16) 300 mg/m2/d x 3. Seventy-two hours after the last dose of VP 16, histologically tumor-free and 4-hydroperoxycyclophosphamide (4-HC; 100 mumol/L)-purged autologous bone marrow (ABMT) was infused. Acute toxicities included grade 3 to 4 oral mucositis, grade 1 to 2 diarrhea, and fevers. No patient required infusion of unpurged reserve autografts. At ABMT, 16 patients (group I) were progression-free 6.5 months to 14 months (median, 9 months) from diagnosis: seven remain progression-free 20 months to 46 months (median, 39 months) off therapy, six relapsed 4 months to 17 months post-ABMT, and three died of toxicity (candidiasis, metabolic derangement, and venoocclusive disease [VOD]). The event-free survival of group I patients is 44% at 24 months post-ABMT. Nine patients (group II) were in second remission at ABMT, including three who had relapsed after other transplant procedures: two are progression-free 24 months and 41 months off therapy, four relapsed 3 months to 12 months post-ABMT, and three died of toxicity (aspergillosis, hemorrhagic cystitis, VOD). Only one of 10 relapses involved a primary site, suggesting a beneficial effect of local radiation. In terms of survival or toxicity, an advantage for melphalan or thiotepa was not evident. Regimens such as this may prolong the survival of selected patients with poor-risk neuroblastoma, but concerns over late relapses and toxicity mandate continuing efforts to devise alternative, less risky, and more clearly beneficial approaches for definitive ablation of neuroblastoma.