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1.
J Appl Clin Med Phys ; 20(2): 24-29, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30653831

RESUMO

Volumetric modulated arc therapy (VMAT) has been implemented for left breast irradiation to reduce prescription dose to the heart and improve dose homogeneity across the targeted breast. Our in-house method requires application of a bolus during the optimization process with a target outside of the body, then removing the bolus during the final calculation in order to incorporate skin flash in VMAT plans. To quantify the dosimetric trade-offs between traditional 3D field-in-field tangents and VMAT with integrated skin flash for these patients, we compared nine consecutive patients who recently received radiation to their entire left breast but not their regional lymphatics. Tangent plans used non-divergent tangents of mixed energies and VMAT plans utilized four 6 MV arcs of roughly 260°. Mean dose to the heart, contralateral lung, and contralateral breast and their volume receiving 5%, 10%, and 20% of the prescription dose were higher in all nine VMAT plans than in the static tangential beam plans. For all critical structures, the mean VMAT DVH was higher in the low-dose region and crossed the 3D field-in-field DVH between 23.13% and 34.18% of the prescription dose (984.75-1454.70 cGy). However, the volume of the contralateral breast and heart receiving the prescription dose was slightly lower in the VMAT plans, but not statistically significant. VMAT provided superior homogeneity, with a mean homogeneity index of 9.41 ± 1.64 compared to 11.05 ± 1.82 for 3D tangents. Results indicate that VMAT spares the heart, contralateral lung, and contralateral breast from prescription dose at the cost of increasing their mean and low-dose volume and delivers a more homogenous dose distribution to the breast. For these reasons, VMAT is selectively applied at the request of the physician for left breast radiation without respiratory gating to spare the heart from prescription dose in cases of poor anatomical geometry.


Assuntos
Imageamento Tridimensional/métodos , Órgãos em Risco/efeitos da radiação , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Pele/efeitos da radiação , Neoplasias Unilaterais da Mama/radioterapia , Feminino , Coração/efeitos da radiação , Humanos , Pulmão/efeitos da radiação , Prognóstico , Dosagem Radioterapêutica , Tomografia Computadorizada por Raios X/métodos , Neoplasias Unilaterais da Mama/diagnóstico por imagem
2.
Neuro Oncol ; 18(10): 1442-50, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27006176

RESUMO

BACKGROUND: The prognosis for children with malignant glioma is poor. This study was designed to determine whether lomustine and temozolomide following radiotherapy and concurrent temozolomide improves event-free survival (EFS) compared with historical controls with anaplastic astrocytoma (AA) or glioblastoma (GBM) and whether survival is influenced by the expression of O6-methylguanine-DNA-methyltransferase (MGMT). METHODS: Following maximal surgical resection, newly diagnosed children with nonmetastatic high-grade glioma underwent involved field radiotherapy with concurrent temozolomide. Adjuvant chemotherapy consisted of up to 6 cycles of lomustine 90 mg/m(2) on day 1 and temozolomide 160 mg/m(2)/day ×5 every 6 weeks. RESULTS: Among the 108 eligible patients with AA or GBM, 1-year EFS was 0.49 (95% CI, 0.39-0.58), similar to the original CCG-945-based design model. However, EFS and OS were significantly improved in ACNS0423 compared with the 86 AA or GBM participants treated with adjuvant temozolomide alone in the recent ACNS0126 study (1-sided log-rank P = .019 and .019, respectively). For example, 3-year EFS was 0.22 (95% CI, 0.14-0.30) in ACNS0423 compared with 0.11 (95% CI, 0.05-0.18) in ACNS0126. Stratifying the comparison by resection extent, the addition of lomustine resulted in significantly better EFS and OS in participants without gross-total resection (P = .019 and .00085 respectively). The difference in EFS and OS was most pronounced for participants with GBM (P = .059 and 0.051, respectively), and those with MGMT overexpression (P = .00036 and .00038, respectively). CONCLUSION: The addition of lomustine to temozolomide as adjuvant therapy in ACNS0423 was associated with significantly improved outcome compared with the preceding COG ACNS0126 HGG study in which participants received temozolomide alone.


Assuntos
Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Lomustina/administração & dosagem , Lomustina/efeitos adversos , Masculino , Temozolomida , Adulto Jovem
3.
Ann Surg Oncol ; 20(11): 3391-7, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23835652

RESUMO

BACKGROUND: Cutaneous angiosarcoma (CAS) is a rare, aggressive vascular sarcoma with a poor prognosis, historically associated with 5-year overall survival (OS) rates between 10 and 30 %. METHODS: This is a single-institution retrospective review of patients treated for CAS from 1999-2011. Demographics, primary tumor characteristics, treatment, and outcomes were analyzed. RESULTS: A total of 88 patients were identified (median age 70 years and 57 % female). Median tumor size was 3 cm. Median follow-up was 22 months. The 5-year OS and recurrence-free survival (RFS) were 35.2 and 32.3 %, respectively; median was 22.1 months. Also, 36 patients (41 %) received surgery alone, 7 (8 %) received XRT alone, and 41 (47 %) received surgery and XRT. Of the 67 of 88 patients who were disease-free after treatment, 33 (50 %) recurred (median of 12.3 months). Surgery alone had the highest 5-year OS (46.9 %) and RFS (39.9 %) (p = ns). Four presentation groups were identified: (1) XRT-induced, n = 30 (34 %), 26 of 30 occurred in females with a prior breast cancer, (2) sporadic CAS on head and neck (H/N), n = 38, (3) sporadic CAS on trunk/extremities, n = 13, and (4) Stewart-Treves n = 7. Those with trunk/extremity CAS had the highest 5-year OS (64.8 %), with H/N CAS having the worst 5-year OS (21.5 %). On MV analysis, only tumor size <5 cm correlated with improved OS (p = 0.014). DISCUSSION: In this large series, there appears to be a better overall prognosis than historically reported, especially in Stewart-Treves and CAS on trunk or extremities. While surgery alone was associated with better OS and RFS compared with other treatment modalities, this was not statistically significant. Tumor size was a significant prognostic factor for OS.


Assuntos
Hemangiossarcoma/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Seguimentos , Hemangiossarcoma/patologia , Hemangiossarcoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida , Adulto Jovem
5.
J Clin Oncol ; 30(15): 1842-8, 2012 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-22529259

RESUMO

PURPOSE: The primary objective of Children's Oncology Group study P9641 was to demonstrate that surgery alone would achieve 3-year overall survival (OS) ≥ 95% for patients with asymptomatic International Neuroblastoma Staging System stages 2a and 2b neuroblastoma (NBL). Secondary objectives focused on other low-risk patients with NBL and on those who required chemotherapy according to protocol-defined criteria. PATIENTS AND METHODS: Patients underwent maximally safe resection of tumor. Chemotherapy was reserved for patients with, or at risk for, symptomatic disease, with less than 50% tumor resection at diagnosis, or with unresectable progressive disease after surgery alone. RESULTS: For all 915 eligible patients, 5-year event-free survival (EFS) and OS were 89% ± 1% and 97% ± 1%, respectively. For patients with asymptomatic stage 2a or 2b disease, 5-year EFS and OS were 87% ± 2% and 96% ± 1%, respectively. Among patients with stage 2b disease, EFS and OS were significantly lower for those with unfavorable histology or diploid tumors, and OS was significantly lower for those ≥ 18 months old. For patients with stage 1 and 4s NBL, 5-year OS rates were 99% ± 1% and 91% ± 1%, respectively. Patients who required chemotherapy at diagnosis achieved 5-year OS of 98% ± 1%. Of all patients observed after surgery, 11.1% experienced recurrence or progression of disease. CONCLUSION: Excellent survival rates can be achieved in asymptomatic low-risk patients with stages 2a and 2b NBL after surgery alone. Immediate use of chemotherapy may be restricted to a minority of patients with low-risk NBL. Patients with stage 2b disease who are older or have diploid or unfavorable histology tumors fare less well. Future studies will seek to refine risk classification.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/cirurgia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Criança , Pré-Escolar , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Seleção de Pacientes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
6.
Pediatr Blood Cancer ; 58(6): 905-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21990040

RESUMO

BACKGROUND: Choroid plexus tumors (CPT) are rare, and predominate in early childhood. An association with the Li-Fraumeni syndrome (LFS) has been reported, but the biological and clinical implications of this association remain poorly defined. We have investigated the clinical features and overall survival of all CPT patients treated at Children's Hospital Los Angeles (CHLA) over a 20-year period, with particular attention to the association of CPT with LFS. METHODS: A retrospective evaluation of the course of therapy and clinical outcome was undertaken on the 42 patients diagnosed with and treated for CPT at CHLA from January 1991 to December 2010. Any association with multiple primary tumors and family histories consistent with LFS was investigated in all patients. RESULTS: Six of the 42 patients (16.7%), demonstrated either phenotypic and/or genotypic characteristics consistent with LFS, with either a distinct family history of cancer, a synchronous diagnosis of a different type of cancer, or the subsequent development of metachronous cancers. Of 11 patients with choroid plexus carcinoma tested for TP53 germline mutations, four (36.4%) were positive. A single patient with a choroid plexus papilloma had phenotypic characteristics of LFS but tested negative for TP53. CONCLUSIONS: Children with CPC appear to have a high frequency of TP53 germline mutations in association with LFS. This raises the question whether all children with CPC should be tested for TP53 germline mutations in order to institute screening to enhance early detection and treatment of subsequent cancers.


Assuntos
Neoplasias do Plexo Corióideo/complicações , Neoplasias do Plexo Corióideo/mortalidade , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Neoplasias do Plexo Corióideo/terapia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Síndrome de Li-Fraumeni/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Adulto Jovem
7.
Cancer ; 118(3): 761-9, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21766293

RESUMO

BACKGROUND: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML. METHODS: AAML03P1 enrolled 350 children with previously untreated AML. Patients with a matched family donor received 3 courses of chemotherapy followed by hematopoietic stem cell transplantation; those without a matched family donor received 5 courses of chemotherapy. Gemtuzumab ozogamicin 3 mg/m(2)/dose was administered on Day 6 of Course 1 and Day 7 of Course 4. RESULTS: Toxicities observed in all courses of therapy were typical of AML chemotherapy regimens, with infection being most common. Patients achieved a complete remission rate of 83% after 1 course and 87% after 2 courses. The mortality rate was 1.5% after the first gemtuzumab ozogamicin-containing induction course and 2.6% after 2 induction courses. The 3-year event-free survival and overall survival rates were 53 ± 6% and 66 ± 5%, respectively. CONCLUSIONS: This trial determined that it is safe and feasible to include gemtuzumab ozogamicin in combination with intensive chemotherapy. The survival rates compare favorably with the recently published results of clinical trials worldwide.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Adolescente , Adulto , Aminoglicosídeos/administração & dosagem , Amsacrina/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Criança , Pré-Escolar , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Gemtuzumab , Humanos , Lactente , Recém-Nascido , Masculino , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Taxa de Sobrevida , Adulto Jovem
8.
Neuro Oncol ; 13(3): 317-23, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21339192

RESUMO

To determine whether temozolomide is an active agent in the treatment of children with high-grade astrocytomas and whether survival is influenced by the expression of the O6-methylguanine-methyltransferase gene (MGMT) in these patients. In the Children's Oncology Group study ACNS0126, 107 patients with a diagnosis of anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), or gliosarcoma were enrolled. All patients underwent concomitant chemoradiotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide. The outcomes were compared with those of children treated in Children's Cancer Group (CCG) study CCG-945. Formalin-fixed, paraffin-embedded tumor tissue was available in 71 cases for immunohistochemical analysis of MGMT expression. Ninety patients were deemed eligible, 31 with AA, 55 with GBM, and 4 with other eligible diagnoses. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 ± 3% and 22 ± 5%, respectively. There was no evidence that temozolomide given during radiation therapy and as adjuvant therapy resulted in improved EFS compared with that found in CCG-945 (p = 0.98). The 3-year EFS rate for AA was 13 ± 6% in ACNS0126 compared with 22 ± 5.5% in CCG-945 (p = 0.95). The 3-year EFS rate for GBM was 7 ± 4% in ACNS0126 compared with 15 ± 5% in CCG-945 (p = 0.77). The 2-year EFS rate was 17 ± 5% among patients without MGMT overexpression and 5 ± 4% among those with MGMT overexpression (p = 0.045). Temozolomide failed to improve outcome in children with high-grade astrocytomas. MGMT overexpression was adversely associated with survival.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Gliossarcoma/tratamento farmacológico , Adolescente , Adulto , Neoplasias Encefálicas/radioterapia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Dacarbazina/uso terapêutico , Feminino , Seguimentos , Glioblastoma/radioterapia , Gliossarcoma/radioterapia , Humanos , Técnicas Imunoenzimáticas , Masculino , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Dosagem Radioterapêutica , Taxa de Sobrevida , Temozolomida , Resultado do Tratamento , Adulto Jovem
9.
Neuro Oncol ; 13(4): 410-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21345842

RESUMO

An open-label phase II study (ACNS0126) testing the efficacy of chemoradiotherapy with temozolomide (TMZ) followed by adjuvant TMZ was conducted by the Children's Oncology Group. During the period from July 6, 2004 through September 6, 2005, 63 children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) were enrolled in the study. All patients received TMZ at a dosage of 90 mg/m(2)/day for 42 days to a dose of 59.4 Gy. Four weeks following irradiation, TMZ was given at a dosage of 200 mg/m(2)/day for 5 days every 28 days, for a total of 10 cycles. The primary objective of the statistical analysis was to determine whether the current treatment produced a 1-year event-free survival (EFS) rate higher than the historical baseline of 21.9% observed in CCG-9941. The mean 1-year EFS (± standard deviation) was 14% ± 4.5%, compared with 21.9% ± 5% for CCG-9941. The P value of the test of comparison of 1-year EFS, based on a 1-sided, 1-sample test of proportions, was .96. There was no evidence that temozolomide produced a 1-year EFS rate higher than 21.9%. The mean 1-year OS (± standard deviation) was 40% ± 6.5%, compared with 32% ± 6% for CCG-9941. The median time to death was 9.6 months. Chemoradiotherapy with TMZ followed by adjuvant TMZ is not more effective than previously reported regimens for the treatment of children with DIPG.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Dacarbazina/análogos & derivados , Ponte , Adolescente , Neoplasias do Tronco Encefálico/radioterapia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Dacarbazina/uso terapêutico , Feminino , Humanos , Masculino , Dosagem Radioterapêutica , Taxa de Sobrevida , Temozolomida , Resultado do Tratamento
11.
Pediatr Blood Cancer ; 53(4): 615-21, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19533651

RESUMO

BACKGROUND: While carotid artery disease and strokes have been documented in adult cancer patients treated with neck irradiation, little information is available on pediatric patients. The purpose of this study is to determine if carotid disease is more prevalent among pediatric cancer survivors treated with neck irradiation than among healthy controls. PROCEDURE: Thirty pediatric cancer survivors who received neck irradiation (2,000-6,660 cGy) and 30 healthy subjects underwent bilateral carotid ultrasounds. Study outcome measures were common carotid intima-media thickness (IMT) and plaque (present or absent). Multivariate methods were used to compare cases and controls and to identify risk factors related to carotid disease in childhood cancer survivors. RESULTS: IMT was greater for cancer survivors than controls (0.46 mm (SD 0.12) vs. 0.41 mm (SD 0.06), P < 0.001). Plaque was present in 18% of irradiated vessels and 2% of non-irradiated vessels (P < 0.01). Among cancer survivors, IMT was positively associated with female gender (P < 0.05), non-white ethnicity (P < 0.01), positive family history of stroke/heart attack (P < 0.05), BMI (P < 0.001), total cholesterol (P < 0.01), cancer relapse (P < 0.001), and years off treatment (P < 0.0001). Plaque was positively associated with relapse (P < 0.05) and C-reactive protein (P < 0.01). There was no significant relationship between radiation dose at levels >or=2,000 cGy and IMT or plaque. CONCLUSIONS: Carotid artery disease was more prevalent among cancer survivors treated with neck irradiation than among controls. Due to the high risk of stroke associated with advanced carotid disease, larger prospective studies are needed to better define disease risk in these long-term survivors.


Assuntos
Doenças das Artérias Carótidas/etiologia , Pescoço/efeitos da radiação , Neoplasias/radioterapia , Radioterapia/efeitos adversos , Adolescente , Adulto , Artérias Carótidas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sobreviventes , Túnica Íntima/patologia , Túnica Média/patologia
12.
J Pediatr Hematol Oncol ; 29(7): 480-4, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17609626

RESUMO

BACKGROUND: Follow-up studies find an increase in stroke and carotid artery disease incidence in adult cancer patients treated with neck irradiation. These radiation-related late effects are now being detected in young adult survivors of childhood cancer. OBSERVATIONS: This report includes 5 pediatric cancer survivors, ages 23 to 40, who presented with advanced carotid artery stenosis 17 to 36 years after receiving neck irradiation. Radiation doses ranged from 3900 to 7350 cGy. Three of the 5 experienced a stroke. CONCLUSIONS: Prevalence and risk factors associated with premature carotid artery disease after neck irradiation need to be investigated in childhood cancer survivors.


Assuntos
Doenças das Artérias Carótidas/etiologia , Pescoço/efeitos da radiação , Neoplasias/radioterapia , Radioterapia/efeitos adversos , Adulto , Humanos , Masculino , Sobreviventes
14.
Gynecol Oncol ; 95(1): 145-51, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15385124

RESUMO

OBJECTIVE: The survival of cervix cancer patients is associated with their hemoglobin (Hgb) level during radiotherapy. The Southwest Oncology Group (SWOG) conducted a phase II trial to determine whether recombinant human erythropoietin (rHuEPO) safely corrects anemia during chemoradiotherapy for cervix cancer. METHODS: Patients had stage IIB-IVA cervix cancer and a Hgb between 8.0 and 12.5 g/dl. All patients received rHuEPO thrice weekly and oral iron starting 10-15 days before their 5-week course of whole pelvic irradiation and weekly cisplatin followed by intracavitary brachytherapy. RESULTS: Fifty-three patients from 26 institutions received the protocol treatment. The mean Hgb was 10.4 +/- 1.3 g/dl on the first day of rHuEPO administration (baseline), 11.0 +/- 1.6 g/dl on the first day of chemoradiotherapy, 11.6 +/- 1.9 g/dl at the midpoint of chemoradiotherapy, and 11.8 +/- 2.2 g/dl at the end of chemoradiotherapy. The target Hgb level of 12.5 g/dl was achieved in 40% of patients (95% CI 26-56%) by the midpoint of Chemoradiotheraphy. Change in Hgb was associated with baseline serum iron (P = 0.008) and transferrin saturation (P = 0.05) levels, but not with baseline Hgb or serum ferritin, or patient age. Seven patients developed deep vein thrombosis. Two-year progression-free survival (PFS) was 43% and overall survival (OS) was 51%. Survival was significantly associated with Hgb level at the end of chemoradiotherapy, but not with the baseline Hgb level. CONCLUSIONS: rHuEPO and iron gradually increased Hgb levels in anemic women with local advanced cervix cancer during chemoradiotherapy. There was a higher than expected incidence of deep vein thrombosis. The progression-free and overall survival rates were lower than reported for women with normal Hgb levels.


Assuntos
Cisplatino/uso terapêutico , Eritropoetina/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Quimioterapia Adjuvante , Cisplatino/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Esquema de Medicação , Eritropoetina/efeitos adversos , Feminino , Hemoglobinas/metabolismo , Humanos , Ferro/sangue , Pessoa de Meia-Idade , Proteínas Recombinantes , Neoplasias do Colo do Útero/sangue
15.
J Surg Res ; 120(2): 295-303, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15234226

RESUMO

BACKGROUND: The role of tumor hypoxia has become a major focus in cancer research since it influences both local and systemic tumor growth. Oxygen measurements taken in human pancreatic cancer have shown extremely low oxygen tension. The aim of this study was to develop an orthotopic model for pancreatic cancer that mimics the specific tumor microenvironment and to evaluate the role of tumor oxygenation in local tumor growth and systemic dissemination in this model. MATERIALS AND METHODS: We used two established human pancreatic cancer cell lines for xenobiotic tumor induction. After subcutaneous tumor formation one small tumor piece was transplanted into the pancreatic parenchyma of mice of the different study groups. Upon orthotopic tumor induction tumor oxygenation was measured with the Eppendorf histograph. Histological evaluation was performed with pimonidazole, an in vivo marker of hypoxia. RESULTS: The tumor take rate was 100% in this model. Metastatic tumor dissemination occurred within the abdominal cavity, and distant metastasis were observed in the lung parenchyma. Oxygen measurements taken in various abdominal organs and xenograft tumor showed a high variation between different organs and xenografted tumors. Tumor oxygenation correlated well with the metastatic score in this model. Furthermore hypoxia was found both in the tumor center and also at the rim of a growing tumor mass. A high number of hypoxic cells were detectable in metastases located in the lung parenchyma. CONCLUSION: This study provides experimental evidence that tumor hypoxia influences metastatic disease progression and supports recent assumptions that tumor hypoxia is actively involved in progression of pancreatic cancer. It further demonstrates that tumor hypoxia is not only found in the center of a tumor mass, but also occurs at the invasion front.


Assuntos
Neoplasias Abdominais/secundário , Hipóxia Celular , Neoplasias Pulmonares/secundário , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Nitroimidazóis/metabolismo , Oxigênio/metabolismo , Pressão Parcial , Coloração e Rotulagem
16.
Cancer ; 100(1): 201-10, 2004 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-14692041

RESUMO

BACKGROUND: Previous reports indicate that Genistein, a naturally occurring isoflavonoid, exhibits strong antiangiogenic activity. The underlying mechanism of inhibition, however, remains unclear. Among the biologic effects of Genistein are the inhibition of tyrosine kinases and the inhibition of hypoxic activation of hypoxia-inducible factor-1 (HIF-1), one of the main regulators of VEGF gene expression. METHODS: Hypoxic cell culture was performed in a modular incubator chamber. Vascular endothelial growth factor (VEGF) protein secretion was measured using the enzyme-linked immunosorbent assay, binding of DNA by HIF-1 was measured using the electrophoretic mobility shift assay, and mRNA quantification was performed using Northern blot analysis. Pancreatic carcinoma was studied in an orthotopic murine model. Angiogenesis in vivo was quantified by staining xenograft tumors for endothelial cell markers. RESULTS: VEGF protein secretion was dose-dependently suppressed with increasing doses of Genistein. Furthermore, treatment of pancreatic carcinoma cells with Genistein led to impaired activation of HIF-1 under hypoxic culture conditions. Northern blot analysis indicated that VEGF mRNA expression decreased upon treatment with Genistein, both under normoxic and hypoxic culture conditions. In vivo, Genistein inhibited tumor growth for xenograft pancreatic carcinoma cells, whereas extensive hypoxia was observed in xenograft tumors and was not influenced by Genistein therapy. Similarly, decreased VEGF mRNA levels were observed in Genistein-treated Capan-1 xenograft tumors. CONCLUSIONS: The current study indicates that the previously reported antiangiogenic activity of Genistein probably is mediated by the inhibition of HIF-1, an important regulator of VEGF gene homeostasis, particularly under low-oxygen conditions. Therefore, this bioactive compound may well be beneficial to patients with pancreatic carcinoma.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/patologia , Proteínas de Ligação a DNA/biossíntese , Regulação Neoplásica da Expressão Gênica , Genisteína/farmacologia , Neovascularização Patológica , Proteínas Nucleares/biossíntese , Neoplasias Pancreáticas/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Northern Blotting , DNA Complementar , Proteínas de Ligação a DNA/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Ensaio de Desvio de Mobilidade Eletroforética , Sequências Hélice-Alça-Hélice , Homeostase , Humanos , Hipóxia , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Imuno-Histoquímica , Camundongos , Camundongos Nus , Proteínas Nucleares/farmacologia , RNA Mensageiro/análise , Fatores de Transcrição , Transplante Heterólogo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/farmacologia
17.
Surgery ; 134(5): 772-82, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14639356

RESUMO

BACKGROUND: Angiogenesis is important in the development and progression of pancreatic cancer. Therefore antiangiogenic therapy targeting endothelial cells may represent a promising therapeutic option. The aim of the study was to evaluate antiangiogenic therapy as a potential therapeutic option in pancreatic cancer. METHODS: Replication-deficient retroviruses encoding truncated VEGF-RII were used to block vascular endothelial growth factor (VEGF) signaling. Tumor growth of 3 pancreatic cancer cell lines was assayed in a nude mouse model in which each pancreatic cancer cell line was subcutaneously inoculated together with retrovirus-producing cells. Expression of VEGF was assayed by RT-PCR and by enzyme-linked immunosorbent assay. Oxygen tension in tumors was determined polarographically. RESULTS: All 3 pancreatic cancer cell lines expressed VEGF mRNA, with the highest VEGF secretion seen in MIA PaCa-2 cells. In vivo therapeutic intervention through dominant negative inhibition of VEGF-RII significantly reduced the growth rate of subcutaneous tumors and inhibited tumor neoangiogenesis. Tumor oxygenation, however, was not altered in xenograft tumors treated with dominant negative retroviruses. CONCLUSION: The ligand/receptor system consisting of VEGF and VEGF-RII seems to be of biologic significance in the pathogenesis of pancreatic cancer growth. Therefore therapeutic intervention in this angiogenic system by a retroviral-based gene transfer technology represents a rational and feasible new technique to inhibit tumor growth.


Assuntos
Terapia Genética , Neovascularização Patológica/prevenção & controle , Neoplasias Pancreáticas/terapia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Retroviridae/genética , Fator A de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
18.
Am J Clin Oncol ; 26(5): 522-9, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14528084

RESUMO

To achieve the ultimate goal of cancer treatment, which is 100% cancer control with negligible toxicity, the therapeutic window must be enlarged, allowing for higher doses of beneficial treatments with reduced toxicity. The advent of image- and metabolism-guided therapy offers the best opportunity to date for combining modern radiation targeting and imaging techniques. Indeed, for the first time, it is reasonable to locally target metastatic disease with the goal of sterilization. Combining these focal radiation techniques with novel targeted antiproliferative agents and full-dose classic cytotoxic chemotherapy will become more effective as we learn to use these compounds in a less systemically toxic manner and as radiation fields become more defined. In addition, increasing numbers of biologic modifiers of normal tissue response are becoming available, and they suggest great promise for decreasing the normal tissue toxicity resulting from both radiation and chemotherapy treatments. Thus, radiation metastectomy for gross metastases, used together with systemic control of micrometastatic disease, may yield improved survival rates. This hypothesis is ready for testing in cancers of the breast, prostate, colon, and in sarcomas. Enlarging the therapeutic window is a major goal that would allow for an increasingly favorable therapeutic gain.


Assuntos
Neoplasias/radioterapia , Radioterapia (Especialidade)/tendências , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Fatores Imunológicos/uso terapêutico , Radiossensibilizantes/uso terapêutico , Dosagem Radioterapêutica
19.
Radiother Oncol ; 65(3): 165-8, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12464445

RESUMO

INTRODUCTION: An all carbon fiber head fixation system, VBH HeadFix Arc ('HeadFix') modified to optimize conformal radiation therapy, is described and its treatment planning and delivery advantages, positional accuracy and X-ray attenuation are presented. MATERIAL AND METHODS: Serial radiation field isocenter measurements were made from weekly anterior-posterior (AP) and lateral port films taken of 13 children undergoing fractionated external beam radiation therapy for primary brain tumors. Measurements were also made of radiation transmission through the components of the HeadFix system. RESULTS AND CONCLUSION: The mean deviation between simulation and port films in each of the orthogonal directions was 0.8-1.2 mm and the mean 3 dimensional deviation was 1.8+/-0.6 mm. The modified HeadFix system components attenuate between 2 and 4% of the incident beam, allowing a wider range of beam directions for conformal therapy than the previously reported system.


Assuntos
Neoplasias Encefálicas/radioterapia , Cabeça , Imobilização , Planejamento da Radioterapia Assistida por Computador , Radioterapia Conformacional/métodos , Neoplasias Encefálicas/diagnóstico , Carbono , Fibra de Carbono , Criança , Pré-Escolar , Fracionamento da Dose de Radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Masculino , Lesões por Radiação/prevenção & controle , Dosagem Radioterapêutica , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade
20.
J Pediatr Hematol Oncol ; 24(3): 229-33, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11990313

RESUMO

Juvenile granulosa cell tumor (JGCT) of the ovary, a rare pediatric cancer, carries a very poor prognosis in advanced and recurrent cases. A 10-year-old girl with stage IA JGCT, initially treated with resection only, presented with extensive unresectable multifocal pelvic recurrence. She underwent surgery, chemotherapy (cisplatin/paclitaxel alternating with cisplatin/cyclophosphamide/etoposide/bleomycin), myeloablative chemotherapy (carboplatin/etoposide/melphalan) with autologous bone marrow transplant, and pelvic radiation. She tolerated therapy well and is in complete remission 69 months after her recurrence.


Assuntos
Tumor de Células da Granulosa/terapia , Recidiva Local de Neoplasia/terapia , Neoplasias Ovarianas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Criança , Terapia Combinada , Intervalo Livre de Doença , Feminino , Cirurgia Geral , Tumor de Células da Granulosa/patologia , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Resultado do Tratamento
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