RESUMO
PURPOSE: To determine the maximum tolerated dose of upper abdominal low-dose fractionated radiotherapy (<1.0 Gy per fraction) given in combination with, and as a chemopotentiator for, gemcitabine. METHODS AND MATERIALS: Gemcitabine was given at 1,250 mg/m(2) at 10 mg/m(2)/min on Days 1 and 8 of a 3-week cycle. Low-dose fractionated radiotherapy was tested at two dose levels: 60 cGy per fraction and 70 cGy per fraction. Radiotherapy was given b.i.d. on Days 1, 2, 8, and 9. Four cycles were planned. RESULTS: Twenty-seven patients have been put on study. Ten patients have been entered in Phase I: 6 with metastatic/recurrent pancreatic carcinoma and 4 with unresectable pancreatic/small bowel carcinoma. Two of four patients at Dose Level 2 experienced dose-limiting toxicity. The overall radiographic response was 30%, and median survival was 11 months (range, 4-37 months). CONCLUSION: Low-dose fractionated radiotherapy to the upper abdomen is well tolerated at 60 cGy per fraction when combined with gemcitabine. Phase II evaluation is ongoing.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/radioterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Fracionamento da Dose de Radiação , Esquema de Medicação , Feminino , Humanos , Neoplasias Intestinais/mortalidade , Intestino Delgado , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Radiossensibilizantes/efeitos adversos , Radiossensibilizantes/uso terapêutico , GencitabinaRESUMO
TNFalpha was initially described as inducing necrotic death in tumors in vivo, and more recently as a cytokine that mediates cytoprotection and inflammation. The anti-tumor effects of TNFalpha are poorly characterized because TNFalpha-induced death of human tumor cells has largely been studied in the presence of agents that block transcription or protein synthesis. Also, most reports in model cell systems describe apoptosis within relatively early time points as the principal mode of cell death induced by TNFalpha. We investigated the cytotoxic effects of 10 ng/ml TNFalpha on human tumor cells of different histological types without concomitant exposure to these inhibitors. Eleven of 21 human tumor cell lines underwent TNFalpha-induced cell death which ranged from 41% to complete loss of viability. Only one cell line demonstrated caspase-dependent apoptosis within 24 h. Nine cell lines underwent death between 48 h and 21 days. Seven of these lines underwent caspase-3 independent death consistent with necrosis. One tumor line exhibited characteristics of senescence following TNFalpha exposure. Nine of 9 cell lines activated NF-kappaB following TNFalpha exposure by 24 h. In all cell lines studied, with the exception of the epidermoid carcinoma cell line that underwent early apoptosis, expression of one or more NF-kappaB target genes was demonstrated at 24-96 h. BMS-345541, a specific IKK inhibitor, increased TNFalpha killing in TNFalpha resistant tumor cell lines by increasing apoptosis, suggesting that inhibition of NF-kappaB may be an effective strategy to enhance the tumoricidal effects of TNFalpha.
Assuntos
Apoptose/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Necrose Tumoral alfa/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , NF-kappa B/fisiologia , Necrose , Neoplasias/patologia , Quinoxalinas/farmacologiaRESUMO
BACKGROUND: A standardized method for predicting unresectability in pancreatic cancer has not been defined. We propose a system using CT and endoscopic ultrasound (EUS) to assess patients for unresectable pancreatic cancers. METHODS: Radiologic and surgical data from 101 patients who underwent exploration/resection for pancreatic cancer were reviewed. Chi-squares were used to identify five factors significantly correlated with unresectability, which were incorporated into a scoring system (one point for each factor). RESULTS: The resectability rates were 84, 56, and 10% for patients with scores of 0, 1, and 2, respectively. All four patients with three risk factors for unresectability had unresectable tumors. The most accurate results were achieved in patients evaluated with both CT and EUS. DISCUSSION: This scoring system stratifies pancreatic cancer patients into three groups: (1) patients with a score of zero (likely to undergo successful resection), (2) patients with a score of one (likely to benefit from laparoscopic staging prior to attempting resection), and (3) patients with a score of two or higher (low probability of successful resection, who may be better served by neoadjuvant therapy).
Assuntos
Endossonografia , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Valor Preditivo dos Testes , Taxa de SobrevidaRESUMO
We review our recent experience with intensity-modulated radiation therapy (IMRT) and conventional three-dimensional radiation therapy (C3DRT) in advanced head and neck cancer. Sixty-nine patients with Stage IV head and neck cancer (and stage III base of tongue and hypopharynx) enrolled in a Phase II study of definitive chemoradiation; 20 received all or part of their radiation with IMRT. Image-guided set-up, using video subtraction techniques, was used in all patients. Six weekly doses of induction carboplatin (AUC=2) and paclitaxel (135 mg/m2) were followed by alternating weekly chemoradiation to 75 Gy with 1.5 Gy BID fractions, concurrent with paclitaxel (100 mg/m2/week), 5-fluorouracil (600 mg/m2/d) and hydroxyurea (500 mg PO BID). Two consecutive cohorts enrolled, differing in radiation scheme: 75 Gy to gross disease in both, 60 or 54 Gy to first echelon lymphatics and 45 or 39 Gy to second echelon lymphatics. With a median follow-up of 47 months, 3-year overall survival is 68.5% and 3-year locoregional control is 94.0%, with no significant differences between those treated with C3DRT versus IMRT, nor between the two radiation dosing schemes. Actuarial overall survival without tracheostomy or laryngectomy, or without a gastrostomy tube was also similar. Acute mucositis, dermatitis and pain were similar with C3DRT and IMRT. Preliminary data suggests IMRT is well tolerated, and does not compromise locoregional control, indicating that IMRT adequately covers the clinical volume at risk. Building on the present clinical experience, future directions include more directed efforts at reducing toxicity, with better planning software and planning techniques.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Biópsia , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Terapia Combinada/efeitos adversos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Radioterapia/efeitos adversos , Dosagem Radioterapêutica , Análise de SobrevidaRESUMO
Despite the best current therapies, treatment outcomes in pancreatic cancer continue to be poor. Surgery remains the single most important curative modality for the minority of patients who present with resectable disease and continues to be the cornerstone of curative-intent therapy in such patients. The value of adjuvant treatment in these patients has been the subject of much debate and has led to several phase III randomized clinical trials in both the United States and Europe. Inconsistent trial results as well as trial design critiques have led to differing conclusions with regard to the value of adjuvant chemoradiotherapy. This chapter will critically review the randomized trials that have led to this controversy and establish a rationale for the use of adjuvant chemoradiation in patients with resectable pancreatic cancer. Modern radiotherapy delivery techniques will also be discussed and future trial designs suggested.
Assuntos
Neoplasias Pancreáticas/terapia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pancreáticas/mortalidade , Radioterapia Adjuvante , Radioterapia ConformacionalRESUMO
Radiation therapy is an important and effective treatment modality when used in the management of oncologic emergencies. For any patient who has MSCC, ISCM, SVC syndrome, or life-threatening hemoptysis/obstruction, optimal management hinges on efficient multidisciplinary evaluation and communication to arrive at a treatment plan tailored to the individual patient. Optimal management may include steroids, surgery, chemotherapy, or bronchoscopic intervention. When radiation therapy is used, the total dose and fractionation schedule should be tailored to the disease setting and life expectancy of the patient.
Assuntos
Emergências , Radioterapia (Especialidade)/métodos , Compressão da Medula Espinal/radioterapia , Corticosteroides , Terapia Combinada , Fracionamento da Dose de Radiação , Humanos , Compressão da Medula Espinal/tratamento farmacológico , Compressão da Medula Espinal/fisiopatologia , Neoplasias da Medula Espinal/radioterapia , Neoplasias da Medula Espinal/secundárioRESUMO
PURPOSE: To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. METHODS AND MATERIALS: Patients with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint of the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided). RESULTS: Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥ 2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval [CI]: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively. CONCLUSION: The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity.
Assuntos
Quimiorradioterapia Adjuvante/métodos , Radioterapia de Intensidade Modulada , Neoplasias Retais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Quimiorradioterapia Adjuvante/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Diarreia/etiologia , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Cuidados Pré-Operatórios , Qualidade de Vida , Radioterapia de Intensidade Modulada/efeitos adversos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Taxa de SobrevidaRESUMO
The management of locoregionally recurrent or second primary tumors in a previously irradiated head and neck volume presents a challenging clinical problem. Only a small subset of patients are candidates for potentially curative surgery. Chemotherapy alone provides only limited palliation with no long term survivors. Reirradiation, particularly with aggressive concomitant chemotherapy, results in prolonged median survival and long term survival for some patients. The toxicity of reirradiation, while greater than chemotherapy alone or primary irradiation, is lower than expected for the high cumulative radiation doses. The results of reirradiation in recurrent head and neck cancer and the prognostic factors predicting outcome in this patient population are reviewed.
Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Recidiva Local de Neoplasia/radioterapia , Segunda Neoplasia Primária/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/patologia , Prognóstico , SobrevidaRESUMO
PURPOSE: To assess the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in pancreatic and bile duct (cholangiocarcinoma) malignancies. METHODS AND MATERIALS: Twenty-five patients with pancreatic and bile duct cancer were treated with IMRT. Twenty-three received concurrent 5-fluoruracil. One patient with a pancreatic primitive neuroectodermal tumor received concurrent etoposide and ifosfamide. Eight patients had resected tumors, and 17 had unresectable primary (n = 14) or recurrent (n = 3) tumors. Six patients underwent treatment planning with conventional three-dimensional four-field techniques for dosimetric comparison with IMRT. RESULTS: Compared with conventional RT, IMRT reduced the mean dose to the liver, kidneys, stomach, and small bowel. IMRT was well tolerated, with 80% experiencing Grade 2 or less acute upper GI toxicity. At a median follow-up of 10.2 months, no resected patients had local failure, and only 1 of 10 assessable patients with unresectable cancer had local progression. The median survival and distant metastasis-free survival of the 24 patients with adenocarcinoma was 13.4 and 7.3 months, respectively. Grade 4 late liver toxicity occurred in 1 patient surviving >5 years. The remainder of the assessable patients experienced no (n = 9) or Grade 1 (n = 4) late toxicity. CONCLUSION: In this hypothesis-generating analysis, the acute and chronic toxicity profile with IMRT in the treatment of pancreatic and bile duct cancer was encouraging. Local control was not compromised, despite efforts to increase conformality and avoid doses to normal structures. Distant failure remains a major obstacle in pancreatic cancer.
Assuntos
Adenocarcinoma/radioterapia , Neoplasias dos Ductos Biliares/radioterapia , Neoplasias Pancreáticas/radioterapia , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/métodos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/mortalidade , Fluoruracila/uso terapêutico , Humanos , Imageamento Tridimensional/métodos , Pessoa de Meia-Idade , Tumores Neuroectodérmicos/tratamento farmacológico , Tumores Neuroectodérmicos/radioterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Lesões por Radiação/etiologia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodosRESUMO
The benefit of postoperative adjuvant chemoradiation in the treatment of resected pancreatic cancers was first established by a randomized trial conducted by the Gastrointestinal Tumor Study Group in 1974. During the past 3 decades, treatment has evolved toward more dose-intensive regimens of chemoradiation. Historical split-course conventional radiation therapy has been replaced by continuous-course radiotherapy to higher doses, and gemcitabine is being actively investigated as a potentially more effective agent than 5-fluorouracil. This article critically examines the results of important randomized multi-institutional trials and reviews the evolution toward dose-intensive adjuvant treatment regimens. Implications of the recently completed intergroup study are discussed, modern radiation therapy delivery techniques are reviewed, and suggestions for future trials are made.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/radioterapia , Adenocarcinoma/cirurgia , Adulto , Idoso , Ensaios Clínicos Fase III como Assunto , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Cuidados Pós-Operatórios/métodos , Prognóstico , Dosagem Radioterapêutica , Radioterapia Adjuvante , Medição de Risco , Resultado do Tratamento , Estados UnidosRESUMO
Several radiation dose- and time-dependent tissue sequelae develop following acute high-dose radiation exposure. One of the recognized delayed effects of such exposures is lung injury, characterized by respiratory failure as a result of pneumonitis that may subsequently develop into lung fibrosis. Since this pulmonary subsyndrome may be associated with high morbidity and mortality, comprehensive treatment following high-dose irradiation will ideally include treatments that mitigate both the acute hematologic and gastrointestinal subsyndromes as well as the delayed pulmonary syndrome. Currently, there are no drugs approved by the Food and Drug Administration to counteract the effects of acute radiation exposure. Moreover, there are no relevant large animal models of radiation-induced lung injury that permit efficacy testing of new generation medical countermeasures in combination with medical management protocols under the FDA animal rule criteria. Herein is described a nonhuman primate model of delayed lung injury resulting from whole thorax lung irradiation. Rhesus macaques were exposed to 6 MV photon radiation over a dose range of 9.0-12.0 Gy and medical management administered according to a standardized treatment protocol. The primary endpoint was all-cause mortality at 180 d. A comparative multiparameter analysis is provided, focusing on the lethal dose response relationship characterized by a lethal dose50/180 of 10.27 Gy [9.88, 10.66] and slope of 1.112 probits per linear dose. Latency, incidence, and severity of lung injury were evaluated through clinical and radiographic parameters including respiratory rate, saturation of peripheral oxygen, corticosteroid requirements, and serial computed tomography. Gross anatomical and histological analyses were performed to assess radiation-induced injury. The model defines the dose response relationship and time course of the delayed pulmonary sequelae and consequent morbidity and mortality. Therefore, it may provide an effective platform for the efficacy testing of candidate medical countermeasures against the delayed pulmonary syndrome.
Assuntos
Modelos Animais de Doenças , Pulmão/efeitos da radiação , Doses de Radiação , Lesões Experimentais por Radiação , Pneumonite por Radiação , Animais , Dexametasona/farmacologia , Relação Dose-Resposta à Radiação , Fibrose , Testes Hematológicos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Macaca mulatta , Masculino , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/efeitos da radiação , Oxigênio/metabolismo , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Pneumonite por Radiação/diagnóstico por imagem , Pneumonite por Radiação/etiologia , Pneumonite por Radiação/patologia , Pneumonite por Radiação/fisiopatologia , Respiração/efeitos dos fármacos , Respiração/efeitos da radiação , Taxa de Sobrevida , Tórax/efeitos da radiação , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
The objective of this pilot study was to explore whether administration of a catalytic antioxidant, AEOL 10150 (C48H56C15MnN12), could reduce radiation-induced lung injury and improve overall survival when administered after 11.5 Gy of whole thorax lung irradiation in a non-human primate model. Thirteen animals were irradiated with a single exposure of 11.5 Gy, prescribed to midplane, and delivered with 6 MV photons at a dose rate of 0.8 Gy min. Beginning at 24 h post irradiation, the AEOL 10150 cohort (n = 7) received daily subcutaneous injections of the catalytic antioxidant at a concentration of 5 mg kg for a total of 4 wk. All animals received medical management, including dexamethasone, based on clinical signs during the planned 180-d in-life phase of the study. All decedent study animals were euthanized for failure to maintain saturation of peripheral oxygen > 88% on room air. Exposure of the whole thorax to 11.5 Gy resulted in radiation-induced lung injury in all animals. AEOL 10150, as administered in this pilot study, demonstrated potential efficacy as a mitigator against fatal radiation-induced lung injury. Treatment with the drug resulted in 28.6% survival following exposure to a radiation dose that proved to be 100% fatal in the control cohort (n = 6). Computed tomography scans demonstrated less quantitative radiographic injury (pneumonitis, fibrosis, effusions) in the AEOL 10150-treated cohort at day 60 post-exposure, and AEOL 10150-treated animals required less dexamethasone support during the in-life phase of the study. Analysis of serial plasma samples suggested that AEOL 10150 treatment led to lower relative transforming growth factor-Beta-1 levels when compared with the control animals. The results of this pilot study demonstrate that treatment with AEOL 10150 results in reduced clinical, radiographic, anatomic, and molecular evidence of radiation-induced lung injury and merits further study as a medical countermeasure against radiation-induced pulmonary injury.
Assuntos
Antioxidantes/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/efeitos da radiação , Metaloporfirinas/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/uso terapêutico , Catálise , Dexametasona/farmacologia , Pulmão/patologia , Pulmão/fisiopatologia , Macaca mulatta , Masculino , Metaloporfirinas/administração & dosagem , Metaloporfirinas/química , Metaloporfirinas/uso terapêutico , Peso Molecular , Oxigênio/metabolismo , Projetos Piloto , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Pneumonite por Radiação/sangue , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/patologia , Pneumonite por Radiação/fisiopatologia , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/química , Protetores contra Radiação/uso terapêutico , Respiração/efeitos dos fármacos , Respiração/efeitos da radiação , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Fator de Crescimento Transformador beta1/sangueRESUMO
A key difficulty in developing countermeasures against radiation-induced health impairments is the clear lack of controlled clinical studies, due to the relatively low number of radiation victims worldwide. Instead, established and accepted animal models, as well as the recommendations of national and international expert panels and committees, are the main sources of information. Therefore, the development of countermeasures requires comparison of data from many sources and accumulation of information consistent with the U. S. Food and Drug Administration's "Animal Rule." A new approach is the comparative analysis of human data from the SEARCH (System for Evaluation and Archiving of Radiation Accidents based on Case Histories) database and data from nonhuman primate (NHP) animal model studies. The SEARCH database contains 824 clinical cases from 81 radiation accidents in 19 countries. This exceptional collection of clinical data from accidentally radiation-exposed persons is analyzed regarding clinical signs and symptoms of radiation-induced health impairments. To analyze the time course of radiation syndromes, clinical parameters common to the SEARCH and NHP databases have to be assigned into comparable categories of clinical severity for each species. The goal is to establish a method for comparison of human and NHP data, validate the NHP data as a surrogate for human efficacy/clinical studies, and open a way for the extraction of diagnostic and treatment methods for humans after radiation exposure according to relevant regulations.
Assuntos
Primatas , Lesões por Radiação/etiologia , Lesões por Radiação/terapia , Liberação Nociva de Radioativos , Pesquisa Translacional Biomédica , Animais , Bases de Dados Factuais , Relação Dose-Resposta à Radiação , Exposição Ambiental/efeitos adversos , Humanos , Irradiação Corporal Total/efeitos adversosRESUMO
The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min(-1) to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi-organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes.
Assuntos
Síndrome Aguda da Radiação/etiologia , Gastroenteropatias/etiologia , Células-Tronco Hematopoéticas/efeitos da radiação , Insuficiência de Múltiplos Órgãos/etiologia , Lesões Experimentais por Radiação/etiologia , Irradiação Corporal Total/efeitos adversos , Síndrome Aguda da Radiação/fisiopatologia , Animais , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Gastroenteropatias/fisiopatologia , Células-Tronco Hematopoéticas/patologia , Humanos , Dose Letal Mediana , Macaca mulatta , Masculino , Doses de Radiação , Lesões Experimentais por Radiação/fisiopatologia , Análise de Sobrevida , Taxa de SobrevidaRESUMO
PURPOSE: Among patients with upper abdominal malignancies, intensity-modulated radiation therapy (IMRT) can improve dose distributions to critical dose-limiting structures near the target. Whether these improved dose distributions are associated with decreased toxicity when compared with conventional three-dimensional treatment remains a subject of investigation. METHODS AND MATERIALS: 46 patients with pancreatic/ampullary cancer were treated with concurrent chemoradiation (CRT) using inverse-planned IMRT. All patients received CRT based on 5-fluorouracil in a schema similar to Radiation Therapy Oncology Group (RTOG) 97-04. Rates of acute gastrointestinal (GI) toxicity for this series of IMRT-treated patients were compared with those from RTOG 97-04, where all patients were treated with three-dimensional conformal techniques. Chi-square analysis was used to determine if there was a statistically different incidence in acute GI toxicity between these two groups of patients. RESULTS: The overall incidence of Grade 3-4 acute GI toxicity was low in patients receiving IMRT-based CRT. When compared with patients who had three-dimensional treatment planning (RTOG 97-04), IMRT significantly reduced the incidence of Grade 3-4 nausea and vomiting (0% vs. 11%, p = 0.024) and diarrhea (3% vs. 18%, p = 0.017). There was no significant difference in the incidence of Grade 3-4 weight loss between the two groups of patients. CONCLUSIONS: IMRT is associated with a statistically significant decrease in acute upper and lower GI toxicity among patients treated with CRT for pancreatic/ampullary cancers. Future clinical trials plan to incorporate the use of IMRT, given that it remains a subject of active investigation.
Assuntos
Adenocarcinoma/radioterapia , Trato Gastrointestinal/efeitos da radiação , Neoplasias Pancreáticas/radioterapia , Radioterapia de Intensidade Modulada/métodos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ampola Hepatopancreática , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Distribuição de Qui-Quadrado , Neoplasias do Ducto Colédoco/tratamento farmacológico , Neoplasias do Ducto Colédoco/radioterapia , Neoplasias do Ducto Colédoco/cirurgia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , GencitabinaRESUMO
Liposarcomas are uncommon in the pediatric population. We present the case of a boy who had experienced multiple recurrences of liposarcoma in the buccal space before he reached the age of 13 years. We also provide a review of the literature and a discussion of adjuvant therapy, which are important to understanding the nature of this disease.
Assuntos
Lipossarcoma Mixoide/diagnóstico , Mucosa Bucal , Neoplasias Bucais/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Criança , Humanos , Lipossarcoma Mixoide/terapia , Masculino , Neoplasias Bucais/terapia , Recidiva Local de Neoplasia/terapiaRESUMO
PURPOSE: To develop a Radiation Therapy Oncology Group (RTOG) atlas of the elective clinical target volume (CTV) definitions to be used for planning pelvic intensity-modulated radiotherapy (IMRT) for anal and rectal cancers. METHODS AND MATERIALS: The Gastrointestinal Committee of the RTOG established a task group (the nine physician co-authors) to develop this atlas. They responded to a questionnaire concerning three elective CTVs (CTVA: internal iliac, presacral, and perirectal nodal regions for both anal and rectal case planning; CTVB: external iliac nodal region for anal case planning and for selected rectal cases; CTVC: inguinal nodal region for anal case planning and for select rectal cases), and to outline these areas on individual computed tomographic images. The imaging files were shared via the Advanced Technology Consortium. A program developed by one of the co-authors (I.E.N.) used binomial maximum-likelihood estimates to generate a 95% group consensus contour. The computer-estimated consensus contours were then reviewed by the group and modified to provide a final contouring consensus atlas. RESULTS: The panel achieved consensus CTV definitions to be used as guidelines for the adjuvant therapy of rectal cancer and definitive therapy for anal cancer. The most important difference from similar atlases for gynecologic or genitourinary cancer is mesorectal coverage. Detailed target volume contouring guidelines and images are discussed. CONCLUSION: This report serves as a template for the definition of the elective CTVs to be used in IMRT planning for anal and rectal cancers, as part of prospective RTOG trials.
Assuntos
Linfonodos/diagnóstico por imagem , Ilustração Médica , Radioterapia (Especialidade)/normas , Radioterapia de Intensidade Modulada/normas , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/radioterapia , Neoplasias do Ânus/diagnóstico por imagem , Neoplasias do Ânus/radioterapia , Humanos , Ílio , Canal Inguinal/diagnóstico por imagem , Funções Verossimilhança , Pelve , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Reto/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Primary lymphomas of mucosa associated lymphoid tissue (MALT) are exceedingly rare. We report the case of a 51 year old female diagnosed with primary MALT lymphoma of the gallbladder after cholecystectomy. Further staging workup was negative for metastatic disease. When the disease is localized to the gallbladder, primary MALT lymphomas of the gallbladder carry an excellent prognosis, and surgical resection is curative in the majority of cases.
Assuntos
Neoplasias da Vesícula Biliar/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Biópsia , Diagnóstico Diferencial , Endoscopia Gastrointestinal , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
Primary gastric T cell lymphoma is rare and mostly of large cell type. In this paper, we present a case of gastric T cell lymphoma morphologically similar to the gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT). Morphologically, the cells are small with abundant clear cytoplasm. Lymphoepithelial lesions are readily identified with diffuse destruction of gastric glands. Immunohistochemically, the neoplastic cells are CD3+/CD4+/CD8-/Granzyme B-. Molecular studies revealed monoclonal T cell receptor gamma gene rearrangement. Clinically, the patient responded initially to four cycles of R-CHOP, but then progressed. Because peripheral T cell lymphoma is usually associated with a poor prognosis, whereas marginal zone B cell lymphoma is an indolent lymphoproliferative disorder, this morphologic mimicry should be recognized and completely investigated when atypical small lymphoid infiltrates with lymphoepithelial lesions are encountered in the stomach.
RESUMO
Despite recent research and advances in the understanding of the molecular and genetic basis of pancreatic cancer, the poor outcomes experienced by pancreatic cancer patients have changed little during the past 30 years. Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related death in the United States, with only a small fraction of patients achieving long-term survival. According to data from the American Cancer Society, 5-year survival for pancreatic cancer patients is 5%; an estimated 33,730 newly diagnosed cases of pancreatic cancer will be nearly equaled by an estimated 32,300 pancreatic cancer deaths in the United States. This underscores the continued need to develop novel multimodality treatment approaches for this disease. Surgery has proved vital to a curative-intent treatment approach for these patients. However, only 10% to 20% of newly diagnosed patients present with potentially resectable nonmetastatic disease. In light of the minority of patients with resectable disease, there has been considerable debate over the potential advantages of adjuvant chemotherapy and radiotherapy. In recent decades, cooperative groups both in the United States and abroad have conducted randomized clinical trials seeking to define the potential benefit of adjuvant chemotherapy or adjuvant chemoradiotherapy vs. surgery alone for patients with resectable disease. Unfortunately, the results of these trials have been conflicting and no definitive consensus has yet been reached regarding optimal adjuvant therapy. This article reviews cooperative group data pertinent to this debate. It is suggested that (1) patients do benefit from adjuvant therapy, and (2) optimal adjuvant therapy should include gemcitabine-based chemoradiotherapy for select patient subgroups.