RESUMEN
BACKGROUND: Malignant pleural mesothelioma (MPM) tumor cells produce copious amounts of myeloid cell-stimulating factors. The current study examined the prognostic significance of circulating monocytes and tumor-infiltrating macrophages on overall survival in patients with MPM. METHODS: The authors retrospectively reviewed 667 patients with MPM who underwent cytoreductive surgery at the Brigham and Women's Hospital in Boston, Massachusetts between 1989 and 2009. Kaplan-Meier and Cox proportional hazards models were used to determine the impact of preoperative circulating monocytes on overall survival. Immunohistochemical staining for CD68 was performed on a tissue microarray of MPM tumors from 52 patients undergoing cytoreductive surgery. The phenotype of circulating monocytes and tumor-infiltrating macrophages in 7 additional patients was determined by flow cytometry. RESULTS: The median survival for all patients was 13.4 months, and 35% of patients had tumors of nonepithelial histology. For patients with nonepithelial compared with epithelial tumors, survival was significantly worse (9.3 months vs 16.6 months; P < .0001), the number of monocytes was significantly higher (580 ± 20 cells/µL vs 520 ± 10 cells/µL; P = .002), and higher monocyte counts were associated with higher tumor stage. Increasing monocyte counts were correlated with poor survival for all patients with MPM. Within MPM tumors, macrophages comprised 27% ± 9% of the tumor area and demonstrated an immunosuppressive phenotype with high expression of CD163, CD206, and interleukin-4 receptor α. The degree of macrophage infiltration was found to be negatively correlated with survival in patients with nonepithelial (P = .008) but not those with epithelial (P = .7) MPM, independent of disease stage. CONCLUSIONS: Higher numbers of circulating monocytes are associated with poor survival in all patients with MPM and higher densities of tumor-infiltrating macrophages are associated with poor survival in patients with nonepithelial MPM. Both may enable a novel target for immunotherapy.
Asunto(s)
Mesotelioma/mortalidad , Mesotelioma/patología , Células Mieloides/patología , Células Neoplásicas Circulantes/patología , Neoplasias Pleurales/mortalidad , Neoplasias Pleurales/patología , Anciano , Femenino , Humanos , Macrófagos/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Surgery-based multimodality therapy is associated with long-term survival in a significant number of pleural mesothelioma patients. We explored factors associated with 3-year survival in patients with malignant pleural mesothelioma, who underwent extrapleural pneumonectomy, to help refine patient selection criteria for surgery and other therapies. METHODS: With Institutional Review Board approval, we reviewed records in the International Mesothelioma Program Patient Data Registry to identify all patients, who underwent extrapleural pneumonectomy for malignant pleural mesothelioma between 1 January 1988 and 31 May 2007. Vital status as of 31 May 2010 was confirmed. Fisher's exact test was used to compare dichotomous variables for patients who survived at least 3 years with those who did not. Kaplan-Meier analysis was used to estimate the cumulative survival probability for all 3-year survivors. RESULTS: Among 636 patients who underwent extrapleural pneumonectomy, 117 (18%) survived at least 3 years following surgery, including 26 remaining alive and four lost to follow-up. Of the 3-year survivors, 39 (33%) were female, 61 (52%) had left-sided disease, and the median age was 56 years (range 27-77). Relatively more 3-year survivors were younger than, or at the median age (p=0.0005), or female (p=0.0007), had epithelial tumor histology (p<0.0001) and/or had normal white blood cell count (p=0.0001), hemoglobin (p<0.0001), or platelet count (p<0.0001) preoperatively. The median survival of the 117 patients who survived 3-years was 59 months. Among these patients, a significant association between age and survival was found only for women. CONCLUSIONS: A significant proportion of patients undergoing extrapleural pneumonectomy for pleural mesothelioma experienced extended survival. Although favorable prognostic features were more common, the cohort of 3-year survivors included a substantial number of patients with late-stage disease. The longest survival (median greater than 7 years) was experienced by women under the median age of 56 years. These data support the role of macroscopic cytoreduction through extrapleural pneumonectomy in the context of multimodality therapy to extend survival for malignant pleural mesothelioma. Further efforts to treat micrometastatic disease and improve patient selection are warranted.
Asunto(s)
Mesotelioma/cirugía , Neoplasias Pleurales/cirugía , Neumonectomía/métodos , Adolescente , Adulto , Factores de Edad , Anciano , Quimioterapia Adyuvante , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Mesotelioma/patología , Mesotelioma/terapia , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Selección de Paciente , Neoplasias Pleurales/patología , Neoplasias Pleurales/terapia , Pronóstico , Radioterapia Adyuvante , Factores Sexuales , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is higher in men than in women, likely due to increased occupational asbestos exposure among men. Women also appear to experience better long-term survival. This study evaluates the role of gender in relation to established prognostic factors in MPM. METHODS: We reviewed 715 cases of MPM treated with extrapleural pneumonectomy at our institution between July 1987 and December 2008. Data for patients with epithelial and nonepithelial tumors were analyzed separately. Kaplan-Meier and Cox regression analyses were used to estimate survival for various cohorts to assess the relationship between gender and survival independent of age at surgery, stage, side, and preoperative laboratory studies. RESULTS: Of the 702 patients with complete data available, 114 out of 450 patients with epithelial tumors and 31 out of 252 patients with nonepithelial histology were women. Women with epithelial (and not nonepithelial) disease were found to differ significantly from men with respect to younger age, higher rate of thrombocytosis, and longer survival after surgery. The effect of gender on survival of patients with epithelial disease persisted when controlling for age, stage, thrombocytosis, leukocytosis, and anemia with a multivariable analysis. No significant differences in survival were seen among patients with nonepithelial disease with regard to gender, age, or anemia. CONCLUSIONS: In the absence of other negative prognostic factors, women with epithelial MPM demonstrated a survival advantage. These findings support an aggressive approach to treating MPM including extrapleural pneumonectomy in individuals with favorable prognostic predictors, particularly women with epithelial histology and no other risk factors.
Asunto(s)
Mesotelioma/mortalidad , Neoplasias Pleurales/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores Sexuales , Tasa de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: Optimizing the multimodality treatment of malignant pleural mesothelioma depends on many factors including an adequate chemotherapeutic response. Currently, chemotherapy regimens for patients with mesothelioma are empirically selected. In vitro chemotherapy resistance in human mesothelioma has not been reported. Our goal was to determine the prevalence of drug resistance in a large sample of malignant pleural mesothelioma using a commercially available assay. METHODS: Tumors specimens (n = 203) were cultured for analysis of chemoresistance using the extreme drug resistance assay. Evaluable results were obtained in 168 (168/203 = 83%) specimens. Each specimen was tested with 3 drugs: cisplatin, gemcitabine, and vinorelbine. Drug resistance was characterized as low, intermediate, or extreme. Median age was 64 years (30-85 years). Forty-four (26%) patients received neoadjuvant chemotherapy before sampling and testing. The distribution of histopathologic cell types was epithelial (103; 61%), mixed (57; 34%), and sarcomatoid (8; 5%). RESULTS: A significant proportion of tumors had extreme/intermediate drug resistance to cisplatin (27%), gemcitabine (31%), or vinorelbine (59%). Nineteen tumors (11%) had extreme/intermediate resistance to all 3 drugs. Resistance (extreme/intermediate) to cisplatin was more prevalent in epithelial tumors than in nonepithelial (33% vs 18%; P = .0394). No significant differences in chemoresistance were found in tumors of patients who had received neoadjuvant chemotherapy compared with those who had not. CONCLUSIONS: The feasibility of performing off-site in vitro drug resistance assays on resected malignant mesothelioma specimens is reported. A significant proportion of mesothelioma tumors exhibited extreme/intermediate resistance to cisplatin, gemcitabine, or vinorelbine.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Vinblastina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Estudios de Cohortes , Desoxicitidina/farmacología , Estudios de Factibilidad , Humanos , Mesotelioma/patología , Mesotelioma/cirugía , Persona de Mediana Edad , Terapia Neoadyuvante , Selección de Paciente , Neoplasias Pleurales/patología , Neoplasias Pleurales/cirugía , Factores de Tiempo , Células Tumorales Cultivadas , Vinblastina/farmacología , Vinorelbina , GemcitabinaRESUMEN
OBJECTIVE: The purpose of this study was to prospectively assess, in the evaluation of patients with suspected malignant pleural mesothelioma (MPM), apparent diffusion coefficient (ADC) values derived from diffusion-weighted images obtained with a free-breathing single-shot spin-echo echo-planar imaging sequence and to correlate the ADC values with the three histologic subtypes of MPM. SUBJECTS AND METHODS: Sixty-two patients with a known pleural abnormality and clinical findings suggestive of MPM underwent diffusion-weighted 3-T MRI and ADC calculation. The pathologic diagnosis was confirmed by surgical procedure. ADC values were correlated with the histologic subtypes of MPM. Statistical analysis was performed with analysis of variance and the Student's t test. RESULTS: Fifty-seven patients had MPM. Forty of the tumors were epithelioid, 11 were biphasic, and six were sarcomatoid. The other five patients had pleural thickening (two patients), metastatic adenocarcinoma (one patient), chronic inflammation (one patient), and malignant lymphoma (one patient). Because of image distortion, the diffusion-weighted images and ADC maps were not satisfactory for assessment in seven cases. The ADC values of MPM were 1.31 +/- 0.15 x 10(-3) mm(2)/s for the epithelioid, 1.01 +/- 0.11 x 10(-3) mm(2)/s for the biphasic, and 0.99 +/- 0.07 x 10(-3) mm(2)/s for the sarcomatoid subtypes of MPM. The ADC of the epithelioid subtype was statistically significantly higher than that of the sarcomatoid subtype (p < 0.05). The ADC in the two cases of benign plaque was 0.85 +/- 0.17 x 10(-3) mm(2)/s. CONCLUSION: The ADC values of epithelioid mesothelioma are higher than those of sarcomatoid mesothelioma. There is no significant difference between the ACD values of biphasic and those of sarcomatoid MPM.
Asunto(s)
Algoritmos , Imagen de Difusión por Resonancia Magnética/métodos , Interpretación de Imagen Asistida por Computador/métodos , Mesotelioma/clasificación , Mesotelioma/patología , Neoplasias Pleurales/clasificación , Neoplasias Pleurales/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Aumento de la Imagen/métodos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: Rapid fluid evacuation of the pneumonectomy space can cause ipsilateral mediastinal shift, contralateral lung hyperexpansion, compromised caval blood return and a precipitous drop in cardiac output. Conversely, rapid fluid accumulation can cause contralateral mediastinal shift with compression of the remaining lung and respiratory insufficiency. In this retrospective analysis, we evaluate the efficacy of intrathoracic pressure monitoring and intermittent fluid aspiration to manage the pneumonectomy space in the early postoperative period following extrapleural pneumonectomy. METHODS: Prior to chest closure, a 14 F Rob-Nel catheter was placed in the pneumonectomy space and connected to pressure tubing to monitor ipsilateral intrathoracic pressure continuously. Central venous pressure monitoring and serial chest X-rays were performed according to usual intensive care routine. Pneumonectomy space fluid was aspirated intermittently when there was increase in intrathoracic pressure, refractory hypotension, mediastinal shift on chest X-ray, or clinical decline. Postoperative imaging was re-evaluated retrospectively for confirmation of mediastinal shift by a senior radiologist. RESULTS: From January to December 2008, 47 patients underwent extrapleural pneumonectomy for pleural mesothelioma (median age 65 years with range 34-79 years, 77% male). Twenty (43%) patients had left-sided disease and 32 (68%) received local heated intra-operative cisplatin-based chemotherapy. The median baseline pneumonectomy space pressure was 3 cm H(2)O (range: -6 to +12). The median amount of fluid withdrawn over the first 2 days postoperatively was 300 cc (range: 0-1980 cc). Thirty-one (69%) patients had minimal, if any, change in mediastinal position during the first 2 postoperative days with intermittent drainage performed when the pneumonectomy space pressure rose. Eleven (25%) patients had increasing contralateral shift, four of whom had return of the mediastinum to baseline during this time period. The median fluid drained from the four patients whose contralateral shift resolved was 290 cc (range: 220-800 cc) compared to 200 cc (range: 150-480 cc) from the seven patients whose contralateral shift remained, but this difference did not reach significance (p=0.365). CONCLUSIONS: Intrathoracic pressure monitoring may be used as a guide for intermittent fluid evacuation of the pneumonectomy space prior to onset of clinical signs or symptoms, to avoid the cardiopulmonary risks of rapid fluid removal. Contralateral mediastinal shift should be treated with incremental drainage when there is a rise in intrathoracic pressure to prevent cardiovascular complications.
Asunto(s)
Mesotelioma/cirugía , Neoplasias Pleurales/cirugía , Neumonectomía/efectos adversos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Presión Venosa Central , Quimioterapia Adyuvante , Cisplatino/uso terapéutico , Femenino , Humanos , Masculino , Mesotelioma/tratamiento farmacológico , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Neoplasias Pleurales/tratamiento farmacológico , Cuidados Posoperatorios/métodos , Estudios Retrospectivos , SucciónRESUMEN
OBJECTIVE: We sought to prospectively determine the feasibility and safety of hyperthermic intraoperative intracavitary cisplatin perfusion immediately after extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. METHODS: Patients with malignant pleural mesothelioma who were surgical candidates underwent extrapleural pneumonectomy followed by hyperthermic intraoperative intracavitary cisplatin perfusion, consisting of a 1-hour lavage of the chest and abdomen with cisplatin (42 degrees C) at 225 mg/m(2). Pharmacologic cytoprotection consisted of intravenous sodium thiosulfate with or without amifostine. Morbidity and mortality were recorded prospectively. RESULTS: Ninety-six (79%) of 121 enrolled patients underwent extrapleural pneumonectomy, of whom 92 (76%) received hyperthermic intraoperative intracavitary cisplatin perfusion after extrapleural pneumonectomy. Fifty-three (58%) patients had epithelial tumors, and 39 (42%) had nonepithelial histology. Hospital mortality was 4.3%. Morbidity (grade 3 or 4, 49%) included atrial fibrillation in 22 (23.9%) patients, venous thrombosis in 12 (13%) patients, and laryngeal nerve dysfunction in 10 (11%) patients. Nine patients had renal toxicity, which was attributable to cisplatin in 8 of them. Among the 27 patients who also received amifostine (910 mg/m(2)), 1 patient had grade 3 renal toxicity attributable to cisplatin. Recurrence of malignant pleural mesothelioma was documented in 47 (51%) patients, with ipsilateral recurrence in 17.4% of patients. The median survival of the 121 enrolled patients was 12.8 months. CONCLUSIONS: Hyperthermic intraoperative intracavitary cisplatin perfusion following extrapleural pneumonectomy can be performed with acceptable morbidity and mortality. The use of amifostine in addition to sodium thiosulfate might reduce cisplatin-associated renal toxicity. Hyperthermic intraoperative intracavitary cisplatin perfusion following extrapleural pneumonectomy might enhance local control in the chest.