恶性胸膜间皮瘤治疗新进展

恶性胸膜间皮瘤是一种与石棉接触密切的肿瘤,其侵袭性很强,起病隐匿,发现时已在中晚期,目前的治疗方案尚未能有很好的治疗效果.采用溶瘤细胞性单纯性疱疹病毒和顺铂诱导溶瘤细胞性单纯性疱疹病毒产生GADD34蛋白增量调节方案能对间皮瘤癌细胞有相对的特异性,是一种有前景的治疗方案.     

Preoperative assessment and surgical indication for malignant pleural mesothelioma

The standard surgical procedure for patients with malignant pleural mesothelioma (MPM) is extrapleural pneumonectomy (EPP). However, high morbidity and mortality rates have been reported in patients who received EPP, whereas survival rates after EPP remain unsatisfactory. Thus, a carefully and precise preoperative assessment to select appropriate candidates for EPP is essential in patients with MPM, and we conducted a surgical staging with laparoscopy, mediastinoscopy and contralateral thoracoscopy for potentially resectable MPM patients. Among 5 consective patients who received the preoperative surgical staging during past 10 months, 1 patient was judged not to be a surgical candidate due to the presence of contralateral pleural metastasis. In conclusion, this surgical staging is a useful preoperative evaluation to prevent an unnecessary operation.     

Patterns of failure following surgical resection for malignant pleural mesothelioma

The optimum therapeutic strategy for patients with localized malignant mesothelioma continues to evolve. For patients who are eligible candidates, surgical resection plays an important role. An encouraging 45% 5-year survival rate has been reported for patients with early-stage disease who undergo EPP and have the favorable features of epithelial histology and the absence of mediastinal lymph node involvement. Most patients present with more advanced disease, however, and the optimum local and systemic treatment for these patients has not been defined. No randomized trials evaluating the various surgical or adjuvant therapeutic approaches have been performed. Evaluation of treatment efficacy based on observed patterns of failure may suffer from treatment selection biases. Most studies also do not separate out the failure patterns based on the initial stage (clinical or pathologic) of the disease. Consequently, it is difficult to discern the potential impact of a given adjuvant therapy. Given these limitations, however, some consistent observations from the available data can be made. For patients who undergo P/D, local recurrence (within the surgically operated hemithorax) is the most common form of recurrence. Efforts to decrease the chance of local recurrence after P/D have included the use of intrapleural and intravenous chemotherapy, brachytherapy, and external beam radiation therapy. None of these adjuvant treatment trials was randomized, and when compared with historical controls, none of the treatments used suggested a consistent outcome benefit. After P/D, the use of radiation is limited by the potential toxicity of the underlying organs, most importantly, the intact lung. Doses required to treat mesothelioma effectively are above the doses that would lead to damage to the lung parenchyma. Cisplatin and mitomycin have been used as agents have modest activity against mesothelioma. The doses of cisplatin used may not have been optimal, although they were based on prior pharmacokinetic studies. Alternative approaches for patients who undergo P/D, such as the use of escalating doses of heated intrapleural cisplatin (given with a renal protecting agent, sodium thiosulfate, which provides the opportunity to deliver higher doses of chemotherapy), are being pursued by Sugarbaker et al. The availability of more active systemic chemotherapy agents or other intrapleural agents also may offer better therapeutic options for patients who undergo P/D. Recently, Vogelzang et al presented the findings of a large randomized study that compared cisplatin/premetrexed to cisplatin and demonstrated an improvement in response rate (41% for cisplatin/pemetrexed versus 19% for cisplatin) and median survival (12.1 versus 9.3 months, respectively; P = 0.020). Other chemotherapy regimens with encouraging activity in mesothelioma include the combination of cisplatin and gemcitabine, with response rates ranging from 16% to 48%. From a review of available data, patients with mesothelioma who have undergone P/D (with or without intrapleural chemotherapy) who are evaluated at the Dana Farber Cancer Institute and Brigham and Women's Hospital are offered therapy with systemic chemotherapy alone. After P/D, radiation is used only for palliative treatment. Patients who have undergone P/D are also appropriate candidates to receive chemotherapy or other novel therapeutic strategies being evaluated in clinical trials. For patients who have undergone EPP, the pattern of recurrence is predominantly a combination of local and distant failure (Table 1). The local recurrence rates, however, seem to be lower than rates seen after P/D. This observation may represent a shift of the natural history of the disease. Metastatic mesothelioma is often seen late in the course of the disease, but it may become the dominant source of disease after aggressive local surgical management. Many studies define abdominal recurrence as a site of distant recurrence, although this may represent transdiaphragmatic extension of the pleural mesothelioma. Advances in local therapy also may decrease the rate of abdominal recurrences. True distant recurrences (bone, central nervous system, contralateral hemithorax) remain less common. The lowest rate of local recurrence (13%), with a 4% local-only recurrence rate, was seen in the study by Rusch et al, who used 54 Gy hemithorax radiation as adjuvant therapy. This is the lowest rate of local recurrence after an EPP that has been reported. Baldini et al reported a 50% local recurrence rate, with a 13% local-only rate, after trimodality therapy. One possibility for the differences between these two reports is the lower dose of radiation (30.6 Gy) used in the latter study. In the study by Rusch et al, distant failures predominate, and the patients are appropriate candidates for systemic chemotherapy, which could be administered either as neoadjuvant or adjuvant therapy. Kestenholz et al currently are performing a phase II clinical trial of neoadjuvant cisplatin and gemcitabine administered for three cycles followed by EPP and adjuvant radiation therapy. A similar approach also is being pursued in an ongoing clinical trial using neoadjuvant cisplatin/pemetrexed for four cycles before EPP followed by 54 Gy of adjuvant hemithorax radiation. Alternatively, patients who have undergone EPP could be treated with adjuvant chemotherapy in addition to adjuvant radiation therapy. Currently, patients evaluated at the Dana Farber Cancer Institute and Brigham and Women's Hospital who have undergone EPP are offered adjuvant chemotherapy followed by hemithorax radiation to 54 Gy in an effort to maximize local and distant control rates. Further clinical studies are needed for all patients with mesothelioma to define the optimum surgery and duration and types of adjuvant therapy. The appropriate multimodality approaches most likely will differ based on disease stage, histology, and patient performance status. intrapleural chemotheraphy treatments. These two For Patients who have undergone EPP, the pattern     

Diffuse malignant pleural mesothelioma

Malignant pleural mesothelioma is an uncommon neoplasm that caused 647 deaths in Japan in 2004. The incidence of the disease is increasing and is estimated to reach its peak in 2025. We reviewed the clinical features in 11 consecutive patients with pathologically confirmed diffuse malignant pleural mesothelioma in our institution from January 1997 to December 2002. Of the 11 patients, 9 were male and 2 were female with a mean age of 66 (range, 55 to 90) years. Symptoms included dyspnea in 4 patients, chest pain in 3, dyspnea plus chest pain in 2, and cough in 2. Median period between symptom onset and presentation was 1 (range, 0 to 6) month. A history of asbestos exposure was identified in 3 patients and suspected in 5. A definitive diagnosis was made by closed pleural biopsy in 8 patients, pleural fluid cytology in 2, and autopsy in 1. Histological subtypes included epithelioid in 6 patients, sarcomatoid in 2, biphasic in 1, and unknown in 2. International Mesothelioma Interest Group (IMIG) staging included stage II in 6 patients, stage III in 3, and stage IV in 2. Median period between presentation and diagnosis was 1 (range, 0 to 22) month. Treatment included intrapleural chemotherapy in 4 patients, extrapleural pneumonectomy in 3, pleural drainage in 2, and best supportive care in 2. During the follow-up period, 9 patients died and 2 survived. Median survival time after diagnosis was 3 (range, 0 to 51) months. Of the 11 patients, 7 (64%) died within 6 months after the first presentation, and only 1 (9%) lived longer than 2 years after diagnosis.     

Intradural pleural malignant mesothelioma

Summary Pleural malignant mesothelioma is a rare tumour of the pleural epithelium, which progresses by infiltration into the lung parenchyma, the chest wall, and the mediastinum. Haematogenous spreading may occur in the late stages of the disease. Spinal involvement is exceptional and usually occurs in the vertebral body or epidural space, and intradural location of a mesothelioma is even more uncommon. In this article, a MEDLINE literature review on intradural mesothelioma was conducted and four intradural mesothelioma cases in the English literature were retrieved: one in the intradural extramedullary location and three with intramedullary growth. Additionally, we report a 50-year-old patient with a pleural malignant mesothelioma that spreads across the dura into the spinal cord at T5.     

Localized malignant pleural mesothelioma

Localized malignant pleural mesothelioma (LMPM) is a rare tumor; previously only 52 cases have been reported in the English literature. This type of tumor should be distinguished from diffuse malignant pleural mesothelioma, because a good outcome may be obtained by surgical resection. We report a case of LMPM which grew rapidly within 1 year. Surgical resection was performed, and at present, 6 months since the operation, the patient remains free of the disease.     

Problems of diagnosis and surgical treatment in pleural mesothelioma

Twelve patients with pleural mesothelioma were operated on over a period of 6 years. Two of six patients with localized type died of recurrence. One of two patients showed fibrous form with low grade malignancy and the other showed a mixed type on their histological examination. The remaining 4 patients are alive and well with the combined resection of the tumor and the chest wall for the past 2 to 3 years. Three of six patients with diffuse type had an operation of pleuropneumonectomy with the resection of adjacent structures such as the diaphragm, SVC and the chest wall. One of them who had had the implantation at the chest wall where the biopsy needle entered, developed peritoneal mesothelioma. At laparotomy, numerous nodules were found. He was given 470 mg of CDDP and 80 mg of ADM into the cavity through the tubes. Though this patient died eventually, nodules were found to be macroscopically disappeared at autopsy. But they were left in the area where the drugs could not reach. The other two patients are alive and well for 16 to 22 months after the operation. The remaining 3 patients, who did not have the diagnosis preoperatively, died of cardio-pulmonary insufficiency due to local compression by the huge tumor at 3 months, 7 months and 2 years respectively after the exploratory thoracotomy. It is concluded that wide resection including the rib for a case with solitary lesion and early thoracotomy for a case with undiagnosed chest fluid, followed by pleuropneumonectomy or pleurectomy and post-operative local chemotherapy, are recommended for this malignant disease.     

Surgical treatment for malignant pleural mesothelioma in eight cases

Between 1987 and March 2000, we have operated on eight patients for malignant mesothelioma which consisted of four of localized type and four of diffuse type. We have aggressively resected mesothelioma combined with chemotherapy whether the tumor was primary or recurrent, and concluded the following. 1) In localized malignant mesothelioma, en-bloc primary tumor resection was possible and additional resection for recurrence was effective and useful for long time survival. 2) In diffuse malignant mesothelioma, complete tumor resection was impossible to even perform pleuropneumonectomy accompanied with partial resection of pericardium and diaphragm and, therefore, the prognosis was poor in four patients and all died around one year. 3) Because recurrent pattern for localized type was diffuse type, diagnosis and surgical treatment in early stage was essential for long time survival.     

Extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma.

A technique for extrapleural pneumonectomy in diffuse, malignant, pleural mesothelioma is described. The technique used in a protocol at Brigham and Women's Hospital has resulted in improved operative mortality figures and length of hospital stay. The right-sided procedure is presented followed by differences in technique required by the left-sided approach.     

Localized malignant lymphohistiocytoid pleural mesothelioma

We report a case of a 42-year-old man with a right pleural mesothelioma. This neoplasm has 3 rare features. Firstly, it was a localized form: suspected by imaging, visualized by video-assisted thoracoscopy, at the time of the curative-thoracotomy and confirmed by the pathological analysis. The second characteristic is its histological type: "malignant lymphohistiocytoid mesothelioma". This rare subtype has been reported in only 4 papers. Third, after pleuro-pneumonectomy, our patient is alive after 6 years and 5 months postoperatively without any sign of recurrence. Only one case with a long follow-up has been reported but with recurrence at 5 years postoperatively.     

The role of surgery in the treatment of malignant pleural mesothelioma

The role of surgery in the treatment of diffuse pleural malignant mesothelioma is controversial. The procedures proposed to date are extrapleural pneumonectomy, pleurectomy, and thoracoscopy. External radiation or intraoperative implantation of radioisotopes, chemotherapy and intrapleural treatment with various different agents are also considered as adjuvant therapy. Patient selection, postoperative morbidity and mortality and survival rates are discussed. Our personal series of 72 diffuse pleural malignant mesotheliomas is described: 29 had a palliative operation while 43 underwent radical surgery consisting in 24 extrapleural pneumonectomies and 19 pleurectomies.     

Treatment of malignant pleural mesothelioma with chemotherapy preceding versus after surgical resection

Objectives

There are 2 main treatment paradigms recognized by the National Comprehensive Cancer Network for resectable malignant pleural mesothelioma (MPM): induction chemotherapy followed by resection (IC/R), and up-front resection with postoperative chemotherapy (R/PC). These paradigms are being compared in an accruing randomized phase II trial. In the absence of such completed trials, in this study we evaluated overall survival (OS) and postoperative outcomes of IC/R and R/PC.

Histopathologic diagnosis of malignant pleural mesothelioma

Diffuse malignant mesothelioma is a malignant tumor arising in the pleura from mesothelial cells. It has extremely polymorphous varieties of morphological patterns. Thus, confirming histopathologic diagnosis as mesothelioma, it should need not only histological examination but several methods such as special stain, immunohistochemical study, cytology of pleural effusion and electromicroscopy.     

Treatment of malignant pleural mesothelioma]

BACKGROUND: In this study all patients observed between January 1993 and October 1997 with malignant pleural mesothelioma (MPM) have been analyzed in order to describe the impact of treatment modality on survival. METHODS: Medical records of 56 patients with MPM (44 male, 12 female, median age = 59 yrs) were reviewed. In 34 cases the histotype was epithelial, in 4 sarcomatoid, in 4 mixed, in 3 desmoplastic, and in 11 not specified. Four treatment modalities were identified: 1) Surgery (subtotal pleurectomy) = 20 patients; 2) Chemotherapy = 19 patients; 3) Surgery+Chemo-therapy = 8 patients; 4) Supportive care = 9 patients. RESULTS: The median survival was: 1) Surgery = 12.4 months; 2) Chemotherapy = 7.5 months; 3) Surgery+Chemotherapy = 12 months; 4) Supportive care = 11.4 months. Using univariate analysis, 8 prognostic factors were studied (age, sex, asbestos exposure, side, histotype, performance status, stage, treatment). Among these, only the stage and the performance status had shown a prognostic value on survival (p<0.05), while the treatment modality had not significantly influenced the prognosis. Using multivariate analysis only performance status showed to be significatively associated with survival (p=0.01 and odds ratio = 1.9, I.C. 1.2-3.2). CONCLUSIONS: Despite the limits of a retrospective study, personal experience confirms the ineffectiveness of current therapeutical approaches to MPM. A better understanding of MPM is required to develop new therapeutical approaches and alter the dismal prognosis of this disease.     

Clinical diagnosis of malignant pleural mesothelioma

Accurate and rapid diagnosis of malignant pleural mesothelioma is important because of its rapid progress. But diagnosis of this disease is often difficult. We reviewed 64 cases with a pathological diagnosis of malignant pleural mesothelioma in the past 14 years in our hospital. We made diagnosis of this disease by cytologic study of pleural fluid (11 cases), percutaneous needle biopsy (16), thoracoscopic biopsy (34), or surgery (2). When cytologic findings are inconclusive, thoracoscopic biopsy is the most effective method for diagnosis and should be done without delay.     

Extrapleural pneumonectomy of malignant pleural mesothelioma

We analyzed 7 patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy. Six men and a woman had a mean age of 65 years old. The postoperative mortality rate was 14% (1 death) and morbidity, 43% (3 cases). According to staging of International Mesothelioma Interest Group, 2 patients had stage I disease, 1 did stage II, 3 did stage III and 1 did stage IV. Local recurrences were found in 3 patients and metastasis in 2. In patients with local recurrences, 2 had irradiation with chemotherapy and 1, irradiation. In patients with recurrences of metastasis, 1 had chemotherapy and 1, supportive care. Seven patients with extrapleural pneumonectomy and 10 without surgery had median survivals of 16 months and 10 months, 1-year survival rates of 71% and 40% and 2-year survival rates of 57% and 0% respectively (p=0.071). Extrapleural pneumonectomy with adjuvant therapy could be effective treatment for malignant pleural mesothelioma.     

恶性胸膜间皮瘤的实验模型

恶性胸膜间皮瘤(malignant pleural mesothelioma，MPM)是一种少见的肿瘤，近年来发病率逐渐上升，由于诊断和治疗均较困难，所以迫切需要建立实验模型进行研究。通过对模型的种类、制作方法和各种模型的特点进行综述，归纳出其用途。MPM动物模型是临床研究最常用的实验模型，多用大鼠或裸鼠，以诱发性动物模型和异种移植模型较成熟。目前各种模型均存在一些缺点，或周期长、出瘤率低或与人差异较大等，离理想的模型仍有一定的距离。但随着分子生物学和分子遗传学的发展，利用基因或其它途径减少或消除大动物的个体差异，同时提高实验动物产量；研究裸鼠的繁殖、饲养规律，寻找廉价、饲养方便、体大、生命力强的裸鼠，以及对MPM转基因动物模型的研究，将有希望获得多种满足不同需要的理想MPM实验模型。