Preoperative assessment and therapeutic options for patients with malignant pleural mesothelioma

Prompt medical evaluation and aggressive treatment can lead to prolonged survival or successful palliation of symptoms for patients with malignant pleural mesothelioma, but the window for implementing treatment is short. Clinical recognition of the cancer is confounded by numerous factors, including long latency between exposure to asbestos and expression of the disease, nonspecific nature of the presenting symptoms, rarity of the disease, a lack of experience in clinical diagnosis, and rapidly deteriorating clinical course after diagnosis. Heightened clinical suspicion and proper patient selection through accurate staging and pathologic identification are paramount to defining and delivering therapy for this rare, lethal cancer.     

儿童恶性胸膜间皮瘤CT表现1例

正患儿女,14岁,发现头面部肿胀1余月,加重伴气喘1余周入院。CT检查:平扫见前纵隔内见巨大肿块,密度不均,与邻近血管分界不清;增强扫描见前纵隔巨大占位(图1),病灶中心层面大小13.4cm×7.9cm×10.7cm,并包绕纵隔血管生长,实性部分三期强化CT值约45~61HU,上腔静脉腔内见条片状充盈缺损区,考虑侵袭性胸腺瘤侵及心包并上腔静脉、左颈静脉瘤栓形成。经多部位穿刺活检,病理(图2)大体见受检组织呈灰白色,病理结果为(右前上纵隔)恶性肿瘤;免疫组化:(右前上纵隔)HBME-1、Calrentin、CK、Vim、CD117、CgA、     

Extrapleural pneumonectomy or pleurectomy/decortication for malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is associated with a very poor prognosis. Unlike other solid tumors, any type of planned surgery for MPM would be cytoreductive rather than radical. There are two types of surgery for MPM. Extrapleural pneumonectomy (EPP) involves en bloc resection of the lung, pleura, pericardium, and diaphragm. Pleurectomy/decortication (P/D) is a lung-sparing surgery that removes only parietal/visceral pleura. In comparison with EPP, P/D is theoretically less radical but is associated with less perioperative mortality/morbidity and less postoperative deterioration of cardiopulmonary function. It still remains unclear which surgical technique is superior in terms of the risk/benefit ratio. In this context, selection between EPP and P/D has been a matter to debate.     

Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically

BACKGROUND: The factors influencing outcome after resection of malignant pleural mesothelioma (MPM) are controversial. This analysis of a prospective surgical database identifies important prognostic factors. METHODS: Tumors were staged by the International Mesothelioma Interest Group staging system, and patients were followed until death. Prognostic factors were analyzed by log rank and Cox regression, and were considered significant if p was less than 0.05. RESULTS: From Oct 1983 to May 1998, 231 patients underwent thoracotomy, 115 had extrapleural pneumonectomy (EPP), and 59 pleurectomy/decortication (P/D). Among patients having EPP or P/D, 142 received adjuvant therapy. The median survival for stage I tumors was 29.9 months, for stage II 19 months, for stage III 10.4 months, and for stage IV 8 months. By multivariate analysis, stage, histology, gender, adjuvant therapy, but not the type of surgical resection, were significant. CONCLUSIONS: The better survival previously reported for P/D compared with EPP is not seen in a large database with long follow-up. Stages I and II have better survival rates than generally assumed for MPM. Locally advanced T and N status, and nonepithelial histology, identify poor prognosis patients who should be considered for novel treatment regimens.     

The alpha folate receptor is highly activated in malignant pleural mesothelioma

OBJECTIVE: To determine whether the folate receptor gene is overexpressed in malignant pleural mesothelioma. METHODS: Differential display analysis was performed with fresh frozen RNA obtained from normal lung, pleura, and mesothelioma. Sixty differentially expressed genes were identified and characterized. One gene that was over-expressed in mesothelioma versus normal tissue was the human alpha folate receptor. In situ hybridization with antisense probes designed on the basis of the sequence of the folate receptor was performed with frozen sections from 61 patients (33 epithelial and 28 mixed or sarcomatoid tumors) with malignant pleural mesothelioma. The controls included normal pleura, normal lung, other cancers, and sense controls for all of the tumors. Northern analysis with a folate receptor probe and immunohistochemical analysis with anti-alpha folate receptor antibodies were also performed. RESULTS: Forty-four (72%) of the 61 mesothelioma tumors were found to have between 2-fold and 4-fold higher mRNA expression of the folate receptor when compared with the control tissues. The histologic type of the tumor did not affect the rate of folate receptor activation. Northern analysis and immunohistochemical experiments confirmed these findings. CONCLUSIONS: A majority of mesothelioma tumors examined overexpress the alpha folate receptor protein when compared with normal adjacent tissues. This finding may help explain the observations that antifolate drugs have activity in the treatment of mesothelioma. It also encourages further study of folate receptor-related treatment strategies in this malignancy.     

Gene-modified PA1-STK cells home to tumor sites in patients with malignant pleural mesothelioma

BACKGROUND: Malignant mesothelioma is an uncommon but lethal cancer of increasing incidence, particularly among patients with a history of exposure to asbestos. Although numerous treatments have been employed, including chemotherapy, radiation therapy, surgical resection, and combinations of the above, no satisfactory treatment yet exists, and affected patients will die of this disease, usually within 12 months. Gene-based therapies constitute a new approach that offers hope of improved control of these tumors while being associated with less morbidity than conventional chemotherapeutic or surgical regimens. We demonstrated that PA1-STK cells home in vivo to mesothelioma deposits, a phenomenon that is required for optimal exertion of this therapeutic concept. METHODS: Gene-modified ovarian cancer cells expressing the thymidine-kinase gene (PA1-STK) were radiolabeled with 99Tc and infused into the pleural space of 4 patients with malignant pleural mesothelioma, then scanned to determine distribution of the cells. RESULTS: PA1-STK cells recognized and adhered preferentially to mesothelioma lining the chest wall. CONCLUSIONS: Cell-based "suicide gene" therapy utilizing the "bystander effect" with the gene-modified ovarian cancer cell line PA1-STK is feasible in human pleural mesothelioma. We have shown that this trafficking and homing of the therapeutic cells to the intrapleural tumor sites, a requirement for success with this novel therapeutic concept, is also valid in humans.     

h-Caldesmon, a useful positive marker in the diagnosis of pleural malignant mesothelioma, epithelioid type

Although a large number of immunohistochemical markers that can facilitate the differential diagnosis between epithelioid pleural mesothelioma and lung adenocarcinoma involving the pleura have proven to be valuable, no single antibody has demonstrated absolute sensitivity and/or specificity in making this distinction. Using immunohistochemical analysis with h-caldesmon, a specific marker for smooth muscle tumors, we examined 70 cases of epithelial mesotheliomas and 70 cases of lung adenocarcinomas. In addition, immunohistochemistry for muscle markers, such as desmin, alpha-smooth-muscle actin, muscle-specific actin, myoglobin, myogenin, myosin, and MyoD-1, was performed on all mesothelioma cases. Reactivity for h-caldesmon was obtained in 68 (97%) of the 70 epithelial mesotheliomas, but in none of the adenocarcinoma cases. All mesothelioma cases were found to be negative for the other muscle markers examined. We conclude that h-caldesmon is a highly sensitive and specific marker and suggest its inclusion in the immunohistochemical panel for the differential diagnosis of epithelioid mesothelioma versus lung adenocarcinoma.     

Experimental photodynamic therapy for malignant pleural mesothelioma with pegylated mTHPC

BACKGROUND AND OBJECTIVES: Experimental assessment of photodynamic therapy (PDT) for malignant pleural mesothelioma using a polyethylene glycol conjugate of meta-tetrahydroxyphenylchlorin (PEG-mTHPC). STUDY DESIGN/MATERIALS AND METHODS: (a) PDT was tested on H-meso-1 xenografts (652 nm laser light; fluence 10 J/cm(2); 0.93, 9.3, or 27.8 mg/kg of PEG-mTHPC; drug-light intervals 3-8 days). (b) Intraoperative PDT with similar treatment conditions was performed in the chest cavity of minipigs (n = 18) following extrapleural pneumonectomy (EPP) using an optical integrating balloon device combined with in situ light dosimetry. RESULTS: (a) PDT using PEG-mTHPC resulted in larger extent of tumor necrosis than in untreated tumors (P < or = 0.01) without causing damage to normal tissue. (b) Intraoperative PDT following EPP was well tolerated in 17 of 18 animals. Mean fluence and fluence rates measured at four sites of the chest cavity ranged from 10.2 +/- 0.2 to 13.2 +/- 2.3 J/cm(2) and 5.5 +/- 1.2 to 7.9 +/- 1.7 mW/cm(2) (mean +/- SD). Histology 3 months after light delivery revealed no PDT related tissue injury in all but one animal. CONCLUSIONS: PEG-mTHPC mediated PDT showed selective destruction of mesothelioma xenografts without causing damage to intrathoracic organs in pigs at similar treatment conditions. The light delivery system afforded regular light distribution to different parts of the chest cavity.     

CT-guided percutaneous selective cordotomy for treatment of intractable pain in patients with malignant pleural mesothelioma

Summary.  Malignant mesotheliomas are neoplasms that arise from mesothelial cells and cause intractable pain in the chest wall, usually located unilaterally. This local pain can be well controlled by computerized tomography (CT)-guided percutaneous cordotomy (PC). One hundred and fifty-three patients suffering from intractable pain due to malignancy were treated with CT-guided cordotomy between 1988 and 2001. Seventy of the 153 patients had pulmonary malignancy. Among these, 40 had bronchogenic carcinoma, 11 had Pancoast tumors and the remaining 19 had mesothelioma. The latter 19 cases with malignant mesothelioma suffering from unilateral pain were treated with CT-guided PC. In 18 cases, pain was controlled totally and, in one, partial pain control was obtained. Selective pain control was obtained in 15 cases, in whom narcotic drugs were discontinued postoperatively. Post-cordotomy dysesthesia was noted in only one case, and no complication or mortality was observed. In the treatment of intractable pain, CT-guided cordotomy is a perfect method in selected cases with malignancy. This is the most effective and suitable treatment modality for local pain due to malignant mesothelioma. Published online June 20, 2002     

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.     

Dual-phase FDG PET/CT for predicting prognosis in operable breast cancer

PurposeWe aimed to investigate the role of dual-phase FDG PET/CT in predicting the prognosis of patients with operable breast cancer.MethodsWe retrospectively reviewed the data of 998 patients who underwent radical treatment for breast cancer. Before treatment, PET/CT scans were performed 1 and 2 h after FDG administration. The maximum standardized uptake value (SUVmax) at both time points (SUVmax1 and SUVmax2) in the primary tumor and the retention index (RI) were calculated. PET recurrence risk (PET-RR) was determined based on the SUVmax1 and RI, and disease-free survival (DFS) and overall survival (OS) were evaluated according to the metabolic parameters. Propensity score matching was performed to adjust for biological characteristics.ResultsThe cut-off values for SUVmax1 and RI were 3 and 5%, respectively. The 5-year DFS was 94.9% and 86.1% (P < 0.001), and the 5-year OS was 97.6% and 92.7% (P < 0.001) in the low and high PET-RR groups, respectively. In multivariate analysis, high T status, nodal metastasis, the triple-negative subtype, and high PET-RR were independent factors of poor DFS. Propensity score matching revealed similar findings (5-year DFS 91.8% vs. 88.6%, P = 0.041 and 5-year OS 97.1% vs. 94.2%, P = 0.240, respectively).ConclusionThe combined parameters of SUVmax1 and RI on dual-phase FDG PET/CT were useful for predicting prognosis of patients with breast cancer. Patients with a high SUVmax1 and a negative time course of FDG uptake had a favorable prognosis.     

Current problems in the diagnosis of malignant pleural mesothelioma

The diagnosis of malignant pleural mesothelioma (MPM) is challenging although MPM is highly aggressive tumor. The current diagnostic gold standard is principally based on light microscopic examination of hematoxylin-eosin and immunohistochemical stains of large tissue sections. However, pathological diagnosis of MPM and classification of histological findings into 1 of the 3 subtypes (epithelial, sarcomatoid, biphasic) are difficult. We studied correlation between initial and final histological diagnosis retrospectively from the records of 21 cases with MPM from 1989 to 2005. The diagnosis of MPM was confirmed by histopathological examination of pleural tissue samples obtained by closed biopsy under computed tomography (CT) or ultrasonography-guided (5 cases), by biopsy under thoracoscopy with local anesthesia (9), by open biopsy via thoracotomy (2), and by video-assisted thoracoscopic surgery (VATS) [5] . Pleural biopsy under those diagnostic methods led to initial diagnosis of MPM in 15 of 21 cases (71.4%) . In 6 cases (28.6%) , initial diagnosis of MPM were not confirmed because of missing malignant tissue (1 case) and relatively small and sarcomatous element (5). In 2 cases examined by closed biopsy and in 3 examined by thoracoscopy under local anesthesia, initial diagnosis of MPM were not confirmed. To get the accurate diagnosis of MPM, obtaining large tissue samples in the initial examination by less invasive thoracoscopy is recommended.     

99mTc-Sestamibi SPECT is a useful technique for viability detection: results of a comparison with NH3/FDG PET.

OBJECTIVE: Assessment of myocardial viability by 99mTc-Sestamibi Single Photon Emission Computerized Tomography (SPECT) has been suggested as a more readily available and cheaper alternative to Positron Emission Tomography (PET) with 13N-ammonia (NH3) and 18F-fluoro-deoxy-glucose (FDG). We hypothesized that a semi-quantitative evaluation by SPECT could delineate myocardial viability with an acceptable concordance to PET. DESIGN: Fifty patients (age 57+/-7 years; ejection fraction 28 +/- 8%), with ischemic cardiomyopathy, underwent SPECT and PET imaging in random order. Viability by SPECT was defined as a defect size <50% of the segment area, or a defect representing > or =50% of the segment but with a mean activity > or =50% of peak activity. PET viability was defined as a perfusion score >2 and FDG score < or =2 (five-point scale, 0 = normal, 4 = absent activity). RESULTS: By segmental comparison to PET. SPECT yielded a sensitivity and specificity of 87% and 82% for detection of viable myocardium. The positive and negative predictive values were 96% and 58%, respectively. CONCLUSION: In patients with severe ischemic cardiomyopathy 99mTc-Sestamibi SPECT can delineate viable myocardium with an acceptable segmental concordance to NH3/FDG PET.     

Intrathoracic chemo-thermotherapy with radiofrequency waves after extrapleural pneumonectomy for malignant pleural mesothelioma

Although multimodal treatment is advocated for malignant pleural mesothelioma (MPM), a standard therapeutic regimen has not been established. This study evaluated the outcome of our aggressive treatment including extrapleural pneumonectomy (EPP) and postoperative intrathoracic chemo-thermotherapy (PICT). Moreover, we assessed the association between the clinical effect and an in vitro chemosensitivity test. Eleven patients with MPM underwent treatment including EPP followed by PICT using 8 MHz radiofrequency waves. In vitro chemosensitivity was examined using the collagen gel droplet embedded culture drug-sensitivity test (CD-DST). Complete resection was performed in nine patients. More than two courses of PICT with sufficient heating were completely performed in seven patients. There was no perioperative mortality. Grade 3 or 4 toxicity was not recognized. The median overall survival was 19 months, and the median local relapse-free survival was 17 months. Local recurrence was recognized in four patients (36.4%). Of these patients, three had received incomplete PICT. Four patients with complete PICT including a CD-DST-sensitive chemoagent did not develop local recurrence. Of three patients who received complete PICT including a CD-DST-resistant chemoagent, one tumor recurred locally. The present multimodal treatment including EPP and PICT is promising in local control for MPM. Furthermore, CD-DST may provide clinically useful information for MPM.     

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.