Pleural malignant mesothelioma causing cord infiltration through the nerve root. Case report.

Neurol Med Chir (Tokyo). 2009 Apr;49(4):167-71

Authors: Okura H, Suga Y, Akiyama O, Kudo K, Tsutsumi S, Abe Y, Yasumoto Y, Ito M, Izumi H,

Shiomi K A 61-year-old man presented with a rare pleural malignant mesothelioma of the spine manifesting as progressive weakness of the bilateral lower extremities, numbness in the body and both legs, and dysfunction of the bladder and bowel. He had previous occupational exposure to asbestos while working at a car repair shop and had undergone right panpleuropneumonectomy under a diagnosis of sarcomatous type mesothelioma in the right pleural space. Magnetic resonance imaging of the spine with gadolinium showed an enhanced intramedullary tumor at the T4 level. Operative findings disclosed the clouded and swollen right posterior nerve root, and the pial surface was covered by clouded arachnoid-like membrane. The removed part of the T4 posterior nerve root and intramedullary tumor revealed malignant mesothelioma with invasion spreading along the posterior nerve root. He died of respiratory failure 3 months after the diagnosis. This case shows that spinal metastasis must be considered if a patient with pleural malignant mesothelioma shows neurological worsening and neuroimaging shows an abnormal lesion in the thoracic spinal cord. However, the patient's neurological condition is very difficult to improve in the presence of spinal cord infiltration.

PMID: 19398862 [PubMed - indexed for MEDLINE]

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Malignant pleural mesothelioma: medical treatment update.

Clin Lung Cancer. 2009 Mar;10(2):112-7

Authors: Vorobiof DA, Mafafo K

Malignant pleural mesothelioma (MPM) is a disease usually unaffected by current therapeutic strategies, but for the majority of patients, the use of systemic chemotherapeutic drugs remains the only therapeutic option available.

Mesothelioma cells escape heat stress by upregulating Hsp40/Hsp70 expression via mitogen-activated protein kinases.

J Biomed Biotechnol. 2009;2009:451084

Authors: Roth M, Zhong J, Tamm M, Szilard J Therapy with hyperthermal chemotherapy in pleural diffuse malignant mesothelioma had limited benefits for patients. Here we investigated the effect of heat stress on heat shock proteins (HSP), which rescue tumour cells from apoptosis. In human mesothelioma and mesothelial cells heat stress (39-42 degrees C) induced the phosphorylation of two mitogen activated kinases (MAPK) Erk1/2 and p38, and increased Hsp40, and Hsp70 expression. Mesothelioma cells expressed more Hsp40 and were less sensitive to heat stress compared to mesothelial cells. Inhibition of Erk1/2 MAPK by PD98059 or by Erk1 siRNA down-regulated heat stress-induced Hsp40 and Hsp70 expression and reduced mesothelioma cell survival. Inhibition of p38MAPK by SB203580 or siRNA reduced Hsp40, but not Hsp70, expression and also increased mesothelioma cell death. Thus hyperthermia combined with suppression of p38 MAPK or Hsp40 may represent a novel approach to improve mesothelioma therapy.

PMID: 19551156 [PubMed - indexed for MEDLINE]

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Placenta growth factor expression has prognostic value in malignant pleural mesothelioma. Ann Thorac Surg. 2009 Aug;88(2):426-31 Authors: Pompeo E, Albonici L, Doldo E, Orlandi A, Manzari V, Modesti A, Mineo TC BACKGROUND: Malignant pleural mesothelioma is highly aggressive and recurs rapidly despite radical multimodality treatment. Progression of mesothelioma is thought to be governed by various growth factors, including vascular endothelial growth factor (VEGF). Placenta growth factor (PlGF) belongs to the VEGF family, although no study has yet investigated its expression in mesothelioma. We hypothesized that PlGF is overexpressed in mesothelioma and could have prognostic value in patients treated by extrapleural pneumonectomy. METHODS: We assessed by immunohistochemistry with semiquantitative classification (0 = no staining; 3 = strong staining), the expression levels of PlGF and its cognate receptors VEGF receptor 1, neuropilin-1, and neuropilin-2 in 27 patients with malignant pleural mesothelioma undergoing extrapleural pneumonectomy, in 14 patients with reactive mesothelium, and in 10 patients with normal mesothelium. RESULTS: Whereas PlGF was not expressed in normal mesothelium, it was overexpressed (grade 3) more frequently in mesothelioma than in reactive mesothelium specimens (11 or 41% versus 1 or 7%, respectively, p = 0.03). Furthermore, in mesothelioma, VEGF receptor 1 and neuropilin-1 and -2 were overexpressed in 18 specimens (67%), 8 specimens (30%), and 9 specimens (33%), respectively. Mean survival after extrapleural pneumonectomy was 17 months. An inverse relationship was found between the degree of PlGF expression and survival in months (R = -0.45, p = 0.01). No correlation was found between tumor stage and survival (R = -0.33) and between tumor stage and PlGF expression (R = 0.07). CONCLUSIONS: We have shown that PlGF can be overexpressed in malignant pleural mesothelioma. In addition, the finding of an inverse relationship between PlGF expression levels and survival suggests a pivotal role of this factor in the recurrence and progression of mesothelioma after extrapleural pneumonectomy. PMID: 19632388 [PubMed - indexed for MEDLINE]

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Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy.

PLoS One. 2009;4(5):e5735

Authors: Lubin M, Lubin A

BACKGROUND: The gene for methylthioadenosine phosphorylase (MTAP) lies on 9p21, close to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously co-deleted, with a frequency of 35 to 70%, in lung and pancreatic cancer, glioblastoma, osteosarcoma, soft-tissue sarcoma, mesothelioma, and T-cell acute lymphoblastic leukemia. In normal cells, but not in tumor cells lacking MTAP, MTAP cleaves the natural substrate, 5'-deoxy-5'-methylthioadenosine (MTA), to adenine and 5-methylthioribose-1-phosphate (MTR-1-P), which are then converted to adenine nucleotides and methionine. This distinct difference between normal MTAP-positive cells and tumor MTAP-negative cells led to several proposals for therapy. We offer a novel strategy in which both MTA and a toxic adenine analog, such as 2,6-diaminopurine (DAP), 6-methylpurine (MeP), or 2-fluoroadenine (F-Ade), are administered. In MTAP-positive cells, abundant adenine, generated from supplied MTA, competitively blocks the conversion of an analog, by adenine phosphoribosyltransferase (APRT), to its active nucleotide form. In MTAP-negative tumor cells, the supplied MTA cannot generate adenine; hence conversion of the analog is not blocked.

PRINCIPAL FINDINGS: We show that this combination treatment--adenine analog plus MTA--kills MTAP-negative A549 lung tumor cells, while MTAP-positive human fibroblasts (HF) are protected. In co-cultures of the breast tumor cell line, MCF-7, and HF cells, MCF-7 is inhibited or killed, while HF cells proliferate robustly. 5-Fluorouracil (5-FU) and 6-thioguanine (6-TG) may also be used with our strategy. Though neither analog is activated by APRT, in MTAP-positive cells, adenine produced from supplied MTA blocks conversion of 5-FU and 6-TG to their toxic nucleotide forms by competing for 5-phosphoribosyl-1-pyrophosphate (PRPP). The combination of MTA with 5-FU or 6-TG, in the treatment of MTAP-negative tumors, may produce a significantly improved therapeutic index.

CONCLUSION: We describe a selective strategy to kill tumor cells lacking MTAP.

PMID: 19478948 [PubMed - indexed for MEDLINE]

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Surgical biology for the clinician: peritoneal mesothelioma: current understanding and management.

Can J Surg. 2009 Feb;52(1):59-64 Authors: Chua TC, Yan TD, Morris DL

Mesothelioma is an asbestos-related tumour. Mesothelioma in the thorax occurs on the pleura and is known as pleural mesothelioma. It is the more common form of mesothelioma, accounting for 70% of cases.