Ramalingam SS, Belani CP, Ruel C, Frankel P, Gitlitz B, Koczywas M, Espinoza-Delgado I, Gandara D.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA. suresh.ramalingam@emory.edu

Abstract

Background: Belinostat (PXD 101) is a novel inhibitor of class I and II histone deacetylases. This class of compounds has demonstrated anticancer activity in malignant mesothelioma. We conducted a phase II study of belinostat in patients with relapsed malignant pleural mesothelioma.

Methods: Patients with advanced mesothelioma, progression with one prior chemotherapy regimen and Eastern Cooperative Oncology Group performance status 0-2 were eligible. Belinostat was administered at 1000 mg/m intravenously over 30 minutes on days 1-5 of every 3 week cycle. The primary end point was response rate. The Simon two-stage design was used. Disease assessments were performed every two cycles.

Results: Thirteen patients were enrolled. Baseline characteristics were: median age of 73 years; Eastern Cooperative Oncology Group performance status 0 (n = 4), 1 (8) and 2 (1). A median of two cycles of therapy were administered. Disease stabilization was seen in two patients. No objective responses were noted and the study did not meet criteria to proceed to the second stage of accrual. Median survival was 5 months with a median progression-free survival of 1 month. Salient toxicities included nausea, emesis, fatigue, and constipation. One patient died as a consequence of cardiac arrhythmia which was deemed ‘possibly’ related to therapy.

Conclusions: Belinostat is not active as monotherapy against recurrent malignant pleural mesothelioma. Evaluation of combination strategies or alternate dosing schedules may be necessary for further development of this novel agent in mesothelioma.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

regimen

(rej-uh-men) a strict, regulated plan (such as diet, exercise, or other activity) designed to reach certain goals. In cancer treatment, a plan to treat cancer.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

emesis

(em-eh-sis) vomiting

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Pass HI, Brewer GJ, Dick R, Carbone M, Merajver S.

Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016, USA. harvey.pass@med.nyu.edu

Abstract

Background: Tetrathiomolybdate (TM) is an oral copper-depleting agent that has been shown to inhibit angiogenesis, and angiogenesis is a predictor of poor prognosis in malignant pleural mesothelioma. We hypothesized that cytoreduction of malignant pleural mesothelioma followed by TM will delay time to progression.

Methods: Between November 2000 and August 2003, 30 patients with malignant pleural mesothelioma received postoperative TM beginning 4 to 6 weeks after surgery at a dose adjusted to keep ceruloplasmin between 5 and 15 mg/dL). Time to progression was compared with the 55 stage I and II patients and 109 stage III patients previously treated with cytoreduction by one of us (H.P.).

Results: The 30 patients (25 men, 5 women; 13 stage I and II, 17 stage III), median age 67 years (range, 49–81 years), remained on TM a median of 14.9 months (range, 2 to 57 months). All patients reached target ceruloplasmin levels at a mean of 34 ± 2 days (95% confidence interval, 30 to 39 days), and vascular endothelial growth factor levels at baseline (ceruloplasmin = 45.2 ± 2 mg/dL) decreased from 2,086 ± 390 pg/mL to 1,250 ± 712 pg/mL (p < 0.002) at target ceruloplasmin (13 ± 2 mg/dL; p < 0.0001 from baseline). The time to progression for all stage I or II TM patients was 20 months whereas that of 55 stage I or II non–TM-treated patients was 10 months (p = 0.046 versus TM). No differences in time to progression for the stage III TM patents from surgery were seen (7 months).

Conclusions: Tetrathiomolybdate has antiangiogenic effects in malignant pleural mesothelioma patients after resection of gross disease, and exhibits minimal toxicity and comparable efficacy to previous multimodality trials. Tetrathiomolybdate should be evaluated for efficacy in combination with standard malignant pleural mesothelioma regimens, as well as for postsurgical maintenance therapy.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

resection

surgery to remove part or all of an organ or other structure.

prognosis

(prog-no-sis) a prediction of the course of disease; the outlook for the cure of the patient. For example, women with breast cancer that was detected early and who received prompt treatment have a good prognosis.

angiogenesis

(an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Salzberg M, Kirson E, Palti Y, Rochlitz C.

University Hospital Basel, Switzerland. msalzberg@pharmabrains.ch

Abstract

Background: The transmission of electric fields using insulated electrodes has demonstrated that very low-intensity, properly tuned, intermediate-frequency electric fields, termed tumor-treating fields (TTFields), selectively stunts tumor cell growth and is accompanied by a decrease in tumor angiogenesis.

Patients and Methods: This open, prospective pilot study was designed to evaluate the safety, tolerability, and efficacy profile of TTFields treatment in patients with locally advanced and/or metastatic solid tumors using the NovoTTF100A^TM device. All 6 patients were heavily pre-treated with several lines of therapy; no additional standard treatment option was available to them. TTFields treatment using continuous NovoTTF-100A lasted a minimum of 14 days and was very well tolerated.

Results: No related serious adverse events occurred. Outcomes showed 1 partial response of a treated skin metastasis from a primary breast cancer, 3 cases where tumor growth was arrested during treatment, and 1 case of disease progression. One mesothelioma patient experienced lesion regression near TTFields with simultaneous tumor stability or progression in distal areas.

Conclusion: Although the number of patients in this study is small, the lack of therapy toxicity and the efficacy observed in data gathered to date indicate the potential of TTFields as a new treatment modality for solid tumors, definitely warranting further investigation.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

metastasis

(meh-tas-teh-sis) the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream.

lesion

(lee-zhun) a change in body tissue; sometimes used as another word for tumor.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

angiogenesis

(an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Nikolinakos P, Heymach JV.

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA. jheymach@mdanderson.org

Abstract

Cediranib (AZD2171; Recentin, AstraZeneca, Wilmington, Delaware) is a once-daily oral tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3, c-KIT, and platelet-derived growth factor receptors. In preclinical testing it inhibits tumor angiogenesis and inhibits tumor growth in a wide range of tumor models. Phase 1 studies show cediranib to be generally well tolerated as monotherapy at doses of 45 mg/d or less, with a pharmacokinetic profile that supports once-daily oral administration and toxic effects consistent with those seen in other agents that target the vascular endothelial growth factor pathway. Encouraging results from phase 1 studies as monotherapy or in combination with chemotherapy have prompted further investigation in several thoracic malignancies, including ongoing trials in malignant mesothelioma, small cell lung cancer, and an ongoing phase 2/3 trial in non-small cell lung cancer (NSCLC) in combination with chemotherapy. The NSCLC trials include patients with squamous cell histologic features and treated brain metastases, populations for which bevacizumab is currently not indicated. These trials will determine whether cediranib will join the growing armamentarium of therapeutic options for thoracic malignancies and broaden the number of patients with NSCLC who could potentially benefit from antiangiogenic therapy.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

platelet

a part of the blood that helps it "stick together" (clot) to promote healing after an injury. Chemotherapy can cause a drop in the platelet count--a condition called thrombocytopenia.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

angiogenesis

(an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Giesel FL, Choyke PL, Mehndiratta A, Zechmann CM, von Tengg-Kobligk H, Kayser K, Bischoff H, Hintze C, Delorme S, Weber MA, Essig M, Kauczor HU, Knopp MV.

Radiologie, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany; Ohio State University, Columbus, OH.

Abstract

Rationale and Objectives: Malignant mesothelioma (MM) of the pleura is an aggressive and often fatal neoplasm. Because MM frequently demonstrates marked angiogenesis, it may be responsive to antiangiogenic therapy, but effective methods for selecting and monitoring of patients are further needed. We employed dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and quantitative immunohistochemistry (IHC) to characterize the microvascularity of MM using both a physiologic and ultrastructural method.

Materials and Methods: Nineteen patients diagnosed with MM were enrolled and DCE-MRI was performed before antiangiogenic treatment. For each patient, tumor regions were characterized by their DCE-MRI–derived pharmacokinetic parameters (Amp, kep, kel), which were also compared to those of normal tissue (aorta, liver, spleen, and muscle). In addition, quantitative IHC of representative samples was performed with CD-34 staining to compare the calculated microvessel density (MVD) results with DCE-MRI results.

Results: MM demonstrated markedly abnormal pharmacokinetic properties compared with normal tissues. Among the parameters tested, Amp was significantly different in MM (P ≤ .001) compared to normal organs. Despite the observation that the MVD of mesotheliomas in this series was high compared to other tumors, DCE-MRI pharmacokinetic parameters had a moderately positive correlation with MVD (r = 0.5).

Conclusions: DCE-MRI and IHC can be used in patients with MM to visualize tumor microvascularity and to characterize tumor heterogeneity. DCE-MRI and IHC results positively correlated, though moderately, but these two methods present as essential tumor biomarkers. This multimodal characterization may be useful in selecting possible tumor subtypes that would benefit from antiangiogenic therapy.

Keywords: Angiogenesis, malignant mesothelioma, dynamic contrast enhanced MRI, pharmacokinetic analysis, microvascular density, CD-34

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

pleura

(pler-uh) the membrane around the lungs and lining of the chest cavity. (Pleural mesothelioma.)

neoplasm

(nee-o-plas-um) an abnormal growth (tumor) that starts from a single altered cell; a neoplasm may be benign or malignant. Cancer is a malignant neoplasm.

MRI

Stands for magnetic resonance imaging. A method of taking pictures of the inside of the body. Instead of using x-rays, MRI uses a powerful magnet and transmits radio waves through the body; the images appear on a computer screen as well as on film. Like x-rays, the procedure is physically painless, but some people find it psychologically uncomfortable to be in the small core of the MRI machine.

imaging

any method used to produce a picture of internal body structures. Some imaging methods used to detect cancer are x-rays (including mammograms and CT scans), magnetic resonance imaging (MRI), scintigraphy, and ultrasound.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

angiogenesis

(an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.

tissue

a collection of cells, united to perform a particular function.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Amati M, Tomasetti M, Scartozzi M, Mariotti L, Ciuccarelli M, Valentino M, Governa M, Santarelli L.

Università Politecnica delle Marche, Dipartimento di Patologia Molecolare e Terapie Innovative, Clinica di Medicina del Lavoro, Tronto 10/a, 0020 Torrette, AN. m.amati@univpm.it

Abstract

Improved detection methods for diagnosis of asymptomatic malignant pleural mesothelioma (MPM) are essential for an early and reliable detection and treatment of this disease. Thus, focus has been on finding tumour markers in the blood. 94 asbestos-exposed subjects, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the significance of 8-hydroxy-2′-deoxy-guanosine (80HdG) in white blood cells and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors (PDGFbeta, HGF, bFGF, VEGFbeta), and matrix proteases (MMP2, MMP9, TIMP1, TIMP2) for potential early detection of MM. The area under ROC curves (AUC) indicates that 80HdG levels can discriminate asbestos-exposed subjects from controls but not from MPM patients. Significant AUC values were found for SMRP discriminating asbestos-exposed subjects from MPM patients but not from controls. VEGFbeta can significantly differentiate asbestos-exposed subjects from control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, TIMP2. The sensitivity and specificity results of markers were calculated at defined cut-offs. The combination of 80HdG, VEGFbeta and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MPM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

Glossary

diagnosis

identifying a disease by its signs or symptoms, and by using imaging procedures and laboratory findings. The earlier a diagnosis of cancer is made, the better the chance for long-term survival.

detection

finding disease. Early detection means that the disease is found at an early stage, before it has grown large or spread to other sites. Note many forms of cancer can reach an advanced stage without causing symptoms. Mammography can help to find breast cancer early, and the PSA blood test is useful in finding prostate cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

asymptomatic

(A-simp-toh-matic) not having any symptoms of a disease. Many cancers can develop and grow without producing symptoms, especially in the early stages. Screening tests such as mammograms help to find these early cancers, when the chances for cure are usually highest. (See also screening.)

white blood cells

there are several types of blood cells that help defend the body against infections. Certain cancer treatments such as chemotherapy can reduce the number of these cells and make a person more likely to get infections.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Porret E, Madelaine J, Galateau-Sallé F, Bergot E, Zalcman G.

Service de Pneumologie, Pôle Coeur-Poumons-Vaisseaux, Université Basse-Normandie, CHU de Caen, France.

Abstract

Malignant pleural mesothelioma (MPM) is a rare tumour due to occupational asbestos exposure. The incidence of MPM will continue to increase until 2020-2030. The incidence reaches 100 cases/million/year in occupationally exposed populations as opposed to 1 case/million/year in the general population, leading to 800 to 1,000 cases per year in France. The molecular carcinogenesis of MPM is incompletely understood but alterations to genes NF2, c-met, WT1 RASSF and p16 have been described. These genes are involved in cell invasion and motility, cell division and apoptosis control. Histological diagnosis remains difficult and depends on immunohistochemical analysis as described by the French Mesopath group. Clinical diagnosis relies on thoracoscopy and large pleural biopsies, with increasing use of CT-PET for the evaluation of disease extent. Therapeutic strategy includes prophylactic irradiation following drainage or thoracoscopy to prevent tumour nodule development along drainage channels and puncture sites. In selected patients, extensive extra-pleural pneumonectomy can be performed with curative intent. First line chemotherapy is based on a combination of pemetrexed and cisplatin that has demonstrated an improvement in overall survival and quality of life in phase 3 trials. Antiangiogenic agents such as bevacizumab (Avastatin) may be of interest but need to be tested in phase 3 trials. The Mesothelioma Avastatin Pemetrexed Study (MAPS) is ongoing, coordinated by the French Thoracic Cancer Intergroup (IFCT).

Glossary

diagnosis

identifying a disease by its signs or symptoms, and by using imaging procedures and laboratory findings. The earlier a diagnosis of cancer is made, the better the chance for long-term survival.

DES

abbreviation for diethylstilbestrola (die-eth-l-steh-BES-ter-ol),  synthetic form of estrogen.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

Egleton RD, Brown KC, Dasgupta P.

Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, 1 John Marshall Drive, Huntington, WV 25755, USA.

Abstract

Nicotinic acetylcholine receptors (nAChRs) constitute a heterogeneous family of ion channels that mediate fast synaptic transmission in neurons. They have also been found on non-neuronal cells such as bronchial epithelium and keratinocytes, underscoring the idea that they have functions well beyond neurotransmission. Components of cigarette smoke, including nicotine and NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone], are agonists of nAChRs. Given the association of tobacco use with several diseases, the non-neuronal nAChR signaling pathway has considerable implications for cancer and cardiovascular disease. Recent studies have shown that alpha7 is the main nAChR subunit that mediates the proliferative effects of nicotine in cancer cells. As a result, alpha7 nAChR might be a valuable molecular target for therapy of cancers such as lung cancer and mesothelioma. Future studies involving the design of nAChR antagonists with improved selectivity might identify novel strategies for the treatment of tobacco-related cancers. Here we review the cellular roles of non-neuronal nAChRs, including regulation of cell proliferation, angiogenesis, apoptosis, migration, invasion and secretion.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

angiogenesis

(an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

Kothmaier H, Quehenberger F, Halbwedl I, Morbini P, Demirag F, Zeren H, Comin CE, Murer B, Cagle PT, Attanoos R, Gibbs AR, Gallateau-Salle F, Popper HH.

Institute of Pathology, Medical University of Graz, Austria.

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short-term survivors (survival <3 years; STS) and long-term survivors (survival >3 years; LTS) of MPM. In order to do this, 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, anti-apoptosis, angiogenesis, and other cellular activities were investigated by tissue microarray (TMA) technology. Epidermal growth factor receptor (EGFR) is expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling is more abundant in STS. The expression of TIE2/Tek, a receptor tyrosine kinases involved in angiogenesis, is differentially regulated via PDGFR and thus is more important in STS. Anti-apoptosis is upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS. We demonstrate that small scale proteomics can be carried out by a powerful linkage of TMA, immunohistochemistry, and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.

Glossary

platelet

a part of the blood that helps it "stick together" (clot) to promote healing after an injury. Chemotherapy can cause a drop in the platelet count--a condition called thrombocytopenia.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

angiogenesis

(an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.

tissue

a collection of cells, united to perform a particular function.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

epidermal growth factor receptor

The process of cell division, growth, differentiation and death is a highly regulated process. Several class of trans membrane receptors play a pivot role in this process, of these, epidermal growth factor receptor (EGFR) a member of Receptor Tyrosine Kinase (RTK) family are best known. These comprises of four receptors Erb B1/HER 1, Erb B2 / HER 2, Erb B3/ HER 3, and Erb B4 / HER 4. Of these HER 2 is the most favoured target. (Source: Manoj Pandey and K Chandramohan)

Filho AL, Baltazar F, Bedrossian C, Michael C, Schmitt FC.

Life and Health Sciences Research Institute, Health Sciences School, University of Minho, Braga, Portugal.

Abstract

Homogeneity of mesothelial and lymphatic endothelial cells, express some markers that are presumed to be exclusive of the endothelium was recently reported. This similarity is important to improve the diagnosis and prognosis of malignant mesothelioma (MM). Additionally, some of these markers provide the rationale for specific molecular-targeted novel therapies aimed at MM, an aggressive malignant neoplasm, with an usually dismal prognosis. The goal of our study was to determine the prevalence and expression pattern of VEGF receptor-3 (VEGFR-3) immunoreactivity in MM and whether this immunoreactivity occurs in different phenotypes of this neoplasm. Formalin-fixed and paraffin-embedded samples from 29 MM cases and 5 metastatic carcinomas were immuno-stained for VEGFR-3 according to the streptavidin-biotin-peroxidase complex technique using a primary antibody (Zymed Laboratories, CA, USA) diluted at 1:200. Lymphatic vessels (LV) were outlined mainly in the peripheral area surrounding the neoplasms. Blood vessels were only rarely positive for VEGFR-3 in a pattern easily distinguishable from LV. In 25 out of 29 cases (86.2%) LV were strongly positive for VEGFR-3: 14 cases (48.2%) exhibited positive VEGFR-3 reactivity in malignant cells. Epitheliod MM showed a moderate to intense VEGFR-3 positive reaction in LV from 8 out of 19 cases. Among the other histological subtypes, a positive VEGFR-3 reaction was noted in malignant cells from two cases of transitional and one case of pleomorphic MM. Malignant cells from two out of three biphasic and one out of three sarcomatoid MM were also positive for VEGFR-3. Interestingly, one case of the multicystic subtype was negative for VEGFR-3 in malignant cells and faintly positive in an occasional LV. All cases of metastatic carcinoma were negative for VEGFR-3 in the neoplastic cells. In conclusion, VEGFR-3 was expressed in malignant cells from different subtypes of MM, reinforcing the putative role of this marker as a potential therapeutic target in this group of neoplasia.

Keywords: lymphangiogenesis, angiogenesis, vascular endothelial growth factor receptor 3, mesothelioma

Glossary

prognosis

(prog-no-sis) a prediction of the course of disease; the outlook for the cure of the patient. For example, women with breast cancer that was detected early and who received prompt treatment have a good prognosis.

prevalence

a measure of the proportion of persons in the population with a certain disease at a given time.

neoplasm

(nee-o-plas-um) an abnormal growth (tumor) that starts from a single altered cell; a neoplasm may be benign or malignant. Cancer is a malignant neoplasm.

diagnosis

identifying a disease by its signs or symptoms, and by using imaging procedures and laboratory findings. The earlier a diagnosis of cancer is made, the better the chance for long-term survival.

carcinoma

(car-sin-o-ma) a malignant tumor that begins in the lining layer (epithelial cells) of organs. At least 80% of all cancers are carcinomas.

antibody

a protein in the blood that defends against foreign agents, such as bacteria. These agents contain certain substances called antigens. Each antibody works against a specific antigen. (See also antigen.)

angiogenesis

(an-gee-o-JEN-uh-sis) the formation of new blood vessels. Some cancer treatments work by blocking angiogenesis, thus preventing blood from reaching the tumor.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.