Preface

Malignant mesothelioma (MM) is a highly invasive tumor arising from the mesothelial cells of serosal surfaces. It shows an extremely poor progression and is diagnosed mostly in locally advanced or metastatic stage, thus drastically limiting its treatment options. Past asbestos exposure has been shown to be the most important predictor of MM, although other environmental and genetic factors like Simian Virus-40 (SV-40) infection and genetic predisposition might also play important roles.

This book brings together the knowledge of experts in the filed of malignant mesothelioma who provide their invaluable insights into this deadly disease from different perspectives.

The book starts with a *tour de force* account of MM epidemiology in South Africa (SA) by scholars who have spent major part of their professional careers working in this field. In a gripping *tell-a-tale*, they recall how South Africa benefitted financially from the exploitation of its asbestos mineral reserves, but at a huge cost of human lives due to asbestos related diseases, including MM and lung cancer. South Africa plays a historically important role in our understanding of epidemiology of MM, thanks mainly to the seminal work by Dr. J. C. Wagner who showed definitive link between asbestos exposure and mesothelioma. In this chapter, the authors give a detailed account of the cases of mesothelioma in South Africa meticulously linking them to different forms of asbestos exposure (both occupational and non-occupational). They further dissect the carcinogenic potentials of the most common asbestos fibers mined in SA. There are many important lessons to be learnt from this SA experience, aptly summarized at the end of this chapter.

In the next chapter, Yasumitsu Nishimura et al. describe in detail the anti-tumor immunity and immunological alterations in MM, a hitherto neglected but nevertheless important aspect of MM-geneis. The authors show that exposure to asbestos might cause a suppressive effect on anti-tumor immunity in addition to the tumorigenic effect on mesothelial cells. This 'immunological' insight could not have come at a better time as only recently it is shown that blockade of PD-1, an inhibitory receptor expressed by T cells, gives promising therapeutic results in patients of many advanced cancers (Suzanne L. Topalian et al., and Julie R. Brahmer et al.; NEJM, 2012).

In the following chapter, Loredana Albonici and colleagues describe the roles of inflammation and angiogenic growth factors in MM. Angiogenesis plays a key role in the growth of any tumor as shown by the seminal work of Judah Folkman in 1971. Here the authors go beyond this basic fact by showing that asbestos driven inflammation plays an important role in MM and that there is a cross-talk between inflammation and angiogenesis in the genesis and progression of MM. They describe how mesothelial cells work as sentinels sensing a variety of signals and stimuli, including asbestos fibers. In response, the mesothelial cells can release a host of chemokines, cytokines and reactive oxygen and nitrogen species, thus triggering chronic inflammatory reactions potentially leading to MM. The authors show in great details the roles of various transcription factors like NF-kB, AP-1 and NFAT in this process. Furthermore, they also explore the roles of various angiogenic growth factors, many of which could be potential targets for therapy.

The penultimate chapter by Rossella Galati links the inflammation in MM to upregulation of the inducible cyclooxygenase-2 (COX-2), leading to an increase in its product prostaglandin-E2 (PGE-2), which in turn is associated with increased risk of cancers. The author describes the complex interaction between COX-2, EGFR and Aromatase (CYP19A1), which has the potential to open new therapeutics in MM.

The last chapter by Giulia Pasello and Adolfo Favaretto describes neoadjuvant chemotherapy in malignant pleural mesothelioma (MPM). In this deadly malignancy that is refractory to almost all treatments, the possibility to pursue novel and rational strategies is extremely exciting. The chapter begins with the rationale of neoadjuvant therapy, followed by the current path to neoadjuvant chemotherapy in MPM. It culminates in an extensive review of various neoadjuvant chemotherapeutic regimens and strategies in MPM.

We would like to thank all the contributing authors for making this book possible. Our special thanks goes to publishing process managers Ms. Sandra Bakic, Ms. Martina Blecic and Mr. Vedran Greblo for their continuous help during the entire process. We would like to dedicate this book to the readers in the hope that they will find it useful in the ultimate quest for the cure of malignant mesothelioma.

> **Carmen Belli and Santosh Anand** San Raffaele Hospital, and San Raffaele Scientific Institute, Milan, Italy

VIII Preface

In the following chapter, Loredana Albonici and colleagues describe the roles of inflammation and angiogenic growth factors in MM. Angiogenesis plays a key role in the growth of any tumor as shown by the seminal work of Judah Folkman in 1971. Here the authors go beyond this basic fact by showing that asbestos driven inflammation plays an important role in MM and that there is a cross-talk between inflammation and angiogenesis in the genesis and progression of MM. They describe how mesothelial cells work as sentinels sensing a variety of signals and stimuli, including asbestos fibers. In response, the mesothelial cells can release a host of chemokines, cytokines and reactive oxygen and nitrogen species, thus triggering chronic inflammatory reactions potentially leading to MM. The authors show in great details the roles of various transcription factors like NF-kB, AP-1 and NFAT in this process. Furthermore, they also explore the roles of various angiogenic growth factors,

The penultimate chapter by Rossella Galati links the inflammation in MM to upregulation of the inducible cyclooxygenase-2 (COX-2), leading to an increase in its product prostaglandin-E2 (PGE-2), which in turn is associated with increased risk of cancers. The author describes the complex interaction between COX-2, EGFR and Aromatase (CYP19A1), which has the potential to open new therapeutics in MM.

The last chapter by Giulia Pasello and Adolfo Favaretto describes neoadjuvant chemotherapy in malignant pleural mesothelioma (MPM). In this deadly malignancy that is refractory to almost all treatments, the possibility to pursue novel and rational strategies is extremely exciting. The chapter begins with the rationale of neoadjuvant therapy, followed by the current path to neoadjuvant chemotherapy in MPM. It culminates in an extensive review of various neoadjuvant chemotherapeutic regimens

We would like to thank all the contributing authors for making this book possible. Our special thanks goes to publishing process managers Ms. Sandra Bakic, Ms. Martina Blecic and Mr. Vedran Greblo for their continuous help during the entire process. We would like to dedicate this book to the readers in the hope that they will find it useful

San Raffaele Hospital, and San Raffaele Scientific Institute, Milan,

**Carmen Belli and Santosh Anand**

Italy

in the ultimate quest for the cure of malignant mesothelioma.

many of which could be potential targets for therapy.

and strategies in MPM.

**Chapter 1** 

© 2012 Phillips et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 Phillips et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Mineralogy and Malignant Mesothelioma:** 

South Africa is a uniquely mineral rich country. Of the six types of asbestiform minerals found in the country, three, namely crocidolite, amosite and chrysotile were mined and milled on a large commercial scale. Asbestos was used locally in South Africa, but the majority of its production was exported worldwide. In the 1970s, South Africa was the world's third largest producer of asbestos, behind Canada and the USSR. About 97% of the world's production of crocidolite and virtually all of the amosite came from South Africa.

The output from the South African asbestos mining industry peaked at 380,000 tonnes in 1977 and declined thereafter as export markets declined due to restrictive legislation in countries that imported asbestos (Virta, 2006; Kielkowski et al., 2011). Legislation in South Africa banning the use of all types of asbestos came into effect in 2008, well after the last asbestos mine ceased production in 2001 and closed in 2002. Although South Africa benefitted financially from the exploitation of its asbestos mineral reserves, the revenue from asbestos never accounted for more than 3% of the value of its total minerals output (McCulloch, 2003). There is however a high price to pay in terms of a legacy of disease and environmental contamination through mining activities and the transport of asbestos and

This account records, in the main, work done in Johannesburg at the National Institute for Occupational Health (NIOH) - formerly the Pneumoconiosis Research Unit (PRU), thereafter, the National Research Institute for Occupational Diseases and later the National Centre for Occupational Health - at the Medical Bureau for Occupational Diseases and its Division of Epidemiology Research. All the authors have spent the major part of their

All types of asbestos are crystalline silicates. Chrysotile, known locally in South Africa as white asbestos, occurs in ultramafic rock formations. It is a hydrated magnesium silicate and

James I. Phillips, David Rees, Jill Murray and John C.A. Davies

**The South African Experience** 

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/47974

asbestos containing products.

professional careers working at the NIOH.

**1. Introduction** 
