Mesothelioma

Photodynamic Therapy and Applications in Cancer

The idea of using light as a therapeutic tool has been popular for thousands of years. Scientific discoveries in line with technological innovations have contributed to the advancement of photodynamic therapy as a therapeutic modality. Photodynamic therapy is based on the generation of highly reactive species that alter the molecular systematics of cells through interactions between light, photosensitizer, and molecular oxygen. It has a minimally invasive protocol that can be combined with other clinical methods or can be stand-alone. The development of photosensitizers with the integration of nanotechnological approaches has provided favorable results over the years in malignant and non-malignant diseases by facilitating target-site action, selectivity, and controllable drug release. This chapter presents a review of photodynamic therapy with its important aspects; history, mechanism of action, cellular effects, integration into nanoscale drug delivery systems, and combinational therapeutic approaches in cancer.

Toxicity of Nanomaterials-Physicochemical Effects

Nanoparticles (NPs) have the potential to produce deleterious effects on organ, tissue, cellular, subcellular, and protein levels due to their peculiar physicochemical features. Metal NPs are gaining prominence and are being used in a variety of medicinal, consumer, industrial, and military applications. Furthermore, as particle size falls, some metal-based NPs become increasingly poisonous, despite the fact that the same substance is rather innocuous in its bulk form. NPs can also interact with proteins and enzymes within human cells, causing reactive oxygen species to be produced, an inflammatory response to be initiated, and mitochondrial disruption and destruction, ending in apoptosis or necrosis. As a result, deciding whether the advantages of NPs outweigh the hazards presents various challenges.

Cancer Pathophysiology

Cancer prevalence across the globe has increased substantially in the last two decades despite significant progress in inpatient care. Cancer, a multifactorial disease, evolved several theories to establish pathophysiological conditions. Uncontrolled proliferation, dedifferentiation and metastasis mainly describe the cancer progression, which must be characterized by cellular and molecular changes. Understanding these processes helps devise the strategy for effectively delivering the drugs to the target sites. The present review described the essential features of cancer pathophysiology and challenges to achieving drug concentration in the targeted area.

Mechanistic Insight into the Chemotherapeutic Potential of Dietary Phytochemicals

Globally, cancer is the main cause of mortality and morbidity. Unfortunately, existing medical procedures are not adequate due to a lack of appropriate therapy, adverse health effects, chemoresistance and disease recurrence. In recent years, epidemiological findings have illustrated the connection between the consumption of several phytochemical-enriched foods and nutrients, and the lower risk of different types of cancer. Natural compounds named ‘phytochemicals’, commonly found in fruits, vegetables, and whole grains, have shown convincing beneficial biological effects on human well-beings, including curing different types of cancers. Phytochemicals, which are non-nutritive chemicals present in plants, have come up as modulators of essential cellular signaling pathways exerting proven anti-cancer benefits. Dietary phytochemicals have received major interest in chemoprevention as they are thought to be safe for human use. Chemo-preventive agents restrain the growth of cancer either by impeding DNA damage, which contributes to malignancy or by preventing or restricting the division of premalignant cells through DNA damage. Phytochemicals may prevent carcinogenesis by contributing to cell cycle arrest, autophagy and apoptosis. The bioactive compounds have been reported to reverse adverse epigenetic control, including modifying DNA methylation and histone alteration, modulating the expression of miRNA, inhibiting phase I enzymes, and activation of phase II enzymes, scavenging DNA reactive agents, preventing the excessive proliferation of early, preneoplastic lesions, and suppress other properties of the cancer cells. These have all been a part of indirect yet successful and innovative approaches to cancer treatment utilizing phytochemicals.

Chromosome 22

When the collection of human Chromosome 22 was first suggested in 1999, it became the most extended, non-stop stretch of DNA ever decoded and assembled. Chromosome 22 became the first of the 23 human chromosomes to decode due to its minimal length and affiliation with numerous diseases. Chromosome 22 involves several genes that contribute to cancer genetics in one way or the other. The contribution of chromosome 22 in abnormalities is evident through somatic translocations, germline and somatic, and in certain cases, overexpression of genes. One famous example is the Philadelphia translocation, particularly in chronic myeloid leukemia cells. Various gene contributions about types of cancer such as Acute Myeloid Leukemia, colorectal, lung, breast cancer and many more have been reported in studies related to chromosome 22. This chapter takes a run-through of important targeted studies of a gene that facilitates itself as a part of cancer genetics.

Chromosome 20

Over the years, many scientists and doctors have been treating the deadly disease of cancer but are not able to find a permanent treatment for this disease. Also, sometimes it becomes very difficult to understand the mechanisms and causes of cancer as it is a very complex disease that involves many biological processes. Due to the redundancy in our biological system, cancer progression becomes very easy, thus making it difficult to cure. To find the root cause of this disease, we should know what genetic alterations are undergoing, which is causing cancer to progress, and know who is participating in these alterations, like proteins, signaling pathways, or genes. Cancer is caused due to various reasons; it can be due to genetics but mostly due to carcinogens, causing mutations in the genes, thereby making them an oncogene. The Proto-oncogenes are those genes that usually assist the growth of tumor cells. The alteration, mutation, or increased copy number of a particular gene may turn into a proto-oncogene which could end up completely activated or turned on. Many Tumor-causing alterations or mutations related to oncogenes are usually acquired and not inherited. These tumor-causing mutations often actuate oncogenes via chromosomal rearrangement, or alterations in the chromosome, which sequestrates one gene after another, thereby permitting the first gene to prompt the alternative. Search which genes are involved in different cancer types would help scientists proceed with new methods for finding a cure for this disease. This article will depict which genes and their location on which chromosomes, specifically on chromosome 20, are related to different types of cancer.

Chromosome 16

Cancer is a heterogeneous disorder with invasive and metastatic potential. It is a deadly disorder affecting 1 in 6 people worldwide. Hence, it is important to eliminate the disease. Genetic alterations remain an underlying cause of cancer, and several gene mutations were involved in causing different types of cancer. Recently, researchers have been investigating the role of genetic mutations in causing cancer. For this reason, the genes associated with chromosome 16 were investigated for their role in causing cancer. This study revealed 70 genes associated with cancer. Of which, the cadherin genes (CDH11, CDH13, and CDH1), AXIN-1, ANKRD11, BANP, CYLD, CBFA2T3, IR8, MVP, MT1F, NQO1 and PYCARD was the tumor suppressor, and the gene MSLN is the potential oncogene. CBFB and MYH11 are well-known fusion genes associated with this chromosome. Loss of heterogeneity was noted in the q arm of this chromosome. The chromosome translocations, t (16;16) (16) (p13q22), t (16;21) (21) (p11;q22), t (12;16) (q13; p13; p11), t(16;21) (p11;q22) and t(7;16) (q33; p11) led to the development of acute myeloid leukemia, leukemia, and sarcoma. Several other genes associated with chromosome 16 responsible for cancer initiation and proliferation are summarized in this chapter. A novel insight into the genetic biomarkers and therapeutic targets has been provided to develop potential therapeutic strategies against cancer.

Chromosome 15

The genomic alteration at chromosome 15 has been widely recognized as the utmost significant and prevalent alteration in several cancers, including non-small-cell lung cancer, breast cancer, ovarian cancer, prostate cancer, gastrointestinal cancer, acute lymphoblastic leukemia, colorectal carcinoma, hepatocellular carcinoma, myeloma, pituitary adenomas, etc. Emerging reports suggest that the abnormalities of prime genes in chromosome 15 have drastic effects on tumor development and progression, and can be candidate biomarkers of disease prognosis, disease progression, and response to treatment. The translocations involving chromosome 15 and other chromosomes have been found in tumors, including mucoepidermoid carcinomas, mixed-lineage leukemia, colorectal cancer, pancreatic cancer, sarcoma, lung adenocarcinoma, melanoma, brain cancer, cholangiocarcinoma, spitz tumor, congenital mesoblastic nephroma, papillary thyroid cancer, pontine glioma tumors, and acute promyelocytic leukemia. The tumor suppressor genes such as C15orf65, CSK, CRABP1, DAPK2, FES, GREM1, KNSTRN, NEDD4-1, NTRK3, PML, SPRED1, TPM1, and TCF12 under chromosome 15 play a crucial role by enhancing cellular growth, proliferation, migration, invasion, metastasis, cellular differentiation, and development in various cancer, including colorectal cancer, acute promyelocytic leukemia, myeloid leukemia, breast cancer, thyroid carcinoma, glioblastoma, intrahepatic cholangiocarcinoma, chondrosarcoma, cartilaginous cancer, Squamous cell carcinoma, non- small-cell lung carcinomas, mucosal melanoma, and oral squamous cell carcinoma. Chapter 15 discusses the significance of each important gene under chromosome 15 in mediating oncogenesis. The elevated or attenuated expression levels of these cardinal genes can either act as an oncogene or a tumor suppressor. Thus, shedding light on these genes would be a game changer in the field of cancer genetics and theragnostic.

Chromosome 3

Myriad genes in the genome have been implicated in cancer. However, a focused compilation of genes from the same chromosome would provide a valuable detailed yet succinct catalog for researchers, advantageous in quickly understanding the leading roles played by these genes in cancer. This chapter fulfills the above aim of furnishing a pocket dictionary- like a concise yet meticulous explanation of many genes from Chromosome 3, describing these genes’ functional essentialities in various cancers. Such a judicious collection of genes from a single chromosome is probably the first of its kind. The multiple inputs in this chapter from Chromosome 3 include oncogenes (BCL6, RAF1), tumor suppressor genes (SRGAP3, FHIT), transcription factors (FOXP1, MITF), fusion genes (MECOM), and many other types. With approximately 1085 genes spanning 198 million base pairs, Chromosome 3 constitutes 6.5% of the total DNA.

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Section C Pleural Procedures

Immunotherapy and Cancer Stem Cells

Immunotherapy is one of the important modalities in the treatment of cancer since it can directly target the tumor and its microenvironment with lesser side effects and cytotoxicity. The main goal of immunotherapy in the treatment of cancer is the reactivation of the immune system against cancer cells. In this way, the body fights against cancer using its immune system rather than relying on external agents which might be harmful to other healthy parts of the body. The development of monoclonal antibodies (Mabs) has delivered a significant therapeutic effect. Mab therapy is one of the most evolving techniques in cancer immunotherapy and has shown efficacy in controlling several types of malignancies. There are several other methods by which the activation of the immune system can be achieved, such as by using small molecules or by targeting ligands. Interestingly, studies have demonstrated that cancer stem cells have also been found as a target for effective immunotherapy. Additionally, the complete elimination of the cancer cells requires longer sustainability of tumor-specific T cells. Primitive results suggest that these T cells can be localized to tumor cells, mediating highly effective immunotherapy. However, despite these huge successes, several problems still persist and must be overcome. This chapter discusses the current and cutting-edge immunotherapeutic approaches to fight against cancer cells.

Transcription Factors in Cancer

Different types of signalling pathways have been approved to be involved in cancer imitation and progression. These signalling pathways include the JAK-STAT signalling, NF-κB signalling, Wnt, Notch and Hedgehog. STAT (Signal Transducer and Activator of Transcription) transports signals between proteins from the cell membrane into the nucleus to contribute to cancer progression. NF-κB signalling is essential for the survival of the B cell tumor types. The Wnt, Notch, and Hedgehog signalling pathways play a significant role in carcinogenesis by upregulating the genes associated with these pathways. Hence, pharmacological inhibitors of WNT, NOTCH, and HH pathways are required in clinical studies. Such inhibitors have features that make them important during the clinical trial since they offer great potential as novel therapeutics for cancer. They also have an antitumor response which should be taken into consideration. The three signalling pathways are also known to shape cell fate determination and differentiation. In case of depletion of a single molecular component within the three pathways, embryonic lethality will form.

Biology of Cancer

Loss of genomic stability in the cell due to defects in the checkpoint of DNA damage, mitotic checkpoint, and telomere maintenance led to increased incidences of base pair alterations. Therefore, that genomic instability plays a critical role in tumor initiation and progression. Tumor progression requires a dynamic tumor/normal exchange in their microenvironment to support tumor growth. The histological alteration seen in the tumor at early stages confirms that the surface between the epithelium and the stroma undergoes progressive disturbance. Tumor progression is also affected by the immune system in which chronic inflammations promote the growth of tumor. Tumor cells experience altered metabolic profiling to support their growth. Cancer cells are characterized by uncontrolled cell division. For that, they utilize glucose as a source of energy to help them grow faster than normal cells. Hence, Glycolysis is a key metabolomics pathway consumed at a high rate during carcinogenesis.

Cancer Traits; Present and Future

This chapter on “Cancer Traits; Present and Future” begins with a description of the process of carcinogenesis and, finally, the abnormal process leading to carcinogenesis.
Cancer is a multi-step mechanism in which cells undergo biochemical and behavioral changes, causing them to proliferate in an unnecessary and untimely manner. These changes occur from modifications in mechanisms that regulate cell proliferation and longevity, relationships with neighboring cells, and the ability to escape the immune system. Modifications that contribute to cancer require genetic modifications that alter the DNA sequence. Another way to alter the program of cells is to adjust the conformation of chromatin, the matrix that bundles up DNA and controls its access through DNA reading, copying and repair machinery. These modifications are called “epigenetic. The abnormal process that leads to carcinogenesis includes early mutational events in carcinogenesis, microRNAs in human cancer and cancer stem cell hypothesis, Contact inhibition of proliferation, autophagy, necroptosis, signaling pathways, telomere deregulation, microenvironment, growth suppressors evasion, resisting cell death and sustained cell survival, enabling replicative immortality through activation of telomeres, inducing angiogenesis, ability to oppose apoptosis, and activating invasion and metastasis. Intensive research efforts during the last several decades have increased our understanding of carcinogenesis and have identified a genetic basis for the multi-step process of cancer development. Recognition and understating of the prevalent applicability of cancer cell characterization will increasingly affect the development of new means to treat human cancer.

Basics of the Drug Development Process

Drug discovery and development is a complex and lengthy process aimed at producing therapeutic substances that can be both effective in terms of pharmacological activity, specificity, good affinity to its target molecule, and safe for humans. It is a necessary step due to many emerging diseases of microbial, parasitic and genetic diseases affecting the entire world so that effective prophylaxis and treatment could be provided. The successful process of discovering a new drug relies on proper discovery and characterization of the lead compound followed by the preclinical studies that ascertain the safety and efficacy of the newly discovered compound. A number of information gathered from preclinical studies that, include information about the formulation, dosage, delivery, pharmacokinetic, pharmacodynamic, mode of action of the drug as well as its relation with other drugs when they interacted, could determine the fate of the new drug’s approval by the regulatory agency for a clinical trial on humans. Human clinical trials with the new drug under investigation are carried out on volunteers in different phases with a common goal to ascertain the new drug's safety, efficacy, and possible side effect in the actual environment. Since the human body is more dynamic, optimal dosage and effect of other substances on the drug itself are determined so as to ensure better treatment; satisfactory results from the human trial could pave the way for application and approval for a human trial in phase IV where the drug may subsequently go for commercialization but with strict monitoring for any unforeseen side effect most especially in a vulnerable group. Although this is an expensive, tedious and risky process for the pharmaceutical industry and volunteers, which takes many years, it is necessary. This chapter discusses the necessary steps for developing a new drug from the initial discovery from bench-top up to human trial and commercialization as an over-the-counter drug.

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miRNAs as Epigenetic Cancer Biomarker

Despite the fact that the mortality rate of many types of cancer has decreased in the last decades, cancer remains one of the most challenging diseases in the world. The number of newly diagnosed cases with advanced stages in different types of cancer is still high because available tests are not efficient enough to be used for screening. In addition, the available diagnostic tests failed to diagnose certain types of cancer until late presentation. Furthermore, therapeutic agents currently in clinical use to treat a certain type of malignant tumours still show a high rate of resistance in some patients. Many types of available cancer biomarkers failed to manage and resolve this problem because of the lack of both sensitivity and specificity of these markers. Advanced researches in epigenetics highlight the importance of certain non-coding genes in diagnosing and follow-up of patients with different types of cancer. One of these substances is microRNAs (miRNAs) which showed high sensitivity and specificity as cancer biomarkers. miRNAs are highly stable and expressed in different types of human body samples; some of them are tissue specific. These features make them available as cancer biomarkers, and they are started to be in clinical use recently.

Glycoproteins and Cancer Biomarkers

Glycoproteins or glycosylated proteins are carbohydrates (oligosaccharide chains or glycan’s) linked proteins and execute important functions in the biological systems, such as embryonic development, cell-to-cell recognition, adhesion, pathogen identification and immune functions. It is evident that the alteration of glycoproteins in cells are associated with a number of human diseases, including cancer, rheumatoid arthritis, inflammatory diseases as well as immunodeficiency diseases. Recent advances in modern technologies in cancer treatment are promising. However, researchers and clinicians are still searching for appropriate biomarkers for the early detection and management of patients with cancer. Altered glycoprotein levels are associated with critical events in cancer pathogenesis and progression. Also, abnormal glycosylation of protein is a common regulatory event in carcinogenesis, therefore, aberrant glycosylation could act as a promising resource in identifying a cancer biomarker for diagnosis and monitoring of the progression of patients with cancers. This chapter summarizes the major clinically approved glycoproteins utilized for screening, diagnosis, and monitoring of the treatment response of patients with cancers.

Protein Cancer Biomarkers

Cancer is one of the leading causes of death worldwide and it is becoming increasingly important to be able to efficiently identify and map the progression of cancers. The study of the diagnostic, predictive and prognostic value of protein biomarkers has become one of the main aspects at the forefront of cancer research. The diversity of various biomarkers for different cancers and their varying roles in each disease presents a continual challenge for researchers to understand, with new biomarkers still being discovered today. Understanding the role of protein biomarkers ensures patients are diagnosed with greater confidence and helps clinicians with treatment regimes. This chapter aims to discuss the clinical significance of various protein biomarkers in terms of their diagnostic, prognostic, and predictive value in the treatment of their respective cancers.

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The Role of IARC in Causation of Occupational Diseases: Case Study of the Carcinogenic Evaluation of Crystalline Silica

The importance of causation of occupational diseases and the role of the International Agency for Research on Cancer (IARC) are discussed in this chapter. As a case study, the process by which silica dust was judged a known human carcinogen by IARC is reviewed. Silicosis is a chronic occupational lung disease known to be caused by inhaling crystalline silica, and the pulmonary cancer risk after the diagnosis of silicosis is a part of the IARC review of evidence. Laboratory animal evidence and mechanistic findings supporting IARC evaluation are also described. There remains a need to explore the association between silica exposure and other nonlung tumors, especially gastrointestinal cancers. The Occupational Safety and Health Administration (OSHA) developed a new regulatory standard that lowered the permissible exposure to 50ug/m3 in 2016. OSHA labeled silica as a known human carcinogen because of the IARC assessment. Occupational medicine leaders need to address several current silica dust problems such as silicosis/coal workers pneumoconiosis among coal miners, acute silicosis and auto-immune diseases among countertop workers, and intervention programs to lower silico-tuberculosis among South African miners. Future research studies need good silica dust monitoring estimates and high-quality industrial hygiene samples to evaluate the associations between silica exposure and many diverse diseases.

Occupational Cancer

This chapter provides an up-to-date review of the occurrence and causes of occupational cancer based on epidemiologic studies and discusses the epidemiology of occupational cancer, the characteristics, research priorities, prevention, and surveillance. Epidemiologic methods have been very successful in documenting cancer risks associated with agents. Epidemiologic data is useful when an exposure-response relationship can be demonstrated. Examples of agents for which epidemiologic studies provide evidence of an exposure-response relationship include benzene and myelogenous leukemia. Vinyl chloride causes liver cancer which is an example of associations between single agents and rare histologic types of cancer. It is more difficult to conduct epidemiologic studies to identify cancer risks associated with complex mixtures. Studies of diesel exhaust, lung cancer, and metal machining oils are cited as having employed advanced industrial hygiene and epidemiologic methods for studies of complex mixtures. At present, less than 20 known occupational carcinogenic agents have been evaluated based on studies in humans and animals by the International Agent for Research on Cancer. Furthermore, exciting developments in epidemiologic and animal studies will contribute to identifying additional carcinogenic agents in the workplace. New biologic markers of exposure and cancer-related outcomes must be identified and integrated into epidemiologic studies. Because epidemiologic data regarding the carcinogenicity of many exposures are not available, research methods to evaluate and improve the predictive value of animal and in vitro systems must be developed. A complete understanding of occupational cancer trends will be required further to research occupational cancer risks and means of prevention.

Malignant Mesothelioma

Malignant mesothelioma often develops because of exposure to asbestos. The global incidence and mortality of mesothelioma remain unclear because many developing countries do not report it or the data they report are unreliable. Asbestos usage increased over centuries and reached its peak in 1970s. By the 90s the use of asbestos had been banned or tight regulated in many western countries, including the U.S. Asbestos usage continues to increase exponentially in developing countries. In addition to occupational asbestos exposure, environmental exposure to asbestos and other mineral fibers can cause mesothelioma. Asbestos carcinogenesis is largely caused by the chronic inflammatory process driven by the extracellular release of HMGB1 by mesothelial cells and macrophages. In addition, germline mutations of the BRCAassociated protein 1(BAP1) gene and less frequently of other tumor suppressor genes and DNA repair genes can cause or predispose to mesothelioma. Germline BAP1 mutant carriers develop additional malignancies during their lifetime. Fortunately, several of these malignancies, including mesothelioma, are less aggressive than their sporadic counterparts. BAP1 is also the gene most frequently mutated somatically in sporadic mesothelioma underscoring the critical role of this gene in suppressing mesothelioma growth. The preventive measure aimed at reducing occupational exposure to asbestos and environmental exposure to various carcinogenic fiber effectively reduces the incidence of mesothelioma. Carriers of germline BAP1 mutations benefit from close follow-up for early cancer detection. Because they may be susceptible to asbestos carcinogenesis, they should avoid trades or living in areas where carcinogenic fibers may be present.

Coal Workers Pneumoconiosis

Coal Worker’s Pneumoconiosis (CWP) was thought to be an archaic disease, but after an initial decline because of the Coal Mine Health and Safety Act in 1969, there has been a resurgence of this disease in the 21st century. For centuries, miners have been exposed to varied types and degrees of coal mine dust. Lung diseases in coal miners are caused by the inhalation, retention, and tissue reaction to the mixed constituents of this dust, which include carbon, silica, and silicates. Respirable dust particles of less than 5 microns are deposited in the proximal and distal airways and the smaller particles are deposited in the alveoli. The tissue reaction to these particles results in a variety of pathologic lesions, including coal macules, silicotic nodules, mixed dust pneumoconiosis, interstitial fibrosis, progressive massive fibrosis, bronchitis, and emphysema. These disorders are recognized primarily through occupational exposure history and characteristic radiographic imaging. With a latency of approximately 20 years, cumulative lifetime exposures appear to be most predictive of the disease severity. Prevention of these diseases should be the primary focus of the industry, the workforce, and the public health agencies. In the US, federal programs of screening and surveillance are in place and active. The treatment of these disorders as with other chronic respiratory conditions, is focused on vaccinations against respiratory infection, bronchodilator therapy when indicated, supplemental oxygen therapy when required, pulmonary rehabilitation programs, smoking cessation, vigilant observation for chronic respiratory infections, and if necessary, lung transplantation should be considered as the last resort.

Asbestosis

Asbestos, due to its unique physical properties and abundance, was widely used in commercial applications at the beginning of the 20th century. By the 1930s, reports of respiratory illnesses in workers with occupational exposure to asbestos began to surface. Inhalation of asbestos leads to a localized inflammatory response that attempts to clear inhaled asbestos fibers. This inflammatory response and retained asbestos fibers are central to the pathogenesis of asbestosis-related pulmonary disease. Asbestos causes a range of pulmonary diseases ranging from benign, incidental pleural abnormalities to progressive, fatal pulmonary fibrosis to malignant neoplasms of the lung and pleura. The benign manifestations of asbestos exposure, the focus of this chapter, can be grouped into pleural and parenchymal diseases. Asbestosis is a fibrotic, parenchymal disease caused by asbestos exposure. After several decades from initial asbestos exposure, patients develop dyspnea, exercise intolerance, and hypoxia with restrictive physiology on pulmonary function testing similar to other interstitial lung diseases. The most common pleural manifestation is pleural plaques, which are localized areas of pleural fibrosis that are often found incidentally. While normally asymptomatic, they are a marker of asbestos exposure. Other pleural manifestations tend to be symptomatic and include diffuse pleural thickening and acute benign pleural effusion. This chapter discusses pathogenesis, clinical presentation, radiographic and physiologic manifestations, and management of benign asbestos lung diseases.

Subject Index

Updates on Pediatric Hepatoblastoma

The developing human liver is embryologically central in embryogenesis. It plays a significant role as a hematopoietic and endocrine organ. During the development, hepatocytes change their phenotype. They vary from blueish cells to cells with an eosinophilic nuance and decreased nucleus to cytoplasm ratio. Apart from congenital abnormalities of this organ and inflammatory conditions that can populate medical charts in childhood and youth, the liver's neoplastic transformation in childhood and adolescence is a rare event. In children younger than three years, the liver's most dramatic neoplasm is represented by the occurrence of hepatoblastoma. It is an embryologic tumor. It retains the suffix “blastoma,” similar to neuroblastoma as any other embryologic tumor. Hepatoblastoma originates presumably from the primitive embryo-fetal progenitors. In this chapter, we update our knowledge of this pediatric tumor, specifically the pathology and the treatment

Monitoring Therapeutic Response in Cancers: A Raman Spectroscopy Approach

Cancer is a multifactorial disease that is often asymptomatic and is thus

detected at an advanced stage. Late detection and resistance to treatment are two of the

major reasons for poor prognosis. The inherent limitations of conventional tools in

evaluating therapeutic responses, raise the need to monitor such responses during

treatment. Raman spectroscopy is a rapid, label-free, minimally invasive optical

vibrational spectroscopy technique that has been widely employed for cancer detection.

There is also significant literature on its applications in intraoperative surgical margin

assessment, chemotherapeutic drug monitoring, and prediction of radiation response.

However, most books and reviews focus on the diagnostic and screening applications

of Raman spectroscopy. This chapter describes the role of Raman spectroscopy in the

therapeutic monitoring of cancers and discusses its prospective applications. The

present work provides a brief introduction to the basic principles of Raman

spectroscopy, concise information on cancer aetiology, pathogenesis, diagnosis and

therapeutics, and applications of Raman spectroscopy in the therapeutic monitoring of

cancers. The role of Raman spectroscopy in monitoring conventional treatment

modalities such as surgery, radiotherapy, and chemotherapy, along with novel

treatment approaches such as immunotherapy and cold atmospheric plasma therapy, is

discussed in detail. The chapter concludes with a brief introduction to the emerging

field of Raman spectroscopy and artificial intelligence.

MDM2-p53 Antagonists Under Clinical Evaluation: A Promising Cancer Targeted Therapy for Cancer Patients Harbouring Wild-Type TP53

Mutation of TP53 occurs in about 50% of both sporadic and familial cancer cases. In the remaining malignant tumours harbouring wild-type TP53, it seems that p53 function is suppressed via other mechanisms, including MDM2 upregulation. In addition to frequent loss of p53 function in most types of tumours, the multi-functional transcription activity and tumour suppressor impact of p53 encouraged an enormous effort to introduce novel anti-cancer agents targeting p53. Different synthetic nongenotoxic inhibitors have been advanced to prevent the interaction between p53 and MDM2 and correct p53 dysfunction, of which some are still at early stages of development, and many have recently entered into clinical trials. In spite of the potential merits of targeting p53, including less damage to normal cells, fewer adverse events, and more efficiency, it has its potential drawbacks, which are needed to be addressed. Moreover, activated p53 impacts other biological processes making p53 restoration therapy more complicated. This issue can be resolved through the identification of biomarkers that predict sensitivity to these anti-cancer drugs, combined treatment, and optimization of p53-targeted therapy.

In this chapter, we review the role of TP53 as a tumour suppressor gene, targeting the interaction between p53 and MDM2 as a strategy for the treatment of malignancies and p53-MDM2 antagonists with emphasis on those that have been used in clinical trials. Other aspects of MDM2 inhibitors, including their predictive biomarkers, their side effects, resistance mechanisms, and combined treatment of MDM2 antagonists with other anti-cancer drugs, which potentially improve their clinical efficacy and patient stratification, will also be discussed briefly.

Prospects for Therapeutic Targeting of MicroRNAs in Brain Tumors

MicroRNAs (miRNAs) are small non-coding RNAs 18–24 nucleotides long and function as a post-transcriptional regulator of the expression of protein-coding target genes. It has been proven that normally microRNAs play an important role in various biological processes, including proliferation, differentiation, and apoptosis. Importantly, dysregulation of miRNAs is found to be involved in the pathogenesis of various human tumors, including brain tumors. Throughout the world, the problem of morbidity and mortality associated with brain tumors (e.g., glioblastomas multiforme (GBM)) has occupied a leading position for many years. Modern treatment strategies are based on surgery, chemotherapy, and radiation therapy. However, none of these treatments, alone or in combination, is considered effective. The data show that miRNAs can act as both a suppressor and an oncogene of tumor growth, regulating the processes of proliferation, tumor invasion, apoptosis, angiogenesis, immune response, metastasis, and drug resistance. While discussing recent studies targeting miRNAs to treat neuro-oncological conditions, we will discuss the advantages and possible limitations of miRNA-based gene therapy, the feasible methods for miRNA-based gene delivery, and the clinical therapeutic prospects of miRNA-based gene therapy for brain tumors.

Theranostic Approaches for Combating Cancers

Cancer theranostics has witnessed the new era translational medicine leading to the development of new treatment possibilities for cancer patients. The approach of ‘one-size-fits-all’ has changed from traditional methods of surgery, chemo- and radiotherapy to that of personalised cancer medicine, molecular targeted therapy, cancer immunotherapy, nanomedicine, alternative medicine and integrative therapy. The clinical trials for cancer drugs have complicated, requiring better regulatory and health policies, and collaborative efforts from the stakeholders involved in cancer drug discovery and development. A lot has been achieved, mainly in terms of knowledge and biological data, and the same is needed to be integrated and implemented into the development of successful cancer theranostics. The tumour heterogeneity still poses a challenge for scientists, but the last decade has paved a concrete pathway for the future in precise and personalised cancer therapy.

shRNA-Nanoparticle Conjugate as a Therapeutic Option

The recent trend of gene therapy includes the RNAi therapeutic approach. RNAi therapy comprises the delivery of siRNA, shRNA and miRNA molecules to the cells for gene silencing. Among these types, shRNA is a more stable knockdown method. However, bare shRNA molecules are large and they can not penetrate the cell membrane due to their negative charge and also they are fragile and degradable by RNase enzymes in the body. To overcome these problems, nanoparticles play a vital role. They encapsulate the shRNA within their structure and protect them from degradation. The nanoparticles are sometimes positively charged so they readily penetrate the cell membrane and are internalized by the cell. These features of the nanoconjugate made them a potential therapeutic agent. In this study, we intended to discuss the wide variety of nanoconjugates and their applications in diseases.

Clinical Milestones in Nanotherapeutics: Current Status and Future Prospects

An aging population and poor clinical solutions for several diseases have propelled the rapid emergence of nanotherapeutics. Advanced drug delivery has turned out to be an important aspect of the medical field. A targeted delivery system transports the drug to the place of action hence, minimizing its adverse side effects on other vital tissues. Cell-specific targeting can be achieved by coupling drugs to specially framed carriers. Various nanoparticles, including solid lipid nanoparticles, nanosuspensions, nanoliposomes, micelles, polymeric nanoparticles, magnetic nanoparticles, dendrimers, carbon nanotubes, and fullerenes have been developed as carriers in drug delivery systems. In this chapter, the aforementioned nanocarriers and their clinical milestones achieved in various arenas including cancer, CNS disorder, rheumatoid arthritis, thyroid, cardiac diseases, ocular drug delivery, and vaccines so far, are scrutinized. This chapter outlines the current status of pharmacological and clinical studies of nanoparticles in the development process.

Artificial Intelligence Played an Active Role in the COVID-19 Epidemic in China

This perspective aims to summarize the COVID-19 experience of the Chinese people, which included psychological assistance and open datasets. We hope that countries across the world can utilize the lessons learned and tools developed by China in response to the COVID-19 pandemic and share their fighting experience in academic publication freely so the world can solve this crisis. This perspective focuses on psychological assistance and open datasets in China's COVID-19 pandemic; they played an important role in fighting with COVID-19 and acquired major contributions to calm people in the restless environment. We hope other countries can absorb the quintessence from this experience and utilize their situation to prevent and protect citizens from being infected and get rid of sequela in the COVID-19 epidemic.

Applications and Implementations of 6G Internet of Things

The Internet of things (IoT) has been the information infrastructure of a digitalized society and drives the newest wave of industrial development. With the rise of smart vehicular IoT applications, such as intelligent transport, smart navigation, and automatic driving, vehicular IoT is gaining some new features that cannot be fully addressed by current 5G networks. This chapter presents an overview of the vehicular IoT developing trend and discusses its relationship to 5G and the coming generation. It also presents some survey results from recent literature on the challenges and promising technologies for vehicular massive IoT.

Pathologies of the Peritoneum, Mesentery and Diaphragm

Pathologies of the peritoneum, mesentery and diaphragm are uncommon, making their diagnosis more challenging. We present the main issues in diagnosis and treatment. Peritonitis represents acute inflammation of the peritoneum that can be caused by perforation, inflammation or gangrene of an intra- or retroperitoneal structure. The most frequently encountered peritoneal tumours are metastases originating in gastrointestinal, ovarian, lung, pancreatic and breast adenocarcinomas. Lymphomas can primarily or secondary affect the peritoneum. There are two main categories of diseases affecting the mesentery: diseases that start from the mesentery (which can also affect neighbouring organs) and diseases that originate in neighbouring organs. The most encountered hernias of the diaphragm are those occurring through the oesophageal hiatus, but there can also be congenital hernias (oesophageal, Morgagni and Bochdalek) or through post-traumatic defects. As in all other organs, primary diaphragmatic tumours can be classified as benign (cyst and lipomas) or malignant (rhabdomyosarcoma and fibrosarcoma), with other types of primary tumours than those aforementioned being very rarely seen.

Clinical Diagnosis of Tuberculosis

Symptoms and signs of active tuberculosis (TB) depend on its anatomical location. Pulmonary disease is the most common presentation of tuberculosis in the adult patient (more than 80% of the cases in the immunocompetent patient). Signs and symptoms can appear after just a few weeks from the primary infection, or many years later due to the reactivation of latent disease anywhere in the body.

Symptoms of pulmonary tuberculosis are nonspecific and may occur in many other pulmonary conditions; however, in high-burden regions, they remain a valuable tool for initial screening.

Signs and symptoms of extrapulmonary tuberculosis (EPTB) are protean, and chest xrays of the chest frequently do not show abnormalities. TB lymphadenitis is the most common form of EPTB, especially in children and young individuals.

Miliary tuberculosis is characterized by the presence of disseminated innumerable small nodules. It is secondary to the hematogenous spread of the bacilli throughout the body after the primary infection or the reactivation of a latent focus.

Although TB can involve any segment of the gastrointestinal tract, the ileocecal region is the most frequently affected. It is due to the ingestion of milk or milk products contaminated with M. bovis, the swallowing of secretions infected with M. tuberculosis, hematogenous dissemination of active TB disease, or from direct spread from contiguous organs.

Central nervous system tuberculosis is a consequence of hematogenous dissemination and the most severe form of the disease, with high morbimortality.

Biobank for Personalized Immunotherapy

A biobank is a resource for keeping blood and tissue samples, which is going to play an increasing role for personalized immunotherapy, called precision immunotherapy. Moreover, large profits from biobanks are their futures of patients' personalized immunotherapy. A new generation of immunotherapy often relies on a person's tissues/cells/molecules/data so that personalized immunotherapy starts to deposit the patient's specimens and clinical information with genomics data. If tumor patients can save their specimens such as tumor tissues or blood before treatment, furthermore, if patients can achieve some genomic data for future treatment, the specimens saved in biobanks and the genomics data observed from their tissues can contribute clinical physicians and clinical scientists to develop a new generation of treatment, for example, patients respond to immunotherapy predicted by individualized measurement and undergoing personalized T-cell immunotherapy. This chapter introduces biobank, one of the most up-to-date personalized immunotherapies, which enable conducting research and development (R&D) for professional collection of clinical specimens and clinical data. The chapter aims at describing the concept of biobank and future potential to treat patients. It also includes sample preservation protocols and data management as well as online service of samples and clinical data. Thus, some standard operating procedures apply for personalized immunotherapy of diagnostic and treatment procedures. Finally, ethics for sampling, clinical information, and genomics data are mentioned to support the biobank chapter.

Environmental and Human Health Issues in Campania Region Italy

Waste generation rates continue to grow around the world, creating a need for more comprehensive waste management strategies to meet sustainability needs. Uncontrolled disposal generates complex and challenging situation that involves the entire population. In particular, the illegal dumping and burning of toxic waste in Campania (Italy) has caused immense environmental damage and an increase in cancer rate among the population. Different epidemiological studies were commissioned by the Ministry of Health to assess the magnitude of contamination under an illegal dump in Campania and to evaluate the population health impact. The data and other available evidence testify the dramatic situation in Caserta and Naples provinces about the severe impairment of the environmental conditions in several places and increase of cancer incidence. For this reason, the Campania region is known, such as Triangle of Death” and “Land of Fires” (LoF) (or Terra dei fuochi-TdF), as reported both in academic publications and the national press. This chapter is aimed to provide the findings regarding human health and environmental contamination in this region.

Microbe-based Antiangiogenesis Therapies for Cancer Management

The recent scientific advancements have aroused the attention towards the role of microbes in the therapeutic management of various maladies that have transformed the pharmaceutical research. Although certain bacteria are widely known to cause cancer, recent research has shown exciting outcomes signifying the role of bacteria as an effective therapeutic agent for cancer. Different bacterial strains have been scrutinized for their inherent potentials to colonize the tumors environment and subsequent oncolytic properties in animal models. Moreover, their inherent anti-cancer properties can be boosted through genetic engineering, which allows the bacterial species to transfer the therapeutic molecules into tumor cells. During the previous few years, the studies have focused on the use of genetically modified bacteria for cancer therapy with an emphasis on blocking tumor angiogenesis. Although the studies regarding the microbial-based anti-angiogenesis therapy for cancer management are quite a few, it seems to be an innovative and attractive approach, particularly for solid tumors which usually possess increased vascularization. This chapter aimed to provide recent information relating to the candidates for anti-angiogenesis therapy, including angiostatin, tumstatin, endostatin, interleukin-12, metargidin peptide with a focus on recent developments in the newly identified field of microbe-based angiogenesis suppression. The advanced approaches for the use of modified bacteria as anti-cancer therapeutics have been discussed, particularly the DNA vaccination, bactofection, alternative gene therapy, and RNA interference with an emphasis on their antiangiogenesis potential.

Therapeutic Targeting of the Tumor Vasculature: Past, Present and Future

Tumor progression relies on a constant supply of oxygen and nutrients. Angiogenesis, the formation of neovessel from existing microvessels, is a prerequisite for the growth of many tumors. Significant advances have been made in delineating the interplay between pro- and anti-angiogenic factors that foster an environment that promotes the angiogenic phenotype in tumors. Of these angiogenic regulators, vascular endothelial growth factor-A (VEGF-A) and its cognate receptor, vascular endothelial growth factor receptor-2 (VEGFR-2) have been the most studied.

Various angiogenesis inhibitors (AIs) that target VEGF-A and VEGFR-2 have been developed for use as monotherapy or as part of combination therapies with standard chemotherapy. However, these AIs have thus far produced modest results, in part owing to compensatory pathways that have led to disease refractory.

To overcome refractory to disease, normalization of the tumor vasculature and broadening of the scope of therapeutic targeting are necessary. Furthermore, predictive biomarkers can enhance efficacy by enabling the early detection of resistance as well as the determination of clinical benefit. Herein, the therapeutic approaches that target multiple pathways and components of the tumor microenvironment, as well as those that normalize the vasculature are explored. In addition, the future application of noninvasive imaging to monitor the effects of AIs on the tumor vessels is discussed.

The Role of Palliative Care in Lung Cancer

Patients with lung cancer are often diagnosed late and the disease in such cases is often advanced. Common symptoms include breathlessness, haemoptysis and pain and these can have an impact on their quality of life. Patients might have challenging palliative and supportive care needs and in order to address these, palliative care should be offered earlier in the disease trajectory. An interdisciplinary approach, working jointly with the oncologists, respiratory teams and palliative care teams provide a holistic, comprehensive assessment in response to their changing needs. Advance care planning is best to be started early on especially in patients with a prognosis of about a year, in a sensitive manner, in order to involve the patient in discussion about their future wishes and priorities for care. It is important to recognise dying to be able to communicate with the patient and their family, recognise any symptoms and manage them proactively and achieve preferred place of care and death; a patient-centred approach is needed.

Subject Index

Cancer as an Occupational Hazard

Cancer is one of the most dreaded diseases of mankind that causes alarming mortality and morbidity in humans. According to International Labour Office (ILO), Occupational cancer is the most common work-related cause of death, leaving accidents and account for 32% of all work-related deaths worldwide leaving accidents and other occupational diseases well behind. It has long been evident that cancer has a multi-factorial etiology and is a multi-stepped process involving initiation, promotion and tumor progression. Studying occupational cancer is very challenging because of the long latency of cancer and the involvement of many factors in the development of cancer including family history, personal characteristics, dietary and personal habits besides exposure to cancer-causing agents in the workplace and environment. Occupational factors continue to be highly prevalent in new or upgraded IARC (International Agency for Research on Cancer) classifications in last decade. Inhalation, skin exposure and ingestion are significant modes of exposure of chemicals resulting in Cancer.Prevention of occupational cancer is a multistep strategy which involves eradication/minimization of carcinogenic process or agent coupled with good work /hygiene practices, employee education /counselling and workplace monitoring.

Indirubins as Multi-target Anti-Tumor Agents

The traditional use of indirubin for the treatment of leukaemia has opened a vast field of research, studying the anti-tumor properties of indirubin and its derivatives (IRDs) against a wide range of malignancies. The cytotoxic effects of indirubin has been primarily attributed to its inhibitory function on a number of protein kinases, including cyclin-dependent kinases (CDKs), glycogen-synthase kinase 3 (GSK-3), and receptor tyrosine kinases (RTKs). In the past few decades, a lot of effort has been directed to the chemical modification of indirubin’s backbone towards better pharamcokinetic properties. This has led to the synthesis of various derivatives with new biological activities. We here review from the discovery of indirubin to the development of novel IRDs, and highlight the recent progress on how indirubins influence multiple cancer-associated signaling networks, leading to anti-proliferative and pro-apoptotic effects. Furthermore, we discuss the therapeutic use of indirubins in anti-cancer settings, as well as their potential for future clinical application.

Subject Index

Cancer as an Occupational Hazard

Environmental Pollutants and Risk of Cancer

Cancer is characterized by cell proliferation, prevention or bypass of programmed cell death, genomic instability, angiogenesis, invasion and metastasis which are influenced by environmental pollutants. It is the major cause of death in world wide. Lifestyle factors such as diet, smoking and use of alcohol are responsible for the development of cancer in a large part of the population of developed countries. Existence of carcinogens or co-carcinogens in polluted air and drinking water, as well as in food, played a significant contribution in our country. Endocrine disrupters modify the risk of breast, endometrial and prostate cancer. Laryngeal, oropharyngeal, hypopharyngeal, sinonasal, nasopharyngeal, oral and lung cancer are positively associated with smoking and air pollutants. Tobacco smoking induces DNA adducts formation which is responsible for mutations at K-RAS and TP53 gene in the lung and pancreatic adenocarcinomas. Tobacco smoking induces promoter hypermethylation of p16 and DAPK genes in Non-Small Cell Lung Cancer (NSCLCs). Aflatoxin B1 (AFB1) causes promoter hypermethylation of tumour-suppressor genes RASSF1, MGMT, and p16 in human hepatocellular carcinoma (HCC) patients. Down-regulation of p15, p16, PRKG1, PARD3, and EPHA8 genes at mRNA level due to hypermethylation and increased expression of STAT3, IFNGR1 at mRNA level due to hypomethylation were reported in patients having benzene exposure. Methylationinduced transcriptional inactivation of tumor suppressor genes, including p53, CDKN2A (p16INK4A), Ras association domain family member 1 (RASSF1A), and death-associated protein kinase (DAPK) were reported in arsenic exposed individuals. The genetic and epigenetic alterations respond to environmental carcinogens have significant contribution for biomarker development in assessment of health risk.

Impact on Health of Artichoke and Cardoon Bioactive Compounds: Content, Bioaccessibility, Bioavailability, and Bioactivity

Artichoke, cultivated cardoon, and their common relative, the wild cardoon are botanical varieties of the species Cynara cardunculus L., a perennial plant native to the Mediterranean Basin and belonging to the Asteraceae family. While commonly used as food, leaf extracts of this plants have been traditionally used as a natural remedy in folk medicine. These plants are in fact a rich source of bioactive compounds such as polyphenols, inulin, and sesquiterpene lactones. Many studies demonstrated that these compounds and their metabolites are responsible for several beneficial properties attributed to the extracts of artichoke and cardoon. As we gain knowledge on the effects and mode of action of these compounds, artichoke and cardoon are considered ‘functional food’ and are increasingly used to extract bioactive compounds and for numerous pharmaceutical applications. In this chapter, after a brief introduction on the origin and the importance of these crops, each class of bioactive compounds is presented summarizing the specific chemical properties, the biosynthesis, and the concentration range in plant tissues. The third section discusses the main factors (plant portion, physiological stage, plant genotype, environment, pre-harvest agronomic practices, post-harvest handling and processing) influencing the concentration of bioactive compounds in artichoke and cardoon. The following section is focused on the physiological fate of the bioactive compounds, reviewing the results of the most recent in vitro and in vivo studies conducted to assess their bioaccessibility, bioavailability, and pharmacokinetics. Finally, in the last section the main health-promoting effects attributed to artichoke and cardoon polyphenols are reviewed.

Carbon Nanotubes in Drug Delivery

Carbon nanotubes are one of the most commonly used nanomaterials in research field and consumer industries. They have attained popularity in biomedical applications pertaining to novel drug delivery carriers, as building blocks for tissue regeneration as well as probes for bio-imaging and bio-sensing. Both multi-walled and single walled CNTs have been employed for therapeutic activity for the treatment of several diseases such as cancer therapy, Neurodegenerative Diseases and Alzheimer Syndrome via multiple approaches. Potential application of CNTs as nano-carrier is their ability to translocate through cellular membranes, facilitate their use for the delivery of therapeutically active molecules resembling cell-penetrating peptides. This chapter highlights the importance of CNTs as a vehicle for delivering wide variety of payloads including drugs, small organic molecules, oligonucleotides, proteins, siRNA, vaccines and nutrients. We have focussed on demonstrating their synthesis and functionalization as important procedural steps for creating a smart and intelligent system for delivery.

Human Beings: Adverse Effects of Transformations

World population growth, concentration in megacities, development of the technosphere and numerous novel chemical substances, industry, and agriculture have exposed humans to new kinds of health threats. Insufficient sewerage systems in megacities resulted in cholera epidemics. London smog caused impairment of the respiratory tract and rickets. Los Angeles smog brought about the presence of ground level toxic ozone in urban aerosol plumes. Mortality increased significantly in cities during summer heat waves. Permanent availability of artificial light has entailed unhealthy night and shift work. Rapid increase in global traffic resulted in annual losses of more than 1 million lives. Excess artificial noise causes 61,000 disability adjusted life years annually. Global annual fatalities due to air pollution run up to 5.5 millions. Clean-up of industrial brownfields impose financial burdens on public budgets. Health costs of Hg released into the environment are estimated at a minimum of 23,000 euros/kg. A positive correlation exists between health impairment and CO2 emissions. Financial pressure is rising to organise constructions to shelter coastal cities against sea level rise. Growth of cropland has not kept pace with population growth since 1960. Ailments arise because of mass-consumption of cheap foodstuffs, luxury food, and stimulants. Globally, 1.8 billion persons lack access to good quality drinking water. Detected detrimental effects of certified chemicals and pharmaceuticals resulted in numerous health impairments. Global distillation has deteriorated the health status of the Arctic population. Health burdens arise due to industrial and nuclear havaries, and above ground nuclear tests. Intentional application of industrially produced warfare has caused ca. 145 million fatalities since 1800.

The Role of Palliative Care/ Hospice Medicine in Interventional Pulmonology

Palliative care has been defined as “the active total care of patients whose disease is not responsive to curative treatment.” The focus of palliative care/ hospice medicine according to the World Health Organization (WHO), is to prevent and relieve suffering by early identification, assessment, and treatment of pain and other debilitating symptoms. Unfortunately, lung cancer and chronic obstructive pulmonary disease are among the leading causes of death in the United States. Therefore, pulmonologists are often called upon to participate in the care of terminally ill patients. By incorporating components of palliative care, pulmonologists can help relieve their suffering. When conservative therapies fail, interventional pulmonologists can palliate the symptoms associated with disorders such as malignant pleural effusion, airway obstruction and hemoptysis. Commonly offered interventions in this regard include, indwelling pleural catheters (IPC), pleurodesis, endobronchial laser, electrocautery, argon plasma coagulation (APC), endobronchial brachytherapy, rigid bronchoscopy and airway stenting.

Medical Pleuroscopy

In recent years, an increasing trend has been recognized in the number of centers performing medical thoracoscopy across the world, mainly as a gold standard investigation for undiagnosed exudative effusion. It is a particularly useful diagnostic and therapeutic tool with a very low rate of complications that should be incorporated in the respiratory physicians’ armamentarium. Pleural biopsies under direct vision, therapeutic evacuation of effusions, and pleurodesis can be performed in one sitting. This chapter summarizes the important literature relating to the equipment, clinical indications, safety, complications and technical aspects of the procedure. We also aim to inform the reader regarding the latest research advances and potential areas of that MT will have a role in the future.

Management of Malignant Pleural Effusion

Malignant pleural effusion (MPE) is common and the management options available for MPE are often limited. The key goal in the management of MPE is to relieve patient’s symptoms with the least invasive means and in the most cost-effective manner. The approach to the management of MPE should be tailored according to patient’s overall prognosis, symptoms, functional status, social support, treatment availability, and financial situation. Pleurodesis has been the standard of care for the management of MPE for years and talc continues to be the most effective sclerosant available for pleurodesis in MPE. However, it is also associated with more invasive procedure and longer hospitalization. Most clinical studies on MPE treatments in the past were focused on the creation of successful pleurodesis in an attempt to stop reaccumulation of pleural fluid rather than patient-related outcome measures (PROM). The current trend of incorporating indwelling pleural catheter (IPC) in the management of MPE has been shown to be as equally effective as talc pleurodesis with significantly fewer hospitalization days and may be less costly compared to pleurodesis .

Cancer and its Treatment: Development of Anticancer Chemotherapeutic Agents from Natural Products

Over the last 5 decades, biologically active compounds derived from natural resources have provided a number of useful cancer chemotherapeutic drugs. The search for natural product based drug candidates is growing rapidly with the advancements in drug discovery and development techniques in recent years, with the active fractions and isolates of marine organisms along with terrestrial plants. Microorganisms are also being explored for their anti-cancer activities. The present review highlights the information about occurrence, types, clinical features pathophysiology and etiology of cancer as well as conventional and recent advancements in anticancer drug development along with description of selected medicinal plants and compounds derived from natural sources or their derivatives with potential use as cancer chemotherapeutic agents. It is expected that such promising leads from natural origin tend to create extensive interest among researchers including medicinal chemists and pharmacologists working in anticancer drug research and therefore the availability of a given brief information about cancer and anticancer drug development focused on natural product may be proved useful to develop preliminary ideas of biochemical pathways and key enzymes regulating these pathways as well as new targets involved in different stages of the disease along with chemotherapeutic agents which selectively target a specific signaling pathway through structure-activity relationships and preclinical trials.

Molecular Mechanisms of Cellular Transport, Resistance and Cytotoxic Side Effects of Platinum and Adjuvant Anti-cancer Drugs – A Molecular Orbital Study

The side effects, acquired resistance, reversal of resistance, and combination of Pt drugs with adjuvant drugs has been examined using an extensive review of the literature and molecular orbital computations. It is concluded that Pt chemotherapeutical regimes are dominated by side reactions, particularly hydrolysis in blood serum and delivery efficiency. For example, it is shown that transplatin is therapeutically inactive because it hydrolyses faster in blood serum than cisplatin, so little transplatin reaches its target DNA. The reactivity of charged hydrolysis products determines the severity of side effect. The reactivity determining properties of the approved Pt drugs and their various hydrolysed species are calculated. The cellular uptake of Pt and adjuvant drugs is fastest for neutral species, with high lipophilicity, since their desolvation penalties for crossing the cell membrane are lowest. Pt resistant cell lines generally have lower levels of drug uptake, indicating this is a dominant first order cause of cellular resistance. Resistance can be caused by complexation of charged Pt species to phosphatidylserine (PS) headgroups, or by Pt complexation to the inner terminii of the trans-membrane pore of the hCtr1 transporter. Drugs that are known to reverse induced Pt resistance can decomplex the Pt-PS or Pt-hCtr1 complexes, restoring normal PS or hCtr1 functions. Molecular biophysical properties of adjuvant drugs used in combination with Pt drugs (e.g., paclitaxel, doxorubicin, gemcitabine, Folfox) can assist the clinical evaluation of combinatorial Pt based chemotherapeutic regimes. These drugs have similar properties to the approved Pt drugs, and fit into the same “therapeutic window” in sterms of their likely cellular uptakes and reduction potentials. The role of free radical species involved in Pt drug induced apoptosis via electron transfer from the guanine base of DNA, and the reactions of oxidizing hydroxyl radicals and reducing hydrated electrons reactions with cisplatin, transplatin and carboplatin under physiological pH and Cl ion condition have been examined.

Free radical sensitisers such as TMPD and TETA when combined with Pt drugs may allow targeting of the more hypoxic environments in solid cancerous tumours (and less damage to normal cells). The calculated biophysical parameters ionization energy and electron affinity, which are related to the redox environments found in cells, may be useful predictors of likely cytotoxic efficacy of combination therapies involving sensitisers and Pt drugs.

The Latest Developments in Anti-Pancreatic Cancer Drugs: A Promising Future Ahead

Pancreatic cancer has been increasingly diagnosed in the recent decades. Although the cornerstone treatment for pancreatic cancer is surgery, unfortunately, only 15-20% has a resectable disease at the time of initial diagnosis. Owing to the majority of patients having either locally advanced diseases or metastases, chemotherapy plays an important role in the management of pancreatic cancer. Because conventional chemotherapy has its limitations in the management of pancreatic cancer, recently developed molecular targeted therapy has emerged as an important modality of treatment of the disease. Drugs targeting growth factors such as epidermal growth factor and anti-angiogenesis have been studied and have promising results. Some of these drugs such as erlotinib have been already approved for the treatment of pancreatic cancer. Newer drugs such as those targeting hedgehog signaling pathway are now being tested. In this chapter, we will comprehensively review the current and also the latest development of anti-pancreatic cancer drugs.

Malignant Pleural Mesothelioma (MPM): Latent Disease

Malignant pleural mesothelioma (MPM) is a cancer with aggressive nature and poor prognosis (the median survival ranges from 9-18 months). The worldwide incidence of this disease is increasing, with 2180 estimated new cases diagnosed in the United States in 2013. Despite the apparent benefits offered by the multimodal approach (a combination of surgery, chemotherapy -cisplatin/ pemetrexed- and radiotherapy), survival remains poor. As a consequence, multiple therapies aiming to improve the evolution of the disease are under investigation. In this chapter, we will summarize some of the new preclinical and early clinical developments in the treatment of MPM, which include mesothelin specific antibody and toxin therapies, gene therapy, interleukin-4 (IL-4) receptor toxins and dendritic cell vaccines, among others.

Subject Index

Advances in Cancer Therapy: Novel Approaches in Combined Drug Treatments

Drug resistance and poor efficacy of anticancer therapies prompt to investigate innovative therapeutic strategies aimed to improving efficacy and lowering toxicity. Recent advances in chemotherapeutics have been achieved using specific pharmaceutical combinations or ameliorating drug delivery by drug encapsulation.

Novel combined treatments are based on the use of drugs, typically natural active or intended for other uses combined with the classical anti-cancer drug. These compounds promote synergistic effects even more enhanced when drug delivery is achieved by nanocarriers. Nanotechnologies provide a site-specific delivery at the tumor site, resulting from receptor-mediated endocytosis and prolonged circulation time. Nanocarriers also increase drug bioavailability and biocompatibility contributing to a drug increase inside the tumor and determining a minor toxicity and a better efficacy.

This chapter reports recent findings about novel anticancer combined treatments and about the latest drug delivery systems based on the use of nanocarriers.

Bioactive Compounds in Coffee as Health Promotors

Coffee is the most consumed beverage in the world after water. In 2014 approximately 141 million tons of coffee bags were produced. In terms of international trade only crude oil has a bigger share. The world coffee trade is increasing every year showing the importance of coffee to the world economy. The composition of the two main coffee species (Arabica and Robusta) varies according to the origin, storage and terroir conditions. During the roasting process there are a number of reactions that give rise to the organoleptic properties of coffee. The main bioactive compounds in coffee are chlorogenic acids, caffeine, trigonelline, melanoidins and diterpenes. These compounds are known to have a number of beneficial health effects. Many epidemiological studies suggest that coffee consumption can lead to health benefits in several diseases such as type 2 diabetes, several types of cancers, Parkinson’s and Alzheimer’s disease. These benefits are related with coffee antioxidant, antiinflammatory, anti-mutagenic and anti-carcinogenic properties. Chlorogenic acids are known to have chemopreventive and anticarcinogenic activities and also to act as antithrombotic agents. Caffeine is the most recognized bioactive constituent of coffee and can have a number of positive effects in health, most of them associated with the antagonism of the A1 and A2 subtypes of the adenosine receptor. Its stimulatory effect is due to the synergetic interaction with adrenalin and noradrenaline. Trigonelline is connected to neuroprotective, estrogenic, hypoglycemic, anti-invasive, and antibacterial responses.

The biological activities commonly associated with melanoidins are antioxidant and metal chelating, antimicrobial, and anticarcinogenic. These compounds also have the ability to modulate colonic microflora. Research has showed that the diterpenes, cafestol and kahweol have a chemopreventive potential by enhancing defense systems against oxidative stress. It is clear from the epidemiological studies that coffee has indeed health benefits. Nevertheless some caution has to be taken into account since there are a number of issues regarding these studies, as many of them were not designed specifically for coffee. Furthermore, health problems history and individual lifestyle can introduce misleading factors.

Oxaliplatin-mediated Inhibition of Survivin Increases Sensitivity of Head and Neck Squamous Cell Carcinoma Cell Lines to Paclitaxel

Oxaliplatin, is a platinum-based antineoplastic agent used in cancer chemotherapy and paclitaxel is one of several cytoskeletal drugs that target tubulin. Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Survivin is one of the key anti-apoptotic proteins which is over-expressed in most of the human cancers; and is associated with their biologically aggressive characteristics and drug resistance. Investigations presented deals with the evaluation of the efficacy of oxaliplatin and paclitaxel combination as a potential strategy in controlling HNSCC cell proliferation and the assessment of correlation between occurrence of apoptosis and changes in expression of survivin (IAP) by employing two HNSCC cell lines (Cal27 and NT8e) and one normal cell line (293) panel with differential level of survivin expression in accordance with chemosensitivity. The combined treatment of cells with paclitaxel and oxaliplatin resulted in a significantly higher cytotoxicity compared to individual single drug treatment. Cytotoxicity was prominent in paclitaxel to oxaliplatin (pacl-oxal) sequence treatment with an approximate two-fold increase in apoptosis compared to oxaliplatin to paclitaxel (oxal-pacl) sequence treatment.

Paclitaxel treatment also significantly increased survivin expression with reduced apoptosis at low concentration. Oxaliplatin, when combined with paclitaxel, decreased the survivin level with increased cell death. Study was further designed to explore the effect(s) of survivin-inhibition by a small interfering RNA (siRNA therapy) method on the apoptosis in HNSCC cells expressing increased sensitivity of the cancer cell lines to paclitaxel whereas over-expression of survivin in the transfected 293-cell line provided resistance. Survivin played a critical role in paclitaxel resistance through the suppression of apoptosis, and a significant induction of apoptosis was observed when oxaliplatin was combined with paclitaxel at least in part by the down-regulation of survivin. In conclusion, the interaction between drugs was synergistic and scheduledependent.

Points of Therapeutic Intervention along the Wnt Signaling Pathway in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause related to cancer mortality worldwide. Due to frequently late diagnosis, overall prognosis of patients with liver cancer is poor. Unfortunately, there is no targeted therapeutics for the treatment of HCC except sorafenib, which has exhibited notable results in certain advanced HCC. Increasing evidences indicate that deregulation of Wnt/β-catenin signaling pathway plays a critical role in hepatic oncogenesis and mainly occurs at the early stage of hepatocarcinogenesis. In addition, aberrant activation of the Wnt/β- catenin signaling pathway has been linked with more aggressive HCCs. The major mechanism for aberrant activation of the signaling in HCC is caused by genetic mutations and/or altered expression of upstream components of the Wnt/β-catenin signaling. This leads to abnormal expression of the β-catenin/TCF-responsive target genes, which regulate cell growth, apoptosis, cell motility, and invasion. Thus, intervention of the Wnt/β-catenin signaling activity can be potential therapeutics for HCC. This review will discuss the identified potential molecular targets related to the Wnt/β-catenin signaling pathway and their potential therapeutic applications.

Subject Index

Analysis of Therapies for Malignant Pleural Mesothelioma: Words that Count, Numbers that Speak

Evaluating the benefit of therapies for malignant mesothelioma is a quite difficult task. The difficulty lies in identifying patients who might have benefited from a given treatment but knowingly did not receive it. Unless these 'suitable' patients have been identified in advance of any treatment and the process of allocation to one treatment or another is without bias. This is best achieved by randomization and in our view, for relatively small trials with heterogeneous patients, that is best done with the additional step of minimization.

Clinical Impact of Surgery for Malignant Pleural Mesothelioma

The prognosis of malignant pleural mesothelioma remains very poor. The role of the two intentionally-curative surgical procedures, extra-pleural pneumonectomy and radical pleurectomy/decortication, is widely debated and mainly focused on the impact on survival, which is not significantly improved whatever the operation may be.

On these bases the clinical impact of these procedures may assume a relevant importance on immunology, symptoms and quality of life.

Despite the unsatisfactory results on survival these two procedures proved effective in ameliorating symptoms and quality of life. In the early-postoperative period, greater improvements are detected after pleurectomy/decortication, whereas extrapleural pneumonectomy produced better symptom-relief later. Conversely this procedure may have a negative impact on immunological conditions thus producing a significantly greater risk of postoperative infection implying a higher morbidity rate.

Complications after Surgery for Malignant Pleural Mesothelioma

Malignant pleural mesothelioma prognosis is still dire. Since results are not optimal via single modality protocols, combined treatments have been proposed with more encouraging results. However, the likelihood of severe complications should be taken into the account. In this chapter, we will discuss complications due to the surgical treatment. In particular, cardiovascular complications are frequently encountered after mesothelioma surgery. Atrial fibrillation may occur in more than 50% of patients after extrapleural pneumonectomy. Myocardial infarction and serious ventricular arrhythmias are seen more rarely. Respiratory complications may include prolonged air-leak, ARDS and pneumonia. Meticulous surgical technique, proper anesthetic management with preoperative fluid restriction, and early mobilization are of paramount importance to decrease postoperative morbidity.

Results after Intraoperative Therapy in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a virulent disease that is essentially incurable. Although surgery cannot currently be considered standard of care, there is general agreement that a certain subset of patients appear to benefit from surgery-based multimodal treatments beyond what would be expected with the current standard of care, pemetrexed-based chemotherapy alone. Exactly who those patients are remains to be defined. One intuitively appealing aspect of surgery-based therapies is that they allow for the employment of an intraoperative adjuvant therapy. There are multiple intraoperative adjuvant therapies, each with their own advantages and disadvantages. This chapter is a review of these treatments.

Surgical Treatment after Chemotherapy in Malignant Pleural Mesothelioma

Management of malignant pleural mesothelioma is still a clinical challenge. Currently, the best survival figures are described after multimodality regimen including macroscopic complete resection achieved by either extrapleural pneumonectomy or extended pleurectomy/decortication in patients selected for tumor biology, stage, and risk factors. One particular approach is to perform neoadjuvant chemotherapy followed by macroscopic complete resection, which will be discussed in the following chapter.

Surgical Treatment after Radiotherapy in Malignant Pleural Mesothelioma

alignant Pleural Mesothelioma (MPM) is a diagnosis that implies a poor prognosis and lack of effective treatment options. As a consequence of the lag time between exposure to asbestos and onset of disease, the incidence of MPM is expected to keep rising in the coming years. Although many treatment algorithms have been tried in the past, mortality is still very high due to both high local recurrence rates and development of distant disease. A new protocol was thus developed in an attempt to improve overall survival from this disease - Surgery for Mesothelioma After Radiation Therapy (SMART). The SMART involves a fractionated administration of 25 Gy over seven days to the whole chest by intensity modulated radiation therapy (IMRT). A concomitant boost of 5 Gy is also delivered to high risk volumes - based on imaging findings (CT and PET). Within 15 days of the completion of the radiation treatment, therapy, extra-pleural pneumonectomy is performed. This protocol may yield satisfactory results in case of epithelial-type MPM.

Lung Sparing Surgery for Malignant Pleural Mesothelioma

Malignant pleural mesothelioma is a diffuse tumor that does not easily lend itself to surgical resection. However, there are several observations that seemingly support the use of surgery in this disease. A variety of surgical procedures have been utilized in an attempt to provide the maximum therapeutic benefit to patients with malignant pleural mesothelioma. They vary from a small thorascopic pleurodesis procedure to a radical extrapleural pneumonectomy. Pleurectomy/decortication (P/D) and partial pleurectomy, have been used in many centers as an alternative procedure in patients who cannot undergo extrapleural pneumonectomy (EPP). Mortality of partial pleurectomy and P/D ranges between 0% and 8%. Survival statistics showed a slight trend for longer disease-free survival in extended P/D versus P/D, but there were no differences in median overall survival. Partial pleurectomy appeared to be inferior, with an overall median survival ranging from 7.1 to 14 months. Overall, current evidence supports the claim that P/D produces similar or better outcomes than EPP. The results of the Mesothelioma And Radical Surgery 2 trial will hopefully provide a stronger evidence on these topics.

Value of Extrapleural Pneumonectomy in Malignant Pleural Mesothelioma

Although there is lack of consensus regarding the “standard of care” for malignant pleural mesothelioma, surgery-based multimodality therapy has demonstrated long-term survivors in multiple retrospective and prospective trials. The authors advocate radical or extended pleurectomy/decortication when possible, but for patients with adequate cardiopulmonary function in whom disease is resectable only by extrapleural pneumonectomy, this operation now has a long track record of safety and serves a critical role in the treatment of this aggressive disease.

Thoracoscopy in Diagnosis and Treatment of Malignant Pleural Mesothelioma

In malignant pleural mesothelioma (MPM) diagnostic success of noninvasive procedures is generally reported to be unsatisfactory. Both medical and surgical thoracoscopy seem to be ideal tools causing little discomfort, with very low risk of complication and short hospital stay. Both procedures therefore represent the diagnostic gold standard whilst also offering effective palliation at the same time. In this chapter all these aspects as well as anesthesiological patterns, technical tricks, conditions for associating pleurodesis, role of partial thoracoscopic pleurectomy are discussed.

Staging Systems and Current Guidelines in Malignant Pleural Mesothelioma

The earliest documented staging system for malignant pleural mesothelioma was proposed by Dr. Eric Butchart in 1976, who defined four stages of disease using clinical and pathological data from 29 patients who underwent extrapleural pneumonectomy. In the 1990s, Dr. David Sugarbaker from Brigham and Women’s Hospital proposed a new ‘functional’ staging system that aimed to predict resectability and extended survival, with particular attention given to nodal involvement. Not long after, a separate staging system was proposed by the International Mesothelioma Interest Group, led by Dr.Valerie Rusch from the Memorial Sloan-Kettering Cancer Center. For the first time, a collaborative effort was made to define T and N descriptors according to anatomic definitions consistent with the traditional TNM staging system. More recently, the International Association for the Study of Lung Cancer Staging Committee developed an international database to revise the TNM staging system. The implications of staging criteria on clinical research are discussed, and a brief summary of existing international Guidelines is presented.

Future Prospects in Chemotherapy for Malignant Pleural Mesothelioma

After a wide review of the role of palliative chemotherapy in non-resectable malignant pleural mesothelioma, this chapter illustrates promising future research directions. The role of thymidylate synthase and of excision repair crosscomplementation group 1 expression has been found to significantly correlate with prognosis. Several approaches to improve the efficacy of platinum salts are being explored. The search for novel antifolates (i.e. pralaxate and GW1843) as well as thymidilate synthase (i.e. plevitrexed and BGC 945) is ongoing. The platinum-based regimens could benefit from the addition of bevacizumab and amatuximab, monoclonal antibody against the vascular endothelial growth factor and mesothelin, respectively.

Virus Therapies in Malignant Pleural Mesothelioma

This chapter will review the utilization of therapeutic viruses for the treatment of mesothelioma. For a variety of reasons, certain viruses can preferentially infect mesothelioma cells and through natural replication cycle result in cancer cell lysis and spread of virus to surrounding cancer cells. Since the host antiviral response is a major limitation to clinical application of virotherapy, viruses have mainly been employed in tumor types that are directly injectable. Because mesothelioma is predominantly localized to the pleural or peritoneal cavity and is hallmarked by local progression rather than distant metastasis, it has been seen as an ideal candidate tumor for treatment with virus therapy. Thus far several viruses have demonstrated preclinical activity in mesothelioma models. These data have led to the first clinical trial testing oncolytic measles virus specifically in patients with mesothelioma. The rationale and available data for the potential efficacy of oncolytic viruses for mesothelioma will be reviewed in this chapter.

Novel Genetic Therapies in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an uncommon, but lethal malignancy resistant to most current therapies. It represents a good field of investigation for gene therapy because the disease remains confined for a long time during its growth and the neoplasm is quite accessible through the chest wall. Translational mechanisms for the treatment of this disease are emerging from the novel high-throughput molecular techniques, but a therapeutic gene capable of inhibiting the disease progression through specific gene therapy has not yet been identified. Several trials on gene therapy have been conducted in the last two decades showing safety but limited efficacy. Recent progress in the field has provided optimism for successful molecular strategies in the future.

Radiation Therapy of Malignant Pleural Mesothelioma

The role of radiation therapy in malignant pleural mesothelioma is controversial. It has been used as part of multimodal definitive treatment to ameliorate locoregional control after removal of early disease, as prophylaxis to decrease the probability of recurrence and pain at sites of diagnostic or therapeutic instrument insertion and as symptom palliation in patients with advanced disease. Intensity modulated radiotherapy in the adjuvant mode after extrapleural pneumonectomy achieves good local control with acceptable toxicity. Increasing interest can be seen with radical pleural intensity modulated radiotherapy with intact lung. Prophylactic irradiation can be performed for patients who are in good performance status with a longer life expectancy. So far, pain control seems to be the best evidenced application of radiation therapy.

Chemotherapy in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma is usually diagnosed as advanced disease, and treatment is not considered curative. Chemotherapy may palliate symptoms and improve both quality of life and survival for patients with advanced cancer, including those with mesothelioma. For the past decade, the combination of cisplatin with pemetrexed has been the standard of care for first line treatment of mesothelioma. This practice is predicated upon the results of the EMPHACIS trial, a phase III study comparing pemetrexed with cisplatin to cisplatin alone in patients with untreated mesothelioma. Most subsequent studies in cytotoxic chemotherapy have been small, non-randomized phase II studies and have not translated to new developments in the systemic treatment of this disease. Most recent trials use novel targeted therapies rather than cytotoxic chemotherapy, resulting in a paucity of recent data on cytotoxic chemotherapy and no clear advances over this decade, although recent data suggests that the addition of bevacizumab to cisplatin and pemetrexed provides a survival benefit. Herein, we review the current state of the art on chemotherapy in malignant mesothelioma.

Pleural Effusion Management in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) kills one person every four hours in the UK and every 12 hours in Australia. The global incidence of MPM continues to rise. MPM has no cure and symptom control is the key. Most MPM patients suffer from a pleural effusion; proficient care of malignant effusions and the associated breathlessness is essential to all MPM programs. MPM has unique characteristics in its pathobiology, clinical presentation and disease course that must be distinguished from those associated with metastatic cancers to the pleura. Recognizing these differences, e.g. the longer survival of MPM patients and higher risk of procedural tract metastases, are important. Patients with MPM-related pleural effusions are more likely to require definitive interventions for pleural fluid control, such as pleurodesis or indwelling pleural catheter (IPC) placement. One-third of MPM patients will fail talc pleurodesis, whether it is delivered by poudrage or slurry. IPC is well accepted as a treatment in patients with a trapped lung or when pleurodesis failed. Increasing evidence support the use of IPC instead of pleurodesis. However, effective use of IPC involves appropriate aftercare and optimal management of potential complications. Breathlessness in MPM is often multi-factorial; optimizing care of concurrent (non-effusion) causes of breathlessness is paramount. MPM cohorts are heterogeneous and disease courses can vary; only ~50% will require definitive therapies for pleural effusion management. Developing a personalized management plan based on predictions of survival, symptomatic response to pleural fluid drainage and effusion recurrence is the goal of contemporary research.

Prognostic Factors in Malignant Pleural Mesothelioma

Despite recent diagnostic and therapeutic advances the prognosis of malignant pleural mesothelioma remains extremely poor. We reviewed the role of some classic (i.e. age, gender, histology, staging) and novel clinical (i.e. occult residual disease, quality of life and fluorodeoxyglucose uptake at positron emission tomography) prognosticators. Many biological and genetic machineries have been lately related with the etiology and the natural history of mesothelioma. These new factors might have a significant function in predicting the prognosis of the disease and in the next future they could reveal an important role for targeted therapies.

Serum Biomarkers in Malignant Pleural Mesothelioma

The interest in identifying circulating soluble biomarkers for malignant pleural mesothelioma is quite high. The studies aim at identifying a tool that could enable early detection of the disease before symptoms develop. Blood-based fibulin-3 and osteopontin studies are currently ongoing. Serum concentrations of YKL-40 had a moderate ability to discriminate between mesothelioma and other clinically relevant controls. Despite a large number of biomarkers being reported for mesothelioma in the literature, mesothelin remains the single-best blood-based biomarker for the cancer and is considered to be the ‘gold standard’.

Present Role of Cytology in Diagnosing Malignant Pleural Mesothelioma

The possibility to diagnose malignant pleural mesothelioma (MPM) based on an effusion gives cytology a central role in handling of these patients. Audits have shown that effusion cytology, supported by one or more ancillary techniques, can diagnose a majority of all MPMs. When a definite diagnosis is obtained, this is beneficial for both patient and clinic. The cytological sample is easily accessible with less invasive means. However, the sensitivity for reaching this diagnosis based on cytology is 60-75%, i.e., somewhat lower than for the histopathologic examination of a biopsy, the exact level depending on the extent of ancillary analyses available. The cytological diagnoisis require support from immunohistochemistry and/or electron microscopy, and the sensitivity can be improved by testing soluble biomarkers (hyaluronan and mesothelin).

Imaging Evaluation in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma continues to be a challenging tumor to image and treat. A multimodality multidisciplinary team approach including surgery, oncology, radiology and radiation therapy is required for successful outcomes. Reliable and reproducible methods of assessing treatment response are crucial for guiding management, whether for clinical practice, research, or to meet the requirements of a clinical trial. Computed Tomography is the first line imaging modality due to its superb spatial resolution and volumetric data set, allowing for 3D reconstructions that aid in tumor volume assessment and surgical planning. MRI has the potential to provide qualitative, quantitative, anatomical and functional information without the use of ionizing radiation or intravenous contrast administration. Newer advances and optimization of existing protocols can help identify imaging biomarkers that can serve as surrogates of survival.

Anatomic Pathology of Malignant Pleural Mesothelioma

Mesothelioma is a rare tumor that derives from the mesothelial cells lining of body cavities. About 90-95% of mesotheliomas originate in the pleura and 5-10% in the peritoneal space. Other sites, such as pericardium and tunica vaginalis are very rare. Generally, mesotheliomas disseminate locally and tend to coat the organs in the different body cavities. The aim of this chapter is to describe the histological, histochemical, and immunohistochemical features of pleural mesotheliomas.

Somatic and Germline BAP1 Mutations in Malignant Mesothelioma

BRCA1-associated protein 1 (BAP1) has recently emerged as a novel important tumor suppressor gene in malignant mesothelioma. BAP1 is a nuclear deubiquitinating enzyme with several critical biological functions, including regulation of gene transcription, DNA damage response and chromosome stability. Somatic BAP1 mutations are found in about 60% of mesotheliomas, and germline BAP1 mutations have been reported to increase the incidence of malignant mesothelioma and to cause a novel hereditary cancer predisposition syndrome characterized also by higher incidence of several other cancers. In this chapter, we reviewed all the current evidences on the biology of BAP1 and on the clinical implications of its somatic and germline mutations in regards to malignant mesothelioma.

Biomolecular Pathways and Malignant Pleural Mesothelioma

Although asbestos is banned in several countries, malignant pleural mesothelioma (MPM) incidence is increasing worldwide, and this cancer remains a disease of concern. MPM is a very severe cancer, with no curative treatment despite the development of different kinds of therapeutic approaches. To date the treatments are based on multimodal chemotherapy and surgery. The longest survival data in patients is obtained with the combination of chemotherapy, radical surgery and radiotherapy. The development of targeted therapies offers new strategies to kill cancer cells. To be efficient, they need a precise identification of the critical targets. This objective can be reached by a deep knowledge of the molecular and physiological changes associated with the neoplastic transformation of MPM cells. One approach consists in the identification of gene mutations, epigenetic alterations, study of gene expression profiles and identification of the deregulated signalling pathways in malignant cells, with the goal to select molecules or mechanisms that could kill cancer cells or abolish tumour growth. The present knowledge on the main alterations in genes and signalling pathways indicates that MPM have recurrent mutations in a limited number of tumour suppressor genes, and oncogenic mutation in the promoter of TERT. A number of studies have emphasized the role of receptor tyrosine kinase (RTK) driven signalling, although not related to mutations in RTK. Multiple signalling pathways are altered in MPM. Transcriptomic analyses permitted to classify mesotheliomas in subgroups, according to prognosis. They showed heterogeneity of MPM, not only defined by the histological subtype, but also by molecular features. So far, targeted therapy was unsuccessful, at least partly due to the heterogeneity of MPM. Moreover, the complexity stands in the interconnection between pathways, which is a challenge to choose the most critical target for an efficient therapy. This review summarizes the main alterations identified in genes and signalling pathways in MPM, the impact on therapeutics, and discusses the future of these approaches to improve MPM outcome, especially knowing molecular and physiological characteristics of MPM to define their diversity.

Genetics of Malignant Pleural Mesothelioma

Malignant pleural mesotheliomais characterised by a large range of complex genetic alterations and peculiarof this disease. The mesothelioma genome contains extensive copy number alterations and aneuploidy which may correlate with response to treatment and survival. The genetics of mesothelioma has increased considerably over the last decade with major advances in whole genome and next generation sequencing. The knowledge of the genomics of mesothelioma is essential for identifying new, effective personalised therapeutic approaches therapies for improving clinical outcomes in patients with mesothelioma.

Virus Oncogenesis of Malignant Pleural Mesothelioma

Simian Vacuolating Virus 40 (SV40) was isolated in 1960 from polio vaccines contaminated during the manufacturing process. SV40 is able to induce tumors in animals and is causally associated with human malignant mesothelioma, lymphoma, and bone and brain tumors. SV40 is a co-factor for malignant mesothelioma development in hamsters and mice exposed to asbestos, based on different mechanisms. In addition, SV40 cooperates with asbestos and possibly other mineral fibers, leading to in vitro transformation of primary human mesothelial cells (HM). SV40 induces transformation of HM, rather than cell lysis as occurs in other human cell types, due to the transcription of antisense RNA repressing late viral gene expression. The mechanism of SV40 carcinogenesis relies on the activity of the two SV40 early proteins, large T antigen (Tag) and small t antigen (tag). In SV40-infected mesothelial cells, Tag binds p53 and the resulting complex associates with retinoblastoma protein (Rb), p300, p400 and CREB-binding protein (CBP). This larger complex establishes a potent transcriptional regulator, able to induce IGF-1, Met and Notch-1 expression and the associated downstream signaling pathways. The induction of calretinin expression is also a part of Tag activity in host cells. The interaction of Tag with other binding partners suggests additional mechanisms of interference with cell cycle or survival of the host infected cells.

Environmental Non-Asbestos Related Causes of Malignant Pleural Mesothelioma

Of the ~400 fibrous minerals that are present in the natural environment, only six were commercially used and regulated under the term “asbestos”. The carcinogenicity of asbestos minerals has been largely demonstrated. Properties associated with mineral fiber toxicity include structure, length/diameter ratio, surface area, and bio-persistence. Unregulated mineral fibers that share similar properties are known or suspected of causing similar hazards to asbestos, and specifically malignant pleural mesothelioma (MPM). For example the fibrous serpentine antigorite in material used to pave roads has been correlated to high MPM rates in New Caledonia. Erionite fibers present in material used for construction has been associated with a MPM epidemic in Central Turkey, and was more potent than asbestos in causing disease in animal experiments. The asbestiform amphiboles winchite and richterite in the vermiculite mined in Libby, Montana, USA, caused an epidemic of asbestos-related disease in workers and the local population. Potential geological sources of fibrous minerals are numerous; they represent a hazard when soil erosion and/or human activities disperse the fibers in places where they may be in contact with population. Environmental exposure to these carcinogens is increasing due to the development of population and human activities in rural areas; geological and environmental investigations should be carried out before any mining, road-making and other dust-producing activities in order to prevent from possible exposure to carcinogenic mineral fibers.

Asbestos and Malignant Pleural Mesothelioma

There is strong scientific evidence demonstrating that exposure to airborne asbestos fibres is considered to be the single major cause of malignant pleural mesothelioma (MPM). There are different aetiological explanations for MPM that remain controversial or unresolved including the role of biological gender differences, genetic risk, as well as the association between maternal asbestos exposure and subsequent mesothelioma in children. Nevertheless, MPM is an important epidemiological marker of asbestos exposure through which it is possible to track a country’s current and prior asbestos consumption and current or future patterns of asbestos-related disease. Quantifying the association between population-level asbestos consumption and MPM disease trends is an important yet challenging task as the morbid effects of asbestos use remain hidden for several decades. This is due to the long latency period between first asbestos exposure and a diagnosis of MPM, with this latency period ranging between 20 and 50 years. There have been significant shifts in global asbestos consumption with the most striking change occurring in the geographical regions in which asbestos is being used. The Asian region has become by far the largest asbestos consumer today. The deleterious human health, social, economic and environmental impacts of asbestos-related disease are preventable. Implementing a universal ban on asbestos and organising comprehensive occupational health and safety programmes are top priorities.

Epidemiology of Malignant Pleural Mesothelioma in Africa

Although asbestos was produced and consumed by many African countries throughout most of the 20^th century, the only producers of significant amounts were South Africa, Swaziland and Zimbabwe. South Africa mined all three types of commercially viable asbestos, viz. chrysotile, amosite and crocidolite, while the latter two countries mined only chrysotile. South Africa was the global leader in the production of crocidolite asbestos, the fibre most strongly linked with the development of mesothelioma; and it was in this country that the link was first established and reported in 1960. While sporadic case reports of mesothelioma have been published from the continent, they are few and far between, and the only epidemiological studies have been conducted in South Africa, showing that mesothelioma rates in the country are amongst the highest in the world. The disease burden did not dissipate with the closure of the crocidolite and amosite mines in the 1990s. South Africa has a legacy of asbestos contamination in the form of mine tailings dumps and asbestos-containing building materials and other products. As fibre, including South African crocidolite and amosite, was widely exported from the three major asbestos-producing African countries to the rest of Africa, so was the risk of mesothelioma. We can expect many more people to suffer from this debilitating disease in future years.

Epidemiology of Malignant Pleural Mesothelioma in Australia

Australia has one of the highest rates of mesothelioma in the world. The burden will continue for many years with an increasing number of subjects at risk of the disease. Earlier detection of the neoplasm may favor a better treatment of the disease. Therefore, development of early markers of disease progression will be useful in better screening or early detection in high-risk groups. However, continued vigilance and awareness of asbestos-induced risks need be maintained.

Epidemiology of Malignant Pleural Mesothelioma in Japan and South Korea

The increasing recognition of serious asbestos exposure-induced health issues resulted in the decline and eventual ban of asbestos use in most developed countries. However, the history of asbestos use in East Asian countries is quite different, Japan and South Korea completely banned all forms of asbestos in 2006 and 2009, respectively. In Japan, mesothelioma mortality was low until the early 1990s, with fewer than 200 reported deaths in 1991. The 10th Revision of the International Classification of Diseases, which introduced the category of “malignant mesothelioma,” was adopted in Japan in 1995. Since then, the annual number of deaths from mesothelioma in Japan has been reported. Out of 6030 cases in death certificate in Japan(2003-2008), 929 were pathologically reconfirmed to be mesothelioma; the affected areas were the pleura (85.5%), peritoneum (13.2%), pericardium (0.8%), and tunica vaginalis testis (0.5%). A total of 399 mesothelioma cases were reported in South Korea from 2001 to 2010, revealing a relatively larger proportion of female patients (33.8%). The relatively large proportion of mesothelioma in women in South Korea is likely due to the large proportion of mesothelioma cases in women working in asbestos textile factories in the 1970s–1980s. In summary, the incidence of malignant mesothelioma in Japan and South Korea is rising sharply, and the incidence of mesothelioma is expected to increase dramatically and peak in the near future.

Epidemiology of Malignant Pleural Mesothelioma in the Americas

Mesothelioma mortality statistics, and to a lesser extent incidence, are reliable for Canada and the United States only over the last two decades. Difficulties still exist, and in the rest of the Americas available statistics are not reliable. A brief history of the recognition, diagnosis, and development of knowledge about mesothelioma in North America is presented. Cohort studies important to mesothelioma epidemiology are discussed, with particular emphasis on Quebec miners and millers, textile workers in the Carolinas, and asbestos insulators in the United States. These studies are highly influential in current risk assessments for asbestos-related disease. Finally, there is a country-by-country selected epidemiological and related investigations of mesothelioma in the countries of North and South America. These emphasize new observations of apparent lack of compensation for registered cases in Canada, and studies of regulatory and public health importance in the United States. Although little work has been published from Latin American countries, some observations of interest include those related to asbestos mining and cement manufacture in Brazil, crocidolite exploitation in Bolivia and the recent identification of naturally occurring erionite causing disease in one locality in Mexico.

Epidemiology of Malignant Pleural Mesothelioma in Europe

Asbestos has been used extensively in Europe for well over 100 years and annual mesothelioma mortality is still increasing. However, the rapid decline in usage led to a substantial reduction in exposures in European worker populations. This effect can be seen in declining death rates in younger age groups in most countries. Projections suggest that peaks will typically occur over the next decade. Although asbestos is now banned in European Union member states, some countries in the east of Europe continue to produce and consume asbestos in large quantities. Even within the EU, however, much asbestos remains in place in older buildings and strict control of abatement work will be required.

Natural History of Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleural surfaces which is most closely linked to asbestos exposure. The prognosis of MPM is poor; morbidity and mortality results primarily by local extension or invasion of adjacent structures and less commonly by distant metastasis. Death typically results from extensive local involvement from primary lesions due to respiratory failure or infection. Involvement of the heart or of the abdominal viscera may also contribute to mortality. The best-known and commonly used clinical prognostic scoring systems for MPM are based on work performed by European Organization for Research and Treatment of Cancer and Cancer and Leukemia Group B which incorporate a combination of biologic and clinical factors. This chapter will provide an overview of the presenting symptoms and signs, prognostic factors and outcomes of MPM.

History of Malignant Pleural Mesothelioma

Scholars differ about the date when mesothelioma was discovered as a discrete disease. There is dispute also about when a causal association between mesothelioma and exposure to asbestos dust was established. On balance it appears that the 1960s was the crucial decade in both respects. This was long after asbestos became a mineral of commercial significance in the 1870s. It was also long after the unequivocal discovery, in 1930, that inhalation of asbestos dust could cause the fatal disease of asbestosis. Suggestions of an association between asbestos and mesothelioma emerged in South Africa in the 1950s and by the mid-1960s a causal connection was widely accepted. Protective measures were put in place in the United Kingdom, USA and elsewhere. From the 1970s regulations were progressively tightened. Partial or total bans were enacted and in the west asbestos use declined markedly. But for various reasons mesothelioma remained a significant killer. In America, but not Europe, the peak of the epidemic may have passed in the 1990s. The position is very different in those parts of the world where asbestos is still mined and used but lack of data renders calculation and prediction impossible. Finally, it is noted that mesothelioma may occur in individuals with no exposure to asbestos.