Equitable inclusion of diverse populations in oncology clinical trials: deterrents and drivers.

The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.

Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets.

Cancers of the lung and pleura remain a major cause of cancer deaths, both in men and women, with strong causal relationships between cigarette smoking and asbestos fibres, and deaths from lung cancer and mesothelioma, respectively. The poor survival rates for small cell lung cancer and mesotheliomas argue powerfully for greater understanding of mechanisms of carcinogenesis, genetic abnormalities and the role of tumour suppressor genes and proteins in carcinomas of the lung and pleura. Despite progress in the development of newer cytotoxic drugs, lung cancer remains a lethal disease. Chemotherapy and radiotherapy produce only a modest improvement in survival of patients with advanced disease. Increased knowledge of molecular mechanisms of lung cancer and apoptosis are providing opportunities for treating lung cancer with new classes of molecularly targeted drugs. These novel therapies should target the abnormalities in lung cancer by maximizing the effects of anti-tumour molecules, with minimal side effects on normal tissues. Of the several molecular targets, those receiving attention are p53 gene replacement, Bcl-2 downregulation, apoptosis by induced by TNF, the FAS/CD95 receptor system and TRAIL, and inhibition of NF-kappaB. Although several studies have shown benefits, there is a need for well planned clinical trials of drugs that target the apoptotic cascade. Stem cell therapy and gene replacement offer the prospect of novel approaches that are likely in the near future to play a definitive role in the treatment of advanced lung cancer. Furthermore, with their apparent minimal toxicity to normal tissues, the newer molecular targets represent attractive investigational directions for innovative cancer therapies.

Upregulation of tissue kallikrein, kinin B1 receptor, and kinin B2 receptor in mast and giant cells infiltrating oesophageal squamous cell carcinoma.

BACKGROUND: The mitogenic kinin peptides formed by the serine protease, tissue kallikrein (TK1), stimulate the proliferation of tumour cells and, by increasing vascular permeability, enhance metastasis. Oesophageal mucosal epithelial cells are derived from the epithelial cell germ layer, which expresses the kallikrein-kinin cascade. AIM: To determine the cellular distribution of active TK1, prokallikrein, and the kinin B(1) and B(2) receptors in oesophageal carcinoma by immunocytochemistry and in situ hybridisation (ISH). METHODS: Fifty oesophageal specimens (33 biopsies and 17 resections) and 10 control specimens adjacent to tumour or normal oesophageal biopsies were studied. Specific antibodies were used to determine the cellular localisation of TK1, prokallikrein, and the kinin B(1) and B(2) receptors in normal and oesophageal specimens by standard immunohistochemical techniques. The intensity of immunolabelling was quantified by image analysis. Antisense probes for TK1 and the kinin B(1) and B(2) receptors were also used to localise mRNA. RESULTS: TK1 (active and prokallikrein) was expressed in the mucosa of normal and tumour oesophageal epithelium. In general, expression was highest in activated mast cells, followed by giant tumour cells. Immunolabelling results were confirmed by ISH experiments. CONCLUSIONS: This is the first demonstration that TK1 and kinin B(1) and B(2) receptors are expressed in oesophageal carcinoma. Because TK1 released from tumour cells enzymatically generates mitogenic kinins from its endogenous substrate, kininogen, it is possible that third generation kinin receptor antagonists, which have been shown to be cytotoxic to cancer cells, may be useful therapeutic agents in this disease.

The molecular mechanisms of oesophageal cancer.

Apoptosis is a process of programmed cell death, which is as essential as cell growth, for the maintenance of homeostasis. When these processes loose integration such as cancer, then uncontrolled cell growth occurs. Cancer of the oesophagus ranks as the ninth most common malignancy in the world, and recent evidence shows that its incidence is increasing. Prognosis of this disease is poor, with an overall 5-year survival rate of less than 10%. Unraveling the mechanisms or developing animal models for oesophageal carcinoma have thus far not been successful. It is believed that oesophageal cancer has an intricate molecular mechanism of evading apoptosis by the down-regulation of Bax, up-regulation of Bcl-2, Bcl-xl and Survivin, mutation of p53 and alteration in Fas expression. A great deal of research has been performed in order to determine the key genes that initiate and promote the growth of oesophageal cancer. This review focuses on apoptosis and candidate genes linked to the development of oesophageal cancer, which it is hoped may provide diagnostic and therapeutic tools, and potential therapeutic strategies for the management of this carcinoma.

Kallikrein and kinin receptor expression in inflammation and cancer.

The kallikrein family of serine proteases has been investigated in many inflammatory disorders as molecular mapping, gene characterisation and cloning of kinin receptor genes have unfolded experimentally. In the molecular events of the inflammatory response the kallikrein cascade plays a significant role, since it is considered to initiate and maintain systemic inflammatory responses and immune-modulated disorders. A primary event is the chemotactic attraction of neutrophils which deliver the kallikrein-kinin cascade to sites of cellular injury and carcinogenic transformation of cells. The present study establishes the casual involvement of the kallikrein cascade in infection, inflammatory joint disease, acute transplant rejection, renal glomerular diseases, angiogenesis and carcinoma. We provide strong evidence for new or enhanced expression of kinin B1 receptors in inflammation, and additionally the induction of kallikrein genes in angiogenesis and carcinoma. The results provide insights into possible roles of kallikrein inhibitors and kinin receptor antagonists.

Visualisation of tissue kallikrein and kinin receptors in oesophageal carcinoma.

Gene expression of tissue kallikrein (TK) and the subsequent formation of kinins may stimulate proliferation of tumour cells by increasing vascular permeability, and enhancing metastasis. Our study was undertaken to immunolocalise TK and B2 receptor in specimens of oesophageal carcinoma immediately following oesophagectomy. The diagnosis and grading of oesophageal carcinoma was performed histologically. For localisation of TK, tissue prokallikrein (T proK) and the kinin receptors, slide-mounted tissue sections were subjected to peroxidase-antiperoxidase method and immunofluorescent staining using primary antibodies raised against each antigen. TK was immunolocalised in giant cells of both well and poorly differentiated squamous cell carcinomas (SCCs). The precursor of the enzyme, T proK, was also immunolocalised. The most intense tissue-prokallikrein labelling was observed in giant tumour cells. Kinin receptors were immunolocalised in giant tumour cells, and the mature squamous cells. These findings suggests that TK, tissue-prokallikrein and kinin receptors are present in oesophageal carcinoma, and may be important in the process of tumourogenesis in this disease.