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Naqvi N, Ahuja Y, Zarin S, Alam A, Ali W, Shariq M, Hasnain SE, Ehtesham NZ. BCG's role in strengthening immune responses: Implications for tuberculosis and comorbid diseases. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2025; 127:105703. [PMID: 39667418 DOI: 10.1016/j.meegid.2024.105703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 10/20/2024] [Accepted: 12/06/2024] [Indexed: 12/14/2024]
Abstract
The BCG vaccine represents a significant milestone in the prevention of tuberculosis (TB), particularly in children. Researchers have been developing recombinant BCG (rBCG) variants that can trigger lasting memory responses, thereby enhancing protection against TB in adults. The breakdown of immune surveillance is a key link between TB and other communicable and non-communicable diseases. Notably, TB is more prevalent among people with comorbidities such as HIV, diabetes, cancer, influenza, COVID-19, and autoimmune disorders. rBCG formulations have the potential to address both TB and HIV co-pandemics. TB increases the risk of lung cancer and immunosuppression caused by cancer can reactivate latent TB infections. Moreover, BCG's efficacy extends to bladder cancer treatment and blood glucose regulation in patients with diabetes and TB. Additionally, BCG provides cross-protection against unrelated pathogens, emphasizing the importance of BCG-induced trained immunity in COVID-19 and other respiratory diseases. Furthermore, BCG reduced the severity of pulmonary TB-induced influenza virus infections. Recent studies have proposed innovations in BCG delivery, revaccination, and attenuation techniques. Disease-centered research has highlighted the immunomodulatory effects of BCG on TB, HIV, cancer, diabetes, COVID-19, and autoimmune diseases. The complex relationship between TB and comorbidities requires a nuanced re-evaluation to understand the shared attributes regulated by BCG. This review assessed the interconnected relationships influenced by BCG administration in TB and related disorders, recommending the expanded use of rBCG in healthcare. Collaboration among vaccine research stakeholders is vital to enhance BCG's efficacy against global health challenges.
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Affiliation(s)
- Nilofer Naqvi
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India
| | - Yashika Ahuja
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India
| | - Sheeba Zarin
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India
| | - Anwar Alam
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India
| | - Waseem Ali
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India
| | - Mohd Shariq
- GITAM School of Science, GITAM University, Rudraram, Hyderabad Campus, Telangana 502329, India
| | - Seyed E Hasnain
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India; Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi (IIT-D), Hauz Khas, New Delhi 110 016, India..
| | - Nasreen Z Ehtesham
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India.
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Mowday AM, van de Laak JM, Fu Z, Henare KL, Dubois L, Lambin P, Theys J, Patterson AV. Tumor-targeting bacteria as immune stimulants - the future of cancer immunotherapy? Crit Rev Microbiol 2024; 50:955-970. [PMID: 38346140 PMCID: PMC11523919 DOI: 10.1080/1040841x.2024.2311653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 01/11/2024] [Accepted: 01/24/2024] [Indexed: 03/22/2024]
Abstract
Cancer immunotherapies have been widely hailed as a breakthrough for cancer treatment in the last decade, epitomized by the unprecedented results observed with checkpoint blockade. Even so, only a minority of patients currently achieve durable remissions. In general, responsive patients appear to have either a high number of tumor neoantigens, a preexisting immune cell infiltrate in the tumor microenvironment, or an 'immune-active' transcriptional profile, determined in part by the presence of a type I interferon gene signature. These observations suggest that the therapeutic efficacy of immunotherapy can be enhanced through strategies that release tumor neoantigens and/or produce a pro-inflammatory tumor microenvironment. In principle, exogenous tumor-targeting bacteria offer a unique solution for improving responsiveness to immunotherapy. This review discusses how tumor-selective bacterial infection can modulate the immunological microenvironment of the tumor and the potential for combination with cancer immunotherapy strategies to further increase therapeutic efficacy. In addition, we provide a perspective on the clinical translation of replicating bacterial therapies, with a focus on the challenges that must be resolved to ensure a successful outcome.
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Affiliation(s)
- Alexandra M. Mowday
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Jella M. van de Laak
- The M-Lab, Department of Precision Medicine, GROW—Research School of Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
| | - Zhe Fu
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Kimiora L. Henare
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Ludwig Dubois
- The M-Lab, Department of Precision Medicine, GROW—Research School of Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
| | - Philippe Lambin
- The M-Lab, Department of Precision Medicine, GROW—Research School of Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
| | - Jan Theys
- The M-Lab, Department of Precision Medicine, GROW—Research School of Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
| | - Adam V. Patterson
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
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Doroud D, Hozouri H. Role of Intravesical BCG as a Therapeutic Vaccine for Treatment of Bladder Carcinoma. IRANIAN BIOMEDICAL JOURNAL 2022; 26:340-9. [PMID: 36369747 PMCID: PMC9763876 DOI: 10.52547/ibj.3676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/08/2022] [Indexed: 12/12/2022]
Abstract
Bacterial products have attracted much attention as potential antitumor agents, with the ability to provide direct tumoricidal effects, leading to the inhibition of tumor growth. Treatment of superficial bladder cancer with intravesical Bacillus Calmette-Guérin (BCG) has a more reduction potential than surgery in tumor recurrence rate. BCG, the gold standard for nonmuscle invasive bladder cancer, is manufactured from different strains and produced commercially with varied strengths. There are a few countries known as the manufacturer of this strategic biopharmaceutical product, and Iran as a member of the Eastern Mediterranean Region plays a vital role in supplying this vaccine. Studies have failed to uncover the exact mechanism of action of the intravesical; however, evidence points toward an immunogenic mechanism that proficiently modifies a biologic response and provokes the immune cells in order to kill and suppress tumors. Among various underlying mechanisms, BCG bacillus attachment to fibronectin through its fibronectin attachment protein is a pivotal mechanism for BCG tumoricidal activity.
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Affiliation(s)
- Delaram Doroud
- Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran
| | - Hamidreza Hozouri
- Department of Quality Management, Pasteur Institute of Iran, Tehran, Iran
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Brown M. Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity. Cancer Treat Res 2022; 183:91-129. [PMID: 35551657 DOI: 10.1007/978-3-030-96376-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Malignant tumors frequently exploit innate immunity to evade immune surveillance. The priming, function, and polarization of antitumor immunity fundamentally depends upon context provided by the innate immune system, particularly antigen presenting cells. Such context is determined in large part by sensing of pathogen specific and damage associated features by pathogen recognition receptors (PRRs). PRR activation induces the delivery of T cell priming cues (e.g. chemokines, co-stimulatory ligands, and cytokines) from antigen presenting cells, playing a decisive role in the cancer immunity cycle. Indeed, endogenous PRR activation within the tumor microenvironment (TME) has been shown to generate spontaneous antitumor T cell immunity, e.g., cGAS-STING mediated activation of antigen presenting cells after release of DNA from dying tumor cells. Thus, instigating intratumor PRR activation, particularly with the goal of generating Th1-promoting inflammation that stokes endogenous priming of antitumor CD8+ T cells, is a growing area of clinical investigation. This approach is analogous to in situ vaccination, ultimately providing a personalized antitumor response against relevant tumor associated antigens. Here I discuss clinical stage intratumor modalities that function via activation of PRRs. These approaches are being tested in various solid tumor contexts including melanoma, colorectal cancer, glioblastoma, head and neck squamous cell carcinoma, bladder cancer, and pancreatic cancer. Their mechanism (s) of action relative to other immunotherapy approaches (e.g., antigen-defined cancer vaccines, CAR T cells, dendritic cell vaccines, and immune checkpoint blockade), as well as their potential to complement these approaches are also discussed. Examples to be reviewed include TLR agonists, STING agonists, RIG-I agonists, and attenuated or engineered viruses and bacterium. I also review common key requirements for effective in situ immune activation, discuss differences between various strategies inclusive of mechanisms that may ultimately limit or preclude antitumor efficacy, and provide a summary of relevant clinical data.
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Affiliation(s)
- Michael Brown
- Department of Neurosurgery, Duke University, Durham, NC, USA.
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Jain M, Vadboncoeur J, Garg SJ, Biswas J. Bacille Calmette-Guérin: An ophthalmic perspective. Surv Ophthalmol 2022; 67:307-320. [PMID: 34343536 PMCID: PMC8325561 DOI: 10.1016/j.survophthal.2021.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 01/20/2023]
Abstract
Vaccines such as bacille Calmette-Guérin (BCG) are known for their heterologous effects mediated through a number of mechanisms, including trained immunity constituted by monocyte-macrophage based innate immunity. Other events such as direct hematogenous spread and induction of autoimmunity are also described. There has been a resurgent interest in harnessing some of the benefits of trained immunity in the management of COVID-19, even as several specific vaccines have been approved. We summarize the current knowledge of ocular effects of BCG. Potential effect of granulomatous inflammation on angiotensin converting enzyme activity and accentuation of cytokine storm that may result in undesirable ocular and systemic effects are also discussed.
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Affiliation(s)
- Manish Jain
- Himalayan Institute of Medical Sciences, Jolly Grant, Dehradun, UK, India
| | - Julie Vadboncoeur
- Department of Ophthalmology, Université de Montréal, Montréal, Uveitis Service, University Ophthalmology Center, Maisonneuve-Rosemont Hospital, Montréal, Canada
| | - Sunir J Garg
- Thomas Jefferson University, Philadelphia, PA USA
| | - Jyotirmay Biswas
- Director of Uveitis & Ocular Pathology Department, Sankara Nethralaya, Chennai, TN, India
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Sekar P, Ravitchandirane R, Khanam S, Muniraj N, Cassinadane AV. Novel molecules as the emerging trends in cancer treatment: an update. Med Oncol 2022; 39:20. [PMID: 34982273 DOI: 10.1007/s12032-021-01615-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/19/2021] [Indexed: 12/15/2022]
Abstract
As per World Health Organization cancer remains as a leading killer disease causing nearly 10 million deaths in 2020. Since the burden of cancer increases worldwide, warranting an urgent search for anti-cancer compounds from natural sources. Secondary metabolites from plants, marine organisms exhibit a novel chemical and structural diversity holding a great promise as therapeutics in cancer treatment. These natural metabolites target only the cancer cells and the normal healthy cells are left unharmed. In the emerging trends of cancer treatment, the natural bioactive compounds have long become a part of cancer chemotherapy. In this review, we have tried to compile about eight bioactive compounds from plant origin viz. combretastatin, ginsenoside, lycopene, quercetin, resveratrol, silymarin, sulforaphane and withaferin A, four marine-derived compounds viz. bryostatins, dolastatins, eribulin, plitidepsin and three microorganisms viz. Clostridium, Mycobacterium bovis and Streptococcus pyogenes with their well-established anticancer potential, mechanism of action and clinical establishments are presented.
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Affiliation(s)
- Priyanka Sekar
- Sri Venkateshwaraa Medical College Hospital and Research Centre, Pondicherry, 605102, India
| | | | - Sofia Khanam
- Calcutta Institute of Pharmaceutical Technology and Allied Health Sciences, Howrah, WB, 711316, India
| | - Nethaji Muniraj
- Centre for Cancer Immunology Research, Children's National Hospital, Children's National Research Institute, 111 Michigan Ave NW, Washington, D.C, 20010, USA.
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Unsworth-White SR, Kitchen MO, Bryan RT. Immunotherapy for non-muscle-invasive bladder cancer: from the origins of BCG to novel therapies. Future Oncol 2021; 18:105-115. [PMID: 34763531 DOI: 10.2217/fon-2021-0781] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Supplies of intravesical Bacillus Calmette-Guérin (BCG), the first-line treatment for most intermediate- and high-risk non-muscle-invasive bladder cancers (NMIBC), have proven unreliable over the past decade. This review considers the evolution of BCG immunotherapy for NMIBC: from the discovery of the antitumour side effects of tuberculosis and subsequently the BCG vaccine, to recent advances in novel immunotherapeutic agents. We summarize the evidence for alternative options to standard intravesical BCG therapy regimens and describe the potential for immune response manipulating drugs in the treatment of NMIBC. These new agents, including immune checkpoint inhibitors, toll-like receptor agonists and recombinant viral vectors, may provide better options in the management of NMIBC in the future.
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Affiliation(s)
- Samantha R Unsworth-White
- Bladder Cancer Research Centre, Institute of Cancer & Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, UK
| | - Mark O Kitchen
- School of Medicine, Keele, UK.,Urology Department, University Hospitals of North Midlands NHS Trust, UK
| | - Richard T Bryan
- Bladder Cancer Research Centre, Institute of Cancer & Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, UK
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Yang Z, Xu Y, Bi Y, Zhang N, Wang H, Xing T, Bai S, Shen Z, Naz F, Zhang Z, Yin L, Shi M, Wang L, Wang L, Wang S, Xu L, Su X, Wu S, Yu C. Immune escape mechanisms and immunotherapy of urothelial bladder cancer. J Clin Transl Res 2021; 7:485-500. [PMID: 34541363 PMCID: PMC8445627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 05/12/2021] [Accepted: 06/25/2021] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND AND AIM Urothelial bladder cancer (UBC) is a common malignant tumor of the urogenital system with a high rate of recurrence. Due to the sophisticated and largely unexplored mechanisms of tumorigenesis of UBC, the classical therapeutic approaches including transurethral resection and radical cystectomy combined with chemotherapy have remained unchanged for decades. However, with increasingly in-depth understanding of the microenvironment and the composition of tumor-infiltrating lymphocytes of UBC, novel immunotherapeutic strategies have been developed. Bacillus Calmette-Guerin (BCG) therapy, immune checkpoint blockades, adoptive T cell immunotherapy, dendritic cell (DC) vaccines, etc., have all been intensively investigated as immunotherapies for UBC. This review will discuss the recent progress in immune escape mechanisms and immunotherapy of UBC. METHODS Based on a comprehensive search of the PubMed and ClinicalTrials.gov database, this review included the literature reporting the immune escape mechanisms of UBC and clinical trials assessing the effect of immunotherapeutic strategies on tumor or immune cells in UBC patients published in English between 1999 and 2020. RESULTS Immune surveillance, immune balance, and immune escape are the three major processes that occur during UBC tumorigenesis. First, the role of immunosuppressive cells, immunosuppressive molecules, immunosuppressive signaling molecules, and DCs in tumor microenvironment is introduced elaborately in the immune escape mechanisms of UBC section. In addition, recent progress of immunotherapies including BCG, checkpoint inhibitors, cytokines, adoptive T cell immunotherapy, DCs, and macrophages on UBC patients are summarized in detail. Finally, the need to explore the mechanisms, molecular characteristics and immune landscape during UBC tumorigenesis and development of novel and robust immunotherapies for UBC are also proposed and discussed. CONCLUSION At present, BCG and immune checkpoint blockades have been approved by the US Food and Drug Administration for the treatment of UBC patients and have achieved encouraging therapeutic results, expanding the traditional chemotherapy and surgery-based treatment for UBC. RELEVANCE FOR PATIENTS Immunotherapy has achieved desirable results in the treatment of UBC, which not only improve the overall survival but also reduce the recurrence rate and the occurrence of treatment-related adverse events of UBC patients. In addition, the indicators to predict the effectiveness and novel therapy strategies, such as combination regimen of checkpoint inhibitor with checkpoint inhibitor or chemotherapy, should be further studied.
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Affiliation(s)
- Zhao Yang
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China,2Department of Bioscience, College of Life Science, Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin of Xinjiang Production and Construction Corps, Tarim University, Alar 843300, Xinjiang, China,
Corresponding authors: Zhao Yang College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.College of Life Science, Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin of Xinjiang Production and Construction Corps, Tarim University, Alar 843300, Xinjiang, China. E-mail:
| | - Yinyan Xu
- 3Department of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China
| | - Ying Bi
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Nan Zhang
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Haifeng Wang
- 4Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China
| | - Tianying Xing
- 5Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Suhang Bai
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Zongyi Shen
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Faiza Naz
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Zichen Zhang
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Liqi Yin
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Mengran Shi
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Luyao Wang
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Lei Wang
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Shihui Wang
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Lida Xu
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Xin Su
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Song Wu
- 3Department of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China,
Song Wu Department of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China.
| | - Changyuan Yu
- 1Department of Biomedical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China,
Changyuan Yu College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
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Adesanya OA, Uche-Orji CI, Adedeji YA, Joshua JI, Adesola AA, Chukwudike CJ. Bacillus Calmette-Guerin (BCG): the adroit vaccine. AIMS Microbiol 2021; 7:96-113. [PMID: 33659771 PMCID: PMC7921379 DOI: 10.3934/microbiol.2021007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 01/31/2021] [Indexed: 12/27/2022] Open
Abstract
Background The Bacillus Calmette-Guerin (BCG) vaccine has been in use for 99 years, and is regarded as one of the oldest human vaccines known today. It is recommended primarily due to its effect in preventing the most severe forms of tuberculosis, including disseminated tuberculosis and meningeal tuberculosis in children; however, its efficacy in preventing pulmonary tuberculosis and TB reactivation in adults has been questioned. Several studies however have found that asides from its role in tuberculosis prevention, the BCG vaccine also has protective effects against a host of other viral infections in humans, an effect which has been termed: heterologous, non-specific or off-target. Objectives As we approach 100 years since the discovery of the BCG vaccine, we review the evidence of the non-specific protection offered by the vaccine against viral infections, discuss the possible mechanisms of action of these effects, highlight the implications these effects could have on vaccinology and summarize the recent epidemiological correlation between the vaccine and the on-going COVID-19 pandemic. Results Several epidemiological studies have established that BCG does reduce all-cause mortality in infants, and also the time of vaccination influences this effect significantly. This effect has been attributed to the protective effect of the vaccine in preventing unrelated viral infections during the neonatal period. Some of such viral infections that have been investigated include: herpes simplex virus (HSV), human Papilloma virus (HPV), yellow fever virus (YFV), respiratory syncytial virus (RSV) and influenza virus type A (H1N1). These effects are thought to be mediated via induction of innate immune memory as well as heterologous lymphocytic activation. While epidemiological studies have suggested a correlation, the potential protection of the BCG vaccine against COVID-19 transmission and mortality rates is currently unclear. Ongoing clinical trials and further research may shed more light on the subject in the future. Conclusion BCG is a multifaceted vaccine, with many numerous potential applications to vaccination strategies being employed for current and future viral infections. There however is a need for further studies into the immunologic mechanisms behind these non-specific effects, for these potentials to become reality, as we usher in the beginning of the second century since the vaccine's discovery.
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Affiliation(s)
- Oluwafolajimi A Adesanya
- Institute for Advanced Medical Research and Training (IAMRAT), College of Medicine, University of Ibadan, Ibadan, Nigeria.,Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Yeshua A Adedeji
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - John I Joshua
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Adeniyi A Adesola
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
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Breban R, Bisiaux A, Biot C, Rentsch C, Bousso P, Albert ML. Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response. Oncoimmunology 2021; 1:9-17. [PMID: 22720207 DOI: 10.4161/onci.1.1.17884] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Treatment for non-muscle invasive carcinoma of the bladder represents one of the few examples of successful tumor immunity. Six weekly intravesical instillations of Bacillus Calmette-Guerin (BCG), often followed by maintenance schedule, result in up to 50-70% clinical response. Current models suggest that the mechanism of action involves the non-specific activation of innate effector cells, which may be capable of acting in the absence of an antigen-specific response. For example, recent evidence suggests that BCG-activated neutrophils possess anti-tumor potential. Moreover, weekly BCG treatment results in a prime-boost pattern with massive influx of innate immune cells (107-108 PMN/ml urine). Calibrating in vivo data, we estimate that the number of neutrophil degranulations per instillation is approximately 106-107, more than sufficient to potentially eliminate ~106 residual tumor cells. Furthermore, neutrophils, as well as other innate effector cells are not selective in their targeting-thus surrounding cells may be influenced by degranulation and / or cytokine production. To establish if these observed conditions could account for clinically effective tumor immunity, we built a mathematical model reflecting the early events and tissue conditioning in patients undergoing BCG therapy. The model incorporates key features of tumor growth, BCG instillations and the observed prime / boost pattern of the innate immune response. Model calibration established that each innate effector cell must kill 90-95 bystander cells for achieving the expected 50-70% clinical response. This prediction was evaluated both empirically and experimentally and found to vastly exceed the capacity of the innate immune system. We therefore conclude that the innate immune system alone is unable to eliminate the tumor cells. We infer that other aspects of the immune response (e.g., antigen-specific lymphocytes) decisively contribute to the success of BCG immunotherapy.
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Affiliation(s)
- Romulus Breban
- Institut Pasteur; Unité d'Epidémiologie des Maladies Emergentes; Paris, France
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11
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Adesanya OA, Uche-Orji CI, Adedeji YA, Joshua JI, Adesola AA, Chukwudike CJ. Expanded Scope of Bacillus Calmette-Guerin (BCG) Vaccine Applicability in Disease Prophylaxis, Diagnostics, and Immunotherapeutics. INFECTIOUS MICROBES & DISEASES 2020; 2:144-150. [PMID: 38630099 PMCID: PMC7769055 DOI: 10.1097/im9.0000000000000040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/02/2020] [Accepted: 10/06/2020] [Indexed: 11/29/2022]
Abstract
Following the discovery of the Bacillus Calmette-Guerin (BCG) vaccine, its efficacy against Mycobacterium tuberculosis was soon established, with several countries adopting universal BCG vaccination schemes for their populations. Soon, however, studies aimed to further establish the efficacy of the vaccine in different populations discovered that the vaccine has a larger effect in reducing mortality rate than could be explained by its effect on tuberculosis alone, which sparked suggestions that the BCG vaccine could have effects on other unrelated or non-mycobacterial pathogens causing diseases in humans. These effects were termed heterologous, non-specific or off-target effects and have been shown to be due to both innate and adaptive immune system responses. Experiments carried out in a bid to further understand these effects led to many more discoveries about the applicability of the BCG vaccine for the prevention, diagnosis, and treatment of certain disease conditions. As we approach the second century since the discovery of the vaccine, we believe it is timely to review these interesting applications of the BCG vaccine, such as in the prevention of diabetes, atherosclerosis, and leukemia; the diagnosis of Kawasaki disease; and the treatment of multiple sclerosis, non-muscle invading bladder cancer, and stage III melanoma. Furthermore, complications associated with the administration of the BCG vaccine to certain groups of patients, including those with severe combined immunodeficiency and HIV, have been well described in literature, and we conclude by describing the mechanisms behind these complications and discuss their implications on vaccination strategies, especially in low-resource settings.
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Affiliation(s)
- Oluwafolajimi A. Adesanya
- Institute for Advanced Medical Research and Training (IAMRAT), College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Yeshua A. Adedeji
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - John I. Joshua
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Adeniyi A. Adesola
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
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Ottley EC, Pell R, Brazier B, Hollidge J, Kartsonaki C, Browning L, O'Neill E, Kiltie AE. Greater utility of molecular subtype rather than epithelial-to-mesenchymal transition (EMT) markers for prognosis in high-risk non-muscle-invasive (HGT1) bladder cancer. J Pathol Clin Res 2020; 6:238-251. [PMID: 32374509 PMCID: PMC7578305 DOI: 10.1002/cjp2.167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/10/2020] [Accepted: 03/20/2020] [Indexed: 01/21/2023]
Abstract
Approximately 75% of bladder cancers are non-muscle invasive (NMIBC). Of these, up to 53% of cases progress to life-threatening muscle-invasive bladder cancer (MIBC). Patients with high-grade stage T1 (HGT1) NMIBC frequently undergo radical cystectomy (RC), although this represents overtreatment for many. Identification of progressors versus non-progressors could spare unnecessary treatment. Recent studies have confirmed that urothelial carcinoma is composed of two main molecular subtypes, basal and luminal, with 12% of basal tumours exhibiting epithelial-to-mesenchymal transition (EMT). Levels of immune cell infiltration have been shown to be subtype-specific. Here, we performed immunohistochemistry (IHC) for 11 antibodies relating to molecular subtypes or EMT in 26 cases of HGT1 urothelial carcinoma cases with 6 matched samples subsequently obtained at cystectomy (n = 6; 1 muscle-invasive, 5 non-muscle-invasive; 3 = pTis, 1 = pT1, 1 = pTa) and at recurrence (n = 2, pT2). RNAScope was also conducted in a subset. Expression patterns in HGT1 specimens versus MIBC (pT2+) were examined, and correlated with disease-specific survival (DSS). Levels of stromal tumour-infiltrating lymphocytes (sTILs) were assessed manually to determine whether lymphocyte infiltration was associated with DSS and whether differences existed between HGT1 and MIBC. Molecular subtype markers demonstrated increased prognostic potential compared to the EMT markers assessed. Increased expression of the luminal markers FOXA1 and SCUBE2, were found to be significantly associated with better DFS. No EMT markers were significantly associated with DFS. In areas of non-invasive papillary urothelial carcinoma, but not invasive carcinoma, sTIL levels were found to be significantly associated with DFS. While differences were observed between HGT1 cases that progressed versus those that did not, a larger cohort study is required for validation of these findings. Taken together, an emphasis on molecular subtype markers, rather than EMT markers, may be preferable when studying biomarkers of HGT1 urothelial carcinoma in the future.
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Affiliation(s)
- Edward C Ottley
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Robert Pell
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Benedict Brazier
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Julianne Hollidge
- Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
| | | | - Lisa Browning
- Department of Cellular Pathology, and the NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
| | - Eric O'Neill
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Anne E Kiltie
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
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Osama El-Gendy A, Saeed H, Ali AMA, Zawbaa HM, Gomaa D, Harb HS, Madney YM, Osama H, Abdelrahman MA, Abdelrahim MEA. Bacillus Calmette-Guérin vaccine, antimalarial, age and gender relation to COVID-19 spread and mortality. Vaccine 2020; 38:5564-5568. [PMID: 32654907 PMCID: PMC7332946 DOI: 10.1016/j.vaccine.2020.06.083] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 05/18/2020] [Accepted: 06/30/2020] [Indexed: 01/22/2023]
Abstract
COVID-19 is affecting different countries all over the world with great variation in infection rate and death ratio. Some reports suggested a relation between the Bacillus Calmette-Guérin (BCG) vaccine and the malaria treatment to the infection prevention. Some reports related infant's lower-susceptibility to the BCG vaccine. Some other reports a higher risk in males compared to females in such a COVI-19 pandemic. Some other reports claimed the possible use of chloroquine and hydroxychloroquine as prophylactic in such a pandemic. The-present commentary is to discuss the possible relation between those-factors and SARS-CoV-2 infection. COVID-19 is affecting different countries all over the world with great variation in infection rate and death ratio. Some reports suggested a relation between the Bacillus Calmette-Guérin (BCG) vaccine and the malaria treatment to the prevention of SARS-CoV-2 infection. Some reports related infant's lower susceptibility to the COVID-19. Some other reports a higher risk in males compared to females in such COVID-19 pandemic. Also, some other reports claimed the possible use of chloroquine and hydroxychloroquine as prophylactic in such a pandemic. The present commentary is to discuss the possible relation between those factors and SARS-CoV-2 infection.
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Affiliation(s)
- Ahmed Osama El-Gendy
- Microbiology and Immunology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Haitham Saeed
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed M A Ali
- Pharmaceutics Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; Pharmaceutics Department, Faculty of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Hossam M Zawbaa
- Faculty of Computers and Artificial Intelligence, Beni-Suef University
| | - Dina Gomaa
- Egyptian Drug authority, Cairo, Egypt; RAMEDA pharmaceuticals, Cairo, Egypt
| | - Hadeer S Harb
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Yasmin M Madney
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Hasnaa Osama
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mona A Abdelrahman
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed E A Abdelrahim
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
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14
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Vidovic D, Giacomantonio C. Insights into the Molecular Mechanisms Behind Intralesional Immunotherapies for Advanced Melanoma. Cancers (Basel) 2020; 12:cancers12051321. [PMID: 32455916 PMCID: PMC7281646 DOI: 10.3390/cancers12051321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/17/2020] [Accepted: 05/20/2020] [Indexed: 12/12/2022] Open
Abstract
The incidence of cutaneous melanoma, a highly malignant skin cancer, is increasing yearly. While surgical removal of the tumor is the mainstay of treatment for patients with locally confined disease, those with metastases face uncertainty when it comes to their treatment. As melanoma is a relatively immunogenic cancer, current guidelines suggest using immunotherapies that can rewire the host immune response to target melanoma tumor cells. Intralesional therapy, where immunomodulatory agents are injected directly into the tumor, are an emerging aspect of treatment for in-transit melanoma because of their ability to mitigate severe off-target immune-related adverse events. However, their immunomodulatory mechanisms are poorly understood. In this review, we will summarize and discuss the different intralesional therapies for metastatic melanoma with respect to their clinical outcomes and immune molecular mechanisms.
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15
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Yamazaki-Nakashimada MA, Unzueta A, Berenise Gámez-González L, González-Saldaña N, Sorensen RU. BCG: a vaccine with multiple faces. Hum Vaccin Immunother 2020; 16:1841-1850. [PMID: 31995448 DOI: 10.1080/21645515.2019.1706930] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BCG has been recommended because of its efficacy against disseminated and meningeal tuberculosis. The BCG vaccine has other mechanisms of action besides tuberculosis protection, with immunomodulatory properties that are now being discovered. Reports have shown a significant protective effect against leprosy. Randomized controlled trials suggest that BCG vaccine has beneficial heterologous (nonspecific) effects on mortality in some developing countries. BCG immunotherapy is considered the gold standard adjuvant treatment for non-muscle-invasive bladder cancer. BCG vaccine has also been tested as treatment for diabetes and multiple sclerosis. Erythema of the BCG site is recognized as a clinical clue in Kawasaki disease. BCG administration in the immunodeficient patient is associated with local BCG disease (BCGitis) or disseminated BCG disease (BCGosis) with fatal consequences. BCG administration has been associated with the development of autoimmunity. We present a brief review of the diverse facets of the vaccine, with the discovery of its new modes of action providing new perspectives on this old, multifaceted and controversial vaccine.
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Affiliation(s)
| | - Alberto Unzueta
- Gastroenterology and Transplant Hepatology, Geisinger Medical Center , Danville, PA, USA
| | | | | | - Ricardo U Sorensen
- Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Primary Immunodeficiency Network , New Orleans, LA, USA.,Faculty of Medicine, University of La Frontera , Temuco, Chile
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16
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Flores-Carbajal J, Sousa-Escandón A, Sousa-Gonzalez D, Rodriguez Gomez S, Lopez Saavedra M, Fernandez Martinez ME. Recirculating chemohyperthermia as a treatment for non-muscle invasive bladder cancer: Current and future perspectives. World J Clin Urol 2017; 6:34-39. [DOI: 10.5410/wjcu.v6.i2.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 12/19/2016] [Accepted: 03/13/2017] [Indexed: 02/05/2023] Open
Abstract
About 75% of all bladder cancer diagnosed are non-muscle invasive bladder cancer (NMIBC), recurring over 50% of them after transurethral resection of the bladder tumor. In order to prevent recurrences, adjuvant intravesical chemotherapy with mitomycin C and immunotherapy with bacillus Calmette-Guérin (BCG) is traditionally used. Unfortunately, many patients relapse after receiving these treatments and a significant proportion of them require surgery. After a one-to-three years BCG maintenance, the risk for progression at 5 years was 19.3% for T1G3 tumors. Many new treatment approaches are being investigated to increase the effectiveness of adjuvant intravesical therapy. One of the developing treatments for intermediate and high-risk NMIBC is the combination of intravesical chemotherapy and hyperthermia, called chemohyperthermia. This article provides a review of the mechanism of action, current status and indications, results and future perspectives.
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17
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Mehta K, Patel K, Parikh RA. Immunotherapy in genitourinary malignancies. J Hematol Oncol 2017; 10:95. [PMID: 28434403 PMCID: PMC5402074 DOI: 10.1186/s13045-017-0457-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 03/29/2017] [Indexed: 01/05/2023] Open
Abstract
Treatment of cancer patients involves a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Traditionally, patients with metastatic disease are treated with combination chemotherapies or targeted agents. These cytotoxic agents have good response rates and achieve palliation; however, complete responses are rarely seen. The field of cancer immunology has made rapid advances in the past 20 years. Recently, a number of agents and vaccines, which modulate the immune system to allow it to detect and target cancer cells, are being developed. The benefit of these agents is twofold, it enhances the ability the body’s own immune system to fight cancer, thus has a lower incidence of side effects compared to conventional cytotoxic chemotherapy. Secondly, a small but substantial number of patients with metastatic disease are cured by immunotherapy or achieve durable responses lasting for a number of years. In this article, we review the FDA-approved immunotherapy agents in the field of genitourinary malignancies. We also summarize new immunotherapy agents being evaluated in clinical studies either as single agents or as a combination.
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Affiliation(s)
- Kathan Mehta
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Keyur Patel
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Rahul A Parikh
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. .,University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. .,Division of Hematology/Oncology, Department of Medicine, UPMC Cancer Pavilion, 5th Floor, 5150 Centre Avenue, Pittsburgh, PA, 15232, USA.
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18
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Woldu SL, Şanli Ö, Lotan Y. Tackling non-muscle invasive bladder cancer in the clinic. Expert Rev Anticancer Ther 2017; 17:467-480. [PMID: 28359179 DOI: 10.1080/14737140.2017.1313119] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Non-muscle invasive bladder cancer (NMIBC) is a common disease process with a high propensity for recurrence and risk of progression to muscle-invasive or systemic disease. Optimal management of NMIBC depends on appropriate resection and staging, risk-based use of intravesical therapy and tailored surveillance. Current challenges include compliance with guideline recommendations and cancers which are refractory to standard therapies. Areas covered: This review summarizes the conventional management of NMIBC - which relies on strict cystoscopic surveillance and intravesical therapies with chemotherapy and/or immunotherapy in the form of bacillus Calmette-Guerin (BCG). As many patients will be resistant to conventional treatment, investigational therapies and novel prognostic models will also be discussed. Expert commentary: For decades, the management of NMIBC has been predicated on intravesical therapies, most often through the instillation of BCG which has proven clinical efficacy over transurethral resection alone. Despite this, many patients will recur or progress after BCG therapy. While radical cystectomy remains the standard for such patients, suitable alternatives are being actively investigated. An increased interest in immunotherapy for malignancy has reinvigorated this field and on-going advances in disease prognostication are likely to improve upon the existing treatment paradigms for NMIBC.
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Affiliation(s)
- Solomon L Woldu
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Öner Şanli
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA.,b Department of Urology, Istanbul Faculty of Medicine , Istanbul University , Istanbul , Turkey
| | - Yair Lotan
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
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19
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Simar J, Belkhir L, Tombal B, André E. Ruptured aortic aneurysm due to Mycobacterium bovis BCG with a delayed bacteriological diagnosis due to false negative result of the MPB 64 immunochromatographic assay. BMC Res Notes 2017; 10:64. [PMID: 28126017 PMCID: PMC5270368 DOI: 10.1186/s13104-017-2382-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 01/09/2017] [Indexed: 01/05/2023] Open
Abstract
Background Adjuvant therapy with bacillus Calmette–Guerin (BCG), a live attenuated strain of Mycobacterium bovis, has become the treatment of choice for low-risk superficial bladder carcinoma following transurethral resection of the bladder. Complications following vesical BCG instillations are uncommon but, in some cases, severe side-effects can occur such as sepsis or mycotic aneurysm. Besides usual laboratory techniques used for the diagnosis of Mycobacterium tuberculosis complex (MTBC) infections (smear microscopy and cultures), commercial immunochromatographic assays detecting MBP64, a 24 kDa M. tuberculosis complex-specific secretory protein, can rapidly distinguish MTBC and non-tuberculosis mycobacteria (NTM). MPB64 is found in M. tuberculosis, M. bovis and some but not all substrains of M.bovis BCG. Therefore, these immunochromatographic tests can lead to false negative results and delayed bacteriological diagnosis depending on the presence or absence of MPB64 protein in BCG substrains used for intravesical therapy. Case presentation We report the case of a 78-year-old male patient who was admitted to the hospital because of a 1-month history of unexplained fever, thrill, weight-loss and general malaise. His past medical history was marked by a non-muscle-invasive bladder carcinoma treated by transurethral resection followed by BCG instillations (Oncotice, Merck, USA). The patient was initially treated for a urinary tract infection but as fever persists after 72 h of antibiotherapy, urinary tract ultrasound was performed and revealed a large abdominal aortic aneurysm confirmed by computed tomography. Surgery was performed after multidisciplinary discussion. Direct smear of perioperative samples revealed acid-fast bacilli and both solid and liquid cultures were massively positive. Rapid identification of the positive mycobacterial culture was performed using an immunochromatographic assay based on the detection of the Mycobacterium tuberculosis MPB 64 antigen. The result was negative for Mycobacterium tuberculosis complex. After review of the medical record, a polymerase chain reaction (PCR) was performed and gave a positive result for M. tuberculosis complex. Anti-tuberculosis therapy was started immediately and the patient evolved favorably. Conclusions Through this case, we showed how the utilisation of MPB64 immunochromatographic assays can provide misleading information due to the variable presence of this protein among the different BCG strains. This case further illustrates the utility of rapid TB complex-specific PCR assays which provide a more reliable identification of all MTBC species.
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Affiliation(s)
- J Simar
- Microbiology Unit, Laboratory Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
| | - L Belkhir
- Infectious Diseases Unit, Department of Internal Medicine, Cliniques Universitaires Saint Luc, Brussels, Belgium
| | - B Tombal
- Urology Unit, Department of Surgery, Cliniques Universitaires Saint Luc, Brussels, Belgium
| | - E André
- Microbiology Unit, Laboratory Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium.,Pôle de Microbiologie Médicale, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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20
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21
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Chehab M, Caza T, Skotnicki K, Landas S, Bratslavsky G, Mollapour M, Bourboulia D. Targeting Hsp90 in urothelial carcinoma. Oncotarget 2015; 6:8454-73. [PMID: 25909217 PMCID: PMC4496161 DOI: 10.18632/oncotarget.3502] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review.
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MESH Headings
- Angiogenesis Inhibitors/therapeutic use
- Antineoplastic Agents/therapeutic use
- Apoptosis
- BCG Vaccine/therapeutic use
- Carcinoma, Transitional Cell/epidemiology
- Carcinoma, Transitional Cell/metabolism
- Carcinoma, Transitional Cell/pathology
- Carcinoma, Transitional Cell/therapy
- Cell Cycle/drug effects
- Cell Division
- Cell Transformation, Neoplastic
- Chemoradiotherapy
- Chemotherapy, Adjuvant
- Clinical Trials as Topic
- Combined Modality Therapy
- Cystectomy
- Drug Resistance, Neoplasm
- Drugs, Investigational/therapeutic use
- HSP90 Heat-Shock Proteins/antagonists & inhibitors
- HSP90 Heat-Shock Proteins/chemistry
- HSP90 Heat-Shock Proteins/physiology
- Histone Code/drug effects
- Humans
- Models, Biological
- Molecular Targeted Therapy
- Muscle, Smooth/pathology
- Neoplasm Invasiveness
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/physiology
- Protein Kinase Inhibitors/therapeutic use
- Signal Transduction/drug effects
- Transcription, Genetic/drug effects
- Urologic Neoplasms/epidemiology
- Urologic Neoplasms/metabolism
- Urologic Neoplasms/pathology
- Urologic Neoplasms/therapy
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Affiliation(s)
- Mahmoud Chehab
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Tiffany Caza
- Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Kamil Skotnicki
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Steve Landas
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Gennady Bratslavsky
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Mehdi Mollapour
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Dimitra Bourboulia
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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22
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Kazemi T, Younesi V, Jadidi-Niaragh F, Yousefi M. Immunotherapeutic approaches for cancer therapy: An updated review. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2015; 44:769-79. [PMID: 25801036 DOI: 10.3109/21691401.2015.1019669] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In spite of specific immune effector mechanisms raised against tumor cells, there are mechanisms employed by the tumor cells to keep them away from immune recognition and elimination; some of these mechanisms have been identified, while others are still poorly understood. Manipulation or augmentation of specific antitumor immune responses are now the preferred approaches for treatment of malignancies, and traditional therapeutic approaches are being replaced by the use of agents which potentiate immune effector mechanisms, broadly called "immunotherapy". Cancer immunotherapy is generally classified into two main classes including active and passive methods. Interventions to augment the immune system of the patient, for example, vaccination or adjuvant therapy, actively promote antitumor effector mechanisms to improve cancer elimination. On the other hand, administration of specific monoclonal antibodies (mAbs) against different tumor antigens and adoptive transfer of genetically-modified specific T cells are currently the most rapidly developing approaches for cancer targeted therapy. In this review, we will discuss the different modalities for active and passive immunotherapy for cancer.
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Affiliation(s)
- Tohid Kazemi
- a Immunology Research Center, Tabriz University of Medical Sciences , Tabriz , Iran.,b Department of Immunology , Faculty of Medicine, Tabriz University of Medical Sciences , Tabriz , Iran
| | - Vahid Younesi
- c Department of Immunology , School of Public Health, Tehran University of Medical Sciences , Tehran , Iran
| | - Farhad Jadidi-Niaragh
- c Department of Immunology , School of Public Health, Tehran University of Medical Sciences , Tehran , Iran
| | - Mehdi Yousefi
- a Immunology Research Center, Tabriz University of Medical Sciences , Tabriz , Iran.,b Department of Immunology , Faculty of Medicine, Tabriz University of Medical Sciences , Tabriz , Iran
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23
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Alcorn J, Burton R, Topping A. BCG treatment for bladder cancer, from past to present use. INTERNATIONAL JOURNAL OF UROLOGICAL NURSING 2014. [DOI: 10.1111/ijun.12064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Jason Alcorn
- Mid Yorkshire Hospitals NHS Trust; Pinderfields Hospital; Aberford Road West Yorkshire WF1 4DG UK
| | - Rob Burton
- Head of International Business; School Of Human and Health Sciences, Ramsden R2/41; University Of Huddersfield; West Yorkshire HD1 3DH UK
| | - Annie Topping
- Assistant Executive Director of Nursing Hamad Medical Corporation; Department of Nursing Education; Qatar
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Challenges to Improve the Stability and Efficacy of an Intravesical BCG Product. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2014; 13:143-50. [PMID: 24711840 PMCID: PMC3977064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this investigation was to improve the storage stability and survival rate of an intravesical BCG product, manufactured with an attenuated strain of Mycobacterium bovis (Pasteur strain 1173P2 of BCG) in the presence of sodium glutamate. Formulations with various concentrations of trehalose (a known protectant) were developed as liquid and lyophilized forms. Formulations were evaluated by different methods, including optical density measurement, safety assessment, skin reaction test, moisture content determination, viability assay, bacterial and fungal contaminations and the results were compared with those obtained for sodium glutamate-containing formulations. The stability tests were also carried out in various storage durations and different temperatures. To develop the lyophilization protocol, glass transition temperatures in the presence of both stabilizers were determined using differential scanning calorimetry. In general, results showed that trehalose could considerably increase the stability of the product against freezing and drying processes, increase the survival rate even in the liquid formulations, as well as the production of an acceptable cake. However, further studies are required to optimize the product characteristics.
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Abstract
Better understanding of the underlying principles of tumor biology and immunology, enhanced by recent insights into the mechanisms of immune recognition, regulation, and tumor escape has provided new approaches for cancer immunotherapy. This article reviews the current status and future directions of cancer immunotherapy, with a focus on the recent encouraging results from immune-modulating antibodies and adoptive cell therapy.
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Affiliation(s)
- Fumito Ito
- Department of Surgery, University of Michigan Health System, 3410 Cancer Center/5932, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5932, USA
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Takeuchi A, Taguchi M, Satoh Y, Ishida M, Takeuchi M. Bilateral orbital inflammation following intravesical bacille Calmette–Guérin immunotherapy for bladder cancer. Jpn J Ophthalmol 2012; 56:187-9. [DOI: 10.1007/s10384-012-0120-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Accepted: 12/19/2011] [Indexed: 10/28/2022]
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27
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Lestre SIA, Gameiro CD, João A, Lopes MJP. Granulomas do pênis: uma complicação rara da terapia intravesical com Bacilo Calmette-Guérin. An Bras Dermatol 2011; 86:759-62. [DOI: 10.1590/s0365-05962011000400021] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Accepted: 06/21/2010] [Indexed: 11/22/2022] Open
Abstract
A imunoterapia com o Bacilo Calmette-Guérin é amplamente usada no tratamento e profilaxia da neoplasia urotelial superficial. As complicações associadas ao tratamento são comuns. Os autores relatam um caso de inflamação granulomatosa do pênis, associada à terapia intravesical com Bacilo Calmette-Guérin, com múltiplos nódulos eritematosos indolores localizados na glande. É também efetuada uma revisão da literatura. A balanopostite granulomatosa é uma complicação rara associada à imunoterapia com Bacilo Calmette-Guérin, com uma apresentação clinicamente heterogênea que pode dificultar o diagnóstico. O seu reconhecimento clínico é essencial para o início precoce de tuberculostáticos e interrupção de Bacilo Calmette-Guérin
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Gangawar R, Ahirwar D, Mandhani A, Mittal RD. Impact of nucleotide excision repair ERCC2 and base excision repair APEX1 genes polymorphism and its association with recurrence after adjuvant BCG immunotherapy in bladder cancer patients of North India. Med Oncol 2009; 27:159-66. [PMID: 19242824 DOI: 10.1007/s12032-009-9187-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2008] [Accepted: 02/10/2009] [Indexed: 12/01/2022]
Abstract
BACKGROUND Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette-Guerin (BCG) immunotherapy for high risk superficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic/apyriminidic endonuclease (APEX1) gene in tumor recurrence after BCG immunotherapy in SBC patients. MATERIALS AND METHODS The study included 135 SBC patients, of which BCG immunotherapy was received by 74 patients. Genotyping was performed for ERCC2 Asp(312)Asn (G > A), Lys751Gln (A > C), and APEX1 Asp(148)Glu (T > G) polymorphisms by restriction fragment length polymorphism PCR and amplification refractory mutation system (ARMS) methods. RESULTS Multiple Cox regression analysis demonstrated association of variant genotype of ERCC2 (312)AA polymorphism with high risk of recurrence in BCG treated patients (HR = 3.07, P = 0.016, P ( c ) = 0.048). Patients with the ERCC2 (312)AA polymorphic genotypes showed shorter recurrence free survival (log-rank, P = 0.005; AA/GA + AA = 14/44) who received BCG treatment. Overall, risk of recurrence in bladder cancer was observed with smokers and size of tumors (1-3 cm) (HR = 1.86, P = 0.023 and HR = 3.19, P = 0.031, respectively). Smokers were identified to be at elevated risk in BCG treated patients (HR = 2.84, P = 0.005). No association was observed with the (ERCC2 Lys(751)Gln and APEX1 Asp(148)Glu) polymorphisms and risk of recurrence. CONCLUSION Our data suggested variant (AA) of ERCC2 312 AA genotype to be associated with high risk of tumor recurrence and reduced recurrence free survival in superficial bladder cancer patients.
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Affiliation(s)
- Ruchika Gangawar
- Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh 226014, India
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Bunimovich-Mendrazitsky S, Byrne H, Stone L. Mathematical Model of Pulsed Immunotherapy for Superficial Bladder Cancer. Bull Math Biol 2008; 70:2055-76. [PMID: 18716846 DOI: 10.1007/s11538-008-9344-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2007] [Accepted: 05/23/2008] [Indexed: 11/28/2022]
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Kwitniewski M, Juzeniene A, Glosnicka R, Moan J. Immunotherapy: a way to improve the therapeutic outcome of photodynamic therapy? Photochem Photobiol Sci 2008; 7:1011-7. [DOI: 10.1039/b806710d] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Jose Manzanera Escribano M, Morales Ruiz E, Odriozola Grijalba M, Gutierrez Martínez E, Rodriguez Antolín A, Praga Terente M. Acute renal failure due to interstitial nephritis after intravesical instillation of BCG. Clin Exp Nephrol 2007; 11:238-240. [PMID: 17891353 DOI: 10.1007/s10157-007-0483-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2007] [Accepted: 06/08/2007] [Indexed: 11/29/2022]
Abstract
Intravesical chemotherapy with bacilli Calmette-Guerin (BCG) has been an established therapy for preventing recurrence of, and for treatment of, superficial transitional cell carcinoma of the bladder, but it is not without side effects. A variety of renal complications have been reported and attributed to mycobacterial infection. Although renal complications are uncommon, several cases of interstitial nephritis (with or without granulomas) and mesangial glomerulonephritis have been reported. We report a 76-year-old male patient who developed acute renal failure due to interstitial nephritis after intravesical instillation of BCG. Corticosteroids may serve the recovery of renal function without concomitant use of anti-tubercular therapy, provided systemic signs and mycobacterial infection are absent. Serum creatinine should be checked in at-risk patients in order to detect this complication early.
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Lysaght J, Jarnicki AG, Mills KHG. Reciprocal effects of Th1 and Treg cell inducing pathogen-associated immunomodulatory molecules on anti-tumor immunity. Cancer Immunol Immunother 2007; 56:1367-79. [PMID: 17279412 PMCID: PMC11030904 DOI: 10.1007/s00262-007-0288-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2006] [Accepted: 01/07/2007] [Indexed: 10/23/2022]
Abstract
We have addressed the hypothesis that pathogen-associated immunomodulatory molecules may influence anti-tumor immunity through their pro- and anti-inflammatory activities and abilities to induce effector and regulatory T (Treg) cells. We found that CpG oligonucleotides (CpG) and cholera toxin (CT), which promote Th1 or Th2/Treg cell biased responses, respectively, had differential effects on tumor growth. Therapeutic peritumoral administration of CpG significantly reduced subcutaneous tumor growth and prolonged survival, whereas CT enhanced tumor growth and reduced survival. Peritumoral administration of CpG enhanced the frequency of IFN-gamma-secreting and reduced IL-10-secreting CD4(+) and CD8(+) T cells, in the tumor and in the draining lymph nodes, whereas, CT significantly enhanced the frequency of CD4(+)CD25(+)Foxp3(+) Treg cells, but reduced IFN-gamma-secreting T cells infiltrating the tumor. In contrast to the beneficial effect of CpG in mice with subcutaneous tumors, CpG or CT had no protective effect against tumor growth in the lungs when given therapeutically by the nasal route. However, prophylactic intranasal administration of CpG significantly reduced the number of lung metastases and this was associated with an enhanced frequency of IFN-gamma-secreting CD8(+) T cells in the draining lymph node and enhanced tumor-specific CTL responses. Our findings demonstrate that pathogen-associated molecules can either inhibit or enhance anti-tumor immunity by selectively promoting the induction of effector or regulatory T cells, and that the environment of the growing tumor influences the protective effect.
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Affiliation(s)
- Joanne Lysaght
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
| | - Andrew G. Jarnicki
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
| | - Kingston H. G. Mills
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
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Sighinolfi MC, Micali S, De Stefani S, Mofferdin A, Ferrari N, Giacometti M, Bianchi G. Bacille Calmette-Guérin intravesical instillation and erectile function: is there a concern? Andrologia 2007; 39:51-4. [PMID: 17430423 DOI: 10.1111/j.1439-0272.2007.00762.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The aim of our study was to evaluate the effect of bacille Calmette-Guérin (BCG) therapy on erectile function in a cohort of male patients affected by non-muscle invasive bladder cancer. Thirty male patients undergoing BCG treatment for non-muscle invasive bladder cancer were enrolled in the study. Their mean age was 60.4 years. None of the patients had risk factors for erectile dysfunction (ED). All subjects underwent a BCG standard schedule therapy (once weekly instillation for 6 weeks). International Index of Erectile Function (IIEF-5) and International Prostate Symptom score (I-PSS) were addressed to the patients during the treatment schedule (at fourth or fifth instillation) and 1 month after the last instillation. The mean IIEF-5 score was 17.6 +/- 6.7 during therapy and 21.7 +/- 2.92 a month after the last instillation (P=0.008). Baseline ED and the association with lower urinary tract symptoms are variables significantly connected with post-treatment results (P=0.016 and 0.00 respectively) whereas the age seems not to be related to ED (P=0.256). No major side effects were recorded. It is concluded that BCG treatment is effective for prophylaxis of non-muscle invasive bladder cancer; however, it may induce a high incidence of ED. Although this effect is transient and reversible, erectile failure is another source of psychological distress that adversely affects the quality of life of men undergoing BCG treatment.
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Affiliation(s)
- M C Sighinolfi
- Department of Urology, University of Modena, Modena, Italy.
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Fry A, Saleemi A, Griffiths M, Farrington K. Acute renal failure following intravesical bacille Calmette-Guerin chemotherapy for superficial carcinoma of the bladder. Nephrol Dial Transplant 2005; 20:849-50. [PMID: 15772275 DOI: 10.1093/ndt/gfh688] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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