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Gill GS, Kharb S, Goyal G, Das P, Kurdia KC, Dhar R, Karmakar S. Immune Checkpoint Inhibitors and Immunosuppressive Tumor Microenvironment: Current Challenges and Strategies to Overcome Resistance. Immunopharmacol Immunotoxicol 2025:1-45. [PMID: 40376861 DOI: 10.1080/08923973.2025.2504906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025]
Abstract
Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.
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Affiliation(s)
- Gurpreet Singh Gill
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Simmi Kharb
- Department of Biochemistry, Pt. B.D. Sharma Postgraduate Institute of Medical Sciences, Rohtak, India
| | - Gitanjali Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Bathinda, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Kailash Chand Kurdia
- Department of GI Surgery & Liver Transplantation, All India Institute of Medical Sciences, New Delhi, India
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Azbergenov NK, Akhmetova SZ, Nurulla TA, Kaliev AR, Ramankulova AB, Tulyayeva AB, Kereeva NM. Biomarkers used in the diagnosis and prognosis of gastric cancer in young patients: a scientometric analysis. Front Med (Lausanne) 2025; 12:1586742. [PMID: 40270496 PMCID: PMC12014542 DOI: 10.3389/fmed.2025.1586742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Accepted: 03/27/2025] [Indexed: 04/25/2025] Open
Abstract
Introduction Gastric cancer in young people is a global health burden, although it is less common than in other age groups. The use of biomarkers is developing in the diagnosis, treatment selection and prognosis of gastric cancer in young patients. In this bibliometric analysis we aim to evaluate the progress of this knowledge, trend topic development and scientific teams and countries involvements in the topic of biomarkers role in gastric cancer in young patients. Methods The data were obtained from Scopus (536 publications) for the period 1993-2024, all relevant metadata were analyzed using RStudio and Biblioshiny package to perform global trends and hotspots analysis. Results Publication trends show a constant increase in interest in gastric cancer biomarkers used in the diagnosis and prognosis of gastric cancer in young patients (7.71% per year). The leading countries were China, USA, and Japan, between which there is strong and sustained collaborations. International co-authorship is relatively low (19.4%). The most prolific research centers were Sungkyunkwan University, Sun Yat-sen University, and Fudan University. The most productive researchers were Zhang X., Wang Y., and Li Y. Keywords analysis showed an increase in mentions of topics related to diagnostics (biomarkers, immunohistochemistry), personalized medicine and prognosis. Conclusion Bibliometric analysis of more than three decades research articles on gastric cancer biomarkers in young patients showed a steady increase, with strong contributions from leading countries and institutions, highlighting the growing focus on diagnostics, personalized medicine, and prognosis.
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Affiliation(s)
- Nurbek Kozhakhmetuly Azbergenov
- Department of Pathological Anatomy and Forensic Medicine, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Saule Zhumabaevna Akhmetova
- Department of Pathological Anatomy and Forensic Medicine, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Talshyn Amirkhanovna Nurulla
- Department of Pathological Anatomy and Forensic Medicine, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Abdiraman Rsalievich Kaliev
- Department of Pathological Anatomy and Forensic Medicine, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Aigul Bulatovna Ramankulova
- Department of Pathological Anatomy and Forensic Medicine, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Anar Balkashevna Tulyayeva
- Department of Oncology, Medical Center of West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Nurgul Meirimovna Kereeva
- Department of Oncology, Medical Center of West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
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Madera G, Hodge A, Roskelly L, Greenbaum C. What Is the Impact of Novel Systemic Anticancer Therapy on Acute Oncology Education and Service Delivery? Semin Oncol Nurs 2025; 41:151842. [PMID: 39986898 DOI: 10.1016/j.soncn.2025.151842] [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: 12/03/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 02/24/2025]
Abstract
OBJECTIVES To discuss the importance of educating healthcare professionals about oncological emergencies linked to novel systemic anticancer therapy (SACT) and the impact on acute oncology (AO) services. METHODS This discussion is based on clinical expertise and informed by current literature. RESULTS Novel SACT, such as immune-checkpoint inhibitors, have more complex toxicity profiles and can be challenging to recognize and treat. An increasing prevalence of toxicity is expected as new drugs are developed and the numbers of patients living with and beyond cancer expand; more data are required to capture the full extent of this. There are knowledge gaps within the healthcare workforce, particularly outside oncology-specialist settings. Focused research in this area will provide direction for targeted educational interventions. CONCLUSIONS Insufficient SACT education is a safety issue; severe toxicities can be fatal but initial symptoms can be subtle and may be missed. We argue that emergency care pathways can help to streamline the appropriate management of patients with SACT toxicity, but awareness of AO issues remains "everyone's business." Continuing clinical education is key to maintaining awareness of newly developed SACT. AO service models may vary, but AO competence assessment passports can provide a standardized method of evidencing AO knowledge and skills. IMPLICATIONS FOR NURSING PRACTICE Oncology nurses, as a highly specialized and knowledgeable part of the healthcare workforce, are key in supporting interprofessional education. By using existing cancer nursing frameworks, this can support the implementation of the AO Passports. The learning and development of AO services in the UK can be transferred internationally.
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Affiliation(s)
- Gina Madera
- Medical Oncology/Networked Services, The Christie NHS Foundation Trust, Manchester, UK.
| | - Ali Hodge
- Immunotherapy and Acute Oncology, Cancer Services Division, University Hospitals Sussex NHS Foundation Trust, Brighton, UK
| | - Lara Roskelly
- Macmillan Acute Oncology Team, Cancer Division, Frimley Health NHS Foundation Trust, UK
| | - Clare Greenbaum
- Workforce and Education, Greater Manchester Cancer Alliance, The Christie NHS Foundation Trust, Manchester, UK
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Maccio U, Wicki A, Ruschitzka F, Beuschlein F, Wolleb S, Varga Z, Moch H. Frequency and Consequences of Immune Checkpoint Inhibitor-Associated Inflammatory Changes in Different Organs: An Autopsy Study Over 13 -Years. Mod Pathol 2025; 38:100683. [PMID: 39675428 DOI: 10.1016/j.modpat.2024.100683] [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: 07/01/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024]
Abstract
Although immune checkpoint inhibitors (ICIs) have revolutionized modern oncology, they are also associated with immune-related adverse events (irAEs). Previous histopathologic descriptions of organ-related inflammatory changes do not consider systemic effects of ICIs, because of the absence of comprehensive autopsy studies. We performed a retrospective study on 42 whole-body autopsies of patients treated with ICIs from January 2011 to March 2024 to determine the frequency, organ distribution, and morphology of ICI-associated inflammatory changes as well as their clinical relevance. Twenty-three of 42 (54.8%) patients presented irAEs with inflammatory changes in at least one organ. Most frequent irAEs were ICI-related hypophysitis (N = 12; 28.6%), myocarditis (N = 8; 19.0%), pneumonitis (N = 5; 11.9%), hepatitis (N = 6; 14.3%), and adrenalitis (N = 5; 11.9%). ICI-related inflammation was mainly characterized by lymphohistiocytic and macrophage-rich tissue infiltrates, whereas a granulomatous "sarcoid-like" reaction was observed in 1 patient. Cause of death was attributable to ICI therapy in 7 (16.7%) patients, with ICI-associated myocarditis as the most common cause of death (N = 5; 71.4%). Clinically, irAEs were unsuspected in 5 of 7 ICI-related deaths (71.4%). Among irAEs, myocarditis has been clinically undiagnosed in 5 out of 8 cases (62.5%). Encephalitis was identified only at autopsy in all cases (N = 2). Hypophysitis was clinically unsuspected in 8 of 12 (66.7%) cases. Patients who died from irAEs developed more frequently a complete tumor regression than patients who died from other causes (P = .018). Of note, ICI-related myocarditis and pneumonitis were both associated with a systemic occurrence irAEs. Our study demonstrates that some irAEs, especially myocarditis, hypophysitis, and encephalitis, are clinically underdiagnosed. Autopsy remains a valuable tool to monitor diagnostic accuracy and therapeutic side effects in patients who died under ICI therapy.
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Affiliation(s)
- Umberto Maccio
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland.
| | - Andreas Wicki
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
| | - Frank Ruschitzka
- University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center, University Hospital of Zurich and University of Zurich, Zurich, Switzerland; Department of Cardiology, Center for Translational and Experimental Cardiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Felix Beuschlein
- University of Zurich, Zurich, Switzerland; Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland; The LOOP Zurich-Medical Research Center, Zurich, Switzerland
| | - Sibylle Wolleb
- Division of Medical Oncology, Hospital of Uster, Uster, Switzerland
| | - Zsuzsanna Varga
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
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Tülüce Y, Köstekci S, Karakuş F, Keleş AY, Tunçyürekli M. Investigation the immunotherapeutic potential of miR-4477a targeting PD-1/PD-L1 in breast cancer cell line using a CD8 + co-culture model. Mol Biol Rep 2025; 52:326. [PMID: 40106025 DOI: 10.1007/s11033-025-10435-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND In the present study, we investigated the immunotherapeutic and anticancer activities of microRNA-4477a (miR-4477a) as a PD-L1 inhibitor in breast cancer cells (MCF-7). METHODS To this end, a series of analytical procedures were conducted, including bioinformatic analysis, RT-PCR analysis, PD-L1 ELISA, in vitro co-culture analysis, cytotoxicity assays, cell migration assays, and colony formation assays, with the objective of determining the anticancer activity of the compound in question. RESULTS The results demonstrated that miR-4477a can bind to three distinct regions of PD-L1 mRNA with high scores (94%, 88% and 80%), effectively targeting and suppressing the crucial regulatory pathways of cancer cells. In vitro studies demonstrated that a 25 nM dose of miR-4477a caused relatively high cytotoxicity in the MCF-7 cell line, suppressed PD-L1 gene expression, and decreased sPD-L1 protein levels, strongly inhibited cell migration, and significantly reduced colony formation. The in vitro co-culture analysis revealed that cancer cells were unable to evade the surveillance and cytotoxic activity of T cells (CD8+) due to the blockade of PD-L1 expression by miR-4477a. CONCLUSIONS In conclusion, miRNA-4477a has the capacity to regulate immune responses in breast cancer cells and may therefore be a promising candidate for use in cancer immunotherapy as a therapeutic agent.
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Affiliation(s)
- Yasin Tülüce
- Department of Medical Biology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, 65080, Türkiye.
| | - Sedat Köstekci
- Department of Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Van Yüzüncü Yıl University, Van, 65080, Türkiye
| | - Fuat Karakuş
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Van Yüzüncü Yıl University, Van, 65080, Türkiye
| | - Ahmet Yasin Keleş
- Department of Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Van Yüzüncü Yıl University, Van, 65080, Türkiye
| | - Merve Tunçyürekli
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Van Yüzüncü Yıl University, Van, 65080, Türkiye
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Farì R, Besutti G, Pattacini P, Ligabue G, Piroli F, Mantovani F, Navazio A, Larocca M, Pinto C, Giorgi Rossi P, Tarantini L. The role of imaging in defining cardiovascular risk to help cancer patient management: a scoping review. Insights Imaging 2025; 16:37. [PMID: 39961941 PMCID: PMC11832977 DOI: 10.1186/s13244-025-01907-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
OBJECTIVE This scoping review explores the potential role of cancer-staging chest CT scans in assessing cardiovascular (CV) risk in cancer patients. It aims to evaluate: (1) the correlation between non-gated chest CT and the conventional Agatston score from cardiac CT; (2) the association between coronary calcium scores from non-gated chest CT and CV risk in non-oncological patients; (3) the link between coronary calcium assessed by non-gated chest CT and CV events or endothelial damage in cancer patients. METHODS Three different searches were performed on PubMed, according to the three steps described above. Both original articles and systematic reviews were included. RESULTS Many studies in the literature have found a strong correlation between coronary calcium scores from non-gated chest CTs and the conventional Agatston scores from gated cardiac CTs. Various methodologies, including Agatston scoring, ordinal scoring, and the "extent" and "length" methods, have been successfully adapted for use with non-gated chest CTs. Studies show that non-gated scans, even those using iodinated contrast, can accurately assess coronary calcification and predict CV risk, with correlations as high as r = 0.94 when compared to cardiac CTs. In oncological settings, studies demonstrated a significant link between coronary calcium levels on non-gated chest CTs and higher CV risk, including MACE and overall mortality. CONCLUSIONS Radiological assessment of coronary calcium on non-gated CT scans shows potential for improving CV risk prediction. CRITICAL RELEVANCE STATEMENT Non-gated chest CT scans can detect endothelial damage in cancer patients, highlighting the need for standardized radiological practices to assess CV risks during routine oncological follow-up, thereby enhancing radiology's role in comprehensive cancer care. KEY POINTS Cancer therapies improve outcomes but increase cardiovascular risk, requiring balanced management. Coronary calcification on non-gated CT correlates with Agatston scores, predicting cardiovascular risk. Routinely performed CTs predict cardiovascular risk, optimizing the management of cancer patients.
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Affiliation(s)
- Roberto Farì
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
- Radiology Unit, Department of Diagnostic Imaging and Laboratory Medicine, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
| | - Giulia Besutti
- Radiology Unit, Department of Diagnostic Imaging and Laboratory Medicine, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Pierpaolo Pattacini
- Radiology Unit, Department of Diagnostic Imaging and Laboratory Medicine, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Guido Ligabue
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Piroli
- Cardiology Unit, Department of Specialized Medicine, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Francesca Mantovani
- Cardiology Unit, Department of Specialized Medicine, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alessandro Navazio
- Cardiology Unit, Department of Specialized Medicine, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Mario Larocca
- Oncology Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Carmine Pinto
- Oncology Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Paolo Giorgi Rossi
- Epidemiology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123, Reggio Emilia, Italy
| | - Luigi Tarantini
- Cardiology Unit, Department of Specialized Medicine, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
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7
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Guo F, McGee EE, Chiu YH, Giovannucci E, Mucci LA, Dickerman BA. Evaluating recommendation-based dietary and physical activity strategies for prostate cancer prevention: a target trial emulation in the Health Professionals Follow-up Study. Am J Epidemiol 2025; 194:449-459. [PMID: 38973750 PMCID: PMC12034833 DOI: 10.1093/aje/kwae184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 05/13/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024] Open
Abstract
The 2018 World Cancer Research Fund/American Institute for Cancer Research recommends sustained strategies of physical activity and diet for cancer prevention, but evidence for long-term prostate cancer risk is limited. Using observational data from 27 859 men in the Health Professionals Follow-up Study, we emulated a target trial of recommendation-based physical activity and dietary strategies and 26-year risks of prostate cancer, adjusting for risk factors via the parametric g-formula. Compared with no intervention, limiting sugar-sweetened beverages showed a 0.4% (0.0%-0.9%) lower risk of lethal (metastatic or fatal) disease and 0.5% (0.1%-0.9%) lower risk of fatal disease. Restricting consumption of processed foods showed a 0.4% to 0.9% higher risk of all prostate cancer outcomes. Estimated risk differences for clinically significant disease were close to null for strategies involving fruits and nonstarchy vegetables, whole grains and legumes, red meat, and processed meat, as well as under a joint strategy of physical activity and diet. Compared with a "low-adherence" strategy, maintaining recommended physical activity levels showed a 0.4% (0.1%-0.8%) lower risk of lethal and 0.5% (0.2%-0.8%) lower risk of fatal disease. Adhering to specific components of current physical activity and dietary recommendations may help to prevent lethal and fatal prostate cancer over 26 years.
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Affiliation(s)
- Fuyu Guo
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
| | - Emma E McGee
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, United States
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
| | - Yu-Han Chiu
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
| | - Edward Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
| | - Lorelei A Mucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- Discovery Science, American Cancer Society, Atlanta, GA 30303, United States
| | - Barbra A Dickerman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
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Jiang X, Nik Nabil WN, Ze Y, Dai R, Xi Z, Xu H. Unlocking Natural Potential: Antibody-Drug Conjugates With Naturally Derived Payloads for Cancer Therapy. Phytother Res 2025; 39:789-874. [PMID: 39688127 DOI: 10.1002/ptr.8407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 11/06/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024]
Abstract
Natural compound-derived chemotherapies remain central to cancer treatment, however, they often cause off-target side effects that negatively impact patients' quality of life. In contrast, antibody-drug conjugates (ADCs) combine cytotoxic payloads with antibodies to specifically target cancer cells. Most approved and clinically investigated ADCs utilize naturally derived payloads, while those with conventional synthetic molecular payloads remain limited. This review focuses on approved ADCs that enhance the efficacy of naturally derived payloads by linking them with antibodies. We provide an overview of the core components of ADCs, their working mechanisms, and FDA-approved ADCs featuring naturally derived payloads, such as calicheamicin, camptothecin, dolastatin 10, maytansine, pyrrolbenzodiazepine (PBD), and the immunotoxin Pseudomonas exotoxin A. This review also explores recent clinical advancements aimed at broadening the therapeutic potential of ADCs, their applicability in treating heterogeneously composed tumors and their potential use beyond oncology. Additionally, this review highlights naturally derived payloads that are currently being clinically investigated but have not yet received approval. By summarizing the current landscape, this review provides insights into promising avenues for exploration and contributes to the refinement of treatment protocols for improved patient outcomes.
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Affiliation(s)
- Xue Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Wan Najbah Nik Nabil
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- National Pharmaceutical Regulatory Agency, Ministry of Health, Selangor, Malaysia
| | - Yufei Ze
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Rongchen Dai
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Zhichao Xi
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Hongxi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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9
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Arafat Hossain M. A comprehensive review of immune checkpoint inhibitors for cancer treatment. Int Immunopharmacol 2024; 143:113365. [PMID: 39447408 DOI: 10.1016/j.intimp.2024.113365] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 09/28/2024] [Accepted: 10/05/2024] [Indexed: 10/26/2024]
Abstract
Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.
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Affiliation(s)
- Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh.
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10
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Chen Q, Wan W, Zhao Q, Li J, Xiong Y, Yuan Y, Tang L, Wu X, Xing W, Guo W, Lu D, Ao L, Xu X, Ao X. Decoding the prognostic landscape of LUAD: the interplay between N 6-methyladenosine modification and immune microenvironment. Front Immunol 2024; 15:1514497. [PMID: 39720723 PMCID: PMC11666524 DOI: 10.3389/fimmu.2024.1514497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/21/2024] [Indexed: 12/26/2024] Open
Abstract
Background To determine the role of N6-methyladenosine (m6A) modification in the tumor immune microenvironment (TIME), as well as their association with lung adenocarcinoma (LUAD). Methods Consensus clustering was performed to identify the subgroups with distinct immune or m6A modification patterns using profiles from TCGA. A risk score model was constructed using least absolute shrinkage and selection operator regression and validated in two independent cohorts and LUAD tissue microarrays. For experimental validation, the regulation of METTL3/m6A axis in the expression of candidate genes by RIP-qPCR assay in A549 and H460 cell lines. Co-culture experiments with human T cells were performed to evaluate the impact of METTL3 on the enhancement of anti-tumor immunity through in vitro experiments. Results We identified 282 m6A regulator genes and 955 immune-related genes, selecting seven key genes (SFTPC, CYP24A1, KRT6A, PTTG1, S100P, FAM83A, and ANLN) to develop a risk score model using Lasso regression. High-risk patients, determined by this model, exhibited poorer prognosis, increased immune infiltration, higher tumor mutational burden, more neoantigens, and elevated PD-L1 expression. These findings were validated by two independent databases and LUAD tissue microarrays. METTL3 was found to impact the mRNA expression of these genes, with METTL3 deficiency abolishing these interactions. Inhibition of METTL3 enhanced anti-tumor immunity, T cell activation, exhaustion, and infiltration in vitro. Conclusion This risk score system shows promise for prognostic prediction and the development of personalized treatment strategies for LUAD patients.
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Affiliation(s)
- Quan Chen
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, China
| | - Weijun Wan
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Qing Zhao
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Juan Li
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Yanli Xiong
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Yuchuan Yuan
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Lu Tang
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaofeng Wu
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Xing
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Guo
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Di Lu
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, China
| | - Luoquan Ao
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiang Xu
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, China
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Xiang Ao
- State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Department of orthopedics, 953 Hospital of PLA Army, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
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11
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Esha JF, Islam T, Pranto MAM, Borno AS, Faruqui N, Yousuf MA, Azad AKM, Al-Moisheer AS, Alotaibi N, Alyami SA, Moni MA. Multi-View Soft Attention-Based Model for the Classification of Lung Cancer-Associated Disabilities. Diagnostics (Basel) 2024; 14:2282. [PMID: 39451604 PMCID: PMC11506595 DOI: 10.3390/diagnostics14202282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/24/2024] [Accepted: 09/29/2024] [Indexed: 10/26/2024] Open
Abstract
Background: The detection of lung nodules at their early stages may significantly enhance the survival rate and prevent progression to severe disability caused by advanced lung cancer, but it often requires manual and laborious efforts for radiologists, with limited success. To alleviate it, we propose a Multi-View Soft Attention-Based Convolutional Neural Network (MVSA-CNN) model for multi-class lung nodular classifications in three stages (benign, primary, and metastatic). Methods: Initially, patches from each nodule are extracted into three different views, each fed to our model to classify the malignancy. A dataset, namely the Lung Image Database Consortium Image Database Resource Initiative (LIDC-IDRI), is used for training and testing. The 10-fold cross-validation approach was used on the database to assess the model's performance. Results: The experimental results suggest that MVSA-CNN outperforms other competing methods with 97.10% accuracy, 96.31% sensitivity, and 97.45% specificity. Conclusions: We hope the highly predictive performance of MVSA-CNN in lung nodule classification from lung Computed Tomography (CT) scans may facilitate more reliable diagnosis, thereby improving outcomes for individuals with disabilities who may experience disparities in healthcare access and quality.
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Affiliation(s)
- Jannatul Ferdous Esha
- Department of Information and Communication Technology, Bangladesh University of Professionals, Mirpur Cantonment, Dhaka 1216, Bangladesh; (J.F.E.); (T.I.); (M.A.M.P.); (A.S.B.)
| | - Tahmidul Islam
- Department of Information and Communication Technology, Bangladesh University of Professionals, Mirpur Cantonment, Dhaka 1216, Bangladesh; (J.F.E.); (T.I.); (M.A.M.P.); (A.S.B.)
| | - Md. Appel Mahmud Pranto
- Department of Information and Communication Technology, Bangladesh University of Professionals, Mirpur Cantonment, Dhaka 1216, Bangladesh; (J.F.E.); (T.I.); (M.A.M.P.); (A.S.B.)
| | - Abrar Siam Borno
- Department of Information and Communication Technology, Bangladesh University of Professionals, Mirpur Cantonment, Dhaka 1216, Bangladesh; (J.F.E.); (T.I.); (M.A.M.P.); (A.S.B.)
| | - Nuruzzaman Faruqui
- Department of Software Engineering, Daffodil International University, Daffodil Smart City, Birulia 1216, Bangladesh;
| | - Mohammad Abu Yousuf
- Institute of Information Technology, Jahangirnagar University, Dhaka 1342, Bangladesh
| | - AKM Azad
- Department of Mathematics and Statistics, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia; (A.A.); (A.S.A.-M.); (N.A.); (S.A.A.)
| | - Asmaa Soliman Al-Moisheer
- Department of Mathematics and Statistics, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia; (A.A.); (A.S.A.-M.); (N.A.); (S.A.A.)
| | - Naif Alotaibi
- Department of Mathematics and Statistics, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia; (A.A.); (A.S.A.-M.); (N.A.); (S.A.A.)
| | - Salem A. Alyami
- Department of Mathematics and Statistics, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia; (A.A.); (A.S.A.-M.); (N.A.); (S.A.A.)
| | - Mohammad Ali Moni
- AI & Digital Health Technology, AI and Cyber Futures Institute, Charles Sturt University, Bathurst, NSW 2795, Australia
- AI & Digital Health Technology, Rural Health Research Institute, Charles Sturt University, Orange, NSW 2800, Australia
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12
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Bafaloukos D, Gazouli I, Bousmpoukea A, Molfeta A, Chatzichristou E, Samonis G, Vathiotis I. Occult checkpoint inhibitor myocarditis during adjuvant nivolumab plus ipilimumab: a smoldering but severe toxicity. Immunotherapy 2024; 16:937-942. [PMID: 39258778 PMCID: PMC11486303 DOI: 10.1080/1750743x.2024.2385286] [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: 04/22/2024] [Accepted: 07/24/2024] [Indexed: 09/12/2024] Open
Abstract
Checkpoint inhibitor myocarditis is a rare but life-threatening toxicity of immunotherapy, occasionally manifesting as persistent troponin elevation. Dual checkpoint blockade with ipilimumab and nivolumab has been found to induce immune-related myocarditis in patients with metastatic melanoma. We herein report a case of smoldering immune-related myocarditis in a 54-year-old male after a single infusion of nivolumab plus ipilimumab as adjuvant treatment for completely resected stage IV melanoma. High-dose steroid treatment resulted in decrease in the levels of cardiac enzymes, without any major complications.
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Affiliation(s)
| | | | | | | | | | - George Samonis
- 1 Medical Oncology Department, Neon Faliron, Athens
- Department of Medicine, University of Crete, Heraklion, Greece
| | - Ioannis Vathiotis
- 3rd Department of Internal Medicine, Sotiria General Hospital for Chest Diseases, NKUA, Athens, Greece
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13
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De Santis MC, Bockorny B, Hirsch E, Cappello P, Martini M. Exploiting pancreatic cancer metabolism: challenges and opportunities. Trends Mol Med 2024; 30:592-604. [PMID: 38604929 DOI: 10.1016/j.molmed.2024.03.008] [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: 01/15/2024] [Revised: 03/12/2024] [Accepted: 03/15/2024] [Indexed: 04/13/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer, known for its challenging diagnosis and limited treatment options. The focus on metabolic reprogramming as a key factor in tumor initiation, progression, and therapy resistance has gained prominence. In this review we focus on the impact of metabolic changes on the interplay among stromal, immune, and tumor cells, as glutamine and branched-chain amino acids (BCAAs) emerge as pivotal players in modulating immune cell functions and tumor growth. We also discuss ongoing clinical trials that explore metabolic modulation for PDAC, targeting mitochondrial metabolism, asparagine and glutamine addiction, and autophagy inhibition. Overcoming challenges in understanding nutrient effects on immune-stromal-tumor interactions holds promise for innovative therapeutic strategies.
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Affiliation(s)
- Maria Chiara De Santis
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy.
| | - Bruno Bockorny
- BIDMC Department of Medicine, Harvard Medical School, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Emilio Hirsch
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy
| | - Miriam Martini
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy.
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14
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Conroy MR, O'Sullivan H, Collins DC, Bambury RM, Power D, Grossman S, O'Reilly S. Exploring the prognostic impact of absolute lymphocyte count in patients treated with immune-checkpoint inhibitors. BJC REPORTS 2024; 2:31. [PMID: 39516713 PMCID: PMC11523911 DOI: 10.1038/s44276-024-00058-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 03/05/2024] [Accepted: 03/17/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND The role of immune checkpoint inhibitors (ICI) expands but affordable and reproducible prognostic biomarkers are needed. We investigated the association between baseline and 3-month absolute lymphocyte count (ALC) and survival for patients on ICI. METHODS A retrospective study investigated patients who received ICI July 2014-August 2019. Survival probabilities were calculated for lymphocyte subsets. Univariate and multivariate analyses were performed to investigate risk factors for lymphopenia. RESULTS Among 179 patients, median age was 62 and 41% were female. The most common diagnoses were melanoma (41%) and lung cancer (40%). Median PFS was 6.5 months. 27% had baseline lymphopenia (ALC < 1 × 109cells/L) and no significant difference in PFS or OS to those with normal ALC. However, 31% had lymphopenia at 3 months and significantly shorter OS than those without (9.8 vs 18.3 months, p < 0.001). Those with baseline lymphopenia who recovered counts at 3 months had no difference in PFS (median NR vs 13.0 months, p = 0.48) or OS (22 vs 18.3 months, p = 0.548) to those never lymphopenic. The strongest risk factor for lymphopenia on multivariable analysis was previous radiation therapy (RT). CONCLUSIONS 3-month lymphopenia is a negative prognostic marker in cancer patients on ICI. Previous RT is significantly associated with lymphopenia.
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Affiliation(s)
- M R Conroy
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer research @UCC, Western Gateway Building, Western Road, Cork, Ireland
| | - H O'Sullivan
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer research @UCC, Western Gateway Building, Western Road, Cork, Ireland
| | - D C Collins
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer research @UCC, Western Gateway Building, Western Road, Cork, Ireland
| | - R M Bambury
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer research @UCC, Western Gateway Building, Western Road, Cork, Ireland
| | - D Power
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer research @UCC, Western Gateway Building, Western Road, Cork, Ireland
- Mercy University Hospital, Grenville Pl, Centre, Cork, Ireland
| | - S Grossman
- Johns Hopkins University, Baltimore, MD, USA
| | - S O'Reilly
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland.
- Cancer research @UCC, Western Gateway Building, Western Road, Cork, Ireland.
- Mercy University Hospital, Grenville Pl, Centre, Cork, Ireland.
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15
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Kubo A, Murakami S, Iwata T. Drug Interaction-induced Hemolytic Anemia: An Unresolved Diagnostic Process. Intern Med 2024; 63:631-633. [PMID: 37438134 PMCID: PMC10982025 DOI: 10.2169/internalmedicine.2119-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 07/14/2023] Open
Affiliation(s)
- Akihito Kubo
- Oncology Center, Aichi Medical University Hospital, Japan
- Department of Respiratory Medicine and Allergology, Aichi Medical University, Japan
| | - Satsuki Murakami
- Oncology Center, Aichi Medical University Hospital, Japan
- Department of Hematology, Aichi Medical University, Japan
| | - Takashi Iwata
- Oncology Center, Aichi Medical University Hospital, Japan
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16
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Saad R, Ghaddar A, Zeenny RM. Pembrolizumab-induced myocarditis with complete atrioventricular block and concomitant myositis in a metastatic bladder cancer patient: a case report and review of the literature. J Med Case Rep 2024; 18:107. [PMID: 38383436 PMCID: PMC10882824 DOI: 10.1186/s13256-024-04397-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 01/19/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND The cardiovascular system is among the least systems affected by immune-related adverse events. We report a rare life-threatening case of pembrolizumab-induced myocarditis with complete atrioventricular block and concomitant myositis in a metastatic bladder cancer patient. CASE PRESENTATION An 82-year-old Caucasian female with invasive urothelial carcinoma, started on first-line pembrolizumab, was admitted four days after receiving her second dose for severe asthenia, diffuse muscle aches, neck pain, and lethargy. In the emergency department, she had several episodes of bradycardia reaching 40 beats per minute associated with general discomfort and fatigue. Electrocardiography showed a third-degree atrioventricular heart block, while the patient remained normotensive. Cardiac damage parameters were altered with elevated levels of creatine phosphokinase of 8930 U/L, suggestive of immune checkpoint inhibitor-induced myositis, and troponin T of 1.060 ng/mL. Transthoracic echocardiography showed a preserved ejection fraction. Pembrolizumab-induced myocarditis was suspected. Therefore, treatment was initiated with high-dose glucocorticoids for 5 days, followed by a long oral steroid taper. A pacemaker was also implanted. Treatment resulted in the resolution of heart block and a decrease in creatine phosphokinase to the normal range. CONCLUSION Life-threatening cardiac adverse events in the form of myocarditis may occur with pembrolizumab use, warranting vigilant cardiac monitoring. Troponin monitoring in high-risk patients, along with baseline echocardiography may help identify this complication promptly to prevent life-threatening consequences.
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Affiliation(s)
- R Saad
- Department of Pharmacy, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon
| | - A Ghaddar
- Department of Pharmacy, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon
| | - R M Zeenny
- Department of Pharmacy, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon.
- INSPECT-LB (Institut National de Santé Publique, d'Épidémiologie Clinique et de Toxicologie-Liban), Beirut, Lebanon.
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17
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Baretton G, Lordick F, Gaiser T, Hofheinz R, Horst D, Lorenzen S, Möhler M, Röcken C, Schirmacher P, Stahl M, Thuss-Patience P, Tiemann K. [Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. German version]. PATHOLOGIE (HEIDELBERG, GERMANY) 2024; 45:51-58. [PMID: 38170268 PMCID: PMC10827825 DOI: 10.1007/s00292-023-01215-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/09/2023] [Indexed: 01/05/2024]
Abstract
As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD‑1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
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Affiliation(s)
- G Baretton
- Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Deutschland.
| | - F Lordick
- Medizinische Klinik II (Onkologie, Gastroenterologie, Hepatologie und Pneumologie) und Universitäres Krebszentrum Leipzig, Universitätsmedizin Leipzig, Leipzig, Deutschland.
| | - T Gaiser
- PATHOLOGIE SPEYER Gemeinschaftspraxis GbR, Speyer, Deutschland
| | - R Hofheinz
- Universitätsmedizin Mannheim, Mannheim, Deutschland
| | - D Horst
- Institut für Pathologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - S Lorenzen
- III. Medizinische Klinik, Klinikum rechts der Isar, München, Deutschland
| | - M Möhler
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - C Röcken
- Institut für Pathologie, Christian-Albrechts-Universität, Kiel, Deutschland
| | - P Schirmacher
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - M Stahl
- Klinik für Internistische Onkologie & Onkologische Palliativmedizin, KEM | Evang. Kliniken Essen-Mitte, Evang. Huyssens-Stiftung Essen-Huttrop, Essen, Deutschland
| | - P Thuss-Patience
- Charité Centrum Tumormedizin CC14, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - K Tiemann
- Institut für Hämatopathologie, Hamburg, Deutschland
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18
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Duarte Mendes A, Freitas AR, Vicente R, Ferreira R, Martins T, Ramos MJ, Baptista C, Silva BM, Margarido I, Vitorino M, Silva M, Braga S. Beta-Adrenergic Blockade in Advanced Non-Small Cell Lung Cancer Patients Receiving Immunotherapy: A Multicentric Study. Cureus 2024; 16:e52194. [PMID: 38348009 PMCID: PMC10859721 DOI: 10.7759/cureus.52194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2024] [Indexed: 02/15/2024] Open
Abstract
Introduction The standard treatment of cancer has dramatically improved with immune checkpoint inhibitors (ICIs). Despite their proven advantage, many patients fail to exhibit a meaningful and lasting response. The beta-adrenergic signalling pathway may hold significant promise due to its role in promoting an immunosuppressive milieu within the tumour microenvironment. Inhibiting β-adrenergic signalling could enhance ICI activity; however, blocking this pathway for this purpose has yielded conflicting results. The primary objective of this study was to evaluate the effect of beta-blocker use on overall survival and progression-free survival during ICI therapy. Methods A multicentric, retrospective, observational study was conducted in four Portuguese institutions. Patients with advanced non-small cell lung cancer treated with ICIs between January 2018 and December 2019 were included. Those using beta blockers for non-oncological reasons were compared with non-users. Results Among the 171 patients included, 36 concomitantly received beta blockers and ICIs. No significant increase was found in progression-free survival among patients who took β-blockers (HR 0.74, 95% confidence interval (CI) 0.48-1.12, p = 0.151), and no statistically significant difference was found in overall survival. An apparent trend was observed towards better outcomes in the beta-blocker group, with a median overall survival of 9.93 months in the group not taking β-blockers versus 14.90 months in the β-blocker group (p = 0.291) and a median progression-free survival of 5.37 in the group not taking β-blockers versus 10.87 months in the β-blocker group (p = 0.151). Nine (25%) patients in the beta-blocker group and 16 (12%) in the non-beta-blocker group were progressive disease-free at the end of follow-up. This difference between the two groups is statistically significant (p = 0.047). Conclusion Our study found no statistically significant evidence that beta blockers enhance the effectiveness of immunotherapy. Using adrenergic blockade to modulate the immune system shows promise, warranting the need to develop prospective clinical studies.
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Affiliation(s)
- Ana Duarte Mendes
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
| | - Ana Rita Freitas
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
| | - Rodrigo Vicente
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
| | - Ricardo Ferreira
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
| | - Telma Martins
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
| | - Maria João Ramos
- Medical Oncology Department, Centro Hospitalar Universitário de Santo António, Porto, PRT
| | - Carlota Baptista
- Medical Oncology Department, Hospital Beatriz Ângelo, Loures, PRT
| | | | - Inês Margarido
- Medical Oncology Department, Hospital da Luz Lisboa, Lisboa, PRT
| | - Marina Vitorino
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
| | - Michelle Silva
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
| | - Sofia Braga
- Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, PRT
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19
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Baretton GB, Lordick F, Gaiser T, Hofheinz R, Horst D, Lorenzen S, Moehler M, Röcken C, Schirmacher P, Stahl M, Thuss-Patience P, Tiemann K. Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. J Cancer Res Clin Oncol 2023; 149:16231-16238. [PMID: 37874352 PMCID: PMC10620316 DOI: 10.1007/s00432-023-05180-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 10/25/2023]
Abstract
As a result of the high approval dynamics and the growing number of immuno-oncological concepts, the complexity of treatment decisions and control in the area of cancers of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD-1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
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Affiliation(s)
- Gustavo B Baretton
- Institute for Pathology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Florian Lordick
- Department of Medicine II (Oncology, Gastroenterology, Hepatology and Pulmonology) and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany.
| | - T Gaiser
- Institute of Applied Pathology, 67346, Speyer, Germany
| | - R Hofheinz
- University Medicine Mannheim, Mannheim, Germany
| | - D Horst
- Institute of Pathology of the Charité-University Medicine Berlin, Berlin, Germany
| | - S Lorenzen
- Department of Medicine III, Klinikum Rechts der Isar, Munich, Germany
| | - M Moehler
- Department of Medicine I, University Medicine Mainz, Mainz, Germany
| | - C Röcken
- Institute of Pathology, Christian-Albrechts University, Kiel, Germany
| | - P Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - M Stahl
- Department of Oncology and Palliative Care, Kliniken Essen Mitte, Evangelische Huyssens-Stiftung, Essen-Huttrop, Essen, Germany
| | - P Thuss-Patience
- Charité Center of Tumor Medicine CC14, Charité Campus Virchow-University Medicine Berlin, Berlin, Germany
| | - K Tiemann
- Institute of Hematopathology, Hamburg, Germany
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20
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Yu S, Zhai S, Gong Q, Xiang C, Gong J, Wu L, Pu X. Neoadjuvant Immunotherapy and Non-Small Cell Lung Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Am J Clin Oncol 2023; 46:517-528. [PMID: 37749786 PMCID: PMC10589427 DOI: 10.1097/coc.0000000000001046] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
OBJECTIVES To systematically evaluate the effectiveness and safety of neoadjuvant immunotherapy for patients with non-small cell lung cancer (NSCLC). METHODS Randomized controlled trials of neoadjuvant immunotherapy in treating patients with NSCLC were comprehensively retrieved from electronic databases, eligible studies, previous systematic reviews and meta-analyses, guidelines, and conference abstracts. The meta-analysis was performed by the Stata/SE 12.0 software. RESULTS Eleven randomized controlled trials were eventually included. The results of the meta-analysis showed that neoadjuvant immunochemotherapy significantly improved the objective response rate compared with neoadjuvant chemotherapy (CT; 62.46% vs 41.88%, P = 0.003), but the objective response rate of neoadjuvant double-immunotherapy was roughly comparable to that of neoadjuvant single-immunotherapy (15.74% vs 10.45%, P = 0.387). Major pathologic response (MPR) rate and pathologic complete response (pCR) rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT alone and neoadjuvant single-immunotherapy, respectively. Compared with neoadjuvant CT alone, neoadjuvant immunochemotherapy increased the down-staging rate (40.16% vs 26.70%, P = 0.060), the surgical resection rate (83.69% vs 73.07%, P = 0.231), and R0 resection rate (86.19% vs 77.98%, P = 0.502), but there were no statistically significant differences. Neoadjuvant immunochemotherapy did not increase the postoperative complications rate than neoadjuvant CT alone (40.20% vs 41.30%, P = 0.920). In terms of safety, neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy did not increase the incidence of treatment-related adverse events (TRAEs) and the grade 3 or higher TRAEs. CONCLUSIONS In summary, neoadjuvant immunochemotherapy had better clinical efficacy than neoadjuvant CT for patients with NSCLC. MPR rate and pCR rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT and neoadjuvant single-immunotherapy, respectively, for patients with NSCLC, showing that MPR rate and pCR rate were probably considered as alternative endpoints for survival benefit. TRAEs were comparable between the corresponding groups. The long-term survival outcome of neoadjuvant immunotherapy for patients with NSCLC needs to be further confirmed to better guide clinical practice.
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Affiliation(s)
- Shaofu Yu
- Department of Clinical Pharmacy, the Second People’s Hospital of Huaihua
- The Second Department of Thoracic Medical Oncology, Hunan Cancer Hospital, Changsha
| | - Shasha Zhai
- Department of Trauma Surgery, the First Affiliated Hospital of Hunan University of Medicine, Huaihua
| | - Qian Gong
- Department of Clinical Pharmacy, Hunan Cancer Hospital, Changsha, Hunan, China
| | - Chunhong Xiang
- Department of Clinical Pharmacy, the Second People’s Hospital of Huaihua
| | - Jianping Gong
- Department of Clinical Pharmacy, the Second People’s Hospital of Huaihua
| | - Lin Wu
- The Second Department of Thoracic Medical Oncology, Hunan Cancer Hospital, Changsha
| | - Xingxiang Pu
- The Second Department of Thoracic Medical Oncology, Hunan Cancer Hospital, Changsha
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Abstract
OBJECTIVE This study aims to evaluate geographic disparities in access to cancer clinical trials across Canada. METHODS Cancer clinical trial data recorded within the clinicaltrials.gov and reporting the conduct of any of these trials in Canada, 2005 to 2023 were reviewed. Frequency analyses of the number of clinical trials that were registered on clinicaltrials.gov for Canada, individual Canadian provinces, main Canadian urban centers, and different cancer types, according to the funding source (industry versus non-industry), as well as according to different periods (using 3-y intervals) were conducted. Moreover, a comparison of cancer clinical trials per 10,000 persons was done between Canada and the United States. RESULTS The number of cancer clinical trials per 10,000 individuals (according to the 2021 census) in each province/territory varied between 6.79 (New Brunswick) to 0 (the 3 territories). The number of cancer clinical trials in relation to 1000 projected cancer cases for some of the common tumor types in Canada was then reviewed. The highest number was for lymphoma clinical trials (32.85), whereas the lowest number was for bladder cancer clinical trials (7.06). Most of the trials have industry funding (69%). Using 3-year intervals, the highest number of cancer clinical trials was observed from 2014 to 2016 (778 trials), and the lowest number was observed from 2020 to 2022 (633 trials). CONCLUSIONS Access to clinical trials in Canada is not equitably distributed, with geographical and primary tumor site disparities. Moreover, access to cancer clinical trials has been negatively impacted during the time of the COVID-19 pandemic.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
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22
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Zakout GA. Practicing equitable principles in cancer clinical research: Has the EU got it right? J Cancer Policy 2023; 37:100435. [PMID: 37507086 DOI: 10.1016/j.jcpo.2023.100435] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/17/2023] [Accepted: 07/25/2023] [Indexed: 07/30/2023]
Abstract
Clinical trials are a fundamental part of cancer research as they establish the efficacy and safety of new cancer treatments for everyone. The lack of sociodemographic diversity among cancer clinical trial participants leaves a vacuum in scientific knowledge, which can distort credible evidence from being accessible and represents a major barrier to advancing cancer care for the entire patient population. It can also cause avoidable harm to the public, undermine patients trust and result in wasteful allocation of healthcare resources. It is therefore imperative that there is representation of all population groups who may use these new cancer treatments in clinical trial settings. Europeans are disproportionately affected by cancer with cancer mortality rates being substantially affected by inequities in socioeconomic education status. General and political recognition of cancer injustices in the EU have further increased given the contemptuously unequal impacts of the legal and policy responses to it. While innovative advances in cancer research have bridged much of these critical gaps particularly in the last few decades more work needs to be done to circumvent implications of cancer health disparities. To reduce cancer health disparities, systemic and individual-level barriers to cancer clinical trial participation must be addressed through effective and ethically rigorous EU health laws and policies.
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Affiliation(s)
- Ghada A Zakout
- Erasmus University Rotterdam, Erasmus School of Law, Burg. Oudlaan 50, 3062 PA Rotterdam, Netherlands.
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23
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Liang ZQ, Bian Y, Gu JF, Yin G, Sun RL, Liang Y, Wan LL, Yin QH, Wang X, Gao J, Zhao F, Tang DC. Exploring the anti-metastatic effects of Astragalus mongholicus Bunge-Curcuma aromatica Salisb. on colorectal cancer: A network-based metabolomics and pharmacology approach. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154772. [PMID: 37015187 DOI: 10.1016/j.phymed.2023.154772] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 02/28/2023] [Accepted: 03/14/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is a common malignancy that can significantly diminish patients' quality of life. Astragalus mongholicus Bunge-Curcuma aromatica Salisb. (AC) is an ancient Chinese medicinal combination used for the treatment of CRC. However, the core ingredients and targets involved in regulating lipid and amino acid metabolism in CRC remain unknown. We aimed to explore the key components and pharmacological mechanisms of AC in the treatment of CRC through a comprehensive analysis of network metabolomics, network pharmacology, molecular docking, and biological methods. METHODS Ultra-performance liquid chromatography/mass spectrometry (MS) was used for quality control. Gas chromatography/MS and liquid chromatography/MS were used to detect metabolites in the feces and serum of CRC mice. A network pharmacology approach and molecular docking were used to explore the potential genes involved in the CRC-target-component network. The effect of AC on tumor immunity was investigated using flow cytometry and polymerase chain reaction. RESULTS AC, high-dose AC, and 5-fluorouracil treatment reduced liver metastasis and tumor mass. Compared with the CRC group, 2 amino acid metabolites and 14 lipid metabolites (LPC, PC, PE) were upregulated and 15 amino acid metabolites and 9 lipid metabolites (TG, PE, PG, 12-HETE) were downregulated. Subsequently, through network analysis, four components and six hub genes were identified for molecular docking. AC can bind to ALDH1B1, ALDH2, CAT, GOT2, NOS3, and ASS1 through beta-Elemene, canavanine, betaine, and chrysanthemaxanthin. AC promoted the responses of M1 macrophages and down-regulated the responses of M2 macrophages, Treg cells, and the gene expression of related factors. CONCLUSION Our research showed that AC effectively inhibited the growth and metastasis of tumors and regulated metabolism and immunity in a CRC mouse model. Thus, AC may be an effective alternative treatment option for CRC.
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Affiliation(s)
- Zhong Qing Liang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Yong Bian
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; Laboratory Animal Center, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Jun Fei Gu
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Gang Yin
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Ruo Lan Sun
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Yan Liang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Lin Lu Wan
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Qi Hang Yin
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Xu Wang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - Jin Gao
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; School of Acupuncture and Tuina, School of Health and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210046, Jiangsu, China
| | - Fan Zhao
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China
| | - De Cai Tang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
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24
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Chauhan A, Singh J, Sangwan N, Singh H, Prakash A, Medhi B, Avti PK. Designing the 5HT 2BR structure and its modulation as a therapeutic target for repurposing approach in drug-resistant epilepsy. Epilepsy Res 2023; 194:107168. [PMID: 37302343 DOI: 10.1016/j.eplepsyres.2023.107168] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/24/2023] [Accepted: 05/22/2023] [Indexed: 06/13/2023]
Abstract
The study intends to repurpose FDA drugs and investigate the mechanism of (5HT2BR) activation by comprehending inter-residue interactions. The 5HT2BR is a novel thread, and its role in reducing seizures in Dravet syndrome is emerging. The crystal structure (5HT2BR) is a chimera with mutations; hence 3D-structure is modeled (4IB4: 5HT2BRM). The structure is cross-validated to simulate the human receptor using enrichment analysis (ROC: 0.79) and SAVESv6.0. Virtual screening of 2456 approved drugs yielded the best hits that are subjected to MM/GBSA and molecular dynamic (MD) simulations. The 2 top drugs Cabergoline (-53.44 kcal/mol) and Methylergonovine (-40.42 kcal/mol), display strong binding affinity, and ADMET/SAR analysis also suggests their non-mutagenic or non-carcinogenic nature. Methylergonovine has a weaker binding affinity and lower potency than standards [Ergotamine (agonist) and Methysergide (antagonist)] due to its higher Ki (1.32 M) and Kd (6.44 ×10-8 M) values. Compared to standards, Cabergoline has moderate binding affinity and potency [Ki = 0.85 M and Kd = 5.53 × 10-8 M]. The top 2 drugs primarily interact with conserved residues (ASP135, LEU209, GLY221, ALA225, and THR140) as in agonists, unlike the antagonist. The top 2 drugs, upon binding to the 5HT2BRM, modify the helices VI, V, and III and shift the RMSD 2.48 Å and 3.07 Å. LEU209 forms a latch with residues 207-214 (forms a lid) in the 5HT2BRM receptor, which enhances agonist binding and prevents drug escape. Methylergonovine and Cabergoline interact more stongly with ALA225 than the antagonist. The post-MD analysis of Cabergoline suggests a better MM/GBSA value (-89.21 kcal/mol) than Methylergonovine (-63.54 kcal/mol). In this study, Cabergoline and Methylergonovine's agonistic mechanism and solid binding properties suggest their strong role in regulating the 5HT2BR and might target drug-resistant epilepsy.
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Affiliation(s)
| | | | | | | | - Ajay Prakash
- Department of Pharmacology, PGIMER, Chandigarh, India
| | - Bikash Medhi
- Department of Pharmacology, PGIMER, Chandigarh, India
| | - Pramod K Avti
- Department of Biophysics, PGIMER, Chandigarh, India.
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25
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Iivanainen S, Baird AM, Balas B, Bustillos A, Castro Sanchez AY, Eicher M, Golding S, Mueller-Ohldach M, Reig M, Welslau M, Ammann J. Assessing the impact of digital patient monitoring on health outcomes and healthcare resource usage in addition to the feasibility of its combination with at-home treatment, in participants receiving systemic anticancer treatment in clinical practice: protocol for an interventional, open-label, multicountry platform study (ORIGAMA). BMJ Open 2023; 13:e063242. [PMID: 37076159 PMCID: PMC10124208 DOI: 10.1136/bmjopen-2022-063242] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2023] Open
Abstract
INTRODUCTION Digital patient monitoring (DPM) tools can enable more effective clinical care and improved patient outcomes in cancer. However, their broad adoption requires ease of use and demonstration of real-world clinical utility/impact. ORIGAMA (MO42720) is an interventional, open-label, multicountry platform study investigating the clinical utility of DPM tools and specific treatments. ORIGAMA will begin with two cohorts that aim to assess the impact of the atezolizumab-specific Roche DPM Module (hosted on the Kaiku Health DPM platform (Helsinki, Finland)) on health outcomes and healthcare resource usage, and its feasibility to support at-home treatment administration, in participants receiving systemic anticancer treatment. Other digital health solutions may be added to future cohorts. METHODS AND ANALYSIS In Cohort A, participants with metastatic non-small cell lung cancer (NSCLC), extensive-stage SCLC or Child Pugh A unresectable hepatocellular carcinoma will be randomised to a locally approved anticancer regimen containing intravenous atezolizumab (TECENTRIQ, F. Hoffmann-La Roche Ltd/Genentech) and local standard-of-care support, with/without the Roche DPM Module. Cohort B will assess the feasibility of the Roche DPM Module in supporting administration of three cycles of subcutaneous atezolizumab (1875 mg; Day 1 of each 21-day cycle) in the hospital, followed by 13 cycles at home by a healthcare professional (ie, flexible care), in participants with programmed cell-death ligand 1-positive, early-stage NSCLC. The primary endpoints are the mean difference in change of the participant-reported Total Symptom Interference Score at Week 12 from baseline (Cohort A) and flexible care adoption rate at Cycle 6 (Cohort B). ETHICS AND DISSEMINATION This study will be conducted according to the Declaration of Helsinki, and/or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study received its first Ethics Committee approval in Spain in October 2022. Participants will provide written informed consent in a face-to-face setting. The results of this study will be presented at national and/or international congresses and disseminated via publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT05694013.
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Affiliation(s)
- Sanna Iivanainen
- Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
| | - Anne-Marie Baird
- Trinity Translational Medicine Institute, Trinity College Dublin School of Medicine, Dublin, Ireland
- Lung Cancer Europe, Bern, Switzerland
| | - Bogdana Balas
- Product Development Safety, F Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Alberto Bustillos
- Product Development Medical Affairs, F Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - Manuela Eicher
- Institute of Higher Education and Research in Health Care, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland
| | - Sophie Golding
- Product Development Data Sciences, F Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - Maria Reig
- BCLC Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Manfred Welslau
- Department of Oncology, Medical Care Center, Hospital Aschaffenburg GmbH, Aschaffenburg, Germany
| | - Johannes Ammann
- Product Development Medical Affairs, F Hoffmann-La Roche Ltd, Basel, Switzerland
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26
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Howard FM, Dolezal J, Kochanny S, Khramtsova G, Vickery J, Srisuwananukorn A, Woodard A, Chen N, Nanda R, Perou CM, Olopade OI, Huo D, Pearson AT. Integration of clinical features and deep learning on pathology for the prediction of breast cancer recurrence assays and risk of recurrence. NPJ Breast Cancer 2023; 9:25. [PMID: 37059742 PMCID: PMC10104799 DOI: 10.1038/s41523-023-00530-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 03/30/2023] [Indexed: 04/16/2023] Open
Abstract
Gene expression-based recurrence assays are strongly recommended to guide the use of chemotherapy in hormone receptor-positive, HER2-negative breast cancer, but such testing is expensive, can contribute to delays in care, and may not be available in low-resource settings. Here, we describe the training and independent validation of a deep learning model that predicts recurrence assay result and risk of recurrence using both digital histology and clinical risk factors. We demonstrate that this approach outperforms an established clinical nomogram (area under the receiver operating characteristic curve of 0.83 versus 0.76 in an external validation cohort, p = 0.0005) and can identify a subset of patients with excellent prognoses who may not need further genomic testing.
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Affiliation(s)
| | - James Dolezal
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Sara Kochanny
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | | | - Jasmine Vickery
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | | | - Anna Woodard
- Department of Medicine, University of Chicago, Chicago, IL, USA
- Department of Computer Science, University of Chicago, Chicago, IL, USA
| | - Nan Chen
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Rita Nanda
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Charles M Perou
- Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Dezheng Huo
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
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27
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Ozone in Chemotherapy-Induced Peripheral Neuropathy—Current State of Art, Possibilities, and Perspectives. Int J Mol Sci 2023; 24:ijms24065279. [PMID: 36982352 PMCID: PMC10049472 DOI: 10.3390/ijms24065279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/01/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most detrimental toxicity to a patient’s quality of life. Pathophysiological mechanisms involved in CIPN pathogenesis are complex, multifactorial, and only partially examined. They are suspected to be associated with oxidative stress (OS), mitochondrial dysfunction, ROS-induced apoptosis, myelin sheath and DNA damage, and immunological and inflammatory processes. Unfortunately, medications commonly used for the management of other neuropathic pain syndromes, including gabapentinoids, opioids, and tricyclic antidepressants (such as desipramine and nortriptyline), do not bring satisfactory results in CIPN. The aim of this review is to evaluate the existing literature on the potential use of medical ozone as a treatment for CIPN. This paper would explore the potential therapeutic benefits of medical ozone. The review would evaluate the existing literature on the use of medical ozone in other contexts, as well as its potential application in treating CIPN. The review would also suggest possible research methods, such as randomized controlled trials, to evaluate the efficacy of medical ozone as a treatment for CIPN. Medical ozone has been used to disinfect and treat diseases for over 150 years. The effectiveness of ozone in treating infections, wounds, and a variety of diseases has been well documented. Ozone therapy is also documented to inhibit the growth of human cancer cells and has antioxidative and anti-inflammatory effects. Due to its ability to modulate oxidative stress, inflammation, and ischemia/hypoxia, ozone may have a potentially valuable effect on CIPN.
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Tack L, Schofield P, Boterberg T, Chandler R, Parris CN, Debruyne PR. Practical Implementation of the Comprehensive Geriatric Assessment to Optimise Care for Older Adults with Cancer. Geriatrics (Basel) 2023; 8:geriatrics8010018. [PMID: 36826360 PMCID: PMC9957492 DOI: 10.3390/geriatrics8010018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 01/18/2023] [Indexed: 01/25/2023] Open
Abstract
Whilst cancer remains a very serious health problem at any stage, cancer combined with increasing age creates an even more challenging situation for health care providers [...].
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Affiliation(s)
- Laura Tack
- Department of Medical Oncology, Kortrijk Cancer Centre, General Hospital Groeninge, 8500 Kortrijk, Belgium
- Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium
| | - Patricia Schofield
- School of Nursing and Midwifery, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
| | - Tom Boterberg
- Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium
| | - Rebecca Chandler
- School of Allied Health, Faculty of Health, Education, Medicine and Social Care, Chelmsford CM1 1SQ, UK
| | - Christopher N. Parris
- Medical Technology Research Centre (MTRC), School of Life Sciences, Faculty of Science and Engineering, Anglia Ruskin University, Cambridge CB1 1PT, UK
| | - Philip R. Debruyne
- Department of Medical Oncology, Kortrijk Cancer Centre, General Hospital Groeninge, 8500 Kortrijk, Belgium
- School of Nursing and Midwifery, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
- Medical Technology Research Centre (MTRC), School of Life Sciences, Faculty of Science and Engineering, Anglia Ruskin University, Cambridge CB1 1PT, UK
- Correspondence:
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Fenton SE, VanderWeele DJ. Antibody-drug conjugates and predictive biomarkers in advanced urothelial carcinoma. Front Oncol 2023; 12:1069356. [PMID: 36686762 PMCID: PMC9846350 DOI: 10.3389/fonc.2022.1069356] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/06/2022] [Indexed: 01/05/2023] Open
Abstract
The use of antibody-drug conjugates (ADCs) is expanding in several malignancies, including urothelial carcinoma where two of these medications have been approved for use and several others remain under study. ADCs act by binding to specific cell surface proteins, delivering anticancer agents directly to the target cells. Preclinical studies suggest that loss of these surface proteins alters sensitivity to therapy and expression of target proteins vary significantly based on the tumor subtype, prior therapies and other characteristics. However, use of biomarkers to predict treatment response have not been regularly included in clinical trials and clinician practice. In this review we summarize what is known about potential predictive biomarkers for ADCs in UC and discuss potential areas where use of biomarkers may improve patient care.
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Affiliation(s)
- Sarah E. Fenton
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, United States
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - David J. VanderWeele
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, United States
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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30
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Tack L, Schofield P, Boterberg T, Parris CN, Debruyne PR. Editorial: Clinical cancer research in vulnerable populations. Front Oncol 2023; 13:1166714. [PMID: 36937380 PMCID: PMC10019276 DOI: 10.3389/fonc.2023.1166714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Affiliation(s)
- Laura Tack
- Kortrijk Cancer Centre, Department of Medical Oncology, General Hospital Groeninge, Kortrijk, Belgium
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Patricia Schofield
- School of Nursing and Midwifery, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
| | - Tom Boterberg
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Christopher N. Parris
- Medical Technology Research Centre (MTRC), School of Life Sciences, Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, United Kingdom
| | - Philip R. Debruyne
- Kortrijk Cancer Centre, Department of Medical Oncology, General Hospital Groeninge, Kortrijk, Belgium
- School of Nursing and Midwifery, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
- Medical Technology Research Centre (MTRC), School of Life Sciences, Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, United Kingdom
- *Correspondence: Philip R. Debruyne,
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Ershov P, Poyarkov S, Konstantinova Y, Veselovsky E, Makarova A. Transcriptomic Signatures in Colorectal Cancer Progression. Curr Mol Med 2023; 23:239-249. [PMID: 35490318 DOI: 10.2174/1566524022666220427102048] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/05/2021] [Accepted: 03/09/2022] [Indexed: 02/08/2023]
Abstract
AIMS Due to a large number of identified hub-genes encoding key molecular regulators, which are involved in signal transduction and metabolic pathways in cancers, it is relevant to systemize and update these findings. BACKGROUND Colorectal cancer (CRC) is the third leading cause of cancer death in the world, with high metastatic potential. Elucidating the pathogenic mechanisms and selection of novel biomarkers in CRC is of great clinical significance. OBJECTIVE This analytical review aims at the systematization of bioinformatics and experimental identification of hub-genes associated with CRC for a more consolidated understanding of common features in networks and pathways in CRC progression as well as hub-genes selection. RESULTS In total, 301 hub-genes were derived from 40 articles. The "core" consisted of 28 hub-genes (CCNB1, LPAR1, BGN, CXCL3, COL1A2, UBE2C, NMU, COL1A1, CXCL2, CXCL11, CDK1, TOP2A, AURKA, SST, CXCL5, MMP3, CCND1, TIMP1, CXCL8, CXCL1, CXCL12, MYC, CCNA2, GCG, GUCA2A, PAICS, PYY and THBS2) mentioned in not less than three articles and having clinical significance in cancerassociated pathways. Of them, there were two discrete clusters enriched in chemokine signaling and cell cycle regulatory genes. High expression levels of BGN and TIMP1 and low expression levels of CCNB1, CXCL3, CXCL2, CXCL2 and PAICS were associated with unfavorable overall survival of patients with CRC. Differently expressed genes such as LPAR1, SST, CXCL12, GUCA2A, and PYY were shown as down regulated, whereas BGN, CXCL3, UBE2C, NMU, CXCL11, CDK1, TOP2A, AURKA, MMP3, CCND1, CXCL1, MYC, CCNA2, PAICS were up regulated genes in CRC. It was also found that MMP3, THBS2, TIMP1 and CXCL12 genes were associated with metastatic CRC. Network analysis in ONCO.IO showed that upstream master regulators RELA, STAT3, SOX2, FOXM1, SMAD3 and NF-kB were connected with "core" hub-genes. Conclusión: Results obtained are of useful fundamental information on revealing the mechanism of pathogenicity, cellular target selection for optimization of therapeutic interventions, as well as transcriptomics prognostic and predictive biomarkers development.
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Affiliation(s)
- Pavel Ershov
- Department of Analysis and Forecasting of Medical and Biological Health Risks, Federal State Budgetary Institution "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical Biological Agency, Moscow, Russia
| | - Stanislav Poyarkov
- Department of Analysis and Forecasting of Medical and Biological Health Risks, Federal State Budgetary Institution "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical Biological Agency, Moscow, Russia
| | - Yulia Konstantinova
- Oncology Department, Federal Research and Clinical Center of Specialized Kinds of Medical Care and Medical Technology of the Federal Medical Biological Agency, Moscow, Russia
| | - Egor Veselovsky
- Department of Analysis and Forecasting of Medical and Biological Health Risks, Federal State Budgetary Institution "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical Biological Agency, Moscow, Russia
| | - Anna Makarova
- Department of Analysis and Forecasting of Medical and Biological Health Risks, Federal State Budgetary Institution "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical Biological Agency, Moscow, Russia
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Saxe GN, Bickman L, Ma S, Aliferis C. Mental health progress requires causal diagnostic nosology and scalable causal discovery. Front Psychiatry 2022; 13:898789. [PMID: 36458123 PMCID: PMC9705733 DOI: 10.3389/fpsyt.2022.898789] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 10/10/2022] [Indexed: 11/17/2022] Open
Abstract
Nine hundred and seventy million individuals across the globe are estimated to carry the burden of a mental disorder. Limited progress has been achieved in alleviating this burden over decades of effort, compared to progress achieved for many other medical disorders. Progress on outcome improvement for all medical disorders, including mental disorders, requires research capable of discovering causality at sufficient scale and speed, and a diagnostic nosology capable of encoding the causal knowledge that is discovered. Accordingly, the field's guiding paradigm limits progress by maintaining: (a) a diagnostic nosology (DSM-5) with a profound lack of causality; (b) a misalignment between mental health etiologic research and nosology; (c) an over-reliance on clinical trials beyond their capabilities; and (d) a limited adoption of newer methods capable of discovering the complex etiology of mental disorders. We detail feasible directions forward, to achieve greater levels of progress on improving outcomes for mental disorders, by: (a) the discovery of knowledge on the complex etiology of mental disorders with application of Causal Data Science methods; and (b) the encoding of the etiological knowledge that is discovered within a causal diagnostic system for mental disorders.
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Affiliation(s)
- Glenn N. Saxe
- Department of Child and Adolescent Psychiatry, New York University Grossman School of Medicine, New York, NY, United States
| | - Leonard Bickman
- Ontrak Health, Inc., Henderson, NV, United States
- Department of Psychology, Florida International University, Miami, FL, United States
| | - Sisi Ma
- Program in Data Science, Department of Medicine, Clinical and Translational Science Institute, Institute for Health Informatics, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Constantin Aliferis
- Program in Data Science, Department of Medicine, Clinical and Translational Science Institute, Institute for Health Informatics, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Sun L, Zhu Z, Jia X, Ying X, Wang B, Wang P, Zhang S, Yu J. The difference of human gut microbiome in colorectal cancer with and without metastases. Front Oncol 2022; 12:982744. [PMID: 36387258 PMCID: PMC9665410 DOI: 10.3389/fonc.2022.982744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 01/24/2023] Open
Abstract
Metastasis of colorectal cancer is deemed to be closely related to the changes in the human gut microbiome. The purpose of our study is to distinguish the differences in gut microbiota between colorectal cancer with and without metastases. Firstly, this study recruited colorectal cancer patients who met the established inclusion and exclusion criteria in the Oncology Department of Zhejiang Hospital of Traditional Chinese Medicine from February 2019 to June 2019. Fresh stool samples from healthy volunteers, non-metastatic patients, and metastatic patients were collected for 16S rRNA gene sequencing, to analyze the diversity and abundance of intestinal microorganisms in each group. The results showed that the microbial composition of the control group was more aplenty than the experimental group, while the difference also happened in the Tumor and the metastases group. At the phylum level, the abundance of Bacteroidetes significantly declined in the Tumor and the metastases group, compared with the control group. At the class level, Bacilli increased in experimental groups, while its abundance in the Tumor group was significantly higher than that in the metastases group. At the order level, the Tumor group had the highest abundance of Lactobacillales, followed by the metastases group and the control group had the lowest abundance. Overall, our study showed that the composition of the flora changed with the occurrence of metastasis in colorectal cancer. Therefore, the analysis of gut microbiota can serve as a supplement biological basis for the diagnosis and treatment of metastatic colorectal cancer which may offer the potential to develop non-invasive diagnostic tests.
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Affiliation(s)
- Leitao Sun
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Zhenzheng Zhu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xinru Jia
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiangchang Ying
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Binbin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Peipei Wang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China,*Correspondence: Jieru Yu, ; Shuo Zhang, ; Peipei Wang,
| | - Shuo Zhang
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Xinhua Hospital of Zhejiang Province), Hangzhou, Zhejiang, China,*Correspondence: Jieru Yu, ; Shuo Zhang, ; Peipei Wang,
| | - Jieru Yu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China,*Correspondence: Jieru Yu, ; Shuo Zhang, ; Peipei Wang,
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Krendyukov A, Singhvi S, Green-Morrison Y, Zabransky M. Early access provision: Awareness, educational needs and opportunities to improve oncology patients' access to care. Front Oncol 2022; 12:714516. [PMID: 36387084 PMCID: PMC9643861 DOI: 10.3389/fonc.2022.714516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 10/03/2022] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND An unmet medical need exists for many oncology patients who cannot be treated satisfactorily by available therapeutic options. Early access provision (EAP) is endorsed by competent authorities to improve patient access to innovative medicinal products (InMPs). This paper determined awareness and understanding among practicing physicians of integrated EAP protocols, and of the procedures involved in EAP applications for oncology trials prior to marketing authorization. METHODS An on-line, fully anonymous survey reaching out to more than 3,258 physicians (including practicing oncologists) was initiated between November 2020 - January 2021. Participants were questioned about their knowledge and understanding of EAP and the decision processes involved, level of experience, interest for further educational activities and opportunities to improve the process, both in general and specifically during the COVID-19 pandemic. The frequency of EAP protocols for oncology InMPs was identified by a search of ClinicalTrials.gov and EU Clinical Trials registers. RESULTS Survey results (75% oncologists) indicated 75% of respondents were 'very comfortable' or 'comfortable' with using EAP for their patients, but only 54.5% correctly answered the specific knowledge-based question related to the EAP definition. For 56% of respondents, experience with EAP in daily practice was very limited. Two-thirds indicated an average or lower level of understanding about the application process and regulatory requirements involved (65.2% and 66.0%, respectively). Knowledge on data collection and serious adverse event reporting under EAP was lower at 57.8% and 50.5% of respondents, respectively. Awareness of physician responsibilities was high in 59.7% of respondents, but fewer understood roles and responsibilities of manufacturing companies (31.2%). Most indicated they would consider clinical efficacy and safety data from comparative phase III randomized controlled trials as of high importance to support their decision to apply for EAP (93.4% and 86.8%, respectively). During the COVID-19 pandemic, the majority of respondents highlighted the need to improve and adapt EAP with regard to the application process and documentation (83.8%), InMP supply and logistics (88.4), and safety reporting process (78.0%). Of identified oncology trials with a ClinicalTrials.gov protocol, only 149 (0.4%) included EAP, and 23 used the data to receive a marketing authorization during the period Jan 2015 to December 2020. Of oncology trials with a EudraCT protocol, only 21 (0.23%) included EAP, of which 6 were used to receive a conditional or full marketing authorisation over the same period. CONCLUSION Use of EAP in daily practice remains limited. Challenges posed by the EAP process, together with a lack of education on this topic, might contribute to its under-utilization and influence access of oncology patients to care. Continuous educational efforts from different stakeholders are required to better inform and support practicing oncologists during the EAP application process and regulatory framework follow up. Education should also be provided on EAP roles and responsibilities, monitoring, and potential adaptations when faced with specific challenges, such as the current COVID-19 pandemic.
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Affiliation(s)
- Andriy Krendyukov
- Andriy Krendyukov VP Medical Affairs, Apogenix AG, Heidelberg, Germany
| | - Sanjay Singhvi
- Sanjay Singhvi/Yianick Green-Morrison VMLY&R Health, London, United Kingdom
| | | | - Markus Zabransky
- Markus Zabransky, Global Medical Affairs, Sandoz GmbH, Holzkirchen, Germany
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Su Y, Ding J, Yang F, He C, Xu Y, Zhu X, Zhou H, Li H. The regulatory role of PDE4B in the progression of inflammatory function study. Front Pharmacol 2022; 13:982130. [PMID: 36278172 PMCID: PMC9582262 DOI: 10.3389/fphar.2022.982130] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/22/2022] [Indexed: 11/20/2022] Open
Abstract
Inflammation is a response of the body to external stimuli (eg. chemical irritants, bacteria, viruses, etc.), and when the stimuli are persistent, they tend to trigger chronic inflammation. The presence of chronic inflammation is an important component of the tumor microenvironment produced by a variety of inflammatory cells (eg. macrophages, neutrophils, leukocytes, etc.). The relationship between chronic inflammation and cancer development has been widely accepted, and chronic inflammation has been associated with the development of many cancers, including chronic bronchitis and lung cancer, cystitis inducing bladder cancer. Moreover, chronic colorectitis is more likely to develop into colorectal cancer. Therefore, the specific relationship and cellular mechanisms between inflammation and cancer are a hot topic of research. Recent studies have identified phosphodiesterase 4B (PDE4B), a member of the phosphodiesterase (PDEs) protein family, as a major cyclic AMP (cAMP) metabolizing enzyme in inflammatory cells, and the therapeutic role of PDE4B as chronic inflammation, cancer. In this review, we will present the tumors associated with chronic inflammation, and PDE4B potential clinical application.
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Affiliation(s)
- Yue Su
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Public Foundation, Bengbu Medical University, Bengbu, China
| | - Jiaxiang Ding
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Public Foundation, Bengbu Medical University, Bengbu, China
| | - Fan Yang
- Department of Ophthalmology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Cuixia He
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Yuanyuan Xu
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Xingyu Zhu
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
| | - Huan Zhou
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- School of Public Foundation, Bengbu Medical University, Bengbu, China
- School of Pharmacy, Bengbu Medical University, Bengbu, China
- *Correspondence: Hongtao Li, ; Huan Zhou,
| | - Hongtao Li
- First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- *Correspondence: Hongtao Li, ; Huan Zhou,
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Inaki K, Shibutani T, Maeda N, Eppenberger-Castori S, Nicolet S, Kaneda Y, Koyama K, Qiu Y, Wakita K, Murakami M. Pan-cancer gene expression analysis of tissue microarray using EdgeSeq oncology biomarker panel and a cross-comparison with HER2 and HER3 immunohistochemical analysis. PLoS One 2022; 17:e0274140. [PMID: 36137139 PMCID: PMC9498941 DOI: 10.1371/journal.pone.0274140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 08/23/2022] [Indexed: 11/19/2022] Open
Abstract
Molecular and protein biomarker profiling are key to oncology drug development. Antibody-drug conjugates (ADCs) directly deliver chemotherapeutic agents into tumor cells based on unique cancer cell biomarkers. A pan-cancer tissue microarray (TMA) data set and gene panel were validated and gene signature analyses were conducted on normal and cancer tissues to refine selection of ADC targets. Correlation of mRNA and protein levels, and human epidermal growth factor receptor (HER) expression patterns were assessed. An EdgeSeq biomarker panel (2862 genes) was used across 8531 samples (23 solid cancer types/subtypes; 16 normal tissues) with an established TMA data set, and immune cell and cell cycle gene signatures were analyzed. Discriminating gene expression signatures were defined based on pathological classification of cancer subtypes. Correlative analyses of HER2 and HER3 mRNA (EdgeSeq) and protein expression (immunohistochemistry [IHC]) were performed and compared with publicly available data (The Cancer Genome Atlas [TCGA]; Cancer Cell Line Encyclopedia [CCLE]). Gene expression patterns among cancer types in the TMA (EdgeSeq) and TCGA (RNA-seq) were similar. EdgeSeq gene signature analyses aligned with the majority of pathological cancer types/subtypes and identified cancer-specific gene expression patterns. TMA IHC H-scores for HER3 varied across cancer types/subtypes. In a few cancer types, HER3 mRNA and protein expression did not align, including lower liver hepatocellular carcinoma IHC H-score, compared with mRNA. Although all TNBC and ovarian cancer subtypes expressed mRNA, some had lower protein expression. This was seen in TMA and TCGA data sets, but not in CCLE. The EdgeSeq TMA data set can expand upon current biomarker data by including cancers not currently in TCGA. The primary analysis of EdgeSeq and IHC comparison suggested a unique protein-level regulation of HER3 in some tumor subtypes and highlights the importance of investigating protein levels of ADC targets in both tumor and normal tissues.
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Affiliation(s)
- Koichiro Inaki
- Translational Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
- * E-mail:
| | - Tomoko Shibutani
- Translational Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Naoyuki Maeda
- Translational Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | | | | | - Yuki Kaneda
- Translational Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Kumiko Koyama
- Translational Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Yang Qiu
- Global Oncology R&D, Daiichi Sankyo, Inc., Basking Ridge, NJ, United States of America
| | - Kenichi Wakita
- Translational Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Masato Murakami
- Translational Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
- Global Oncology R&D, Daiichi Sankyo, Inc., Basking Ridge, NJ, United States of America
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Garattini SK, Valent F, Minisini AM, Riosa C, Favaretti C, Regattin L, Fasola G. Analysis of workload generated in the two years following first consultation by each new cancer patient: studying the past to plan the future of cancer care. BMC Health Serv Res 2022; 22:1184. [PMID: 36131286 PMCID: PMC9494889 DOI: 10.1186/s12913-022-08573-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 09/14/2022] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION Prevalence of cancer patients is dramatically increasing. We aimed at quantifying the oncology workload generated by each new cancer patient in the two years following first consultation. METHODS In this record-based retrospective study, we retrieved data of all newly diagnosed patients treated at the Oncology Department of Udine Academic Hospital between 01.01.2012 and 31.12.2017. We calculated mean number and standard deviation of the activity type generated by each new cancer patient during the following 2 years. RESULTS Seven thousand four hundred fifty-two cancer patients generated a total of 85,338 clinical episodes. The two-years mean number of oncology episodes generated was 11.31 (i.e., for every 1,000 new cancer patients, 11,310 oncology activities are generated overall in the following two-year lapse). Patients with advanced disease generated the highest workload (24.3; SD 18.8) with a statistically significant difference compared to adjuvant and follow-up patients (p < 0.001). The workload generated in the period 0-6 and 0-12 months was significantly higher than in the following months (p < 0.001) and it was also higher for patients initially designated to treatment (p < 0.001). CONCLUSION This is the first study reporting on the mean oncology workload generated during the 2 years following first consultation. Workload is the highest for patient with advanced disease, especially in the first months and in patients in active treatment. A detailed analysis of workloads in oncology is feasible and could be crucial for planning a sustainable framework for cancer care in the next future.
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Affiliation(s)
- SK. Garattini
- Department of Oncology, Academic Hospital of Udine ASUFC, Piazzale Santa Maria della Misericordia 15, Udine, UD 33100 Italy
| | - F. Valent
- Institute of Hygiene and Clinical Epidemiology, Academic Hospital of Udine ASUFC, 33100 Udine, UD Italy
| | - AM. Minisini
- Department of Oncology, Academic Hospital of Udine ASUFC, Piazzale Santa Maria della Misericordia 15, Udine, UD 33100 Italy
| | - C. Riosa
- Department of Oncology, Academic Hospital of Udine ASUFC, Piazzale Santa Maria della Misericordia 15, Udine, UD 33100 Italy
| | - C. Favaretti
- Center for Leadership in Medicine, Catholic University of Sacred Heart, 000168 Rome, RO Italy
| | - L. Regattin
- Medical Director, Academic Hospital of Udine ASUFC, Piazzale Santa Maria della Misericordia 15, Udine, UD 33100 Italy
| | - G. Fasola
- Department of Oncology, Academic Hospital of Udine ASUFC, Piazzale Santa Maria della Misericordia 15, Udine, UD 33100 Italy
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A Gold Nanoparticle Bioconjugate Delivery System for Active Targeted Photodynamic Therapy of Cancer and Cancer Stem Cells. Cancers (Basel) 2022; 14:cancers14194558. [PMID: 36230480 PMCID: PMC9559518 DOI: 10.3390/cancers14194558] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/11/2022] [Accepted: 09/15/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer stem cells (CSCs), also called tumor-initiating cells, are a subpopulation of cancer cells believed to be the leading cause of cancer initiation, growth, metastasis, and recurrence. Presently there are no effective treatments targeted at eliminating CSCs. Hence, an urgent need to develop measures to target CSCs to eliminate potential recurrence and metastasis associated with CSCs. Cancer stem cells have inherent and unique features that differ from other cancer cells, which they leverage to resist conventional therapies. Targeting such features with photodynamic therapy (PDT) could be a promising treatment for drug-resistant cancer stem cells. Photodynamic therapy is a light-mediated non-invasive treatment modality. However, PDT alone is unable to eliminate cancer stem cells effectively, hence the need for a targeted approach. Gold nanoparticle bioconjugates with PDT could be a potential approach for targeted photodynamic therapy of cancer and CSCs. This approach has the potential for enhanced drug delivery, selective and specific attachment to target tumor cells/CSCs, as well as the ability to efficiently generate ROS. This review examines the impact of a smart gold nanoparticle bioconjugate coupled with a photosensitizer (PS) in promoting targeted PDT of cancer and CSC.
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Myer NM, Shitara K, Chung HC, Lordick F, Kelly RJ, Szabo Z, Cao ZA, Leong S, Ilson DH, Weichert W. Evolution of predictive and prognostic biomarkers in the treatment of advanced gastric cancer. J Cancer Res Clin Oncol 2022; 148:2023-2043. [PMID: 35551464 PMCID: PMC11110882 DOI: 10.1007/s00432-021-03902-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/24/2021] [Indexed: 12/30/2022]
Abstract
Despite new therapeutic options, advanced gastric cancer remains associated with a poor prognosis compared with other cancers. Recent gains in the treatment of gastric cancer were accompanied by the identification of novel biomarkers associated with various cellular pathways and corresponding diagnostic technologies. It is expected that the standardization of clinical workflow and technological refinements in biomarker assessment will support greater personalization and further improve treatment outcomes. In this article, we review the current state of prognostic and predictive biomarkers in gastric cancer.
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Affiliation(s)
- Nicole M Myer
- Merck & Co., Inc., 90 E. Scott Avenue, Rahway, NJ, 07065, USA.
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - Hyun C Chung
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Florian Lordick
- Medical Department (Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases), University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany
| | - Ronan J Kelly
- Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Zsolt Szabo
- Merck & Co., Inc., Ringstrasse 27 Kriens, LUZERN, 6010, Switzerland
| | - Z Alexander Cao
- Merck & Co., Inc., 90 E. Scott Avenue, Rahway, NJ, 07065, USA
| | - Stephen Leong
- Merck & Co., Inc., 351 N Sumneytown Pike, North Wales, PA, 19454, USA
| | - David H Ilson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wilko Weichert
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
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Wei X, Lin L, Zhang G, Zhou X. Cardiovascular Magnetic Resonance Imaging in the Early Detection of Cardiotoxicity Induced by Cancer Therapies. Diagnostics (Basel) 2022; 12:1846. [PMID: 36010197 PMCID: PMC9406931 DOI: 10.3390/diagnostics12081846] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
The significant progress in cancer treatment, including chemotherapy, immunotherapy, radiotherapy, and combination therapies, has led to higher long-term survival rates in cancer patients, while the cardiotoxicity caused by cancer treatment has become increasingly prominent. Cardiovascular magnetic resonance (CMR) is a non-invasive comprehensive imaging modality that provides not only anatomical information, but also tissue characteristics and cardiometabolic and energetic assessment, leading to its increased use in the early identification of cardiotoxicity, and is of major importance in improving the survival rate of cancer patients. This review focused on CMR techniques, including myocardial strain analysis, T1 mapping, T2 mapping, and extracellular volume fraction (ECV) calculation in the detection of early myocardial injury induced by cancer therapies. We summarized the existing studies and ongoing clinical trials using CMR for the assessment of subclinical ventricular dysfunction and myocardial changes at the tissue level. The main focus was to explore the potential of clinical and preclinical CMR techniques for continuous non-invasive monitoring of myocardial toxicity associated with cancer therapy.
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Affiliation(s)
| | | | - Guizhi Zhang
- Department of Radiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518036, China; (X.W.); (L.L.)
| | - Xuhui Zhou
- Department of Radiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518036, China; (X.W.); (L.L.)
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de Araújo RA, da Luz FAC, da Costa Marinho E, Nascimento CP, de Andrade Marques L, Delfino PFR, Antonioli RM, Araújo BJ, da Silva ACAL, Dos Reis Monteiro MLG, Neto MB, Silva MJB. Epidermal growth factor receptor (EGFR) expression in the serum of patients with triple-negative breast carcinoma: prognostic value of this biomarker. Ecancermedicalscience 2022; 16:1431. [PMID: 36158981 PMCID: PMC9458269 DOI: 10.3332/ecancer.2022.1431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Indexed: 11/15/2022] Open
Abstract
Background Epidermal growth factor receptor (EGFR) overexpression has been considered a poor prognostic factor in breast cancer. Methodology A prospective study of 206 women with breast cancer analysed by stages (I, II, III and IV) and by immunohistochemical subtype (Luminal A, Luminal B, HER2+ and triple-negative (TN)); 89 healthy controls with normal recent mammography were included. The EGFR measured in the serum (sEGFR) was detected by the Enzyme-Linked Immunosorbent Assay (ELISA) method (R&D Systems kit DY231) collected by blood before any treatment in patients. Kaplan-Meier method and Cox regression were carried out to obtain the prognostic value, considering significance if p < 0.05. Results With a median follow-up of 36.6 months, 47 deaths occurred. Multivariable Cox regression showed difference of overall survival (OS) associated with sEGFR levels (sEGFR ≤ or > 47.8 ng/mL) in patients with TN cancers, but not of Luminal A, Luminal B or HER2+ subtypes; adjusted by stage, the death risk increased by approximately 415% [hazard ratio (HR): 5.149 (1.900-13.955), p = 0.001] for patients with sEGFR > 47.8 ng/mL compared to patients with a lower sEGFR value. There was no significant correlation of sEGFR with staging, histological tumour grade (G1/G2/G3), Ki67 (< or ≥14%) or body mass index. Conclusions Increased sEGFR expression in patients with TN tumours is a significant predictor of lower OS and its quantification is inexpensive and straightforward.
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Affiliation(s)
- Rogério Agenor de Araújo
- Federal University of Uberlândia, Avenida Pará, Bloco 2U, 1720, Campus Umuarama, Uberlândia, MG, CEP 38400-902, Brazil
- Cancer Research and Prevention Nucleus, Grupo Luta Pela Vida, Cancer Hospital in Uberlândia, Uberlândia, MG, CEP 38405-302, Brazil
- https://orcid.org/0000-0003-4653-6786
| | - Felipe Andrés Cordero da Luz
- Cancer Research and Prevention Nucleus, Grupo Luta Pela Vida, Cancer Hospital in Uberlândia, Uberlândia, MG, CEP 38405-302, Brazil
- https://orcid.org/0000-0002-9381-4913
| | - Eduarda da Costa Marinho
- Cancer Research and Prevention Nucleus, Grupo Luta Pela Vida, Cancer Hospital in Uberlândia, Uberlândia, MG, CEP 38405-302, Brazil
- https://orcid.org/0000-0002-1307-9104
| | - Camila Piqui Nascimento
- Cancer Research and Prevention Nucleus, Grupo Luta Pela Vida, Cancer Hospital in Uberlândia, Uberlândia, MG, CEP 38405-302, Brazil
- https://orcid.org/0000-0002-0955-8559
| | - Lara de Andrade Marques
- Cancer Research and Prevention Nucleus, Grupo Luta Pela Vida, Cancer Hospital in Uberlândia, Uberlândia, MG, CEP 38405-302, Brazil
- https://orcid.org/0000-0002-2734-8352
| | - Patrícia Ferreira Ribeiro Delfino
- Cancer Research and Prevention Nucleus, Grupo Luta Pela Vida, Cancer Hospital in Uberlândia, Uberlândia, MG, CEP 38405-302, Brazil
- https://orcid.org/0000-0002-2196-9318
| | - Rafael Mathias Antonioli
- Cancer Research and Prevention Nucleus, Grupo Luta Pela Vida, Cancer Hospital in Uberlândia, Uberlândia, MG, CEP 38405-302, Brazil
- https://orcid.org/0000-0003-3886-1562
| | - Breno Jeha Araújo
- São Paulo State Cancer Institute of the Medical School of the University of São Paulo, São Paulo, SP, CEP 38405-302, Brazil
- https://orcid.org/0000-0003-4892-9911
| | - Ana Cristina Araújo Lemos da Silva
- Federal University of Uberlândia, Avenida Pará, Bloco 2U, 1720, Campus Umuarama, Uberlândia, MG, CEP 38400-902, Brazil
- https://orcid.org/0000-0002-8220-938X
| | | | - Morun Bernardino Neto
- Department of Basic and Environmental Sciences, University of São Paulo, Lorena, SP, CEP 12602-810, Brazil
- https://orcid.org/0000-0003-4292-7800
| | - Marcelo José Barbosa Silva
- Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, MG, CEP 38405-320, Brazil
- https://orcid.org/0000-0002-5807-4286
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Mukherji R, Yin C, Hameed R, Alqahtani AZ, Kulasekaran M, He AR, Weinberg BA, Marshall JL, Hartley ML, Noel MS. The current state of molecular profiling in gastrointestinal malignancies. Biol Direct 2022; 17:15. [PMID: 35668531 PMCID: PMC9172079 DOI: 10.1186/s13062-022-00322-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/19/2022] [Indexed: 11/10/2022] Open
Abstract
This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead.
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Affiliation(s)
- Reetu Mukherji
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Chao Yin
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Rumaisa Hameed
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Ali Z Alqahtani
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Monika Kulasekaran
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Aiwu R He
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Benjamin A Weinberg
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - John L Marshall
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Marion L Hartley
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Marcus S Noel
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA.
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA.
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Nitipir C, Parosanu AI, Olaru M, Popa AM, Pirlog C, Iaciu C, Vrabie R, Stanciu MI, Oprescu-Macovei A, Bumbacea D, Negrei C, Orlov-Slavu C. Infection and reinfection with SARS-CoV-2 in cancer patients: A cohort study. Exp Ther Med 2022; 23:399. [PMID: 35619634 PMCID: PMC9115626 DOI: 10.3892/etm.2022.11326] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/24/2022] [Indexed: 11/23/2022] Open
Abstract
COVID-19 reinfection, although a controversial issue, is an important clinical problem in cancer patients and beyond. The present study aimed to identify the risk factors associated with worse outcomes in cancer patients with Covid-19 in both first infection and reinfection and to describe the involvement of vaccines in reinfection outcome. The present study enrolled 85 patients with solid tumors who had Covid-19 infection and had not been previously vaccinated. Classical risk factors associated with worse outcomes in cancer patients with second SARS-Cov infection were considered. The patients were followed up retrospectively, measuring mortality at the first and second infection and the vaccination rate after the first infection. The factors associated with the highest risk of mortality at the first infection were, in order of importance: intensive care unit (ICU) admission, unfavorable performance status, radiologically quantifiable presence of oncological disease, and administration of cytotoxic chemotherapy in the period immediately before infection. The risk factors associated with higher mortality from reinfection were ECOG 3-4 performance status and administration of cytotoxic chemotherapy in the period immediately before infection. In the studied patients, mortality from reinfection was not affected by prior vaccination. Thus, bearing in mind all of these risk factors for poor outcomes in cancer patients with solid tumors presenting with Covid-19 can help the treating oncologists make personalized decisions about patient care during the pandemic.
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Affiliation(s)
- Cornelia Nitipir
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Andreea Ioana Parosanu
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mihaela Olaru
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ana Maria Popa
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Cristina Pirlog
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Cristian Iaciu
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Radu Vrabie
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Miruna Ioana Stanciu
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
| | - Anca Oprescu-Macovei
- Department of Gastroenterology, Agrippa Ionescu Emergency Hospital, 011356 Bucharest, Romania
- Department of Gastroenterology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Dragos Bumbacea
- Department of Pneumology, Elias University Emergency Hospital, 11468 Bucharest, Romania
| | - Carolina Negrei
- Department of Toxicology, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Cristina Orlov-Slavu
- Department of Medical Oncology, Elias University Emergency Hospital, 11468 Bucharest, Romania
- Department of Oncology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Modi ND, Danell NO, Perry RNA, Abuhelwa AY, Rathod A, Badaoui S, McKinnon RA, Haseloff M, Shahnam A, Swain SM, Welslau M, Sorich MJ, Hopkins AM. Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer. ESMO Open 2022; 7:100475. [PMID: 35490579 PMCID: PMC9271483 DOI: 10.1016/j.esmoop.2022.100475] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/08/2022] [Accepted: 03/29/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.
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Affiliation(s)
- N D Modi
- College of Medicine and Public Health, Flinders University, South Australia
| | - N O Danell
- College of Medicine and Public Health, Flinders University, South Australia
| | - R N A Perry
- College of Medicine and Public Health, Flinders University, South Australia
| | - A Y Abuhelwa
- College of Medicine and Public Health, Flinders University, South Australia
| | - A Rathod
- College of Medicine and Public Health, Flinders University, South Australia
| | - S Badaoui
- College of Medicine and Public Health, Flinders University, South Australia
| | - R A McKinnon
- College of Medicine and Public Health, Flinders University, South Australia
| | - M Haseloff
- College of Medicine and Public Health, Flinders University, South Australia
| | - A Shahnam
- Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia
| | - S M Swain
- University of Georgetown Medical Center, Washington DC, USA
| | - M Welslau
- Onkologie Aschaffenburg, Aschaffenburg, Germany
| | - M J Sorich
- College of Medicine and Public Health, Flinders University, South Australia
| | - A M Hopkins
- College of Medicine and Public Health, Flinders University, South Australia.
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Dwivedi AR, Kumar V, Prashar V, Verma A, Kumar N, Parkash J, Kumar V. Morpholine substituted quinazoline derivatives as anticancer agents against MCF-7, A549 and SHSY-5Y cancer cell lines and mechanistic studies. RSC Med Chem 2022; 13:599-609. [PMID: 35694693 PMCID: PMC9132193 DOI: 10.1039/d2md00023g] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/01/2022] [Indexed: 11/21/2022] Open
Abstract
A series of morpholine substituted quinazoline derivatives have been synthesized and evaluated for cytotoxic potential against A549, MCF-7 and SHSY-5Y cancer cell lines. These compounds were found to be non-toxic against HEK293 cells at 25 μM and hence display anticancer potential. In these series compounds, AK-3 and AK-10 displayed significant cytotoxic activity against all the three cell lines. AK-3 displayed IC50 values of 10.38 ± 0.27 μM, 6.44 ± 0.29 μM and 9.54 ± 0.15 μM against A549, MCF-7 and SHSY-5Y cancer cell lines. Similarly, AK-10 showed IC50 values of 8.55 ± 0.67 μM, 3.15 ± 0.23 μM and 3.36 ± 0.29 μM against A549, MCF-7 and SHSY-5Y, respectively. In the mechanistic studies, it was found that AK-3 and AK-10 inhibit the cell proliferation in the G1 phase of the cell cycle and the primary cause of death of the cells was found to be through apoptosis. Thus, morpholine based quinazoline derivatives have the potential to be developed as potent anticancer drug molecules.
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Affiliation(s)
- Ashish Ranjan Dwivedi
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Bathinda Punjab 151401 India +91 164 286 4214
| | - Vijay Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Bathinda Punjab 151401 India +91 164 286 4214
| | - Vikash Prashar
- Department of Zoology, School of Biological Sciences, Central University of Punjab Bathinda Punjab 151401 India
| | - Akash Verma
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Bathinda Punjab 151401 India +91 164 286 4214
| | - Naveen Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Bathinda Punjab 151401 India +91 164 286 4214
| | - Jyoti Parkash
- Department of Zoology, School of Biological Sciences, Central University of Punjab Bathinda Punjab 151401 India
| | - Vinod Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Bathinda Punjab 151401 India +91 164 286 4214
- Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab Bathinda Punjab 151401 India
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Bai X, Chen H, Oliver BG. miRNAs-mediated overexpression of Periostin is correlated with poor prognosis and immune infiltration in lung squamous cell carcinoma. Aging (Albany NY) 2022; 14:3757-3781. [PMID: 35508298 PMCID: PMC9134939 DOI: 10.18632/aging.204056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 04/13/2022] [Indexed: 11/25/2022]
Abstract
Lung cancer is one of the most common malignancies with a high mortality rate worldwide. POSTN has been shown to be strongly correlated with the poor prognosis of lung cancer patients. However, the function and mechanism of action of POSTN in lung cancer remain unclear. Here, we carried out a pan-cancer analysis to assess the clinical prognostic value of POSTN based on the TCGA, TIMER, Oncomine, Kaplan-Meier, and UALCAN databases. We found that upregulated POSTN can be a promising biomarker to predict the prognosis of patients with lung cancer. High levels of POSTN correlated with immune cell infiltration in lung cancer, especially lung squamous cell carcinoma (LUSC), which was further confirmed based on the results from the TISIDB database. Moreover, the expression analysis, correlation analysis, and survival analysis revealed that POSTN-targeted miRNAs, downregulation of has-miR-144-3p and has-miR-30e-3p, were significantly linked to poor prognosis in patients with LUSC. Taken together, we identified that POSTN can act as a novel biomarker for determining the prognosis related to immune infiltration in patients with LUSC and deserves further research.
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Affiliation(s)
- Xu Bai
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Hui Chen
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Brian G Oliver
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.,Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, Sydney, NSW 2037, Australia
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Immune Checkpoint Inhibitors in Cancer Therapy. Curr Oncol 2022; 29:3044-3060. [PMID: 35621637 PMCID: PMC9139602 DOI: 10.3390/curroncol29050247] [Citation(s) in RCA: 607] [Impact Index Per Article: 202.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/20/2022] [Accepted: 04/20/2022] [Indexed: 11/17/2022] Open
Abstract
The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab). Unfortunately, not all patients respond favourably to these drugs, highlighting the role of biomarkers such as Tumour mutation burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, and ECM in predicting responses to ICIs-based immunotherapy. The current study aims to review the literature and updates on ICIs in cancer therapy.
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Mudhish EA, Siddique AB, Ebrahim HY, Abdelwahed KS, King JA, El Sayed KA. The Tobacco β-Cembrenediol: A Prostate Cancer Recurrence Suppressor Lead and Prospective Scaffold via Modulation of Indoleamine 2,3-Dioxygenase and Tryptophan Dioxygenase. Nutrients 2022; 14:1505. [PMID: 35406118 PMCID: PMC9003379 DOI: 10.3390/nu14071505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 11/17/2022] Open
Abstract
Prostate cancer (PC) is the second leading cause of death in men in the US. PC has a high recurrence rate, and limited therapeutic options are available to prevent disease recurrence. The tryptophan-degrading enzymes 2,3-indoleamine dioxygenase (IDO1) and tryptophan dioxygenase (TDO2) are upregulated in invasive PC. (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (β-CBT) and its C-4 epimer α-CBT are the precursors to key flavor ingredients in tobacco leaves. Nearly 40-60% of β- and α-CBT are purposely degraded during commercial tobacco fermentation. Earlier, β-CBT inhibited invasion, reversed calcitonin-stimulated transepithelial resistance decrease, and induced tighter intercellular barriers in PC-3M cells. This study demonstrates the in vitro β-CBT anti-migratory (wound-healing assay) and anti-clonogenicity (colony-formation assay) activities against five diverse human PC cell lines, including the androgen-independent PC-3, PC-3M, and DU-145, the castration-recurrent CWR-R1ca, and the androgen-dependent CWR-22rv1. Meanwhile, β-CBT potently suppressed in vivo locoregional and distant recurrences after the primary tumor surgical excision of PC-3M-Luc cell tumor engrafted in male nude mice. β-CBT treatments suppressed organ and bone metastasis and lacked any major toxicity over the 60-day study course. β-CBT treatments significantly suppressed IDO1, TDO2, and their final metabolite kynurenine levels in PC-3M cells. β-CBT treatments significantly suppressed the tumor recurrence marker PSA and kynurenine levels in treated animals' plasma. β-CBT emerges as a promising PC recurrence suppressive lead.
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Affiliation(s)
- Ethar A. Mudhish
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (E.A.M.); (A.B.S.); (H.Y.E.); (K.S.A.)
| | - Abu Bakar Siddique
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (E.A.M.); (A.B.S.); (H.Y.E.); (K.S.A.)
| | - Hassan Y. Ebrahim
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (E.A.M.); (A.B.S.); (H.Y.E.); (K.S.A.)
| | - Khaldoun S. Abdelwahed
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (E.A.M.); (A.B.S.); (H.Y.E.); (K.S.A.)
| | - Judy Ann King
- Department of Pathology and Translational Pathobiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA;
| | - Khalid A. El Sayed
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (E.A.M.); (A.B.S.); (H.Y.E.); (K.S.A.)
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Miyai Y, Sugiyama D, Hase T, Asai N, Taki T, Nishida K, Fukui T, Chen-Yoshikawa TF, Kobayashi H, Mii S, Shiraki Y, Hasegawa Y, Nishikawa H, Ando Y, Takahashi M, Enomoto A. Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade. Life Sci Alliance 2022; 5:5/6/e202101230. [PMID: 35236758 PMCID: PMC8897596 DOI: 10.26508/lsa.202101230] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 02/18/2022] [Accepted: 02/18/2022] [Indexed: 12/18/2022] Open
Abstract
Meflin/ISLR is the marker of a cancer-associated fibroblast subset that enhances tumor response to immune checkpoint blockade therapy. Cancer-associated fibroblasts (CAFs) are an integral component of the tumor microenvironment (TME). Most CAFs shape the TME toward an immunosuppressive milieu and attenuate the efficacy of immune checkpoint blockade (ICB) therapy. However, the detailed mechanism of how heterogeneous CAFs regulate tumor response to ICB therapy has not been defined. Here, we show that a recently defined CAF subset characterized by the expression of Meflin, a glycosylphosphatidylinositol-anchored protein marker of mesenchymal stromal/stem cells, is associated with survival and favorable therapeutic response to ICB monotherapy in patients with non-small cell lung cancer (NSCLC). The prevalence of Meflin-positive CAFs was positively correlated with CD4-positive T-cell infiltration and vascularization within non-small cell lung cancer tumors. Meflin deficiency and CAF-specific Meflin overexpression resulted in defective and enhanced ICB therapy responses in syngeneic tumors in mice, respectively. These findings suggest the presence of a CAF subset that promotes ICB therapy efficacy, which adds to our understanding of CAF functions and heterogeneity.
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Affiliation(s)
- Yuki Miyai
- Department of Pathology, Nagoya University Hospital, Nagoya, Japan.,Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Daisuke Sugiyama
- Department of Immunology, Nagoya University Hospital, Nagoya, Japan
| | - Tetsunari Hase
- Department of Respiratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Naoya Asai
- Department of Pathology, Nagoya University Hospital, Nagoya, Japan
| | - Tetsuro Taki
- Department of Pathology, Nagoya University Hospital, Nagoya, Japan
| | - Kazuki Nishida
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Takayuki Fukui
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Hiroki Kobayashi
- Department of Pathology, Nagoya University Hospital, Nagoya, Japan
| | - Shinji Mii
- Department of Pathology, Nagoya University Hospital, Nagoya, Japan
| | - Yukihiro Shiraki
- Department of Pathology, Nagoya University Hospital, Nagoya, Japan
| | - Yoshinori Hasegawa
- Department of Respiratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Hiroyoshi Nishikawa
- Department of Immunology, Nagoya University Hospital, Nagoya, Japan.,Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | | | - Atsushi Enomoto
- Department of Pathology, Nagoya University Hospital, Nagoya, Japan
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Stefanska B, Tucker SJ, MacEwan DJ. Themed issue: 'New avenues in cancer prevention and treatment'. Br J Pharmacol 2022; 179:2789-2794. [PMID: 35146753 DOI: 10.1111/bph.15715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Barbara Stefanska
- Food Nutrition and Health Program, Faculty of Land and Food Systems, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Steven J Tucker
- School of Medicine, Medical Science and Nutrition, University of Aberdeen, Aberdeen, UK
| | - David J MacEwan
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
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