(searched for: 10.29328/journal.jccm.1001111)
Published: 12 March 2021
Journal of Cardiology and Cardiovascular Medicine, Volume 6, pp 019-022; https://doi.org/10.29328/journal.jccm.1001111
This presentation gives a description of the muscle and sarcomere followed by the main content summarized.
EBioMedicine, Volume 57; https://doi.org/10.1016/j.ebiom.2020.102859
Liver cirrhosis consists of an asymptomatic compensated phase and a decompensated phase, which can cause two pulmonary vascular complications: hepatopulmonary syndrome (HPS) characterized by hypoxia, intrapulmonary microvasculature dilatation, angiogenesis and arterio-venous malformations (AVMs) [1Koch D.G. Fallon M.B. Hepatopulmonary syndrome.Clin Liver Dis. 2014; 18: 407-420http://dx.doi.org/10.1016/j.cld.2014.01.003Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar]; and portopulmonary hypertension (PoPH) characterized by increased pulmonary vascular resistance and pulmonary arterial hypertension (PAH) in the absence of other etiologies of PAH [2Iqbal S. Smith K.A. Khungar V. Hepatopulmonary syndrome and portopulmonary hypertension.Clin Chest Med. 2017; 38: 785-795http://dx.doi.org/10.1016/j.ccm.2017.08.002Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. Previous studies have shown that PoPH and HPS are associated with markedly reduced bone morphogenetic protein (BMP) 9/10 [3Rochon E.R. Krowka M.J. Bartolome S. Heresi G.A. Bull T. Roberts K. et al.. BMP 9/10 in pulmonary vascular complications of liver disease.Am J Respir Crit Care Med. 2020; http://dx.doi.org/10.1164/rccm.201912-2514leCrossref PubMed Scopus (2) Google Scholar, 4John M. Kim K.J. Bae S.D.W. Qiao L. George J. Role of BMP-9 in human liver disease.Gut. 2019; 68: 2097-2100http://dx.doi.org/10.1136/gutjnl-2018-317543Crossref PubMed Scopus (5) Google Scholar] and increased soluble endoglin (sEng) levels [5Owen N.E. Alexander G.J. Sen S. Bunclark K. Polwarth G. Pekpe-zaba J. et al.Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis.EBioMedicine. 2020; 56102794http://dx.doi.org/10.1016/j.ebiom.2020.102794Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Approximately 4–40% of cirrhotic patients could develop into HPS [6Soulaidopoulos S. Cholongitas E. Giannakoulas G. Vlachou M. Goulis I. Review article: update on current and emergent data on hepatopulmonary syndrome.World J Gastroenterol. 2018; 24: 1285-1298http://dx.doi.org/10.3748/wjg.v24.i12.1285Crossref PubMed Scopus (14) Google Scholar] and PoPH can develop in 1–6% of patients with portal vein hypertension [7Savale L. Guimas M. Ebstein N. Fertin M. Jevnikar M. Renard S. et al.. Portopulmonary hypertension in the current era of pulmonary hypertension management.Journal of Hepatology. 2020; http://dx.doi.org/10.1016/j.jhep.2020.02.021Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. Both of these complications can increase the mortality rate in liver cirrhotic patients and there are few effective precautionary or therapeutic measurements except liver transplantation [8Cosarderelioglu C. Cosar A.M. Gurakar M. Pustavoitau A. Russell S.D. Dagher N.N. et al.Portopulmonary hypertension and liver transplant: recent review of the literature.Exp Clin Transplant. 2016; 14: 113-120PubMed Google Scholar, 9Sendra C. Carballo-Rubio V. Sousa J.M. Hepatopulmonary syndrome and portopulmonary hypertension: management in liver transplantation in the horizon 2020.Transplant. Proc. 2020; http://dx.doi.org/10.1016/j.transproceed.2020.02.057Crossref PubMed Scopus (1) Google Scholar]. The study recently published in EBioMedicine by Owen and co-workers contribute to the literature from three aspects.
Frontiers in Oncology, Volume 9; https://doi.org/10.3389/fonc.2019.00365
Editorial on the Research TopicManagement of Immune-Related Adverse Events for Patients Undergoing Treatment With Checkpoint Inhibitors Immunotherapy with immune checkpoint inhibitors has emerged as the most significant advance in the treatment of cancer in recent years and has revolutionized cancer management (1). Until recently, it had been assumed that the immune system was not effective in protecting humans against the development of neoplastic diseases. Checkpoints inhibitors are co-receptors expressed by T cells. These co-receptors regulate T cell activation negatively and play a central role in the maintenance of peripheral self-tolerance. Co-inhibitory receptor ligands are significantly expressed in a variety of malignancies resulting in evasion of anti-cancer immunity. These molecules include programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and were discovered by Tasuku Honjo and James P. Allison in 1992 and 1996, respectively (2, 3). These scientists were jointly awarded the 2018 Nobel Prize for Physiology or Medicine in recognition of this ground-breaking research. Monoclonal antibodies targeting the CTLA-4 and PD-1 and their ligands have produced significant clinical responses against a variety of malignancies (4). FDA registered checkpoint inhibitors include pembrolizumab (5), nivolumab (6), cemiplimab (7), atezolizumab (8), darvolumab (9) and avelumab (10) for numerous indications including melanoma, lung cancer (small and non-small cell types), bladder cancer, Hodgkin's disease and others (5–10). Other co-inhibitory molecules under research include T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) (11), Lymphocyte activation gene-3 (LAG-3) (12), V-domain Ig-containing Suppressor of T cell Activation (VISTA) (13), and B- and T-lymphocyte attenuator (BTLA) (14). Treatment with antibodies inhi biting immune checkpoints are well-tolerated by the vast majority of patients and are less toxic compared to standard anticancer chemotherapy agents. These immune side-effects are referred to as immune-related adverse events (IrAE) (15). These toxicities include fatigue, dermatological, gastrointestinal, hepatic, pulmonary, endocrine, ocular, neurological, and rare toxicities such as diabetes, cardiac and hematological. Dermatological toxicities can appear following the first dose of an immune checkpoint inhibitor and can be ongoing. These rashes are frequently maculopapular and mild in nature (16). Rash, and generalized pruritus occur more commonly with CTLA-4 inhibitors compared to anti-PD-1 inhibitors (17). Rare cases of serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported (18). The development of vitiligo occurs in a small percentage of patients receiving immunotherapy with checkpoint inhibitors and is associated with long term survival and clinical benefit (19). Gastrointestinal side effects can occur in the form of mucositis, aphthous ulcers, gastritis, colitis, and abdominal pain. Diarrhea, with blood or mucus in the stool, can be observed. In severe cases, these complications can evolve to toxic megacolon and perforation and must be ruled out in patients with peritonitis symptoms (20). Other infectious causes of diarrhea such as Clostridium difficile infection can be associated in severe cases (20). Immune-related pneumonitis is a serious IrAE reported in patients undergoing immune checkpoint inhibition. Pneumonitis is more common with PD-1 and PDL-1 blockers, however the incidence is < 1% and presents later during the treatment phase (21). Patients undergoing immunotherapy, experiencing new symptoms of dyspnea or cough, should alert the clinician. This complication could be fatal (21). Endocrine IrAE symptoms are generally non-specific and include fatigue, mental state changes, headaches and dizziness related to hypotension (22). Hypophysitis and hypothyroidism are the most common abnormalities documented (22). Clinicians should screen for thyroid abnormalities and baseline thyroid function tests. Other hormone assays may be indicated in some patients. Ophthalmological IrAE in the form of mild, moderate or severe episcleritis, uveitis or conjunctivitis has been described (23). Neurological IrAE includes posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis, and Guillain-Barre syndrome (24). Less frequent IrAE's include red cell aplasia (25), neutropenia (25), acquired hemophilia A (25), thrombocytopenia (25), hemolytic-uremic syndrome (25), pancreatitis (26), asymptomatic raise in amylase and lipase (26), renal insufficiency with nephritis (27), arthritis (28), and myocarditis (Tajiri and Ieda). Contributors to this research topic in Frontiers in Pharmacology and Frontiers in Oncology describe the importance of understanding this new class of drugs and their unique toxicities. Other areas covered include a description the current understanding of the basic mechanism of immune dysregulation in cancer patients undergoing immune checkpoint inhibitor treatment as well as potential predictive strategies for future clinical practice (Anderson and Rapoport). A second manuscript describes an unusual patient with persistent pruritus and lichenoid reaction secondary to anti-PD1 checkpoint inhibitor managed with narrowband ultraviolet B phototherapy (Donaldson et al.). A third manuscript explains the management of gastrointestinal toxicity with special reference to the immune homeostasis in the gastrointestinal tract (Dougan) and lastly a meta-analysis describing the relative risk and incidence of immune checkpoint inhibitor related pneumonitis in patients with advanced cancer (Ma et al.). It must be emphasized that IrAEs are usually low-grade and controllable; however, the reporting of these irAEs is generally suboptimal (29). Oncologists should be aware that there is a wide range of additional distinctive toxicities and side effects that can be unpredictable and severe in nature. As these agents will, in the future, be administered with targeted therapies, vaccines, chemotherapy or radiation therapy it is possible that the incidence and severity of these toxocities may change. The different mechanisms of action of anti-CTLA-4 and anti-PD-1/anti-PD-L1 antibodies resulted in the development of clinical studies investigating combination therapies in a variety of malignancies including metastatic renal cell cancer and metastatic malignant melanoma. The incidence of serious grade 3 and grade 4 adverse events due to the combination of ipilimumab and nivolumab were present in approximately half of patients. The incidence of these toxicities was significantly higher than either antibody administered separately resulting in treatment interruption in one-third of patients (30). Clinical recommendations for managing irAEs arise from general clinical consensus and experience, as there are no prospective trials to assess whether one treatment strategy is superior to another. Although controversial; there are reports suggesting that the development of irAEs is associated with improvement in survival in patients with advanced or recurrent malignancy treated with immune checkpoint inhibitors (31). Finally, early detection of IrAEs and proactive and adressive management by clinicians is critical to lower morbidity and mortality. The author confirms being the sole contributor of this work and has approved it for publication. MDS: Advisory Board and Speaker Engagements; BMS: Advisory Board and Speaker Engagements; AstraZeneca: Advisory Board and Speaker Engagements. 1. D'Arrigo P, Tufano M, Rea A, Vigorito V, Novizio N, Russo S, et al. Manipulation of the immune system for cancer defeat: a focus on the T cell inhibitory checkpoint molecules. Curr Med Chem. (2018). doi: 10.2174/0929867325666181106114421. [Epub ahead of print]. PubMed Abstract | CrossRef Full Text | Google Scholar 2. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. (1992) 11:3887–95. PubMed Abstract | Google Scholar 3. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. (1996) 271:1734–6. PubMed Abstract | Google Scholar 4. Sledzinska A, Menger L, Bergerhoff K, Peggs KS, Quezada SA. Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy. Mol Oncol. (2015) 10:1936–65. doi: 10.1016/j.molonc.2015.10.008 CrossRef Full Text | Google Scholar 5. Khoja L, Butler MO, Kang SP, Ebbinghaus S, Joshua AM. Pembrolizumab. J Immunother Cancer. (2015) 3:36. doi: 10.1186/s40425-015-0078-9 PubMed Abstract | CrossRef Full Text | Google Scholar 6. Scott LJ. Nivolumab: a review in advanced melanoma. Drugs. (2015) 12:1413–24. doi: 10.1007/s40265-015-0442-6 CrossRef Full Text | Google Scholar 7. Markham A, Duggan S. Cemiplimab: first global approval. Drugs. (2018) 17:1841–6. doi: 10.1007/s40265-018-1012-5 CrossRef Full Text | Google Scholar 8. Shah NJ, Kelly WJ, Liu SV, Choquette K, Spira A. Product review on the Anti-PD-L1 antibody atezolizumab. Hum Vaccin Immunother. (2018) 2:269–76. doi: 10.1080/21645515.2017.1403694 CrossRef Full Text | Google Scholar 9. Syed YY. Durvalumab: first global approval. Drugs. (2017) 12:1369–76. doi: 10.1007/s40265-017-0782-5 CrossRef Full Text | Google Scholar 10. Kim ES. Avelumab: first global approval. Drugs. (2017) 8:929–37. doi: 10.1007/s40265-017-0749-6 CrossRef Full Text | Google Scholar 11. Du W, Yang M, Turner A, Xu C, Ferris RL, Huang J, et al. TIM-3 as a Target for cancer immunotherapy and mechanisms of action. Int J Mol Sci. (2017) 3:E645. doi: 10.3390/ijms18030645 CrossRef Full Text | Google Scholar 12. Andrews LP, Marciscano AE, Drake CG, Vignali DA. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. (2017) 1:80–96. doi: 10.1111/imr.12519 CrossRef Full Text | Google Scholar 13. Nowak EC, Lines JL, Varn FS, Deng J, Sarde A, Mabaera R, et al. Immunoregulatory functions of VISTA. Immunol Rev. (2017) 1:66–79. doi: 10.1111/imr.12525 CrossRef Full Text | Google Scholar 14. Spodzieja M, Lach S, Iwaszkiewicz J, Cesson V, Kalejta K, Olive D, et al. Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses. PLoS ONE. (2017) 6:e0179201. doi: 10.1371/journal.pone.0179201 CrossRef Full Text | Google Scholar 15. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. (2018) 360:k793. doi: 10.1136/bmj.k793 PubMed Abstract | CrossRef Full Text | Google Scholar 16. Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. (2018) 3:345–61. doi: 10.1007/s40257-017-0336-3 CrossRef Full Text | Google Scholar 17. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. (2015) 5:560–75. doi: 10.3978/j.issn.2218-6751.2015.06.06 CrossRef Full Text | Google Scholar 18. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. (2012) 21:2691–7. doi: 10.1200/JCO.2012.41.6750 CrossRef Full Text | Google Scholar 19. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. (2016) 1:45–51. doi: 10.1001/jamadermatol.2015.2707 CrossRef Full Text | Google Scholar 20. Rapoport BL, van Eeden R, Sibaud V, Epstein JB, Klastersky J, Aapro M, et al. Supportive care for patients undergoing immunotherapy. Support Care Cancer. (2017) 10:3017–30. doi: 10.1007/s00520-017-3802-9 CrossRef Full Text | Google Scholar 21. Possick JD. Pulmonary toxicities from checkpoint immunotherapy for malignancy. Clin Chest Med. (2017) 2:223–32. doi: 10.1016/j.ccm.2016.12.012 CrossRef Full Text | Google Scholar 22. Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. (2017) 58:70–6. doi: 10.1016/j.ctrv.2017.06.002 PubMed Abstract | CrossRef Full Text | Google Scholar 23. Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. (2016) 4:288–94. doi: 10.1097/CCO.0000000000000296 CrossRef Full Text | Google Scholar 24. Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol. (2017) 6:659–68. doi: 10.1097/WCO.0000000000000503 CrossRef Full Text | Google Scholar 25. Delanoy N, Michot JM, Comont T, Kramkimel N, Lazarovici J, Dupont R, et al. Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study. Lancet Haematol. (2019) 1:e48–57. doi: 10.1016/S2352-3026(18)30175-3 PubMed Abstract | CrossRef Full Text | Google Scholar 26. Ikeuchi K, Okuma Y, Tabata T. Immune-related pancreatitis secondary to nivolumab in a patient with recurrent lung adenocarcinoma: a case report. Lung Cancer. (2016) 99:148–50. doi: 10.1016/j.lungcan.2016.07.001 PubMed Abstract | CrossRef Full Text | Google Scholar 27. Murakami N, Motwani S, Riella LV. Renal complications of immune checkpoint blockade. Curr Probl Cancer. (2017) 2:100–10. doi: 10.1016/j.currproblcancer.2016.12.004 CrossRef Full Text | Google Scholar 28. Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. (2017) 1:43–50. doi: 10.1136/annrheumdis-2016-209595 CrossRef Full Text | Google Scholar 29. Chen TW, Razak AR, Bedard PL, Siu LL, Hansen AR. A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol. (2015) 9:1824–9. doi: 10.1093/annonc/mdv182 CrossRef Full Text | Google Scholar 30. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. (2015) 1:23–34. doi: 10.1056/NEJMoa1504030 CrossRef Full Text | Google Scholar 31. Ricciuti B, Genova C, De Giglio A, Bassanelli M, Dal Bello MG, Metro G, et al. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. J Cancer Res Clin Oncol. (2019) 2:479–85. doi: 10.1007/s00432-018-2805-3 CrossRef Full Text | Google Scholar Keywords: immune related adverse effects, colitis, pneumonitis, anti CTLA 4, anti-PD 1 Citation: Rapoport BL (2019) Editorial: Management of Immune-Related Adverse Events for Patients Undergoing Treatment With Checkpoint Inhibitors. Front. Oncol. 9:365. doi: 10.3389/fonc.2019.00365 Received: 28 February 2019; Accepted: 18 April 2019; Published: 08 May 2019. Edited and reviewed by: Copyright © 2019 Rapoport. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Bernardo Leon Rapoport, [email protected]
Journal of Contingencies and Crisis Management, Volume 23, pp 183-183; https://doi.org/10.1111/1468-5973.12089