Real-world cardiovascular toxicity of immune checkpoint inhibitors in cancer patients: a retrospective controlled cohort study

Over the past decade, immune checkpoint inhibitors (ICI) have dramatically improved the prognosis of many cancer patients, but many immune-related adverse cardiovascular events (ACEs) have been observed. We aimed to investigate the occurrence of ACEs in the real world after receiving ICI and provide clinical reference for how to evaluate it. The study retrospectively included 204 patients who received ICI from October 2019 to November 2020 and 205 patients who only received traditional chemotherapy. The mean duration of follow-up for ICI group was 4.88 months, and the control group was 4.79 months. Patients in the control group did not develop myocarditis, only 2 cases of new-onset pericardial effusion occurred. In contrast, among ICI group, there were 3 cases of ICI-associated myocarditis, accounting for 1.47% (3/204), 6 cases of pericardial effusion. The incidence of new-onset ECG abnormalities in the ICI group was significantly higher than that of the control group (38/180 VS 16/178, HR 2.71, 95% CI: 1.449-5.067, P=0.001). In the ICI group, after receiving ICI treatment, cardiac biomarkers including average cardiac troponin T and N terminal pro B type natriuretic peptide increased significantly, peak in about 1 month, and then gradually decreasing. After the third or fourth month, the cardiac biomarkers gradually increased again. In conclusion, ICI may lead to various ACEs, and its incidence is higher than that of patients who only receive traditional chemotherapy. The changing trend of cardiac biomarkers reflects that ICI may cause acute and chronic myocardial damage. Regularly performing ECG, echocardiogram and cardiac biomarker examinations are helpful for early detection of ACEs caused by ICI and providing timely treatment.     

Similarities and differences in the coupling of human beta1- and beta2-adrenoceptors to Gs(alpha) splice variants

The human beta1-adrenoceptor (beta1AR) and beta2-adrenoceptor (beta2AR) couple to Gs-proteins to activate adenylyl cyclase (AC). There are differences in desensitization between the beta2AR and the originally cloned Gly389-beta1AR, but with respect to ternary complex formation, constitutive activity, and AC activation the picture is unclear. To learn more about the similarities and differences between the beta1AR and beta2AR, we analyzed coupling of the Gly389-beta1AR to the G(s(alpha)) splice variants Gs(alpha)L and Gs(alpha)S using beta1AR-Gs(alpha) fusion proteins expressed in Sf9 cells and compared the data with previously published data on beta2AR-Gs(alpha) fusion proteins (Seifert et al., J Biol Chem 1998;273:5109-16). Fusion ensures defined receptor/G-protein stoichiometry and efficient coupling. The agonist (-)-isoproterenol stabilized the ternary complex at beta1AR-Gs(alpha)S, beta1AR-Gs(alpha)L, beta2AR-Gs(alpha)S, and beta2AR-Gs(alpha)L with similar efficiency. beta1AR-Gs(alpha)L but not beta1AR-Gs(alpha)S showed the hallmarks of constitutive activity as assessed by increased potencies and efficacies of partial agonists and AC activation by the agonist-free receptor. Similar differences were observed previously for beta2AR-Gs(alpha)S and beta2AR-Gs(alpha)L. beta1AR-Gs(alpha)S and beta2AR-Gs(alpha)S were similarly efficient at activating AC, but beta1AR-Gs(alpha)L was approximately 4-fold more efficient at activating AC than beta2AR-Gs(alpha)L. Our data show that (i) the beta1AR and beta2AR are similarly efficient at stabilizing the ternary complex with Gs(alpha) splice variants, (ii) Gs(alpha)L confers constitutive activity to the beta1AR and beta2AR, and (iii) the beta1AR coupled to Gs(alpha)L is more efficient at activating AC than the beta2AR coupled to Gs(alpha)L. These data help us understand some of the discrepancies regarding similarities and differences between the beta1AR and beta2AR.     

Checkpoint inhibitor myasthenia-like syndrome and myositis associated with extraocular muscle atrophy

A patient with metastatic melanoma developed myasthenia-like syndrome and paraspinal myositis with subsequent extraocular muscle atrophy associated with immune checkpoint inhibitor treatment. MRI scan of the ocular muscles on admission was normal, however 3 months later revealed significant extraocular muscle atrophy.     

免疫检查点抑制剂耐药机制的研究进展

肿瘤免疫治疗尤其是免疫检查点抑制剂（ICI）治疗已成为目前肿瘤治疗研究领域的热点。随着ICI在肿瘤领域广泛应用,ICI治疗给人类带来新的希望,但是真实世界里的数据显示：部分患者从中获益,部分患者治疗有效一段时间后,病情出现进展或复发,还有部分患者一开始就对ICI治疗无应答,因此可以将ICI的耐药分为原发性、适应性和获得性耐药。本文就肿瘤ICI治疗的各耐药机制作一综述。     

Pathology of immune checkpoint inhibitor-induced injury of the gastrointestinal tract and hepatobiliary system

Immune checkpoint inhibitors (ICIs) are becoming the standard of care treatment for many malignancies. ICIs are associated with a unique spectrum of immune-related adverse events (irAEs) due to the blockade of inhibitory signals of immune activation. The main objective of this study is to review the characteristic histological features and pathologic differential diagnosis of ICI-related injury of the gastrointestinal (GI) tract and hepatobiliary system. Diarrhea and hepatitis are some of the more common irAEs. The pathology of ICI-related injury is both diverse and largely non-specific, with various site-specific findings to become familiar with. Early and accurate recognition of an irAE is important in order to initiate proper management. This generally includes withdrawal of ICI therapy, and possibly the administration of a corticosteroid or other immunosuppressives depending on the severity of injury.     

Effects of Oestradiol and the Oestrogen Antagonist lei 182,780 on the Delayed Type Hypersensitivity (DTH) Index and on Serum Levels of lgM and lgG in Ovariectomised Balb/C and MRL/Mp-Lpr/Lpr Mice,a Model of Systemic Lupus Erythematosus (SLE)

The effects of oestradiol and the oestrogen receptor antagonist ICI 182,780 were investigated on the DTH index, serum IgG and IgM levels and spleen weight in female BALB/c and MRLIMP-Ipr/lpr mice. At six weeks, the mice were ovariectomisecl, and one week later, over a four-week period, given biweekly s.c. doses of (i) 5μJ l of oli ve oil, or (i i) 5 μ1 of oil containing 3.2 μg of 17β-oestradiol (E2), or (iii) 5 μl of oil containing (3.2 μl of E2 + ICI 182,780 , at a dose of 30 mg/kg), or (iv) the same dose of ICI 182,780 alone. E2 significantly raised the DTH index in BALB/c mice; this effect was prevented if ICI 182,780 was included in the injectio n . The DTH index in MRL mice was unaffected by any of the treatments. All steroid u·eatments raised serum IgG levels in BALB/c mice, but those in sera of MRL were un affected and were significantly higher than those measured in BALB/c mice . ICI 182,780 depressed TgM in BALB/c mice, while all steroidtreatments increased JgM in MRL mice. ICI 182,780 de pressed spleen weights in both strains. Oes u·ogen may influence Bcell functiontlu·ough ICI 182,780-se nsitive receptors, and ICI 182,780 may have agonist actions on the immune system. (200 words)     

17β-Estradiol stimulates the translocation of endogenous estrogen receptor α at the plasma membrane of normal anterior pituitary cells

In the present work we aimed at identifying ERα in the plasma membrane of normal anterior pituitary cells and investigated if 17β-estradiol was able to induce their subcellular redistribution. Our results show that about 8% of anterior pituitary cells expressed ERα in the plasma membrane, with the geometrical mean fluorescence intensity being increased after steroid hormone treatment. 17β-Estradiol and the selective ERα agonist PPT induced an increase of ERα expression in the plasma membrane and activated the PKCα/ERK 1/2 pathway in a time-course not compatible with genomic actions, thus supporting the notion of membrane-initiated effects. These findings suggest that 17β-estradiol stimulates the translocation of endogenous ERα to the plasma membrane, consequently modulating this ER pool and leading to cellular biological effects in normal anterior pituitary gland.