Atherosclerotic Cardiovascular Events in Cancer Patients Treated With Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective therapies for numerous cancers, but have been associated with atherosclerotic cardiovascular disease (ASCVD). This study aimed to identify predictors for ASCVD events among cancer patients treated with ICIs and the cardiovascular risk factor (CVRF) control of those who developed ASCVD. METHOD: A single-centre retrospective study of 366 cancer patients who received ICIs from 2018 to 2020 was performed. Demographic, baseline CVRF, cancer history, and ICI regimen data were obtained from medical records. The primary end point of ASCVD events was defined as myocardial infarction, coronary revascularisation, ischaemic stroke, or acute limb ischaemia. Cox proportional multivariable modelling and competing risks analysis were performed to assess ASCVD predictors. Descriptive analysis was performed to describe CVRF management among those who developed ASCVD events. RESULTS: Over a median follow-up of 3.4 years (2.8-4.3), 26 patients (7.1%) experienced 27 ASCVD events (seven myocardial infarction, one coronary revascularisation, 13 ischaemic stroke, and six acute limb ischaemia events). There were 226 (61.8%) cancer-related deaths and no cardiac deaths. History of ASCVD before ICI initiation was independently associated with ASCVD events on traditional Cox modelling (hazard ratio [HR] 4.00; 95% confidence interval [CI] 1.79-8.91; p<0.01) and competing risks analysis (HR 4.23; 95% CI 1.87-9.60; p<0.01). A total of 17 patients developed ASCVD events after ICI cessation (median 1.4 years). Among those with ASCVD events, 12 had prior ASCVD, 16 had hypertension, nine had hypercholesterolaemia, and four had diabetes, and nine were actively smoking. Variable prescription of cardiovascular preventative therapies was noted. CONCLUSIONS: History of ASCVD was associated with subsequent ASCVD events among patients treated with ICIs, which could occur even after active treatment was stopped. Identification and aggressive management of modifiable CVRFs should be considered throughout cancer survivorship in patients who received ICI treatment.

Inter-software and inter-scan variability in measurement of epicardial adipose tissue: a three-way comparison of a research-specific, a freeware and a coronary application software platform.

OBJECTIVES: Epicardial adipose tissue (EAT) is a proposed marker of cardiovascular risk; however, clinical application may be limited by variability in post-processing software platforms. We assessed inter-vendor agreement of EAT volume (EATv) and attenuation on both contrast-enhanced (CE) and non-contrast CT (NCT) using a standard coronary CT reporting software (Vitrea), an EAT research-specific software (QFAT) and a freeware imaging software (OsiriX). METHODS: Seventy-six consecutive patients undergoing simultaneous CE and NCT had complete volumetric EAT measurement. Between-software, within-software NCT vs. CE, and inter- and intra-observer agreement were evaluated with analysis by ANOVA (with post hoc adjustment), Bland-Altman with 95% levels of agreement (LoA) and intraclass correlation coefficient (ICC). RESULTS: Mean EATv (freeware 53 ± 31 mL vs. research 93 ± 43 mL vs. coronary 157 ± 64 mL) and attenuation (freeware - 72 ± 25 HU vs. research - 75 ± 3 HU vs. coronary - 61 ± 10 HU) were significantly different between all vendors (ANOVA p < 0.001). EATv was consistently higher in NCT vs. CE for all software packages, with most reproducibility found in research software (bias 26 mL, 95% LoA: 2 to 56 mL), compared to freeware (bias 11 mL 95% LoA: - 46 mL to 69 mL) and coronary software (bias 10 mL 95% LoA: - 127 to 147 mL). Research software had more comparable NCT vs. CE attenuation (- 75 vs. - 72 HU) compared to freeware (- 72 vs. - 57 HU) and coronary (- 61 vs. - 39 HU). Excellent inter-observer agreement was seen with research (ICC 0.98) compared to freeware (ICC 0.73) and coronary software (ICC 0.75) with narrow LoA on Bland-Altman analysis. CONCLUSION: There are significant inter-vendor differences in EAT assessment. Our study suggests that research-specific software has better agreement and reproducibility compared to freeware or coronary software platforms. KEY POINTS: • There are significant differences between EAT volume and attenuation values between software platforms, regardless of scan type. • Non-contrast scans routinely have higher mean EAT volume and attenuation; however, this finding is only consistently seen with research-specific software. • Of the three analyzed packages, research-specific software demonstrates the highest reproducibility, agreement, and reliability for both inter-scan and inter-observer agreement.

Breast arterial calcification and epicardial adipose tissue volume, but not density are independently associated with cardiovascular risk.

BACKGROUND: Mammographically detected breast arterial calcification (BAC) has been proposed as surrogate marker for coronary artery disease (CAD) in women. Epicardial adipose tissue (EAT) and peri-coronary adipose tissue (PCAT) are inflammatory fat depots linked to atherogenesis. BAC has demonstrated association with inflammation, therefore we aimed to determine the association between BAC, EAT and PCAT. METHODS: Single-centre, retrospective, cross-sectional study of women with digital mammography and coronary computed tomography angiography (CCTA). EAT and PCAT were quantitively assessed using semi-automated software. Patient demographics and cardiovascular risk factors were obtained from medical records and mammograms reviewed for BAC. Pre-test cardiovascular risk was determined with CAD Consortium Score. Chi-square, t-test and Mann-Whitney U tests were used to assess between group differences. Multivariable linear and logistic regression modelling was conducted to adjust for confounders. RESULTS: Among 153 patients (age 61, SD 11) included in this study, BAC was present in 37 (24%) patients. BAC-positive patients had higher EAT volume (EATv) (110.2 mL, SD 41 mL vs 94.4 mL, SD 41 mL, p = 0.02) but this association was not significant after adjusting for cardiovascular risk factors (p = 0.26). BAC did not associate with EAT density or PCAT. BAC and EATv were strongly associated with cardiovascular risk and CAD independent of each other: CV risk (BAC OR 7.55 (3.26-18.49), p < 0.001, EATv OR 1.02 (1.01-1.03), p < 0.001), CAD presence (BAC OR 4.26 (1.39-13), p = 0.01; EATv OR 1.01 (1.0-1.03), p = 0.04). CONCLUSION: BAC and EATv are independent predictors of CV risk and CAD, but don't independently associate with each other, the relationship confounded by shared cardiovascular risk factors. BAC doesn't appear to associate with adipose tissue density and its presence may be cumulative result of long-term exposure to CV risk factors.

A pilot randomized placebo-controlled study on modified MaZiRenWan: a formulated Chinese medicine to relieve constipation for palliative cancer patients.

BACKGROUND: Constipation is a common problem among advanced cancer patients; however, many of them find limited effective from current therapies. Thus, we aimed to test the effect of a traditional Chinese herbal formula, modified MaZiRenWan (MZRW), by comparing with placebo among palliative cancer patients with constipation. METHODS: This is a randomized, double-blind, placebo-controlled trial. Participants aged over 18 were recruited and randomized to MZRW or placebo group in addition to current prescriptions (including ongoing laxatives treatment) for two weeks. Exclusion criteria included cognitive impairment, presence of a colostomy or gastrointestinal obstruction and estimated life expectancy of less than one month. Individualized modification of MZRW was allowed according to the traditional Chinese medicine (TCM) pattern of patient. The primary outcome was the global assessment of improvement, which reflected whether the constipation had improved, remained the same or worsened. RESULTS: Sixty patients, with mean age 75.2 years (range 47-95 years), were randomized to MZRW or placebo group. Among the MZRW group, 59.3% (16/27) had improvement in the global assessment score, as compared with 28.6% (8/28) of the placebo group (p-value = 0.022). Besides, the MZRW group had significant increase in stool frequency, and reduction in constipation severity and straining of defecation (p-value < 0.05). No serious adverse event was reported due to the research medication. CONCLUSION: This pilot trial suggests modified MZRW is well-tolerated and effective for relief of constipation in patients with advance cancer. It could be considered as a potential treatment option for constipation in palliative care. TRIAL REGISTRATION: The trial had been registered in ClinicalTrials.gov with identifier number NCT02795390 [ https://clinicaltrials.gov/ct2/show/NCT02795390 ] on June 10, 2016.

Stroke in patients with cancer in the era of hyperacute stroke intervention.

BACKGROUND: The natural history of patients with stroke and cancer remains poorly understood in the modern era of hyperacute stroke therapies (recombinant tissue plasminogen activator and endovascular clot retrieval (ECR)). Prior to these advances in stroke treatment, a highly cited study reported median overall survival (mOS) 4.5 months after stroke in a cohort of patients with cancer (2004, n = 96). AIMS: Our hypothesis is that patients with stroke and cancer have better outcome than in earlier studies. METHODS: Retrospective analysis of admission to a tertiary Stroke Unit between January 2015 and September 2017 (n = 1910), evaluation of hospital records and cancer treatment records. Cancer was categorised as early stage (Stages I and II) and advanced stage (Stage III or IV) using the RD-Staging system. Survival analysis was performed in R. RESULTS: There were 143 stroke patients with cancer (62% male) with mean age 73.2 ± 12.5 years. Ischaemic stroke occurred in 74.1% and 45 of 106 (42.5%) patients received intravenous thrombolysis (34/45) and/or ECR (11/45). One patient who received ECR died within 30 days of stroke. Those with early stage disease had mOS of 19.6 months (interquartile range (IQR) 3.1-31.5 months) and in advanced stage cancer mOS was 2.5 months (IQR 0.4-6.3 months; P < 0.01). CONCLUSION: In the modern era of stroke therapy, our cohort of patients with advanced cancer has lower survival post-stroke compared to those with early stage cancer.

Combination of slide tracheoplasty and side-to-side bronchoplasty for complex congenital tracheobronchial stenosis.

Congenital tracheal stenosis is a rare but serious condition with high mortality and morbidity. We present a 6-month-old patient with complex congenital tracheal stenosis involving the trachea, carina and right bronchus intermedius, which was corrected with a combination of slide tracheoplasty and side-to-side bronchoplasty.

Paediatric arachnoid cysts: Surgical outcomes from a Singapore children's hospital.

Arachnoid cysts (AC) are reported to have a prevalence of up to 2.6% in children. Most AC remain indolent, but others may expand or rupture to cause life-threatening symptoms of raised intracranial pressure. Currently, there are 2 controversial topics with regards to the management of ACs: the indications for surgery and the choice of surgical procedure. We therein report our institution's neurosurgical experience for symptomatic AC over a 22-year period and corroborate our results with published literature. This is a single institution, retrospective study conducted at KK Women's and Children's Hospital from 01 January 1998 to 31 December 2019. A total of 38 patients with ACs that required surgery were recruited. The 3 most common anatomical locations were in the middle cranial fossa (40.5%), posterior fossa (24.3%) and interhemispheric (13.5%). Typical clinical presentations included symptoms of raised intracranial pressure (34.2%), obstructive hydrocephalus (28.9%) and AC rupture (21.1%). Surgical approaches included 17 craniotomy-based procedures, 7 endoscopic fenestrations, 11 cystoperitoneal shunts, 2 burrhole drainage operations and 1 excision of spinal AC. Thirteen patients (34.2%) underwent either another operation due to the lack of resolution of their AC-related symptoms or secondary to complications directly related to their initial surgery. Average length of followup from time of first operation was 84.1 months. Overall, our results demonstrate similarities in epidemiology, clinical presentation and surgical experience, in comparison to larger cohort studies. We advocate collaborative efforts to better understanding of the pathophysiology of paediatric ACs, particularly for deciding between the various surgical treatment modalities.

Long-term clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: A prospective cohort study.

UNLABELLED: There is ongoing debate on whether screening for nonalcoholic fatty liver disease (NAFLD) is worthwhile in high-risk groups. Because of shared risk factors, NAFLD is highly prevalent in patients with coronary artery disease. We aimed to test the hypothesis that NAFLD screening in patients requiring coronary angiogram would identify high-risk patients and predict long-term clinical outcomes. This was a prospective cohort study. NAFLD screening was performed by abdominal ultrasonography before coronary angiogram in 612 consecutive patients. At baseline, 356 (58.2%) patients had NAFLD. NAFLD patients, compared with those without, were more likely to have >50% stenosis in one or more coronary arteries (84.6% vs. 64.1%; P < 0.001) and therefore require percutaneous coronary intervention (68.3% vs. 43.4%; P < 0.001). During 3,679 patient-years of follow-up, 47 (13.2%) NAFLD patients and 59 (23.0%) patients without NAFLD died (age- and sex-adjusted hazard ratio [aHR]: 0.36; 95% confidence interval [CI]: 0.18-0.70; P = 0.003). Composite cardiovascular outcomes (cardiovascular deaths, nonfatal myocardial infarction, heart failure, or secondary interventions) were similar between groups (36.5% vs. 37.1%; aHR, 0.90; 95% CI: 0.69-1.18). Older age and diabetes were the only independent factors associated with cardiovascular events. Only 2 patients, both in the NAFLD group, died of primary liver cancer. No other patients developed liver-related complications. CONCLUSION: In patients with clinical indications for coronary angiogram, the presence of NAFLD is associated with coronary artery stenosis and need for coronary intervention, but not increased mortality or cardiovascular complications. Liver cancer and cirrhotic complications are rare. Our data do not support NAFLD screening in this patient group at present, but studies with a longer duration of follow-up are needed.

Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established tumours, we evaluated potential immune mechanisms associated with survival in HCC. METHODS: Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation). RESULTS: The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation. CONCLUSIONS: Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation.

Gab2 antisense oligonucleotide blocks rat basophilic leukemic cell functions.

Adapter molecule Grb2-associated binder-like protein 2 (Gab2) plays a critical role in FcepsilonRI-induced mast cell degranulation and activation. The present study aimed to investigate the pharmacological effects of an antisense oligonucleotide (ASO) targeted at Gab2 on the immune responses of rat basophilic leukemic (RBL)-2H3 cells. Gab2 ASOs were rationally designed and transfected into RBL-2H3 cells. Gab2 mRNA and protein knockdown was confirmed by real-time RT-PCR and immunoblotting, respectively. Effects of Gab2 ASO on FcepsilonRI-induced release of histamine and beta-hexosaminidase was measured by EIA and an enzymatic assay, respectively; signaling events by immunoblotting; and cytokine mRNA expression by RT-PCR. Effects of Gab2 ASO on cell adhesion and migration were performed on fibronectin-coated 96-well plate and transwells cell culture chambers, respectively. We have characterized a phosphorothioate-modified ASO targeted at Gab2 mRNA that was able to knockdown Gab2 mRNA and protein in RBL-2H3 cells. Gab2 ASO significantly blocked IgE-mediated mast cell release of beta-hexosaminidase and histamine; phosphorylation of Akt, p38 mitogen-activated protein kinase and PKCdelta; and up-regulation of cytokine mRNA levels (e.g. IL-4, -6, -9 and -13, and TNF-alpha). In addition, Gab2 ASO markedly prevented mast cell adhesion to fibronectin-coated plates and restrained random migration of RBL-2H3 cells in cell culture chambers. Our findings show that Gab2 knockdown in RBL-2H3 cells by ASO strategy can suppress many aspects of the mast cell functions and, therefore, a selective Gab2 ASO may have therapeutic potential for mast cell-dependent allergic disorders.

Antisense oligonucleotides: from design to therapeutic application.

1. An antisense oligonucleotide (ASO) is a short strand of deoxyribonucleotide analogue that hybridizes with the complementary mRNA in a sequence-specific manner via Watson-Crick base pairing. Formation of the ASO-mRNA heteroduplex either triggers RNase H activity, leading to mRNA degradation, induces translational arrest by steric hindrance of ribosomal activity, interferes with mRNA maturation by inhibiting splicing or destabilizes pre-mRNA in the nucleus, resulting in downregulation of target protein expression. 2. The ASO is not only a useful experimental tool in protein target identification and validation, but also a highly selective therapeutic strategy for diseases with dysregulated protein expression. 3. In the present review, we discuss various theoretical approaches to rational design of ASO, chemical modifications of ASO, ASO delivery systems and ASO-related toxicology. Finally, we survey ASO drugs in various current clinical studies.

Identification of a stretch of six divergent amino acids on the alpha5 helix of Galpha16 as a major determinant of the promiscuity and efficiency of receptor coupling.

A broad repertory of G-protein-coupled receptors shows effective coupling with the haematopoietic G16 protein. In the present study, individual residues along the C-terminal alpha5 helix of Galpha16 were examined for their contributions in defining receptor-coupling specificity. Residues that are relatively conserved within, but diverse between, the subfamilies of cloned Galpha subunits were mutated into the corresponding Galpha(z) residues. Six G(i)-linked receptors with different coupling efficiencies to Galpha16 were examined for their ability to utilize the various Galpha16 mutants to mediate agonist-induced inositol phosphate accumulation and Ca2+ mobilization. Co-operative enhancements of receptor coupling were observed with chimaeras harbouring multiple mutations at Glu350, Lys357 and Leu364 of Galpha16. Mutation of Leu364 into isoleucine appeared to be more efficient in enhancing receptor recognition compared with mutations at the other two sites. Mutation of a stretch of six consecutive residues (362-367) lying towards the end of the alpha5 helix was found to broaden significantly the receptor-coupling profile of Galpha16, and the effect was mediated partly through interactions with the beta2-beta3 loop. These results suggested that a stretch of six distinctive residues at the alpha5 helix of Galpha16 is particularly important, whereas other discrete residues spreading along the alpha5 helix function co-operatively for determining the specificity of receptor recognition.

IL-10 synergistically enhances GM-CSF-induced CCR1 expression in myelomonocytic cells.

CC chemokine receptor 1 (CCR1) has been implicated in inflammation. The present study examined the signaling mechanisms that mediate GM-CSF/IL-10-induced synergistic CCR1 protein expression in monocytic U937 cells. GM-CSF alone markedly increased both the mRNA and protein expression of CCR1. IL-10 augmented GM-CSF-induced CCR1 protein expression with no effect on mRNA expression. PD098059 and U0126 (two MEK inhibitors), and LY294002 (a PI3K inhibitor) inhibited GM-CSF/IL-10-induced CCR1 gene and protein expression. PD098059, U0126, and LY294002 also attenuated chemotaxis of GM-CSF/IL-10-primed U937 cells in response to MIP-1alpha. Immunoblotting studies show that GM-CSF alone induced ERK2 phosphorylation; whereas, IL-10 alone induced p70(S6k) phosphorylation in U937 cells. Neither cytokine when used alone induced PKB/Akt phosphorylation. Combined GM-CSF/IL-10 treatment of U937 cells induced phosphorylation of ERK2, p70(S6k), and PKB/Akt. PD098059 and U0126 completely abrogated ERK2 phosphorylation; whereas, LY294002 completely blocked PKB/Akt and p70(S6k) phosphorylation. Our findings indicate that IL-10 may potentiate GM-CSF-induced CCR1 protein expression in U937 cells via activation of PKB/Akt and p70(S6k).