From a Position of Known Angiographic Perfect Patency: What Happens Next?

BACKGROUND AND AIM: The biological behaviour of coronary graft conduits over time may be considered by serial angiography. METHODS: A single institution retrospective cohort received mostly clinically indicated angiography between 1997 and 2020, following coronary bypass surgery. Only perfectly patent grafts (absence of any lumen irregularity) for each conduit type at the first postoperative angiogram were selected for a later comparison. The latest angiograms were at least 5 years postoperatively, and at least 1 year after first postoperative angiogram. Analysis was done according to each graft (anastomosis). Comparisons used generalised estimating equations, adjusted for binary logistic regression. RESULTS: Of 143 patients, there were 410 of 468 (87.6%) perfectly patent grafts at the first angiogram, analysed at 6.8±4.0 years postoperative, of which 157 were internal mammary arteries, 228 were radial arteries, and 25 were saphenous veins. At the latest angiogram (12.2±3.8 years postoperative), comparison with the first angiogram for each individual graft found preserved perfect patency for internal mammary arteries 156 of 157 (99.4%), and for radial arteries, 227 of 228 (99.6%) but saphenous veins deteriorated considerably 13 of 25 (52.0%). The two arterial grafts (internal mammary and radial) were superior to vein grafts (odds ratio 163; 95% confidence interval [CI] 22-1,211; p<0.001), but not different from each other (odds ratio 0.95; 95% CI 0.78-1.16; p=0.584). CONCLUSIONS: From a position of known angiographic perfect patency post-CABG, internal mammary artery and radial artery grafts retained their perfect patency in the longer term, but saphenous vein grafts did not.

Sex differences in long-term survival after total arterial coronary artery bypass grafting.

OBJECTIVES: It is uncertain if the evidence on improved long-term survival of total arterial coronary artery bypass grafting applies to female patients. This study aims to compare the long-term survival outcomes of using total arterial revascularization (TAR) versus at least 1 saphenous vein graft separately for men and women. METHODS: This retrospective analysis of the Australian and New Zealand Society of Cardiac-Thoracic Surgical Database had administrative linkage to the National Death Index. We identified all patients undergoing primary isolated coronary bypass from June 2001 to January 2020 inclusive. Following sex stratification, propensity score matching with 36 variables and Cox proportional hazard regression were used to facilitate adjusted comparisons. A Cox interaction-term analysis was performed to investigate the impact of sex on TAR survival benefit. The primary outcome was all-cause mortality. RESULTS: Of the 69 624 eligible patients receiving at least 2 grafts, 13 019 (18.7%) were female patients. Matching generated 14 951 male and 3530 female pairs. Compared to vein-dependent procedures, TAR was associated with significantly reduced incidence of long-term all-cause mortality for both male (hazard ratio, 0.86; 95% confidence interval, 0.81-0.91; P < 0.001) and female (hazard ratio, 0.82; 95% confidence interval, 0.73-0.91; P < 0.001) cohorts. Interaction-term analysis indicated no significant subgroup effect from sex (P = 0.573) on the survival advantage of TAR. The treatment effect provided by TAR remained significant across most sex-stratified disease subgroups. CONCLUSIONS: TAR, when compared to the use of at least 1 saphenous vein graft, provides comparable superior long-term survival outcomes in both females and males.

Survival Benefit of Multiple Arterial Revascularization With and Without Supplementary Saphenous Vein Graft.

Background It is unknown if the presence of saphenous vein grafting (SVG) adversely affects late survival following coronary surgery with multiple arterial grafting (MAG) versus single arterial grafting. Methods and Results A retrospective, observational, multicenter cohort study from 2001 to 2020 was conducted using the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Database linked to the National Death Index. Patients undergoing primary isolated coronary artery bypass grafting with ≥2 grafts were included, and exclusions were patients aged <18 years, reoperations, concomitant or previous cardiac surgery, and the absence of arterial grafting. Demographics, comorbidities, medication, and operative configurations were propensity score matched between cohorts. The primary outcome was all-cause late death. Of 59 689 eligible patients, 35 113 were MAG (58.8%), and 24 576 were single arterial grafting (41.2%). Of the MAG cohort, 17 055 (48.6%) patients did not receive supplementary SVG (total arterial revascularization). Matching separately generated 22 764 patient pairs for MAG versus single arterial grafting, and 11 137 patient pairs for MAG with total arterial revascularization versus MAG with ≥1 supplementary vein grafts. At a median follow-up duration of 5.0 years postoperatively, the mortality rate was significantly lower for MAG than single arterial grafting (hazard ratio [HR], 0.79 [95% CI, 0.76-0.83]; P<0.001). The stratified MAG analysis found that MAG with total arterial revascularization had a lower risk of late death (HR, 0.85 [95% CI, 0.80-0.91]; P<0.001) compared with MAG with ≥1 supplementary vein grafts. Sensitivity analyses produced consistent outcomes as the primary analysis. Following adjustment for the presence of SVG in the Cox model, the survival advantage of incremental number of arteries was lost. Conclusions Multiple arterial grafting has significantly improved long-term survival compared with single arterial grafting. A further incremental survival benefit exists when no SVG is used.

Late Clinical Outcomes of Total Arterial Revascularization or Multiple Arterial Grafting Compared to Conventional Single Arterial with Saphenous Vein Grafting for Coronary Surgery.

Coronary surgery provides better long-term outcomes than percutaneous coronary intervention. Conventional practice is to use a single arterial conduit supplemented by saphenous vein grafts. The use of multiple arterial revascularization (MAG), or exclusive arterial revascularization (TAR), however, is reported as having improved late survival. Survival is a surrogate for graft failure that may lead to premature death, and improved survival reflects fewer graft failures in the non-conventional strategy groups. The reasons for not using MAG or TAR may be due to perceived technical difficulties, a lack of definitive large-scale randomized evidence, a lack of confidence in arterial conduits, or resources or time constraints. Most people consider radial artery (RA) grafting to be new, with use representing approximately 2-5% worldwide, despite select centers reporting routine use in most patients for decades with improved results. In conclusion, the current body of evidence supports more extensive use of total and multiple arterial revascularization procedures in the absence of contraindications.

Long-Term Survival of Multiple Versus Single Arterial Coronary Bypass Grafting in Elderly Patients.

Multiple arterial grafting (MAG) utilizes more than one arterial graft with any additional grafts being saphenous vein grafts (SVG). It remains an infrequently used coronary surgical revascularization technique, especially in elderly patients. Our study aims to evaluate the age-related association with the relative outcomes of multiple versus single arterial grafting (SAG). The Australian and New Zealand national registry was used to identify adult patients undergoing primary isolated CABG with at least two grafts. Exclusion criteria included reoperations, concomitant or previous cardiac surgery, and the absence of arterial grafting. Propensity score matching was used to match patient groups. The primary outcome was all-cause late mortality and the secondary outcomes were 30-day mortality and 30-day hospital readmission. We selected 69,624 eligible patients with a mean (standard deviation) age of 65.0 (10.2) years old. Matching between MAG and SAG generated 16,882 pairs of patients < 70 years old and 10,921 pairs of patients ≥ 70 years old. At a median [interquartile range] follow-up duration of 5.9 [3.2-9.6] years, MAG was associated with significantly reduced mortality compared to SAG (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.68-0.78; p < 0.001) in the younger subgroup as well as the elderly subgroup (HR, 0.84; 95% CI, 0.79-0.88; p < 0.001). In conclusion, MAG offers a survival benefit over SAG, in both younger and elderly patients.

Survival of multiple arterial grafting in diabetic populations: a 20-year national experience.

OBJECTIVES: Diabetics may have diminished survival after coronary artery bypass grafting even with multiple arterial revascularization. We compared multi-arterial versus single-arterial grafting (SAG) survival in diabetic and non-diabetic patients undergoing primary isolated bypass surgery. METHODS: This is a retrospective analysis of the Australian and New Zealand Society of Cardiac-Thoracic Surgical Database from June 2001 to January 2020. Patients were classified as having either single or multiple arterial grafting irrespective of the number of venous grafts. The end points were long-term all-cause mortality and 30-day clinical outcomes, which was compared in 1:1 propensity score-matched patients. Cox regression model was used to assess interactions between diabetes and the treatment effect of multi-arterial grafting, reported as hazard ratios (HRs) and confidence intervals (CIs). Short-term outcomes were compared with McNemar's paired t-test. RESULTS: From 69 624 patients, matching generated 17 474 non-diabetic and 10 989 diabetic patient pairs. At a median [interquartile range] of 5.9 [3.2-9.6] years postoperative, mortality was significantly lower after multi-arterial grafting for both diabetic (HR, 0.83; 95% CI, 0.76-0.90, P < 0.001) and non-diabetic (HR, 0.88; 95% CI, 0.82-0.95; P < 0.001) cohorts than SAG. The incidence of 30-day myocardial infarction was significantly higher in single than multiple arterial grafting for both cohorts (diabetic, P = 0.029; non-diabetic, P < 0.001). The interaction analysis suggested an insignificant effect of diabetes (P = 0.55) on the observed survival advantage. Further stratification by diabetic management generated consistent results. CONCLUSIONS: Multi-arterial grafting was associated with improved overall survival compared to SAG for both non-diabetic and diabetic patients.

Coronary Artery Bypass Surgery Without Saphenous Vein Grafting: JACC Review Topic of the Week.

Approximately 95% of patients of any age undergoing contemporary, coronary bypass surgery will receive at least 1 saphenous vein graft (SVG). It is recognized that SVG will develop progressive and accelerated atherosclerosis, resulting in a stenosis, and in occlusion that occurs in 50% by 10 years postoperatively. For arterial conduits, there is little evidence of progressive failure as for SVG. Could avoidance of SVG (total arterial revascularization [TAR]) lead to a different late (>5 year) survival? A literature review of 23 studies (N = 100,314 matched patients) at a mean 8.8 years postoperative found reduced all-cause mortality for TAR (HR: 0.77; 95% CI: 0.71-0.84; P < 0.001). An expanded analysis with a new unpublished data set (N = 63,288 matched patients) was combined with the literature review (N = 127,565). It found reduced all-cause mortality for TAR (HR: 0.78; 95% CI: 0.72-0.85; P < 0.001). Additional Bayesian analysis found a very high probability of a TAR-associated reduction all-cause mortality.

Long-term observational angiographic patency and perfect patency of radial artery compared with saphenous vein or internal mammary artery in coronary bypass surgery.

OBJECTIVES: It is uncertain if the long-term biological behavior of the radial artery as a conduit for coronary bypass surgery has a similar resistance to the development of atherosclerosis as for the internal mammary artery. We aimed to examine long-term angiographic patency and disease-free patency (perfect patency) for internal mammary artery, radial artery, and saphenous vein grafts. METHODS: A retrospective, single-center, individual patient cohort study of angiographic observations from patients' latest postoperative angiogram from 1997 to 2020 was performed. Analysis was per anastomosis and assessed for patency and perfect patency. A generalized linear mixed model premised upon logistic regression was used to minimize confounding bias. RESULTS: A total of 983 patients with 3064 grafts were included, with a median follow-up of 8.6 (interquartile range, 4.4-12.6) years after the operation. Multivariable analysis revealed differences for radial (patency, 86.9%; perfect patency, 86.4%) and internal mammary artery (patency, 93.9%; perfect patency, 93.5%) versus saphenous vein graft (patency, 72.8%; perfect patency, 46.2%). There were no differences between the 2 arterial conduits for patency (odds ratio, 1.40; 95% CI, 0.85-2.33; P = .189) and perfect patency (odds ratio, 1.14; 95% CI, 0.71-1.84; P = .578). If a conduit was patent, then 99.4% of radial artery, 99.6% of internal mammary artery, and 63.5% of saphenous vein graft were reported as perfectly patent. CONCLUSIONS: Radial artery and internal mammary artery had similar patency and perfect patency while both were superior to saphenous vein graft.

Benefits of combination therapy with immune checkpoint inhibitors and predictive role of tumour mutation burden in hepatocellular carcinoma: A systematic review and meta-analysis.

OBJECTIVES: To investigate the clinical benefits of combination therapy with immune checkpoint inhibitors (ICIs) and best combination regimen for people with advanced hepatocellular carcinoma (HCC) and to explore the predictive performance of tumour mutation burden (TMB). METHODS: We conducted a systematic literature search to identify clinical trials. Meta-analysis and subgroup analyses were performed to estimate the benefits of combination regimens with PD-1/PD-L1 inhibitors for patients with advanced HCC and compare the effectiveness of PD-1/PD-L1 inhibitors and sorafenib as first-line therapy. Individualized analysis and Kaplan-Meier were used to assess the prognostic value of TMB. RESULTS: A total of 29 studies with 5396 patients were included. ICIs' combination therapy had higher ORR (26 % vs 15 %) and DCR (73 % vs 55 %), longer PFS (5.5 vs 3.1 months) and OS (15.9 vs 12.6 months) compared to monotherapy. Anti-PD-1/PD-L1 agents provided improved ORR, DCR, PFS and OS compared to sorafenib. The overall ORs of ORR and DCR in subgroup analysis were 3.49 (95 % CI 2.36-5.17, p < 0.01) and 1.60 (95 % CI 1.15-2.21, p < 0.01). The overall HRs of PFS and OS were 0.68 (95 % CI 0.48-0.96, p = 0.03) and 0.73 (95 % CI 0.62-0.85, p < 0.01). PD-1/PD-L1 inhibitors plus anti-VEGF agents had an advantage in DCR (0.80 vs 0.48, meta-regression =  - 0.32, P < 0.001), but an equal ORR (0.29 vs 0.26) compared to dual immune checkpoint inhibitors. The total OS in Dua-ICIs were 16.5 months (95 % CI 14.2-18.7), yet not reached in the major studies of ICI plus anti-VEGF regimen. In individualized analysis, the 1-year OS was superior for patients who had high-TMB (>10, mutations/Mb) than moderate-TMB (1-10, mutations/Mb; 28 % vs 15 %, P = 0.025). CONCLUSION: Immune checkpoint inhibitors' combination therapy improved clinical outcomes in the management of advanced hepatocellular carcinoma. However, the overall objective response rate still did not exceed 30%. PD-1/PD-L1 inhibitors plus anti-angiogenic agents and dual immunotherapy provided significantly increased survival over sorafenib, which also pose new challenges for future research, and more appropriate and guided control regimens are required. Also, TMB may be a promising prognostic biomarker for immunotherapy in HCC. However, the validation of prospective and large sample studies is needed.

Iodide Analogs of Arsenoplatins-Potential Drug Candidates for Triple Negative Breast Cancers.

Patients with triple negative breast cancers (TNBCs)-highly aggressive tumors that do not express estrogen, progesterone, and human epidermal growth factor 2 receptors-have limited treatment options. Fewer than 30% of women with metastatic TNBC survive five years after their diagnosis, with a mortality rate within three months after a recurrence of 75%. Although TNBCs show a higher response to platinum therapy compared to other breast cancers, drug resistance remains a major obstacle; thus, platinum drugs with novel mechanisms are urgently needed. Arsenoplatins (APs) represent a novel class of anticancer agents designed to contain the pharmacophores of the two FDA approved drugs cisplatin and arsenic trioxide (As2O3) as one molecular entity. Here, we present the syntheses, crystal structures, DFT calculations, and antiproliferative activity of iodide analogs of AP-1 and AP-2, i.e., AP-5 and AP-4, respectively. Antiproliferative studies in TNBC cell lines reveal that all AP family members are more potent than cisplatin and As2O3 alone. DFT calculations demonstrate there is a low energy barrier for hydrolysis of the platinum-halide bonds in arsenoplatins, possibly contributing to their higher cytotoxicities compared to cisplatin.

Characterization With KRAS Mutant Is a Critical Determinant in Immunotherapy and Other Multiple Therapies for Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a frequent type of cancer, which is mainly characterized clinically by high aggressiveness and high mortality. KRAS oncoprotein is the most common molecular protein detected in NSCLC, accounting for 25% of all oncogenic mutations. Constitutive activation of the KRAS oncoprotein triggers an intracellular cascade in cancer cells, leading to uncontrolled cell proliferation of cancer cells and aberrant cell survival states. The results of multiple clinical trials have shown that different KRAS mutation subtypes exhibit different sensitivities to different chemotherapy regimens. Meanwhile, anti-angiogenic drugs have shown differential efficacy for different subtypes of KRAS mutated lung cancer. It was explored to find if the specificity of the KRAS mutation subtype would affect PD-L1 expression, so immunotherapy would be of potential clinical value for the treatment of some types of KRAS mutations. It was discovered that the specificity of the KRAS mutation affected PD-L1, which opened up immunotherapy as a potential clinical treatment option. After several breakthrough studies, the preliminary test data of many early clinical trials showed that it is possible to directly inhibit KRAS G12C mutation, which has been proved to be a targeted treatment that is suitable for about 10%-12% of patients with advanced NSCLC, having a significant impact on the prolongation of their survival and the improvement of their quality of life. This article reviews the latest progress of treatments for NSCLC with KRAS mutation, in order to gain insight into the biological diversity of lung cancer cells and their potential clinical implications, thereby enabling individualized treatment for patients with KRAS-mutant NSCLC.