Effects of Reishimmune-S, a Fungal Immunomodulatory Peptide Supplement, on the Quality of Life and Circulating Natural Killer Cell Profiles of Patients With Early Breast Cancer Receiving Adjuvant Endocrine Therapy.

OBJECTIVES: To evaluate the effects of Reishimmune-S, a fungal immunomodulatory peptide, on the quality of life (QoL) and natural killer (NK) cell subpopulations in patients receiving adjuvant endocrine therapy (ET) for breast cancer (BC). METHODS: Patients who received adjuvant ET for stage I-III hormone receptor-positive BC without active infection were enrolled in this prospective pilot study. Reishimmune-S was administered sublingually daily for 6 months. QoL scores, circulating immune cell levels, including lymphocyte/NK cell subpopulations, and plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured at baseline and every 4 weeks. Data were analyzed using linear mixed-effect regression models. RESULTS: Nineteen participants were included in the analyses. One patient with underlying asthma did not complete the study owing to the occurrence of skin rashes 15 days after the initiation of Reishimmune-S. No other adverse events were reported. Reishimmune-S supplementation significantly improved the cognitive function at 3 months and significantly decreased the fatigue and insomnia levels at 3 and 6 months, respectively. There was no significant change in the global health/QoL score between baseline and week 4 of treatment. The proportion of CD19+ lymphocytes was significantly higher at 3 and 6 months, and that of NKG2A+ and NKp30+ NK cells was significantly lower at 6 months than at baseline. In addition, fatigue positively correlated with the proportion of NKp30+ NK cells (ß ± standard error: 24.48 ± 8.75, P = .007 in the mixed-effect model). CONCLUSIONS: Short-term supplementation with Reishimmune-S affected the circulating immune cell composition and exerted positive effects on cognitive function, fatigue, and insomnia in patients with BC undergoing adjuvant ET, providing a potential approach for the management of treatment-related adverse reactions in this patient population.

Ubiquitin-specific peptidase 5 facilitates cancer stem cell-like properties in lung cancer by deubiquitinating ß-catenin.

BACKGROUND: Lung cancer has the highest mortality rate in the world, and mounting evidence suggests that cancer stem cells (CSCs) are associated with poor prognosis, recurrence, and metastasis of lung cancer. It is urgent to identify new biomarkers and therapeutic targets for targeting lung CSCs. METHODS: We computed the single-sample gene set enrichment analysis (ssGSEA) of 1554 Reactome gene sets to identify the mRNA expression-based stemness index (mRNAsi)-associated pathways using the genome-wide RNA sequencing data of 509 patients from The Cancer Genome Atlas (TCGA) cohort of lung adenocarcinoma (LUAD). Phenotypic effects of ubiquitin-specific peptidase 5 (USP5) on the CSC-like properties and metastasis were examined by in vitro sphere formation assay, migration assay, invasion assay, and in vivo xenografted animal models. Cycloheximide chase assay, co-immunoprecipitation assay, and deubiquitination assay were performed to confirm the effect of USP5 on the deubiquitination of ß-catenin. RESULTS: We demonstrated that USP5 expression were positively correlated with the stemness-associated signatures and poor outcomes in lung cancer specimens. Silencing of endogenous USP5 reduced CSC-like characteristics, epithelial-mesenchymal transition (EMT), and metastasis in vitro and in vivo. Furthermore, USP5 interacted with ß-catenin, which resulted in deubiquitination, stabilization of ß-catenin, and activation of Wnt/ß-catenin pathway. Accordingly, expression of USP5 was positively correlated with the enrichment score of the Wnt/TCF pathway signature in human lung cancer. Silencing of ß-catenin expression suppressed USP5-enhancing sphere formation. Targeting USP5 with the small molecule WP1130 promoted the degradation of ß-catenin, and showed great inhibitory effects on sphere formation, migration, and invasion. Finally, we identified a poor-prognosis subset of tumors characterized by high levels of USP5, Wnt signaling score, and Stemness score in both TCGA-LUAD and Rousseaux_2013 datasets. CONCLUSIONS: These findings reveal a clinical evidence for USP5-enhanced Wnt/ß-catenin signaling in promoting lung cancer stemness and metastasis, implying that targeting USP5 could provide beneficial effects to improve lung cancer therapeutics.

Assessment of Tyrosine Kinase Inhibitors and Survival and Cardiovascular Outcomes of Patients With Non-Small Cell Lung Cancer in Taiwan.

Importance: Tyrosine kinase inhibitors (TKIs) have been recognized as the standard treatment for patients with non-small cell lung cancers (NSCLCs) and epidermal growth factor receptor (EGFR) sequence variation. Although TKIs have been reported to cause cardiotoxicity, they are widely administered owing to the high prevalence of EGFR sequence variation in Taiwan. Objective: To compare the outcomes of death and major adverse cardiac and cerebrovascular events among patients with NSCLC who use and do not use TKIs in a national cohort. Design, Setting, and Participants: Using data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, patients treated for NSCLC from 2011 to 2018 were identified, and their outcomes were analyzed, including death and major adverse cardiac and cerebrovascular events (MACCEs; such as heart failure, acute myocardial infarction, and ischemic stroke) after adjusting for age, sex, cancer stage, comorbidities, anticancer therapies, and cardiovascular drugs. The median follow-up duration was 1.45 years. The analyses were performed from September 2022 to March 2023. Exposures: TKIs. Main Outcomes and Measures: Cox proportional hazards models were used to estimate death and MACCEs in patients treated with and without TKIs. Given that death may reduce the incidence of cardiovascular events, the competing risk method was used to calculate the MACCE risk after adjustment for all potential confounders. Results: Overall, 24 129 patients treated with TKIs were matched with 24 129 patients who did not receive TKIs (24 215 [50.18%] were female; and the mean [SD] age was 66.93 [12.37] years). Compared with those not receiving TKIs, the TKI group presented with a significantly lower hazard ratio (HR) of all-cause death (adjusted HR, 0.76; 95% CI, 0.75-0.78; P < .001), and the reason for death was primarily cancer. In contrast, the HR of MACCEs significantly increased (subdistribution HR, 1.22; 95% CI, 1.16-1.29; P < .001) in the TKI group. Furthermore, afatinib use was associated with a significantly reduced risk of death among patients receiving various TKIs (adjusted HR, 0.90; 95% CI, 0.85-0.94; P < .001) compared with those receiving erlotinib and gefitinib, although the outcomes of MACCEs were similar between the 2 groups. Conclusions and Relevance: In this cohort study of patients with NSCLC, TKI use was associated with reduced HRs of cancer-related death but increased HRs of MACCEs. These findings suggest the importance of close monitoring of cardiovascular problems in individuals receiving TKIs.

The association between tyrosine kinase inhibitors and fatal arrhythmia in patients with non-small cell lung cancer in Taiwan.

Objective: As a standard therapy, tyrosine kinase inhibitors (TKIs) improved survival in patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutation. However, treatment-related cardiotoxicity, particularly arrhythmia, cannot be ignored. With the prevalence of EGFR mutations in Asian populations, the risk of arrhythmia among patients with NSCLC remains unclear. Methods: Using data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified patients with NSCLC from 2001 to 2014. Using Cox proportional hazards models, we analyzed outcomes of death and arrhythmia, including ventricular arrhythmia (VA), sudden cardiac death (SCD), and atrial fibrillation (AF). The follow-up duration was three years. Results: In total, 3876 patients with NSCLC treated with TKIs were matched to 3876 patients treated with platinum analogues. After adjusting for age, sex, comorbidities, and anticancer and cardiovascular therapies, patients receiving TKIs had a significantly lower risk of death (adjusted HR: 0.767; CI: 0.729-0.807, p < 0.001) than those receiving platinum analogues. Given that approximately 80% of the studied population reached the endpoint of mortality, we also adjusted for mortality as a competing risk. Notably, we observed significantly increased risks of both VA (adjusted sHR: 2.328; CI: 1.592-3.404, p < 0.001) and SCD (adjusted sHR: 1.316; CI: 1.041-1.663, p = 0.022) among TKI users compared with platinum analogue users. Conversely, the risk of AF was similar between the two groups. In the subgroup analysis, the increasing risk of VA/SCD persisted regardless of sex and most cardiovascular comorbidities. Conclusions: Collectively, we highlighted a higher risk of VA/SCD in TKI users than in patients receiving platinum analogues. Further research is needed to validate these findings.

Hepatic arterial infusion chemotherapy and immune checkpoint inhibitors, alone or in combination, in advanced hepatocellular carcinoma with macrovascular invasion: a single-centre experience in Taiwan.

Background: The presence of vascular invasion is associated with poor survival in advanced hepatocellular carcinoma (HCC). We compared the effectiveness of hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs), alone or in combination, in patients with advanced HCC. Methods: We retrospectively reviewed medical records of adult patients with unresectable HCC and macrovascular invasion (MVI) who were treated with HAIC or ICIs alone or in combination at a single centre in Taiwan. Overall tumour response, vascular thrombi response, overall survival (OS) and progression-free survival (PFS) in 130 patients were analysed. Results: The treatment group showed no significant effect on the overall tumour response [objective response rate (ORR), 22.86% for HAIC, 26.09% for ICI, 50.00% for HAIC+ICI; P=0.111], but showed a significant effect on vessel response (objective response rate of tumour thrombi (ORRT), 38.57% for HAIC, 45.65% for ICI, 78.57% for HAIC+ICI; P=0.023). Post-hoc comparisons followed by Bonferroni correction revealed that vessel ORRT was significantly different between the HAIC+ICI and HAIC groups (P=0.014). A significant effect of treatment group on portal vein tumour thrombus (PVTT) was also detected (ORRT, 40.00% for HAIC, 50.00% for ICI, 90.00% for HAIC; P=0.013), with significant difference between the HAIC+ICI and HAIC groups (P=0.005). Patients treated with HAIC, ICI, and HAIC+ICI respectively had 12-month OS rates of 44.9%, 31.4%, and 67.5% (P=0.127) and 12-month PFS rates of 21.2%, 24.6%, and 33.2% (P=0.091). In multivariate analysis of PFS, HAIC+ICI was associated with reduced risk of progression or death compared with HAIC alone (adjusted hazard ratio: 0.46; 95% confidence interval: 0.23-0.94; P=0.032). Conclusions: HAIC combined with ICIs had a superior response of PVTT compared to HAIC alone, and was associated with reduced risk of progression or death. Future studies are needed to address the survival benefit of the combination therapy in advanced HCC with MVI.

Association of Statin Use With Cancer- and Noncancer-Associated Survival Among Patients With Breast Cancer in Asia.

Importance: In addition to protective effects on the cardiovascular system, statins may reduce the risk of breast cancer recurrence owing to potential anti-inflammatory benefits. Given that patients with breast cancer in Asia are relatively younger at diagnosis and most are free from traditional cardiovascular risk factors, it is uncertain whether the use of statins can improve survival. Objective: To investigate the association of statin use with cancer- and noncancer-associated survival in patients with breast cancer. Design, Setting and Participants: This cohort study used the Taiwanese National Health Insurance Research Database and National Cancer Registry to identify patients diagnosed with breast cancer from January 2012 to December 2017. Age, cancer stage, anticancer therapies, comorbidities, socioeconomic status, and cardiovascular drugs were matched by propensity score method. Statistical analyses, including Cox proportional hazards models, were performed from June 2022 to February 2023. The mean (SD) follow-up duration was 4.10 (2.96) years. Interventions: Patients receiving statins within 6 months before the diagnosis of breast cancer were compared with those not receiving statins. Main Outcomes and Measures: Outcomes included death, heart failure, and arterial and venous events. Results: Overall, 7451 patients (mean [SD] age, 64.3 [9.4] years) treated with statins were matched with 7451 nonusers (mean [SD] age, 65.8 [10.8] years). Compared with nonusers, statin users had a significantly lower risk of all-cause death (adjusted hazard ratio [HR], 0.83; 95% CI, 0.77-0.91; P < .001). Notably, the risk reduction was mainly attributed to cancer-related death (adjusted HR, 0.83; 95% CI, 0.75-0.92; P < .001). Only a small number of patients died of cardiovascular causes, and the ratios were similar between statin users and nonusers. No significant differences were observed in cardiovascular outcomes, including heart failure and arterial and venous events, between statin users and nonusers. Using a time-dependent analysis, statin users also presented a significantly lower risk of cancer-related death (adjusted HR, 0.28; 95% CI, 0.24-0.32; P < .001) than nonusers, and notably, the risk was even lower in high-dose statin (HDS) users compared with non-HDS users (HDS users: adjusted HR, 0.84; 95% CI, 0.73-0.98; P = .002; non-HDS users: adjusted HR, 0.79; 95% CI, 0.68-0.91; P = 001). Conclusions and Relevance: In this cohort study of Asian patients with breast cancer, statin use was associated with a reduced risk of cancer-associated death rather than cardiovascular death. Our findings provide evidence to support the use of statins in patients with breast cancer; however, randomized studies are necessary.

Real-World Effectiveness of Sorafenib versus Lenvatinib Combined with PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICIs) combined with multitarget tyrosine kinase inhibitors (MTKIs) exert a synergistic effect and are effective in unresectable hepatocellular carcinoma (uHCC). However, precise data regarding the real-world clinical applications of these combination therapies in uHCC are lacking. This study compared the treatment efficacy of sorafenib versus lenvatinib in combination with programmed cell death protein-1 (PD-1) inhibitors in patients with uHCC in a clinical setting. Among 208 patients with uHCC treated with PD-1 inhibitors, 88 were administered with ICIs in combination with sorafenib or lenvatinib. The treatment response and survival outcomes were evaluated. Predictors of survival were assessed by multivariate analysis. A total of 49 patients were treated with PD-1 inhibitors combined with sorafenib, and 39 patients were treated with PD-1 inhibitors combined with lenvatinib. The lenvatinib group exhibited a stronger objective response rate (ORR) (20.51% vs. 16.33%) and had a higher disease control rate (41.03% vs. 28.57%) than did the sorafenib group. The median overall survival was longer in the lenvatinib group than the sorafenib group (13.1 vs. 7.8 months; hazard ratio = 0.39, p = 0.017). The incidence of treatment-related adverse events was similar. PD-1 inhibitors combined with lenvatinib can be a feasible treatment strategy for HCC patients receiving MTKI-based combination therapy. PD-1 inhibitors combined with lenvatinib resulted in more favorable survival outcomes without increased toxic effects compared with PD-1 inhibitors with sorafenib. Additional larger-scale and prospective studies should be conducted to verify the study results.

All-Cause Standardized Mortality Ratio in Hemodialysis and Peritoneal Dialysis Patients: A Nationwide Population-Based Cohort Study.

Patients with end-stage renal disease (ESRD) are at a higher mortality risk compared with the general population. Previous studies have described a relationship between mortality and patients with ESRD, but the data on standardized mortality ratio (SMR) corresponding to different causes of death in patients undergoing hemodialysis (HD) and peritoneal dialysis (PD) are limited. This study was designed as a nationwide population-based retrospective cohort study. Incident dialysis patients between January 2000 and December 2015 in Taiwan were included. Using data acquired from the Taiwan Death Registry, SMR values were calculated and compared with the overall survival. The results showed there were a total of 128,966 patients enrolled, including 117,376 incident HD patients and 11,590 incident PD patients. It was found that 75,297 patients (58.4%) died during the period of 2000-2017. The overall SMR was 5.21. The neoplasms SMR was 2.11; the endocrine, nutritional, metabolic, and immunity disorders SMR was 13.53; the circulatory system SMR was 4.31; the respiratory system SMR was 2.59; the digestive system SMR was 6.1; and the genitourinary system SMR was 27.22. Therefore, more attention should be paid to these diseases in clinical care.

Real-World Comparative Effectiveness of Nivolumab versus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma.

PURPOSE: Immune checkpoint inhibitors are effective therapies for advanced hepatocellular carcinoma (HCC); however, comparisons of the clinical efficacy and safety profile for these drugs are still scarce. Thus, the aims of this study were to investigate the differences in efficacy and safety between nivolumab and pembrolizumab in unresectable HCC patients in a real-world setting. PATIENTS AND METHODS: A total of 115 patients who received treatment with nivolumab (n = 73) or pembrolizumab (n = 42) in combination with or without tyrosine kinase inhibitors was enrolled. Therapeutic response, survival outcomes, and safety profiles were compared among these groups. Multivariate analysis of survival response was performed using Cox proportional hazards regression. RESULTS: Patients treated with pembrolizumab demonstrated a significantly higher objective response rate than those with nivolumab (38.1% vs. 15.1%; odds ratio 4.18, p = 0.005) regardless of the combination strategies. In addition, pembrolizumab performed a better overall survival (OS) than nivolumab, (34.9 vs. 9.5 months; hazard ratio (HR) = 0.39, p = 0.004). In subgroup analysis, pembrolizumab exhibited favorable OS than nivolumab for monotherapy (HR = 0.16, p = 0.001) or combination therapy (HR = 0.33, p = 0.006) as second-line or later-line (HR = 0.19, p = 0.001) therapy and those with (HR = 0.31, p = 0.006) or without (HR = 0.15, p = 0.004) well-compensated liver disease. The incidence of adverse events was comparable for both treatments. CONCLUSION: Both pembrolizumab and nivolumab had significant effects for HCC therapy, and pembrolizumab had a significant survival benefit as compared with nivolumab.

Profiling antibody signature of schizophrenia by Escherichia coli proteome microarrays.

Schizophrenia (SZ) is influenced by genetic and environmental factors, and associated with chronic neuroinflammation. If the symptoms express after adolescence, environmental impacts are more substantial, and the disease is defined as adult-onset schizophrenia (AOS). Effects of environmental factors on antibody responses such as Escherichia coli (E. coli) to immunoglobulin G (IgG) and immunoglobulin M (IgM) might increase the severity of symptoms in SZ via the gut-brain axis. The purpose of this study is to reveal antibody profiles of SZ against bacterial protein antigens. We analyzed the IgG and IgM antibodies using E. coli proteome microarrays from 80 SZ patients and 40 healthy controls (HC). Using support vector machine to select panels of proteins differentiating between groups and conducted enrichment analysis for those proteins. We identified that the groL, pldA, yjjU, livG, and ftsE can classify IgGs in AOS vs HC achieved accuracy of 0.7. The protein yjjU, livG and ftsE can form the best combination panel to classify IgG in AOS vs HC with accuracy of 0.8. The enrichment results are highly related to ABC (ATP binding cassette) transporter in the protein domain and cellular component. We further found that the human ATP binding cassette subfamily b member 1 (ABCB1) autoantibody level in AOS is significantly higher than in HC. The findings suggest that AOS had different immunoglobulin production compared to early-onset schizophrenia (EOS) and HC. We also identified potential antibody biomarkers of AOS and found their antigens are enriched in ABC transporter related domains, including human ABCB1 protein.

Risks of Aromatase Inhibitor-Related Cardiotoxicity in Patients with Breast Cancer in Asia.

BACKGROUND: Despite a preferred endocrine therapy for women with estrogen and progesterone receptor-positive breast cancer, aromatase inhibitors (AIs) have been reported to increase risks of cardiovascular events. Given that breast cancer patients in Asia are younger at diagnosis, it is urgent to investigate this safety concern. METHODS: Through the Taiwanese National Cohort, we identified breast cancer patients initiating selective estrogen receptor modulators (SERMs) or AIs from 2010 to 2016. Outcomes includes major adverse cardio- and cerebrovascular events (MACCEs). The average follow-up duration was five years. RESULTS: We identified 16,730 breast cancer patients treated with SERMs and 11,728 receiving AIs. The population was older and had more comorbidities in the AI group than in the SERM group. After adjusting for age, cancer stage, cancer therapies, cardiovascular drugs and comorbidities, despite similar risks of MACCEs between AI and SERM users, the risk of HF was significantly higher in patients treated with SERMs after adjusted mortality as a competing risk. When divided by the age of 50 years, despite a similar MACCEs in the younger population, MACCEs remained significantly higher in the older population who received SERMs. CONCLUSIONS: In this Asian cohort, we found that among patients of old age or with advanced cancer stage, the use of SERMs was associated with a higher risk of cardiovascular events than the use of AIs.

Commercial Cu2 Cr2 O5 Decorated with Iron Carbide Nanoparticles as a Multifunctional Catalyst for Magnetically Induced Continuous-Flow Hydrogenation of Aromatic Ketones.

Copper chromite is decorated with iron carbide nanoparticles, producing a magnetically activatable multifunctional catalytic system. This system (ICNPs@Cu2 Cr2 O5 ) can reduce aromatic ketones to aromatic alcohols when exposed to magnetic induction. Under magnetic excitation, the ICNPs generate locally confined hot spots, selectively activating the Cu2 Cr2 O5 surface while the global temperature remains low (≈80 °C). The catalyst selectively hydrogenates a scope of benzylic and non-benzylic ketones under mild conditions (3 bar H2 , heptane), while ICNPs@Cu2 Cr2 O5 or Cu2 Cr2 O5 are inactive when the same global temperature is adjusted by conventional heating. A flow reactor is presented that allows the use of magnetic induction for continuous-flow hydrogenation at elevated pressure. The excellent catalytic properties of ICNPs@Cu2 Cr2 O5 for the hydrogenation of biomass-derived furfuralacetone are conserved for at least 17 h on stream, demonstrating for the first time the application of a magnetically heated catalyst to a continuously operated hydrogenation reaction in the liquid phase.

Omental Macrophagic "Crown-like Structures" Are Associated with Poor Prognosis in Advanced-Stage Serous Ovarian Cancer.

The tumor microenvironment is a well-recognized framework in which immune cells present in the tumor microenvironment promote or inhibit cancer formation and development. A crown-like structure (CLS) has been reported as a dying or dead adipocyte surrounded by a 'crown' of macrophages within adipose tissue, which is a histologic hallmark of the inflammatory process in this tissue. CLSs have also been found to be related to formation, progression and prognosis of some types of cancer. However, the presence of CLSs in the omentum of advanced-stage high-grade serous ovarian carcinoma (HGSOC) has not been thoroughly investigated. By using CD68, a pan-macrophage marker, and CD163, an M2-like polarization macrophage marker, immunohistochemistry (IHC) was performed to identify tumor-associated macrophages (TAMs) and CLSs. This retrospective study analyzed 116 patients with advanced-stage HGSOC who received complete treatment and had available clinical data from July 2008 through December 2016 at National Cheng Kung University Hospital (NCKUH) (Tainan, Taiwan). Based on multivariate Cox regression analysis, patients with omental CD68+ CLSs had poor OS (median survival: 24 vs. 38 months, p = 0.001, hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.41-3.61); patients with omental CD163+ CLSs also had poor OS (median survival: 22 vs. 36 months, HR: 2.14, 95%CI: 1.33-3.44, p = 0.002). Additionally, patients with omental CD68+ or CD163+ CLSs showed poor PFS (median survival: 11 vs. 15 months, HR: 2.28, 95%CI: 1.43-3.64, p = 0.001; median survival: 11 vs. 15 months, HR: 2.17, 95%CI: 1.35-3.47, respectively, p = 0.001). Conversely, the density of CD68+ or CD163+ TAMs in ovarian tumors was not associated with patient prognosis in advanced-stage HGSOC in our cohort. In conclusion, we, for the first time, demonstrate that the presence of omental CLSs is associated with poor prognosis in advanced-stage HGSOC.

Risks of trastuzumab-related cardiotoxicity in breast cancer patients in Taiwan.

AIMS: In contrast to Western patients with breast cancer, Asian patients are relatively younger at diagnosis, and most are free from traditional cardiovascular risk factors. Despite trastuzumab-related major adverse cardiac and cerebrovascular event (MACCE) being reported, its incidence and predictors remain unknown in Taiwan. METHODS AND RESULTS: Through a three-hospital retrospective cohort study, we analysed the incidence of MACCE in 386 breast cancer patients' exposure to trastuzumab from 2010 to 2018. To further reconfirm our findings, in a nationwide study using the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified 13 502 women diagnosed with breast cancer who received chemotherapy from 2010 to 2015 and found 6751 women who received initial treatment with trastuzumab. After 1:1 propensity score matching with trastuzumab non-users, the incidence of MACCE was measured with a median follow-up of 36 months. In the hospital-based study, among 386 patients receiving trastuzumab, the 5-year incidences of MACCE and heart failure (HF) were 5.4 and 2.8%, respectively. In the national cohort, the crude incidences of MACCEs and HF were 4.67 and 3.21%, respectively. After adjustment for age and comorbidities, the hazard ratio of MACCE was 1.485 (95% CI 1.246-1.769). Notably, among the endpoints, only the hazard ratio of HF was significantly higher in patients receiving trastuzumab than in nonusers. In the subgroup analysis, except for patients also using taxanes, those receiving trastuzumab had a higher risk of MACCE than non-users. CONCLUSIONS: From clinical observations in a nationwide cohort, we found an increased risk of MACCE, especially HF, in patients receiving trastuzumab. Given that its cardiotoxicity is independent of traditional cardiovascular risks, our findings highlight critical concerns regarding the cardiac safety of trastuzumab use.

Effect of aspirin treatment duration on clinical outcomes in acute coronary syndrome patients with early aspirin discontinuation and received P2Y12 inhibitor monotherapy.

Recent clinical trials showed that short aspirin duration (1 or 3 months) in dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy reduced the risk of bleeding and did not increase the ischemic risk compared to 12-month DAPT in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). However, it is unclear about the optimal duration of aspirin in P2Y12 inhibitor monotherapy. The purpose of this study was to evaluate the influence of aspirin treatment duration on clinical outcomes in a cohort of ACS patients with early aspirin interruption and received P2Y12 inhibitor monotherapy. From January 1, 2014 to December 31, 2018, we included 498 ACS patients (age 70.18 ± 12.84 years, 71.3% men) with aspirin stopped for various reasons before 6 months after PCI and received P2Y12 inhibitor monotherapy. The clinical outcomes between those with aspirin treatment ≤ 1 month and > 1 month were compared in 12-month follow up after PCI. Inverse probability of treatment weighting was used to balance the covariates between groups. The mean duration of aspirin treatment was 7.52 ± 8.10 days vs. 98.05 ± 56.70 days in the 2 groups (p<0.001). The primary composite endpoint of all-cause mortality, recurrent ACS or unplanned revascularization and stroke occurred in 12.6% and 14.4% in the 2 groups (adjusted HR 1.19, 95% CI 0.85-1.68). The safety outcome of BARC 3 or 5 bleeding was also similar (adjusted HR 0.69, 95% CI 0.34-1.40) between the 2 groups. In conclusion, patients with ≤ 1 month aspirin treatment had similar clinical outcomes to those with treatment > 1 month. Our results indicated that ≤ 1-month aspirin may be enough in P2Y12 inhibitor monotherapy strategy for ACS patients undergoing PCI.

Baseline plasma KL-6 level predicts adverse outcomes in patients with idiopathic pulmonary fibrosis receiving nintedanib: a retrospective real-world cohort study.

BACKGROUND: Nintedanib is effective for treating idiopathic pulmonary fibrosis (IPF), but some patients may exhibit a suboptimal response and develop on-treatment acute exacerbation (AE-IPF), hepatic injury, or mortality. It remains unclear which patients are at risk for these adverse outcomes. METHODS: We analysed the demographic and clinical data, baseline plasma levels of Krebs von den Lungen-6 (KL-6) and surfactant protein A (SPA), and longitudinal clinical courses of a real-world cohort of IPF patients who received nintedanib ≥ 14 days between March 2017 and December 2020. Cox proportional-hazards regression, subdistribution hazards regression, and sensitivity analyses were performed to investigate the association between baseline predictors and AE-IPF, mortality, and nintedanib-related hepatic injury. The relationship between baseline predictors and pulmonary function decline was determined. RESULTS: Fifty-seven patients were included, of whom 24 (42%) developed hepatic injury, 20 (35%) had AE-IPF, and 16 (28%) died on-treatment. A baseline plasma KL-6 level ≥ 2.5 ng/mL, and diffusion capacity for carbon monoxide (DLCO) < 55% predicted, were associated with increased risk of hepatic injury (adjusted hazard ratio [aHR] was 3.46; 95% CI 1.13-10.60; p = 0.029 for KL-6, and 6.05; 95% CI 1.89-19.32; p = 0.002 for DLCO). Both factors also predicted severe and recurrent hepatic injury. Patients with baseline KL-6 ≥ 2.5 ng/mL also had a higher risk of AE-IPF (aHR 4.52; 95% CI 1.63-12.55; p = 0.004). For on-treatment mortality, baseline KL-6 ≥ 3.5 ng/mL and SPA ≥ 600 pg/mL were significant predictors (aHR 5.39; 95% CI 1.16-24.97; p = 0.031 for KL-6, and aHR 12.28; 95% CI 2.06-73.05; p = 0.006 for SPA). Results from subdistribution hazard regression and sensitivity analyses supported these findings. Patients with elevated baseline plasma KL-6 levels also exhibited a trend towards faster pulmonary function decline. CONCLUSIONS: For patients with IPF who are receiving nintedanib, we have identified baseline predictors, in particular plasma KL-6 levels, for the risk of adverse outcomes. Patients with these predictors may require close monitoring for unfavourable responses during treatment. Our findings also support the prognostic role of molecular markers like KL-6 and may contribute to future formulation of more individualized therapeutic strategies for IPF.

Dynamic Changes of Generic Quality of Life after Different Treatments for Localized Prostate Cancer.

Generic quality of life (QoL) is an important issue in decision making related to the primary treatment of localized prostate cancer (PC). This study assessed the dynamic changes of QoL in patients with localized PC under different treatment modalities. From 2013 to 2018, we prospectively assessed QoL scores in patients with localized PC under unitary treatment using the World Health Organization Quality of Life (WHOQOL) BREF version. The trajectories of the QoL scores after different treatments were estimated using a kernel-smoothing method. Dynamic changes in the major determinants were analyzed using a mixed effects model. The clinical features of the participants in our institute were compared with PC patients in Taiwan's cancer registry. A total of 196 patients were enrolled with 491 repeated assessments. The participants shared similar clinical characteristics with the PC patients in Taiwan as a whole. Patients with lower household incomes showed statistically significant lower scores on all four domains and related facets, while PC survivors with comorbidities of anxiety and/or diabetes appeared to be affected on the physical domain and related facets. After controlling for these determinants, patients under active surveillance or observation demonstrated significantly higher QoL scores in the physical and social domains, as well as several facets belonging to these domains, in mixed models compared with patients undergoing radical prostatectomy or radiotherapy within the first year. The generic QoL scores were higher within the first year in patients receiving active surveillance or observation after controlling other significant factors. The difference diminished after one year of post management. More studies are needed to corroborate our findings.