Long-term use and risk of major adverse cardiac events: Comparing enzalutamide and abiraterone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

Systemic Therapy for Gastrointestinal Stromal Tumor: Current Standards and Emerging Challenges.

OPINION STATEMENT: Gastrointestinal stromal tumor (GIST), though rare, is the most common mesenchymal tumors of the gastrointestinal tract. KIT or PDGFRα mutation plays as an oncogenic driver in the majority of GISTs. Surgical resection is the only curative treatment for localized disease. The discovery of imatinib with promising anti-tumor effect and successive tyrosine kinase inhibitors (TKI), including second-line sunitinib and third-line regorafenib, revolutionized the management of advanced and metastatic GIST over the past two decades. Recently, ripretinib and avapritinib were approved for the fourth line setting and for PDGFRA exon 18-mutant GIST in first-line setting, respectively. Despite multi-line TKIs exerted ability of disease control, drug resistance remained an obstacle for preventing rapid disease progression. Experimental TKIs or novel therapeutic targets may further improve treatment efficacy. Immune checkpoint inhibitors such as anti-programmed cell death protein-1 (PD1) and anti-CTL-associated antigen 4 (CTLA-4) showed moderate response in early phase trials composed of heavily pretreated patients. KIT/PDGFRα wild-type GISTs are generally less sensitive to imatinib and late-line TKIs. Recent studies demonstrated that targeting fibroblast growth factor receptor signaling may be a potential target for the wild-type GISTs.

Telmisartan use and risk of dementia in type 2 diabetes patients with hypertension: A population-based cohort study.

BACKGROUND: Angiotensin receptor blockers (ARBs) may have protective effects against dementia occurrence in patients with hypertension (HTN). However, whether telmisartan, an ARB with peroxisome proliferator-activated receptor γ (PPAR-γ)-modulating effects, has additional benefits compared to other ARBs remains unclear. METHODS AND FINDINGS: Between 1997 and 2013, 2,166,944 type 2 diabetes mellitus (T2DM) patients were identified from the National Health Insurance Research Database of Taiwan. Patients with HTN using ARBs were included in the study. Patients with a history of stroke, traumatic brain injury, or dementia were excluded. Finally, 65,511 eligible patients were divided into 2 groups: the telmisartan group and the non-telmisartan ARB group. Propensity score matching (1:4) was used to balance the distribution of baseline characteristics and medications. The primary outcome was the diagnosis of dementia. The secondary outcomes included the diagnosis of Alzheimer disease and occurrence of symptomatic ischemic stroke (IS), any IS, and all-cause mortality. The risks between groups were compared using a Cox proportional hazard model. Statistical significance was set at p < 0.05. There were 2,280 and 9,120 patients in the telmisartan and non-telmisartan ARB groups, respectively. Patients in the telmisartan group had a lower risk of dementia diagnosis (telmisartan versus non-telmisartan ARBs: 2.19% versus 3.20%; HR, 0.72; 95% CI, 0.53 to 0.97; p = 0.030). They also had lower risk of dementia diagnosis with IS as a competing risk (subdistribution HR, 0.70; 95% CI, 0.51 to 0.95; p = 0.022) and with all-cause mortality as a competing risk (subdistribution HR, 0.71; 95% CI, 0.53 to 0.97; p = 0.029). In addition, the telmisartan users had a lower risk of any IS (6.84% versus 8.57%; HR, 0.79; 95% CI, 0.67 to 0.94; p = 0.008) during long-term follow-up. Study limitations included potential residual confounding by indication, interpretation of causal effects in an observational study, and bias caused by using diagnostic and medication codes to represent real clinical data. CONCLUSIONS: The current study suggests that telmisartan use in hypertensive T2DM patients may be associated with a lower risk of dementia and any IS events in an East-Asian population.

Gonadotropin-releasing hormone antagonist associated with lower cardiovascular risk compared with gonadotropin-releasing hormone agonist in prostate cancer: A nationwide cohort and in vitro study.

BACKGROUND: We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those who receive GnRH antagonist therapy. METHODS: Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages. RESULTS: GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively. CONCLUSION: GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.

Imatinib Regulates miR-483-3p and Mitochondrial Respiratory Complexes in Gastrointestinal Stromal Tumors.

Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment.

Postdiagnostic metformin use and survival of patients with colorectal cancer: A Nationwide cohort study.

Epidemiological evidence for the association between postdiagnostic metformin use and survival in patients with colorectal cancer (CRC) remains limited. Using the Taiwan Cancer Registry database, a cohort of 16,676 diabetic patients newly diagnosed with CRC from January 1, 2004 through December 31, 2014, followed until December 31, 2016, was identified. Postdiagnostic use of metformin (two or more prescriptions after CRC diagnosis) was defined as a time-dependent covariate with 6-month lag. Multivariate Cox regression model and stabilized inverse probability of treatment weighting (IPTW) were used to estimate adjusted effects of metformin on all-cause mortality and CRC-specific mortality during follow-up. A number of 11,438 (69%) received metformin after CRC diagnosis. Overall, 7,393 deaths, including 4,845 CRC-specific deaths, were observed during 64,322 person-years of follow-up. After adjustment for demographic and clinical covariates, metformin users had lower all-cause mortality than did nonusers (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.40-0.44) and lower CRC-specific mortality (HR, 0.41; 95% CI, 0.39-0.44). Similar but somewhat attenuated effects were observed after stabilized IPTW (HR for all-cause mortality, 0.56; 95% CI, 0.53-0.59; HR for CRC-specific mortality, 0.58; 95% CI, 0.55-0.61). Similar results were observed in stratified analyses of 2,112 patients with no prediagnostic metformin use and 14,564 patients with prediagnostic metformin use. Findings for both outcomes were consistent in multiple sensitivity analyses. Use of postdiagnostic metformin was associated with significantly lower all-cause mortality and CRC-specific mortality, regardless of prior metformin use. These findings support the use of metformin as an adjunct to standard care of diabetic patients with CRC.

Cardiovascular toxicity of immune checkpoint inhibitors in cancer patients: A review when cardiology meets immuno-oncology.

Immune checkpoint inhibitors (ICIs) are a novel treatment option for cancer therapy, which help direct the immune system to recognize and target cancer cells. ICIs have been shown to provide significant mortality benefits for cancer patients, but they are also associated with immune-mediated toxicity. Unlike most immune-related adverse events, which are a common occurrence, reversible and can be treated effectively with glucocorticoid therapy, ICI-associated cardiotoxicities are uncommon, with serious complications and a relatively high mortality even when treated with glucocorticoids. ICI-associated cardiotoxicity can manifest in various ways, including myocarditis, arrhythmias and conduction disease, pericardial disease, myocardial infarction, non-inflammatory cardiomyocyte dysfunction, and even Takotsubo-like cardiomyopathy. The present review summarizes the current understanding of ICI-associated cardiotoxicities, examining the epidemiology and timing of onset, as well as their clinical presentation, diagnostic modalities, pathophysiology, clinical management and outcomes. Although the literature describing ICI-associated cardiotoxicity remains limited to case reports, case series and early clinical trials, strategies for the surveillance, diagnosis and management of this potentially fatal cardiovascular complication of cancer therapy have been proposed.

Baseline circulating stem-like cells predict survival in patients with metastatic breast Cancer.

BACKGROUND: Circulating tumor cells (CTCs) are associated with breast cancer prognosis. Research is limited regarding the role of circulating cancer stem-like cells (cCSCs) considering the treatment response and survival among patients with metastatic breast cancer. Accordingly, we performed this prospective study to clarify the prognostic significance of baseline cCSCs for metastatic breast cancer in terms of first-line chemotherapy. METHODS: Between April 2014 and January 2016, we prospectively enrolled 48 patients with stage IV breast invasive ductal carcinoma who underwent first-line chemotherapy. We identified and analyzed CTCs and cCSCs by using a protocol based on negative selection and flow cytometry before chemotherapy. CTCs were identified as EpCAM+Hoechst+CD45- cells and cCSCs as CD133+EpCAM+Hoechst+CD45- cells. cCSCs were expressed as a percentage of CTCs. The associations between CTCs, cCSCs, and the clinicopathological variables that were predictive of the treatment response and survival outcome were analyzed using univariate and multivariate analyses. RESULTS: We identified CTCs in all the enrolled patients, with a median number of 33.9/mL CTCs. CSCs were isolated in 97.9% of the patients; the median percentage of cCSCs was 14.7%. A high baseline level of cCSCs was correlated with an inferior tumor response rate (54.2% vs. 95.8%, p < 0.001), overall survival (OS; median: 27.7 months vs. not reached, p < 0.001), and progression-free survival (PFS; median: 5.7 vs. 18.0 months, p < 0.001). Multivariate analysis revealed that along with other clinical variables, baseline cCSCs remained an independent prognostic factor for OS and PFS. CONCLUSIONS: Baseline cCSCs predict the treatment response as well as survival in patients with metastatic breast cancer undergoing first-line chemotherapy. Therefore, the measurement of cCSCs may assist in identifying early cancer treatment response and prognosis.

miR-125a-5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors.

The use of imatinib mesylate has greatly improved the clinical outcome for gastrointestinal stromal tumor (GIST) patients. However, imatinib resistance is still a major clinical challenge, and the molecular mechanisms are not fully understood. We have previously shown that miR-125a-5p and its mRNA target PTPN18 modulate imatinib response in GIST cells. Herein, we evaluated phosphorylated FAK (pFAK) as a candidate downstream target of PTPN18 and the possible association of this regulation with imatinib resistance in GIST. FAK and pFAK expressions were evaluated in GIST882 cells transfected with short hairpin RNA or short interfering RNA targeting PTPN18 or miR-125a-5p mimic, imatinib-resistant GIST882R subclones and clinical samples using Western blot analyses. FAK phosphorylation was blocked using the FAK inhibitor 14 (FAKi) and the effects on cell viability and apoptosis were evaluated using WST-1 assay and cleaved PARP expression. Clinical associations of FAK and pFAK expression with imatinib resistance, KIT mutation and patient outcome were assessed by Fisher's exact test or log-rank test. Over-expression of miR-125a-5p and silencing of PTPN18 increased pFAK, but not FAK, expression in GIST cells. Higher pFAK expression was observed in the GIST882R subclones with acquired imatinib resistance compared to their imatinib-sensitive parental cells. Treatment with FAKi in imatinib-resistant GIST882R cells reduced cell viability and increased apoptosis upon imatinib treatment. Additionally, FAKi could rescue the imatinib resistance effect mediated by miR-125a-5p over-expression. In clinical samples, high FAK and pFAK expressions were associated with KIT mutation status, and high FAK expression was also associated with metastasis in GIST. Higher pFAK was found in cases with shorter overall survival. Our findings highlight an important role for miR-125a-5p regulation and its downstream target pFAK for imatinib resistance in GIST. pFAK and FAK may have prognostic values in GIST.

Cytoplasmic and nuclear parathyroid hormone-related proteins are opposing prognostic factors in patients with non-small-cell lung cancer who have undergone curative resection.

OBJECTIVE: Parathyroid hormone-like related protein was a prognostic factor for non-small-cell lung cancer, but the results were conflicting. The present study was to examine the role of cytoplasmic and nuclear parathyroid hormone-like related protein in patients with non-small-cell lung cancer who have undergone surgical therapy. METHODS: The expression of parathyroid hormone-like related protein was examined by immunohistochemical staining in 56 patients with resectable non-small-cell lung cancer. The impact of parathyroid hormone-like related protein expression on cancer recurrence and survival was assessed in combination with clinicopathologic features. RESULTS: Patients with a high expression of cytoplasmic parathyroid hormone-like related protein had a significantly unfavorable prognosis in both disease-free survival (median 16.7 vs. 58.0 months, P = 0.029) and overall survival (median 31.6 months vs. not reached, P = 0.046). In contrast, the patients with high expression of nuclear parathyroid hormone-like related protein had favorable disease-free survival (median 35.1 vs. 19.9 months, P = 0.069) and a significantly better overall survival (median not reached vs. 36.9 months, P = 0.033). There was no correlation between the expression of cytoplasmic and nuclear parathyroid hormone-like related protein (P = 1.00). Furthermore, multivariate analysis using a Cox regression model confirmed that high expression of cytoplasmic parathyroid hormone-like related protein (disease-free survival, hazard ratio: 1.973, P = 0.079; overall survival, hazard ratio: 2.461, P = 0.067) and nuclear parathyroid hormone-like related protein (disease-free survival, hazard ratio: 0.436, P = 0.029; overall survival, hazard ratio: 0.375, P = 0.018) were independently prognostic factors for disease-free survival and overall survival. CONCLUSION: Cytoplasmic and nuclear parathyroid hormone-like related protein play opposing prognostic roles for the disease-free survival and overall survival of patients with early non-small-cell lung cancer who have undergone curative resection.

No overall increased risk of cancer in patients with rheumatoid arthritis: a nationwide dynamic cohort study in Taiwan.

The association between rheumatoid arthritis (RA) and cancer is still controversial. This study aimed to estimate cancer incidence (both overall and site-specific) among patients with RA and to determine whether their cancer risk was higher than in the general population. We used the nationwide dynamic cohort from the National Health Insurance Research Database of Taiwan and obtained a total of 30,504 patients with no history of cancer who were newly diagnosed with RA between 1996 and 2008; they were followed up until 2010. Standardized incidence ratios (SIR) by age for various types of cancer were calculated in 5-year calendar periods by 5-year age intervals (quinquinquennium) to compare elevated risk of increasing age and increased cancer rate in later calendar years in Taiwan. During 225,432 person-years of follow-up, 1,595 cancers occurred, corresponding to 7.08 per 1,000 person-years. The SIR for all cancers was 0.93 (95 % CI 0.88-0.97). Most cancers were found in the first 2 years after diagnosis of RA, but the incidence decreased afterward. A significant excess of Hodgkin's lymphoma (SIR 3.31, 95 % CI 1.24-8.81) and non-Hodgkin's lymphoma (SIR 3.18, 95 % CI 2.64-3.83) was seen among patients with RA, whereas the risk of colorectal cancer was 29 % lower than the general population. In conclusion, this study showed that patients with RA do not have increased overall risk of cancers but have higher risk of hematologic malignancies and lower risk of colorectal cancer, than the general population.

The cold temperature associated with new-onset heart failure after incorporating dynamic status of multimorbidity: nationwide cohort, Taiwan 2012-2019.

AIMS: Cold temperatures are known to affect heart failure (HF) hospitalizations, but the dynamic status of multi-morbidity of HF was rarely incorporated. We investigated the relationship between temperature and new-onset HF by risk strata. METHODS AND RESULTS: This nationwide cohort study analysed daily data on ambient temperature, the dynamic status of risk factors (age, diabetes, chronic obstructive pulmonary disease, coronary artery disease, chronic kidney disease, hypertension, myocardial infarction, and atrial fibrillation), and new-onset HF among the Taiwan population from 2012 to 2019. Poisson regression, Austin's algorithm, and classification and regression tree (CART) were used to determine risk strata and obtain the predicted HF rate. 148 708 patients developed new-onset HF over 152.52 million person-years. Three risk strata for HF were identified: Stratum 1 was predominantly those without any comorbidity (89.9%); Stratum 2 was those aged 60-69 with 2-3 comorbidities or aged 70+ with 1-2 comorbidities (9.0%), and Stratum 3 was those aged 70+ and had four or more comorbidity (1.1%). The HF incidence rates for these three strata were 25.54, 555.27, and 2315.52 per 100 000 person-years, respectively. The R2 of the Poisson regression with the three risk strata and the daily minimum temperature on the ln HF incidence rates was 77.99%. The risk of HF increased as temperatures decreased, and the slopes were 1.032, 1.040, and 1.034 for Strata 1-3, respectively. The rate ratios of HF at the winter median temperature of 17°C vs. the summer median temperature of 29°C were 1.45, 1.58, and 1.49 for Strata 1-3, respectively. Cross-validation reveals a good fit and predicted HF rates by ambient temperature for the three strata were provided. CONCLUSION: Cold temperatures are associated with an increased risk of new-onset HF. Stratum 2 (aged 60-69 with 2-3 comorbidities or aged 70+ with 1-2 comorbidities) are particularly susceptible to cold-related new-onset HF.

Cold temperatures are known to affect heart failure (HF) hospitalizations, but the dynamic status of multi-morbidity of HF was rarely incorporated. Three risk strata for HF were determined for the Taiwan population from 2012 to 2019: Stratum 1 was predominantly young or without comorbidities (89.9%); Stratum 2 was those aged 60­69 with 2­3 comorbidities or aged 70+ with 1­2 comorbidities (9.0%), and Stratum 3 was those aged 70+ and had four or more risk factors (1.1%). The HF incidence rates for these three strata were 25.54, 555.27, and 2315.52 per 100 000 person-years, respectively. The rate ratios of HF at the winter median temperature of 17°C vs. the summer median temperature of 29°C were 1.45, 1.58, and 1.49 for Strata 1­3, respectively. Other than cold temperatures are associated with an increased risk of new-onset HF, Stratum 2 (those aged 60­69 with 2­3 comorbidities or aged 70+ with 1­2 comorbidities) are particularly susceptible to cold-related new-onset HF. Predicted HF rates by ambient temperature for the three strata were provided so that individuals can find their predicted HF rate based on the risk score and the current temperature and, therefore, be amenable to primary preventive efforts.

Mortality after major bleeding in Asian atrial fibrillation patients receiving different direct oral anticoagulants: a nationwide, propensity score study.

In this research, we assessed mortality after major bleeding events in atrial fibrillation (AF) patients taking four direct oral anticoagulants (DOACs). Drawing data from the Taiwan National Health Insurance Research Database between 2016 and 2019, we focused on AF patients on DOACs who had major bleeding episodes. Using propensity score stabilized weighting, we established four comparable pseudo-DOAC groups. Among 2770 patients (460 dabigatran, 1322 rivaroxaban, 548 apixaban, 440 edoxaban), 85.3% were prescribed low-dose regimens. The 7-day mortality rate was 9.0%, surging to 16.0% by the 30th day. Compared with dabigatran, there was a distinct divergence in 7-day mortality of factor Xa inhibitors (p = 0.012), with hazard ratios of 1.83 (95% CI 1.11-3.00, p = 0.017) for rivaroxaban, 2.13 (95% CI 1.23-3.66, p = 0.007) for apixaban, and 2.41 (95% CI 1.39-4.19, p = 0.002) for edoxaban. This pattern remained consistent when analyzing the subgroup that received lower dosages of DOACs. In conclusion, factor Xa inhibitors were associated with a significantly higher risk of 7-day mortality following major bleeding events than dabigatran among AF patients.

Synergistic effects of the combination of trametinib and alpelisib in anaplastic thyroid cancer with BRAF and PI3KCA co-mutations.

Background: Anaplastic thyroid cancer (ATC), a rare and aggressive malignancy with a poor prognosis, has shown promise with the approved dabrafenib/trametinib combination for BRAFV600E mutation. Co-occurring PI3KCA mutations, identified as negative prognostic factors in lung cancer with BRAFV600E mutation, emphasize the need to target both pathways. Exploring trametinib and alpelisib combination becomes crucial for ATC. Methods: A patient-derived xenograft (PDX) and primary cell line were obtained from an ATC patient with BRAF and PI3KCA co-mutation. Individual testing of targeted therapies against BRAF, MEK, and PI3KCA was followed by a combination treatment. Synergistic effects were evaluated using the combination index. Immunoblotting assessed the efficacy, with validation performed using a PDX model. Results: In this study, the ATC0802 cell line and PDX were established from a refractory ATC patient. NGS revealed BRAF and PI3KCA co-mutations pre- and post-dabrafenib/trametinib treatment. Trametinib/alpelisib combination showed synergy, suppressing both pERK and pAKT levels, unlike monotherapies or BRAF knockdown. The combination induced apoptosis and, in the PDX model, demonstrated superior tumor growth inhibition compared to monotherapies. Conclusions: The combination of trametinib and alpelisib showed promise as a strategy for treating ATC with co-mutations in BRAF and PI3KCA, both in vitro and in vivo. This combination offers insights into overcoming resistance to BRAF-targeted treatments in ATC with mutations in BRAF and PI3KCA.

Effect of Clinical Complete Remission Following Neoadjuvant Pembrolizumab or Chemotherapy in Bladder-Preservation Strategy in Patients with Muscle-Invasive Bladder Cancer Declining Definitive Local Therapy.

This study aimed to evaluate the outcomes and identify the predictive factors of a bladder-preservation approach incorporating maximal transurethral resection of bladder tumor (TURBT) coupled with either pembrolizumab or chemotherapy for patients diagnosed with muscle-invasive bladder cancer (MIBC) who opted against definitive local therapy. We conducted a retrospective analysis on 53 MIBC (cT2-T3N0M0) patients who initially planned for neoadjuvant pembrolizumab or chemotherapy after maximal TURBT but later declined radical cystectomy and radiotherapy. Post-therapy clinical restaging and conservative bladder-preservation measures were employed. Clinical complete remission was defined as negative findings on cystoscopy with biopsy confirming the absence of malignancy if performed, negative urine cytology, and unremarkable cross-sectional imaging (either CT scan or MRI) following neoadjuvant therapy. Twenty-three patients received pembrolizumab, while thirty received chemotherapy. Our findings revealed that twenty-three (43.4%) patients achieved clinical complete response after neoadjuvant therapy. The complete remission rate was marginally higher in pembrolizumab group in comparison to chemotherapy group (52.1% vs. 36.7%, p = 0.26). After a median follow-up of 37.6 months, patients in the pembrolizumab group demonstrated a longer PFS (median, not reached vs. 20.2 months, p = 0.078) and OS (median, not reached vs. 26.8 months, p = 0.027) relative to those in chemotherapy group. Those achieving clinical complete remission post-neoadjuvant therapy also exhibited prolonged PFS (median, not reached vs. 10.2 months, p < 0.001) and OS (median, not reached vs. 24.4 months, p = 0.004). In the multivariate analysis, clinical complete remission subsequent to neoadjuvant therapy was independently associated with superior PFS and OS. In conclusion, bladder preservation emerges as a viable therapeutic strategy for a carefully selected cohort of MIBC patients without definitive local therapy, especially those achieving clinical complete remission following neoadjuvant treatment. For patients unfit for chemotherapy, pembrolizumab offers a promising alternative treatment option.

PLK1 and its substrate MISP facilitate intrahepatic cholangiocarcinoma progression by promoting lymphatic invasion and impairing E-cadherin adherens junctions.

Intrahepatic cholangiocarcinoma (iCCA) is a subtype of CCA and has a high mortality rate and a relatively poor prognosis. However, studies focusing on increased cell motility and loss of epithelial integrity during iCCA progression remain relatively scarce. We collected seven fresh tumor samples from four patients to perform RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to determine the transcriptome profile and chromatin accessibility of iCCA. The increased expression of cell cycle regulators, including PLK1 and its substrate MISP, was identified. Ninety-one iCCA patients were used to validate the clinical significance of PLK1 and MISP. The upregulation of PLK1 and MISP was determined in iCCA tissues. Increased expression of PLK1 and MISP was significantly correlated with tumor number, N stage, and lymphatic invasion in an iCCA cohort. Knockdown of PLK1 or MISP reduced trans-lymphatic endothelial migration and wound healing and affected focal adhesions in vitro. In cell‒cell junctions, MISP localized to adherens junctions and suppressed E-cadherin dimerization. PLK1 disrupted adherens junctions in a myosin-dependent manner. Furthermore, PLK1 and MISP promoted cell proliferation in vitro and tumorigenesis in vivo. In iCCA, PLK1 and MISP promote aggressiveness by increasing lymphatic invasion, tumor growth, and motility through the repression of E-cadherin adherens junctions.

Efficacy of first-line combination therapies versus gemcitabine monotherapy for advanced pancreatic cancer: a systematic review and network meta-analysis.

Various first-line gemcitabine-based or fluorouracil-based combination regimens were approved in patients with advanced pancreatic cancer. Recent randomized clinical trials (RCTs) have investigated chemotherapy backbones in combination with novel investigational drugs, including chemotherapy agents or targeted drugs. However, the comparative efficacy of these different combination therapies remains limited. This systematic review and network meta-analysis aimed to assess the efficacy of first-line combination therapies for advanced pancreatic cancer. The study included 46 RCTs with 10,499 patients and 47 distinct regimens, using data sources from MEDLINE, EMBASE, Cochrane Clinical Trials, and ClinicalTrials.gov from January 1, 2010 to April 23, 2024. The primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included overall response rate (ORR) and disease control rate (DCR). The analysis revealed that gemcitabine+nab-paclitaxel (GA), GA with platinum and fluorouracil (GA+Plat+FU), gemcitabine with fluorouracil (G+FU), G+Plt+FU, and FOLFIRINOX were associated with superior OS and PFS compared to gemcitabine monotherapy. Triplet or quadruplet polychemotherapy combinations, such as GA+Plat+FU, G+Plt+FU, and FOLFIRINOX, demonstrated better OS benefit with hazard ratios of 0.42 (95% CI, 0.26-0.68), 0.41 (95% CI, 0.24-0.71), and 0.58 (95% CI, 0.48-0.71), respectively, compared to doublet regimens like GA and G+FU, which had hazard ratios of 0.70 (95% CI, 0.59-0.82) and 0.82 (95% CI, 0.72-0.95), respectively. Notably, no targeted drugs, monoclonal antibodies, or other medications showed improved survival when added to chemotherapy backbones. These findings support the use of gemcitabine-based or fluorouracil-based triplet or quadruplet regimens for better survival outcomes in patients with advanced pancreatic cancer. Further research is warranted to explore the potential benefits of adding chemotherapy agents, such as fluorouracil, to the GA doublet regimen.

Comparison of the safety, effectiveness, and usability of swab robot vs. manual nasopharyngeal specimen collection.

Background: Healthcare workers face a risk of infection during aerosol-generating procedures, such as nasal swabbing. Robot-assisted nasopharyngeal sampling aims to minimize this risk and reduce stress for healthcare providers. However, its effectiveness and safety require validation. Methods: We conducted a controlled trial with 80 subjects at two teaching hospitals and compared robot-collected vs manually-collected nasopharyngeal swabs. The primary outcomes included specimen quality and success rate of nasopharyngeal swab collection. We also recorded the pain index, duration of the collection, and psychological stress using a post-collection questionnaire. Results: During the study period, from September 23 to October 27, 2020, 40 subjects were enrolled in both the robotic and manual groups. The cycle threshold (Ct) value for nasopharyngeal specimens was statistically higher in the robotic group compared to the manual group (30.9 vs 28.0, p < 0.01). Both groups had Ct values under 35, indicating good quality specimens. In the robotic group, 3 out of 40 subjects required a second attempt at specimen collection, resulting in a success rate of 92.5 %. Further, although the pain levels were lower in the robotic group, the difference was not statistically significant (2.8 vs 3.6, p = 0.07). The manual group had a shorter sampling time, which was 29 s (201 vs 29, p < 0.05). However, when factoring in the time needed to put on personal protective equipment, the average time for the manual group increased to 251 s (201 vs 251, p < 0.05). Participants' questionnaire results show comparable psychological stress in both groups. Medical staff expressed that using a robot would reduce their psychological stress. Conclusions: We propose a safe and effective robotic technology for collecting nasopharyngeal specimens without face-to-face contact, which may reduce the stress of physicians and nurses. This technology can also be optimized for efficiency, making it useful in situations where droplet-transmitted infectious diseases are a concern.

A Potential Association of Zinc Deficiency and Tyrosine Kinase Inhibitor-Induced Hand-Foot Skin Reaction.

Hand-foot skin reaction (HFSR) is a common skin-related adverse event induced by multikinase inhibitors targeting both platelet-derived growth factor receptor and vascular endothelial growth factor receptor, possibly due to inadequate repair following frictional trauma. Zinc is a trace element and essential nutrient in humans that plays critical roles in the development and differentiation of skin cells. Zinc transporters (Zrt- and Irt-like proteins and Zn transporters) and metallothioneins are involved in zinc efflux, uptake, and homeostasis and have been reported to be involved in skin differentiation. The underlying mechanism of HFSR remains unclear, and the association between HFSR and zinc has not been previously studied. However, some case reports and case series provide potential evidence to suggest that zinc deficiency may be involved in HFSR development and zinc supplementation may relieve HFSR symptoms. However, no large-scale clinical studies have been conducted to examine this role. Therefore, this review summarizes the evidence supporting a possible link between HFSR development and zinc and proposes potential mechanisms underlying this association based on current evidence.