Search

Objectives: The primary goal of this research is to develop treatment-related genomic predictive markers for non-small cell lung cancer by integrating various machine learning algorithms that recommends near-optimal individualized patient treatment for chemotherapy in an effort to maximize efficacy or minimize treatment-related toxicity. This research can contribute toward developing a more refined, accurate and effective therapy accounting for specific patient needs. Methods: To accomplish our research goal, we implement ensemble learning algorithms, bagging with regularized Cox regression models and nonparametric tree-based models via Random Survival Forests. A comprehensive meta-database was compiled from the NCBI Gene Expression Omnibus data repository for lung cancer patients to capture and utilize complex genomic patterns that can predict treatment outcomes more accurately. Results: The developed novel prediction algorithm demonstrates the ability to support complex clinical decision-making processes in the treatment of NSCLC. It effectively addresses patient heterogeneity, offering predictions that are both refined and personalized in improving the precision of chemotherapy regimens prescribed to the eligible patients. Conclusion: This research should contribute substantial advancement of cancer treatments by improving the accuracy and efficacy of chemotherapy treatments for a targeted group of patients who need the right treatment. The integration of complex machine learning techniques with genomic data holds substantial potential to transform current cancer treatment paradigms by providing robust support in clinical decision-making. [ABSTRACT FROM AUTHOR]

Purpose: Because only a subset of cancer patients can benefit from immunotherapy, identifying predictive biomarkers of ICI therapy response is of utmost importance. Methods: We analyzed the association between hemoglobin (HGB) levels and clinical outcomes in 1,479 ICIs-treated patients across 16 cancer types. We explored the dose-dependent associations between HGB levels and survival and immunotherapy response using the spline-based cox regression analysis. Furthermore, we investigated the associations across subgroups of patients with different clinicopathological characteristics, treatment programs and cancer types using the bootstrap resampling method. Results: HGB levels correlated positively with clinical outcomes in cancer patients receiving immunotherapy but not in those without immunotherapy. Moreover, this association was independent of other clinicopathological characteristics (such as sex, age, tumor stage and tumor mutation burden (TMB)), treatment program and cancer type. Also, this association was independent of the established biomarkers of immunotherapy response, including TMB, PD-L1 expression and microsatellite instability. The combination of TMB and HGB level are more powerful in predicting immunotherapy response than TMB alone. Multi-omics analysis showed that HGB levels correlated positively with antitumor immune signatures and negatively with tumor properties directing antitumor immunosuppression, such as homologous recombination defect, stemness and intratumor heterogeneity. Conclusion: The HGB measure has the potential clinical value as a novel biomarker of immunotherapy response that is easily accessible from clinically routine examination. The combination of TMB and HGB measures have better predictive performance for immunotherapy response than TMB. [ABSTRACT FROM AUTHOR]

Objective: The aim was to explore the effectiveness of the International Myeloma Working Group Frailty Index (IMWG-FI), Mayo Score, UK Myeloma Research Alliance Risk Profile (MRP), and Intergroupe Francophone du Myélome (IFM) simplified frailty scale for classifying frailty in elderly multiple myeloma (MM) patients and compare the validity of different frailty tools. Methods: Eighty-four newly diagnosed MM patients aged ≥ 60 years in HeBei University Hospital were evaluated by the IMWG-FI, Mayo score, MRP score and IFM scale, and consistency and survival analyses were performed using Cohen's kappa coefficients and the Kaplan‒Meier method, respectively. Results: A total of 64 patients (76.2%) were identified as frail by at least one frailty tool; 14 (21.9%) were identified as frail by all four tools, and although moderate concordance was achieved between the IMWG-FI and MRP and the Mayo Score (0.432–0.474, P < 0.001), the concordance among the four assessment tools was relatively low (Cohen's kappa 0.218–0.474). The median overall survival (OS, P = 0.006, 0.025, and 0.028) and progression-free survival (PFS, P = 0.002, 0.006, and 0.03) of patients in the frail group and the nonfrail group identified by the IMWG-FI, Mayo score, and MRP were significantly different, while the median OS (P = 0.139) and PFS (P = 0.167) were not significantly different for the frail patients identified by the different frailty assessment tools. Conclusion: In this study, the consistency of the different frailty assessment tools was low, whereas that between the MRP and IMWG-FI was high. Therefore, combining IMWG-FI and MRP may reduce assessment subjectivity and improve frailty identification. [ABSTRACT FROM AUTHOR]

Background: According to long-term follow-up data of malignant tumor patients, assessing treatment effects requires careful consideration of competing risks. The commonly used cause-specific hazard ratio (CHR) and sub-distribution hazard ratio (SHR) are relative indicators and may present challenges in terms of proportional hazards assumption and clinical interpretation. Recently, the restricted mean time lost (RMTL) has been recommended as a supplementary measure for better clinical interpretation. Moreover, for observational study data in epidemiological and clinical settings, due to the influence of confounding factors, covariate adjustment is crucial for determining the causal effect of treatment. Methods: We construct an RMTL estimator after adjusting for covariates based on the inverse probability weighting method, and derive the variance to construct interval estimates based on the large sample properties. We use simulation studies to study the statistical performance of this estimator in various scenarios. In addition, we further consider the changes in treatment effects over time, constructing a dynamic RMTL difference curve and corresponding confidence bands for the curve. Results: The simulation results demonstrate that the adjusted RMTL estimator exhibits smaller biases compared with unadjusted RMTL and provides robust interval estimates in all scenarios. This method was applied to a real-world cervical cancer patient data, revealing improvements in the prognosis of patients with small cell carcinoma of the cervix. The results showed that the protective effect of surgery was significant only in the first 20 months, but the long-term effect was not obvious. Radiotherapy significantly improved patient outcomes during the follow-up period from 17 to 57 months, while radiotherapy combined with chemotherapy significantly improved patient outcomes throughout the entire period. Conclusions: We propose the approach that is easy to interpret and implement for assessing treatment effects in observational competing risk data. [ABSTRACT FROM AUTHOR]

G0 arrest (G0A) is widely recognized as a crucial factor contributing to tumor relapse. The role of genes related to G0A in lung adenocarcinoma (LUAD) was unclear. This study aimed to develop a gene signature based on for LUAD patients and investigate its relationship with prognosis, tumor immune microenvironment, and therapeutic response in LUAD. We use the TCGA-LUAD database as the discovery cohort, focusing specifically on genes associated with the G0A pathway. We used various statistical methods, including Cox and lasso regression, to develop the model. We validated the model using bulk transcriptome and single-cell transcriptome datasets (GSE50081, GSE72094, GSE127465, GSE131907 and EMTAB6149). We used GSEA enrichment and the CIBERSORT algorithm to gain insight into the annotation of the signaling pathway and the characterization of the tumor microenvironment. We evaluated the response to immunotherapy, chemotherapy, and targeted therapy in these patients. The expression of six genes was validated in cell lines by quantitative real-time PCR (qRT-PCR). Our study successfully established a six-gene signature (CHCHD4, DUT, LARP1, PTTG1IP, RBM14, and WBP11) that demonstrated significant predictive power for overall survival in patients with LUAD. It demonstrated independent prognostic value in LUAD. To enhance clinical applicability, we developed a nomogram based on this gene signature, which showed high reliability in predicting patient outcomes. Furthermore, we observed a significant association between G0A-related risk and tumor microenvironment as well as drug susceptibility, highlighting the potential of the gene signature to guide personalized treatment strategies. The expression of six genes were significantly upregulated in the LUAD cell lines. This signature holds the potential to contribute to improved prognostic prediction and new personalized therapies specifically for LUAD patients. [ABSTRACT FROM AUTHOR]

Recent studies have linked elevated tumor aneuploidy to anti-tumor immune suppression and adverse survival following immunotherapy. Herein, we provide supportive evidence for tumor aneuploidy as a biomarker of response to immunotherapy in patients with non-small cell lung cancer (NSCLC). We identify a dose–response relationship between aneuploidy score and patient outcomes. In two independent NSCLC cohorts (n = 659 patients), we demonstrate a novel association between elevated aneuploidy and non-smoking-associated oncogenic driver mutations. Lastly, we report enrichment of TERT amplification and immune-suppressive phenotypes of highly aneuploid NSCLC. Taken together, our findings emphasize a potentially critical role for tumor aneuploidy in guiding immunotherapy treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Anticoagulant drugs are a valuable tool for minimizing thrombotic risks in at-risk patients. The purpose of this study is to conduct a literature review highlighting the management of these drugs during daily clinical dental practice. Materials and Methods: We limited our search to English-language papers published between 1 January 1989, and 7 March 2024, in PubMed, Scopus and Web of Science that were relevant to our topic. In the search approach, the Boolean keywords "anticoagulant AND dentistry" were used. Results: Twenty-five clinical trials were included for final review from 623 articles obtained from the databases Web of Science (83), PubMed (382), and Scopus (158), eliminating duplicates and 79 off-topic items, resulting in 419 articles after removing 315 entries and confirming eligibility. Overall, these studies support the use of local hemostatic measures to manage the risk of bleeding in patients on anticoagulant therapy undergoing dental procedures and highlight the importance of greater education and collaboration among healthcare professionals. Conclusions: Research and clinical investigation have improved understanding and management of dental procedures in patients undergoing anticoagulant or antiplatelet therapy. Hemostatic agents, clinical protocols, risk factors, and continuous education are essential for navigating the complexities of anticoagulant therapy, ensuring optimal outcomes and enhancing patient well-being. [ABSTRACT FROM AUTHOR]

Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting. There is high prevalence of whole genome duplication (WGD) in high grade serous ovarian cancer. Here, the authors compare tumours with and without WGD and find that those that acquired WGD early during tumour evolution are associated with worse survival and have the lowest expression of MHC-II. [ABSTRACT FROM AUTHOR]

Background: The effect of whole-brain radiation therapy (WBRT) plus simultaneous integrated boost (SIB) in brain metastasis from breast cancers has not been demonstrated. Method: In this single-center retrospective study, we reviewed consecutive breast cancer patients who developed brain metastasis and were treated with hypofractionated radiation therapy plus WBRT using intensity-modulated radiation therapy (IMRT)-SIB approaches. We analyzed clinical outcomes, prognostic factors and patterns of treatment failure. Result: A total of 27 patients were eligible for analysis. Four (14.8%) patients achieved clinical complete response and 14 (51.9%) had partial response of brain lesions. The other nine patients were not evaluated for brain tumor response. The median brain progression-free survival was 8.60 (95% CI [6.43–13.33]) months and the median overall survival was 16.8 (95% CI [13.3–27.7]) months. Three patients had in-field failure, five had out-field failure and two had in-field and out-field failure. Conclusion: WBRT plus SIB led to improved tumor control and clinical outcome in breast cancer patients with brain metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: This study addresses the challenge of interpreting the efficacy of immunotherapy in biliary tract cancer (BTC) in terms of overall survival (OS). Traditional methods often rely on the proportional hazard assumption, which may not hold in this context. Instead, we performed a meta-analysis of available phase 3 trials using restricted median survival time (RMST) to measure temporal benefits, providing a clearer picture of the real effects of immunotherapy-based regimens. By incorporating anti-PD-1/anti-PD-L1 agents, our analysis confirmed improvements in estimated mean OS and progression-free survival (PFS) at 24 months, as indicated by RMST, of 1.21 (95% CI: 0.49–1.93) and 1.31 (95% CI: 0.66–1.96) months, respectively. This approach not only offers a more nuanced understanding of clinical benefits, but also aids healthcare providers and patients in making informed decisions about treatment options, emphasizing a methodology that can adapt to the complexities of data. Background: For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan–Meier curves violate the proportional hazards (PH) assumption. Analysis using restricted mean survival time (RMST) allows quantification of the benefits in the absence of PH. This systematic review and meta-analysis aims to assess the benefit of immunotherapy-based regimens for OS at 24 months using RMST analysis. Methods: A systematic review was conducted using studies published up to 8 November 2023. Only phase 3 RCTs evaluating the use of anti-PD-1/PD-L1 combined with GemCis and reporting OS were included. KM curves for OS were digitized, and the data were reconstructed. A meta-analysis for OS by RMST at 24 months was performed. Results: A total of 1754 participants from the TOPAZ-1 and KEYNOTE-966 trials were included. In TOPAZ-1, RMSTs at 24 months were 13.52 (7.92) and 12.21 (7.22) months with GemCis plus durvalumab and GemCis alone, respectively. In KEYNOTE-966, RMSTs at 24 months were 13.60 (7.76) and 12.45 (7.73) months with GemCis plus pembrolizumab and GemCis alone, respectively. Immunotherapy-based regimens showed a mean OS difference at 24 months by an RMST of 1.21 months [(95% CI: 0.49–1.93), p < 0.001, I2 = 0%]. Conclusions: Immunotherapy-based regimens improve OS in advanced BTC. Given this magnitude of benefit, it is essential to weigh up individual patient factors, preferences, and potential risks. RMST analysis provides valuable information to patients and physicians, facilitating decision-making in a value-based medical environment. [ABSTRACT FROM AUTHOR]

Simple Summary: In a comprehensive analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and the CLL13 trials, we assessed the impact of first-line treatments with targeted agents (TAs), or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT), on overall survival (OS) compared to age- and sex-matched individuals in the general population. TAs demonstrated a higher 5-year restricted mean survival time (RMST) (58.1 months; 95% CI: 57.4 to 58.8) compared to CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Moreover, the comparison with age- and gender-matched general populations (AGMGP) suggested that TAs may mitigate CLL's impact on OS during the first five years post-treatment initiation. In contrast, CLL patients treated with FCR exhibited sustained OS differences compared to both the Italian and US AGMGP cohorts. These results support TAs as the preferred first-line treatment for younger/fit CLL patients but imply the need for a careful interpretation due to variations in patient selection criteria and clinical profiles across trials. Longer follow-up is essential to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was −0.4 months (95% CI: −0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: −0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: −1.6 months; 95% CI: −2.4 to −0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: −0.9 months; 95% CI: −1.7 to −0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. [ABSTRACT FROM AUTHOR]

Simple Summary: A subset of advanced melanoma patients have a mutant BRAF protein. Two classes of therapy options are available to these patients, but it is unclear which is more effective in this population. We analyzed patient samples treated with either immunotherapy or BRAF-targeted therapy and found that those treated with immunotherapy had notably better outcomes. We further analyzed if aneuploidy or cGAS expression could act as a biomarker for how patients responded to either treatment. We found no association between aneuploidy and clinical outcomes. We observed that cGAS expression may correlate with outcome, but it appears to be a nuanced relationship and requires more study. BRAF-mutant melanoma patients can be treated with targeted therapy or immunotherapies, and it is not clear which should be provided first. Targeted treatments do not work in up to one-third of cases, while immunotherapies may only be effective in up to 60% and come with a high risk of immune-related side effects. Determining which treatment to provide first is thus of critical importance. Recent studies suggest that chromosomal instability and aneuploidy and cyclic GMP-AMP synthase (cGAS) can act as biomarkers for cancer severity and patient outcome. Neither potential biomarker has been extensively studied in melanoma. We examined 20 BRAF-mutant melanomas treated with immunotherapy or targeted therapy and measured chromosomal aneuploidy and cGAS expression levels. Treatment type, aneuploidy, and cGAS expression were correlated with progression-free survival (PFS) in these patients. Those treated with immunotherapy first had significantly better outcomes than those treated with targeted therapy, suggesting immunotherapy should be strongly considered as the first-line therapy for patients bearing BRAF-mutant melanoma. We found that there was no correlation of aneuploidy with outcome while there was some positive correlation of cGAS levels with PFS. Further studies are needed to confirm these findings and to test other potential biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: There is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors (ICIs). Methods: We systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS. Results: 61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HRPFS and HRmPFS both had a strong surrogacy value (R2 = 0.74 and R2 = 0.81, respectively). In comparisons testing ICI as monotherapy, HRPFS was the best surrogate, although having a moderate correlation (R2 = 0.58). In comparisons testing ICI plus other treatment(s), the associations were very weak for all the surrogate endpoints and treatment effect measures, with R2 ranging from 0.01 to 0.22. Conclusion: In RCTs testing ICIs, the value of potential surrogates for HROS was strongly affected by the type of treatment(s) tested. The evidence available supports HRPFS as the best surrogate, and disproves the use of alternative endpoints, such as the mPFS, or treatment effect measures, such as the RMST. [ABSTRACT FROM AUTHOR]

Simple Summary: In clinical practice, human epidermal growth factor receptor (HER2)-negative tumors include triple-negative or luminal breast cancer. HER2-negative breast cancer can be further characterized by immunohistochemical (IHC) and in situ hybridization (ISH) scores into HER2 IHC0 or HER2-low (IHC 1+, 2+/ISH−. Interest in HER2-low tumors has increased as data show the efficacy of HER2-targeted therapies in this subgroup. While several studies have examined treatment variations in the overall breast cancer population, there is limited information on the real-world treatment patterns among patients with HER2 (IHC0/-low) metastatic or recurrent breast cancer. Our study addresses this gap by analyzing treatment and outcomes by HER2 status and found that outcomes were similar in the HER2 IHC0 and -low groups. Our findings add value to the general understanding of the clinical differences between HER2 IHC0/-low and de novo/recurrent disease and have important implications for new effective treatment strategies designed for varying levels of HER2 expression. Improved understanding of the biological heterogeneity of breast cancer (BC) has facilitated the development of more effective and personalized approaches to treatment. This study describes real-world evidence on treatment patterns and outcomes for a population-based cohort of patients with human epidermal growth factor receptor (HER2) IHC0 and -low BC with de novo or recurrent disease from Alberta, Canada. Patients 18+ years old diagnosed with HER2 IHC0/-low, de novo/recurrent BC from 2010 to 2019 were identified using Alberta's cancer registry. Analyses of these patients' existing electronic medical records and administrative claims data were conducted to examine patient characteristics, treatment patterns, and survival outcomes. A total of 3413 patients were included in the study, of which 72.10% initiated first line hormonal and non-hormonal systemic therapy. The 1-year overall survival (OS) was 81.09% [95% CI, 79.52–82.69]. Recurrent patients had a higher OS compared to de novo patients: 54.30 months [95% CI, 47.80–61.90] vs. 31.5 months [95% CI, 28.40–35.90], respectively. Median OS was 43.4 months [95% CI, 40.70–47.10] and 35.80 months [95% CI, 29.00–41.70] among patients with HER2-low and HER2 IHC0 cancer, respectively. The study results provide real-world evidence regarding the clinical outcomes of HER2 IHC0/-low and de novo/recurrent disease. [ABSTRACT FROM AUTHOR]

Background: Amyloid beta (Ab) plaque density was examined in the amygdala of rhesus macaques, to elucidate the influence of age, diet and hormonal environment. Methods: Luminex technology was used to measure cerebrospinal fluid (CSF) concentrations of Ab40 and Ab42 across three decades, while immunohistochemistry was used to examine Ab plaque density in the amygdala. Results: Ab40 was found to be the predominant isoform of Ab in the CSF, but neither Ab40 or Ab42 concentrations showed an age-related change, and the ratio of Ab42 to Ab40 showed only a marginal increase. Significantly fewer Ab plaques were detected in the amygdala of old ovariectomized animals if they received estradiol HRT (p < 0.001); similar results were obtained regardless of whether they had been maintained on a regular monkey chow for ~48 months or on a high-fat, high-sugar, Western-style diet for ~30 months. Conclusion: The results demonstrate that HRT involving estrogen can reduce Ab plaque load in a cognitive brain region of aged non-human primates. The results from this translational animal model may therefore have clinical relevance to the treatment of AD in post-menopausal women, whether used alone, or as a supplement to current pharmacological and monoclonal antibody-based interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. Developing liquid biopsies that aid in the detection and monitoring of recurrent CRC may improve clinical management and patient outcomes. In this study, we investigated a serially sampled blood assay of methylated DNA markers (MDMs) in combination with carcinoembryonic antigen as a clinical tool to surveil and monitor recurrent cancer in a prospective cohort of patients who completed curative-intent therapy for CRC. We demonstrated that the MDMs detected recurrent CRC before the clinical or radiographic detection of recurrence. In a small number of patients, we further showed that the MDMs may correlate with the tumor burden. These data highlight the importance of incorporating epigenetic signatures into liquid biopsies and support further research to validate the correlations of circulating tumor DNA with the tumor burden. Background: Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. Methods: A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. Results: Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90–232 days). Conclusions: Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring. [ABSTRACT FROM AUTHOR]

Simple Summary: Depression and cognitive problems are common in breast cancer survivorship and reduce quality of life. Depression, a risk factor for cognitive decline, is often accompanied by elevated inflammation and a "leaky gut", which can also impact cognitive function. This study assessed whether depression in tandem with either elevated inflammation or intestinal permeability predicted poorer subjective or objective cognitive function among breast cancer survivors. In secondary analyses of data from 613 survivors with 1015 total study visits, we found that depression combined with either heightened inflammation or intestinal permeability enhanced subjective cognitive complaints, especially focus problems. On neuropsychological tests, depressed survivors performed worse regardless of inflammation or intestinal permeability. These findings suggest that survivors with depression accompanied by immune dysregulation may be more aware of depression-related cognitive deficits compared to other depressed survivors. About one-in-three breast cancer survivors have lingering cognitive complaints and objective cognitive impairment. Chronic inflammation and intestinal permeability (i.e., leaky gut), two risk factors for cognitive decline, can also fuel depression—another vulnerability for cognitive decline. The current study tested whether depression accompanied by high levels of inflammation or intestinal permeability predicted lower subjective and objective cognitive function in breast cancer survivors. We combined data from four breast cancer survivor studies (n = 613); some had repeated measurements for a total of 1015 study visits. All participants had a blood draw to obtain baseline measures of lipopolysaccharide binding protein—a measure of intestinal permeability, as well as three inflammatory markers that were incorporated into an inflammatory index: C-reactive protein, interleukin-6, and tumor necrosis factor-α. They reported depressive symptoms on the Center for Epidemiological Studies depression scale (CES-D), and a binary variable indicated clinically significant depressive symptoms (CES-D ≥ 16). The Kohli (749 observations) and the Breast Cancer Prevention Trial (591 observations) scales assessed subjective cognitive function. Objective cognitive function tests included the trail-making test, Hopkins verbal learning test, Conners continuous performance test, n-back test, FAS test, and animal-naming test (239–246 observations). Adjusting for education, age, BMI, cancer treatment type, time since treatment, study visit, and fatigue, women who had clinically elevated depressive symptoms accompanied by heightened inflammation or intestinal permeability reported poorer focus and marginally poorer memory. However, poorer performance across objective cognitive measures was not specific to inflammation-associated depression. Rather, there was some evidence of lower verbal fluency; poorer attention, verbal learning and memory, and working memory; and difficulties with visuospatial search among depressed survivors, regardless of inflammation. By themselves, inflammation and intestinal permeability less consistently predicted subjective or objective cognitive function. Breast cancer survivors with clinically significant depressive symptoms accompanied by either elevated inflammation or intestinal permeability may perceive greater cognitive difficulty, even though depression-related objective cognitive deficits may not be specific to inflammation- or leaky-gut-associated depression. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advances in treating elderly patients with chronic lymphocytic leukemia (CLL) have emphasized the importance of geriatric assessment (GA) to evaluate patient fitness and predict treatment outcomes. Targeted therapies (BTK inhibitors and venetoclax) have demonstrated significant clinical benefits and are now a reality in CLL treatment. They have a different toxicity profile that may affect frailty. Therefore, incorporating GA before treatment initiation, considering physical and cognitive function, emotional health, comorbidity, polypharmacy, nutrition, and social support, is essential. Chronic lymphocytic leukemia (CLL) is a disease of the elderly, but chronological age does not accurately discriminate frailty status at the inter-individual level. Frailty describes a person's overall resilience. Since CLL is a stressful situation, it is relevant to assess the patient´s degree of frailty, especially before starting antineoplastic treatment. We are in the era of targeted therapies, which have helped to control the disease more effectively and avoid the toxicity of chemo (immuno) therapy. However, these drugs are not free of side effects and other aspects arise that should not be neglected, such as interactions, previous comorbidities, or adherence to treatment, since most of these medications are taken continuously. The challenge we face is to balance the risk of toxicity and efficacy in a personalized way and without forgetting that the most frequent cause of death in CLL is related to the disease. For this purpose, comprehensive geriatric assessment (GA) provides us with the opportunity to evaluate multiple domains that may affect tolerance to treatment and that could be improved with appropriate interventions. In this review, we will analyze the state of the art of GA in CLL through the five Ws. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockades (ICBs) therapy has produced durable clinical responses in many cancer types, but only a fraction of patients can benefit from ICB treatment. Previous studies have reported multiple transcriptomic biomarkers to predict ICB responses and improve treatment precision in various cancer types. However, a timely and unbiased assessment of these biomarkers has yet to be conducted due to the lack of large-scale uniformly curated ICB-treated datasets. To address the needs, we developed ICB-Portal, a comprehensive resource about ICB including RNA-seq data of 29 datasets from public sources and standardized metadata of each study through a uniform pre-processing, 48 biomarker scores associated with ICB response, results of a systematic benchmark analysis evaluating the efficacy, and generalization ability for each biomarker in various scenarios such as different cancer types, anti-bodies, biopsy time, and combinatory treatments with other drugs by a standardized bioinformatics workflow and an online benchmark platform. Immune checkpoint blockades (ICBs) have revolutionized cancer therapy by inducing durable clinical responses, but only a small percentage of patients can benefit from ICB treatments. Many studies have established various biomarkers to predict ICB responses. However, different biomarkers were found with diverse performances in practice, and a timely and unbiased assessment has yet to be conducted due to the complexity of ICB-related studies and trials. In this study, we manually curated 29 published datasets with matched transcriptome and clinical data from more than 1400 patients, and uniformly preprocessed these datasets for further analyses. In addition, we collected 39 sets of transcriptomic biomarkers, and based on the nature of the corresponding computational methods, we categorized them into the gene-set-like group (with the self-contained design and the competitive design, respectively) and the deconvolution-like group. Next, we investigated the correlations and patterns of these biomarkers and utilized a standardized workflow to systematically evaluate their performance in predicting ICB responses and survival statuses across different datasets, cancer types, antibodies, biopsy times, and combinatory treatments. In our benchmark, most biomarkers showed poor performance in terms of stability and robustness across different datasets. Two scores (TIDE and CYT) had a competitive performance for ICB response prediction, and two others (PASS-ON and EIGS_ssGSEA) showed the best association with clinical outcome. Finally, we developed ICB-Portal to host the datasets, biomarkers, and benchmark results and to implement the computational methods for researchers to test their custom biomarkers. Our work provided valuable resources and a one-stop solution to facilitate ICB-related research. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) play important roles in the regulation of cancer. However, the clinical implications and regulatory networks of circRNAs in cancer patients receiving immune checkpoint blockades (ICB) have not been fully elucidated. Here, we characterize circRNA expression profiles in two independent cohorts of 157 ICB-treated advanced melanoma patients and reveal overall overexpression of circRNAs in ICB non-responders in both pre-treatment and early during therapy. Then, we construct circRNA-miRNA-mRNA regulatory networks to reveal circRNA-related signaling pathways in the context of ICB treatment. Further, we construct an ICB-related circRNA signature (ICBcircSig) score model based on progression-free survival-related circRNAs to predict immunotherapy efficacy. Mechanistically, the overexpression of ICBcircSig circTMTC3 and circFAM117B could increase PD-L1 expression via the miR-142-5p/PD-L1 axis, thus reducing T cell activity and leading to immune escape. Overall, our study characterizes circRNA profiles and regulatory networks in ICB-treated patients, and highlights the clinical utility of circRNAs as predictive biomarkers of immunotherapy. Circular RNAs are known to be linked to cancer regulation. Here, the authors identify a circular RNA signature associated with immune checkpoint response in melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and despite best efforts to stratify patients recurrence remains a major issue. Our study attempted to identify what variables are involved in recurrence of HCC after resection and if they be used to stratify an individual patient's risk of recurrence. We developed a simple-to-implement RESected Tumor Outcome and Recurrence (RESTORE) index comprising three commonly assessed variables: alpha-fetoprotein level, vascular invasion, and tumor burden. The RESTORE index was highly predictive of HCC recurrence risk after resection. The RESTORE index will help identify patients who would potentially benefit from more intensive post-resection surveillance or adjuvant therapeutics. Although many variables have been associated with increased risk of hepatocellular carcinoma (HCC) recurrence after resection, no simple-to-implement risk score has been developed to determine this post-resection risk. Objective: We aimed to identify risk factors for HCC recurrence and develop a risk score for predicting recurrence of HCC in patients who undergo resection with curative intent. Design: Single-center retrospective analysis Setting: Single-center tertiary care referral hospital (University of San Francisco, California). Participants: Patients who underwent resection with curative intent for HCC between January 2005 and May 2019 with complete pathologic findings and recorded follow up. Main Outcomes and Measures: Univariate and multivariate Cox regression analysis were used to identify independent risk factors for HCC recurrence. A multivariable Cox proportional-hazard regression model with listwise deletion was used to create a risk score. Results: A total of 179 patients were included in the study; 129 (72.9%) were men, and the median (IQR) age was 63 (57–67) years. Median alpha-fetoprotein (AFP) was 12.3 ng/mL at time of resection. Most patients (82%) had a single tumor nodule, and the mean aggregate nodule size was 6.75 cm; 28.4% had evidence of vascular invasion. On multivariable Cox proportional-hazards regression, AFP ≥1000 ng/mL, multinodularity, and vascular invasion were independently associated with HCC recurrence. The RESTORE index was created using stratified pre-operative AFP, vascular invasion, and the presence of a single lesion within or beyond Milan Criteria versus multiple lesions. The RESTORE index ranged from 0–9 (highest patient score was 8) and was highly predictive of HCC recurrence (C statistic 0.70). RESTORE could stratify 5-year post-resection HCC recurrence risk, ranging from less than 25% with a score of 0 to more than 80% with a score of 5–8. Conclusions and Relevance: The RESTORE index that we developed and validated is a simple-to-implement and novel risk score for patients undergoing resection for HCC and may help identify those who would benefit most from intensive surveillance strategies or adjuvant therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA repair pathways play a crucial role in maintaining the stability of a cell's genetic material. When these pathways are defective, it can lead to genomic instability in cancer cells, which can increase their ability to stimulate an immune response. Inhibiting DNA damage response, the process that helps repair DNA damage, has been shown to increase the effectiveness of anticancer immunotherapies. In this review, we will explore how deficits in the DNA repair pathway can affect the immune system's ability to fight cancer. We will also examine clinical trials that have combined inhibition of DNA damage response with immune-oncology treatments. A better understanding of these pathways could help improve the effectiveness of cancer immunotherapies and other treatments for various types of cancer. Defects in DNA repair pathways can lead to genomic instability in multiple tumor types, which contributes to tumor immunogenicity. Inhibition of DNA damage response (DDR) has been reported to increase tumor susceptibility to anticancer immunotherapy. However, the interplay between DDR and the immune signaling pathways remains unclear. In this review, we will discuss how a deficiency in DDR affects anti-tumor immunity, highlighting the cGAS-STING axis as an important link. We will also review the clinical trials that combine DDR inhibition and immune-oncology treatments. A better understanding of these pathways will help exploit cancer immunotherapy and DDR pathways to improve treatment outcomes for various cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Goals-of-care discussions can help patients to understand their illness and to share their values and treatment preferences with their clinicians. Here, we compared the impact of an institution-wide goals-of-care program on intensive care unit (ICU) mortality between patients with hematologic malignancies and solid tumors. We found that patients with blood cancers had improved goals-of-care documentation, but no change in ICU mortality; in contrast, patients with solid tumors had lesser improvement in goals-of-care documentation, but significantly lower ICU mortality. These findings highlight the need to overcome other barriers to improve care for patients with hematologic malignancies. We recently reported that an interdisciplinary multicomponent goals-of-care (myGOC) program was associated with an improvement in goals-of-care (GOC) documentation and hospital outcomes; however, it is unclear if the benefit was uniform between patients with hematologic malignancies and solid tumors. In this retrospective cohort study, we compared the change in hospital outcomes and GOC documentation before and after myGOC program implementation between patients with hematologic malignancies and solid tumors. We examined the change in outcomes in consecutive medical inpatients before (May 2019–December 2019) and after (May 2020–December 2020) implementation of the myGOC program. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included GOC documentation. In total, 5036 (43.4%) patients with hematologic malignancies and 6563 (56.6%) with solid tumors were included. Patients with hematologic malignancies had no significant change in ICU mortality between 2019 and 2020 (26.4% vs. 28.3%), while patients with solid tumors had a significant reduction (32.6% vs. 18.8%) with a significant between-group difference (OR 2.29, 95% CI 1.35, 3.88; p = 0.004). GOC documentation improved significantly in both groups, with greater changes observed in the hematologic group. Despite greater GOC documentation in the hematologic group, ICU mortality only improved in patients with solid tumors. [ABSTRACT FROM AUTHOR]

Interactions between Tumor microenvironment (TME) cells shape the unique growth environment, sustaining tumor growth and causing the immune escape of tumor cells. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the identification of cancer-related TME cells. Here, we proposed a novel network-based computational method, named as iATMEcell, to identify the abnormal TME cells associated with the biological outcome of interest based on a cell–cell crosstalk network. In the method, iATMEcell first manually collected TME cell types from multiple published studies and obtained their corresponding gene signatures. Then, a weighted cell–cell crosstalk network was constructed in the context of a specific cancer bulk tissue transcriptome data, where the weight between cells reflects both their biological function similarity and the transcriptional dysregulated activities of gene signatures shared by them. Finally, it used a network propagation algorithm to identify significantly dysregulated TME cells. Using the cancer genome atlas (TCGA) Bladder Urothelial Carcinoma training set and two independent validation sets, we illustrated that iATMEcell could identify significant abnormal cells associated with patient survival and immunotherapy response. iATMEcell was further applied to a pan-cancer analysis, which revealed that four common abnormal immune cells play important roles in the patient prognosis across multiple cancer types. Collectively, we demonstrated that iATMEcell could identify potentially abnormal TME cells based on a cell–cell crosstalk network, which provided a new insight into understanding the effect of TME cells in cancer. iATMEcell is developed as an R package, which is freely available on GitHub (https://github.com/hanjunwei-lab/iATMEcell). [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to compare effectiveness and cost profile in non-small-cell lung cancer (NSCLC) patients harboring synchronous brain metastases (BMs) who received non-chemo first-line systemic therapy with or without advanced radiotherapy (aRT). A total of 177 lung cancer patients, of whom 58 were treated with systemic treatment (either TKIs or pembrolizumab) plus aRT (STRT) and 119 with systemic treatment alone, were selected. The addition of aRT to systemic treatment was associated with a significantly better OS (p = 0.020) and PFS (p = 0.041) than systemic therapy alone. The incremental cost-effectiveness ratio (ICER) value indicated an average cost of €3792 for each month of survival after STRT and confirmed clinical effectiveness but higher healthcare costs. This real-world study suggests that upfront aRT in this setting represents a valid treatment strategy, boosting the efficacy of emerging drug classes with sustainable costs for the health service. Aim: Healthcare administrative databases represent a valuable source for real-life data analysis. The primary aim of this study is to compare effectiveness and cost profile in non-small-cell lung cancer (NSCLC) patients harboring synchronous brain metastases (BMs) who received non-chemo first-line systemic therapy with or without advanced radiotherapy (aRT). Methods: Diagnostic ICD-9-CM codes were used for identifying all patients with a new diagnosis of lung cancer between 2012 and 2019. Among these, patients who had started a first-line systemic treatment with either TKIs or pembrolizumab, alone or in combination with intensity-modulated or stereotactic RT, were selected. Clinical outcomes investigated included overall survival (OS), progression-free survival (PFS), and time-to-treatment failure (TTF). The cost outcome was defined as the average per capita cumulative healthcare direct costs of the treatment, including all inpatient and outpatient costs. Results: The final cohort included 177 patients, of whom 58 were treated with systemic treatment plus aRT (STRT) and 119 with systemic treatment alone. The addition of aRT to systemic treatment was associated with a significantly better OS (p = 0.020) and PFS (p = 0.041) than systemic therapy alone. The ICER (incremental cost-effectiveness ratio) value indicated an average cost of €3792 for each month of survival after STRT treatment and confirmed clinical effectiveness but higher healthcare costs. Conclusions: This real-world study suggests that upfront aRT for NCLSC patients with synchronous BMs represents a valid treatment strategy, boosting the efficacy of novel and emerging drug classes with sustainable costs for the health service. Translational relevance: The present real-world study reports that the use of upfront advanced radiotherapyaRT and new-generation systemic agents, such as TKIs and pembrolizumab, may have higher oncological control and an improved cost-effectiveness profile than the use of new-generation systemic agents alone in NCLSC patients with synchronous brain metastases. Acquired evidence can also be used to inform policymakers that adding advanced radiotherapy results is a sustainable cost for the health service. Since approximately 50% of patients do not meet RCT inclusion criteria, a significant proportion of them is receiving treatment that is not evidence-informed; therefore, these results warrant further studies to identify the best radiotherapy timing and possible dose escalation approaches to improving treatment efficacy in patient subgroups not typically represented in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Background: Immune interactions play important roles in the regulation of T cells' cytotoxic function, further impacting the anti-tumor efficacy of immunotherapy. A comprehensive analysis of immune cell types in HCC and immune-cell-related signatures predicting prognosis and monitoring immunotherapy efficacy is still absent. Methods: More than 1,300 hepatocellular carcinomas (HCC) patients were collected from public databases and included in the present study. The ssGSEA algorithm was applied to calculate the infiltration level of 28 immunocyte subpopulations. A cell pair algorithm was applied to construct an immune-cell-related prognostic index (ICRPI). Survival analyses were performed to measure the survival difference across ICRPI risk groups. Spearman's correlation analyses were used for the relevance assessment. A Wilcoxon test was used to measure the expression level's differences. Results: In this study, 28 immune subpopulations were retrieved, and 374 immune cell pairs (ICPs) were established, 38 of which were picked out by the least absolute shrinkage and selection operator (LASSO) algorithm. By using the selected ICPs, the ICRPI was constructed and validated to play crucial roles in survival stratification and dynamic monitoring of immunotherapy effect. We also explored several candidate drugs targeting ICRPI. A composite ICRPI and clinical prognostic index (ICPI) was then constructed, which achieved a more accurate estimation of HCC's survival and is a better choice for prognosis predictions in HCC. Conclusions: In conclusion, we constructed and validated ICRPI based on the cell pair algorithm in this study, which might provide some novel insights for increasing the survival estimation and clinical response to immune therapy for individual HCC patients and contribute to the personalized precision immunotherapy strategy of HCC. [ABSTRACT FROM AUTHOR]

A holistic concept based on traditional Persian medicine (TPM) describes a headache with a gastrointestinal (GI) origin (gastric-headache). Although the neurological manifestations of this headache are similar to those of other headaches, its etiology is different. Considering its simultaneous effects on the brain and GI system, a formulation was designed based on this concept. This study aimed to determine the safety and efficacy of the designed formulation on migraine headache (MH) associated with functional dyspepsia (FD). A total of 75 diagnosed cases of MH patients with concurrent FD were randomly divided equally into 3 groups: (i) the polyherbal formulation, sodium valproate (VPA), and amitriptyline group, (ii) VPA, amitriptyline, and polyherbal formulation placebo group, and (iii) the polyherbal formulation and VPA placebo group. The primary outcomes, including frequency, duration, and severity of MH attacks, were measured at baseline and weeks 4, 8, and 12. However, secondary outcomes, including the Headache Impact Test 6 (HIT-6) Questionnaire and Parkman's score, were evaluated at baseline and end of treatment. The frequency, duration, and severity of migraine (P < 0.001 for all cases), HIT-6 (P < 0.001 for all cases), and FD (P < 0.001 for all cases) scores at the end of treatment showed a significant decrease in the 3 groups compared to the baseline. However, the differences in those variables between the 3 groups were not significant at the end of the study. The polyherbal formulation alone may improve the symptoms of migraine patients and other groups. This effect could be due to improving digestion and FD in migraine patients. [ABSTRACT FROM AUTHOR]

Individual participant data (IPD) from oncology clinical trials is invaluable for identifying factors that influence trial success and failure, improving trial design and interpretation, and comparing pre-clinical studies to clinical outcomes. However, the IPD used to generate published survival curves are not generally publicly available. We impute survival IPD from ~500 arms of Phase 3 oncology trials (representing ~220,000 events) and find that they are well fit by a two-parameter Weibull distribution. Use of Weibull functions with overall survival significantly increases the precision of small arms typical of early phase trials: analysis of a 50-patient trial arm using parametric forms is as precise as traditional, non-parametric analysis of a 90-patient arm. We also show that frequent deviations from the Cox proportional hazards assumption, particularly in trials of immune checkpoint inhibitors, arise from time-dependent therapeutic effects. Trial duration therefore has an underappreciated impact on the likelihood of success. Analysis of more than 150 Phase 3 oncology clinical trials supports parametric statistical analysis, significantly increasing the precision of small early-phase trials and relating deviations from the Cox proportional hazards model to trial duration. [ABSTRACT FROM AUTHOR]

Simple Summary: Anti-hormonal therapie regimes are well established in oncological treatments in breast cancer. In contrast there is limited knowledge of their effects on metastatic brain metastases in advanced breast cancer and their ability to cross the blood brain-barrier. In this review, we point out the usual antihormonal therapy options in the primary disease, but also in metastatic breast cancer. In addition, we explain the epidemiological facts of brain metastases, as well as the basics of the blood-brain barrier and how this is overcome by metastase. Last but not least, we deal with the known anti-hormonal therapy options and present clinical studies on their intracerebral effect, as well as the known basics of their blood-brain barrier penetration. Not all common anti-hormonal therapeutics are able to penetrate the CNS. It is therefore important for the treating oncologists to use substances that have been proven to cross the BBB, despite the limited data available. Aromataseinhibitors, especially letrozole, probably also tamoxifen, everolimus and CDK4/6 inhibitors, especially abemaciclib, appear to act intracerebrally by overcoming the blood-brain barrier. Nevertheless, further data must be obtained in basic research, but also health care research in relation to patients with brain metastases. The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer. [ABSTRACT FROM AUTHOR]

Background: For the design and analysis of clinical trials with time-to-event outcomes, the Cox proportional hazards model and the logrank test have been the cornerstone methods for many decades. Increasingly, the key assumption of proportionality-or time-fixed effects-that underpins these methods has been called into question. The availability of novel therapies with new mechanisms of action and clinical trials of longer duration mean that non-proportional hazards are now more frequently encountered.Methods: We compared several regression-based methods to model time-dependent treatment effects. For illustration purposes, we used selected endpoints from a large, community-based clinical trial of low dose daily aspirin in older persons. Relative and absolute estimands were defined, and analyses were conducted in all participants. Additional exploratory analyses were undertaken by selected subgroups of interest using interaction terms in the regression models.Discussion: In the trial with median 4.7 years follow-up, we found evidence for non-proportionality and a time-dependent treatment effect of aspirin on cancer mortality not previously reported in trial findings. We also found some evidence of time-dependence to an aspirin by age interaction for major adverse cardiovascular events. For other endpoints, time-fixed treatment effect estimates were confirmed as appropriate.Conclusions: The consideration of treatment effects using both absolute and relative estimands enhanced clinical insights into potential dynamic treatment effects. We recommend these analytical approaches as an adjunct to primary analyses to fully explore findings from clinical trials. [ABSTRACT FROM AUTHOR]

Aims: We aim to investigate the additive effect of B‐lines on lung ultrasound (LUS) for predicting outcome in patients with heart failure (HF) when combined with conventional assessment of clinical congestion. Methods and results: This study prospectively enrolled 117 hospitalized HF patients (61 ± 16 years, 70.1% males) who underwent congestion assessment by the 'wet/dry' status, clinical congestion score (CCS), and B‐lines on LUS. The primary endpoint was all‐cause mortality or hospitalization for HF during the 180‐day follow‐up after discharge. The 'Wet', CCS ≥ 3, and B‐lines >5, indicators of congestion positive (+), were observed in 83.8%, 76.1%, and 70.1% of the patients on admission, respectively; and the numbers significantly decreased to 41.9%, 41.9%, and 35.9% at discharge, respectively. The agreement between the 'wet/dry' status and B‐lines (58.1%) or between CCS and B‐lines (56.4%) was moderate at discharge, in terms of both positive and both negative. By incorporating the B‐lines with assessment of clinical congestion, the patients at discharge were divided into three phenotypes as clinical congestion (+), clinical congestion (−) with B‐lines (+), and clinical congestion (−) with B‐lines (−). The Kaplan–Meier analysis showed a better survival in the both (−) group ('wet/dry' with B‐lines: Chi‐square 10.591, P = 0.005; CCS with B‐lines: χ2 6.239, P = 0.031). When the 'wet' patients (n = 49) being taken as the reference, the 'dry' patients with B‐lines (+) (n = 21) had an identical risk of the composite endpoint (hazard ratio [HR] adjusted for clinical covariates 1.021, 95% confidence interval [CI] 0.480–2.134, P = 0.974), while the 'dry' patients with B‐lines (−) (n = 47) had a lower risk (HR 0.264, 95% CI 0.113–0.617, P = 0.002). When the CCS (+) patients (n = 49) being regarded as the reference, similar results were obtained in the patients with CCS (−) but B‐lines (+) (n = 22) (HR 1.348, 95% CI 0.627–2.896, P = 0.444) as well as in those with both CCS (−) and B‐lines (−) (n = 46) (HR 0.447, 95% CI 0.202–0.992, P = 0.048). Conclusions: The combination of B‐lines on LUS and conventional assessment helped to identify new phenotypes of congestion that aid in the risk stratification of discharged HF patients. Further investigation is warranted to determine whether this strategy could be adopted as a guide for decongestion therapy. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy is considered as one of the most promising methods in cancer treatment in recent years. Immune checkpoint blockade (ICB) can activate immune cells to destroy tumors by relieving the inhibitory pathway of tumor cells to immune cells. In silico prediction of the ICB response is an important step toward achieving effective and personalized cancer immunotherapy. Although immune checkpoint inhibitors have shown exciting clinical effects in the treatment of many types of tumors, there are still some clinical problems in practical application, such as low response rate and large individualized differences. How to predict the efficacy of effective individualized immune checkpoint inhibitors for tumor patients based on specific biomarkers and computational models is one of the key issues in the immunotherapy of this kind of tumor. In our work, from the five levels of genome level, transcription level, epigenetic level, microbial taxonomy level, and the immune cell infiltration profile level, the biomarkers and in silico calculation methods that affect the efficacy of tumor immune checkpoint inhibitors are comprehensively summarized. [ABSTRACT FROM AUTHOR]

Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response in anti-PD1 treated melanoma. SERPINB3 was the most significant response-related gene in melanoma and mutations in either SERPINB3 or PEG3 can serve as an independent risk factor in melanoma. Some recurrent mutations in CSMD3 were only in responders or non-responders, indicating their diverse impacts on patient response. Enrichment scores (ES) of gene mutations in 12 biological pathways were significantly higher in responders or non-responders. Next, the P-TMB calculated from genes in these pathways was significantly related to patient response with prediction AUC 0.74–0.82 in all collected datasets. In conclusion, our work provides new insights into the application of TMB in predicting patient response, which will benefit to immunotherapy research. [ABSTRACT FROM AUTHOR]

Cancer-associated venous thromboembolism is a devastating complication of cancer and is associated with significant morbidity and mortality. The cornerstone of cancer-associated venous thromboembolism treatment is anticoagulation, and in recent years, there have been notable randomized clinical trials that have revealed insights into the efficacy and safety of direct oral anticoagulants and low-molecular-weight heparin in the treatment of cancer-associated thrombosis. Deciding on the ideal anticoagulation treatment plan for a patient with a cancer-associated thrombosis is a complex task that requires an understanding of clinical trial data, society guidelines, and, most importantly, consideration of many cancer-related, treatment-related, and patient-related factors. This article summarizes important factors to consider when deciding on anticoagulation therapy for a patient with cancer-associated thrombosis. [ABSTRACT FROM AUTHOR]

Background: Pulmonary congestion (PC) is associated with an increased risk of hospitalization and death in patients with heart failure (HF). Lung ultrasound is highly sensitive for detecting PC. The aim of this study is to evaluate whether lung ultrasound-guided therapy improves 6-month outcomes in patients with HF. Methods: A randomized, multicenter, single-blind clinical trial in patients discharged after hospitalization for decompensated HF. Participants were assigned 1:1 to receive treatment guided according to the presence of lung ultrasound signs of congestion (semi-quantitative evaluation of B lines and the presence of pleural effusion) versus standard of care (SOC). The primary endpoint was the combination of cardiovascular death, readmission, or emergency department or day hospital visit due to worsening HF at 6 months. In September 2020, after an interim analysis, patient recruitment was stopped. Results: A total of 79 patients were randomized (mean age 81.2 +/− 9 years) and 41 patients (51.8%) showed a left ventricular ejection fraction >50%. The primary endpoint occurred in 11 patients (29.7%) in the SOC group and in 11 patients (26.1%) in the LUS group (log-rank = 0.83). Regarding nonserious adverse events, no significant differences were found. Conclusions: LUS-guided diuretic therapy after hospital discharge due to ADHF did not show any benefit in survival or a need for intravenous diuretics compared with SOC. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to evaluate whether the MADIT-ICD benefit score can predict who benefits most from the addition of implantable cardioverter-defibrillator (ICD) to cardiac resynchronization therapy (CRT) in real-world patients with heart failure with reduced ejection fraction (HFrEF) and to compare this with selection according to a multidisciplinary expert centre approach.Methods and Results: Consecutive HFrEF patients who received a CRT for a guideline indication at a tertiary care hospital (Ziekenhuis Oost-Limburg, Genk, Belgium) between October 2008 and September 2016, were retrospectively evaluated. The MADIT-ICD benefit groups (low, intermediate, and high) were compared with the current multidisciplinary expert centre approach. Endpoints were (i) sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and (ii) non-arrhythmic mortality. Of the 475 included patients, 165 (34.7%) were in the lowest, 220 (46.3%) in the intermediate, and 90 (19.0%) in the highest benefit group. After a median follow-up of 34 months, VT/VF occurred in 3 (1.8%) patients in the lowest, 9 (4.1%) in the intermediate, and 13 (14.4%) in the highest benefit group (P < 0.001). Vice versa, non-arrhythmic death occurred in 32 (19.4%) in the lowest, 32 (14.6%) in the intermediate, and 3 (3.3%) in the highest benefit group (P = 0.002). The predictive power for ICD benefit was comparable between expert multidisciplinary judgement and the MADIT-ICD benefit score: Uno's C-statistic 0.69 vs. 0.69 (P = 0.936) for VT/VF and 0.62 vs. 0.60 (P = 0.790) for non-arrhythmic mortality.Conclusion: The MADIT-ICD benefit score can identify who benefits most from CRT-D and is comparable with multidisciplinary judgement in a CRT expert centre. [ABSTRACT FROM AUTHOR]

This retrospective observational study analyzed the postoperative outcomes of bicanalicular intubation using different diameters of tube stents for treating postsaccal nasolacrimal duct obstruction. A total of 130 patients diagnosed with postsaccal obstruction who underwent endoscopic-assisted silicone tube intubation were included in the study. Patients intubated with a 1.5-mm large-diameter tube were designated as the LD group, and those with a 1.0-mm normal-diameter tube were designated as the ND group. The patency rates of the two groups at 1 year after tube removal were compared using the Kaplan–Meier curve and restricted mean survival time (RMST) method with τ = 365 days. Results demonstrated that the recurrence rate after tube removal was significantly lower in the LD group as compared with the ND group (p = 0.001). The patency rates at 1 year after removal in the LD and ND group were 85.7% (95% confidence interval [CI]: 75.4, 91.9) and 73.9% (95% CI: 61.7, 82.8), respectively. When comparing the patency rates by the RMST method at τ = 365 days, the RMST difference, RMST ratio, and RMTL ratio were higher in the LD group at p = 0.045, 0.052, and 0.046, respectively. [ABSTRACT FROM AUTHOR]

Background: Ideal biomarkers to predict the response to immunotherapy in lung cancer are still lacking. Therefore, there is a need to explore effective biomarkers in large populations. Objective: The objective of this study is to explore novel immunological classifications that are associated with immunotherapy response through the ssGSEA algorithm. Methods: Six independent lung cancer cohorts were collected for analysis including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the EMBL-EBI database. The ssGSEA algorithm was performed to extract immune terms. Then, TCGA samples were involved as a training group and other cohorts were used as a validation group. After LASSO and Cox regression, prognostic associated immune terms were extracted and an immune-related risk score (IRS) signature was constructed. Furthermore, the association between IRS signature and clinical data, genome features, stemness indices analysis, tumor immune microenvironment, immunotherapy efficiency, and targeted therapy response was also investigated. Results: A total of 1,997 samples were enrolled in this study including six large lung cancer cohorts. Fifty-four immune terms were calculated through the ssGSEA algorithm in combined cohorts. Then, a nine-immune-term risk score model named IRS signature was established to predict the prognosis in combined cohorts. We classified patients into high-risk and low-risk subgroups according to the cutoff point. Subsequently, analysis of clinical data and genome features indicated that the patients in the high-IRS group tend to have advanced clinical features (clinical stage and T classification), as well as a higher level of copy number variation burden, higher tumor burden mutation, and higher tumor stemness indices. Immune landscape analysis demonstrated that high-IRS groups exhibited lower immune cell infiltration and immune-suppressive state. More importantly, the predicted result of the Tumor Immune Dysfunction and Exclusion analysis showed that high-IRS groups might be more insensitive to immunotherapy. Meanwhile, we have also identified that high-IRS groups were associated with better efficiency of several targeted drugs. Conclusion: To summarize, we identified a novel IRS model based on nine immune terms, which was quantified by the ssGSEA algorithm. This model had good efficacy in predicting overall survival and immunotherapy response in non-small cell lung cancer patients, which might be an underlying biomarker. [ABSTRACT FROM AUTHOR]

Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identify six distinct genetic subtypes. These subtypes are differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three genetic subtypes are associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification models. Existing clinical models cannot fully capture smoldering multiple myeloma (SMM) heterogeneity. Here, integration of 42 genetic alterations from 214 SMM patients using an unsupervised binary matrix factorization clustering approach results in the identification of 6 distinct molecular and clinical subtypes. [ABSTRACT FROM AUTHOR]

Aims Elevated left ventricular filling pressure (LVFP) is a powerful indicator of worsening clinical outcomes in heart failure with preserved ejection fraction (HFpEF); however, detection of elevated LVFP is often challenging. This study aimed to determine the association between the newly proposed echocardiographic LVFP parameter, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score, and clinical outcomes of HFpEF. Methods and results We retrospectively investigated 310 well-differentiated HFpEF patients in stable conditions. VMT was scored from 0 to 3 using two-dimensional echocardiographic images, and VMT ≥2 was regarded as a sign of elevated LVFP. The primary endpoint was a composite of cardiac death or heart failure hospitalization during the 2 years after the echocardiographic examination. In all patients, Kaplan–Meier curves showed that VMT ≥2 (n  = 54) was associated with worse outcomes than the VMT ≤1 group (n  = 256) (P  < 0.001). Furthermore, VMT ≥2 was associated with worse outcomes when tested in 100 HFpEF patients with atrial fibrillation (AF) (P  = 0.026). In the adjusted model, VMT ≥2 was independently associated with the primary outcome (hazard ratio 2.60, 95% confidence interval 1.46–4.61; P  = 0.001). Additionally, VMT scoring provided an incremental prognostic value over clinically relevant variables and diastolic function grading (χ 2 10.8–16.3, P  = 0.035). Conclusions In patients with HFpEF, the VMT score was independently and incrementally associated with adverse clinical outcomes. Moreover, it could also predict clinical outcomes in HFpEF patients with AF. [ABSTRACT FROM AUTHOR]

Objectives To assess the applicability of Electronic Frailty Index (eFI) and Hospital Frailty Risk Score (HFRS) algorithms to Japanese administrative claims data and to evaluate their association with long-term outcomes. Study Design and Setting A cohort study using a regional government administrative healthcare and long-term care (LTC) claims database in Japan 2014–18. Participants Plan enrollees aged ≥50 years. Methods We applied the two algorithms to the cohort and assessed the scores' distributions alongside enrollees' 4-year mortality and initiation of government-supported LTC. Using Cox regression and Fine–Gray models, we evaluated the association between frailty scores and outcomes as well as the models' discriminatory ability. Results Among 827,744 enrollees, 42.8% were categorised by eFI as fit, 31.2% mild, 17.5% moderate and 8.5% severe. For HFRS, 73.0% were low, 24.3% intermediate and 2.7% high risk; 35 of 36 predictors for eFI, and 92 of 109 codes originally used for HFRS were available in the Japanese system. Relative to the lowest frailty group, the highest frailty group had hazard ratios [95% confidence interval (CI)] of 2.09 (1.98–2.21) for mortality and 2.45 (2.28–2.63) for LTC for eFI; those for HFRS were 3.79 (3.56–4.03) and 3.31 (2.87–3.82), respectively. The area under the receiver operating characteristics curves for the unadjusted model at 48 months was 0.68 for death and 0.68 for LTC for eFI, and 0.73 and 0.70, respectively, for HFRS. Conclusions The frailty algorithms were applicable to the Japanese system and could contribute to the identifications of enrollees at risk of long-term mortality or LTC use. [ABSTRACT FROM AUTHOR]

(1) Background: Behavioral and psychological symptoms of dementia (BPSD) are a threat for people with dementia and their caregivers. Doll therapy is a non-pharmacological person-centered therapy to promote attachment, company, and usefulness with the aim of minimizing challenging behaviors. However, the results are not clear. (2) Objective: To know the effectiveness of doll therapy in reducing behavioral and psychological symptoms of people with dementia at a moderate-severe phase. (3) Methodology: The systematic review was informed according to the criteria established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Searches were conducted in eight databases: Cochrane, PubMed, Web of Science, Cinahl, Embase, Lilacs, PeDro, and Scopus before October 2021. Studies were selected when they accomplished the simple majority of Consolidated Standards of Reporting Trials (CONSORT). The risk of bias was appraised with the Cochrane Collaboration Risk of Bias Tool. The review protocol was recorded in Inplasy:1539. (4) Results: The initial search strategy showed 226 relevant studies, 7 of which met the eligibility criteria. In the included studies, a total number of 295 participants (79% female) with a mean age of 85 years were enrolled. There was found to be a reduction in challenging and aggressive behaviors, the participants were less rough and irritable, and their communication skills and emotional state were also improved. (5) Conclusion: Our findings suggest that doll therapy improves the emotional state of people with dementia, diminishes disruptive behaviors, and promotes communication. However, randomized studies with a larger sample size and higher methodological rigor are needed, as well as follow-up protocols in order to reaffirm these results. [ABSTRACT FROM AUTHOR]

Individual participant data (IPD) from oncology clinical trials is invaluable for identifying factors that influence trial success and failure, improving trial design and interpretation, and comparing pre-clinical studies to clinical outcomes. However, the IPD used to generate published survival curves are not generally publicly available. We impute survival IPD from ~500 arms of Phase 3 oncology trials (representing ~220,000 events) and find that they are well fit by a two-parameter Weibull distribution. Use of Weibull functions with overall survival significantly increases the precision of small arms typical of early phase trials: analysis of a 50-patient trial arm using parametric forms is as precise as traditional, non-parametric analysis of a 90-patient arm. We also show that frequent deviations from the Cox proportional hazards assumption, particularly in trials of immune checkpoint inhibitors, arise from time-dependent therapeutic effects. Trial duration therefore has an underappreciated impact on the likelihood of success. Analysis of more than 150 Phase 3 oncology clinical trials supports parametric statistical analysis, significantly increasing the precision of small early-phase trials and relating deviations from the Cox proportional hazards model to trial duration. [ABSTRACT FROM AUTHOR]

Background. Several immune checkpoint inhibitors (ICIs) are approved for the treatment of advanced urothelial carcinoma (UC). There are limited biomarkers for ICI-treated patients with UC.We investigated the association between body composition and clinical outcomes in ICI-treated UC patients. Materials and Methods. We conducted a retrospective analysis of 70 ICI-treated patients with advanced UC at Winship Cancer Institute from 2015 to 2020. Baseline computed tomography images within 2 months of ICI initiation were collected at mid-L3 and muscle and fat compartments (subcutaneous, intermuscular, and visceral) were segmented using SliceOMatic v5.0 (TomoVision, Magog, Canada). A prognostic body composition risk score (high: 0-1, intermediate: 2-3, or low-risk: 4) was created based on the β coefficient from the multivariate Cox model (MVA) following best-subset variable selection. Our body composition risk score was skeletal muscle index (SMI) + 2 x attenuated skeletal muscle (SM) mean + visceral fat index (VFI). Concordance statistics (C-statistics) were used to quantify the discriminatory magnitude of the predictivemodel. Results. Most patients (70%) were men and the majority received ICIs in the second- (46%) or third-line (21%) setting. High-risk patients had significantly shorter overall survival (OS; hazard ratio [HR], 6.72; p < .001), progressionfree survival (HR, 5.82; p < .001), and lower chance of clinical benefit (odds ratio [OR], 0.02; p = .003) compared with the low-risk group in MVA. The C-statistics for our body composition risk group and myosteatosis analyses were higher than body mass index for all clinical outcomes. Conclusion. Body composition variables such as SMI, SM mean, and VFI may be prognostic and predictive of clinical outcomes in ICI-treated patients with UC. Larger, prospective studies are warranted to validate this hypothesis-generating data. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy. [ABSTRACT FROM AUTHOR]

The infiltration of tumor-reactive T cells in the tumor site is associated with better survival and immunotherapy response. However, tumor-reactive T cells were often represented by the infiltration of total CD8+ T cells, which was confounded by the presence of bystander T cells. To identify tumor-reactive T cells at the cancer lesion, we performed integration analyses of three scRNA-seq data sets of T cells in melanoma. Extensive heterogeneous functional states of T cells were revealed in the tumor microenvironment. Among these states, we identified a subset of tumor-reactive T cells which specifically expressed tumor-reactive markers and T cell activation signature, and were strongly enriched for larger T cell receptor (TCR) clones. We further identified and validated a tumor-reactive T cell signature (TRS) to evaluate the tumor reactivity of T cells in tumor patients. Patients with high TRS scores have strong immune activity and high mutation burden in the TCGA-SKCM cohort. We also demonstrated a significant association of the TRS with the clinical outcomes of melanoma patients, with higher TRS scores representing better survival, which was validated in four external independent cohorts. Furthermore, the TRS scores exhibited greater performance on prognosis prediction than infiltration levels of CD8+ T cells and previously published prognosis-related signatures. Finally, we observed the capability of TRS to predict immunotherapy response in melanoma. Together, based on integrated analysis of single-cell RNA-sequencing, we developed and validated a tumor-reactive-related signature that demonstrated significant association with clinical outcomes and response to immunotherapy. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool. Using a lasso-penalized Cox regression model (n = 273), performance status, HCT-CI, refined disease-risk index (rDRI), donor and recipient CMV status, and donor age were identified as predictors of disease-free survival (DFS). The results for overall survival (OS) were similar except for recipient CMV status not being included in the model. Models were validated in an external dataset (n = 378) and resulted in a c-statistic of 0.61 and 0.62 for DFS and OS, respectively. Importantly, this tool incorporates donor age as a variable, which has an important role in HSCT outcomes. This needs to be further studied in prospective models. An easy-to-use and a web-based nomogram can be accessed here: https://allohsctsurvivalcalc.iowa.uiowa.edu/. [ABSTRACT FROM AUTHOR]

Chronic heart failure is one of the common causes of hospitalization and death. Pulmonary congestion is the common disease feature of patients with chronic heart failure, which could be correctly diagnosed by lung ultrasound. Efficacy of lung ultrasound‐guided pulmonary congestion management for patients with acute heart failure is well documented, however, more evidence is needed to establish the clinical value of pulmonary congestion detection by lung ultrasound examination in patients with chronic heart failure. This review summarized current evidence related to the use and clinical value of pulmonary congestion assessment by lung ultrasound in patients with chronic heart failure, aiming to provide new suggestions on promoting the widespread use of lung ultrasound in patients with chronic heart failure to improve the quality of life and outcome of patients with chronic heart failure. [ABSTRACT FROM AUTHOR]

When multiple treatments are available, network meta-analysis can evaluate data to rank the relative effectiveness. We applied this approach to first-line treatments for paroxysmal atrial fibrillation (medical therapy, radiofrequency ablation or cryoballoon ablation). Individual trials were analysed based on the restricted mean survival time (RMST). Randomised controlled trials (RCT) assessing first-line treatments for paroxysmal atrial fibrillation were referenced from PubMed and the websites of regulatory agencies. The primary end-point was atrial fibrillation recurrence-free survival at 12 months. The treatments assessed for their relative effectiveness were medical therapy, radiofrequency ablation and cryoballoon ablation. Individual trials were examined based on RMST. A Bayesian network meta-analysis was conducted to comparatively evaluate these treatments. Five trials were included in the analysis: two compared radiofrequency with medical treatment and three cryoballoon ablation with medical treatment. The indirect comparison of radiofrequency ablation vs cryoballoon ablation was assessed in the absence of RCTs. Differences in RMST (with 95% credible intervals) were estimated for all binary comparisons (direct or indirect). Radiofrequency and cryoballoon ablation showed significantly increased effectiveness compared with medical treatment. In the indirect comparison, radiofrequency showed a non-significant advantage over cryoballoon ablation. The ranking of effectiveness was as follows: (1) radiofrequency; (2) cryoballoon ablation; (3) medical treatment. In conclusion, we found that radiofrequency was the most effective treatment for paroxysmal atrial fibrillation according to a Bayesian probabilistic model. [ABSTRACT FROM AUTHOR]