Comprehensive patient-level classification and quantification of driver events in TCGA PanCanAtlas cohorts

There is a growing need to develop novel therapeutics for targeted treatment of cancer. The prerequisite to success is the knowledge about which types of molecular alterations are predominantly driving tumorigenesis. To shed light onto this subject, we have utilized the largest database of human cancer mutations–TCGA PanCanAtlas, multiple established algorithms for cancer driver prediction (2020plus, CHASMplus, CompositeDriver, dNdScv, DriverNet, HotMAPS, OncodriveCLUSTL, OncodriveFML) and developed four novel computational pipelines: SNADRIF (Single Nucleotide Alteration DRIver Finder), GECNAV (Gene Expression-based Copy Number Alteration Validator), ANDRIF (ANeuploidy DRIver Finder) and PALDRIC (PAtient-Level DRIver Classifier). A unified workflow integrating all these pipelines, algorithms and datasets at cohort and patient levels was created. We have found that there are on average 12 driver events per tumour, of which 0.6 are single nucleotide alterations (SNAs) in oncogenes, 1.5 are amplifications of oncogenes, 1.2 are SNAs in tumour suppressors, 2.1 are deletions of tumour suppressors, 1.5 are driver chromosome losses, 1 is a driver chromosome gain, 2 are driver chromosome arm losses, and 1.5 are driver chromosome arm gains. The average number of driver events per tumour increases with age (from 7 to 15) and cancer stage (from 10 to 15) and varies strongly between cancer types (from 1 to 24). Patients with 1 and 7 driver events per tumour are the most frequent, and there are very few patients with more than 40 events. In tumours having only one driver event, this event is most often an SNA in an oncogene. However, with increasing number of driver events per tumour, the contribution of SNAs decreases, whereas the contribution of copy-number alterations and aneuploidy events increases.

Patient-Level DNA Damage Repair Pathway Profiles and Anti-Tumor Immunity for Gastric Cancer

DNA damage repair (DDR) comprises the detection and correction of alterations in the chemical structure of DNA. The dysfunction of the DDR process has been determined to have important implications for tumor carcinogenesis, malignancy progression, treatment resistance, and prognosis assessment. However, the role of the DDR process in gastric cancer (GC) remains to be fully understood. Thus, a total of 2,019 GC samples from our hospital (Harbin Medical University Cancer Hospital in china) and 12 public data sets were included in our study. In this study, single-sample gene set enrichment analysis (ssGSEA) was used to generate the DDR pathway activity profiles of 8 DDR sub-pathways and identify a DDR pathway signature by combining the DDR sub-pathway gene sets. The DDR pathway profiling’s impacts on the clinical outcomes, biological functions, genetic variants, immune heterogeneity, and treatment responses were analyzed through multidimensional genomics and clinical data. The results demonstrate that the DDR pathway profiling was clearly distinguished between tumor and normal tissues. The DDR pathway profiling reveals patient-level variations, which may contribute to explaining the high heterogeneity of human GC for the biological features and treatment outcomes. Thus, tumors with low DDR signature scores were independently correlated with shorter overall survival time and significantly associated with mesenchymal, invasion, and metastasis phenotypes. The statistical model integrating this DDR pathway signature with other clinical predictors outperforms each predictor alone for predicting overall survival in discrimination, calibration, and net clinical benefit. Moreover, low DDR signature scores were tightly associated with genome stability, characterized by low tumor mutational burden (TMB) and low fractions of genome alteration. Furthermore, this study confirms that patients with low DDR pathway signature scores might not benefit from adjuvant chemotherapy and a monoclonal antibody directed against programmed cell death-1 ligand 1 (anti-PD1) therapy. These findings highlighted that the DDR pathway profiling confers important implications for patients with GC and provides insights into the specific clinical and molecular features underlying the DDR process, which may help to facilitate clinical management.

From a View of the Hospital as a System to a View of the Suffering Patient

Purpose: Hospitals aspire to provide patient-centered care but are far from achieving it. This qualitative mixed methods study explored the capacity of hospital directors to shift from a hospital systemic-view to a suffering patient-view applying the Salutogenic theory.Methods: Following IRB, we conducted in-depth narrative interviews with six directors of the six Israeli academic tertiary public hospitals, focusing on their managerial role. In a second meeting we conducted vignette interviews in which we presented each director with a narrative of a suffering young patient who died at 33 due to medical misconduct, allowing self-introspection. Provisional coding was performed for data analysis to identify categories and themes by the three dimensions of the sense-of-coherence, an anchor of Salutogenics: comprehensibility, manageability, and meaningfulness.Results: While at the system level, directors reported high comprehensibility and manageability in coping with complexity, at the patient level, when confronted with the vignette, directors acknowledged their poor comprehensibility of patients' needs and patient's experience during hospitalizations. They acknowledged their poor capacity to provide patient-centered care. Meaningfulness in the narrative interview focused on the system while meaningfulness in the vignette interview focused on providing patient care.Conclusions: The evident gaps between the system level and the patient level create lack of coherence, hindering the ability to cope with complexity, and are barriers to providing patient-centered care. To improve the delivery of patient-centered care, we suggest ways to consolidate the views, enabling the shift from a systemic-view to a patient-view.

Resource Utilization and Caring Cost of People Living with Human Immunodeficiency Virus (PLHIV) in Saudi Arabia: A Tertiary Care University Hospital Experience

The human immunodeficiency virus (HIV) is associated with a significant burden of disease, including medical and non-medical costs. Therefore, it is considered to be a priority for all health authorities. The aim of this study is to determine healthcare and treatment costs of caring for PLHIV at one of the tertiary care university hospitals in Riyadh, Saudi Arabia. This was a micro-costing, retrospective, observational study from a tertiary care university hospital and included all confirmed HIV-infected patients who visited infectious disease clinics in the period from 1 January 2015 to 31 December 2018. A total of 42 PLHIV were included in this study. The mean age of the study participants was 38.76 ± 11.47 years with a mean disease duration of 5.27 ± 4.81 years. The majority of patients were male (85.7%) and Saudi (88.1%). More than half of included patients (59.5%) had a CD4 count of more than 500. During the study period, 26 patients (61.9%) were initiated on a single-tablet regimen. Overall, the main cost-driver was antiretroviral medications, which cumulatively represented more than 64% of the total cost. Patients who developed opportunistic infections had a statistically significant (p = 0.033) higher financial impact, both as a total and on a patient level, than those presented without opportunistic infections. On a patient level, the mean and median costs were higher and statistically significant for those with co-morbidities than those without co-morbidities (p = 0.002). The majority of the economic burden of PLHIV is attributable to antiretroviral therapy use. The healthcare costs of PLHIV can vary greatly, depending on the presenting illness, clinical stage, developed opportunistic infection, co-morbidity, and pharmacological therapy.

Service use, clinical outcomes and user experience associated with urgent care services that use telephone-based digital triage: a systematic review

ObjectiveTo evaluate service use, clinical outcomes and user experience related to telephone-based digital triage in urgent care.DesignSystematic review and narrative synthesis.Data sourcesMedline, Embase, CINAHL, Web of Science and Scopus were searched for literature published between 1 March 2000 and 1 April 2020.Eligibility criteria for selecting studiesStudies of any design investigating patterns of triage advice, wider service use, clinical outcomes and user experience relating to telephone based digital triage in urgent care.Data extraction and synthesisTwo reviewers extracted data and conducted quality assessments using the mixed methods appraisal tool. Narrative synthesis was used to analyse findings.ResultsThirty-one studies were included, with the majority being UK based; most investigated nurse-led digital triage (n=26). Eight evaluated the impact on wider healthcare service use following digital triage implementation, typically reporting reduction or no change in service use. Six investigated patient level service use, showing mixed findings relating to patients’ adherence with triage advice. Evaluation of clinical outcomes was limited. Four studies reported on hospitalisation rates of digitally triaged patients and highlighted potential triage errors where patients appeared to have not been given sufficiently high urgency advice. Overall, service users reported high levels of satisfaction, in studies of both clinician and non-clinician led digital triage, but with some dissatisfaction over the relevance and number of triage questions.ConclusionsFurther research is needed into patient level service use, including patients’ adherence with triage advice and how this influences subsequent use of services. Further evaluation of clinical outcomes using larger datasets and comparison of different digital triage systems is needed to explore consistency and safety. The safety and effectiveness of non-clinician led digital triage also needs evaluation. Such evidence should contribute to improvement of digital triage tools and service delivery.PROSPERO registration numberCRD42020178500.

Preoperative Diagnosis of Hepatocellular Carcinoma Patients with Bile Duct Tumor Thrombus using Deep Learning Method

Preoperative diagnosis of bile duct tumor thrombus (BDTT) is clinically important as the surgical prognosis of hepatocellular carcinoma (HCC) patients with BDTT is significantly different from that of patients without BDTT. The current diagnosis of BDTT is usually based on identifying dilated bile ducts (DBDs) on medical images (eg., CT and MRI images). However, it is easy for doctors to ignore DBDs when reporting imaging scan results, leading to a high misdiagnosis rate in practice. The aim of the present study was to develop an artificial intelligence (AI) pipeline for diagnosing HCC patients with BDTT using medical images. The proposed AI pipeline includes two stages. First, the object detection neural network Faster R-CNN is adopted to identify DBDs; then, an HCC patient is diagnosed to have BDTT if the proportion of images with at least one identified DBD exceeds some threshold value. The proposed AI pipeline was applied to a real dataset consisting of 2,611 CT images collected from 34 HCC patients (16 with BDTT and 18 without BDTT). The average true positive rate for identifying DBDs per patient was 0.92, while the patient-level true positive rate for diagnosing BDTT was 0.94. The area under ROC curve for patient-level diagnosis of BDTT was 0.92 (95% CI: 0.83, 1.00), compared with 0.71 (95% CI: 0.52, 0.89) by random forest based on preoperative clinical variables. These results demonstrated that the proposed AI pipeline is successful in the diagnosis of BDTT. The automatic detection of DBDs is a key step in early diagnosis of HCC patients with BDTT, and is helpful in the treatment and prognosis of these patients.

Clinical profiles of Asians with NAFLD: A systematic review and meta-analysis

Introduction: NAFLD is increasingly prevalent in Asia, where people suffer more metabolic comorbidities at a lower body mass index (BMI), suggesting potential differences in their clinical profile. Therefore, we attempted to characterize the clinical profile of Asians with NAFLD via a meta-analytic approach. Methods: We searched Pubmed, EMBASE, and Cochrane databases from January 1, 2000 to January 17, 2019. Two authors independently reviewed and selected 104 articles (2,247,754 persons) that identified NAFLD in Asians and reported relevant data, especially BMI and ALT, and excluded individuals with other liver disease and excessive alcohol consumption. Individual patient-level data were obtained from seven cohorts in Asia to complement meta-analyzed data. Results: Overall, the mean age was 52.07 (95%CI:51.28-52.85) years with those from Southeast Asia (42.66, 95%CI: 32.23-53.11) being significantly younger. The mean BMI was 26.2 kg/m2, higher in moderate-severe vs. mild hepatic steatosis (28.3 vs. 25.7) patients and NFS ≥-1.455 vs. <-1.455 (27.09 vs. 26.02), with 34% having non-obese NAFLD. The mean ALT was 31.74 U/L, higher in NFS <-1.455 vs. ≥-1.455 (33.74 vs. 27.83), though no differences were found by obesity or steatosis severity. The majority of males (85.7%) and females (60.7%) had normal to minimally elevated ALT (1-1.5x 95% ULN). Individual patient-level data analysis (N=7,668) demonstrated similar results. Conclusion: About one-third of Asians with NAFLD were non-obese and the majority did not have markedly elevated ALT. Therefore, abnormal ALT or BMI are not recommended as a criterion for NAFLD screening in this population. Additionally, there were significant differences in the clinical profiles of NAFLD among the different regions of Asia.

CytoSorb Therapy in COVID-19 (CTC) Patients Requiring Extracorporeal Membrane Oxygenation: A Multicenter, Retrospective Registry

Introduction: CytoSorb extracorporeal blood purification therapy received FDA Emergency Use Authorization (EUA) to suppress hyperinflammation in critically ill COVID-19 patients. The multicenter CTC Registry was established to systematically collect patient-level data, outcomes, and utilization patterns of CytoSorb under the EUA.Methods: Patient-level data was entered retrospectively at participating centers. The primary outcome of the registry was ICU mortality. Patient disposition of death, continuing ICU care, or ICU discharge was analyzed up to Day 90 after start of CytoSorb therapy. Demographics, comorbidities, COVID-19 medications, inflammatory biomarkers, and details on CytoSorb use were compared between survivors and non-survivors in the veno-venous extracorporeal membrane oxygenation (ECMO) cohort.Results: Between April 2020 and April 2021, 52 patients received veno-venous ECMO plus CytoSorb therapy at 5 U.S. centers. ICU mortality was 17.3% (9/52) on day 30, 26.9% (14/52) on day 90, and 30.8% (16/52) at final follow-up of 153 days. Survivors had a trend toward lower baseline D-Dimer levels (2.3 ± 2.5 vs. 19.8 ± 32.2 μg/mL, p = 0.056) compared to non-survivors. A logistic regression analysis suggested a borderline association between baseline D-Dimer levels and mortality with a 32% increase in the risk of death per 1 μg/mL increase (p = 0.055). CytoSorb was well-tolerated without any device-related adverse events reported.Conclusions: CytoSorb therapy for critically ill COVID-19 patients on ECMO was associated with high survival rates suggesting potential therapeutic benefit. Elevated baseline D-Dimer levels may suggest increased risk of mortality. Prospective controlled studies are warranted to substantiate these results.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT0439192, identifier: NCT04391920.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.