Cox Hazard Ratio Research Articles

Efficacy of meropenem against ceftazidime-avibactam-resistant Klebsiella pneumoniae producing KPC-31, KPC-33, KPC-90, KPC-106 and KPC-114.

Klebsiella pneumoniae producing KPC variants conferring resistance to ceftazidime-avibactam often remain susceptible to meropenem, suggesting a potential therapeutic use of this antibiotic. In this study, the efficacy of clinically relevant concentrations of meropenem was evaluated against high-risk clones of ceftazidime-avibactam-resistant K. pneumoniae strains producing KPC variants, in a tandem in vitro time-kill/in vivo Galleria mellonella survival model. In vitro/in vivo efficacy of meropenem against ceftazidime-avibactam-resistant K. pneumoniae of CG16, CG25 and CG258, producing KPC-31, KPC-33, KPC-90, KPC-106 and KPC-114 variants, was evaluated using EUCAST dosing recommendation adjusted to the G. mellonella model. For in vivo assays, untreated, meropenem (40 mg/kg × 1)-treated and ceftazidime-avibactam (40 mg/kg ceftazidime-10 mg/kg avibactam × 1)-treated groups were established, with 60 larvae per group. Kaplan-Meier curves, log-rank tests, univariate Cox regression and hazard ratios (HR) were used to assess treatment effects (P < 0.05). For all KPC-variant producers, time-kill assays showed >3 log-kills reduction (-6.91 ± 1.28 SD) after 6 h interaction when exposed to 8-32 mg/L meropenem MIC values (i.e. ≥ × 4 MIC). In the assessment of in vivo efficacy of meropenem, at the 4-day follow-up, mortality rates were 96.7% (untreated), 83.3% (ceftazidime-avibactam-treated) and 13.3% (meropenem-treated) (P < 0.05). Univariate Cox regression analysis showed significantly lower risk in the meropenem group compared to untreated group [HR 0.02 (95% CI: 0.01-0.05)]. These pre-clinical results might support use of meropenem as a potential alternative for treatment of infections due to KPC-variant producers displaying in vitro susceptibility to meropenem.

What happens after the free flap? Evaluation of aesthetic and functional elective revisions

BackgroundMicrovascular free flap reconstruction of a defect, as a single-stage procedure, does not always achieve the desired functional and esthetic result. Revisions may be necessary to achieve ideal contour, symmetry, and suspension of soft tissues, or to support dental rehabilitation. PurposeThe study purpose was to estimate the incidence and identify factors associated with elective free flap revisions.Study design, setting, sample: A retrospective cohort study of subjects who underwent free flap reconstruction was conducted to characterize the rate of elective free flap revision surgery. The study included subjects >18 years old, who underwent head and neck microvascular free flap surgery for any etiology, and both primary and secondary reconstructions, between 2014-2021. Subjects were excluded if they had incomplete records. Predictor variableThe predictor variable was composed of a set of variables, grouped into the following categories: subject demographic data, medical history, disease etiology, anatomical site, and postoperative complications. Main outcome variableThe outcome variable was time to elective revision surgery measured as months from the date of the initial operation to date of elective revision surgery. Elective revision surgery was defined as a procedure to enhance esthetics or function, which directly modifies the original surgical site, not including procedures to correct a complication, treat the original disease process, or emergencies. CovariatesNot applicable. AnalysisKaplan-Meier method was used to analyze the data, with p-value <0.05. Risk factors for elective revisions were analyzed with Cox Hazard ratio. ResultsThe sample was composed of 377 subjects that underwent free flap surgery, with a mean age of 55.9 +/- 15.9. Of these 67% were male, and 33% female, and sixty-two had an elective revision surgery (16.4%), with median follow-up period of 17 months (IQR 9-28). In the Cox regression model, only type of free flap was associated with an elective revision (p<0.05), where radial forearm had the lowest association with elective revision, and fasciocutaneous, latissimus dorsi, and scapula flaps had the highest. Conclusion and RelevanceAchieving basic wound coverage with free flaps can be a challenge, however, surgeons should prepare patients for the potential need for functional and esthetic revisions after free flap surgery to improve patient quality of life.

Depth of Invasion Threshold for Recommending Elective Neck Dissection in T1 or T2 Oral Squamous Cell Carcinoma

BackgroundThere is variability in the literature on the role of the depth of invasion (DOI) for recommending an elective neck dissection (END). PurposeThe purpose of the study is to estimate the DOI threshold for recommending an END. Study Design/Setting/SampleA retrospective cohort study was performed at McGill University Health Centre from 2008-2018 with 5 years of follow-up. The sample was subjects with clinical T1/T2 oral squamous cell carcinoma (OSCC) and clinically negative neck. Subjects with previous head and neck cancer were excluded. Predictor VariableThe primary predictor variable was DOI measured from the basement membrane of the adjacent normal mucosa on final pathology, coded as <4mm or ≥4mm. DOI is a continuous variable converted to a binary variable. Main Outcome VariableThe main outcome variable was time to development of neck disease (RD+) defined as the time from surgery to development of pathologic nodes. Time to RD+ for pathologic nodes discovered from the END was considered 0 months. The secondary outcome variable was overall survival. CovariatesDemographics (age, sex, smoking/alcohol history) and tumor characteristics (tumor location, clinical T, tumor differentiation, perineural invasion, lymphovascular invasion) were analyzed. AnalysesTime to RD+ and survival were analyzed using Cox hazard ratio, Kaplan-Meier curves, and log-rank test. Student T-test and Chi-square test were used for bivariate analyses; p≤0.05 was statistically significant. ResultsThe final sample were 64 subjects (average age 65.25 (SD 13.06) years and 36 (56.2%) males). Twenty-nine subjects had DOI<4mm, and the 5-year RD+ was 3.4% (the 1 occurrence of RD+ was at 5.3 months). Thirty-five subjects had DOI≥4mm, and the 5-year RD+ was 45.7% (15 subjects had RD+ discovered from the END, and 1 subject had RD+ at 7.6 months). DOI≥4mm had significantly higher risk of RD+ than DOI<4mm (HR 17.91; 95% CI 2.37-135.3; p=0.01), which remained significant after adjusting for clinical T, tumor differentiation, perineural invasion, and lymphovascular invasion (HR 9.53; 95% CI 1.12-81.44; p<0.05). The shallowest DOI with >20% risk of RD+ was in the DOI 4-4.9mm group. Conclusions/Relevance: Among patients with OSCC of T1 or T2 and clinically negative necks, END should be considered with DOI≥4mm.

Survivorship of Primary NexGen Knee Replacement: Comparing Cementless Trabecular Metal to Other Designs of Tibial Component.

The impact of cementless trabecular metal (TM) implants on implant survivorship are not well delineated. This study compares primary total knee arthroplasty (TKA) revision rates of cemented knee replacements with two cementless knee replacement designs-cementless TM and a non-TM cementless design. Data from a national registry queried TKA procedures performed for osteoarthritis from 1999 to 2020. The risk of revision of Zimmer NexGen TKA using cementless TM, cementless non-TM, and cemented non-TM were compared. Analyses included Kaplan-Meier estimates of survivorship and Cox hazard ratios (HR), stratified by age and gender. Cementless TM components had higher risks of revision compared with cementless non-TM implants (HR = 1.49; p ≤ 0.001). Cementless TM implants showed higher risks of revision compared with cemented non-TM prostheses for the first 2 years (HR = 1.75, p < 0.001). Non-TM prostheses posed equal risk of revision for cementless and cemented fixations (HR = 0.95, p = 0.522). Patients aged 55 to 64 years and 65 to 74 years had a higher risk of revision for cementless TM compared with cementless non-TM (HR = 1.40, p = 0.033 and HR = 1.79, p < 0.001, respectively) and cemented non-TM implants (HR = 1.51, p < 0.001 and HR = 1.54, p < 0.001, respectively). The study shows there is an increased risk of revision with TM cementless implants for patients aged 55 to 74 years. These results do not support the use of TM tibial implants for patients of this age group for primary TKA.

Gender and contemporary risk of adverse events in atrial fibrillation.

The role of gender in decision-making for oral anticoagulation in patients with atrial fibrillation (AF) remains controversial. The population cohort study used electronic healthcare records of 16 587 749 patients from UK primary care (2005-2020). Primary (composite of all-cause mortality, ischaemic stroke, or arterial thromboembolism) and secondary outcomes were analysed using Cox hazard ratios (HR), adjusted for age, socioeconomic status, and comorbidities. 78 852 patients were included with AF, aged 40-75 years, no prior stroke, and no prescription of oral anticoagulants. 28 590 (36.3%) were women, and 50 262 (63.7%) men. Median age was 65.7 years (interquartile range 58.5-70.9), with women being older and having other differences in comorbidities. During a total follow-up of 431 086 patient-years, women had a lower adjusted primary outcome rate with HR 0.89 vs. men (95% confidence interval [CI] 0.87-0.92; P < .001) and HR 0.87 after censoring for oral anticoagulation (95% CI 0.83-0.91; P < .001). This was driven by lower mortality in women (HR 0.86, 95% CI 0.83-0.89; P < .001). No difference was identified between women and men for the secondary outcomes of ischaemic stroke or arterial thromboembolism (adjusted HR 1.00, 95% CI 0.94-1.07; P = .87), any stroke or any thromboembolism (adjusted HR 1.02, 95% CI 0.96-1.07; P = .58), and incident vascular dementia (adjusted HR 1.13, 95% CI 0.97-1.32; P = .11). Clinical risk scores were only modest predictors of outcomes, with CHA2DS2-VA (ignoring gender) superior to CHA2DS2-VASc for primary outcomes in this population (receiver operating characteristic curve area 0.651 vs. 0.639; P < .001) and no interaction with gender (P = .45). Removal of gender from clinical risk scoring could simplify the approach to which patients with AF should be offered oral anticoagulation.

A Cost Analysis of Traditional Versus Robotic Total Knee Arthroplasty Performed With an Imageless, Second-generation Robotic System.

This study compared perioperative outcomes as well as encounter and 90-day costs between patients undergoing traditional vs robotic total knee arthroplasty (rTKA). A total of 430 TKAs (215 rTKAs, 215 traditional) were retrospectively reviewed. All rTKAs were performed with an imageless, second-generation robotic system. Cohorts were propensity score matched by age, sex, body mass index, and American Society of Anesthesiologists score. Perioperative data and 90-day complications were subsequently compared. Cox regression analyses evaluated survival to all-cause revisions. Univariable analyses compared total cost of care for the initial encounter and 90-day postoperative period. Multivariable regression analyses were then performed to evaluate associations with increased encounter and 90-day costs. Patients undergoing rTKA had a higher incidence of discharge home (86.5% vs 60.0%; P<.001). The rTKA cohort trended toward a lower incidence of 90-day emergency department visits, and there was a significantly lower percentage of 90-day readmissions (4.2% vs 13.5%; P=.001). Cox hazard ratio demonstrated no difference in survival to all-cause revisions (hazard ratio, 1.3; 95% CI, 0.5-3.7; P=.64). The cost of surgery was significantly higher in the rTKA cohort ($9292 vs $8392; P<.001); however, there was no difference in cost of encounter ($10,356.86 vs $10,396.44; P=.110) or at 90 days postoperatively ($11,103.89 vs $11,040.13; P=.739). rTKA did not have a significant association with increased cost at 90 days postoperatively (odds ratio, 0.96; 95% CI, 0.90-1.02; P=.180). rTKA had a higher intraoperative cost compared with traditional TKA. However, with increased home discharges and fewer 90-day readmissions, rTKA was not associated with increased cost at 90 days. [Orthopedics. 202x;4x(x):xx-xx.].

The observational EURACAN prospective clinical registry dedicated to epithelioid hemangioendothelioma: The protocol of an international and collaborative effort on an ultra-rare entity.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease. Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE. To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern. Settings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression. The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual.

Association of aberrant expression of CD39 with the outcome of patients with cholangiocarcinoma.

93 Background: Cholangiocarcinoma is defined as a kind of malignant tumor originating from bile ducts. Due to the lack of effective diagnostic and treatment methods, the prognosis of cholangiocarcinoma is dismal. Accumulating evidence indicates that CD39 could promote the progression of several types of cancer. However, the biological function and the underlying mechanism of CD39 in cholangiocarcinoma have not been well investigated. Methods: Quantitative reverse transcription PCR (RT-qPCR), western blot (WB), and immunohistochemistry staining was used to evaluate the expression level of CD39 in cholangiocarcinoma. Kaplan-Meier and Cox hazard ratio regression analyses were implicated to evaluate the prognostic significance of CD39. Cell counting kit-8 (CCK-8) was carried out to evaluate the proliferative capacity, while transwell assay was used to detect the migration and invasion ability. In addition, B-NDG mice were used for the in vivo assay. The potential protein binding with the CD39 was identified through co-immunoprecipitation. Results: We observed that CD39 was aberrantly expressed in the tumor tissue and cholangiocarcinoma cell lines. Our analysis indicated that the high expression level of CD39 correlated with aggressive clinicopathological characteristics, and CD39 was identified as an independent poor prognostic factor in cholangiocarcinoma. In addition, our in vitro and in vivo data indicated that the knockdown of CD39 could suppress the proliferation, migration, invasion ability, and the epithelial-mesenchymal transition (EMT) process of cholangiocarcinoma. Opposite results were observed when CD39 was overexpressed. Mechanistically, CD39 could bind with Annexin A2 (ANXA2), which influences the phosphorylation level of ANXA2 at the Tyr24 site, thereby promoting the activation of PI3K/AKT signaling, which resulted in the biological change in cholangiocarcinoma. Conclusions: Our data indicated that CD39 was overexpressed in the tumor tissue. Meanwhile, CD39 was identified as an independent prognostic factor of poor overall survival for patients withcholangiocarcinoma. In terms of the biological role of CD39, our data indicated that CD39 promoted the progression and metastasis of cholangiocarcinoma through binding with ANXA2, and through activating the PI3K/AKT signaling. In brief, CD39 is a potential prognostic factor and therapeutical target for cholangiocarcinoma.

Analysis of IDH and EGFR as biomarkers in glioblastoma multiforme: A case-control study

BackgroundGlioblastoma multiforme (GBM) is a very aggressive primary central nervous system (CNS) tumor with limited therapeutic options and poor prognosis. This study aimed to analyze the association between single nucleotide polymorphisms (SNPs), including IDH1 rs121913500C > T, IDH2 rs11540478G > A, and EGFR rs1468727C > T, and their association on the risk and overall survival of GBM patients in Jordan. MethodsUsing a case-control study design involving 63 GBM patients and 226 healthy controls was conducted at King Abdullah University Hospital in Jordan. DNA extraction was performed using formalin-fixed and paraffin-embedded tissue for GBM samples and blood samples for controls. SNPs analysis was performed using the Sequenom iPLEX assay sequencing technique. Survival outcomes were assessed using Cox models and hazard ratios (HR), and single-cell RNA (scRNA) analysis was performed from GSE70630. ResultsThe study showed a significant association between genotype frequency in GBM cases and controls for specific SNPs, including IDH1 rs121913500C > T, and EGFR rs1468727C > T. The G/G genotype of rs11540478 (IDH2) was associated with better prognostic outcomes in GBM patients. The scRNA analysis demonstrated the differential expression of IDH1, IDH2, and EGFR in GBM, with enrichment in central carbon metabolism in cancer. ConclusionOur findings suggest that SNPs, particularly in IDH1 and IDH2 genes and EGFR, may serve as diagnostic and prognostic biomarkers for GBM. While the study underscores the clinical relevance of these genetic variants, further investigations with larger and more diverse populations are essential to validate and extend these associations.

Results of the COMPASS Trial Analyzed Using Win Ratio Compared With Conventional Analytic Approaches

BackgroundWin ratio (WR) is a newer analytic approach for trials with composite end points that accounts for the relative importance of individual components. Our objective was to compare the results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial analyzed using WR with those obtained using conventional statistical approaches. MethodsWe used an unmatched WR analysis for first and total (first plus recurrent) events to examine effects of rivaroxaban with aspirin and rivaroxaban alone vs aspirin alone on primary efficacy (cardiovascular death, stroke, myocardial infarction), safety (modified International Society on Thrombosis and Haemostasis major bleeding), and net clinical benefit (primary efficacy plus fatal or critical organ bleeding) end points. We compared the WR results with those obtained using the Cox proportional hazards regression model for first events and Anderson-Gill method for total events. We calculated the win difference to estimate absolute treatment effects. ResultsThe WR approach produced results consistent with those obtained using conventional statistical methods for the primary composite end point (first event: WR, 1.32 [95% confidence interval (CI), 1.14-1.52]; 1/Cox hazard ratio, 1.32 [95% CI, 1.16-1.52]; total [first plus recurrent] events: WR, 1.32 [95% CI, 1.14-1.52]; 1/Anderson-Gill hazard ratio, 1.32 [95% CI, 1.16-1.54]) as well as for main safety and net clinical benefit end points. The absolute benefits of the combination of rivaroxaban and aspirin compared with aspirin alone calculated using the win difference were greatest in those with multiple high-risk features. ConclusionsReanalysis of the COMPASS trial results using WR produced results that were consistent with those obtained using conventional statistical approaches. Clinical Trial RegistrationNCT01776424

Multipronged Electronic Health Record Analysis of Antidepressant Effectiveness on Depression Remission in Patients With Concurrent Depression and Irritable Bowel Syndrome.

Background Patients with irritable bowel syndrome (IBS) often experience chronic abdominal pain and bowel habit changes, with a heightened risk of depression and anxiety compared to the general population. Methods Using TriNetX data from 61 U.S. healthcare organizations, we conducted a retrospective study of three electronic health record (EHR) analyses. We usedInternational Classification of Diseases, Tenth Revision (ICD-10) and Anatomical Therapeutic Chemical Classification (ATC) codes to analyze depression remission among IBS patients, comparing those using antidepressants to those who were not and comparing outcomes among different types of medication. Statistical methods included risk difference, risk ratio, hazard ratio, Kaplan-Meier survival analysis, log-rank tests, and Cox hazard ratios Results Among 78,673 patients with both depression and IBS, those using antidepressants showed significantly higher rates of depressive remission compared to non-users: risk difference (RD), -0.056; risk ratio (RR), 0.380; and hazard ratio (HR), 0.413. Both atypical antidepressants bupropion and trazodone exhibited greater efficacy in achieving remission compared to selective serotonin reuptake inhibitors (SSRIs), sertraline and escitalopram. For SSRI vs bupropion, RD is -0.041, RR is 0.664, and HR is 0.655. For SSRIs vstrazodone, RD is -0.018 , RR is 0.822, and HR is 0.806. The comparative impact of bupropion versus trazodone on remission remains inconclusive. Conclusion Depression presents a significant comorbidity in IBS patients, with atypical antidepressants potentially offering superior efficacy in achieving remission compared to SSRIs. Further research should explore these medications' psychiatric outcomes in this population to better understand their therapeutic benefits beyond gastrointestinal (GI) symptoms.

Enfortumab vedotin-related cutaneous toxicity correlates with overall survival in patients with urothelial cancer: a retrospective experience.

Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR). Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model. Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925). In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.

AI/ML-derived mechanistically interpretable whole-genome biomarkers of patient survival in pre-treatment primary neuroblastoma tumors and whole blood.

10043 Background: Prediction, understanding, and management, of neuroblastoma (NBL) outcomes, from spontaneous regression to relapse and death, remain limited, and rely mostly on the International Neuroblastoma Staging System (INSS) stage, age, and the one-gene test for MYCN amplification. The entire multi-ome affects every aspect of the disease. But typical artificial intelligence and machine learning (AI/ML) cannot discover effective biomarkers from real-life, small-cohort, multi-omic, and noisy data. Methods: We use our AI/ML to identify two whole-genome biomarkers from open-source pre-treatment NBL patient-matched primary tumor and whole blood DNA copy numbers, and primary tumor mRNA expression. Our data-agnostic, unsupervised algorithms extend the mathematics that underlies quantum mechanics to overcome the limitations of typical AI/ML [1,2]. Our platform- and reference genome-agnostic biomarkers in astrocytoma, including glioblastoma, and lung, ovarian, and uterine adenocarcinomas, were mathematically discovered, and computationally and experimentally validated, repeatedly, in federated, imbalanced datasets from as few as 50–100 patients [3]. Results: We discover the biomarkers in “skinny” datasets of minimally preprocessed ≈3M-bin whole-genome sequences from tumors and blood of a set of 101 patients. Blindly, i.e., label-free, we separate both biomarkers from the normal X chromosome-number variation, demonstrating sex-agnostic learning. Combined, the biomarkers are statistically independent of all standard-of-care indicators, with the univariate Cox hazard ratio of 4.0 (log-rank P-value=2.3×10–5) within the 95% confidence intervals of the bivariate ratios. The risk that the tumor’s whole genome confers upon outcome, as is reflected by the bivariate ratios, is greater than that conferred by all standard-of-care indicators, including DNA ploidy, the Children’s Oncology Group (COG) risk, and the mitosis-karyorrhexis index (MKI), except for histopathology. We validate the biomarkers in ≈10K-bin target-capture sequences of a mutually-exclusive set of 419 patients, demonstrating generalizability as well as site-, platform-, and protocol-agnostic transfer learning. At 73–80% concordance, in both the tumor and blood profiles of both the discovery and validation sets, the biomarkers combined are more accurate than MYCN. We show that the biomarkers identify known and previously unrecognized disease mechanisms and druggable gene alterations, including co-amplification of MYCN with genes encoding for extra-embryonic transcripts, as well as the hijacking of embryonic development toward aneuploidy, which can spontaneously regress via embryonic self-correction. Conclusions: Our AI/ML is uniquely suited for personalized medicine. 1. doi: 10.1063/1.5099268 2. doi: 10.1073/pnas.0530258100 3. doi: 10.1063/1.5142559.

Prospective validation from a retrospective trial that validated an AI/ML-derived whole-genome biomarker as the most accurate and precise predictor of survival and response to treatment in glioblastoma.

e14028 Background: For 70 years, the best indicator of glioblastoma (GBM) survival has remained age at diagnosis. Factors across the entire genome affect every aspect of the disease. But typical artificial intelligence and machine learning (AI/ML) would require 3B-patient training sets to generate predictive models from the whole 3B-nucleotide genome. As a result, all other attempts to associate a tumor’s DNA copy-number alterations (CNAs) with the patient’s outcome failed. Methods: A genome-wide pattern of DNA CNAs in primary GBM tumors was recently validated in a retrospective clinical trial as the most accurate and precise predictor of survival and response to treatment [doi: 10.1063/1.5142559 ]. Applicable to the general population, this biomarker, the first to encompass the whole genome, and biomarkers in lung, nerve, ovarian, and uterine cancers, were repeatedly identified in open-source datasets from as few as 50–100 patients by using our data-agnostic unsupervised AI/ML, which extends the mathematics of quantum mechanics to overcome the limitations of typical AI/ML [doi: 10.1063/1.5099268 , 10.1073/pnas.0530258100 ]. Results: At 75–95% concordance, our biomarker is more accurate than and independent of age and all other indicators, including the one-gene tests for MGMT, IDH1, and TERT. Platform- and reference genome-agnostic, the biomarker’s &gt;99% precision is greater than the community consensus of &lt;70% reproducibility. It describes disease mechanisms and identifies drug targets and combinations of targets to sensitize tumors to treatment. Now, in follow-up results from the trial we, first, show correct prospective prediction of the outcome of the five of the 79 patients who were alive four years earlier, at the time of first results (log-rank P-value=3.9×10–2). Two patients, who were predicted to have shorter survival, lived less than five years from diagnosis, whereas of the three patients predicted to have longer survival, one lived more than five, and the remaining two are alive &gt;11.5, years from diagnosis. Second, we demonstrate 100%-precise clinical prediction for the 59/79 patients with remaining tumor DNA, by using whole-genome sequencing in a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) laboratory. Third, we establish that the risk that a tumor’s whole genome confers upon outcome, as is reflected by the biomarker’s univariate Cox hazard ratio of 4.2 and Kaplan-Meier median survival difference of 2.25 years (log-rank P-value=6.0×10–4), is greater than that conferred by the patient’s Karnofsky performance score and access to chemotherapy, and the tumor’s percent resection, and is surpassed only by the patient’s access to radiotherapy. Conclusions: This is a proof of principle that our AI/ML is uniquely suited for personalized medicine.

Comparing a robotic imageless second-generation system to traditional instrumentation in total knee arthroplasty: A matched cohort analysis

IntroductionRobotic-assisted total knee arthroplasty (rTKA) has gained interest from patients and surgeons alike. Robotic systems assist with gap balancing and bone cut accuracy, which can theoretically minimize post-operative pain by decreasing soft tissue damage. This study compared perioperative results, 30- and 90-day complications, patient-reported outcomes (PROs), and survivorship to all-cause revisions between patients undergoing traditional versus rTKA. MethodsA total of 430 TKAs (215 rTKA, 215 traditional) by two fellowship trained arthroplasty surgeons were retrospectively reviewed from 2017 to 2022. All rTKAs were performed using the CORI Surgical System (Smith & Nephew, Memphis, Tennessee). Cohorts were propensity score matched by age, sex, body mass index, and American Society of Anesthesiologist classification. Blood loss, surgical times, length of stays, 30- and 90-day complications, pain scores and PROs were compared with univariable analyses. Cox regression analyses evaluated survival to all-cause revisions. ResultsPatients undergoing rTKA had a higher incidence of discharge home (86.5 %–60.0 %) (p < 0.01). There was no difference in blood loss or surgical time. rTKA pain scores were lower in-hospital mean 2 (range, 0 to 9) vs 3 (range, 0 to 9) (p = 0.02) as well as at one-year post-operatively, mean 1 (range, 0 to 7) vs 2 (range, 0 to 10) (p = 0.02). Cox hazard ratio demonstrated no difference in survival to all-cause revisions (HR 1.3; CI 0.5 to 3.7) (p = 0.64). ConclusionThis matched cohort analysis demonstrated potential short-term benefits associated with imageless second generation rTKA including improved early post-operative pain, without compromising survivorship to all-cause revisions.

Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment

BackgroundStudies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated.ObjectiveThis study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients.MethodsWe retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL).ResultsOur study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21–0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20–0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25–0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11–4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03–4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15–0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02).ConclusionWe found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

RISK FACTOR TO DEVELOP CKD IN GENERAL POPULATION: IMPACT OF HYPERTENSION

Objective: The aim of the present study was to assess the impact of hypertension in the incidence of Chronic Kidney Disease (CKD) in a general population. Design and method: The study analyzed the EHR of a community of 1,450.000 adult subjects &gt;23 years of age. eGFR was calculated using the CKD-EPI formula. Lipid and uric acid was obtained at the beginning of the observational period. HTN was considered when it was recorded in the EHR (CIE9 and 10). Cox hazard ratio of risk to develop. CKD was calculated and plotted. Results: The main characteristics of the study population in the absence of CKD was 53.9 year old, male 56.5%, obese 422,114 (29.1%), diabetes 198242 (13.7%) and 508,477 (35%) hypertensives. The HR of each of the factors analysed is in the Table and the Cox plot in the figure. Conclusions: Hypertension independent of other risk factors increases rate of progression to CKD in general population.

Spontaneous breathing trial with pressure support on positive end-expiratory pressure and extensive use of non-invasive ventilation versus T-piece in difficult-to-wean patients from mechanical ventilation: a randomized controlled trial

BackgroundThe aim of this study is to assess whether a strategy combining spontaneous breathing trial (SBT) with both pressure support (PS) and positive end-expiratory pressure (PEEP) and extended use of post-extubation non-invasive ventilation (NIV) (extensively-assisted weaning) would shorten the time until successful extubation as compared with SBT with T-piece (TP) and post-extubation NIV performed in selected patients as advocated by guidelines (standard weaning), in difficult-to-wean patients from mechanical ventilation.MethodsThe study is a single-center prospective open label, randomized controlled superiority trial with two parallel groups and balanced randomization with a 1:1 ratio. Eligible patients were intubated patients mechanically ventilated for more than 24 h who failed their first SBT using TP. In the extensively-assisted weaning group, SBT was performed with PS (7 cmH2O) and PEEP (5 cmH2O). In case of SBT success, an additional SBT with TP was performed. Failure of this SBT-TP was an additional criterion for post-extubation NIV in this group in addition to other recommended criteria. In the standard weaning group, SBT was performed with TP, and NIV was performed according to international guidelines. The primary outcome criterion was the time between inclusion and successful extubation evaluated with a Cox model with adjustment on randomization strata.ResultsFrom May 2019 to March 2023, 98 patients were included and randomized in the study (49 in each group). Four patients were excluded from the intention-to-treat population (2 in both groups); therefore, 47 patients were analyzed in each group. The extensively-assisted weaning group had a higher median age (68 [58–73] vs. 62 [55–71] yrs.) and similar sex ratio (62% male vs. 57%). Time until successful extubation was not significantly different between extensively-assisted and standard weaning groups (median, 172 [50–436] vs. 95 [47–232] hours, Cox hazard ratio for successful extubation, 0.88 [95% confidence interval: 0.55–1.42] using the standard weaning group as a reference; p = 0.60). All secondary outcomes were not significantly different between groups.ConclusionAn extensively-assisted weaning strategy did not lead to a shorter time to successful extubation than a standard weaning strategy.Trial registration The trial was registered on ClinicalTrials.gov (NCT03861117), on March 1, 2019, before the inclusion of the first patient. https://clinicaltrials.gov/study/NCT03861117.

Abstract CT201: Phase 2 clinical trial of OKN-007 in recurrent malignant glioma

Abstract Background: OKN-007 is a novel nitrone anti-cancer agent. OKN-007 plus Temozolomide (TMZ) increased survival in glioma-bearing mice compared to TMZ alone. Furthermore, OKN-007 increased TMZ sensitivity in both TMZ-sensitive and TMZ-resistant cell lines. Following a phase I study in recurrent glioblastoma (rGBM), we initiated a phase 2 clinical trial (NCT04388475) of OKN-007 combined with TMZ to examine the efficacy, safety, and pharmacokinetic properties of OKN-007 combined with TMZ. Here, we report the safety and efficacy findings of this ongoing trial. Methods: This is a multi-center, open label phase 2 clinical trial in first or second rGBM WHO Grade (Gr) IV. Adult patients with rGBM previously treated with standard radiation and chemotherapy (Stupp regimen) were eligible. Any second-line therapy was acceptable, excluding bevacizumab. Patients were treated with OKN-007, administered intravenously, at 60 mg/kg, three times weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until progression. TMZ was administered orally, at a dose of 150 mg/m2 (Cycle 1) or 200 mg/m2 (subsequent cycles). An initial 3-patient safety lead-In cohort established the safety of the OKN-007 and TMZ combination in this patient population. Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Additionally, a comparative analysis of PFS and OS for a matched external control rGBM population treated with lomustine in other formal randomized clinical trials was performed. Results: 57 patients were enrolled at study completion. Of 57 patients enrolled, there were no adverse events (AEs) deemed as a dose-limiting toxicity in the safety Lead-In cohort with 3 patients. Median age was 56 years (range, 29-82), and 41 patients were treated with one line of prior anti-cancer therapy and 15 were treated with two prior lines. Eighteen patients experienced 46 SAEs and of these 9 (Gr3 nausea, Gr2 vomiting, Gr3 fatigue, Gr2 infusion related reaction, Gr3 acute liver injury, Gr3 generalized weakening upper and lower extremities, Gr3 bilirubin increase, Gr3 AST and ALT increase) were deemed to be possibly related to administration of OKN-007. For 56 patients receiving the combination of OKN-007 and TMZ, median PFS was 2.2 (95% CI, 1.6-3.6) months vs. 1.8 (95% CI, 1.7-1.9) months in control patients. Median OS was 9.7 (95% CI 7.6-12.5) months vs. 7.2 (95% CI, 6.8-7.8) months (Cox hazard ratio (HR) = 0.68, p = 0.034). 6-month PFS rate was 23.6% (95% CI, 13.5-35.4) vs. 13.0% (95% CI, 10.0-16.4) and 12-month OS rate was 38.1% (95% CI, 25.1-50.9) vs. 26.3% (95% CI, 22.0-30.8), respectively. Conclusions: Our data indicate that the combination therapy of OKN-007 and TMZ appears safe and, compared to standard lomustine therapy, may prolong OS in rGBM. Citation Format: James Battiste, Glenn Lesser, Santosh Kesari, Varun Monga, Tobias Walbert, Kaylyn Sinicrope, Burt Nabors, Jason Schroeder, Eric Wong, Barry D. Anderson, Hyun Sook Kim, Shinwook Kang. Phase 2 clinical trial of OKN-007 in recurrent malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT201.

Regression models for average hazard.

Limitations of using the traditional Cox's hazard ratio for summarizing the magnitude of the treatment effect on time-to-event outcomes have been widely discussed, and alternative measures that do not have such limitations are gaining attention. One of the alternative methods recently proposed, in a simple 2-sample comparison setting, uses the average hazard with survival weight (AH), which can be interpreted as the general censoring-free person-time incidence rate on a given time window. In this paper, we propose a new regression analysis approach for the AH with a truncation time τ. We investigate 3 versions of AH regression analysis, assuming (1) independent censoring, (2) group-specific censoring, and (3) covariate-dependent censoring. The proposed AH regression methods are closely related to robust Poisson regression. While the new approach needs to require a truncation time τ explicitly, it can be more robust than Poisson regression in the presence of censoring. With the AH regression approach, one can summarize the between-group treatment difference in both absolute difference and relative terms, adjusting for covariates that are associated with the outcome. This property will increase the likelihood that the treatment effect magnitude is correctly interpreted. The AH regression approach can be a useful alternative to the traditional Cox's hazard ratio approach for estimating and reporting the magnitude of the treatment effect on time-to-event outcomes.