Time-dependent Cox Analysis Research Articles

Conditional survival of male breast cancer

Background The incidence of male breast cancer has been increasing in recent years; however, the long-term survival outcomes of diagnosed patients remain uncertain. This study was designed to evaluate the conditional survival of male breast cancer patients and to predict the future survival of patients through the conditional nomogram, to provide important suggestions for clinical decision-making. Methods Retrospective data from the SEER database included 3600 male breast cancer patients, divided into training and validation groups (7 : 3 ratio). Overall survival rates were calculated using Kaplan–Meier analysis. Conditional survival analysis described survival at specific years. Time-dependent multivariate Cox analysis identified prognostic factors’ impact. The conditional survival nomogram model predicted real-time survival rates. Results Over time, the 5-year real-time survival rate of patients gradually improved, increasing from 70.5 to 74.8, 79.4, 85.8, and 92.9% (respectively, representing 5-year survival rates of 1–4 years after diagnosis). In addition, the improvement in conditional survival rate CS5 showed a nonlinear trend. After 5 years of diagnosis, age, tumor size, and tumor stage had a sustained impact on patient prognosis. Finally, a conditional survival nomogram was constructed to predict the 10-year survival rate in real time. Conclusion Five years after diagnosis, the conditional survival rate of male patients with breast cancer has improved, but it is not nonlinear. In the first 5 years after diagnosis, patients with older age, larger tumor size, poorer tumor stage, and distant metastasis should be actively followed up and treated to improve their long-term survival.

Tumor treating fields in glioblastoma: long-term treatment and high compliance as favorable prognostic factors.

Tumor treating fields (TTFields) have earned substantial attention in recent years as a novel therapeutic approach with the potential to improve the prognosis of glioblastoma (GBM) patients. However, the impact of TTFields remains a subject of ongoing debate. This study aimed to offer real-world evidence on TTFields therapy for GBM, and to investigate the clinical determinants affecting its efficacy. We have reported a retrospective analysis of 81 newly diagnosed Chinese GBM patients who received TTFields/Stupp treatment in the Second Affiliated Hospital of Zhejiang University. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Cox regression models with time-dependent covariates were utilized to address non-proportional hazards and to assess the influence of clinical variables on PFS and OS. The median PFS and OS following TTFields/STUPP treatment was 12.6 months (95% CI 11.0-14.1) and 21.3 months (95% CI 10.0-32.6) respectively. Long-term TTFields treatment (>2 months) exhibits significant improvements in PFS and OS compared to the short-term treatment group (≤2 months). Time-dependent covariate COX analysis revealed that longer TTFields treatment was correlated with enhanced PFS and OS for up to 12 and 13 months, respectively. Higher compliance to TTFields (≥ 0.8) significantly reduced the death risk (HR=0.297, 95%CI 0.108-0.819). Complete surgical resection and MGMT promoter methylation were associated with significantly lower risk of progression (HR=0.337, 95% CI 0.176-0.643; HR=0.156, 95% CI 0.065-0.378) and death (HR=0.276, 95% CI 0.105-0.727; HR=0.249, 95% CI 0.087-0.710). The TTFields/Stupp treatment may prolong median OS and PFS in GBM patients, with long-term TTFields treatment, higher TTFields compliance, complete surgical resection, and MGMT promoter methylation significantly improving prognosis.

Thyroid dysfunction after immune checkpoint inhibitors in a single-centre UK pan-cancer cohort: A retrospective study

PurposeThis study investigated thyroid dysfunction with immune checkpoint inhibitors (ICIs) in terms of proportions affected, risk factors, thyroid sequelae, and overall survival (OS). MethodsAmong patients with normal baseline free T4 (fT4) and thyroid stimulating hormone (TSH) receiving ICIs at a large cancer centre, proportions of hyperthyroidism/hypothyroidism were determined (any, subclinical [normal fT4, abnormal TSH], overt [abnormal fT4, abnormal TSH], isolated hyperthyroxinaemia/hypothyroxinaemia and secondary) with onset times and subsequent thyroid statuses. Associations of overt dysfunction with OS were estimated using Cox regression and methods robust to immortal time bias (time-dependent Cox regression and 3- and 6-month landmark analyses). Associations of baseline variables with overt hyperthyroidism and hypothyroidism were estimated using Fine and Gray regression. ResultsOf 1349 patients, 34.2% developed hyperthyroidism (10.3% overt), including 54.9% receiving combination ICIs, while 28.2% developed hypothyroidism (overt 9.3%, secondary 0.5%). A third of overt hypothyroidism cases occurred without preceding hyperthyroidism. Subclinical thyroid dysfunction returned directly to normal in up to half. Overt hyperthyroidism progressed to overt hypothyroidism in 55.4% (median 1.6 months). Melanoma treatment in the adjuvant vs. advanced setting caused more overt hyperthyroidism (12.1% vs. 7.5%) and overt hypothyroidism (14.5% vs. 9.7%). Baseline eGFR < 60 mL/min/1.73 m2 (HR=1.68, 1.07–2.63) was associated with overt hyperthyroidism and sex (HR=0.60, 0.42–0.87) and TSH (4th vs. 1st quartile HR=1.87, 1.10–3.19) with overt hypothyroidism. Overt dysfunction was associated with OS in the Cox analysis (HR=0.65, 0.50–0.85, median follow-up 22.2 months) but not in the time-dependent Cox (HR=0.79, 0.60–1.03) or landmark analyses (3-month HR=0.74, 0.51–1.07; 6-month HR=0.91, 0.66–1.24). ConclusionThyroid dysfunction affects up to half of patients receiving ICIs. The association with OS is unclear after considering immortal time bias. The clinical courses include recovery, thyrotoxicosis and de novo overt hypothyroidism. Adjuvant treatment for melanoma, where longer-term harms are of concern, causes more frequent/aggressive dysfunction.

Gastrointestinal: Weight gain increases the risk of metachronous advanced colorectal neoplasm observed in post-polypectomy surveillance colonoscopy.

Although obesity is a known risk factor for colorectal neoplasms, the correlation between weight change and colorectal neoplasm is unclear. Thus, we aim to evaluate the association between weight change and advanced colorectal neoplasm (ACRN) recurrence during post-polypectomy surveillance colonoscopy. This retrospective cohort study included 7473 participants diagnosed with colorectal neoplasms between 2003 and 2010 who subsequently underwent surveillance colonoscopies until 2020. We analyzed the association between the risk of metachronous ACRN and weight change, defining stable weight as a weight change of <3% and weight gain as a weight increase of ≥3% from baseline during the follow-up period. During a median 8.5years of follow-up, 619 participants (8.3%) developed ACRN. Weight gain was reported as an independent risk factor for metachronous ACRN in a time-dependent Cox analysis. A weight gain of 3-6% and ≥6% had adjusted hazard ratios (AHRs) of 1.48 (95% confidence interval [CI]: 1.19-1.84) and 2.14 (95% CI: 1.71-2.69), respectively. Participants aged 30-49 and 50-75years with weight gain of ≥6% showed AHRs of 2.88 (95% CI: 1.96-4.21) and 1.90 (95% CI: 1.43-2.51), respectively. In men and women, weight gain of ≥3% was significantly correlated with metachronous ACRN. Weight gain is associated with an increased risk of metachronous ACRN. Furthermore, weight gain is associated with the recurrence of ACRN in both men and women regardless of age.

Different patterns of failure in two treatment regimens for primary central nervous system lymphoma, a retrospective analysis of 124 cases in Taiwan

To explore prognostic factors and outcomes of primary central nervous system lymphoma (PCNSL) of diffuse large B-cell lymphoma (DLBCL) in Taiwan, 124 PCNSL-DLBCL patients (from 1995 to 2021) were retrospectively analyzed. Mainly, two treatment modalities including sandwich chemoradiotherapy and modified MATRix regimen were employed in these patients. Overall survival (OS) was determined by log-rank test and time-dependent Cox analysis. Median OS of all patients was 27.1 months. 47 (37.9%) patients who underwent sandwich chemoradiotherapy had a complete remission (CR) rate of 87.2%, median OS of 53.9 months, and progression free survival (PFS) of 42.9 months. 11 (8.9%) patients who underwent modified MATRix regimen had CR rate of 72.7%, median OS of 18.9, and PFS of 11.2 months. There are no significant OS differences between treatment groups or addition of Rituximab. Patients treated with the modified MATRix regimen experienced a higher early mortality rate followed by a survival plateau. IELSG low-risk group had significantly improved OS and PFS than IELSG intermediate- or high-risk group. In multivariant analysis, age > 60 years old and bilateral cerebral lesions are associated with significantly inferior OS. Sandwich chemoradiotherapy demonstrated better early survival and reduced treatment-related toxicity for PCNSL patients compared to the modified MATRix regimen. However, the long-term follow-up revealed a higher rate of treatment failure events in the sandwich chemoradiotherapy group. IELSG and MSKCC scores served as reliable risk assessment models. Incorporating bilateral cerebral lesions as a risk factor further improved risk evaluation.

Time-dependent analysis of the impact on early cytomegalovirus reactivation of HLA mismatch and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation from related donors in acquired aplastic anemia.

Cytomegalovirus (CMV) reactivation is an important issue in allogeneic hematopoietic cell transplantation (HCT). The incidence of early CMV reactivation is notably high in HLA-mismatched HCT. However, the interactions between HLA mismatch and acute graft-versus-host disease (aGvHD), a time-dependent event, make it methodologically challenging to evaluate the independent impact on CMV reactivation of the two variables. We retrospectively analyzed 355 patients with acquired aplastic anemia who received related donor transplants using a unified antithymocyte globulin-based platform. Patients were divided into group 1 (6/6 HLA match), group 2 (1-2/6 HLA allelic mismatch), and group 3 (3/6 HLA allelic mismatch). The impact of covariates was analyzed through two models: (1) time-dependent Cox and (2) dynamic landmarking analysis. The time-dependent Cox model showed that the HLA mismatch of 3/6 alleles (hazard ratio (HR) =1.852, P = .004) and aGvHD (HR = 1.009, P = .019) were independent risk factors for CMV reactivation. With the dynamic landmarking analysis, a higher HLA disparity correlated to increased early CMV reactivation (HR = 1.606, P = .001) at all time points. Developing aGvHD following HCT was generally associated with a higher incidence of CMV reactivation (HR = 1.623, P = .013), though its impact decreased with successive later landmark time points. In conclusion, our data suggest that the higher HLA disparity and aGvHD increases susceptibility to early CMV reactivation. In particular, the dynamic landmarking analysis demonstrated the time-varying effect of aGvHD on CMV reactivation, and HLA mismatch showed a profound impact over time following HCT.

Revisiting prognostic factors in glioma with leptomeningeal metastases: a comprehensive analysis of clinical and molecular factors and treatment modalities

PurposeTo comprehensively investigate prognostic factors, including clinical and molecular factors and treatment modalities, in adult glioma patients with leptomeningeal metastases (LM).MethodsTotal 226 patients with LM (from 2001 to 2021 among 1495 grade 2 to 4 glioma patients, 88.5% of LM patients being IDH-wildtype) with complete information on IDH mutation, 1p/19q codeletion, and MGMT promoter methylation status were enrolled. Predictors of overall survival (OS) of entire patients were determined by time-dependent Cox analysis, including clinical, molecular, and treatment data. Subgroup analyses were performed for patients with LM at initial diagnosis and LM diagnosed at recurrence (herein, initial and recurrent LM). Identical analyses were performed in IDH-wildtype glioblastoma patients.ResultsMedian OS was 17.0 (IQR 9.7–67.1) months, with shorter median OS in initial LM than recurrent LM patients (12.2 vs 20.6 months, P < 0.001). In entire patients, chemotherapy and antiangiogenic therapy were predictors of longer OS, while male sex and initial LM were predictors of shorter OS. In initial LM, higher KPS, chemotherapy, and antiangiogenic therapy were predictors of longer OS, while male sex was a predictor of shorter OS. In recurrent LM, chemotherapy and longer interval between initial glioma and LM diagnoses were predictors of longer OS, while male sex was a predictor of shorter OS. A similar trend was observed in IDH-wildtype glioblastoma.ConclusionActive chemotherapy and antiangiogenic therapy demonstrated survival benefit in glioma patients with LM. There is consistent female survival advantage, whereas longer interval between initial glioma diagnosis and LM development suggests longer OS in recurrent LM.

Mortality of Deep Brain Stimulation and Risk Factors in Patients With Parkinson's Disease: A National Cohort Study in Korea.

This study aimed to investigate 1) long-term outcomes of deep brain stimulation (DBS), such as mortality after DBS as well as the causes of death, 2) demographic and socioeconomic factors influencing mortality, and 3) comorbidities affecting mortality after DBS in patients with Parkinson's disease (PD). This study analyzed the National Health Insurance Service-National Health Information Database. Data on patients with PD diagnosis codes from 2002 to 2019 were extracted and analyzed. Data on the causes of death were obtained by linking the causes of death to data from Statistics Korea. The Kaplan-Meier method with the log-rank test was used for survival analysis. Multivariate Cox regression analyses were used to estimate hazard ratios (HRs) and their 95% confidence intervals. Regarding comorbidities such as PD dementia and fracture, which did not satisfy the assumption for the proportional HR, time-dependent Cox analysis with the Mantel-Byar method was used. From 2005 to 2017, among 156,875 patients diagnosed with PD in Korea, 1,079 patients underwent DBS surgery, and 251 (23.3%) had died by 2019. The most common cause of death (47.1%) was PD. In the multivariate Cox regression analysis, the higher the age at diagnosis and surgery, the higher the mortality rate. The men and medical aid groups had significantly higher mortality rates. PD dementia and fracture were identified as risk factors for mortality. Older age at diagnosis and surgery, being male, the use of medical aid, and the comorbidity of dementia and fractures were associated with a higher risk of mortality after DBS in patients with PD. Neurologists should consider these risk factors in assessing the prognosis of PD patients undergoing DBS.

Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors: a post hoc analysis of ORAL Surveillance.

In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs). To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi). This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi. In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death. Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05. In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi. NCT02092467.

Cancers and cardiovascular diseases in patients with seropositive rheumatoid arthritis treated with JAK inhibitors, biologics and conventional synthetic DMARDs.

Janus kinase inhibitors and biologics (JAKi/biologics) are cornerstone treatments for rheumatoid arthritis (RA). We evaluated the risks of cancers and cardiovascular diseases (CVDs) in patients with seropositive RA (SPRA) treated with JAKi/biologics. Patients with new-onset SPRA during 2010-2020 in the national healthcare database were identified. Events of overall and site-specific cancers, as well as CVD outcomes, including deep vein thrombosis, pulmonary embolism, and composite cardiovascular events, were investigated. The relative risk of cancers and CVDs compared to conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) users was compared by evaluating the incidence rate ratios (IRRs). Time-dependent Cox analyses were performed to evaluate the relationship between JAKi/biologics usage and patient outcomes. A total of 101,816 and 96,220 patients with SPRA were analysed for cancers and CVD outcomes, respectively. Compared with patients treated only with csDMARDs, the IRRs of overall cancers and CVDs in patients administered JAKi/biologics were 0.88 (95% confidence interval [CI] 0.86-0.89) and 0.91 (95% CI 0.90-0.92), respectively. Site-specific lung, liver, prostate, and skin cancers were more frequent in JAKi/biologics users; JAKi did not confer a greater risk of overall CVDs and cancers compared with other biologics and csDMARDs. JAKi/biologics usage was not accounted for overall cancers and CVDs in adjusted Cox analyses. The incidence of overall cancer and CVD were not increased in patients with SPRA treated with JAKi/biologics and was relatively lower than csDMARD only users, underscoring optimal disease control for risk mitigation. The higher incidence of several site-specific cancers requires further investigation.

Non-Renal Risk Factors for Chronic Kidney Disease in Liver Recipients with Functionally Intact Kidneys at 1 Month.

Chronic kidney disease (CKD) is a critical complication of liver transplants, of which non-renal risk factors are not fully understood yet. This study aimed to reveal pre- and post-transplant risk factors for CKD (<60 mL/min/1.73 m2), examining liver recipients with functionally intact kidneys one month after grafting using nationwide cohort data. Baseline risk factors were analyzed with multivariable Cox regression analyses and post-transplant risk factors were investigated with the time-dependent Cox model and matched analyses of time-conditional propensity scores. Of the 2274 recipients with a one-month eGFR ≥ 60 mL/min/1.73 m2, 494 (22.3%) developed CKD during a mean follow-up of 36.6 ± 14.4 months. Age, female sex, lower body mass index, pre-transplant diabetes mellitus, and lower performance status emerged as baseline risk factors for CKD. Time-dependent Cox analyses revealed that recurrent hepatocellular carcinoma (HR = 1.93, 95% CI 1.06–3.53) and infection (HR = 1.44, 95% CI 1.12–1.60) were significant post-transplant risk factors for CKD. Patients who experienced one of those factors showed a significantly higher risk of subsequent CKD compared with the matched controls who lacked these features (p = 0.013 for recurrent hepatocellular carcinoma, and p = 0.003 for infection, respectively). This study clarifies pre- and post-transplant non-renal risk factors, which lead to renal impairment after LT independently from patients’ renal functional reserve.

Metformin use is not associated with colorectal cancer incidence in type-2 diabetes patients: evidence from methods that avoid immortal time bias.

Immortal time bias (ITB) continues to distort many observational studies on metformin use and cancer risk. Our objective was to employ three statistical methods proven to avoid ITB and compare their results to that of a naïve time-fixed analysis in order to provide further evidence of metformin's association, or none thereof, with colorectal cancer (CRC) incidence. A total of 41,533 Korean subjects with newly diagnosed type-2 diabetes in 2005-2015 were selected from a prospectively maintained cohort (median follow-up of 6.3years). Time-to-CRC incidence was regressed upon metformin use (yes/no, average prescription days/year) using time-dependent Cox, landmark, nested case-control, and time-fixed Cox analyses. Other CRC risk factors were included to adjust for possible confounding. Neither metformin ever-use nor average metformin prescription days/year was associated with incident CRC hazard in time-dependent Cox, landmark, and nested case-control analyses with HR (95% CI) of 0.88 (0.68-1.13), 0.86 (0.65-1.12), and 1.10 (0.86-1.40) for metformin ever-use, and 0.97 (0.90-1.04), 0.95 (0.88-1.04), and 1.02 (0.95-1.10) for average metformin prescription days/year, respectively. In contrast, time-fixed Cox regression showed a falsely exaggerated protective effect of metformin on CRC incidence. The association between metformin use and subsequent CRC incidence was statistically nonsignificant after accounting for time-related biases such as ITB. Previous studies that avoided these biases and meta-analyses of RCTs on metformin and cancer incidence were in agreement with our results. A definitive, large-scale RCT is needed to clarify this topic, and future observational studies should be explicit in avoiding ITB and other time-related biases.

The relationship between occupational dust exposure and incidence of diabetes in male workers: A retrospective cohort study.

Previous studies have focused on the association between ambient particulate matter and diabetes. However, the relationship between subacute exposure to occupational dust and diabetes has not been explored. We aimed to assess this relationship. Men who worked in dust-related process factories between January 2013 and December 2017 were recruited from a Korea Health Worker Examination Common Data Model cohort. A history of physician-diagnosed diabetes, use of an anti-diabetic drug, or a fasting blood glucose level of ≥7mmol/L were considered the criteria to diagnose diabetes. Multivariable time-dependent Cox analysis estimated hazard ratios (HRs) and 95% CIs for incident diabetes associated with exposure to occupational dust exposure; interactions with lifestyle factors were analysed. Sensitivity analyses used propensity score matching and landmark analysis. Among 5141male participants (median follow-up duration, 3.85years), 349 participants had diabetes. Occupational dust exposure was related to an increased risk of diabetes in the time-dependent Cox analysis (entire cohort: HR 1.66 [95% CI 1.25-2.19], matched cohort: HR 1.65 [95% CI 1.22-2.24]). The findings showed the same direction in the landmark analysis (HR 1.42 [95% CI 1.01-1.99]). A significant relationship exists between occupational dust exposure and increased risk of diabetes in male workers. Further studies should be conducted to confirm that occupational dust exposure is a possible risk factor for diabetes.

Does severe subacute noise exposure increase risk of new onset hypertension beyond conventional risk factors? A 30 000 person-years cohort study.

Objectives:Previous studies mostly focused on the relationship between chronic environmental noise exposure and hypertension but the effects of subacute (under 4 years) exposure with severe (>85 dB) noise exposure on clinical level hypertension have not been explored. This study aimed to reveal the association between severe noise exposure and hypertension.Methods:The severe noise exposure group was recruited from a Common Data Model conducted for the Korean Participants Health Examination from January 2014 to December 2017. The use of antihypertensive drug and/or blood pressure of at least 140/90 mmHg was defined as new onset clinical hypertension. A multivariate Cox proportional hazard model was implemented to estimate hazard ratios and 95% confidence intervals (CI) by adjusting covariates including demographic, lifestyle, and other chemical exposure factors. Time-dependent Cox analysis and Landmark analysis were further performed as a sensitivity analysis.Results:During the 29 332 person-years follow-up with 12 412 participants of the entire cohort, new onset hypertension occurred in 1222 participants. The findings showed that severe noise exposure was associated with an increased risk of hypertension incidence in the entire cohort [final model hazard ratio 1.28 (95% CI 1.11–1.47)]. Other covariates did not attenuate the association after adjusting age and sex. Time-dependent Cox and Landmark analysis also showed significant results [hazard ratio 1.60 (95% CI 1.38–1.85) and hazard ratio 1.33 (95% CI 1.13–1.57)].Conclusion:Severe noise with subacute exposure is significantly associated with hypertension development. Further studies should be implemented to clarify whether severe exposure to noise could be an important risk factor for hypertension.

Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)

Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)

A comprehensive investigation of nutritional status and psoas muscle mass in predicting five-year survival in patients with liver transplant

Although nutrition and sarcopenia have impacts on the surgery outcome of patients who have received living donor liver transplant (LDLT), the use of the prognostic nutritional index (PNI) or psoas muscle mass index (PMI) as an indicator for five-year survival in those patients is still unclear. A total of 138 patients receiving LDLT were followed at a medical center in Taiwan. As well as analysis of clinical factors using Cox regression, time-varying PNI and PMI values as before surgery (0) and at 3-, 6-, and 12- months after LDLT were analyzed by time-dependent Cox analysis. For those 124 patients who survived after 3 months of LDLT, the values of PNI-3m, PMI-3m and their combination were further analyzed. PNI and PMI were noted to be highly associated with mortality at three months post-LDLT (PNI-3m hazard ratio [HR]=0.89, 95% confidence interval [CI]: 0.85-0.94, p<0.001; PMI-3m HR=0.58, 95% CI: 0.41-0.82, p=0.002). Per the Youden index, the cut-off point of PNI-3m was 42.35, and that of PMI-3m was 1.94. Compared to the subjects with higher levels of PNI-3m and PMI-3m (N-high/M-high), the HRs for subjects with N-high/M-low, N-low/M-high, and N-low/M-low were 5.27 (p=0.004), 4.46 (p=0.010) and 12.97 (p<0.001) respectively. PNI and PMI at the third month post-LDLT serve as excellent predictors for 5-year survival. For patients with lower levels of PNI-3m or PMI-3m, combination use of these indexes is suggested to provide better prognostic information.

Thrombosis and Anticoagulation in Malignant Superior Vena Cava Syndrome

▪Background:Superior Vena Cava (SVC) Syndrome (SVCS), defined by obstruction of blood flow through the SVC, is commonly caused by a mediastinal tumor (i.e. malignant SVCS, m-SVCS). Little is known regarding co-existing SVC thrombosis at diagnosis in this high risk setting. Anticoagulation (AC) is often utilized even in the absence of thrombosis or stents, but evidence is lacking.Aims:1) To determine factors associated with thrombosis and AC at m-SVCS diagnosis; 2) To evaluate the effect of baseline AC and SVC thrombosis on outcomes.Methods:The electronic records of 2 academic medical centers in Israel were screened for diagnostic codes compatible with SVCS and malignancy between 2007 and 2015. Patients were included if they had active cancer and m-SVCS reported in chest computerized tomography (CT) with intravenous (IV) contrast medium. Records were followed from m-SVCS diagnosis for 6 months.Baseline patient, cancer and m-SVCS-related characteristics were collected. AC use and endovascular SVC stent placement were recorded throughout the study. Accessible diagnostic and follow-up IV contrast CTs were reviewed by two radiologists to confirm m-SVCS diagnosis and evaluate thrombosis. The primary endpoint was death from any cause. Secondary endpoints included new/recurrent SVC thrombosis. Baseline variables that had a statistically significant association with baseline thrombosis or death on univariate analysis were entered into a General Linear Model and multivariable cox regression model, respectively, for multivariable analysis. Significance was set at p < 0.05.Results:The cohort included the 183 patients, 70% (129) of whom had a reviewable baseline CT. Baseline characteristics are shown in Table 1. Briefly, 65% (119/183) had newly diagnosed cancer of any histology, 22% (40/183) had hematological malignancy (mainly aggressive lymphoma), and 16% (29/183) had no symptoms attributable to m-SVCS (i.e. clinical grade 0). Thrombosis of the SVC or tributaries at diagnosis was seen in 24% (30/127). Baseline AC (within 21 days of m-SVCS diagnosis) was used in 51% of patients for a median duration of 68 days [range: 14-179]. Thirty percent of thrombotic cases received no AC, while 52% of non-thrombotic cases received AC at varying doses. Patients receiving baseline AC were more likely to have had a SVC stent placed at baseline, and had higher grade venous occlusion and a trend to more thrombosis of SVC and tributaries (univariate analysis; Table 1). On multivariate analysis, only symptomatic m-SVCS (P<0.01) and increasing Khorana score (p<0.05) were associated with baseline thrombosis (univariate analysis shown in Table 1).Over a median FU of 44 [IQR 22-93] days, 49% (90/182) of patients died. A follow up CT was performed in 61/129 (47%) patients at a median of 138 days [IQR 71-182] from diagnosis, 30% (18) of whom died. New thrombosis of SVC and tributaries was identified in 10/61 (16%) at a median of 74 days [IQR: 53-150]. Patients with baseline AC had thrombosis on follow-up CT in 21% of cases (8/40) compared to 10% (2/20) in those without baseline AC (p=0.471). Among the 68/129 without a follow up CT, 45 (66%) died over a median follow up of 72 days (IQR 23-182).In time dependent cox analysis, baseline AC (compared to none) was not associated with risk of death (HR 0.85; 95% CI 0.55-1.29). In multiple regression analysis of baseline variables, increasing age (HR 1.04, 95% CI 1.02-1.06), malignancy stage IV (HR 4.57, 95% CI 2.29-9.13) and refractory cancer (HR 1.95, 95% CI 1.17-3.25) were associated with death.Conclusion:Thrombosis of SVC and tributaries is a common complication of m-SVCS, and is associated with symptomatic presentation and a high Khorana score. Prognosis in m-SVCS is dismal and appears to be determined by the prognosis of the underlying cancer and responsiveness to prior anticancer therapy and not by the presence of thrombosis at diagnosis. The high early death rate, low numbers of thrombotic events and confounding by AC indication, preclude ruling out a role for AC in selected cases. We propose that therapeutic dose AC in thrombotic m-SVCS and prophylactic AC in non-thrombotic m-SVCS be evaluated prospectively in newly diagnosed patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Tissue Factor-Related Biomarkers and Prediction of Cancer-Associated VTE: Correlative Analyses of the Phacs Trial

Background: Cancer patients at high or low risk for venous thromboembolism (VTE) can be predicted by a validated score (Khorana et al, Blood 2008) but the mechanisms underlying this association are not fully understood. We evaluated the association of VTE-related biomarkers with clinical outcomes in patients enrolled in a randomized trial of outpatient prophylaxis in high-risk patients and a control population of low-risk patients.Methods: Cancer patients with risk score ≥3 starting systemic therapy were randomized to dalteparin or observation for 12 weeks; a low-risk group of controls (score=0) was concurrently enrolled. Analyses for tissue factor (TF) using microparticle procoagulant activity, TF pathway inhibitor (TFPI) using ELISA, D-dimer and factor VIIA were conducted on specimens obtained at enrollment and 4-weekly on study as well as at enrollment in control patients.Results: The study populations comprised 89 randomized high-risk patients and 101 low-risk patients. TF MP-PCA levels were more likely to be detectable in high-risk patients (51.7% vs 32.7% of low-risk patients, p=0.01) and levels were elevated at time of enrollment in high-risk compared to low-risk patients (mean 0.67 vs 0.19 pg/mL in low-risk, p=0.002; median 0.03 vs 0 pg/mL, p=0.001). TF levels were particularly high in the subgroup of high-risk patients with pancreatic cancer (N=38, 57.9% detectable, mean 0.87 pg/mL, median 0.13 pg/mL). D-dimer levels were also significantly elevated in high-risk patients (median 1.23 vs 0.92 mg/mL, p=0.006). Levels of F1.2 and FVIIa were not significantly different between the high- and low-risk groups. Patients randomized to dalteparin had a significant decline in median D-dimer levels (median 1.22 mg/mL for timepoint 1 versus 0.7 mg/mL for timepoint 4, p =0.018) whereas there was no significant change over time for patients randomized to observation (median 1.30 vs 1.33 mg/mL, p=0.43). F1.2 levels also declined over time for patients randomized to dalteparin (median 77.17 to 32.37, p=0.01) but not for patients randomized to observation (median 59.06 to 61.63, p=0.99). In multivariate time-dependent Cox analysis in high-risk patients, VTE was associated with both doubling of TF (HR 1.42 95% CI 1.17-1.84, p=0.0003) and doubling of TFPI (HR 3.21, 95% CI 1.14-9.50, p=0.02).Conclusions: Cancer patients at high-risk for VTE are more likely to have increased TF levels at baseline; increased levels of both TF and TFPI were associated with future VTE. Further investigations into the role of TF and TFPI in cancer-associated thrombosis and their roles as predictive biomarkers are warranted. DisclosuresKhorana:Pfizer: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Leo: Consultancy, Honoraria, Research Funding. Francis:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding.

Time-Varying Risk of Atrial Fibrillation in Patient With Medically and Surgically Treated Primary Aldosteronism: A Nationwide Cohort Study

Evidence of increased cardiovascular risk, especially atrial fibrillation, has been accumulating among patients with primary aldosteronism (PA), but there is still limited information about long-term prognosis related to different treatment strategy. The aim of this study was not only to investigate the incidence of atrial fibrillation, but also to evaluate their time-dependent changes after adrenalectomy (surgery group) or mineralocorticoid receptor antagonists (drug group) for patients with PA compared to those with essential hypertension (EH). From a nationwide cohort in Korea (2003–2017), PA were individually matched for sex, age (±10 years), and index year in a 1:5 ratio with EH. The primary end point was the time-varying risk of new-onset atrial fibrillation (NOAF) among PA according to treatment mode compared to EH. The secondary end points were the risks of major adverse cardiovascular events (composite of non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular causes), hospitalization for heart failure, and all-cause mortality. Cox proportional-hazards analysis or time-dependent Cox analysis based on the Schoenfeld residuals testing were performed. We enrolled 1,418 PA patients (755 in PA surgery group and 663 in PA drug group), and matched theses with 7,090 EH controls with a median of 5 years. The risk of incident NOAF was statistically higher in patients with PA (both surgery and drug groups) within the three years after diagnosis (adjusted hazard ratio, 3.02; p<0.001), whereas there was no statistically significance after the three years compared to EH (adjusted hazard ratio, 0.50; p=0.053). Patients in the PA drug group had higher risk of non-fatal stroke during the total followed up period (adjusted hazard ratio, 1.53, p=0.031), although the PA surgery group didn’t. In contrast, patients with PA had no statistically significant difference in risks for other secondary cardiovascular outcomes. In conclusion, this propensity cohort study of adults with PA demonstrated the changeable risk of NOAF over time possibly due to the residual effect of inappropriate aldosterone levels. These findings can provide clinically relevant guidance in the monitoring the cardiovascular complications, especially NOAF and non-fatal stroke, even after treatment among patients with PA. Acknowledgements: This study was supported by Collaborative Research Project of Korean Endocrine Society and National Health Insurance Sharing Service (NHIS-2019-4-005). We also thank Minheui Yu and Doori Cho, the members of the SENTINEL (Severance ENdocrinology daTa scIeNcE pLatform) team for technical assistance in searching and summarizing the relevant literature (4-2018-1215).

Association between the risk of death and serum calcium, phosphate, and intact parathyroid hormone levels in older patients undergoing maintenance hemodialysis: a cohort study in Beijing.

Background:The number of patients ⩾65 years who require maintenance hemodialysis (MHD) is increasing. Although reduced bone turnover in older patients receiving hemodialysis, as reflected by lower serum intact parathyroid hormone (iPTH) and phosphate (P) levels, has been reported, focus on the association between abnormal bone metabolism and the risk of death in older patients receiving MHD has been limited.Methods:We retrospectively examined data from the Beijing Hemodialysis Quality Control and Improvement Center for 1410 older patients who underwent hemodialysis from 1 January 2012 to 31 December 2016. Baseline, time-dependent (TD) Cox proportional hazards models and Kaplan–Meier analyses were used to evaluate the association between the markers of mineral and bone disorder (MBD) [calcium (Ca), P, and iPTH] and survival. The Kidney Disease: Improving Global Outcomes (KDIGO) target ranges were included as reference values.Results:Serum P levels >2.49 mmol/l increased the risk of all-cause death [hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.04–2.07; p = 0.030] and cardiovascular death (HR: 2.01; 95%CI: 1.21–3.34; p = 0.007); iPTH levels >600 pg/ml increased the risk of cardiovascular death (HR: 1.95; 95%CI: 1.20–3.15; p = 0.007). Baseline results and TD Cox analyses were similar. All three MBD parameters were within the respective target ranges at least once during the follow-up period in 399 (28.3%) patients, and these patients had better survival rates than those who achieved two of the three target ranges (715/1410 patients; 50.7%); those who achieved one or no target range (296/1410; 21.0%) had the lowest survival rate (all-cause death: log-rank chi square = 83.96, p < 0.001; cardiovascular death: log-rank chi square = 47.06, p < 0.001).Conclusion:Older patients undergoing MHD who achieved the KDIGO target levels for any two or three MBD parameters had lower risks of all-cause and cardiovascular death.