Multivariable Competing-risks Regression Analyses Research Articles

Long-Term Risk of Subsequent Neoplasms in 5-Year Survivors of Childhood Neuroblastoma: A Dutch Childhood Cancer Survivor Study-LATER 3 Study.

Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors. We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014. Subsequent neoplasms were ascertained by linkages with the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (Palga) and medical chart review. We calculated standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative incidences. Multivariable competing risk regression analysis was used to evaluate risk factors. In total, 23 survivors developed an SMN and 60 an SNMN. After a median follow-up of 23.7 (range, 5.0-56.3) years, the risk of SMN was elevated compared with the general population (SIR, 4.0; 95% CI, 2.5 to 5.9; AER per 10,000 person-years, 15.1). The 30-year cumulative incidence was 3.4% (95% CI, 1.9 to 6.0) for SMNs and 10.4% (95% CI, 7.3 to 14.8) for SNMNs. Six survivors developed an SMN after iodine-metaiodobenzylguanidine (131IMIBG) treatment. Survivors treated with 131IMIBG had a higher risk of developing SMNs (subdistribution hazard ratio [SHR], 5.7; 95% CI, 1.8 to 17.8) and SNMNs (SHR, 2.6; 95% CI, 1.2 to 5.6) compared with survivors treated without 131IMIBG; results for SMNs were attenuated in high-risk patients only (SMNs SHR, 3.6; 95% CI, 0.9 to 15.3; SNMNs SHR, 1.5; 95% CI, 0.7 to 3.6). Our results demonstrate that neuroblastoma survivors have an elevated risk of developing SMNs and a high risk of SNMNs. 131IMIBG may be a treatment-related risk factor for the development of SMN and SNMN, which needs further validation. Our results emphasize the need for awareness of subsequent neoplasms and the importance of follow-up care.

The Effect of Surgical Resection on Cancer-Specific Mortality in Pelvic Soft Tissue Sarcoma According to Histologic Subtype and Stage

Background/Objectives: The impact of surgical resection versus non-resection on cancer-specific mortality (CSM) in soft tissue pelvic sarcoma remains largely unclear, particularly when considering histologic subtypes such as liposarcoma, leiomyosarcoma, and sarcoma NOS. The objective of the present study was to first report data regarding the association between surgical resection status and CSM in soft tissue pelvic sarcoma. Methods: Using data from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2019, we identified 2491 patients diagnosed with pelvic soft tissue sarcoma. Cumulative incidence plots were used to illustrate CSM and other-cause mortality rates based on the histologic subtype and surgical resection status. Competing risk regression models were employed to assess whether surgical resection was an independent predictor of CSM in both non-metastatic and metastatic patients. Results: Among the 2491 patients with soft tissue pelvic sarcoma, liposarcoma was the most common subtype (41%), followed by leiomyosarcoma (39%) and sarcoma NOS (20%). Surgical resection rates were 92% for liposarcoma, 91% for leiomyosarcoma, and 58% for sarcoma NOS in non-metastatic patients, while for metastatic patients, the rates were 55%, 49%, and 23%, respectively. In non-metastatic patients who underwent surgical resection, five-year CSM rates by histologic subtype were 10% for liposarcoma, 32% for leiomyosarcoma, and 27% for sarcoma NOS. The multivariable competing risk regression analysis showed that surgical resection provided a protective effect across all histologic subtypes in non-metastatic patients (liposarcoma HR: 0.2, leiomyosarcoma HR: 0.5, sarcoma NOS HR: 0.4). In metastatic patients, surgical resection had a protective effect for those with leiomyosarcoma (HR: 0.6) but not for those with sarcoma NOS. An analysis for metastatic liposarcoma was not possible due to insufficient data. Conclusions: In non-metastatic soft tissue pelvic sarcoma, surgical resection may be linked to a reduction in CSM. However, in metastatic patients, this protective effect appears to be limited primarily to those with leiomyosarcoma.

Influence of intraoperative blood salvage and autotransfusion on tumor recurrence after deceased donor liver transplantation: a large nationwide cohort study.

The practice of intraoperative blood salvage and autotransfusion (IBSA) during deceased donor liver transplantation for hepatocellular carcinoma (HCC) can potentially reduce the need for allogeneic blood transfusion. However, implementing IBSA remains debatable due to concerns about its possible detrimental effects on oncologic recurrence. This study retrospectively enrolled nationwide recipients of deceased donor liver transplantation for HCC between 2015 and 2020. The focus was on comparing the cumulative recurrence rate and the recurrence-free survival rate. Propensity score matching was conducted repeatedly for further subgroup comparison. Recipients were categorized based on the Milan criteria, macrovascular invasion, and pretransplant α-Fetoprotein (AFP) level to identify subgroups at risk of HCC recurrence. A total of 6196 and 329 patients were enrolled in the non-IBSA and IBSA groups in this study. Multivariable competing risk regression analysis identified IBSA as independent risk factors for HCC recurrence ( P <0.05). Postmatching, the cumulative recurrence rate and recurrence-free survival rate revealed no significant difference in the IBSA group and non-IBSA group (22.4 vs. 16.5%, P =0.12; 60.3 vs. 60.9%, P =0.74). Recipients beyond Milan criteria had higher, albeit not significant, risk of HCC recurrence if receiving IBSA (33.4 vs. 22.5%, P =0.14). For recipients with macrovascular invasion, the risk of HCC recurrence has no significant difference between the two groups (32.2 vs. 21.3%, P =0.231). For recipients with an AFP level <20ng/ml, the risk of HCC recurrence was comparable in the IBSA group and the non-IBSA group (12.8 vs. 18.7%, P =0.99). Recipients with an AFP level ≥20ng/ml, the risk of HCC recurrence was significantly higher in the IBSA group. For those with an AFP level ≥400ng/ml, the impact of IBSA on the cumulative recurrence rate was even more pronounced (49.8 vs. 21.9%, P =0.011). IBSA does not appear to be associated with worse outcomes for recipients with HCC exceeding the Milan criteria or with macrovascular invasion. IBSA could be confidently applied for recipients with a pretransplant AFP level <20ng/ml. For recipients with AFP levels ≥20ng/ml, undertaking IBSA would increase the risk of HCC recurrence.

Histologically Overt Stromal Response and the Risk of Progression after Radical Prostatectomy for Prostate Cancer.

Given the variable clinical course of prostate cancer and the limitations of current prognostic factors, this study was conducted to investigate the impact of a histologically overt stromal response (HOST-response) to prostate cancer on clinical outcomes after radical prostatectomy. This retrospective analysis utilized The Cancer Genome Atlas (TCGA) to evaluate data from individuals with a confirmed diagnosis of prostate cancer who underwent radical prostatectomy and had available pathology slides. These slides were assessed for the presence of a HOST-response, similar to desmoplasia. The primary endpoint was progression-free survival (PFS). A multivariable competing risk regression analysis was used to assess whether a significant association existed between HOST-response and PFS, adjusting for known prostate cancer prognostic factors. Among the 348 patients analyzed, 166 (47.70%) demonstrated a HOST-response. After a median follow-up of 37.87 months (IQR: 21.20, 65.50), the presence of a HOST-response was significantly associated with a shorter PFS (SDHR, 2.10; 95% CI, 1.26 to 3.50; p = 0.004), after adjusting for covariates. HOST-response in prostate cancer patients treated with radical prostatectomy is significantly associated with reduced PFS, suggesting a potential benefit from adjuvant therapy and highlighting the need for further investigation in a prospective randomized clinical trial.

ASCOD phenotyping of acute vertebrobasilar artery occlusion treated by mechanical thrombectomy: insight from the PERSIST registry.

Determining the underlying etiology of acute vertebrobasilar artery occlusion (VBAO) is crucial for selecting an appropriate treatment approach. The authors aimed to investigate the distribution of etiology and the association with functional outcomes in patients with acute VBAO who underwent endovascular treatment in which atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection (ASCOD) phenotyping was used. A retrospective study was conducted at 21 centers in China, involving patients with VBAO who received endovascular treatment within 24 hours of the estimated occlusion time. In the ASCOD phenotyping, each phenotype is graded based on the following categories: 1, likely to be causal; 2, uncertain if causal; and 3, unlikely to be causal. The authors defined a single possible cause as a cause graded 1 in a single domain, and multiple possible causes were graded 1 or 2 regardless of overlap. The primary outcome was unfavorable outcome (modified Rankin Scale [mRS] score of 3-6) at 90 days. The secondary outcomes included shift of mRS score at 90 days, 90-day mortality, successful reperfusion, and National Institutes of Health Stroke Scale score at 24 hours. Multivariable regression analysis was used to assess the association between etiological subtypes and functional outcomes. Multivariate competing-risk regression analysis was performed to analyze the association between etiological subtypes and the risk of recurrent stroke. A total of 577 patients were included in this study. Of these, 521 (90%) had a single possible cause. The most common etiology was A1 (382 cases, 73%), followed by C1 (111 cases, 21%) and O1 (28 cases, 5%-in this study the other causes and dissection subtypes were categorized under the umbrella term of "O" causes). Similar patterns were observed in the multiple possible causes. In the baseline characteristics of the cohort, as rescue therapy, stenting was more frequently used in patients in the A1 group than in the C1 group (53.2% vs 41.7%; p < 0.01). The proportion of atherosclerosis-type etiology increased when the occlusion was located more proximally (p < 0.01). Compared to the A1 group, patients in the C1 group had a lower incidence of unfavorable outcome (OR 0.42, 95% CI 0.24-0.73), which was less likely to shift to a worse mRS score (OR 0.60, 95% CI 0.39-0.91). The O1 subtype was not associated with unfavorable outcome (OR 1.35, 95% CI 0.46-4.01), whereas patients with the O1 subtype were more likely to shift to worse mRS score (OR 2.39, 95% CI 1.09-5.25) and to have a higher 90-day mortality rate (OR 2.60, 95% CI 1.07-6.31). Furthermore, there was no significant association between single etiological subtypes and stroke recurrence within 1 year. The most common etiology in patients with VBAO was atherosclerosis, followed by cardiac pathology and other. Compared to the A1 subgroup, the C1 subgroup showed better functional outcomes, whereas the O1 subgroup showed worse outcomes. Additionally, there was no statistically significant difference in the recurrence risk.

Prognostic Significance of the Cribriform Pattern in Prostate Cancer: Clinical Outcomes and Genomic Alterations.

Given the diverse clinical progression of prostate cancer (PC) and the evolving significance of histopathological factors in its management, this study aimed to explore the impact of cribriform pattern 4 (CP4) on clinical outcomes in PC patients and examine its molecular characteristics. This retrospective study analyzed data from The Cancer Genome Atlas (TCGA) database and included PC patients who underwent radical prostatectomy (RP) and had pathology slides available for the assessment of CP4. A multivariable competing risk regression analysis was used to assess the association between CP4 and progression-free survival (PFS) while adjusting for established PC prognostic factors. The frequency of genomic alterations was compared between patients with and without CP4 using the Fisher's exact test. Among the 394 patients analyzed, 129 (32.74%) had CP4. After a median follow-up of 40.50 months (IQR: 23.90, 65.60), the presence of CP4 was significantly associated with lower PFS (AHR, 1.84; 95% CI, 1.08 to 3.114; p = 0.023) after adjusting for covariates. Seven hub genes-KRT13, KRT5, KRT15, COL17A1, KRT14, KRT16, and TP63-had significantly lower mRNA expression levels in patients with CP4 compared to those without. PC patients with CP4 have distinct genomic alterations and are at a high risk of disease progression following RP. Therefore, these patients may benefit from additional post-RP treatments and should be the subject of a prospective randomized clinical trial.

Higher scores in the Clinical Frailty Scale are associated with covert and overt hepatic encephalopathy in patients with cirrhosis

BackgroundFrailty increases the vulnerability to internal and external stressors and may therefore be an indicator of a higher frequency of cirrhosis complications. We aimed to investigate the association of the Clinical Frailty Scale (CFS) with covert (CHE) and overt HE (OHE) development in patients with cirrhosis. MethodsThis study analyzed data of 228 patients with cirrhosis. Frailty was assessed using CFS. Patients were examined for the presence of CHE (using PHES) at study inclusion and followed for OHE. ResultsMedian CFS was 3 and 26 (11 %) patients were at least pre-frail (CFS>3). In multivariable logistic regression analysis in patients without a history of OHE (n = 195), a higher CFS was associated with the presence of CHE at baseline (OR 1.6, p = 0.039). During follow-up, 42 (18 %) patients developed an episode of OHE. In multivariable competing risk regression analyses, a higher CFS was independently associated with the development of an OHE episode in the total cohort (sHR 1.97, p < 0.001) and in the subcohort of patients without a history of OHE (sHR 1.88, p = 0.008). ConclusionCFS appears to be a reliable tool to identify patients at higher risk of HE in whom intensified monitoring and treatment may be justified.

Competing risk analysis of cardiovascular death in breast cancer: evidence from the SEER database.

Cardiovascular disease (CVD) is the leading cause of death for all non-cancer deaths among breast cancer (BC) patients. The aim of this study was to investigate the risk of cardiovascular mortality (CVM) in patients with BC. Patients diagnosed with primary BC between 2010 and 2018 were identified through the Surveillance, Epidemiology and End Results (SEER) database. The standardized mortality ratio (SMR) for CVD was calculated to compare the CVM of BC patients with that of the general population. Multivariate competing risk models were performed to identify predictors of CVM in BC patients. Overall, 399,014 BC patients were included from the SEER database, of whom 7,023 (1.8%) suffered death from CVD. The significantly higher overall SMR of CVM was observed in BC patients [SMR =4.84, 95% confidence interval (CI): 4.72-4.95]. Multivariate competing risk regression analysis revealed that age, race, American Joint Committee on Cancer (AJCC) stage, year of diagnosis, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, BC subtype, surgery, chemotherapy, radiation therapy, and median household income as independent predictors of CVM in BC patients. Compared to the general population, BC patients have a higher risk of experiencing CVM during the follow-up period after diagnosis. Early detection and intervention of cardiovascular risk factors would improve overall survival (OS) of BC patients.

Outcomes of Moderately Dose Escalated Hypofractionated Chemoradiation for Pancreatic Cancer

A modestly hypofractionated course of chemoradiation (CRT) consisting of 36 Gy/15 fractions (F) concurrent with gemcitabine used in PREOPANC and phase II trials has become increasingly common for the treatment of borderline resectable (BR) and locally advanced (LA) pancreatic cancer (PC). Achieving an R0 resection remains a key prognostic factor in PC. We tested whether escalating dose beyond standard dosing (SD) of 36-39 Gy/15 F (or 50-54 Gy/25-30 F) would improve R0 resection rates and outcomes while respecting nearby organs at risk. This was a retrospective analysis of consecutive patients at our institution from 2012-2022 with BR/LA PC treated with moderate dose escalated (MDE) (45 Gy/15 F, N = 45) or SD (36-39 Gy/15 F, N = 68 or 50-54 Gy/25-30 F, N = 25) CRT. For MDE, a 5 mm expansion from the duodenum, small bowel, and stomach was created (GI_PRV); PTV was cropped from this structure and prescribed 45 Gy/15 F. The primary endpoint was R0 resection rate with secondary endpoints of cumulative incidence of local progression (LP, recurrence after surgery/imaging progression if no surgery) with death as a competing risk (LP after occurrence of distant metastasis [DM] were still captured), cumulative incidence of DM, and overall survival (OS). Univariable and multivariable competing risks regression analyses were performed to determine the association between baseline covariates and LP. We identified 45 patients treated with MDE and 93 treated with SD. Most patients presented with BR disease (55.6% MDE; 54.8% SD) and received neoadjuvant chemotherapy with FOLFIRINOX (98% MDE; 99% SD). All patients in the MDE group and 99% in the SD group received concurrent chemotherapy with gemcitabine used most often (96% MDE; 77% SD). Median follow-up was 17 m (IQR 13-27 m). Surgical resection rates were similar between groups (33.3% MDE vs. 39.8% SD, p = 0.46). Amongst patients that had surgery, R0 resection rates were non-significantly higher in the MDE group (73.3% vs. 47.4%, p = 0.09). Cumulative incidence of LP at 18 m was significantly lower in the MDE group (9.0% vs. 24.8%, p = 0.04). No difference in rates of DM (51.2% MDE vs. 59.6% SD, p = 0.92) or OS at 18 m (53.9% vs. 53.6%, p = 0.89) were observed. On multivariable analysis, MDE (HR = 0.39, p = 0.03) and pancreatic head location (HR = 0.51, p = 0.04) were the only factors independently associated with LP. Rates of grade 2+ gastrointestinal toxicity during CRT (20% MDE vs. 20.9% SD, p = 0.91) and ≤90 days of completing CRT (11.6% MDE vs. 14.8%, p = 0.62) were similar between groups, as were rates of grade 3+ hematologic toxicity (52.3% MDE vs. 41.3% SD, p = 0.23). In this single institutional study, we found MDE is a simple, safe, and effective strategy associated with improved local control, higher R0 resection rates, and similar toxicity to SD CRT for patients with BR/LA PC. Further prospective data is needed to clarify the role of dose-escalated RT in the management of this lethal malignancy.

Investigating Dosimetry and Imaging Biomarkers for Prediction of Major Adverse Cardiac Events Following Locally Advanced Non-Small Cell Lung Cancer Radiotherapy

Thoracic radiotherapy (RT) may confer major adverse cardiac events (MACE) following treatment. Mean heart dose positively associates with MACE and recent studies show cardiac substructure dosimetry improves MACE prediction. Use of imaging biomarkers with cardiac substructure dose has not been studied for prediction of MACE. We sought to develop an integrated model for cardiac substructure dose and baseline coronary artery calcium (CAC) scoring and establish its relationship to MACE. A retrospective cohort analysis was performed of consecutive patients with locally advanced non-small cell lung cancer (NSCLC) treated with definitive RT from 2006-2018 at a single institution. Demographics, medical history, cardiac events, and treatments received were recorded. Cardiac substructures were contoured, including the left descending artery (LAD), left main coronary artery (LMCA), left circumflex (LCX), right coronary artery (RCA), TotalLeft (LAD+LMCA+LCX), and TotalCor (TotalLeft+RCA). Doses were measured in 2 Gy equivalent dose. CAC was scored by visual assessment and compared to established automated Agatston scoring. Primary endpoint was MACE incidence. Receiver operating characteristic (ROC) curves assessed dose and CAC metric model performance. Threshold modeling was conducted using the log rank statistic with 95% confidence intervals measured using bootstrap resampling with 1000 iterations. Competing risk models adjusted for death were used to measure cumulative incidence of MACE as well as in univariable and multivariable risk regression modeling. Pearson correlations were used to validate CAC scoring. P-values were two tailed and considered significant at P≤0.05. Of 233 eligible patients, 61.4% were male with a 68.1 years (range 34.9-90.7) median age. Median follow-up was 73.7 months (range 1.6-153.9). Median overall survival was 34.8 months. Following RT, 22.3% experienced at least one cardiac event at a median time of 21.5 months (range 1.7-118.9). Visual CAC scoring showed significant correlation with automated Agatston scoring (r = 0.72, P=1e-5). While left sided coronary arteries (TotalLeft), mean heart dose (MHD) and CAC scores individually predicted for MACE (AUC = 0.56-0.59), a multivariable model of TotalLeft CAC had the highest ROC analysis performance (AUC = 0.69). On univariable and multivariable competing risk regression analyses, TotalLeft V15 Gy >2.53 cc and CAC score >5 independently associated with MACE (P<0.05). A model incorporating age, TotalLeft CAC>5 and V15>2.53cc, showed incrementally higher MACE incidences for low (9.3%), intermediate (18.4%), and high-risk groups (27.7%) (P<0.01). RT-induced MACE occurs in >20% of those undergoing thoracic RT in a median time of <2 years. We validate significant associations between TotalLeft RT dose and MACE and establish CAC as a predictive risk factor. These findings may serve to inform personalized RT and future cardiac risk in locally advanced NSCLC.

The impact of transmembrane 6 superfamily 2 (TM6SF2) rs58542926 on liver-related events in patients with advanced chronic liver disease.

Genetic factors such as the transmembrane 6 superfamily 2 (TM6SF2) rs58542926 single nucleotide variant(SNV) modulate the susceptibility for (advanced) chronic liver disease ([A]CLD). However, the impact of this variant in patients who have already progressed to ACLD is unknown. The association between TM6SF2-rs58542926 genotype and liver-related events was evaluated in 938 ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement. Mean HVPG was 15±7 mmHg and mean UNOS MELD (2016) 11±5 points. Viral hepatitis (n=495, 53%) was the most common cause of ACLD, followed by alcohol-related (ARLD; n=342, 37%) and non-alcoholic fatty liver disease (NAFLD; n=101, 11%). While 754 (80%) patients harboured the TM6SF2 wild-type (C/C), 174 (19%) and 10 (1%) patients had one or two T-alleles. At baseline, patients with at least one TM6SF2 T-allele had more pronounced portal hypertension (HVPG: 16±7 vs. 15±7 mmHg; p=0.031), higher gamma-glutamyl transferase levels (123 [63-229] vs. 97 [55-174] UxL-1; p=0.002), and more commonly hepatocellular carcinoma (17% vs. 12%; p=0.049). Harbouring the TM6SF2 T-allele was associated with the composite endpoint hepatic decompensation/liver transplantation/liver-related death (SHR: 1.44 [95%CI: 1.14-1.83]; p=0.003). This was confirmed in multivariable competing risk regression analyses that were adjusted for severity of portal hypertension and hepatic dysfunction at baseline. The TM6SF2 variant modulates liver disease progression beyond the development of ACLD, as it modifies the risks of hepatic decompensation and liver-related death, independently of baseline liver disease severity.

Survival After Cryotherapy Versus Radiotherapy in Low and Intermediate Risk Localized Prostate Cancer

BackgroundFocal therapy, including cryotherapy, reduces overtreatment in low- and intermediate-risk prostate cancer (PCa) patients with multiple comorbidities, which seems to increase in popularity compared with whole gland treatment. However, there is currently no consensus regarding the medium-term outcomes of cryosurgery as a prospective alternative to radiotherapy (RT) for such patients. Our study aims to find the available evidence that directly compares the medium-term overall survival (OS) and cancer-specific mortality (CSM) outcomes between cryotherapy and RT in patients with low- and intermediated-risk PCa. Materials and MethodUsing the Surveillance, Epidemiology, and End Results (SEER) database, we identified 47,787 patients with low- and intermediate-risk PCa diagnosed between 2004 and 2015, of which 46,853 (98%) received treatment with RT, while only 934 (2.0%) received treatment with cryotherapy. Kaplan–Meier methods were used to estimateOS and cancer-specific survival (CSS) between the 2 groups. We performed multivariable Cox regression analysis to assess overall mortality (OM), while the cumulative incidence function (CIF) was used to illustrate cancer-specific mortality (CSM) and noncancer-specific mortality (non-CSM) for all patients. Additionally, competing risks regression (Fine-Gray) was implemented to evaluate any differences. After propensity score matching (PSM), all the aforementioned analyses were repeated. After the inverse probability of treatment weighting (IPTW), we repeated Kaplan–Meier methods on OS and CSS, and performed multivariable Cox regression analysis to assess OM in cryotherapy versus RT. Sensitivity analyses were conducted by excluding patients who died of cardiovascular disease. ResultsAfter applying 1:4 PSM to the cryotherapy group with the RT group, the resulting RT cohort consisted of 3,736 patients who were matched with 934 patients in the cryotherapy cohort. The 5‐year OS and cumulative CSM rates for PS-matched groups (N = 4670) receiving cryotherapy (N = 934) or RT (N = 3736) were 89% versus 91.8%, 0.65% versus 0.57, respectively. Multivariable Cox regression analysis demonstrated that cryotherapy was associated with a poorer OS outcome compared to RT (hazard ratio [HR] 1.29, 95% confidence interval [CI]: 1.07-1.55, p < .01). Multivariate competing risk regression analysis revealed that both treatments were not associated with CSS, with HR = 1.07 (95% CI: 0.55-2.08, p = .85). IPTW-adjusted analyses showed that the 5-years OS rates were 89.6% versus 91.8% for cryotherapy versus RT, respectively. Multivariate regression analysis for OS demonstrated that cryotherapy was more likely to have inferior OS in comparison to RT (HR = 1.30; 95%CI: 1.09-1.54; p < .01). The outcome of sensitivity analyses indicates that there was no significant difference in OS and CSS between the 2 groups. ConclusionFor low- and intermediate-risk PCa patients treated by cryotherapy or RT, we could not demonstrate a survival difference. Cryotherapy may be a feasible option as a viable alternative to traditional radiation therapy.

Post-operative mortality and recurrence patterns in pancreatic cancer according to KRAS mutation and CDKN2A, p53, and SMAD4 expression.

Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post-operative survival outcomes. To test this hypothesis, we utilised a multi-institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09-1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10-1.46). Compared to cases with 0-2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09-1.51) and 1.47 (95% CI, 1.22-1.78), respectively (ptrend < 0.001). Patients with an increasing number of altered genes were more likely to have short DFS time (ptrend = 0.003) and to develop liver metastasis (ptrend = 0.006) rather than recurrence at local or other distant sites. In conclusion, loss of SMAD4 expression and an increasing number of altered genes were associated with unfavourable outcomes in pancreatic cancer patients. This study suggests that the accumulation of the four major driver alterations can confer a high metastatic potential to the liver, thereby impairing post-operative survival among patients with pancreatic cancer.

C28 LEFT VENTRICULAR OUTFLOW TRACT VELOCITY–TIME INTEGRAL (LVOT–VTI) IMPROVES RISK STRATIFICATION IN HEART FAILURE PATIENTS WITH SECONDARY MITRAL REGURGITATION

Abstract Background Reduced left ventricular ejection fraction (LVEF) has been used as a key criterion for the management of mitral regurgitation (MR) in patients with heart failure (HF), including the decision about mitral valve repair. However, LVEF, not taking into account mitral regurgitant volume, may be an imprecise predictor of outcome in HF patients with MR. Conversely, the estimation of the forward volume through the LV outflow tract (LVOT) may be a better metric in this setting. In this regard, LVOT velocity time integral (LVOT–VTI), not relying on geometrical assumptions, has been shown to be more reproducible than the calculated stroke volume (i.e., LVOT–VTI * LVOT cross sectional area). Objective To assess the prognostic significance of LVOT–VTI in a contemporary cohort of patients with chronic HF and significant MR. Methods Consecutive patients with chronic HF with reduced (≤40%) or mildly reduced (41–49%) LVEF and moderate–to–severe or severe MR, according to the latest European Society of Cardiology criteria, were selected and followed–up for the endpoint of cardiac death. Results 287 patients were enrolled in the study (74±11 years, 70% men, 46% ischemic etiology, HFrEF 89%, LVEF 30±9%, mean LVOT–VTI 20±5 cm). Most patients showed a NYHA class II (40%) or III (31%) and received beta–blockers (93%), ACE–inhibitors/ARBs or ARNI (77%), and mineralocorticoid receptor antagonists (76%). One hundred and ten patients (39%) had permanent atrial fibrillation and 82 (29%) a cardiac resynchronization therapy device. Over a median follow–up of 33 (16–47) months, 114 patients died, 71 of whom for cardiac cause, and 28 underwent mitral valve repair/replacement. The risk of cardiac death increased proportionally to the decrease of LVOT–VTI (Figure 1, panel A), with an optimal prognostic cut–off of 17 cm (Figure 1, panel B). Reduced LVOT–VTI was associated with higher NYHA class, NT–proBNP concentration, and worse right ventricle systolic function (all p&amp;lt;0.005). At multivariable competing risks regression analysis, a unit decrease of LVOT–VTI (HR 0.87 [95%CI 0.80–0.93], p&amp;lt;0.001), but not of LVEF (p=0.254), was independently associated with a higher risk of cardiac death (Figure 1, panel C). Conclusion Left ventricular forward volume, noninvasively estimated through LVOT–VTI, but not LVEF, predicts the risk of cardiac death in patients with chronic HF and significant MR.

Overall survival and cancer-specific survival were improved in local treatment of metastatic prostate cancer.

For metastatic prostate cancer (mPCa), radical prostatectomy (RP) and radiation therapy (RT) may improve overall survival (OS) and cancer-specific survival (CSS). Compared with RT, RP shows significant advantages in improving patient outcomes. External beam radiation therapy (EBRT) even slightly elevates CSM with no statistical difference in OS compared with no local treatment (NLT). To evaluate OS and CSS after local treatment (LT) (including RP and RT) versus NLT in mPCa. Design, setting, and participants Within the Surveillance, Epidemiology and End Results (SEER) database (2000-2018), 20098 patients with metastatic prostate cancer were selected in this study, of which 19433 patients had no local treatment, 377 patients with radical prostate treatment, and 288 patients with RT. Multivariable competing risks regression analysis after propensity score matching (PSM) was used to calculate CSM. Multivariable Cox regression analysis was used to identify the risk factors. Kaplan-Meier methods were used to calculate OS. A total of 20098 patients were included: NLT (n = 19433), RP (n=377) and RT (n=288). In a competing risk regression analysis after PSM (ratio 1:1), RP resulted in a significantly lower CSM (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.29-0.45) than NLT, while RT showed a slightly lower CSM (HR 0.77, 95% CI 0.63-0.95). In a competing risk regression analysis after PSM (ratio 1:1), RP led to a lower CSM (HR 0.56, 95% CI 0.41-0.76) versus RT. As for all-cause mortality (ACM), RP (HR 0.37, 95% CI 0.31-0.45) and RT (HR 0.66, 95% CI 0.56-0.79). also showed a downward trend. In terms of OS, RP and RT significantly improved the survival probability compared with NLT, with the effect of RP being more pronounced. Obviously, older age, Gleason scores ≥8, AJCC T3-T4 stage, AJCC N1, AJCC M1b-M1c were all associated with higher CSM (P<0.05). The same results held true for ACM. The limitation of this article is that it is not possible to assess the effect of differences in systemic therapy on CSM in mPCa patients and clinical trials are needed to verify the results. For patients with mPCa, both RP and RT are beneficial to patients, and the efficacy of RP is better than RT from the perspective of CSM and ACM. Older age, higher gleason scores and the more advanced AJCC TNM stage all put patients at higher risk of dying. A large population-based cancer database showed that in addition to first-line therapy (hormonal treatment), RP and radiotherapy can also benefit patients with mPCa.

Impact of donor sex on hepatocellular carcinoma recurrence in liver transplantation after brain death.

Hepatocellular carcinoma (HCC) is predominantly seen in males but has a better prognosis in females. No prior studies have investigated HCC recurrence based on sex combination following liver transplant donated after brain death (DBDLT). This study sought to elucidate the effects of donor and recipient sex on HCC recurrence rates. 9232 adult recipients from the United Network for Organ Sharing (UNOS) database who underwent DBDLT for HCC from 2012 to 2018 were included. Donor-recipient pairs were divided into (1) female donor/female recipient (F-F) (n=1089); (2) male donor/female recipient (M-F) (n=975); (3) female donor/male recipient (F-M) (n=2691); (4) male donor/male recipient (M-M) (n=4477). The primary prognostic outcome was HCC recurrence. A multivariable competing risk regression analysis was used to assess prognostic influences. The median recipient age and model for end-stage liver disease (MELD) scores were similar among the four groups. Livers of male recipients demonstrated greater in size and number of HCC (both p-values were <.0001). There was also a higher rate of vascular invasion in male recipients compared to female (p<.0001). Competing risk analyses showed that the cumulative HCC recurrence rate was significantly lower in the M-F group (p=.013). After adjusting for tumor characteristics, liver grafts from male donors were associated with a lower HCC recurrence rate in female recipients (HR: .62 95%CI: .42-.93) (p=.021). In DBDLT, male donor to female recipient pairing exhibited lower HCC recurrence rates. Lowest rates of HCC recurrence were confirmed among the female recipients of male donor grafts group in the deceased donor LT cohort. A competing risk multivariable regression analysis demonstrated that male donor sex was significantly associated with low HCC recurrence in female but not male recipients.

PD29-05 ASSOCIATION OF AGE WITH NON-MUSCLE INVASIVE BLADDER CANCER: A BIOLOGICAL BASIS FOR EPIDEMIOLOGICAL DISPARITIES?

You have accessJournal of UrologyCME1 Apr 2023PD29-05 ASSOCIATION OF AGE WITH NON-MUSCLE INVASIVE BLADDER CANCER: A BIOLOGICAL BASIS FOR EPIDEMIOLOGICAL DISPARITIES? Niyati Lobo, Akshay Sood, Zhigang Duan, Wei Shen Tan, Valentina Grajales, Sia Viborg Lindskrog, Lars Dyrskjøt, Aarhus, Denmark, Hui Zhao, Sharon Giordano, Stephen B. Williams, and Ashish M. Kamat Niyati LoboNiyati Lobo More articles by this author , Akshay SoodAkshay Sood More articles by this author , Zhigang DuanZhigang Duan More articles by this author , Wei Shen TanWei Shen Tan More articles by this author , Valentina GrajalesValentina Grajales More articles by this author , Sia Viborg LindskrogSia Viborg Lindskrog More articles by this author , Lars DyrskjøtLars Dyrskjøt More articles by this author , Aarhus Aarhus More articles by this author , Denmark Denmark More articles by this author , Hui ZhaoHui Zhao More articles by this author , Sharon GiordanoSharon Giordano More articles by this author , Stephen B. WilliamsStephen B. Williams More articles by this author , and Ashish M. KamatAshish M. Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003315.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Age disparity in patients with non-muscle-invasive bladder cancer (NMIBC) exists. Whether this is due to differences in cancer care or tumour biology is unclear. We sought to investigate age disparities in NMIBC using individual patient-level data from two cohorts: the Surveillance, Epidemiology, and End Results (SEER)-Medicare database and the publicly available UROMOL dataset. METHODS: SEER-Medicare linked data was used to identify patients, aged ≥66 years, with clinical stage Ta, Tis and T1 NMIBC between 2005-2019 (n=32 225). Multivariable competing-risks Cox regression analyses were used to examine the association between age and recurrence (defined as receipt of TURBT ≥3 months after index diagnosis of NMIBC or progression), progression (defined as receipt of definitive treatment for bladder cancer) and bladder cancer-specific mortality rates after adjusting for demographic-, cancer- and treatment-related variables. Using the UROMOL cohort (n=834), age disparities across transcriptomic, genomic and spatial proteomic domains were assessed. Differences between groups were testing using Pearson’s Chi-square test or Fisher’s test for categorical variables. RESULTS: Analysis of the SEER-Medicare cohort revealed 10-year recurrence rates of 60.9%, 61.1% and 60.4% in patients aged 66-70 yrs, 71-80 yrs and ≥81 yrs, respectively; 10-year progression rates of 29.3%, 32.2% and 38.2%, respectively; and 10-year bladder-cancer specific mortality rates of 5.5%, 7.9% and 14.3%, respectively. Age ≥ 81 yrs was associated with a higher risk of progression (HR 1.32, 95% CI 1.25-1.40, p<0.001) and bladder cancer-specific mortality (HR 2.58, 95% CI 2.27-2.95, p<0.001). Analysis of UROMOL 2021 transcriptomic classes revealed that Class 2a was more frequently observed in older patients (34% in >75 yrs vs. 22% in ≤65 yrs; p=0.004). Compared to patients <65 yrs, those aged >75 yrs were more likely to have TP53 pathway change (54% vs. 38%; p=0.032). UROMOL genomic class 3 was more frequently observed in patients >75 yrs (42% vs. 24%; p=0.001), who also had higher amounts of altered genome (median: 337.7Mb vs. 168.2Mb; p<0.001). No significant differences were observed in immune cell infiltration scores between age groups. CONCLUSIONS: Among SEER-Medicare patients with NMIBC, advanced age is associated with higher risks of progression and bladder-cancer specific mortality. These results reflect age-related molecular biological differences observed across transcriptomic and genomic domains. Source of Funding: Niyati Lobo was supported by The Urology Foundation-Fulbright Scholar Award © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e826 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Niyati Lobo More articles by this author Akshay Sood More articles by this author Zhigang Duan More articles by this author Wei Shen Tan More articles by this author Valentina Grajales More articles by this author Sia Viborg Lindskrog More articles by this author Lars Dyrskjøt More articles by this author Aarhus More articles by this author Denmark More articles by this author Hui Zhao More articles by this author Sharon Giordano More articles by this author Stephen B. Williams More articles by this author Ashish M. Kamat More articles by this author Expand All Advertisement PDF downloadLoading ...

P1323: PREDICTION OF NON-RELAPSE MORTALITY BY EASIX AND HCT-CI SCORES IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA UNDERGOING ALLOGENEIC STEM CELL TRANSPLANT

Background: The endothelial activation and stress index (EASIX) score has been shown as a predictor of non-relapse morality (NRM) after allogeneic stem cell transplantation (alloSCT) [Luft, et al. Bone Marrow Transplant. 2020;55(3):553–561]. However, data in patients with chronic myelomonocytic leukemia (CMML) is limited. Aims: Our goal was to study the risk of NRM and the impact on overall survival (OS) by EASIX and HCT-CI scores in patients with CMML undergoing alloSCT. Methods: We retrospectively evaluated patients with CMML who underwent alloSCT. We reviewed patient demographics, disease characteristics, and post-transplant outcomes. EASIX score was calculated using the formula: LDH (U/L) × Creatinine (mg/dL) / platelet count (10^9/L) and analyzed based on log2 transformed values. EASIX score was calculated within 45 days of alloSCT, but prior to starting conditioning therapy. The optimal log2 EASIX score cutoff was determined using maximally selected log-rank statistics. Patients with an HCT-CI score ≥ 3 were considered to have a high HCT-CI score. Results: Between, January 1992 to February 2019, a total of 70 CMML patients underwent alloSCT, 13 patients were excluded due to incomplete records and 57 patients (39 males and 18 females) were evaluated for the purposes of the study. CMML-0 was the most common subtype (21 patients, 36.8%), followed by CMML-2 (19 patients, 33.3%)) and CMML-1 (17 patients, 29.8%). Seventeen (29.8%) patients had progressed to CMML blast phase before alloSCT. Of the entire cohort, 18 (31.6%) patients were in complete remission at the time of alloSCT. Median age at transplant for the entire cohort was 58 years (range: 18 – 73 years). Median time of follow-up was 2 years (range: 11 days – 16 years). Median OS was 2 years, with a 3-year OS rate of 49.1%. Eighteen (31.6%) patients were alive at last follow-up. The median log2 EASIX score was 0.88 (range -2.29 to 5.91). The optimal log2 EASIX score cutoff using the maximally selected LogRank statistics was found to be 2.33. Patients with log2 EASIX score > 2.33 were considered to have a high EASIX score. Thirteen (22.8%) patients had a high EASIX score and 44 (77.2%) had a low EASIX score. The cumulative incidence of NRM among patients with high EASIX score was significantly higher compared to those with low EASIX score at 100 days (30.8% vs 0%, p < 0.001), at 1-year (46.2% vs 9.1%, p = 0.002) and at 3-years (53.8% vs 15.9%, p = 0.003) after alloSCT (Figure 1A). A total of 55 patients were evaluated for HCT-CI score, of whom 30 (54.54%) were found to have a low HCT-CI score, i.e., HCT-CI < 3, and 25 (45.45%) were found to have a high HCT-CI score. The median HCT-CI score was 2 (range: 0-7). NRM after alloSCT among patients with high HCT-CI score was not significantly different compared to those with low HCT-CI scores at 100 days (8% vs 6.7%, p = 0.85), at 1 year (24% vs 13.3%, p = 0.33), and at 3 years (24% vs 26.7%, p = 0.92) after alloSCT (Figure 1B). In multivariate competing risk regression analysis, a high EASIX score significantly increased NRM at 3 year (HR 4.14, 95% CI: 1.42 – 12.01, p = 0.009). Patients with a high log2 EASIX score had significantly worse OS at 3 years (median 8 months vs. NA, p = 0.007). OS at 3 years did not differ among patients with high vs. low HCT-CI scores (median 1.02 years vs. NA, p = 0.38). Image:Summary/Conclusion: In CMML, EASIX predicted NRM following alloSCT. EASIX was a better predictor of NRM compared to HCT-CI in this patient population. Larger patient cohort is required to confirm our findings.

PD26-09 PRIMARY TA HIGH GRADE BLADDER TUMORS: DETERMINATION OF THE RISK OF PROGRESSION

You have accessJournal of UrologyCME1 May 2022PD26-09 PRIMARY TA HIGH GRADE BLADDER TUMORS: DETERMINATION OF THE RISK OF PROGRESSION Fahad Quhal, Keiichiro Mori, Ekaterina Laukhtina, Benjamin Pradere, Francesco Soria, Marco Moschini, Alberto Briganti, Pierre I. Karakiewicz, and Shahrokh F. Shariat Fahad QuhalFahad Quhal More articles by this author , Keiichiro MoriKeiichiro Mori More articles by this author , Ekaterina LaukhtinaEkaterina Laukhtina More articles by this author , Benjamin PradereBenjamin Pradere More articles by this author , Francesco SoriaFrancesco Soria More articles by this author , Marco MoschiniMarco Moschini More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Pierre I. KarakiewiczPierre I. Karakiewicz More articles by this author , and Shahrokh F. ShariatShahrokh F. Shariat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002574.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: TaG3 bladder cancer is an under-investigated disease and because of its rarity it is commonly studies together with T1G3 disease. We sought to exclusively study TaG3 disease and to determine the factors associated with disease progression. METHODS: Of 3505 patients with NMIBC, 285 patients had primary TaG3 and with no concomitant carcinoma in-situ. The median follow-up was 43 months; 70% of the patients received adjuvant BCG. RESULTS: Progression to ≥pT1 occurred in 21 patients (7.4%). In a multivariable competing-risk regression analysis, intravesical BCG was significantly associated with a lower risk of progression to ≥pT1 (HR 0.23, 95%CI 0.08-0.64, p=0.005). Recurrence in the first year of diagnosis was significantly associated with an increased risk of stage progression to ≥pT1 (HR 7.81, 95%CI 2.50-24.44, p<0.001). Progression to ≥T2 was observed in 9 patients (3.2%). In univariable competing-risk regression analyses, intravesical BCG was significantly associated with a lower risk of progression to ≥pT2 (HR 0.11, 95%CI 0.04-0.47, p=0.003). On the other hand, recurrence in the first year of diagnosis was significantly associated with an increased risk of stage progression to ≥T2 (HR 7.12, 95%CI 1.50-33.77, p=0.013). In a subgroup of 199 patients who were treated with BCG, there was no statistically significant association between tumor recurrence in the 1st year of diagnosis and stage progression to ≥pT1 (p=0.14) or ≥pT2 (p=0.19). CONCLUSIONS: Patients with TaG3 bladder cancer are considered high risk but if appropriately treated with BCG that risk is considerably mitigated. Our data support that TaG3 without concomitant CIS should not be considered as aggressive as T1G3 as it has a lower risk of progression to muscle-invasive bladder cancer (MIBC). Recurrence in the first year after diagnosis is the strongest predictor of progression to MIBC. Source of Funding: No funding © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e491 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fahad Quhal More articles by this author Keiichiro Mori More articles by this author Ekaterina Laukhtina More articles by this author Benjamin Pradere More articles by this author Francesco Soria More articles by this author Marco Moschini More articles by this author Alberto Briganti More articles by this author Pierre I. Karakiewicz More articles by this author Shahrokh F. Shariat More articles by this author Expand All Advertisement PDF DownloadLoading ...

PD27-06 INCREASED AWARENESS OF SURGICAL OUTCOMES IMPROVES LONG-TERM FUNCTIONAL OUTCOMES AFTER ROBOT-ASSISTED RADICAL PROSTATECTOMY. A PROSPECTIVE ASSESSMENT FOLLOWING IMPLEMENTATION OF PROSPECTIVE DATA COLLECTION

PD27-06 INCREASED AWARENESS OF SURGICAL OUTCOMES IMPROVES LONG-TERM FUNCTIONAL OUTCOMES AFTER ROBOT-ASSISTED RADICAL PROSTATECTOMY. A PROSPECTIVE ASSESSMENT FOLLOWING IMPLEMENTATION OF PROSPECTIVE DATA COLLECTION