Hazard Ratio For Overall Mortality Research Articles

Artificial Intelligence Reveals Distinct Prognostic Subgroups of Muscle-Invasive Bladder Cancer on Histology Images.

Muscle-invasive bladder cancer (MIBC) is a highly heterogeneous and costly disease with significant morbidity and mortality. Understanding tumor histopathology leads to tailored therapies and improved outcomes. In this study, we employed a weakly supervised learning and neural architecture search to develop a data-driven scoring system. This system aimed to capture prognostic histopathological patterns observed in H&E-stained whole-slide images. We constructed and externally validated our scoring system using multi-institutional datasets with 653 whole-slide images. Additionally, we explored the association between our scoring system, seven histopathological features, and 126 molecular signatures. Through our analysis, we identified two distinct risk groups with varying prognoses, reflecting inherent differences in histopathological and molecular subtypes. The adjusted hazard ratio for overall mortality was 1.46 (95% CI 1.05-2.02; z: 2.23; p = 0.03), thus identifying two prognostic subgroups in high-grade MIBC. Furthermore, we observed an association between our novel digital biomarker and the squamous phenotype, subtypes of miRNA, mRNA, long non-coding RNA, DNA hypomethylation, and several gene mutations, including FGFR3 in MIBC. Our findings underscore the risk of confounding bias when reducing the complex biological and clinical behavior of tumors to a single mutation. Histopathological changes can only be fully captured through comprehensive multi-omics profiles. The introduction of our scoring system has the potential to enhance daily clinical decision making for MIBC. It facilitates shared decision making by offering comprehensive and precise risk stratification, treatment planning, and cost-effective preselection for expensive molecular characterization.

1422-P: The Impact of Type 2 Diabetes Mellitus on the Clinical Outcome of Breast Cancer

Objectives: Women with breast cancer and diabetes have worse outcomes than those with breast cancer without diabetes. The objective of this study was to investigate the impact of pre-existing diabetes on breast cancer prognosis. Methods and Materials: This was a retrospective observational study using Cancer database from a single tertiary center. The study population included women aged ≥20 years with breast cancer diagnosed between 1 January 2014 and 31 December 2018. Patients were categorized by diabetes status (T2D: n=111, non-T2D: n= 889). The clinicopathological features and outcomes were collected and compared between women with and without diabetes. Cox proportional hazard regression was used to estimate adjusted hazard ratios for overall mortality. Results: Compared to non-T2D patients, T2D patients were significantly older, had higher BMI, were more post-menopausal state at breast cancer diagnosis, had more comorbid conditions, and were in lower educational states. There were no statistically significant differences in tumor characteristics, including metastasis, lymph nodes, grade, and extent of surgery. Women with T2D had a significantly increased risk of overall mortality after adjusting for demographic and traditional risk factors for breast cancer (HR=2.15; 95%CI=1.10-4.20). Compared to patients with pre-existing T2D (n=111), patients with newly diagnosed T2D after receiving a breast cancer diagnosis (n=34) had a lower risk of breast cancer recurrence (HR=0.30; 95%CI=0.10-0.94). Conclusion: Our study showed that pre-existing T2D and T2D itself increase the risk of recurrence and total mortality among patients with breast cancer. These findings provide important prognostic information for the treatment of women with both T2D and breast cancer. Therefore, diabetes deserves additional attention to assess possible causal relationships that potentially could be modified to improve outcomes. Disclosure Y.Kim: None. I.Goak: None. H.Jin: None. T.Park: None. K.Lee: None.

Trends of Lymph Node Outcomes in Partial Cystectomy for Muscle-Invasive Urothelial Carcinoma of the Bladder

IntroductionLocal tumor invasion depth has been associated with lymph node metastasis in urothelial carcinoma, and, for muscle-invasive bladder cancer (MIBC), pelvic lymph node dissection (PLND) is a critical step in curative surgery. Gold standard treatment includes radical cystectomy (RC), but partial cystectomy (PC) is an important bladder-preserving modality reserved for patients with certain favorable prognostic indicators. There is poor evidence concerning the utility of PLND in PC and we seek to further define its role by comparing survival outcomes when PLND was cursory or omitted. MethodsA retrospective analysis of 13,652 cT2N0M0 patients who underwent PC or RC between 2004 and 2016 was performed using the National Cancer Database. Patients undergoing PC were stratified by the presence of PLND as well as by node yield >15. The primary outcome was overall survival, analyzed using the Kaplan-Meier Method and multivariable Cox-proportional hazards regression. Multivariable models were adjusted for confounding clinicopathologic variables. ResultsFrom 2004 to 2016, PLND in PC increased from 44% to 57% with RC remaining over 90%. Compared to RC, PC was approximately twice as likely to be performed at community centers and approached laparoscopically/robotically (P < .001). When stratifying PC PLND yield into 1 to 15 and > 15 compared to PC without PLND, the adjusted hazard ratios for overall mortality were 0.78 and 0.54, respectively (P < .05). ConclusionsPC patients had a significantly lower rate of PLND compared to RC and improved survival when performed versus PC alone. Furthermore, increased node yield was associated with a larger reduction of adjusted mortality hazard. For MIBC patients that are appropriately selected for PC, high-yield PLND should be prioritized given the significantly improved survival outcomes.

Abstract 5220: Prediagnostic vitamin D status and colorectal cancer survival by vitamin D-binding protein isoforms in the US cohorts

Abstract Background: Lower levels of 25-hydroxyvitamin D [25(OH)D], a major form of circulating vitamin D, have consistently been associated with higher mortality among colorectal cancer (CRC) patients, though the dose-response relation is not well characterized {Ng 2008; Fedirko 2012; Wesa 2015; Zgaga 2014}. A study showed a strong effect modification (P for interaction = 0.0002) {Gibbs 2020} by Gc2 (or, vitamin D-binding protein) isoform where patients with the isoform had significantly higher mortality if they had deficient vitamin D levels. However, it is unknown whether this association differs by Gc isoforms in other populations. Methods: We examined the association between prediagnostic 25(OH)D levels and overall and CRC-specific mortality among CRC patients within the two ongoing prospective US cohorts: Nurses’ Health Study and Health Professionals Follow-Up Study. Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). We evaluated potential nonlinear association using the restricted cubic splines and assessed effect modification by Gc2 isoform with stratified analyses. Individuals with the Gc rs4588 CC, CA and AA genotypes were classified as having Gc1-1, Gc1-2, and Gc2-2 isoforms, respectively. Participants with a minor allele at Gc rs4588 (rs4588*CA or rs4588*AA genotypes) were defined as having the Gc2 isoform. Results: A total of 588 patients were observed until the date of death or last follow-up in 2018, whichever came first. Deficient versus sufficient 25(OH)D concentrations (&amp;lt;30 vs ≥50 nmol/L) were associated with higher overall mortality (HR, 2.06; 95% CI, 1.34-3.18) and suggestively with higher CRC-specific mortality (HR, 1.51; 95% CI, 0.75-3.07). Spline results showed that the potential beneficial role of vitamin D plateaued around 50 nmol/L (P for nonlinearity = 0.04). The HRs for overall mortality comparing deficient versus sufficient concentrations were 2.43 (95% CI, 1.26-4.70) for patients with Gc1-1 isoform (rs4588 CC) and 1.63 (95% CI, 0.88-3.02) for patients with Gc1-2 or Gc2-2 (rs4588 CA or AA) isoforms (P for interaction = 0.54). The HRs for CRC-specific mortality were 1.18 (95% CI, 0.27-5.14) for patients with Gc1-1 isoform and 1.41 (95% CI, 0.62-3.24) for patients with Gc1-2 or Gc2-2 isoforms (P for interaction = 0.94). Conclusions: We found that lower 25(OH)D levels up to 50 nmol/L were associated with higher overall mortality, but this association did not differ by Gc isoforms in the two US cohorts. Citation Format: Hanseul Kim, Chen Yuan, Long H. Nguyen, Kimmie Ng, Edward L. Giovannucci. Prediagnostic vitamin D status and colorectal cancer survival by vitamin D-binding protein isoforms in the US cohorts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5220.

Cibo, salute e mitigazione del cambiamento climatico in Italia.

to provide evidence on how diet can influence health, greenhouse gas (GHG) emissions, and land use. cohort study. data collected in the EPIC Italy cohort (N. 47,749). hazard ratios (HR) for overall mortality and for cancer incidence in association with a sustainable diet (EAT-Lancet). sustainable diets are characterized by lower associated GHG emissions and lower land use (LU). Adherence to the guidelines proposed by the EAT-Lancet Commission was considered. This diet was associated with lower HRs for mortality and cancer incidence in EPIC Italy, estimated with Cox models accounting for potential confounders and stratified by sex. The hazard ratios for overall mortality showed a dose-response relationship with quartiles of diets associated with high GHG emissions, land use, and high distance from the EAT-Lancet diet calculated using a novel index, the EAT-Lancet distance index (EatDI). The HR for overall cancer incidence was also higher in the population with non-sustainable diets. the association among dietary GHG emissions, LU, and EatDI and overall mortality and overall cancer incidence suggests that promoting diets with low associated environmental impact can be an effective mitigation strategy with important co-benefits.

Prediagnostic Vitamin D Status and Colorectal Cancer Survival by Vitamin D Binding Protein Isoforms in US Cohorts.

Lower 25-hydroxyvitamin D (25(OH)D) levels have consistently been associated with higher mortality among participants with colorectal cancer (CRC). To investigate whether the association between 25(OH)D and CRC mortality differs according to vitamin D binding protein (also known as Gc) isoforms. We examined the association between prediagnostic 25(OH)D levels and overall and CRC-specific mortality among participants with CRC within 2 prospective US cohorts. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs. 588 participants with CRC were observed until the date of death or last follow-up (2018), whichever came first. Deficient vs sufficient 25(OH)D concentrations (<30 vs ≥50 nmol/L) were associated with higher overall mortality (HR 2.06; 95% CI 1.34-3.18) but not with CRC-specific mortality (HR 1.51; 95% CI 0.75-3.07). The HRs for overall mortality comparing deficient vs sufficient concentrations were 2.43 (95% CI 1.26-4.70) for those with the Gc1-1 isoform (rs4588 CC) and 1.63 (95% CI 0.88-3.02) for those with the Gc1-2 or Gc2-2 (rs4588 CA or AA) isoform (P for interaction = .54). The HRs for CRC-specific mortality were 1.18 (95% CI 0.27-5.14) for those with the Gc1-1 isoform and 1.41 (95% CI 0.62-3.24) for those with the Gc1-2 or Gc2-2 isoform (P for interaction = .94). In these 2 US cohorts, we found that lower 25(OH)D levels were associated with higher overall mortality, but this association did not differ by Gc isoforms.

Abstract 13132: Uncontrolled Diabetes is Associated With Adverse Cardiovascular Disease Outcomes in Those With Stage B Heart Failure

Background: Among persons with stage B heart failure (HF) (subclinical cardiac dysfunction), diabetes is associated with markedly increased risk of progression to clinical HF. Whether stage B HF indicates greater risk for other cardiovascular disease (CVD) outcomes in the presence of diabetes is unknown. Methods: We included ARIC Visit 5 (2011-13) participants without clinical HF who met criteria for stage A (HF risk factors) or stage B (subclinical cardiac dysfunction by echocardiogram or elevated cardiac biomarkers) HF. Across HF stages A and B, we calculated incidence rates and their differences and used Cox models to estimate hazard ratios for overall mortality, CVD mortality, coronary heart disease (CHD), and HF associated with controlled diabetes (HbA1c &lt;7%) and uncontrolled diabetes (HbA1c ≥ 7%), compared to no diabetes. Results: 4,774 participants (mean age 75.4, 58.3% women, 20.2% black) were followed for a median 7.3 years, with 867 deaths, 237 CVD deaths, 228 CHD events, and 470 HF events. There were significant additive interactions (increased absolute risk) associated with uncontrolled diabetes (vs. no diabetes) for total mortality, CVD death, CHD, and HF for stage B, but not stage A (Table). The incidence rate differences (per 1000 person-years) associated with uncontrolled diabetes (vs. no diabetes) were greater in stage B vs stage A for all outcomes (Table). In multivariable adjusted models, uncontrolled diabetes (vs. no diabetes) was associated with statistically significant hazard ratios (increased relative risk) for all CVD outcomes in stage B, but did not have significant associations with any CVD outcomes in stage A (Table). Conclusion: In stage B HF, diabetes is associated with global CVD risk. Intensive preventive efforts to avert various forms of CVD may be indicated for those with diabetes and subclinical cardiac dysfunction.

Candidacy for heart transplantation in adult congenital heart disease patients: a cohort study

Abstract Objective The object of the present study is to evaluate factors precluding heart transplantation (HTx) in adult congenital heart disease patients (ACHD) with end-stage heart failure (HF) referred for HTx evaluation. Methods This retrospective cohort study enrolled consecutive ACHD patients considered for HTx in our institution between 2014 and 2020 and patients receiving HTx between 2001 and 2013. HTx refusal due to poor candidacy status for excess risk of mortality after transplantation, served as the main study outcome. Results Between 2014 and 2020, 46 ACHD patients were evaluated for HTx, 14 ACHD patients underwent HTx between 2001 and 2013. We compared clinical, anatomical and demographic data of 41 patients suitable for transplantation (including both listed/transplanted patients, not yet listed because too well and patients who chose to refuse transplantation) with 15 patients refused after screening (excluding 4 patients with ongoing screening). Risk factors for refusal were: multiple high risk features (odds ratio [OR]: 3.6; 95% confidence interval [CI]: 1.1 to 12.9; p 0.048); anatomical factors (OR: 14.5; 95% CI: 3.1 to 68.4; p 0.001), out-of-center ACHD/HTx program referral (OR: 5.3; 95% CI: 1.5 to 19.0; p 0.01). HTx refusal identifies a high risk ACHD patient subgroup (hazard ratio for overall mortality: 3.1; 95% CI: 1.1 to 8.3; p 0.02). Conclusions In our study risk factors for refusal from HTx are adverse anatomical features, multiple conventional HTx high risk factors and out-of-center referral. ACHD patients refused from HTx present shorter time to death. Efforts to increase HTx candidacy are strongly necessary for this growing population. Funding Acknowledgement Type of funding sources: None.

Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study.

BackgroundWomen treated for breast cancer (BC) often suffer genitourinary syndrome of menopause. These symptoms may be alleviated by vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT). However, there are concerns of risks of recurrence of BC and death following treatment.MethodsOur study included longitudinal data from a national cohort of postmenopausal women, diagnosed 1997-2004 with early-stage invasive estrogen receptor–positive nonmetastatic BC, who received no treatment or 5 years of adjuvant endocrine therapy. We ascertained prescription data on hormone therapy, VET or MHT, from a national prescription registry. We evaluated mortality and risk of recurrence associated with use of VET and MHT vs non-use using multivariable models adjusted for potential confounders.ResultsAmong 8461 women who had not received VET or MHT before BC diagnosis, 1957 and 133 used VET and MHT, respectively, after diagnosis. Median follow-up was 9.8 years for recurrence and 15.2 years for mortality. The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for VET (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for VET and MHT, respectively.ConclusionsIn postmenopausal women treated for early-stage estrogen receptor–positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.

410-P: Preoperative Diabetes Optimization and Clinical Outcomes

A diabetes optimization pathway for elective surgical patients with uncontrolled diabetes (A1c&amp;gt; 8%) has been in place at our institution for the last 5 years. Although we reported on improvement in glucose control before surgery in patients undergoing the intervention, impact on longer-term clinical outcomes was not known. We extracted EPIC medical record data for adult surgical patients in the diabetes optimization program between January 2016 and October 2021 (n=85) . The control group had uncontrolled diabetes and underwent surgery but had no intervention (n=1,111) . Logistic regression, GLM and Cox proportional hazard models were used to investigate relationship with 30 day complications, glucose at surgery, and overall mortality. Table 1 shows bivariate comparisons for the study cohort. The rates of perioperative complications were numerically lower in the intervention group, however, were not statistically significant. Unadjusted regression analyses found significantly lower glucose at surgery (β =-14.19, 95% CI=-27.94,-0.43) , and significantly lower hazard ratio for overall mortality (HR=0.34, 95% CI=0.13,0.93) for the intervention. After adjusting for demographics, clinical risk, and comorbidities, only glucose at surgery maintained significance (β =-16.89, 95% CI=-30.83,-2.95) . Prospective studies or a larger sample may be needed to confirm findings. Disclosure C.E.Mendez: Advisory Panel; Monarch Medical Technologies . R.J.Walker: None. E.Garacci: None. K.Pfeifer: None.

Candidacy for heart transplantation in adult congenital heart disease patients: A cohort study

ObjectiveThe object of the present study is to evaluate factors precluding heart transplantation (HTx) in adult congenital heart disease patients (ACHD) with end-stage heart failure (HF) referred for HTx evaluation. MethodsThis retrospective cohort study enrolled consecutive ACHD patients considered for HTx in our institution between 2014 and 2020 and patients receiving HTx between 2001 and 2013. HTx refusal due to poor candidacy status for excess risk of mortality after transplantation served as the main study outcome. ResultsBetween 2014 and 2020, 46 ACHD patients were evaluated for HTx, 14 ACHD patients underwent HTx between 2001 and 2013 (final sample size 60 patients). We compared clinical, anatomical and demographic data of 41 patients suitable for transplantation with 15 patients refused after screening (excluding 4 patients with ongoing screening). Risk factors for refusal were: multiple high risk features (odds ratio [OR]: 3.6; 95% confidence interval [CI]: 1.1 to 12.9; p 0.048); anatomical factors (OR: 14.5; 95% CI: 3.1 to 68.4; p 0.001), out-of-center ACHD/HTx program referral (OR: 5.3; 95% CI: 1.5 to 19.0; p 0.01). HTx refusal identifies a high risk ACHD patient subgroup (hazard ratio for overall mortality: 3.1; 95% CI: 1.1 to 8.3; p 0.02). ConclusionsIn our study risk factors for refusal from HTx are adverse anatomical features, multiple conventional HTx high risk factors and out-of-center referral. ACHD patients refused from HTx present shorter time to death. Efforts to increase HTx candidacy are strongly necessary for this growing population.

Intake of local vegetables and decreased risk of mortality and cancer incidence in Amami island regions, Japan.

There is emerging scientific evidence of the health benefits of traditional food plants at both molecular and folk remedy levels; however, epidemiological observations are limited. The Amami island region of Japan has a variety of unique traditions conserved till today, where a cohort study was conducted in 2005. The objective of this study was to investigate the associations between the intake of common and local vegetables and the risk of mortality and cancer incidence in Amami. Participants were enrolled from the general population of Amami as part of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. In total, 5,015 participants (2,053 men and 2,962 women) aged 35-69 years were enrolled in this study. They were followed up to obtain information on movement, death, and cancer incidence. The hazard ratios (HRs) and 95% CIs were estimated using the Cox proportional hazard model after adjusting for potential confounding factors. A significant inverse association was observed between cabbage intake and the HRs for overall mortality (p for trend=0.046) and lung cancer incidence (p=0.016). Intake of handama and togan as local vegetables was associated with decreased HRs for overall mortality (p=0.019 and 0.036, respectively). While the molecular and biochemical reasoning and residual confounding factors behind this association remain unclear, the findings of this study suggest that the dietary lifestyle in Amami has a positive impact on the residents, which can significantly decrease mortality risk.

488 Candidacy for heart transplantation in adult congenital heart disease patients: a single-centre, retrospective, cohort study

Abstract Aims End-stage heart failure (HF) is the leading cause of death in adult congenital heart disease (ACHD) population. Heart transplantation (HTx) improves prognosis in ACHD end-stage HF but candidacy evaluation, referral pattern, and correct listing timing are not fully elucidated in this population. To evaluate factors associated to refusal from Htx in ACHD patients with end-stage HF referred for HTx evaluation. Methods and results This retrospective cohort study enrolled consecutive ACHD patients considered for HTx in our institution between 2014 and 2020 and patients undergone HTx between 2000 and 2013. Refusal from HTx served as primary study endpoint. Between 2014 and 2020, 46 ACHD patients were evaluated for HTx, 14 ACHD patients underwent HTx between 2001 and 2013. The main indication to HTx in patients with single ventricle physiology was Fontan failure, while in patients with systemic left ventricle and systemic right ventricle physiology, it was systemic ventricular dysfunction. We compared clinical, anatomical and demographic data of 41 patients accepted for transplantation with 15 patients refused after screening. Risk factors for refusal were: coexistence of multiple high risk features [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.1–12.9; P 0.048]; anatomical factors (OR: 14.5; 95% CI: 3.1–68.4; P 0.001), out-of-centre ACHD/HTx program referral (OR: 5.3; 95% CI: 1.5 to 19.0; p 0.01). Survival in patients accepted for HTx was significantly higher than survival in patients declined from HTx with landmark comparison at 20, 40 and 60 months of 87%, 78%, and 72% vs. 70%, 59%, and 20%, respectively. HTx refusal identifies a high risk ACHD patient subgroup (hazard ratio for overall mortality: 3.1; 95% CI: 1.1–8.3; P 0.02). Conclusions In our study risk factors for refusal from HTx are adverse anatomical features, coexistence of multiple conventional HTx high risk factors and out-of-centre referral. ACHD patients refused from HTx present shorter time to death. Efforts to increase HTx candidacy and to reduce referral delay in tertiary centre are strongly necessary for this growing population.

Timing of steroid use and outcomes of immune checkpoint inhibitor: A population based study.

6590 Background: Immune checkpoint inhibitors (ICIs) have rapidly become the treatment of choice for multiple cancer types. However, the relationship between the timing of immunosuppressive agents, such as steroids use, preceding ICI initiation and subsequent treatment outcomes remains unknown due to lack of data. This study was undertaken to address this knowledge gap. Methods: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data to identify patients with melanoma receiving Ipilimumab, Nivolumab, Pembrolizumab, or Ipilimumab/Nivolumab combination in 2010-2015. Last steroid exposure within 12 months prior to ICI use was categorized (none, 0-1, 1-3, and 3-12 months prior). Cox models were used to generate covariate-adjusted hazard ratios of overall mortality following ICI initiation. Because the hazards were not proportional over time, we allowed the hazard ratios to differ in three periods (&lt;3, 3-6, and more than 6 months post ICIs). Results: We identified 3,149 melanoma patients (median age 68 years) using ICIs; among these 1,352 received steroid within 12 months prior. Steroid use within 1 month prior to using ICIs was associated with a 93% and 102% increased risk in overall mortality within 3 months and 3-6 months post ICI initiation. The risk diminished over time (Table). A similar pattern was observed for steroid use 1-3 months prior. Steroid use beyond 4 months prior to ICI was not associated with increased mortality. Conclusions: This was the first major study to document that timing of steroid use prior to ICI is associated with the risk of mortality and how the increased risk diminishes over time. Further studies are warranted to confirm the findings and understand potential mechanisms.[Table: see text]

Perianal Fistula-Associated Carcinoma in Crohn's Disease: A Multicentre Retrospective Case Control Study.

Carcinoma associated with perianal fistula in Crohn's disease is a pending threat for patients. This study aimed to improve understanding and facilitate development of diagnostic and therapeutic strategies. A retrospective case-control study was conducted at four German hospitals. The analysis included 40 patients with proven malignancy associated with perianal Crohn's fistulas and 40 randomly selected controls with fistulizing perianal Crohn's disease. Differences between groups were analysed and multivariate calculations were performed to describe risk factors for oncological outcomes. Histology revealed adenocarcinoma in 33/40 patients and squamous cell carcinoma in 7/40 patients. Compared to fistula patients without carcinoma, patients with malignancies associated with fistula had a diagnosis of Crohn's disease at younger age. Crohn's disease lasted longer in patients with malignancy [25.8 ± 9.0 vs 19.6 ± 10.4; p = 0.006]. Fistula-related findings differed significantly between the two groups. Signs of complicated and severe fistulation including complex anatomy and chronic activity occurred significantly more often in patients with malignancy associated with fistula. Significant multivariate hazard ratios for overall mortality and progression-free survival were shown for histological type of cancer, metastatic disease and R1 resection. Overall survival was 45.1 ± 28.6 months and the 5-year survival rate was 65%. In patients with adenocarcinoma or squamous cell carcinoma associated with perianal fistula in Crohn's disease, fistula characteristics determine the risk of malignancy. Early diagnosis influences outcomes, while treatment of chronic fistula activity may be key to preventing malignancy. Expert multimodal therapy is paramount for successful treatment of perianal fistula-associated malignancies.

Prognosis of pregnancy-associated breast cancer: a meta-analysis

BackgroundPregnancy-associated breast cancer (PABC) is defined as breast cancer that is diagnosed during pregnancy and/or the postpartum period. Definitions of the duration of the postpartum period have been controversial, and this variability may lead to diverse results regarding prognosis. Moreover, evidence on the dose-response association between the time from the last pregnancy to breast cancer diagnosis and overall mortality has not been synthesized.MethodsWe systematically searched PubMed, Embase, and the Cochrane Library for observational studies on the prognosis of PABC published up to June 1, 2019. We estimated summary-adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). Subgroup analyses based on diagnosis time, PABC definition, geographic region, year of publication and estimation procedure for HR were performed. Additionally, dose-response analysis was conducted by using the variance weighted least-squares regression (VWLS) trend estimation.ResultsA total of 54 articles (76 studies) were included in our study. PABC was associated with poor prognosis for overall survival (OS), disease-free survival (DFS) and cause-specific survival (CSS), and the pooled HRs with 95% CIs were 1.45 (1.30–1.63), 1.39 (1.25–1.54) and 1.40 (1.17–1.68), respectively. The corresponding reference category was non-PABC patients. According to subgroup analyses, the varied definition of PABC led to diverse results. The dose-response analysis indicated a nonlinear association between the time from the last delivery to breast cancer diagnosis and the HR of overall mortality (P < 0.001). Compared to nulliparous women, the mortality was almost 60% higher in women with PABC diagnosed at 12 months after the last delivery (HR = 1.59, 95% CI 1.30–1.82), and the mortality was not significantly different at 70 months after the last delivery (HR = 1.14, 95% CI 0.99–1.25). This finding suggests that the definition of PABC should be extended to include patients diagnosed up to approximately 6 years postpartum (70 months after the last delivery) to capture the increased risk.ConclusionThis meta-analysis suggests that PABC is associated with poor prognosis, and the definition of PABC should be extended to include patients diagnosed up to approximately 6 years postpartum.

The Prevalence and Incidence of Insomnia in Korea during 2005 to 2013.

ObjectiveThe aim of this study was to estimate the progress of insomnia prevalence and incidence over the past several years. Also, this study compared survival rates between individuals with and without insomnia. MethodsThe National Health Insurance Service-National Sample Cohort (NHIS-NSC) from 2002–2013 was used for this study. Prevalent cases of insomnia were defined using ICD-10 codes F51.0 or G47.0, or a prescription of sedatives. Cox’s proportional hazard analysis was conducted to compare survival rates between insomnia patients and people without insomnia. ResultsIn 2013, there were 46,167 (5.78%) insomnia patients over 20 years old in this cohort. Insomnia was more common among women and the elderly. Annual incidence over the past several years remained steady but the prevalence increased. The survival of insomnia patients was lower than that of people without insomnia, and the hazard ratio for overall mortality was 1.702 (p<0.001). ConclusionThis large-scale population-based cohort study provided current epidemiologic indicators of insomnia in the Korean general population.

Association between pet ownership and cardiovascular risks and mortality: a systematic review and meta-analysis.

: The aim of the study was to determine the association between pet ownership and cardiovascular risk factors and mortality. Electronic search was conducted through nine databases including PubMed for relevant publications reporting cardiovascular events and mortality among pet owners. Meta-analysis was used to pool the results. Of a total of 2818 reports screened, 26 studies were included in our systematic review and meta-analysis. Higher survival rate was observed in the pet owners group after pooling nonadjusted and adjusted hazard ratios for cardiovascular mortality at 0.73 [95% confidence interval (CI) 0.62-0.86] and 0.81 (0.68-0.97), respectively. A similar trend was observed for the pooled nonadjusted hazard ratio for overall mortality 0.73 (0.62-0.87) but not the adjusted hazard ratio 0.40 (0.04-3.78). Cat owners have a reduction in cardiovascular mortality but not overall mortality after pooling the adjusted hazard ratio 0.79 (0.63-0.99) and 1.04 (0.90-1.21), respectively. However, no significant association between dog owners and survival rate was observed for overall and cardiovascular-specific mortality. Pet owners had significantly lower heart rate (mean difference 95% CI: -2.32 (-3.07 to -1.57), mean arterial pressure -2.60 (-4.25 to -0.95) and SBP -1.69 (-3.06 to -0.31) but not DBP -0.23 (-1.05 to 0.60). No significant difference was observed between pet owners and nonpet owners in prevalence of hypertension. Our study draws attention to the beneficial effects of the human--pet bond; therefore, we recommend pet acquisition for better cardiovascular outcomes after controlling for zoonotics and pet-induced allergies.

Immune checkpoint status and tumor microenvironment in vulvar squamous cell carcinoma.

Vulvar squamous cell carcinoma accounts for 5% of cancers of the female genital tract. Current guidelines recommend wide local excision with negative surgical margins as the standard treatment. However, the extent of the tumor-free resection margin after wide local excision is still controversial in many cases. Drugs targeting immune checkpoints such as PD-1 or its ligand PD-L1 have potential clinical utility in these patients. We examined the expression of PD-L1 in tumor cells and immune cells, as well as the proportion of PD-1, CD8, and FOXP3 positive lymphocytes. Twenty-one cases of invasive vulvar squamous cell carcinomas were reviewed. Whole slides of representative formalin-fixed, paraffin-embedded archival material were used for analysis. Odds ratios (OR) and hazard ratios (HR) were used to estimate risk for disease recurrence, overall mortality, and cancer mortality. PD-L1 expression was found in 43% of tumor cells, with higher proportions in intratumoral (67%) and peritumoral (81%) immune cells. OR and HR for disease recurrence and cancer mortality were higher in tumors with higher CD8 expression. OR and HR for overall mortality were also higher in tumors with higher PD-L1 and CD8 expression. In conclusion, nearly half of cases were PD-L1 positive in tumor cells with over two-third of cases demonstrating PD-L1 positivity in immune cells. Immunohistochemical expression of PD-L1 and CD8 could be used to suggest higher risk of disease recurrence, overall mortality, and cancer mortality. Furthermore, our data contributes to the growing evidence that targeting the PD-1/PD-L1 pathway may be beneficial in vulvar squamous cell carcinomas.

Mortality burden in patients born with Ebstein's anomaly: a 40-year nationwide cohort study.

Survival rates for unoperated patients with Ebstein's anomaly (EA) are unknown. We estimated overall long-term mortality in operated and unoperated EA patients, compared with the general population in Sweden. Using national medical registries, Swedish individuals born 1970-93 and diagnosed with EA between 1970 and 2011 were included. The hazard ratio for overall mortality for EA patients (n = 216) vs. the matched comparison cohort (n = 2160) was 43.7 [95% confidence interval (CI): 24.8-82.5]. Mortality risk for EA patients (vs. controls) decreased as birth period progressed, with hazard ratios declining from 63.6 (95% CI: 26.3-191.8) for those born in the 1970s to 34.4 (95% CI: 15.8-83.1) for those born in the 1980s and 20.2 (95% CI: 1.6-632.5) for those born at the beginning of 1990s. The overall mortality hazard ratios for unoperated and operated patients with EA (vs. controls) were 30.2 (95% CI: 13.8-73.3) and 63.7 (95% CI: 28.1-172.5), respectively. The risk of mortality among unoperated EA patients (vs. controls) declined with progressing birth period, with hazard ratios declining from 58.4 (95% CI: 15.1-415.2) in the 1970s to 22.9 (95% CI: 8.0-75.3) in the 1980s and 10.2 (95% CI: 0.3-395.9) in the 1990s. Overall all-cause mortality for patients with EA declined dramatically from 64 times to 20 times that of controls without EA, from the 1970s to the early 1990s. Unoperated patients with EA had better survival than did operated patients, possibly reflecting the higher severity of disease or more severe associated cardiac defects in patients undergoing surgery.