Related Mortality Research Articles

Cardiovascular Risk in Cancer Patients Treated with Immune Checkpoint Inhibitors: Challenges and Future Directions.

Cardiovascular disease is the leading cause of non-cancer related mortality and morbidity among people living with or cured from cancer. Immune checkpoint inhibitors (ICIs) are systemic anti-cancer therapies that have revolutionised the treatment of numerous cancers, even achieving durable long-term responses among patients with metastatic disease. However, the pro-inflammatory effects of ICIs have been postulated to increase the risk of atherosclerotic cardiovascular disease (ASCVD) in cancer survivorship. Standard modifiable cardiovascular risk factors can further contribute to ASCVD risk during cancer survivorship but are not routinely screened and are often untreated in patients with cancer. With the expanding use of ICIs leading to improved cancer survivorship, cardiovascular risk identification and prevention will be paramount in the care of patients with cancer. This review highlights the practical challenges associated with ASCVD prevention among the growing number of patients treated with ICIs for cancer, including balancing competing mortality risks from cancer and ASCVD, the lack of ICI-specific cardiovascular risk stratification tools, potential interactions between cardiovascular and oncological therapies, and barriers to implementation of cardiovascular screening and prevention within existing healthcare systems.

Association between obstructive sleep apnea (OSA) and COVID-19 severity.

Obstructive sleep apnea and sleep-related hypoxia have been associated with higher rates of hospitalization and mortality among patients with Coronavirus disease 2019 (COVID-19). We further explored the association between obstructive sleep apnea, COVID-19 severity and related mortality. In addition, we examined the effects of clinical and demographic parameters on COVID-19. In this retrospective study, we included adult patients who were diagnosed with COVID-19 prior to the Omicron variant identification. We compared the severity of COVID-19 and mortality with the diagnosis of obstructive sleep apnea. The study population included 44,275 patients who tested positive for COVID-19. Of these, 97% had mild or asymptomatic disease, 1.2% had moderate disease, and 1.8% had severe disease. Obstructive sleep apnea was diagnosed in 980 (2.2%) patients. In a multivariate analysis, obstructive sleep apnea diagnosis increased the risk of severe COVID-19 by 1.6 (95% confidence interval: 1.1-2.4) compared with mild disease. However, no increase in mortality was associated with obstructive sleep apnea. Interestingly, patients with moderate and high socioeconomic status had a 1.6 times higher risk for severe COVID-19 than patients from the low socioeconomic status group (95% confidence interval: 1.2-2.1 and 95% confidence interval: 1.1-2.3, respectively). The risk of dying due to COVID-19 was 1.6 (95% confidence interval: 1.1-2.5) and 3.1 (95% confidence interval: 1.8-5.3) times higher in patients with medium and high socioeconomic status, respectively, compared with patients with low socioeconomic status. Diagnosis of obstructive sleep apnea was found to be an independent risk factor for severe COVID-19. The higher the socioeconomic status, the higher the risk of severe COVID-19 morbidity and mortality.

Global burden of type 1 diabetes in adults aged 65 years and older, 1990-2019: population based study

ObjectivesTo estimate the burden, trends, and inequalities of type 1 diabetes mellitus (T1DM) among older adults at global, regional, and national level from 1990 to 2019.DesignPopulation based study.PopulationAdults aged ≥65...

Extreme Humid-Heat Exposure and Mortality Among Patients Receiving Dialysis

Rationale & ObjectiveExposure to extreme heat events has been linked to increased morbidity and mortality in the general population. Patients receiving maintenance dialysis may be vulnerable to greater risks from these events, but this is not well understood. We sought to characterize the association of extreme heat events and the risk of death among patients receiving dialysis in the United States. Study DesignRetrospective cohort study. Setting & ParticipantsData from the United States Renal Data System were used to identify adults living in US urban settlements prone to extreme heat who initiated maintenance dialysis between 1997 and 2016. ExposureAn extreme heat event was defined as a time-updated heat index (a humid-heat metric) exceeding 40.6°C for ≥2 days or 46.1°C for ≥1 day. OutcomeDeath. Analytical ApproachCox proportional hazards regression to estimate the elevation in risk of death during a humid-heat event adjusted for age, sex, year of dialysis initiation, dialysis modality, poverty level, and climate region. Interactions between humid-heat and these same factors were explored. ResultsAmong 945,251 adults in 245 urban settlements, the mean age was 63 years and 44% were female. During a median follow-up of 3.6 years, 498,049 adults were exposed to at least one of 7,154 extreme humid-heat events, and 500,025 deaths occurred. In adjusted models, there was an increased risk of death (hazard ratio 1.18; 95% confidence interval 1.15-1.20) during extreme humid-heat exposure. Relative mortality risk was higher among patients living in the Southeast (P<0.001) compared with the Southwest. LimitationsPossibility of exposure misclassification, did not account for land use and air pollution co-exposures. ConclusionsThis study suggests that patients receiving dialysis face an increased risk of death during extreme humid-heat exposure.

Pathogenesis and clinical significance of reperfusion arrhythmias in acute myocardial infarctio

The problem of ischemia-reperfusion injury, in particular, reperfusion arrhythmias, has remained controversial for many years. To date, there are no one frame of mind on the clinical and prognostic significance of tachyarrhythmias in the acute period of myocardial infarction. In addition, data on the incidence of reperfusion arrhythmias and related mortality are very contradictory. The review summarizes current concepts and results of studies devoted to the study of the clinical role of reperfusion arrhythmias. Their pathogenesis, structure, and impact on the long-term prognosis of patients are discussed. The need to study ischemia-reperfusion injury within the pharmacoinvasive strategy using modern thrombolytic agents is emphasized, which seems especially relevant given the Russian geographical features.

Surgery versus thermal ablation for small-size colorectal liver metastases (COLLISION): An international, multicenter, phase III randomized controlled trial.

LBA3501 Background: The standard of care for local treatment of patients (pts) with colorectal liver metastases (CRLM) is surgical resection. However, growing evidence suggests thermal ablation to be associated with a superior safety profile, lower costs, and shorter hospital stay, while rivaling surgical resection in terms of local control and overall survival (OS). This study aimed to explore the potential non-inferiority of thermal ablation compared to surgical resection for pts with small-size (≤3cm) resectable CRLM. Methods: In this multicenter, phase 3 Dutch Colorectal Cancer Group trial, pts aged 18 years and older with previously untreated CRLM were recruited from 14 centers in the Netherlands, Belgium and Italy. Pts with ≤10 CRLM, no extrahepatic metastases and ECOG 0-2 were stratified into low, intermediate and high disease burden subgroups and randomly assigned (1:1) to undergo surgical resection or thermal ablation. Though approach was left at the discretion of the operator, laparoscopic (+/- robot) resections and percutaneous ablations were favored over open procedures. To avoid drop-outs patients undergoing open procedures were randomized intra-operatively. The primary outcome was overall survival (OS) (log-rank; power 80%, 5% type I error rate; 1-sided). Secondary outcomes include distant and local tumor progression-free survival (PFS), local control, safety, length of hospital stay, quality of life and cost-effectiveness. Results: A total of 341 patients were enrolled; 299 were randomly assigned: 147 assigned to thermal ablation, 148 to surgical resection; 4 were excluded after randomization for not having the disease assessed. The trial was stopped at halftime for having met predefined stopping rules. After a median follow-up time of 28.8 months there was no difference regarding OS (HR 1.042; 95% CI, 0.689-1.576; p = 0.846) with a conditional probability of &gt;90% to prove the hypothesis of non-inferiority. Procedure related mortality was 2.1% (n=3) for resection vs. 0% (n=0) for thermal ablation. The total number of adverse events (p = &lt;0.001), the length of hospital stay (median 4 days [range 1-36] vs 1 day [range 1-44], p = &lt;0.001) and local control also favored thermal ablation (HR 0.184; 95% CI, 0.040-0.838; p = 0.029). No differences were found regarding local (HR 0.833; 95% CI, 0.473-1.469; p = 0.528) and distant PFS (HR 0.982; 95% CI, 0.739-1.303; p = 0898). Conclusions: In conclusion, transitioning from surgical resection to thermal ablation as standard of care for patients with small-size (≤3 cm) CRLM would reduce complications, shorten hospital stay and improve local control, without compromising disease-free and overall survival. COLLISION is funded by a Medtronic-Covidien Investigator Sponsored Research grant. Clinical trial information: NCT03088150 .

Population attributable fractions of cancer mortality related to indoor air pollution, animal contact, and water source as environmental risk factors: Findings from the Golestan Cohort Study.

Environmental risk factors are significant contributors to cancer mortality, which are neglected. This study aimed to estimate the population attributable fraction of cancer mortality due to the environmental risk factors. Golestan cohort study is a population-base cohort on 50045 participants between 40-75 with about 18 years of follow up. We detected 2,196 cancer mortality and applied a multiple Cox model to compute the hazard ratio of environmental risk factor on all cancer and cancer-specific mortality. The population attributable fraction was calculated, accordingly. Biomass fuels for cooking, as an indoor air pollution, increased the risk of colorectal, esophageal, gastric cancer, and all-cancer mortality by 84%, 66%, 37%, and 17% respectively. Using gas for cooking, particularly in rural areas, could save 6% [Population Attributable Fraction: 6.36(95%CI: 1.82, 10.70)] of esophageal cancer, 3% [Population Attributable Fraction: 3.43 (0, 7.33)] of gastric cancer, and 6% [Population Attributable Fraction: 6.25 (1.76, 13.63)] of colorectal cancer mortality. Using a healthy tap water source could save 5% [Population Attributable Fraction:5.50(0, 10.93)] of esophageal cancer mortality, particularly in rural areas. There was no significant association between indoor air pollution for heating purposes and animal contact with cancer mortality. Considering the results of this study, eliminating solid fuel for most daily usage, among the population with specific cancer types, is required to successfully reduce cancer related mortality. Adopting appropriate strategies and interventions by policymakers such as educating the population, allocating resources for improving the healthy environment of the community, and cancer screening policies among susceptible populations could reduce cancer related mortalities.

High-dose chemotherapy and autologous hematopoietic stem cell transplantation for progressive systemic sclerosis: a retrospective study of outcome and prognostic factors

PurposeSystemic sclerosis (SSc) is a rare autoimmune disease associated with high morbidity and mortality. SSc treatment is still challenging, and evidence is scarce. In the last decades high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) has proven to be effective. However, treatment related morbidity and mortality (TRM) are high. We conducted a retrospective, single-center analysis of SSc patients following HD-ASCT focusing on TRM and risk factors.Methods32 patients who underwent HD-ASCT at our hospital between June 2000 and September 2020 were included. Clinical characteristics were evaluated based on chart review before and after HD-ASCT. Analyses focused on overall survival (OS), TRM, and response to HD-ASCT.ResultsMedian OS was 81 months (range 0–243). Within one year, 20 of 32 (76.9%) patients responded to HD-ASCT. Overall, 6 patients (18.8%) died in the context of HD-ASCT. Patients with subjective response to HD-ASCT (p = 0.024) and those with shorter time to platelet engraftment (p = 0.047) had significantly longer OS. Impaired renal function, age at HD-ASCT ≥ 55, disease duration < 12 months, high Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and Charlton Comorbidity Index (CCI) scores were associated with higher TRM. Patients receiving conditioning chemotherapy with thiotepa needed longer time for neutrophil (p = 0.035) and platelet engraftment (p = 0.021).ConclusionThis study confirms the efficacy of HD-ASCT for patients with SSc in a single center real-world setting. High TRM is still a challenge. However, TRM could be reduced by exclusion of high-risk patients and attention to prognostic parameters and scores as suggested in this study.

RATE OF COVID-19 INFECTION AND 30-DAY MORTALITY BETWEEN BLUE AND GREEN (DEDICATED COVID-19 FREE) PATHWAYS: RESULTS FROM UK-FALCON AUDIT

ObjectivesThe primary aim was to determine the differences in COVID-19 infection rate and 30 day mortality in patients undergoing foot and ankle surgery between different treatment pathways over the two phases of the UK-FALCON audit, spanning the first and second national lockdowns.DesignMulticentre retrospective national audit.SettingThis was a combined retrospective (Phase 1) and prospective (Phase 2) national audit of foot and ankle procedures in the UK in 2020.ParticipantsAll adult patients undergoing foot and ankle surgery in an operating theatre during the study period included from 46 participating centres in England, Scotland, Wales and Northern Ireland. Patients were categorised as either a green pathway (designated COVID-19 free) or blue pathway.Results10,846 patients were included, 6,644 from phase 1 and 4,202 from phase 2. Over the 2 phases the infection rate on a blue pathway was 1.07% (69/6,470) and 0.21% on a green pathway (9/4,280). In phase 1, there was no significant difference in the COVID-19 perioperative infection rate between the blue and green pathways in any element of the first phase (pre-lockdown (p = .109), lockdown (p = .923) or post-lockdown (p = .577)). However, in phase 2 there was a significant reduction in perioperative infection rate when using the green pathway in both the pre-lockdown (p &lt; .001) and lockdown periods (p &lt; .001). There was no significant difference in COVID-19 related mortality between pathways.ConclusionsThere was a five-fold reduction in the perioperative COVID-19 infection rate when using designated COVID-19 green pathways; however the success of the pathways only became significant in phase 2 of the study. The study shows a developing success in using green pathways in reducing the risk to patients undergoing foot and ankle surgery.

Cardiovascular mortality in bipolar disorder: Population-based cohort study.

Limited evidence base on cause-specific excess cardiovascular disease (CVD) mortality in bipolar disorder (BD) is a barrier to developing preventive interventions aimed at reducing the persistent mortality gap in BD. To investigate cause-specific CVD mortality in BD. We identified all individuals aged 15+ years during 2004-2018 with a diagnosis of BD using Finnish nationwide routine data. Standardised mortality ratios (SMR) with 95% confidence intervals (CI) were calculated using the mortality rates in the general population as weights. 53,273 individuals with BD (57% women; median age at BD diagnosis, 40 years), were followed up for 428,426 person-years (median, 8.2 years). There were 5988 deaths due to any cause, of which 26% were due to CVD. The leading cause of absolute excess CVD mortality was coronary artery disease (CAD). The leading causes of relative excess mortality were cardiomegaly (SMR, 4.51; 95% CI, 3.58-5.43), venous thromboembolism (3.03; 2.26-3.81), cardiomyopathy (2.46; 1.95-2.97), and hypertensive heart disease (2.12; 1.71-2.54). The leading causes of absolute CVD mortality showed markedly lower relative excess, including CAD (1.47; 1.34-1.61), ischaemic stroke (1.31; 1.06-1.54), and acute myocardial infarction (1.12; 0.98-1.25). Due to the higher relative excess mortality, structural and functional heart disorders contributed as much as atherosclerotic and ischaemic disorders to the absolute excess mortality. Cardiomyopathy and hypertensive heart disease as the leading causes of relative excess mortality emphasise the contribution of structural and functional heart disorders to the overall excess mortality alongside coronary artery disease. Interventions targeted at these modifiable causes of death should be priorities in the prevention of premature excess CVD mortality in BD.

Effects of neuromuscular electrical stimulation, light intensity walking and a seated exercise trainer on venous return in healthy young adults: a quasi-experimental crossover study

Background/Aims The growing prevalence of sedentary behaviour across the life course is linked to an increased risk of chronic venous disease and related mortality, warranting the need for non-invasive interventions to improve blood flow and lower extremity function. The aim of this study was to investigate the change in venous blood flow, heart rate and blood pressure after 8 minutes of using the Leeper device, Circulation Booster and light intensity walking. Methods A quasi-experimental crossover study involving 11 participants (eight women, three men, mean age 23.91 years, standard deviation 1.04 years) was conducted using Leeper and Circulation Booster devices and light intensity walking. During each intervention, participants exercised for 8 minutes, and blood flow was recorded at 0, 4 and 8 minutes. Heart rate and blood pressure were recorded at 0 and 8 minutes. Blood flow was the primary outcome measure, and heart rate and blood pressure were secondary outcomes. Participants rested for 10 minutes between exercise. A two-way repeated measures analysis of variance was used to analyse the effect of intervention and time on blood flow, blood pressure and heart rate. Results There was no significant interaction between intervention and time on blood flow (P=0.180) indicating that blood flow did not change over time depending on intervention. There was no significant main effect of time on blood flow (P=0.206), indicating that no intervention caused a significant increase or decrease in blood flow after 8 minutes of exercise. Conclusions The interventions involving the Leeper and Circulation Booster devices and light intensity walking did not appear to significantly increase blood flow in young adults. Further studies involving participants from older age groups and those with pathological interventions are warranted to examine the potential effectiveness of these interventions. Implications for practice The findings may assist with the advice that allied health professionals provide regarding the use of seated exercise trainers and EMS devices and their ability to influence changes in blood flow.

Trends in the thrombotic complications of myeloproliferative neoplasms: A nationwide analysis.

6581 Background: Thrombotic complications are a well known cause of morbidity and mortality in Philadelphia-negative Myeloproliferative Neoplasms[Polycythemia Vera, Essential thrombocythemia, Primary Myelofibrosis]. Current study evaluated thrombotic events incidence and outcome trends in Myeloproliferative Neoplasms[MPN] from 2012 to 2020. Methods: This is a longitudinal study of thrombotic events in MPN using the Nationwide Inpatient Sample. All patients with a diagnosis of MPN admitted with any thrombotic event including arterial or venous thrombosis were included in the study. Arterial thrombotic events included Myocardial infarction[MI], Ischemic stroke[IS], Transient Ischemic Attack[TIA] while venous thrombotic events included Deep Vein Thrombosis[DVT], Pulmonary Embolism[PE], Budd-Chiari Syndrome[BCS], Portal Vein Thrombosis[PVT]. Thrombosis related inpatient mortality rate, incidence, length of hospital stay, and total hospital charges were calculated. Results: Mortality rate from any thrombotic event overall[arterial plus venous] increased from 2.3% to 2.6% from 2012 to 2020. There was an increase in mortality rates from 2.8% to 3.8% among arterial thrombosis while there was a decrease in venous thrombosis related mortality from 1.7 to 0.4%. Specifically MI and IS related mortality increased from 3.7% to 4.3% and 3% to 4% respectively over the same period. The incidence of any thrombotic event declined from 2 to 1.3 cases/100,000 persons from 2012 to 2020. A similar decline in incidence of arterial, venous events, MI, IS were observed. The mean length of stay decreased from 5.8 days in 2012 to 5.2 days in 2020 among MPN patients with venous thrombosis which was statistically significant. Similar decline was noted in MI patients as well. Though the mean length of stay increased from 7.9 to 9.5 days among MPN patients with IS, this increase was not statistically significant. The mean hospitalization charges for thrombotic events increased from $53,421 in 2012 to $101,598 in 2020 after adjusting for inflation. Similar trends were noted in all types of thrombotic admissions which were all statistically significant. Upon age based stratification of MPN, mortality for those less than 60 years reduced from 2% to 0.3%, while it increased from 4.1 to 5.6% in those more than 60 years from 2012 to 2020. Conclusions: Inpatient mortality from thrombotic events in MPN has shown an increasing trend from 2012 to 2020 though there was a decline in overall incidence of thrombosis during the same period. Despite the decreasing trend in length of stay, the total economic burden of thrombotic complications in MPN is increasing in the US. Specifically the effects were more pronounced in those greater than 60 years. This points to the need for revisiting guidelines regarding thromboprophylaxis in MPN.

Trends in location of death for individuals with pediatric cancer in the United States.

1591 Background: Children and adolescents with cancer face unique symptomatic, psychosocial, and existential challenges at the end of life (EOL). Premature death alongside severe pain and complex symptoms is distressing for the patients and families. Location of death is an important clinical and psychosocial decision for many patients. Therefore, we explored differences in location of death amongst pediatric patients with cancer using a large, national US database. Methods: We performed multinomial logistic regressions and analyzed trends in place of death for children and adolescents (ages 0 to 19) diagnosed with cancer from 2003-2019 using the Centers for Disease Control and Prevention Wide-Range Online Data for Epidemiologic Research database (CDC WONDER). We studied associations in place of death with essential decedent characteristics (age, sex, and race) for ICD10 codes C00-C96 and D00-D49, which encompass the most common causes of cancer death in children and adolescents. Results: Of 1,910 pediatric oncology decedents, 910 died in a hospital, 794 died at home, 12 died in nursing facilities, 59 in hospice, and 135 in outpatient facilities. Over time, death at home decreased by 50%. Death in the hospital increased by 64% and death in hospice increased by 200%. Children 10-19 years-of-age were more likely to die in hospice than children younger than 4 and children between 5-9 years-of-age. Additionally, they were less likely to die in outpatient medical facilities and ED. 1,388 decedents were White, 411 were Black, 18 were American Indian, and 93 were Asian. Children of racial and ethnic minorities were significantly more likely to die in hospitals than White children with cancer (Black: 1.81 [1.44-2.28], Asian: 1.57 [1.03-2.41], and Hispanic: 1.60 [1.26-2.04]). Black children with cancer were also more likely (1.67 [1.11-2.53]) to die in outpatient facilities compared to White children. Asian children &amp; Black children were less likely to die at home (0.48[0.38-0.61] and 0.55 [0.35-0.86] respectively). Conclusions: In contrast to the adult population that has demonstrated steady increases in deaths at home, for children with cancer, relative rates of death at home decreased while death in the hospital increased, with distinct differences among race/ethnic groups. Adequate education and support are needed to facilitate both autonomy and symptom palliation at EOL. Future work must explore underlying reasons for differences in place of death across time and demographic groups, so as to identify and alleviate any potential barriers, and to promote equitable access to a good death for each individual.

Survival analysis and associated factors in metastatic early-onset colorectal cancer vs. metastatic average-onset colorectal cancer.

e15549 Background: Early-onset colorectal cancer (EO-CRC) is defined as colorectal cancer diagnosed before age 50 and its incidence has been increasing during the last decade. Average-onset colorectal cancer (AO-CRC) has presented a steady decline in incidence and related mortality over the past 20 years. There is controversy surrounding the disparities in outcomes and overall survival (OS) in EO-CRC vs. AO-CRC. Our study compared the OS and cause-specific survival (CSS) between metastatic EO-CRC (mEO-CRC) and metastatic AO-CRC (mAO-CRC) and identified associated factors. Methods: Data on patient characteristics, tumor characteristics, incidence and mortality were obtained from the SEER database from 2010 to 2020. We identified 23,278 individuals aged &gt; 18 with confirmed diagnosis of all histologic subtypes of metastatic CRC (M1 on TNM stage) using ICD-O-3 site code C180, C182-9, C209 and histology codes: 8000, 8010, 8012, 8013, 8020-2, 8031-33, 8041, 8045, 8070-2, 8083, 8123-4, 8140, 8144-45, 8201, 8210-11, 8213, 8220-1, 8240, 8243-46, 8249, 8253, 8255, 8260-3, 8261-3, 8265, 8310, 8323, 8480-1, 8490, 8507, 8510, 8550, 8560, 8570, 8574, 8936, 8980. OS distributions and CCS were conducted using the Kaplan-Meier method and log-rank test was used to assess differences between mEO-CRC and mAO-CRC. Cox regression model used to assess associations between variables. Results: mEO-CRC constituted 17.79% of the cases, while 82.21% were mAO-CRC. Most patients with mEO-CRC were between 45-49 years old (47.66%), males (52.16%), white (72.57%), with histology of adenocarcinoma (87.30%). Left colon tumors were most prevalent in both groups (40.26%), but higher among mEO-CRC than in mAO-CRC (49.63% vs 38.23%, p &lt; 0.001). mEO-CRC were more likely to receive chemotherapy (87.23% vs. 66.66%, p &lt; 0.001) and radiotherapy (14.92% vs. 9.51%, p &lt; 0.001), while surgery was similar in both groups (87.71% vs. 88.52%, p = 0.140). Patients with mEO-CRC had a higher OS (HR: 1.53, CI 95% 1.47-1.59, p &lt; 0.001), as well as a higher CSS (HR: 1.33, 95% CI: 1.27-1.39, p &lt; 0.001) when compared to mAO-CRC. mEO-CRC also had a significantly better median overall survival (30 months vs. 18 months p &lt; 0.001). Factors associated with worse OS include mAO-CRC (p &lt; 0.001), mucinous adenocarcinoma (p &lt; 0.001), male sex (p 0.003) and no surgical intervention (p &lt; 0.001). Conclusions: Patients with mEO-CRC had better OS and CSS when compared to patients with mAO-CRC and were more likely to receive cancer-directed therapy which could be explained by the mEO-CRC cohort having a higher performance status, less comorbidities, and better tolerance to cancer-related therapy. Factors associated with worse OS and CSS are mAO-CRC, mucinous adenocarcinoma, male sex and lack of surgical intervention. Furthermore, it is crucial to continue studying potential candidates who would benefit from early CRC screening.

Menopausal hormone therapy and ovarian and endometrial cancers: Long-term follow-up of the Women’s Health Initiative randomized trials.

10506 Background: After decades of use,menopausal hormone therapy influence on ovarian and endometrial cancer remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone use on ovarian and endometrial cancer incidence and mortality in long-term follow-up of the Women’s Health Initiative randomized, placebo-controlled clinical trials. Methods: Long-term follow-up of two placebo-controlled randomized clinical trials that recruited 27,347 postmenopausal women aged 50-79 years without prior breast cancer or invasive cancer within 10 years (and no baseline endometrial pathology in combined hormone trial participants) from 40 US centers from 1993-1998. In 16,608 women with a uterus, 8,506 were randomized to daily 0.625 mg/d of CEE plus 2.5 mg/d of MPA and 8,102, placebo. In 10,739 women with prior hysterectomy, 5,310 were randomized to daily 0.625 mg/d of CEE-alone and 5,429, placebo. Intervention was stopped for cause before the planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Cancers were verified by central pathology report review. Mortality findings were enhanced by serial National Death Index (NDI) queries. The primary study outcomes were ovarian cancer and endometrial cancer incidence and related mortality. Results: After 20-year follow-up, with mortality information for &gt; 98%; in the initial WHI report on CEE-alone influence on ovarian cancer, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041% annualized rate] vs 17 [0.020%]; hazard ratio [HR], 2.04; 95% CI 1.14-3.65; P = 0.01) and ovarian cancer mortality (HR 2.79 95% CI 1.30-5.99, P = 0.006). KM-estimates and cumulative hazard ratios indicate a persistent CEE-alone adverse effect on ovarian cancer incidence that emerged after 12-years follow-up and did not diminish (P = 0.006). In contrast, use of CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] vs 63 [0.045%]; HR, 1.14; 95% CI, 0.82-1.59; P = 0.44) or ovarian cancer mortality (HR 1.21 95% CI 0.84-1.74). CEE plus MPA did significantly lower endometrial cancer incidence (106 cases [0.073%] vs 140 [0.10%]; HR, 0.72; 95% CI, 0.56-0.92; P = 0.01), without statistically significant influence on endometrial mortality (HR 0.58 95% CI 0.29-1.16) Conclusions: In randomized, placebo-controlled, clinical trial settings, CEE-alone, in women with prior hysterectomy, significantly increased ovarian cancer incidence and increased ovarian cancer mortality while CEE plus MPA, in women with a uterus, in contrast to most observational studies, did not. However, CEE plus MPA reduced endometrial cancer incidence. These findings inform decisions regarding menopausal hormone therapy use. Clinical trial information: NCT00000611 .

METAPANC, intensified treatment in patients with oligometastatic pancreatic cancer: Multimodal surgical treatment versus systemic chemotherapy alone—A prospective randomized controlled multicenter phase III trial.

TPS4207 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal overall survival rate due to early metastasis and high therapy resistance. The successful introduction of intensified chemotherapeutic regimen such as FOLFIRINOX (FFX) has significantly increased response rates, disease control and overall survival. Current standards recommend systemic chemotherapy but no surgical approach in metastatic PDAC. FFX has the highest rates of response and overall survival and is a current standard of care in patients with metastatic PDAC and good performance status. Extensive surgical interventions with synchronous or metachronous metastasectomy is not recommended according to current guidelines. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from randomized clinical trials are not available. Methods: METAPANC is a prospective randomized controlled multicenter phase III trial evaluating survival and quality of life after multimodal therapy with perioperative modified FOLFIRINOX (mFFX) chemotherapy (two times 4 cycles prior to resection of the primary tumor and resection of the metastases), followed by 4 cycles of adjuvant mFFX chemotherapy (Arm A) vs. mFFX (without surgery), as standard of care first-line treatment (Arm B). Patients are eligible for randomization after 8 cycles of mFFX if they have at least stable disease on imaging according to RECIST V1.1 (Response Assessment I after 4 cycles and Response Assessment II after 8 cycles of mFFX). Patients with progressive disease will be excluded from the study. This clinical trial will focus on a well-defined patient collective with resectable PDAC and metastatic load limited to the liver with a maximum of three metastases. Patients with metachronous liver metastatic status can also be included, but must have completed adjuvant chemotherapy at least 6 months before start of study treatment. In patients randomized into Arm A with metastatic lesions located in the center of the liver local ablative techniques can be combined. In total 272 patients will be enrolled and will be randomized 1:1. The primary endpoint is overall survival, secondary endpoints are progression free survival, procedure related complications and mortality, quality of life, quality-adjusted time without symptoms and toxicity. METAPANC is accompanied by an exploratory biomarker analysis program of collecting biological and imaging samples to subsequently identify and evaluate molecular-based patient subgroups and biomarkers for identification of a potential target population which may benefit from the intensified multimodal treatment strategy. 22 German participating sites are selected. Further international sites are planned in the Netherlands, Norway, Finland and Sweden. Clinical trial information: 2023-503558-10-00.

Comparative effectiveness of the bivalent COVID-19 mRNA vaccines, mRNA1273-222 and BNT162b2, in immunocompromised adults in the US.

e23057 Background: Despite the decline in COVID-19–related hospitalizations and mortality during the period of omicron predominance, immunocompromised individuals, including those with cancer, remain at an increased risk for severe COVID-19 outcomes. A subanalysis of a retrospective observational cohort study assessed the relative vaccine effectiveness (rVE) of 2 previously approved bivalent vaccines targeting the ancestral SARS-CoV-2 and the omicron BA.4/BA.5 variant, mRNA-1273.222 (Moderna, Inc., Cambridge, MA, USA) and BNT162b2 bivalent (Pfizer Inc., New York, NY, USA; BioNTech GmbH, Mainz, Germany), in immunocompromised adults in the United States. Methods: The study used a US electronic health record dataset (Veradigm) linked with medical and pharmacy claims data of adults aged ≥18 years with at least 1 underlying medical condition associated with increased risk of severe COVID-19 who received a dose of mRNA-1273.222 or BNT162b2 bivalent vaccines between August 31, 2022, and February 28, 2023. A subgroup analysis was conducted among an immunocompromised population, encompassing cancer patients, organ or stem cell transplant recipients, individuals with primary immunodeficiency, individuals with HIV, and individuals receiving immunosuppressing medications. Comorbid conditions were based on prior medical encounters in the 365 days before vaccination. The outcomes measured were rVE of the two bivalent mRNA vaccines against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary outcome). Follow-up started 7 days after vaccination until May 31, 2023 (end of available claims data). Propensity score weighting was used to adjust for baseline differences between groups. Results: The subanalysis included 427,260 immunocompromised individuals, of which 250,573 (58.6%) were identified as having cancer. In the overall weighted immunocompromised population, 169,509 individuals received mRNA-1273.222, and 257,751 received BNT162b2 bivalent. The adjusted rVEs of mRNA-1273.222 versus BNT162b2 bivalent vaccine against COVID-19–related hospitalizations and outpatient visits were 15.0% (95% CI, 7.2%-22.0%; P&lt; 0.001) and 4.8% (95% CI, 1.8%-7.7%; P= 0.002), respectively. Conclusions: In this study, the mRNA-1273.222 vaccine offered greater protection against COVID-19–related hospitalization compared with the BNT162b2 bivalent vaccine among immunocompromised individuals. This study emphasizes the importance of assessing COVID-19 vaccine formulations and optimizing protection, especially in immunocompromised adults, including those with cancer.

Long-term outcomes after cardiac transplantation in AL amyloidosis.

7572 Background: Systemic AL amyloidosis can lead to progressive multi-organ dysfunction including advanced heart failure which may require orthotopic heart transplantation (OHT). Hematologic outcomes of AL amyloidosis post-OHT are not well described. Methods: We report outcomes for patients with AL amyloidosis with cardiac involvement post-OHT from Nov 2008 - Jun 2023 at Vanderbilt University Medical Center. Hematologic response was graded per the ISA guidelines. Results: Fourteen pts underwent OHT of whom 13 had lambda light chain disease. Three (21%) pts had isolated AL amyloidosis (AL) without myeloma (MM), while 11 (79%) also had MM: 6 with bone marrow plasma cells (BMPCs) 10-19% (AL-PCMM-10) and 5 with BMPC ≥20% (AL-PCMM-20). One each with AL-PCMM-10 and AL-PCMM-20 had lytic lesions (AL-CRAB). Median age at OHT was 55.5 yrs (range 37-74). Median time from diagnosis to OHT was 18 mo (range 3-62). Five (35%) pts had biopsy-proven extracardiac amyloid involvement. Median difference in serum free light chains at first evaluation was 70 mg/dL (range 9-289). Three pts were Mayo 2012 stage II, 4 stage III, and 7 stage IV. Four pts had t(11;14) and 1 had 1q gain. Ten (71%) pts received triplet therapy (VCd or VRd) and 3 (21%) received quadruplet therapy (Dara-VCd or Isa-VCd) pre-OHT. Six (43%) pts had autologous stem cell transplantation (ASCT); 1 pre-OHT and 5 post-OHT. Of ASCT pts, 1 pt achieved CHR, 1 VGPR, 2 PR, and 1 had PD pre-ASCT. Pre-OHT, 4 pts achieved CHR, 6 VGPR, 3 PR, and 1 had PD. Eleven pts (79%) received maintenance therapy post-OHT (5 proteosome inhibitors, 6 anti-CD38). At last follow-up, 8 pts were in CHR, 3 in VGPR, 1 in PR, and 2 had PD. Four (29%) pts died post-OHT: 2 from AL recurrence (1 each with AL and AL-PCMM-10), 1 from cardiac allograft vasculopathy (AL-CRAB), and 1 from renal failure (AL-CRAB). Three (21%) pts had hematologic relapse 5, 21 and 48 mo post-OHT, and of those, 2 had recurrent cardiac amyloid in graft 37 and 71 mo post-OHT. Of those with hematologic relapse, 2 had AL-PCMM-10 and 1 had AL. One pt had post-transplant lymphoproliferative disorder 126 mo post-OHT, requiring treatment. Median follow-up and survival of the cohort post-OHT was 2.25 yrs (range 0.5-13.8). Conclusions: In this single-center analysis of pts undergoing OHT for cardiac AL amyloidosis, we demonstrate feasibility of excellent long-term outcomes, in predominantly high-risk AL pts where majority harbored high-risk disease with MM overlap, either by AL-CRAB or AL-BMPC. Induction alone led to ≥VGPR response in 10 (71%) pts pre-OHT and further therapy deepened this to 11 (79%) pts. Both AL-CRAB pts died during follow-up, highlighting the overall poor prognosis in this specific subgroup. In our cohort, non-relapse related mortality was seen in only 2 (14%) pts, demonstrating acceptable post-OHT risk and overall ability to achieve far improved outcomes in the high-risk cardiac AL amyloidosis patient population that otherwise suffers from rapid and universal mortality.

Geographic sources of ozone air pollution and mortality burden in Europe

Ground-level ozone (O3) is a harmful air pollutant formed in the atmosphere by the interaction between sunlight and precursor gases. Exposure to current O3 levels in Europe is a major source of premature mortality from air pollution. However, mitigation actions have been mainly designed and implemented at the national and regional scales, lacking a comprehensive assessment of the geographic sources of O3 pollution and its associated health impacts. Here we quantify both national and imported contributions to O3 and their related mortality burden across 813 contiguous regions in 35 European countries, representing about 530 million people. Imported O3 contributed to 88.3% of all O3-attributable deaths (intercountry range 83–100%). The greatest share of imported O3 had its origins outside the study domain (that is, hemispheric sources), which was responsible for 56.7% of total O3-attributable mortality (range 42.5–87.2%). It was concluded that achieving the air-quality guidelines set out by the World Health Organization and avoiding the health impacts of O3 require not only the implementation of national or coordinated pan-European actions but also global strategies.

OPTIMIZE-1 primary analysis: Safety, efficacy and biomarker results of a phase 1b/2 study combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

4133 Background: With a 5 year overall survival (OS) rate &lt;5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312 . [Table: see text]