Overcoming underestimation of the association of excess weight with pancreatic cancer due to prediagnostic weight loss: Umbrella review of systematic reviews, meta-analyses, and pooled-analyses.

Elevated body mass index (BMI) is linked to increased pancreatic cancer (PC) risk. Cancer-associated weight loss can occur years before the malignancy is diagnosed. This might have led to underestimation of the BMI-PC association. However, it is unknown if and to what extent this issue has been considered in previous epidemiological studies. We searched two databases through February 19, 2024 for systematic reviews, meta-analyses, and pooled analyses examining the BMI-PC association. We extracted information on study design with a special focus on the article's examination of prediagnostic weight loss as a potential source of bias, as well as how included cohort studies addressed this concern. Thirteen review articles, meta-analyses, and pooled analyses were identified. Only five (four pooled analyses, one systematic review) considered prediagnostic weight loss in their analyses. Twenty-four of 32 identified cohort studies reported having excluded initial years of follow-up. However, only 13 studies reported results after such exclusions, and effect estimates generally increased with longer periods of exclusion. We conclude that the association of overweight and obesity with PC risk is likely larger than suggested by published epidemiological evidence. Future studies should pay careful attention to avoid or minimize potential bias resulting from prediagnostic weight loss.

The underestimated impact of excess body weight on colorectal cancer risk: Evidence from the UK Biobank cohort.

BACKGROUND: The association between excess weight and colorectal cancer (CRC) risk may have been underestimated due to potential weight loss during pre-clinical sojourn time of CRC. We aimed to investigate this association and the corresponding population attributable fraction (PAF), accounting for prediagnostic weight loss. METHODS: Data from the UK Biobank prospective cohort were used. Multivariable adjusted hazard ratios (HR) and their 95% confidence intervals (CI) for various periods of follow-up and the corresponding PAF of excess weight were calculated. RESULTS: During a median of 10.0 years of follow-up, of 453,049 participants, 4794 developed CRC. The excess weight-CRC association became substantially stronger with including increasing lengths of follow-up in the analyses and further excluding the initial years of follow-up. HRs (95% CIs) for overweight and obesity were 1.06 (0.97-1.16) and 1.14 (1.03-1.26) after 7 years of follow-up, 1.13 (1.05-1.21) and 1.23 (1.14-1.33) when including complete follow-up length, and 1.26 (1.12-1.43) and 1.42 (1.24-1.63) when excluding the initial 7 years of follow-up. The corresponding PAFs of excess weight were estimated as 6.8%, 11.3%, and 19.0%, respectively. CONCLUSIONS: Comprehensive consideration of the potential effect of prediagnostic weight loss discloses a much stronger impact of excess body weight on CRC risk than previously assumed.

FDA Analysis of Ineligibility for Acute Myeloid Leukemia Clinical Trials by Race and Ethnicity.

BACKGROUND: Patients of certain racial and ethnic groups have been underrepresented in clinical trials for treatment of malignancy. One potential barrier to participation is entry requirements that lead to patients in various racial and ethnic groups not meeting eligibility criteria for studies (ie, "screen failure"). The objective of this study was to analyze the rates and reasons for trial ineligibility by race and ethnicity in trials of acute myeloid leukemia (AML) submitted to the U.S. Food and Drug Administration (FDA) between 2016 and 2019. MATERIALS AND METHODS: Multicenter, global clinical trials submitted to the FDA to support AML drugs and biologics. We examined the rate of ineligibility among participants screened for studies of AML therapies submitted to the FDA from 2016 to 2019. Data were extracted from 13 trials used in approval evaluations, including race, screen status, and reason for ineligibility. RESULTS: Overall, patients in historically underrepresented racial and ethnic groups were less likely to meet entry criteria for studies compared to White patients, with 26.7% of White patients, 29.4% of Black patients, and 35.9% of Asian patients not meeting entry criteria. Lack of relevant disease mutation was the reason for ineligibility more frequently among Black and Asian patients. The findings were limited by the small number of underrepresented patients screened for participation. CONCLUSION: Our results suggest that entry requirements for studies may put underrepresented patients at a disadvantage, leading to less eligible patients and thus lower participation in clinical trials.

Incidence and survival estimates for patients with myelodysplastic syndrome in the early 21st century: no evidence of improvement over time.

We examine changes in population level incidence and survival of patients diagnosed with myelodysplastic syndrome (MDS) in the United States in 2001-2016. Data were extracted from the Surveillance, Epidemiology, and End Results (SEER)-18 database. Period analysis was used to calculate one-, two-, and five-year survival. The incidence peaked at 5.6 per 100,000 in 2010 then decreased to 3.9 by 2016, with a decrease in the diagnoses of refractory anemia (RA) and RA with ringed sideroblasts (RARS) and a relative increase in RA with excess blasts (RAEB). Overall, one-, two-, and five-year relative survival decreased over time, going from 74.3%, 60.9%, and 42.3%, respectively, in 2008-2010 to 70.9%, 55.9%, and 37.6%, respectively, in 2014-2016. When survival was examined by histology, patients with RA/RARS and RAEB had similar survival expectations in 2008-2010 versus 2014-2016 and a decrease was observed for 5q-MDS. Our results highlight the need for new treatment options in MDS.

Changes in long term survival after diagnosis with common hematologic malignancies in the early 21st century.

Five-year survival has increased for many hematologic malignancies in the 21st century. However, whether this has translated into greater long-term survival is unknown. Here, we examine 10- and 20-year survival for patients with multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphoid leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). Data were extracted from the Surveillance, Epidemiology, and End Results-9 database. Patients age 15+ with the above malignancies were included. The newly developed boomerang method was used to examine 10- and 20-year relative survival (RS) for patients in 2002-2006 and 2012-16. Ten and 20-year RS increased for each malignancy examined, with increases ranging from +4.4% units for 20-year RS for AML to +23.1% units for 10-year RS for CML. Ten year RS was >50% in 2012-16 for patients with CLL, CML, HL, NHL, and DLBCL, at 77.1%, 62.1%, 63.9%, 64.5%, and 63.0%, respectively. Survival dropped between 10 and 20 years after diagnosis for most malignancies. Long-term survival is increasing for common hematologic malignancies, but late mortality is an ongoing issue. Further study of long-term outcomes in curable malignancies to determine the reason for these later decreases in survival is indicated.

Changes in population-level survival for advanced solid malignancies with new treatment options in the second decade of the 21st century.

BACKGROUND: Several new treatments that improve survival in clinical trials have been developed for various solid malignancies in advanced stages. The effect of these options on survival in the general population is currently unknown. METHODS: Cancers for which 2 or more new treatment options have been approved by the US Food and Drug Administration during the years 2009 through 2011 for the treatment of advanced disease were identified, including adenocarcinoma of the lung, melanoma, breast cancer, prostate cancer, and renal cell carcinoma. Kaplan-Meier analysis was used to compare overall survival for these conditions in the Surveillance, Epidemiology, and End Results database for the periods 2007 to 2008, 2009 to 2010, and 2011 to 2012. Hazard ratios derived from adjusted, shared frailty models for cancer-specific survival were calculated as well for the years of diagnosis (2007-2008, 2009-2010, and 2011-2012). RESULTS: Two-year survival increased for patients with advanced-stage lung adenocarcinoma (+3.0 percentage points), melanoma (+3.4 percentage points), and breast cancer (+2.7 percentage points). When only patients aged 15 to 64 years were included, 2-year survival for those with melanoma increased by +6.7 percentage points. No change in survival was observed for renal cell carcinoma. Decreases in the hazard ratio for cancer-specific mortality were observed during the period 2011 to 2012 compared with 2007 to 2008 for lung adenocarcinoma, melanoma, and breast cancer. CONCLUSIONS: Small increases in 2-year survival were observed between the periods 2007 to 2008 and 2011 to 2012 for lung adenocarcinoma, melanoma, and prostate cancer. Cancer-specific mortality decreased for each of these cancers among patients who were diagnosed between the periods 2007 to 2008 and 2011 to 2013. These findings suggest that newer treatment options are beginning to increase survival for stage IV cancers at the population level.

Nonsurgical therapies for resected and unresected pancreatic cancer in Europe and USA in 2003-2014: a large international population-based study.

The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This international large-scale population-based study aimed to investigate the real-world application of chemotherapy and radiotherapy for resected and unresected PaC in Europe and USA. Population-based data from multiple European national cancer registries and the US Surveillance, Epidemiology and End Results (SEER)-18 database during 2003-2014 were analyzed. Temporal trends and geographical variations in the application rates of chemotherapy and radiotherapy were quantified using age standardization. Associations of treatment with demographic and clinical characteristics were assessed using multivariable logistic regression. A total of 141,533 PaC patients were analyzed. From 2003-2005 to 2012-2014, chemotherapy administration rates increased in most countries and more strongly among resected patients, while radiation rates were generally low with a slight decline or no obvious trend. In 2012-2014, 12.5% (Estonia) to 61.7% (Belgium) of resected and 17.1% (Slovenia) to 56.9% (Belgium) of unresected patients received chemotherapy. Radiation was administered in 2.6% (Netherlands) to 32.6% (USA) of resected and 1.0% (USA) to 6.0% (Belgium) of unresected patients. Strong temporal and geographical variations were observed. Patterns and strengths of associations of treatment administration with various demographic and clinical factors differed substantially between resected and unresected cancers and varied greatly across countries. Conclusively, administration of chemotherapy but not radiotherapy for PaC increased during the last decade in Europe and USA. Treatment rates were low and the uptake strongly varied across countries, highlighting the need for standardization in PaC treatment to improve patient care.

Disparities in Colon Cancer Survival by Insurance Type: A Population-Based Analysis.

BACKGROUND: Colon cancer is a common cancer with a relatively high survival for nonmetastatic disease if appropriate treatment is given. A lower survival rate for patients with no or inadequate insurance has previously been documented, but the differences have not been explored in detail on a population level. OBJECTIVE: The purpose of this study was to examine survival for patients with colon cancer by insurance type. DESIGN: Complete analysis was used to examine 1-, 2-, and 3-year survival rates. SETTINGS: This was a population-level analysis. PATIENTS: Patients were drawn from the in-patients diagnosed with colon cancer at ages 15 to 64 years between 2007 and 2012 in the Surveillance, Epidemiology, and End Results 18 database by insurance type (Medicaid, uninsured, or other insurance) MAIN OUTCOME MEASURE:: This study measured overall survival. RESULTS: A total of 57,790 cases were included, with insurance information available for 55,432. Of those, 7611 (13.7%), 4131 (7.5%), and 43,690 (78.8%) had Medicaid, no insurance, or other insurance. Patients with Medicaid or without insurance were more likely to have metastatic disease compared with those with other insurance. Survival was higher for patients with insurance other than Medicaid, with 3-year survival estimates of 57.0%, 61.2%, and 75.6% for Medicaid, uninsured, and other insurance. Significant disparities continued to be observed after adjustment for stage, especially for later-stage disease. When only patients with stage I to II disease who had definitive surgery and resection of ≥12 lymph nodes were included in the analysis, the discrepancy was decreased, especially for uninsured patients. LIMITATIONS: Information on chemotherapy use and biological markers of disease severity are not available in the database. CONCLUSIONS: Colon cancer survival is lower for patients with no insurance or with Medicaid than for those with private insurance. Differences in rates of definitive surgery and adequate lymph node dissection explain some of this disparity. See Video Abstract at http://links.lww.com/DCR/A585.

Survival of patients with hepatobiliary tract and duodenal cancer sites in Germany and the United States in the early 21st century.

Hepatobiliary tract cancers (HBTCs) are a heterogeneous group of cancers with high mortality. Because most of these cancers, with the exception of hepatocellular carcinoma (HCC), are rare, few data are available concerning the population level survival expectations of patients with HBTC. Here, we describe survival of patients with HBTC in Germany with comparison to survival in the US. Therefore, data were extracted from 12 databases in Germany and the Surveillance, Epidemiology and End Results (SEER13) database in the US. Period analysis and modeled period analysis were used to calculate 5-year relative survival estimates for patients with HBTC diagnosed from 1997 to 2013. HCC was the most common HBTC in each database, accounting for over 1/3 of HBTC in Germany and about half of cases in the US. Overall age adjusted 5-year relative survival for HBTC in 2006-2013 was 19.1% in Germany and 20.6% in the US. Five-year relative survival increased by 3.8% units in Germany and 4.5% units in the US between 2002-2005 and 2010-2013. Five-year relative survival for individual types of HBTC ranged from 9.8% in Germany and 2.9% in the US for not otherwise specified biliary tract cancers to 44.4% and 50.1%, respectively, in Germany and the US for duodenal cancers. In conclusion, survival for HBTC remains poor in both Germany and the US, although a small increase in survival in the past decade was observed. Further work to find better treatment options for HBTC is needed to improve survival.

A Multidisciplinary Approach to Impact Acute Care Utilization in Sickle Cell Disease.

Sickle cell disease (SCD), an inherited red blood cell disorder, is characterized by anemia, end-organ damage, unpredictable episodes of pain, and early mortality. Emergency department (ED) visits and hospitalizations are frequent, leading to increased burden on patients and increased health care costs. This study assessed the effects of a multidisciplinary care team intervention on acute care utilization among adults with SCD. The multidisciplinary care team intervention included monthly team meetings and development of individualized care plans. Individualized care plans included targeted pain management plans for management of uncomplicated pain crisis. Following implementation of the multidisciplinary care team intervention, a significant decrease in ED utilization was identified among those individuals with a history of high ED utilization. Findings highlight the potential strength of multidisciplinary interventions and suggest that targeting interventions toward high-utilizing subpopulations may offer the greatest impact.

Survival for patients with rare haematologic malignancies: Changes in the early 21st century.

INTRODUCTION: Population-level survival has improved for common haematologic malignancies in the early 21st century. However, relatively few population-level data are available for rare haematologic malignancies. METHODS: Data were extracted from 12 cancer registries in Germany and the Surveillance, Epidemiology and End Results database in the United States (US). Cases of haematologic malignancies with an incidence of less than 1 per 100,000 were selected for analysis. Period analysis was used to determine 5-year relative survival (RS) for the years 2003-2012, and modelled period analysis was used to determine changes in survival between 2003-2007 and 2008-2012. RESULTS: Seven individual haematologic malignancies which met criteria were identified. Overall 5-year age-adjusted RS was 62.4% in Germany and 57.0% in the US in 2003-2012, with a good deal of variability by individual haematologic malignancy, ranging from less than 30% for chronic monomyeloid leukaemia to greater than 85% for hairy cell leukaemia and mycosis fungoides. Five-year RS increased significantly between 2003-2007 and 2008-2012 for patients with mantle cell lymphoma, Burkitt's lymphoma and hairy cell leukaemia in Germany and for patients with mantle cell lymphoma and anaplastic large-cell kinase+ anaplastic lymphoma in the US. CONCLUSIONS: Survival for rare haematologic malignancies varied considerably by cancer entity. Overall 5-year RS was slightly higher in Germany compared to the US. Survival estimates increased for a minority of haematologic malignancies between 2003-2007 and 2008-2012. Further research into the best treatment options for rare malignancies is needed to further improve survival.

Social disparities in survival after diagnosis with colorectal cancer: Contribution of race and insurance status.

BACKGROUND: Both minority race and lack of health insurance are risk factors for lower survival in colorectal cancer (CRC) but the interaction between the two factors has not been explored in detail. METHODS: One to 5-year survival by race/ethnic group and insurance type for patients with CRC diagnosed in 2007-13 and registered in the Surveillance Epidemiology, and End RESULTS: database were explored. Shared frailty models were computed to further explore the association between CRC specific survival and insurance status after adjustment for demographic and treatment variables. RESULTS: Age-adjusted 5-year survival estimates were 70.4% for non-Hispanic whites (nHW), 62.7% for non-Hispanic blacks (nHB), 70.2% for Hispanics, 64.7% for Native Americans, and 73.1% for Asian/Pacific Islanders (API). Survival was greater for patients with insurance other than Medicaid for all races, but the differential in survival varied with race, with the greatest difference being seen for nHW at +25.0% and +20.2%, respectively, for Medicaid and uninsured versus other insurance. Similar results were observed for stage- and age-specific analyses, with survival being consistently higher for nHW and API compared to other groups. After confounder adjustment, hazard ratios of 1.53 and 1.50 for CRC-specific survival were observed for Medicaid and uninsured. Racial/ethnic differences remained significant only for nHB compared to nHW. CONCLUSIONS: Race/ethnic group and insurance type are partially independent factors affecting survival expectations for patients diagnosed with CRC. NHB had lower than expected survival for all insurance types.

Outcome disparities by insurance type for patients with acute myeloblastic leukemia.

Survival for patients with acute myeloblastic leukemia (AML) has increased during the past two decades. However, socioeconomic disparities may affect survival for some patient populations. We examine survival by insurance type for patients with AML. Using data from the Surveillance, Epidemiology, and End Results database we estimated survival according to insurance status (no insurance, Medicaid, and other insurance) for patients diagnosed with AML in the United States in 2007-2013. One, 3-, and 5-year survival was lower for patients with no insurance and Medicaid than for patients with other insurance. Five-year survival estimates were 24.7%, 25.6%, and 35.7%, respectively, for patients with Medicaid, no insurance, and other insurance. After adjustment, hazard ratios of 1.46 for uninsured and 1.35 for Medicaid compared to other insurance for overall survival and 1.50 for uninsured and 1.30 for Medicaid compared to other insurance for AML-specific survival were observed. Similar results were seen in all ages and both genders. Patients with no insurance or Medicaid have lower survival expectations after diagnosis with AML than patients with other insurance. Further research into reasons for the poor outcomes for Medicaid patients and continued reduction of number of uninsured people are urgently needed to improve population-level outcomes for AML.

Population-Level Differences in Rectal Cancer Survival in Uninsured Patients Are Partially Explained by Differences in Treatment.

BACKGROUND: Rectal cancer (RC) is a common malignancy with a substantial mortality but good survival for patients with optimally treated nonmetastatic disease. Lack of insurance may compromise access to care and therefore compromise survival. Here, we examine RC survival by insurance type. METHODS: Data from the Surveillance, Epidemiology, and End Results database were used to determine 1- to 3-year survival for patients with RC by insurance type (Medicaid, uninsured, other insurance). RESULTS: Patients with Medicaid or no insurance presented at later stages and were less likely to receive definitive surgery. Overall 3-year survival was higher for patients with other insurance compared with Medicaid-insured (+22.2% units) and uninsured (+18.8% units) patients. Major differences in survival were still observed after adjustment for stage. When patients with stage II and III RC were considered, 3-year survival was higher for patients with other insurance versus those with Medicaid (+16.2% units) and uninsured patients (+12.2% units). However, when the analysis was limited to patients with stage II and III disease who received radiation therapy followed by definitive surgery, the difference decreased to +11.8% units and +7.3% units, respectively, for Medicaid and no insurance. CONCLUSION: For patients with stage II and III RC, much of the difference in survival between uninsured patients and those with insurance other than Medicaid can be explained by differences in treatment. Further efforts to determine the cause of residual differences as well as efforts to improve access to standard-of-care treatment for uninsured patients may improve population-level survival for RC. The Oncologist 2017;22:351-358 IMPLICATIONS FOR PRACTICE: Insurance status affects survival for patients with rectal cancer, but a substantial proportion of the difference in survival can be corrected if standard-of-care treatment is given. Every effort should be made to ensure that uninsured or publically insured patients receive standard-of-care treatment with as little delay as possible to improve patient outcomes.

Comparison of Emergency Department Wait Times in Adults with Sickle Cell Disease Versus Other Painful Etiologies.

Sickle cell disease is characterized by intermittent painful crises often requiring treatment in the emergency department (ED). Past examinations of time-to-provider (TTP) in the ED for patients with sickle cell disease demonstrated that these patients may have longer TTP than other patients. Here, we examine TTP for patients presenting for emergency care at a single institution, comparing patients with sickle cell disease to both the general population and to those with other painful conditions, with examination of both institutional and patient factors that might affect wait times. Our data demonstrated that at our institution patients with sickle cell disease have a slightly longer average TTP compared to the general ED population (+16 min.) and to patients with other painful conditions (+4 min.) However, when confounding factors were considered, there was no longer a significant difference between TTP of patients with sickle cell disease and the general population nor between patients with sickle cell disease and those with other painful conditions. Multivariate analyses demonstrated that gender, race, age, high utilizer status, fast track use, time of presentation, acuity and insurance type, were all independently associated with TTP, with acuity, time of presentation and use of fast track having the greatest influence. We concluded that the longer TTP observed in patients with sickle cell disease can at least partially be explained by institutional factors such as the use of fast track protocols. Further work to reduce TTP for sickle cell disease and other patients is needed to optimize care.

Changes in the survival of older patients with hematologic malignancies in the early 21st century.

BACKGROUND: Survival for patients with hematologic malignancies has improved during the early 21st century. However, it is unclear whether older patients have benefited to the same extent as younger patients. This study examines changes in survival for older patients with the 7 most common hematologic malignancies. METHODS: Period analysis was used to examine survival for patients who were 65 years old or older and were diagnosed with a common hematologic malignancy between 1992 and 2012 with data from the Surveillance, Epidemiology, and End Results database. RESULTS: Five-year relative survival increased for older patients with hematologic malignancies with the partial exception of acute myelogenous leukemia, for which no change in survival was seen for patients who were 75 years old or older. Patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma, including the oldest patients, had especially strong improvements, with increases in 5-year relative survival for patients who were 85 years old or older of 31.5% and 39.6%, respectively, between 1997-2000 and 2009-2012. CONCLUSIONS: Despite these increases, survival rates did not reach those observed for patients aged 50 to 59 years for any hematologic malignancy. Newer therapies and a better understanding of how to treat older patients have led to increased survival expectations for older patients with most hematologic malignancies, but an age-related survival disparity persists. Cancer 2016;122:2031-40. © 2016 American Cancer Society.

Survival in patients with acute myeloblastic leukemia in Germany and the United States: Major differences in survival in young adults.

Previous epidemiologic studies on AML have been limited by the rarity of the disease. Here, we present population level data on survival of patients with AML in Germany and the United States (US). Data were extracted from 11 population-based cancer registries in Germany and the Surveillance, Epidemiology, and End Results (SEER13) database in the US. Patients diagnosed with AML in 1997-2011 were included. Period analysis was used to estimate 5-year relative survival (RS) and trends in survival in the early 21st century. Overall 5-year age-adjusted RS for patients with AML in 2007-2011 was greater in Germany than in the US at 22.8% and 18.8%, respectively. Five-year RS was higher in Germany than in the US at all ages, with particularly large differences at ages 15-24 for whom 5-year RS was 64.3% in Germany and 55.0% in the US and 35-44, with 5-year RS estimates of 61.8% in Germany and 46.6% in the US. Most of the difference in 5-year RS was due to higher 1-year RS, with overall 1-year RS estimates of 47.0% in Germany and 38.5% in the US. A small increase in RS was observed between 2003-2005 and 2009-2011 in both countries, but no increase in survival was observed in either country for ages 75+. To our knowledge, this is the first detailed description of AML survival in Germany. Comparison to the US suggests that further analysis into risk factors for poor outcomes in AML in the US may be useful in improving survival.

Trends in survival of chronic lymphocytic leukemia patients in Germany and the USA in the first decade of the twenty-first century.

BACKGROUND: Recent population-based studies in the United States of America (USA) and other countries have shown improvements in survival for patients with chronic lymphocytic leukemia (CLL) diagnosed in the early twenty-first century. Here, we examine the survival for patients diagnosed with CLL in Germany in 1997-2011. METHODS: Data were extracted from 12 cancer registries in Germany and compared to the data from the USA. Period analysis was used to estimate 5- and 10-year relative survival (RS). RESULTS: Five- and 10-year RS estimates in 2009-2011 of 80.2 and 59.5%, respectively, in Germany and 82.4 and 64.7%, respectively, in the USA were observed. Overall, 5-year RS increased significantly in Germany and the difference compared to the survival in the USA which slightly decreased between 2003-2005 and 2009-2011. However, age-specific analyses showed persistently higher survival for all ages except for 15-44 in the USA. In general, survival decreased with age, but the age-related disparity was small for patients younger than 75. In both countries, 5-year RS was >80% for patients less than 75 years of age but <70% for those age 75+. CONCLUSIONS: Overall, 5-year survival for patients with CLL is good, but 10-year survival is significantly lower, and survival was much lower for those age 75+. Major differences in survival between countries were not observed. Further research into ways to increase survival for older CLL patients are needed to reduce the persistent large age-related survival disparity.