Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: the multicenter VITALITY study.

BACKGROUND AND AIMS: The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports. METHODS: This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates. RESULTS: In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. CONCLUSIONS: The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. IMPACT AND IMPLICATIONS: The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials.

Development and Validation of a Noninvasive Model for the Detection of High-Risk Varices in Patients with Unresectable HCC.

BACKGROUND & AIMS: Noninvasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a noninvasive algorithm for the prediction of varices in patients with unresectable HCC. METHODS: We performed a retrospective cohort study in 21 centers in the United States including adult patients with unresectable HCC and Child-Pugh A5-B7 cirrhosis diagnosed between 2007 and 2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but before HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients. RESULTS: We included 707 patients (median age, 64.6 years; 80.6% male; 74.0% White). Median time from HCC diagnosis to EGD was 47 (interquartile range, 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved an NPV of 86.3% in the validation cohort, whereas a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in more than half of low-risk patients while misclassifying 7.7% of high-risk patients. CONCLUSIONS: A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients before the initiation of systemic therapy, thus expediting their care and avoiding treatment delays.

The impact of surging transplantation of alcohol-associated liver disease on transplantation for HCC and other indications.

BACKGROUND: Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications. METHODS: Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): <28.4%, Tertile 2 (T2): 28.4%-37.6%, and Tertile 3 (T3): >37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p). RESULTS: Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66-1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96-1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87-1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72-1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67-1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80-1.34]) suggesting a differential impact of ATxV on LT probability. CONCLUSIONS: The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.

Barriers to liver transplant referral in safety net settings: A national provider survey.

Safety net systems care for patients with a high burden of liver disease yet experience many barriers to liver transplant (LT) referral. This study aimed to assess safety net providers' perspectives on barriers to LT referrals in the United States. We conducted a nationwide anonymous online survey of self-identified safety net gastroenterologists and hepatologists from March through November 2022. This 27-item survey was disseminated via e-mail, society platforms, and social media. Survey sections included practice characteristics, transplant referral practices, perceived multilevel barriers to referral, potential solutions, and respondent characteristics. Fifty complete surveys were included in analysis. A total of 60.0% of respondents self-identified as White and 54.0% male. A total of 90.0% practiced in an urban setting, 82.0% in tertiary medical centers, and 16.0% in community settings, with all 4 US regions represented. Perceived patient-level barriers ranked as most significant, followed by practice-level, then provider-level barriers. Patient-level barriers such as lack of insurance (72.0%), finances (66.0%), social support (66.0%), and stable housing/transportation (64.0%) were ranked as significant barriers to referral, while medical mistrust and lack of interest were not. Limited access to financial services (36.0%) and addiction/mental health resources (34.0%) were considered important practice-level barriers. Few reported existing access to patient navigators (12.0%), and patient navigation was ranked as most likely to improve referral practices, followed by an expedited/expanded pathway for insurance coverage for LT. In this national survey, safety net providers reported the highest barriers to LT referral at the patient level and practice level. These data can inform the development of multilevel interventions in safety net settings to enhance equity in LT access for vulnerable patients.

Country-Specific Screening, Prevalence, and Immunity Rates for Hepatitis B Infection in a Large US Safety-Net System.

Country- and region-specific estimates of hepatitis B virus (HBV) screening, prevalence, and immunity rates are provided for 202 868 adults from 174 unique countries in a large urban safety-net system. Of these, 41.8% (95% confidence interval, 41.5%-42.0%) were screened, with age-adjusted HBV prevalence of 0.9% (.9%-1.0%); 55.3% (54.9%-55.7%) had immunity testing, and 32.4% (31.9%-33.0%) were immune.

Increasing risk of hepatocellular carcinoma with successive generations in the United States among Mexican American adults: The Multiethnic Cohort.

BACKGROUND: US-born Latinos have a higher incidence of hepatocellular carcinoma (HCC) than foreign-born Latinos. Acculturation to unhealthy lifestyle behaviors and an immigrant self-selection effect may play a role. In this study, the authors examined the influence of generational status on HCC risk among Mexican American adults. METHODS: The analytic cohort included 31,377 self-reported Mexican Americans from the Multiethnic Cohort Study (MEC). Generational status was categorized as: first-generation (Mexico-born; n = 13,382), second-generation (US-born with one or two parents born in Mexico; n = 13,081), or third-generation (US-born with both parents born in the United States; n = 4914). Multivariable Cox proportional hazards regression was performed to examine the association between generational status and HCC incidence. RESULTS: In total, 213 incident HCC cases were identified during an average follow-up of 19.5 years. After adjusting for lifestyle and neighborhood-level risk factors, second-generation and third-generation Mexican Americans had a 37% (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.98-1.92) and 66% (HR, 1.66; 95% CI, 1.11-2.49) increased risk of HCC, respectively, compared with first-generation Mexican Americans (p for trend = 0.012). The increased risk associated with generational status was mainly observed in males (second-generation vs. first-generation: HR, 1.60 [95% CI, 1.05-2.44]; third-generation vs. first-generation: HR, 2.08 [95% CI, 1.29-3.37]). CONCLUSIONS: Increasing generational status of Mexican Americans is associated with a higher risk of HCC. Further studies are needed to identify factors that contribute to this increased risk.

Neighborhood-level Social Determinants of Health and Waitlist Mortality for Liver Transplantation: The Liver Outcomes and Equity Index.

BACKGROUND AND AIMS: To examine neighborhood-level disparities in waitlist mortality for adult liver transplantation (LT), we developed novel area-based social determinants of health (SDOH) index using a national transplant database. METHODS: ZIP Codes of individuals listed for or received LT in the Scientific Registry of Transplant Recipients database between June 18, 2013, and May 18, 2019, were linked to 36 American Community Survey (ACS) variables across 5 SDOH domains for index development. A step-wise principal component analysis was used to construct the Liver Outcomes and Equity (LOEq) index. We then examined the association between LOEq quintiles (Q1 = worst and Q5 = best neighborhood SDOH) and waitlist mortality with competing risk regression among listed adults in the study period and acuity circle (AC) era. RESULTS: The final LOEq index consisted of 13 ACS variables. Of 59 298 adults waitlisted for LT, 30% resided in LOEq Q5 compared with only 14% in Q1. Q1 neighborhoods with worse SDOH were disproportionately concentrated in transplant regions with low median Model for End-Stage Liver Disease at transplant (MMAT) and shorter wait times. Five years cumulative incidence of waitlist mortality was 33% in Q1 in high MMAT regions versus 16% in Q5 in low MMAT regions. Despite this allocation advantage, LOEq Q1-Q4 were independently associated with elevated risk of waitlist mortality compared with Q5, with highest increased hazard of waitlist deaths of 19% (95% CI, 11%-26%) in Q1. This disparity persisted in the AC era, with 24% (95% CI, 10%-40%) increased hazard of waitlist deaths for Q1 versus Q5. CONCLUSIONS: Neighborhood SDOH independently predicts waitlist mortality in adult LT.

Care for Vulnerable Populations with Chronic Liver Disease: A Safety-Net Perspective.

Safety-net hospitals (SNHs) and facilities are the cornerstone of healthcare services for the medically underserved. The burden of chronic liver disease-including end-stage manifestations of cirrhosis and liver cancer-is high and rising among populations living in poverty who primarily seek and receive care in safety-net settings. For many reasons related to social determinants of health, these individuals often present with delayed diagnoses and disease presentations, resulting in higher liver-related mortality. With recent state-based policy changes such as Medicaid expansion that impact access to insurance and critical health services, an overview of the body of literature on SNH care for chronic liver disease is timely and informative for the liver disease community. In this narrative review, we discuss controversies in the definition of a SNH and summarize the known disparities in the cascade of the care and management of common liver-related conditions: (1) steatotic liver disease, (2) liver cancer, (3) chronic viral hepatitis, and (4) cirrhosis and liver transplantation. In addition, we review the specific impact of Medicaid expansion on safety-net systems and liver disease outcomes and highlight effective provider- and system-level interventions. Lastly, we address remaining gaps and challenges to optimizing care for vulnerable populations with chronic liver disease in safety-net settings.

Factors Associated With Liver Transplant Referral Among Patients With Cirrhosis at Multiple Safety-Net Hospitals.

Importance: A high proportion of underserved patients with cirrhosis receive care at safety-net hospitals (SNHs). While liver transplant (LT) can be a life-saving treatment for cirrhosis, data on referral patterns from SNHs to LT centers are lacking. Objective: To identify factors associated with LT referral within the SNH context. Design, Setting, and Participants: This retrospective cohort study included 521 adult patients with cirrhosis and model for end-stage liver disease-sodium (MELD-Na) scores of 15 or greater. Participants received outpatient hepatology care at 3 SNHs between January 1, 2016, and December 31, 2017, with end of follow-up on May 1, 2022. Exposures: Patient demographic characteristics, socioeconomic status, and liver disease factors. Main Outcomes and Measures: Primary outcome was referral for LT. Descriptive statistics were used to describe patient characteristics. Multivariable logistic regression was performed to evaluate factors associated with LT referral. Multiple chained imputation was used to address missing values. Results: Of 521 patients, 365 (70.1%) were men, the median age was 60 (IQR, 52-66) years, most (311 [59.7%]) were Hispanic or Latinx, 338 (64.9%) had Medicaid insurance, and 427 (82.0%) had a history of alcohol use (127 [24.4%] current vs 300 [57.6%] prior). The most common liver disease etiology was alcohol associated liver disease (280 [53.7%]), followed by hepatitis C virus infection (141 [27.1%]). Median MELD-Na score was 19 (IQR, 16-22). One hundred forty-five patients (27.8%) were referred for LT. Of these, 51 (35.2%) were wait-listed, and 28 (19.3%) underwent LT. In a multivariable model, male sex (adjusted odds ratio [AOR], 0.50 [95% CI, 0.31-0.81]), Black race vs Hispanic or Latinx ethnicity (AOR, 0.19 [95% CI, 0.04-0.89]), uninsured status (AOR, 0.40 [95% CI, 0.18-0.89]), and hospital site (AOR, 0.40 [95% CI, 0.18-0.87]) were associated with lower odds of being referred. Reasons for not being referred (n = 376) included active alcohol use and/or limited sobriety (123 [32.7%]), insurance issues (80 [21.3%]), lack of social support (15 [4.0%]), undocumented status (7 [1.9%]), and unstable housing (6 [1.6%]). Conclusions: In this cohort study of SNHs, less than one-third of patients with cirrhosis and MELD-Na scores of 15 or greater were referred for LT. The identified sociodemographic factors negatively associated with LT referral highlight potential intervention targets and opportunities to standardize LT referral practices to increase access to life-saving transplant among underserved patients.

Association of nativity with survival among adults with hepatocellular carcinoma.

INTRODUCTION: Immigrants comprise a considerable proportion of those diagnosed with hepatocellular carcinoma (HCC) in the United States. Nativity or birthplace affects incidence and risk factors for HCC, but little is known about its influence on survival after diagnosis. METHODS: We identified 51 533 adults with HCC with available birthplace in the California Cancer Registry between 1988 and 2017. HCC cases were categorized as foreign born or US born and stratified by mutually exclusive race and ethnicity groups. Primary outcome was all-cause mortality. Race and ethnicity-specific Cox regression propensity score-weighted models evaluated the relationship between nativity and death as well as region of birth among foreign-born patients. RESULTS: A total of 40% of all HCC cases were foreign born, and 92.2%, 45.2%, 9.1%, and 5.8% of Asian/Pacific Islander (API), Hispanic, White, and Black patients were foreign born, respectively. Five-year survival rates were higher in foreign-born patients compared with US-born patients: 12.9% vs 9.6% for White patients, 11.7% vs 9.8% for Hispanic patients, 12.8% vs 8.1% for Black patients, and 16.4% vs 12.4% for API patients. Nativity was associated with survival, with better survival in foreign-born patients: White patients: hazard ratio (HR) = 0.86 (95% confidence interval [CI] = 0.81 to 0.90), Hispanic patients: HR = 0.90 (95% CI = 0.86 to 0.93), Black patients: HR = 0.89 (95% CI = 0.76 to 1.05), and API patients: HR = 0.94 (95% CI = 0.88 to 1.00). Among foreign-born patients, lower mortality was observed in those from Central and South America compared with Mexico for Hispanic patients, East Asia compared with Southeast Asia for API patients, and East Europe and Greater Middle East compared with West/South/North Europe for White patients. CONCLUSION: Foreign-born patients with HCC have better survival than US-born patients. Further investigation into the mechanisms of this survival disparity by nativity is needed.

Population-attributable risk of modifiable lifestyle factors to hepatocellular carcinoma: The multi-ethnic cohort.

BACKGROUND AND AIMS: Lifestyle factors are well associated with risk of hepatocellular carcinoma (HCC). However, the impact of reducing adverse lifestyle behaviours on population-level burden of HCC is uncertain. METHODS: We conducted prospective analysis of the population-based multi-ethnic cohort (MEC) with linkage to cancer registries. The association of lifestyle factors (smoking, alcohol, diet quality assessed by alternate Mediterranean diet score, coffee drinking, physical activity and body mass index) with HCC incidence was examined using Cox regression. Population-attributable risk (PAR, %) for the overall, lean and overweight/obese populations was determined. RESULTS: A total of 753 incident cases of HCC were identified in 181,346 participants over median follow-up of 23.1 years. Lifestyle factors associated with elevated HCC risk included former/current smoking, heavy alcohol use, poor diet quality, lower coffee intake and obesity, but not physical activity. The lifestyle factor with highest PAR was lower coffee intake (21.3%; 95% CI: 8.9%-33.0%), followed by current smoking (15.1%; 11.1%-19.0%), obesity (14.5%; 9.2%-19.8%), heavy alcohol use (7.1%; 3.5%-10.6%) and lower diet quality (4.1%; 0.1%-8.1%). The combined PAR of all high-risk lifestyle factors was 51.9% (95% CI: 30.1%-68.6%). A higher combined PAR was observed among lean (65.2%, 26.8%-85.7%) compared to overweight/obese (37.4%, 11.7%-58.3%) participants. Adjusting for viral hepatitis status in a linked MEC-Medicare dataset resulted in similar PAR results. CONCLUSIONS: Modifying lifestyle factors, particularly coffee intake, may have a substantial impact on HCC burden in diverse populations, with greater impact among lean adults. Diet and lifestyle counselling should be incorporated into HCC prevention strategies.

Recall patterns and risk of primary liver cancer for subcentimeter ultrasound liver observations: a multicenter study.

BACKGROUND: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC). AIMS: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound. METHODS: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively. RESULTS: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein >10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08). CONCLUSIONS: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels.

Disparities in presentation and management of chronic hepatitis B among Hispanics in a diverse safety net system.

BACKGROUND: Chronic hepatitis B (HBV) prevalence is highest in foreign-born Asian and African individuals in the US, though Hispanics make up the largest proportion of the immigrant population. Differences in the diagnosis and management of chronic HBV in Hispanics might exist due to the lower awareness of risk. We aim to examine racial/ethnic disparities in the diagnosis, presentation, and immediate management of chronic HBV in a diverse safety net system enriched for Hispanics. METHODS: In a large urban safety-net hospital system, we retrospectively identified patients with chronic HBV by serological data and categorized them into mutually exclusive self-identified racial/ethnic groups: Hispanics, Asians, Blacks, and Whites. We then examined differences in screening, disease phenotype and severity, follow-up testing, and referral by race/ethnicity. RESULTS: Among 1063 patients, 302 (28%) were Hispanics, 569 (54%) Asians, 161 (15%) Blacks, and 31 (3%) Whites. More Hispanics (30%) were screened in the acute setting (defined as inpatient or emergency department encounters) than Asians (13%), Blacks (17%), or Whites (23%) (p<0.01). Hispanics also had lower rates of follow-up testing after HBV diagnosis than Asians including HBeAg status (43% vs. 60%, p<0.01) and HBV DNA levels (42% vs. 58%, p<0.01) and lower rates of linkage to specialty care (32% vs. 55%, p<0.01). Among those with available testing, however, the presence of immune-active chronic HBV was infrequent and similar across racial/ethnic groups. 25% of Hispanics had cirrhosis at initial presentation, proportionally higher than other groups (p<0.01). CONCLUSION: Our results underscore the importance of raising chronic HBV awareness and increasing both screening and linkage to care among Hispanic immigrants in addition to the existing risk groups, with the goal of mitigating downstream liver-related complications.

Long-term clinical outcomes of patients with COVID-19 and chronic liver disease: US multicenter COLD study.

BACKGROUND: COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited. METHODS: We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19. RESULTS: We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31-462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19-2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62-2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01-2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26-2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06-2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine. CONCLUSIONS: Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

Geographic hotspot detection for late-stage hepatocellular carcinoma: novel approach to cancer control.

IMPORTANCE: As hepatocellular carcinoma (HCC)-associated mortality continues to rise in the United States, there is a crucial need for strategies to shift diagnoses from late to early stage in order to improve survival. OBJECTIVE: To describe a population-based geospatial approach to identifying areas with high late-stage HCC burden for intervention. DESIGN: Cross-sectional study between 2008 and 2017. SETTING: Los Angeles County. PARTICIPANTS: All incident cases of HCC with residential address at diagnosis in Los Angeles County were identified from a population-based cancer registry. Late stage included AJCC 7th Edition stages III-IV and unstaged cases. EXPOSURE: Sociodemographic factors. MAIN OUTCOME(S): Geographic "hotspots" or areas with a high density of late-stage HCC, identified using kernel density estimation in ArcMap 10.3.1. RESULTS: 51.8% of 7,519 incident cases of HCC were late stage. We identified a total of 23 late-stage hotspots, including 30.0% of all late-stage cases. Cases within hotspots were more often racial/ethnic minorities, foreign-born, under or uninsured, and of lower socioeconomic status. The age-adjusted incidence rate of late-stage HCC was twofold higher within hotspots (6.85 per 100,000 in hotspots vs 3.38 per 100,000 outside of hotspots). The calculated population-attributable risk was 43%, suggesting that a substantial proportion of late-stage HCC burden could be averted by introducing interventions in hotspot areas. We mapped the relationship between hotspots and federally qualified health centers primary care clinics and subspecialty clinics in Los Angeles County to demonstrate how clinic partnerships can be selected to maximize impact of interventions and resource use. Hotspots can also be utilized to identify "high-risk" neighborhoods that are easily recognizable by patients and the public and to facilitate community partnerships. CONCLUSION AND RELEVANCE: Reducing late-stage HCC through geographic late-stage hotspots may be an efficient approach to improving cancer control and equity.

Diverging Incidence Trends for Hepatocellular Carcinoma in Rural and Urban Settings in the United States.

In the United States, hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths and was the 5th most common cause in 2020.1 One in 5 Americans lives in a rural area,2 yet little is known about temporal changes in HCC incidence by rural-urban residence. Area-specific data are critical to guide public health strategies and clinical interventions. Our study compared the overall and subgroup incidence trends for HCC across rural and urban communities in the United States over the past 20 years using the North American Association of Central Cancer Registries database, which covers 93% of the United States and well-represents the rural United States (North American Association of Central Cancer Registries 14.6% rural vs United States 14.8% rural).3.