Patterns of Failure in Patients With Borderline Resectable/Locally Advanced Pancreatic Cancer After Preoperative Chemotherapy and Stereotactic Body Radiation Therapy.

Purpose: The role of preoperative stereotactic body radiation therapy (SBRT) in pancreatic cancer is controversial, and questions regarding the optimal dose and radiation treatment field remain. To better inform future investigations of SBRT dose and radiation fields, we evaluated the patterns of failure in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC) after preoperative chemotherapy and SBRT in patients who underwent surgical resection. Methods and Materials: We performed a single-institution retrospective review of consecutive patients treated from September 2017 to January 2022 with BR/LAPC. Patients who underwent preoperative chemotherapy and SBRT followed by surgical resection were reviewed. SBRT was delivered to a dose of 33 Gy in 5 fractions. Kaplan-Meier overall survival and progression-free survival estimates were calculated. Results: In total, 18 patients (12 BRPC, 6 LAPC) were included. Median age was 69 years (range 41-84 years). Median follow-up was 30 months (range 13-59 months). Seventeen patients (94%) had a R0 resection and 13 (72%) underwent vascular reconstruction. Median overall survival and progression-free survival was 42 months (range 13-59 months) and 23 months (range 1-45 months), respectively. In total, 61% (11/18) patients experienced progression at any point during follow-up. Of the patients who experienced recurrence, 27% (3/11) experienced local progression as component of their first recurrence, whereas 100% (11/11) experienced distant progression as a component of their first recurrence. When examining all recurrences that occurred at any point in follow-up, 28% (5/18) of patients experienced local or locoregional recurrence and 61% (11/18) experienced distant progression. Conclusions: Local control and margin negative resection rates were excellent with preoperative chemotherapy and nondose-escalated SBRT in surgically resected patients with BR/LAPC. Distant recurrence was the predominant site of failure with lower incidences of isolated locoregional recurrences. Additional research is needed to determine the ideal treatment volume and patients who may benefit from dose escalation.

Implications of drug intoxication on donor utilization and outcomes in liver transplantation.

INTRODUCTION: This study evaluates the implications of drug intoxication (DI) on donor utilization and outcomes in liver transplantation (LT). METHODS: The UNOS STAR database was evaluated for all potential donors and adult, first-time, whole LT between 2005 and 2019. Logistic regression analyses evaluated liver utilization; proportional hazards modeling assessed risk of 1-year graft loss. RESULTS: A total of 132 783 potential donors (10 205, 7.7% from DI), and 90 612 adult LT were identified (7490, 8.3% from DI). DI donors had median age 32 years (IQR 26-40 years, p < .001), were 42.6% female (n = 4346), and 15.5% were DCD donors (n = 1583). Utilization of DI donors changed over time, such that by 2015-2019 they were the most likely donor cause of death (COD) to be utilized. Among LT recipients, there were insignificant differences (<2% variance) in age, gender, ethnicity, and etiology of liver disease according to donor COD. Recipients with MELD scores >30 more frequently received grafts from donors with trauma (23.8%) and DI (21.8%) versus cardiovascular (20.0%) and CVA/stroke (19.9%, p < .001). Among DBD donors, DI-COD was associated with superior 1-year graft survival compared to donors from trauma (HR 1.172, 95% CI 1.057-1.300) and CVA/stroke (HR 1.404, 95% CI 1.264-1.561, p < .001). Donor COD was not significantly associated with 1-year graft loss among DCD donors. CONCLUSIONS: There is an increased likelihood of donor utilization when COD is drug overdose and an increased likelihood of 1-year graft survival compared to donors from trauma, CVA/stroke, and other COD.

The Disproportionate Rise in Pancreatic Cancer in Younger Women Is Due to a Rise in Adenocarcinoma and Not Neuroendocrine Tumors: A Nationwide Time-Trend Analysis Using 2001-2018 United States Cancer Statistics Databases.

In previous studies, a significant increase in the incidence of pancreatic cancer among younger women compared to men in the United States was noted. However, the specific histopathologic characteristics were not delineated. This population-based study aimed to assess whether this disproportionate rise in pancreatic cancer in younger women was contributed by pancreatic ductal adenocarcinoma (PDAC) or pancreatic neuroendocrine tumors (PanNET). The United States Cancer Statistics (USCS) database was used to identify patients with pancreatic cancer between 2001 and 2018. The results showed that, in younger adults, the incidence of PDAC has increased in women [average annual percentage change (AAPC) = 0.62%], while it has remained stable in men (AAPC = -0.09%). The PDAC incidence rate among women increased at a greater rate compared to men with a statistically significant difference in AAPC (p < 0.001), with neither identical nor parallel trends. In contrast, cases of PanNET did not demonstrate a statistically significant sex-specific AAPC difference. In conclusion, this study demonstrated that the dramatic increase in the incidence rate of PDAC explains the disproportionate rise in pancreatic cancer incidence in younger women. This prompts further prospective studies to investigate the underlying reasons for these sex-specific disparities in PDAC.

Recent advances in the management of hepatocellular carcinoma.

Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.

Increasing Pancreatic Cancer Incidence in Young Women in the United States: A Population-Based Time-Trend Analysis, 2001-2018.

BACKGROUND & AIMS: Previous studies have shown an increasing incidence of pancreatic cancer (PC), especially in younger women; however, this has not been externally validated. In addition, there are limited data about contributing factors to this trend. We report age and sex-specific time-trend analysis of PC age-adjusted incidence rates (aIRs) using the National Program of Cancer Registries database without Surveillance Epidemiology and End Results data. METHODS: PC aIR, mortality rates, annual percentage change, and average annual percentage change (AAPC) were calculated and assessed for parallelism and identicalness. Age-specific analyses were conducted in older (≥55 years) and younger (<55 years) adults. PC incidence based on demographics, tumor characteristics, and mortality were evaluated in younger adults. RESULTS: A total of 454,611 patients were diagnosed with PC between 2001 and 2018 with significantly increasing aIR in women (AAPC = 1.27%) and men (AAPC = 1.14%) without a difference (P = .37). Similar results were seen in older adults. However, in younger adults (53,051 cases; 42.9% women), women experienced a greater increase in aIR than men (AAPCs = 2.36%, P < .001 vs 0.62%, P = 0.62) with nonparallel trends (P < .001) and AAPC difference of 1.74% (P < .001). This AAPC difference appears to be due to rising aIR in Blacks (2.23%; P < .001), adenocarcinoma histopathologic subtype (0.89%; P = .003), and location in the head-of-pancreas (1.64%; P < .001). PC mortality was found to be unchanged in women but decreasing in counterpart men (AAPC difference = 0.54%; P = .001). CONCLUSION: Using nationwide data, covering ≈64.5% of the U.S. population, we externally validate a rapidly increasing aIR of PC in younger women. There was a big separation of the incidence trend between women and men aged 15-34 years between 2001 and 2018 (>200% difference), and it did not show slowing down.

Pancreatic Cancer Incidence Trends by Race, Ethnicity, Age and Sex in the United States: A Population-Based Study, 2000-2018.

BACKGROUND AND AIMS: Pancreatic cancer (PC) incidence is increasing at a greater rate in young women compared to young men. We performed a race- and ethnicity-specific evaluation of incidence trends in subgroups stratified by age and sex to investigate the association of race and ethnicity with these trends. METHODS: Age-adjusted PC incidence rates (IR) from the years 2000 to 2018 were obtained from the SEER 21 database. Non-Hispanic White (White), Non-Hispanic Black (Black) and Hispanic patients were included. Age categories included older (ages ≥ 55) and younger (ages < 55) adults. Time-trends were described as annual percentage change (APC) and average APC (AAPC). RESULTS: Younger White [AAPC difference = 0.73, p = 0.01)], Black [AAPC difference = 1.96, p = 0.01)] and Hispanic [AAPC difference = 1.55, p = 0.011)] women experienced a greater rate of increase in IR compared to their counterpart men. Younger Hispanic women experienced a greater rate of increase in IR compared to younger Black women [AAPC difference = -1.28, p = 0.028)] and younger White women [AAPC difference = -1.35, p = 0.011)]. CONCLUSION: Younger women of all races and ethnicities experienced a greater rate of increase in PC IR compared to their counterpart men; however, younger Hispanic and Black women experienced a disproportionately greater increase. Hispanic women experienced a greater rate of increase in IR compared to younger Black and White women.

Pancreatoblastoma in Elderly Adults: Report of Two Patients.

Introduction. Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas, which often shows multiple lines of differentiation, but is defined by neoplastic cells with acinar differentiation and characteristic squamoid nests. Pediatric patients are most commonly affected, and although a subset is known to occur in adults, the diagnosis is rarely considered in elderly adults. Methods. The clinicopathologic features of two cases of pancreatoblastoma in elderly patients were examined. Results. Two patients (age 80 and 81 years) presented with pancreatoblastoma, including one with early-stage pancreatic disease and one with liver metastasis. Biopsies and one pancreatic resection specimen showed characteristic histomorphologic features, including prominent acinar differentiation and abundant squamoid nests. Both cases had complete loss of SMAD4 (DPC4) immunolabeling. Next generation sequencing was performed on one case and revealed copy number loss of chromosome 11p and 9p21 (CDKN2A/B) and pathogenic or likely pathogenic variants in APC, SMAD4, and PIK3CA. The APC and SMAD4 variants occurred at allele frequencies suggestive of germline mutations, raising the possibility that this patient may have an inherited cancer predisposition syndrome. Conclusions. We present two cases which extend the upper age limit for reported pancreatoblastoma, including one with genetic findings suggestive of an inherited cancer predisposition syndrome.

HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

Disparities in curative treatments and outcomes for early stage intrahepatic cholangiocarcinoma in the United States.

BACKGROUND: Curative surgical treatments afford the best prognosis for patients with intrahepatic cholangiocarcinoma (iCCA); however, the comparative effectiveness of treatment options and factors associated with curative treatment receipt for early stage iCCA remain unknown. METHODS: The authors identified patients who were diagnosed with early stage iCCA, defined as a unifocal tumor <3 cm, during 2004-2018 from the National Cancer Database. Multivariable logistic and Cox regression analyses were used to identify the factors associated with curative treatment and overall survival (OS), respectively. RESULTS: The proportion of patients with early stage iCCA increased from 4.5% in 2004 to 7.3% in 2018, with the odds of early stage detection increasing by 3.1% per year (odds ratio [OR], 1.031; 95% CI, 1.015-1.049). Of 1093 patients who had early stage iCCA, 464 (42.5%) underwent resection, 113 (10.3%) underwent ablation, 62 (5.7%) underwent liver transplantation, and 454 (41.5%) received noncurative treatments. Hispanic patients (adjusted OR [aOR], 0.57; 95% CI, 0.33-0.97) and Black patients (aOR, 0.47; 95% CI, 0.28-0.77) were less likely to receive curative treatments than White patients. Compared with patients who underwent surgical resection, those who underwent liver transplantation had a trend toward improved OS (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.37-1.08), whereas those who underwent local ablation (aHR, 1.39; 95% CI, 1.01-1.92) and noncurative treatments (aHR, 3.97; 95% CI, 3.24-4.88) experienced worse OS. CONCLUSIONS: More than one third of patients with early stage iCCA did not receive curative treatment, with Hispanic and Black patients being less likely to receive curative treatments than White patients. Surgical resection and liver transplantation were associated with improved survival compared with local ablation. Future studies should investigate disparities in curative treatment receipt and outcomes for early stage iCCA.

Association between sustained virological response and clinical outcomes in patients with hepatitis C infection and hepatocellular carcinoma.

BACKGROUND: Sustained viral response (SVR) improves survival for patients with hepatitis C (HCV) and hepatocellular carcinoma (HCC) after curative treatment; however, the benefit of SVR in those with active HCC with a significant competing risk of mortality is unknown. This study aimed to evaluate the association between SVR and outcomes in patients with active HCC. METHODS: The authors performed a multicenter, retrospective cohort study including consecutive adults with HCV cirrhosis and treatment-naive HCC diagnosed between 2014 and 2018. Patients were stratified into two groups: active viremia (n = 431) and SVR before HCC diagnosis (n = 135). All patients underwent nonsurgical therapy as their initial treatment and were followed until liver transplantation, last follow-up, or death. The primary outcome was incident or worsening hepatic decompensation within 6 months and the secondary outcome was overall survival. All analyses used inverse probability of treatment weights (IPTW) to account for differences between the nonrandomized cohorts. RESULTS: Post-SVR patients had significantly lower odds of hepatic decompensation compared to viremic patients (odds ratio [OR], 0.18; 95% confidence interval [CI], 0.06-0.59). Results were consistent among subgroups of patients with Child Pugh A cirrhosis (OR, 0.22; 95% CI, 0.04-0.77), Barcelona Clinic Liver Cancer stage B/C HCC (OR, 0.20; 95% CI, 0.04-0.65), and those receiving nonablative HCC therapies (OR, 0.21; 95% CI, 0.07-0.67). However, in IPTW multivariable Cox regression, SVR was not associated with improved survival (hazard ratio, 0.79; 95% CI, 0.56-1.12). CONCLUSIONS: Patients with HCV-related HCC and SVR are less likely to experience hepatic decompensation than viremic patients, suggesting patients with HCC who are undergoing nonsurgical therapies may benefit from DAA treatment.

Circulating Fatty Objects and Their Preferential Presence in Pancreatic Cancer Patient Blood Samples.

Human cancers are often complicated with increased incidences of blood vessel occlusion, which are mostly insensitive to anticoagulation therapy. We searched for causal factors of cancer-associated embolism. A total of 2,017 blood samples was examined for visible abnormalities. Examined were peripheral blood samples from cancer patients who were about to undergo surgical treatment for genitourinary, breast, gastrointestinal or abdominal tumors. Samples from ambulatory patients being treated for recurrent or castration-resistant prostate cancers were included in the study. The lipid-rich nature was studied with lipophilic stains and lipid panel analysis, while surface membrane was assessed with specific staining and antibody detection. We identified a new entity, lipid droplet-like objects or circulating fatty objects (CFOs), visible in the blood samples of many cancer patients, with the potential of causing embolism. CFOs were defined as lipid-rich objects with a membrane, capable of gaining in volume through interaction with peripheral blood mononuclear cells in ex vivo culture. Blood samples from pancreatic cancer patients were found to have the highest CFO incidence and largest CFO numbers. Most noticeably, CFOs from many pancreatic cancer samples presented as large clusters entangled in insoluble fiber networks, suggestive of intravascular clotting. This study identifies CFO as an abnormal entity in cancer patient blood, and a contributory factor to intravascular embolism during cancer development and progression.

A Clinical Tool to Guide Selection and Utilization of Marginal Donor Livers With Graft Steatosis in Liver Transplantation.

BACKGROUND: Donor liver biopsy (DLBx) in liver transplantation provides information on allograft quality; however, predicting outcomes from these allografts remains difficult. METHODS: Between 2006 and 2015, 16 691 transplants with DLBx were identified from the Standard Transplant Analysis and Research database. Cox proportional hazard regression analyses identified donor and recipient characteristics associated with 30-d, 90-d, 1-y, and 3-y graft survival. A composite model, the Liver Transplant After Biopsy (LTAB) score, was created. The Mini-LTAB was then derived consisting of only donor age, macrosteatosis on DLBx, recipient model for end-stage liver disease score, and cold ischemic time. Risk groups were identified for each score and graft survival was evaluated. P values <0.05 were considered significant. RESULTS: The LTAB model used 14 variables and 5 risk groups and identified low-, mild-, moderate-, high-, and severe-risk groups. Compared with moderate-risk recipients, severe-risk recipients had increased risk of graft loss at 30 d (hazard ratio, 3.270; 95% confidence interval, 2.568-4.120) and at 1 y (2.258; 1.928-2.544). The Mini-LTAB model identified low-, moderate-, and high-risk groups. Graft survival in Mini-LTAB high-risk transplants was significantly lower than moderate- or low-risk transplants at all time points. CONCLUSIONS: The LTAB and Mini-LTAB scores represent guiding principles and provide clinically useful tools for the successful selection and utilization of marginal allografts in liver transplantation.

S-adenosylmethionine inhibits la ribonucleoprotein domain family member 1 in murine liver and human liver cancer cells.

BACKGROUND AND AIMS: Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion and develop NASH and HCC spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, characterizing the phospho-proteome and determining whether they contribute to liver pathology remain open for study. Our study aimed to provide this knowledge. APPROACH AND RESULTS: We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found that the most striking change was hyperphosphorylation and increased content of La-related protein 1 (LARP1), which, in the unphosphorylated form, negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in KO livers. Translation of TOP mRNAs ribosomal protein S3 and ribosomal protein L18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1-overexpression-mediated increase in translation. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC. CONCLUSIONS: Our results reveal a SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.

Single-session EUS-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) and EUS-guided gallbladder drainage is safe and feasible.

Video 1Single-session EDGE with ERCP and EUS gallbladder drainage.

Covalent Chemistry-Mediated Multimarker Purification of Circulating Tumor Cells Enables Noninvasive Detection of Molecular Signatures of Hepatocellular Carcinoma.

Transcriptomic profiling of tumor tissues introduces a large database, which has led to improvements in the ability of cancer diagnosis, treatment, and prevention. However, performing tumor transcriptomic profiling in the clinical setting is very challenging since the procurement of tumor tissues is inherently limited by invasive sampling procedures. Here, we demonstrated the feasibility of purifying hepatocellular carcinoma (HCC) circulating tumor cells (CTCs) from clinical patient samples with improved molecular integrity using Click Chips in conjunction with a multimarker antibody cocktail. The purified CTCs were then subjected to mRNA profiling by NanoString nCounter platform, targeting 64 HCC-specific genes, which were generated from an integrated data analysis framework with 8 tissue-based prognostic gene signatures from 7 publicly available HCC transcriptomic studies. After bioinformatics analysis and comparison, the HCC CTC-derived gene signatures showed high concordance with HCC tissue-derived gene signatures from TCGA database, suggesting that HCC CTCs purified by Click Chips could enable the translation of HCC tissue molecular profiling into a noninvasive setting.

Comparison of Clinical Features and Outcomes Between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in the United States.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large-scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC. APPROACH AND RESULTS: The Surveillance, Epidemiology, and End Results Program 18 Database (2000-2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (<50 or ≥65), female sex, non-Hispanic White race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis versus HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months; P < 0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR] = 1.02; 95% CI = 0.99-1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥5 cm (aHR = 0.83; 95% CI = 0.80-0.86), lymph node involvement (aHR = 0.76; 95% CI = 0.72-0.81), distant metastasis (aHR = 0.76; 95% CI = 0.73-0.79), poorly/undifferentiated tumors (aHR = 0.88; 95% CI = 0.83-0.94), and those receiving noncurative treatment (aHR = 0.96; 95% CI = 0.93-0.98). CONCLUSIONS: We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with PLC. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features.

The Mortality and Overall Survival Trends of Primary Liver Cancer in the United States.

BACKGROUND: Recent trends of hepatocellular carcinoma (HCC) mortality and outcome remain unknown in the United States. We investigated the recent trends of primary liver cancer (excluding intrahepatic cholangiocarcinoma) mortality and HCC stage, treatment, and overall survival (OS) in the United States. METHODS: The National Center for Health Statistics Database was analyzed to investigate the trend of primary liver cancer mortality. We analyzed the Surveillance, Epidemiology, and End Results 18 Database to assess the temporal trend of tumor size, stage, treatment, and OS of HCC. We investigated the association between HCC diagnosis year and OS using Cox regression analysis. All statistical tests were 2-sided. RESULTS: During 2000-2018, liver cancer mortality rates increased until 2013, plateaued during 2013-2016 (annual percent change = 0.1%/y, 95% confidence interval [CI] = -2.1%/y to 2.4%/y, P = .92), and started to decline during 2016-2018 (annual percent change = -1.5%/y, 95% CI = -3.2%/y to 0.2%/y, P = .08). However, mortality continues to increase in American Indian and Alaska Native, individuals aged 65 years or older, and in 33 states. There was a 0.61% (95% CI = 0.53% to 0.69%, P < .001) increase in localized stage HCC and a 0.86-mm (95% CI = -1.10 to -0.62 mm, P < .001) decrease in median tumor size per year. The 1-year OS rate increased from 36.3% (95% CI = 34.3% to 38.3%) to 58.1% (95% CI = 56.9% to 59.4%) during 2000-2015, and the 5-year OS rate almost doubled from 11.7% (95% CI = 10.4% to 13.1%) to 21.3% (95% CI = 20.2% to 22.4%) during 2000-2011. Diagnosis year (per year) (adjusted hazard ratio = 0.96, 95% CI = 0.96 to 0.97) was independently associated with OS in multivariable analysis. CONCLUSIONS: Primary liver cancer mortality rates have started to decline in the United States with demographic and state-level variation. With an increasing detection of localized HCC, the OS of HCC has improved over the past decades.

State-Level HCC Incidence and Association With Obesity and Physical Activity in the United States.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with a disproportionate impact on racial/ethnic minority groups. However, state-level variation in racial/ethnic disparities and temporal trends of HCC incidence remain unknown. Therefore, we aimed to characterize (1) state-level racial/ethnic disparity in HCC incidence, (2) state-level temporal changes in HCC incidence, and (3) the ecological correlation between HCC incidence and obesity/physical activity levels in the USA. APPROACH AND RESULTS: Trends in HCC incidence between 2001 and 2017 were calculated using data from the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology and End Results, and annual percent change in rates were calculated. State-level percent of obesity and level of physical activity were obtained from the Centers for Disease Control and Prevention, and the correlation among obesity, physical activity, and state-specific average annual percent change was tested by Pearson correlation coefficient. There were striking state-level racial/ethnic disparities in HCC incidence; incidence rate ratios ranged between 6.3 and 0.9 in Blacks, 6.1 and 1.7 in Asians/Pacific Islanders, 3.8 and 0.9 in Hispanics, and 6.0 and 0.9 in American Indians/Alaska Natives (compared with Whites as reference). Despite overall decreasing HCC incidence rates after 2015, HCC incidence continued increasing in 26 states over recent years. HCC incidence trends had a moderate correlation with state-level obesity (r = 0.45, P < 0.001) and a moderate inverse correlation with state-level physical activity (r = -0.40, P = 0.004). CONCLUSIONS: There is wide state-level variation in racial/ethnic disparity of HCC incidence. There are also disparate incidence trends across states, with HCC incidence continuing to increase in over half of the states. Regional obesity and lack of physical activity have moderate correlations with HCC incidence trends, suggesting that interventions targeting these factors may help curb rising HCC incidence.