Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study.

BACKGROUND & AIMS: Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S. METHODS: The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC. RESULTS: Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0-8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m2), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P < .05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P < .001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54-4.07), years with cirrhosis (P = .004; OR, 1.06; 95% CI, 1.02-1.1), family history of liver cancer (P = .02; yes; OR, 2.69; 95% CI, 1.11-5.86), age (per 5 years; P = .02; OR, 1.17; 95% CI, 1.03-1.33), obesity (P = .02; yes; OR, 1.7; 95% CI, 1.08-2.73), aspartate aminotransferase (log(1+AST); P = .06; OR, 1.54; 95% CI, 0.97-2.42), alpha-fetoprotein (log(1+AFP); P = .07; OR, 1.32; 95% CI, 0.97-1.77), and albumin (P = .10; OR, 0.7; 95% CI, 0.46-1.07). CONCLUSIONS: Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years.

Assessment of HCC response to Yttrium-90 radioembolization with gadoxetate disodium MRI: correlation with histopathology.

BACKGROUND AND AIMS: Transarterial 90Y radioembolization (TARE) is increasingly being used for hepatocellular carcinoma (HCC) treatment. However, tumor response assessment after TARE may be challenging. We aimed to assess the diagnostic performance of gadoxetate disodium MRI for predicting complete pathologic necrosis (CPN) of HCC treated with TARE, using histopathology as the reference standard. METHODS: This retrospective study included 48 patients (M/F: 36/12, mean age: 62 years) with HCC treated by TARE followed by surgery with gadoxetate disodium MRI within 90 days of surgery. Two radiologists evaluated tumor response using RECIST1.1, mRECIST, EASL, and LI-RADS-TR criteria and evaluated the percentage of necrosis on subtraction during late arterial, portal venous, and hepatobiliary phases (AP/PVP/HBP). Statistical analysis included inter-reader agreement, correlation between radiologic and pathologic percentage of necrosis, and prediction of CPN using logistic regression and ROC analyses. RESULTS: Histopathology demonstrated 71 HCCs (2.8 ± 1.7 cm, range: 0.5-7.5 cm) including 42 with CPN, 22 with partial necrosis, and 7 without necrosis. EASL and percentage of tumor necrosis on subtraction at the AP/PVP were independent predictors of CPN (p = 0.02-0.03). Percentage of necrosis, mRECIST, EASL, and LI-RADS-TR had fair to good performance for diagnosing CPN (AUCs: 0.78 - 0.83), with a significant difference between subtraction and LI-RADS-TR for reader 2, and in specificity between subtraction and other criteria for both readers (p-range: 0.01-0.04). Radiologic percentage of necrosis was significantly correlated to histopathologic degree of tumor necrosis (r = 0.66 - 0.8, p < 0.001). CONCLUSIONS: Percentage of tumor necrosis on subtraction and EASL criteria were significant independent predictors of CPN in HCC treated with TARE. Image subtraction should be considered for assessing HCC response to TARE when using MRI. KEY POINTS: • Percentage of tumor necrosis on image subtraction and EASL criteria are significant independent predictors of complete pathologic necrosis in hepatocellular carcinoma treated with90Y radioembolization. • Subtraction, mRECIST, EASL, and LI-RADS-TR have fair to good performance for diagnosing complete pathologic necrosis in hepatocellular carcinoma treated with90Y radioembolization.

Comparative assessment of standard and immune response criteria for evaluation of response to PD-1 monotherapy in unresectable HCC.

PURPOSE: To assess response to programmed death-1 (PD-1) monotherapy (nivolumab) in hepatocellular carcinoma (HCC) patients using RECIST1.1, modified RECIST (mRECIST), and immune RECIST (iRECIST). A secondary objective was to identify clinicolaboratory and imaging variables predictive of progressive disease (PD) and overall survival (OS). METHODS: Patients with HCC treated with nivolumab at a single institution from 5/2016 to 12/2019 with MRI or CT performed ≥ 4 weeks post treatment were retrospectively assessed. Patients who received concurrent locoregional, radiation, or other systemic therapies were excluded. Response was assessed by 2 observers in consensus using RECIST1.1, mRECIST, and iRECIST at 3/6/9/12-month time points. Time to progression (TTP) and OS were recorded. Clinicolaboratory and imaging variables were evaluated as predictors of PD and OS using uni-/multivariable and Cox regression analyses. RESULTS: Fifty-eight patients (42M/16F) were included. 118 target lesions (TL) were identified before treatment. Baseline mean TL size was 49.1 ± 43.5 mm (range 10-189 mm) for RECIST1.1/iRECIST and 46.3 ± 42.3 mm (range 10-189 mm) for mRECIST. Objective response rate (ORR) was 21% for mRECIST/iRECIST/RECIST1.1, with no cases of pseudoprogression. Median OS and median TTP were 717 days and 127 days for RECIST1.1/mRECIST/iRECIST-iUPD (unconfirmed PD). Older age, MELD/Child-Pugh scores, AFP, prior transarterial radioembolization (TARE), and larger TL size were predictive of PD and/or poor OS using mRECIST/iRECIST. The strongest predictor of PD (HR = 2.49, 95% CI 1.29-4.81, p = 0.007) was TARE. The strongest predictor of poor OS was PD by mRECIST/iRECIST at 3 months (HR = 2.26, 95% CI 1.00-5.10, p = 0.05) with borderline significance. CONCLUSION: Our results show ORR of 21%, equivalent for mRECIST, iRECIST, and RECIST1.1 in patients with advanced HCC clinically treated with nivolumab.

Assessment of Hepatocellular Carcinoma Response to 90Y Radioembolization Using Dynamic Contrast Material-enhanced MRI and Intravoxel Incoherent Motion Diffusion-weighted Imaging.

Purpose: To quantify diffusion and perfusion changes in hepatocellular carcinoma (HCC) induced by yttrium 90 (90Y) radioembolization and to assess the value of dynamic contrast material-enhanced (DCE) MRI and intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) for predicting HCC response. Materials and Methods: Institutional review board approval was obtained for this prospective study (clinical trial registry NCT01871545). Twenty-four participants with HCC (mean age, 69 years ± 9 [standard deviation], 18 men) underwent multiparametric MRI, including IVIM DWI and gadoxetic acid DCE MRI before (n = 24) and 6 weeks (n = 21) after radioembolization. IVIM DWI and DCE MRI histogram parameters were quantified in HCCs and liver parenchyma. HCC response was assessed by using modified Response Evaluation Criteria in Solid Tumors at 6 weeks and 6-12 months after radioembolization. Logistic regression analysis was used to evaluate the diagnostic performance of baseline MRI and clinical parameters for prediction of response. Results: Twenty-five HCCs were analyzed (mean size, 3.6 cm ± 1.9). Radioembolization resulted in significantly decreased perfusion (DCE MRI arterial flow, P = .002; IVIM pseudodiffusion coefficient [D*], P = .014). Multivariate logistic regression selected combined serum α-fetoprotein and portal flow (F p ) skewness (area under the curve [AUC] = 0.924) and combined D* standard deviation and F p kurtosis (AUC = 0.916) for prediction of objective and complete response at 6 weeks, respectively. Standard deviation of DCE MRI parameter arterial fraction was selected as the optimal predictor for complete response at 6-12 months (AUC = 0.857). Conclusion: Diffusion and perfusion MRI can be used to evaluate the response of HCC to radioembolization. Pretreatment DCE MRI histogram parameters may be useful for radioembolization treatment stratification. Supplemental material is available for this article. © RSNA, 2020.

Outcomes assessment in intrahepatic cholangiocarcinoma using qualitative and quantitative imaging features.

BACKGROUND: To assess the performance of imaging features, including radiomics texture features, in predicting histopathologic tumor grade, AJCC stage, and outcomes [time to recurrence (TTR) and overall survival (OS)] in patients with intrahepatic cholangiocarcinoma (ICC). METHODS: Seventy-three patients (26 M/47F, mean age 63y) with pre-operative imaging (CT, n = 37; MRI, n = 21; CT and MRI, n = 15] within 6 months of resection were included in this retrospective study. Qualitative imaging traits were assessed by 2 observers. A 3rd observer measured tumor apparent diffusion coefficient (ADC), enhancement ratios (ERs), and Haralick texture features. Blood biomarkers and imaging features were compared with histopathology (tumor grade and AJCC stage) and outcomes (TTR and OS) using log-rank, generalized Wilcoxon, Cox proportional hazards regression, and Fisher exact tests. RESULTS: Median TTR and OS were 53.9 and 79.7 months. ICC recurred in 64.4% (47/73) of patients and 46.6% (34/73) of patients died. There was fair accuracy for some qualitative imaging features in the prediction of worse tumor grade (maximal AUC of 0.68 for biliary obstruction on MRI, p = 0.032, observer 1) and higher AJCC stage (maximal AUC of 0.73 for biliary obstruction on CT, p = 0.002, observer 2; and AUC of 0.73 for vascular involvement on MRI, p = 0.01, observer 2). Cox proportional hazards regression analysis showed that CA 19-9 [hazard ratio (HR) 2.44/95% confidence interval (CI) 1.31-4.57/p = 0.005)] and tumor size on imaging (HR 1.13/95% CI 1.04-1.22/p = 0.003) were significant predictors of TTR, while CA 19-9 (HR 4.08/95% CI 1.75-9.56, p = 0.001) and presence of metastatic lymph nodes at histopathology (HR 2.86/95% CI 1.35-6.07/p = 0.006) were significant predictors of OS. On multivariable analysis, satellite lesions on CT (HR 2.79/95%CI 1.01-7.15/p = 0.032, observer 2), vascular involvement on MRI (HR 0.10/95% CI 0.01-0.85/p = 0.032, observer 1), and texture feature MRI variance (HR 0.55/95% CI 0.31-0.97, p = 0.040) predicted TTR once adjusted for the independent predictors CA 19-9 and tumor size on imaging. Several qualitative and quantitative features demonstrated associations with TTR, OS, and AJCC stage at univariable analysis (range: HR 0.35-19; p < 0.001-0.045), however none were predictive of OS at multivariable analysis when adjusted for CA 19-9 and metastatic lymph nodes (p > 0.088). CONCLUSIONS: There was reasonable accuracy in predicting tumor grade and higher AJCC stage in ICC utilizing certain qualitative and quantitative imaging traits. Serum CA 19-9, tumor size, presence of metastatic lymph nodes, and qualitative imaging traits of satellite lesions and vascular involvement are predictors of patient outcomes, along with a promising predictive ability of certain quantitative texture features.

Perioperative Management in Hepatic Resections: Comparative Effectiveness of Neuraxial Anesthesia and Disparity of Care Patterns.

BACKGROUND: Complication rates after hepatic resection can be affected by management decisions of the hospital care team and/or disparities in care. This is true in many other surgical populations, but little study has been done regarding patients undergoing hepatectomy. METHODS: Data from the claims-based national Premier Perspective database were used for 2006 to 2014. The analytical sample consisted of adults undergoing partial hepatectomy and total hepatic lobectomy with anesthesia care consisting of general anesthesia (GA) only or neuraxial and GA (n = 9442). The key independent variable was type of anesthesia that was categorized as GA versus GA + neuraxial. The outcomes examined were clinical complications and health care resource utilization. Unadjusted bivariate and adjusted multivariate analyses were conducted to examine the effects of the different types of anesthesia on clinical complications and health care resource utilization after controlling for patient- and hospital-level characteristics. RESULTS: Approximately 9% of patients were provided with GA + neuraxial anesthesia during hepatic resection. In multivariate analyses, no association was observed between types of anesthesia and clinical complications and/or health care utilization (eg, admission to intensive care unit). However, patients who received blood transfusions were significantly more likely to have complications and intensive care unit stays. In addition, certain disparities of care, including having surgery in a rural hospital, were associated with poorer outcomes. CONCLUSIONS: Neuraxial anesthesia utilization was not associated with improvement in clinical outcome or cost among patients undergoing hepatic resections when compared to patients receiving GA alone. Future research may focus on prospective data sources with more clinical information on such patients and examine the effects of GA + neuraxial anesthesia on various complications and health care resource utilization.

Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States.

A national conference was held to better characterize the long-term outcomes of liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) and to assess whether it is justified to continue the policy of assigning increased priority for candidates with early-stage HCC on the transplant waiting list in the United States. The objectives of the conference were to address specific HCC issues as they relate to liver allocation, develop a standardized pathology report form for the assessment of the explanted liver, develop more specific imaging criteria for HCC designed to qualify LT candidates for automatic Model for End-Stage Liver Disease (MELD) exception points without the need for biopsy, and develop a standardized pretransplant imaging report form for the assessment of patients with liver lesions. At the completion of the meeting, there was agreement that the allocation policy should result in similar risks of removal from the waiting list and similar transplant rates for HCC and non-HCC candidates. In addition, the allocation policy should select HCC candidates so that there are similar posttransplant outcomes for HCC and non-HCC recipients. There was a general consensus for the development of a calculated continuous HCC priority score for ranking HCC candidates on the list that would incorporate the calculated MELD score, alpha-fetoprotein, tumor size, and rate of tumor growth. Only candidates with at least stage T2 tumors would receive additional HCC priority points.

Multicentric evaluation of a clinical and prognostic scoring system predictive of survival after resection of intrahepatic cholangiocarcinomas.

OBJECTIVE: To develop a clinical and prognostic scoring system predictive of survival after resection of intrahepatic cholangiocarcinomas (ICC). PATIENTS: Two hundred and one consecutive ICC patients (83 from Essen, Germany, 54 from New York, USA and 64 from Chiba, Japan). The scoring systems were developed utilizing the data set from Essen University and then applied to the data sets from Mount Sinai Medical Center and Chiba University for validation. Eighteen potential prognostic factors were evaluated. Statistical analysis included multivariable regression analyses with the Cox proportional hazard model, power analysis, internal validation with structural equation modelling bootstrapping and external validation. The prognostic scoring model was based mainly in pathological and demographical variables, whereas the clinical scoring model was based mainly in radiological and demographical variables. RESULTS: Gender (P=0.0086), UICC stage (P=0.0140) and R-class (P=0.0016) were predictive of survival for the prognostic scoring model, while gender (P=0.0023), CA 19-9 levels (P=0.0153) and macrovascular invasion (P=0.0067) were predictive of survival for the clinical scoring model. Prognostic points were assigned as follows: female:male=1:2 points, UICC (I-II):UICC (III-IV)=1:2 points and R0:R1=1:2 points. Clinical points were allocated as follows: female:male=1:2 points, CA 19-9 (<100 U/ml):CA 19-9 (> or =100 U/ml)=1:2 points and no macrovascular invasion:macrovascular invasion=1:2 points. Prognostic groups with 3-4, 5 and 6 points (P=0.000001) and clinical groups with 3-4 and 5-6 points (P=0.0103) achieved statistically significant difference. CONCLUSIONS: We propose a clinical and prognostic scoring system predictive of long-term survival after surgical resections for ICC.

The physician pipeline to rural and underserved areas in Pennsylvania.

CONTEXT: An implicit objective of a state's investments in medical education is to promote in-state practice of state educated physicians. PURPOSE: To present a tool for evaluating this objective by analyzing the "pipeline" from medical education to patient care, primary care, rural areas, and underserved areas in Pennsylvania. METHODS: AMA Masterfile data (2004) including all physicians with a Pennsylvania address or who received medical education in Pennsylvania were analyzed. These data were combined with local physician supply data. RESULTS: About 36% of Pennsylvania medical school graduates provide patient care in the Commonwealth, 16% primary care, 7% rural care, 4% rural primary care, and 0.5% primary care in a rural underserved area. Fifty-four percent of physicians who received both undergraduate and graduate medical education in-state are retained. CONCLUSIONS: These retention rates have developed within the context of a middle-of-the-road educational pipeline policy. If Pennsylvania policy makers consider that further pipeline development is advisable, there is room to amend current policy to that end. Conditions are favorable for other states to consider similar policy amendments.

The pipeline from dental education to practice: the Pennsylvania experience.

The pipeline from Pennsylvania dental education to Pennsylvania practice, rural practice, and low service area practice is described and analyzed. The article contends that pipeline development is an effective vehicle in meeting the public health mandate of ensuring access to dental care for all residents. Data from the American Dental Association served as the basis for addressing the two major research questions: 1) what are the educational origins of the dentist workforce in Pennsylvania, in rural areas of Pennsylvania, and in underserved areas of Pennsylvania? and 2) what is the proportion of Pennsylvania-educated dentists who practice in Pennsylvania, in rural areas of Pennsylvania, and in underserved areas of Pennsylvania? As an overall assessment, one can consider the Pennsylvania dental pipeline inadequate to meet the Commonwealth's public health goals. The pipeline is not adequately developed to repopulate the current Pennsylvania-educated dentist workforce, especially in the most needy areas. Understanding the prospects for further pipeline development is best achieved by considering the pipeline within the context of the practice model of dentistry and the current and future supply of dentists.

The financial impact of interim and prospective payment systems on home health providers in rural communities.

The objective of the study was to examine the financial impact of the interim payment system and prospective payment system (PPS) on home health agencies (HHAs) in rural communities. Data sources used included a survey of administrators in all rural HHAs in Pennsylvania and financial and utilization data provided by 10 rural HHAs in Northwest Pennsylvania. The results of survey showed that, under the PPS, 40% of the HHAs reported financial vulnerability and 24% expressed concern that the fiscal uncertainties arising from the PPS threatened their continued operation. Two prospective analyses were conducted to examine how HHAs would be further affected by payment rate changes implemented in October 2002 and April 2003. The Medicare margin in rural Pennsylvania was 23.3% during the period from October 2000 to June 2002. This margin was slightly higher than the free-standing home health Medicare margin (21.6%) reported in analyses conducted by the Medicare Payment Advisory Commission (MedPac). However, this Medicare margin did not include hospital-based HHAs. The payment rate changes implemented in 2002 and 2003 would increase the proportion of care episodes that incur financial losses, assuming service provision remains constant. As of April 2003, the proportion of all episodes with loss would rise to 46.9%, the proportion of low-utilization payment adjustment (LUPA) episodes with loss would rise to 91.1%, and the proportion of non-LUPA episodes with loss would rise to 40.2%. New payment mechanisms are profoundly affecting the finances of rural HHAs and the use of home health services by Medicare beneficiaries.

Survey of health needs and concerns of rural Pennsylvanians.

INTRODUCTION: This survey was undertaken to determine the most important health and safety needs of farmers and rural citizens of Pennsylvania. METHODS: In June of 2004, a one-page questionnaire was distributed by mail to 32,700 members of the Pennsylvania Farm Bureau as an attachment to their monthly newsletter. RESULTS: The lack of affordable health care insurance was overwhelmingly cited as the most important unmet health care need (73%). No other issue was chosen by more than 10 percent of respondents. This lack of affordable health insurance was also cited as the most important health or safety problem to be addressed in the respondent's communities (71%). When asked the most important health or safety problem affecting them as individuals or their community, the respondents chose "no major problem or need" as the most frequent response (46%). The issue of affordable health insurance was not an option for this question. The predominant concern regarding the lack of affordable health insurance was consistent across all regions of the Commonwealth and for farmers as well as residents of all community sizes sampled. DISCUSSION: This study would indicate that the lack of affordable health insurance is the preeminent health and safety issue for many Pennsylvania farmers and rural citizens.

Liver transplantation in patients with hepatocellular carcinoma.

The preferred therapy for hepatocellular carcinoma (HCC) apparently confined to the liver is surgical removal of the tumor. If the location of the tumor and the functional status of the liver are such that resection with an adequate margin can be achieved with low likelihood of subsequent hepatic failure, liver resection is the preferred approach. When HCC apparently localized to the liver is diagnosed in a patient who, by virtue of tumor characteristics or diminished hepatic reserve, is not a candidate for liver resection, liver transplantation becomes a consideration. This work outlines the approach at The Mount Sinai Hospital to the diagnosis, evaluation, preoperative management, transplantation, and posttransplant follow-up in patients with unresectable HCC. The allocation of livers to patients with HCC is reviewed, and predictors of tumor recurrence and results of liver transplantation for HCC are discussed. Finally, the impact of viral hepatitis and of immunosuppression on transplant outcome are discussed.

Quality of life after lobectomy for adult liver transplantation.

INTRODUCTION: Adult-to-adult living donor liver transplants are being increasingly performed. Although considerable data are available on the quality of life after kidney donation, there is little comparable information on liver donors. METHODS: Between August 1998 and July 2000, 48 adults received liver grafts from living donors. At least 2 months after donation, donors were mailed a structured questionnaire and the standardized Medical Outcomes Study Short-Form Health Survey (SF-36), a generic measure assessing health-related quality of life outcomes using eight scales: mental health, emotional limits, vitality, social function, physical function, physical limits, pain, general health. RESULTS: Thirty donors (62.5%) responded at a mean of 280+/-157 days after donation. Fifteen (50%) of their recipients had major complications (two deaths, four retransplants, nine biliary complications). Regarding overall satisfaction, all said they would donate again. Compared to published U.S. norms (n=2474), our group of donors scored higher than the general population in seven of eight domains on the SF-36. Donors whose recipients had no complications scored significantly higher in mental health (P<0.007) and general health (P<0.008) compared with U.S. norms. Donors whose recipients had major complications scored significantly lower on the mental health scale than those with recipients without major complications. CONCLUSIONS: Donors did not regret their decision to donate; several felt the experience had changed their lives for the better. Donors scored as well as or better than U.S. norms in general health. Quality of life after donation must remain a primary outcome measure when we consider the utility of living-donor liver transplants.