Medicaid expansion and palliative care for advanced-stage liver cancer.

BACKGROUND: Medicaid expansion (ME) has contributed to transforming the United States healthcare system. However, its effect on palliative care of primary liver cancers remains unknown. This study aimed to evaluate the association between ME and the receipt of palliative treatment in advanced-stage liver cancer. METHODS: Patients diagnosed with stage IV hepatocellular carcinoma or intrahepatic cholangiocarcinoma were identified from the National Cancer Database and divided into pre-expansion (2010-2013) and postexpansion (2015-2019) cohorts. Logistic regression identified predictors of palliative treatment. Difference-in-difference (DID) analysis assessed changes in palliative care use between patients living in ME states and patients living in non-ME states. RESULTS: Among 12,516 patients, 4582 (36.6%) were diagnosed before expansion, and 7934 (63.6%) were diagnosed after expansion. Overall, rates of palliative treatment increased after ME (18.1% [pre-expansion] vs 22.3% [postexpansion]; P < .001) and are more pronounced among ME states. Before expansion, only cancer type and education attainment were associated with the receipt of palliative treatment. Conversely, after expansion, race, insurance, location, cancer type, and ME status (odds ratio [OR], 1.23; 95% CI, 1.06-1.44; P = .018) were all associated with palliative care. Interestingly, the odds were higher if treatment involved receipt of pain management (OR, 2.05; 95% CI, 1.23-2.43; P = .006). Adjusted DID analysis confirmed increased rates of palliative treatment among patients living in ME states relative to non-ME states (DID, 4.4%; 95% CI, 1.2-7.7; P = .008); however, racial disparities persist (White, 5.6; 95% CI, 1.4-9.8; P = .009; minority, 2.6; 95% CI, -2.5 to 7.6; P = .333). CONCLUSION: The implementation of ME contributed to increased rates of palliative treatment for patients residing in ME states after expansion. However, racial disparities persist even after ME, resulting in inequitable access to palliative care.

Extended left hepatectomy associated with resection of the vena cava and suprahepatic veins by in situ perfusion to treat intrahepatic cholangiocarcinoma.

Cholangiocarcinoma is a heterogeneous group of aggressive tumors that correspond to the second most common primary liver tumor. They can be classified according to their anatomical position concerning the biliary tree, and each subtype demonstrates different behavior and treatment. A 38-year-old male patient presenting solely right lumbar pain was diagnosed with a 7 cm hepatic tumor involving segments I, Iva, and VIII associated with involvement of the hepatic veins. He underwent a bloc resection of hepatic segments I, II, III, IV, partial V, partial VII, and VIII; right, middle, and left hepatic veins; and inferior vena cava segment, with perfusion of the remaining liver in situ with a preservation solution. As the patient had a large accessory inferior right hepatic vein draining the remaining liver, no reimplantation of hepatic veins was necessary. He remained clinically stable in outpatient follow-up, with excellent performance status-current survival of 2 years 6 months after surgical treatment.

Immunotherapy and Targeted Therapy for Advanced Biliary Tract Cancer: Adding New Flavors to the Pizza.

Biliary tract cancers (BTCs) are a rare pathology and can be divided into four major subgroups: intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and gallbladder cancer. In the era of precision oncology, the development of next-generation sequencing (NGS) allowed a better understanding of molecular differences between these subgroups. Thus, the development of drugs that can target these alterations and inhibit the abnormal pathway activation has changed the prognosis of BTC patients. Additionally, the development of immune checkpoint inhibitors and a better understanding of tumor immunogenicity led to the development of clinical trials with immunotherapy for this scenario. The development of biomarkers that can predict how the immune system acts against the tumor cells, and which patients benefit from this activation, are urgently needed. Here, we review the most recent data regarding targeted treatment and immunotherapy in the scenario of BTC treatment, while also discussing the future perspectives for this challenging disease.

Actual over 3-year survival after stereotactic body radiation therapy in patients with unresectable intrahepatic cholangiocarcinoma.

PURPOSE: As a non-invasive treatment, stereotactic body radiation therapy (SBRT) has been an emerging and effective option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). The Cyber Knife has an SBRT system, which can realize real-time tracking of tumors during treatment. It can protect the surrounding normal liver tissue while the tumor gets the therapeutic dose. The purpose of this study was to evaluate the factors affecting the local control rate for patients after SBRT treatment, and to predict the factors affecting survival rates, then to report the 3-year actual survival rates after treatment and identify the influencing factors of 3-year survival rate. MATERIALS AND METHODS: We conducted a long-term follow-up of 43 patients with unresectable intrahepatic cholangiocarcinoma who underwent Cyber Knife in our hospital from January 2016 to December 2018. Regular medical check-ups were performed every 2-3 months after SBRT to evaluated the effect of treatment. RESULTS: The median follow-up time was 15 months (4-78 months), and the median progression-free survival (PFS) was 6 months (95% CI, 2.788-9.212) and the median overall survival (OS) was 12 months (95% CI, 3.434-20.566), respectively. Based on modified Response Evaluation and Criteria in Solid Tumor (mRECIST), response rate (RR) and disease control rate (DCR) of SBRT in unresectable ICC were 55.2% and 86%. The 1-, 2- and 3-years OS rate were 51.2%, 32.6% and 23.3%. Multivariate analysis based on competing risk survival analysis identified that patients with multiple nodules, large diameter, high level of CA199 and CEA, poor ECOG performance status had worse overall survival (p < 0.05). Patients who survived ≥3 years had significantly lower levels of CEA, CA199, smaller tumor diameters and lower number of lesions (p < 0.05). CONCLUSION: The SBRT might be a candidate option for patients who unable to perform surgery. The rate of 3-year survival after SBRT for unresectable ICC can be expected with 23.3%.

Carcinoembryonic antigen, α-fetoprotein, and Ki67 as biomarkers and prognostic factors in intrahepatic cholangiocarcinoma: A retrospective cohort study.

INTRODUCTION AND OBJECTIVE: The purpose of this study was to investigate the expression levels and prognostic roles of α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and Ki67 in tumor tissues of intrahepatic cholangiocarcinoma (ICC) patients. PATIENTS OR MATERIALS AND METHODS: The study involved ninety-two ICC patients with complete clinicopathological data and follow-up information, who had previously undergone radical surgery. AFP, CEA, CD10, CD34, and Ki67 were detected in tumor tissues using immunohistochemistry. Statistical tests were used to identify independent risk factors and their associations with overall survival (OS) and disease-free survival (DFS). RESULTS: AFP, CEA and Ki67 were strongly correlated with prognosis. Univariate analysis indicated that higher AFP (P = 0.002), CEA (P < 0.0001), Ki67 (P < 0.0001), CA19-9 (P = 0.039), and CA12-5 (P = 0.002), and larger tumor size (P = 0.001), as well as more advanced tumor node metastasis (TNM) staging (P < 0.0001) were all associated with worse OS. Meanwhile, higher AFP (P = 0.002), CEA (P = 0.001), and Ki67 (P < 0.0001), as well as more advanced TNM staging (P = 0.005) were associated with worse DFS. Multivariate analysis showed that higher AFP (HR = 2.004, 95%CI: 1.146-3.504 P = 0.015), CEA (HR = 2.226, 95%CI: 1.283-3.861 P = 0.004), and Ki67 (HR = 3.785, 95%CI: 2.073-6.909 P < 0.0001), as well as more advanced TNM staging (HR = 2.900, 95%CI: 1.498-5.757 P = 0.002) had associations with worse OS. Furthermore, higher AFP (HR = 2.172, 95%Cl: 1.291-3.654 P = 0.003), CEA (HR = 1.934, 95%Cl: 1.180-3.169 P = 0.009), and Ki67 (HR = 2.203, 95%Cl: 1.291-3.761 P = 0.004) had associations with worse DFS. CONCLUSION: High AFP, CEA, and Ki67 are significant prognostic indicators in ICC patients, and can be used to evaluate ICC biological behavior and prognosis.

Downregulation of MGMT promotes proliferation of intrahepatic cholangiocarcinoma by regulating p21.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is one of the most devastating cancers of the gastrointestinal tract. It is crucial to determine the accurate prognostic factors and find new therapeutic strategies. Meanwhile, O6-methylguanine-DNA methyltransferase (MGMT) is associated with malignant tumor progression. Thus, further studies are needed to investigate whether MGMT plays a similar role in ICC. MATERIALS AND METHODS: Quantitative real-time PCR, western blot, and immunohistochemistry staining were used to detect the expression of MGMT in ICC tissues. The correlations between MGMT expression and clinicopathologic features were analyzed. The cell-proliferation assay and colony-formation assay were applied to evaluate proliferation ability, while methylation-specific PCR were used to detect the methylation status of the MGMT promoter CpG island in ICC tissues and cells. RESULTS: Our study found that the expression of MGMT was decreased in ICC tissues when compared with paired normal tissues. In addition, we demonstrated that MGMT expression was positively correlated with overall survival rates and tumor histological grade. Silencing of MGMT significantly promoted cell proliferation in ICC. Further research showed that silencing of MGMT induced cells to enter S phase by inhibiting p21, p27, and Cyclin E expression, ultimately promoting ICC proliferation. We also demonstrated that the MGMT promoter was highly methylated in ICC, and the levels of MGMT and p21 mRNA increased after DNA demethylation. In addition, the levels of MGMT and p21 protein were positively correlated in ICC tissues. CONCLUSION: MGMT may play a critical role in carcinogenesis and the development of ICC, and provides a new marker of clinical prognosis and target for ICC treatment.

Obesity and liver cancer.

Obesity prevalence is rapidly increasing worldwide. It is associated with huge economic and health costs due to its clinical consequences, which includes increased incidence of type 2 diabetes, cardiovascular diseases, and development of different malignancies. In particular, obesity is an independent risk factor for the development of hepatocellular carcinoma (HCC). Indeed, obesity is highly prevalent in patients with non-alcoholic fatty liver disease (NAFLD) that is becoming one of the most frequent causes of liver disease worldwide. NAFLD-related HCC is the most rapidly growing indication for liver transplantation in many countries. The higher mortality rates found in obese HCC patients might be related not only to a worse outcome after HCC treatments, but also to a delayed diagnosis related to a low frequency and a poorer quality of abdominal ultrasonography surveillance that is the test universally used for HCC screening. Given its diffusion, obesity is frequently present in patients with chronic liver diseases related to different etiologies, and in these cases it may increase the HCC risk, acting as an additional co-factor. Indeed, growing evidence demonstrates that a healthy diet and regular physical activity may have an impact in reducing the overall HCC risk. Finally, an impact of obesity in the development of intrahepatic cholangiocarcinoma has been postulated, but more extensive studies are needed to definitively confirm this association.

Intrahepatic cholangiocarcinoma surgery: the impact of lymphadenectomy.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignant tumor and its incidence is increasing over the world. At present times, radical liver resection is still the most effective treatment for ICC patients to achieve long term survival. Pathological lymph node metastases (LMN), found in 15% to 45% of the patients, have been recognized as an extremely poor prognostic risk factor, even if curative resection is performed. So, considering this issue, it acquires relevance to determine the validity of surgical resection for LNM cases that are diagnosed in the preoperative setting, or whether a routine lymphadenectomy should be performed systematically in all hepatectomies for ICC. The role of routine lymphadenectomy in the surgical treatment of ICC remains controversial, with some centers considering it standard whereas other surgeons perform lymphadenectomy only as a selective indication. Recently, a growing widespread adoption of lymphadenectomy was demonstrated that nearly doubled its commonly reported execution rate. The newly updated eight edition of the American Joint Committee on Cancer (AJCC) staging system now recommends that six nodes need to be analyzed to stage patients with ICC. In this review, we analyzed and summarized some anatomic considerations of the lymphatic anatomy of the liver and the current knowledge and potential advantages of performing a routine lymphadenectomy in patients with ICC, especially looking at pathological staging, prognosis, prevention of local recurrence and outcome. New areas like lymphadenectomy in cirrhotic patients and laparoscopic lymphadenectomy are also discussed.

Racial, Ethnic, and Age Disparities in Incidence and Survival of Intrahepatic Cholangiocarcinoma in the United States; 1995-2014.

INTRODUCTION AND AIM: Despite reports of increased incidence of intrahepatic cholangiocarcinoma (iCCA) in the United States, the impact of age or influences of race and ethnicity are not clear. Disparities in iCCA outcomes across various population subgroups also are not readily recognized due to the rarity of this cancer. We examined ethnic, race, age, and gender variations in iCCA incidence and survival using data from the Surveillance, Epidemiology, and End Results Program (1995-2014). MATERIAL AND METHODS: We assessed age-adjusted incidence rates, average annual percentage change in incidence, and hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause and iCCA-specific mortality. RESULTS: Overall, 11,127 cases of iCCA were identified, with an age-adjusted incidence rate of 0.92 per 100,000. The incidence rate increased twofold, from 0.49 per 100,000 in 1995 to 1.49 per 100,000 in 2014, with an average annual rate of increase of 5.49%. The iCCA incidence rate was higher among persons age 45 years or older than those younger than 45 years (1.71 vs. 0.07 per 100,000), among males than females (0.97 vs. 0.88 per 100,000) and among Hispanics than non-Hispanics (1.18 vs. 0.89 per 100,000). Compared to non-Hispanics, Hispanics had poorer 5-year allcause mortality (HR = 1.11, 95%CI: 1.05-1.19) and poorer iCCA-specific mortality (HR = 1.15, 95%CI: 1.07-1.24). Survival rates were poor also for individuals age 45 years or older, men, and Blacks and American Indians/Alaska Natives. CONCLUSION: The results demonstrate ethnic, race, age and gender disparities in iCCA incidence and survival, and confirm continued increase in iCCA incidence in the United States.

Resultados del tratamiento quirúrgico del colangiocarcinoma intrahepático / Intrahepatic cholangiocarcinoma: experience in 30 operated patients

background: Intrahepatic cholangiocarcinoma (ICC) corresponds to 10% of liver primary malignant tumors. Aim: To show the results of surgical treatment of ICC in a biliary surgery center. material and methods: Review of a prospective database of operated patients at a surgical service of a clinical hospital. Thirty operated patients with an ICC, aged 25 to 83 years (20 women), were identified. Results: Twenty six patients had symptoms, 12 of 19 had high levels of CA19-9 and in four the tumor was non resectable. Twenty four patients underwent major hepatectomy and two, a minor hepatectomy. Combined resections were performed in three patients. Lymphadenectomy was performed in 14 patients and five had lymph node metastases. Surgical time was 272 minutes, mean intensive care unit stay was 10 days and mean ventilatory support use was five days. Surgical mortality was 19% and complications appeared in 53% of patients. Tumors were stage I, II, III and IV in 11, 5, 3 and 11 patients respectively. Overall survival was 16 months. Survival in tumors stage I and II was 50% at five years. In stages III and IV, it was 11.2 months. Conclusions: Surgery for ICC has an acceptable mortality and complications rate with a five years survival of 25%.

Introducción: El colangiocarcinoma intrahepático (CCIH), corresponde al segundo cáncer primario hepático, representando alrededor del 10% de los cánceres primarios del hígado; el tratamiento es la hepatectomía. Objetivo: Mostrar los resultados del tratamiento quirúrgico de pacientes con CCIH en Chile en un centro de cirugía hepatobiliar. Pacientes y métodos: Análisis prospectivo de los pacientes con CCIH operados en nuestro centro entre 2005 y 2015. Resultados: 30 pacientes, 20 mujeres (67%), 10 hombres (33%). Edad promedio: 60 años (rango 25-83 ), 26 pacientes sintomáticos (87%), CA19-9 elevado en 12 (63,2%), 4 pacientes (13%) irresecables, 24 pacientes (80%) hepatectomías mayores y 2 resecciones menores. Resecciones combinadas en 3, linfadenectomía en 14 pacientes (47%), metástasis linfonodales en 5 (17%). Tiempo promedio quirúrgico 272 min (rango 45-480). UCI, mediana 10 días, ventilación mecánica mediana 5 días. Hospitalización, mediana 10 días y 7 días postoperatorio. Morbilidad 53%, mortalidad 19%. R0 en 19 pacientes (64%), R1 en 7 pacientes (23%) y R2 en 4 pacientes (13%). Estadio I en 11 pacientes, estadio II en 5 pacientes, estadio III en 3 pacientes, estadio IV en 11 pacientes. Sobrevida general de 16 meses. Sobrevida estadio I 58,4 meses, estadio II 31,1 meses, estadio III 5,9 meses y estadio IV 11,8 meses, p = 0,06. Sobrevida R0 16 meses, R1: 31,1 meses y R2: 9,25 meses, p = 0,53. Sobrevida estadios I y II 50% a 5 años, estadios III-IV 11,2 meses, p < 0,01. Discusión: Este es el primer reporte nacional de una serie importante de pacientes con CCIH, con morbilidad y mortalidad aceptables. Sobrevida de 25% a 5 años.

Locoregional recurrence after curative intent resection for intrahepatic cholangiocarcinoma: implications for adjuvant radiotherapy.

BACKGROUNDS: As for intrahepatic cholangiocarcinoma, the most frequent site of failure after curative intent resection is the liver. We identified the risk factors for locoregional recurrence after curative intent resection for intrahepatic cholangiocarcinoma. METHODS: Medical records of 115 patients treated with surgical resection alone for intrahepatic cholangiocarcinoma from November 2000 to December 2010 were retrospectively reviewed. Locoregional failure was defined as recurrence within 20 mm from resection margin or regional lymph node. Overall survival and locoregional recurrence rates were analyzed using Kaplan-Meier methods, and the prognostic factors were analyzed using Cox proportional hazards model. RESULTS: Median follow-up duration of surviving patients was 61 months (range 8-139). Sixty-six patients had recurrence, and 45 of 66 patients (68 %) had locoregional recurrence. The 5-year overall survival and locoregional control rates were 49.1 and 51.6 %, respectively. ≥ T2b disease and R1 resection were associated with locoregional recurrence in multivariate analysis. Patients were divided into two groups whether these risk factors exist or not. The 5-year locoregional control rates of low (no risk factor n = 64) and high (1 or 2 risk factors n = 51) risk groups were 62.5 and 34.7 %, respectively (P = 0.001). CONCLUSIONS: After curative intent resection, locoregional control and survival of patients with intrahepatic cholangiocarcinoma were far from satisfactory. Further studies are needed to evaluate the potential benefit of adjuvant locoregional treatment such as radiotherapy for patients with high-risk factors (≥ T2b disease or R1 resection).

Association of nonalcoholic fatty liver disease and liver cancer.

AIM: To investigate the association between nonalcoholic fatty liver disease (NAFLD) and liver cancer, and NAFLD prevalence in different liver tumors. METHODS: This is a retrospective study of the clinical, laboratory and histological data of 120 patients diagnosed with primary or secondary hepatic neoplasms and treated at a tertiary center where they underwent hepatic resection and/or liver transplantation, with subsequent evaluation of the explant or liver biopsy. The following criteria were used to exclude patients from the study: a history of alcohol abuse, hepatitis B or C infection, no tumor detected in the liver tissue examined by histological analysis, and the presence of chronic autoimmune hepatitis, hemochromatosis, Wilson's disease, or hepatoblastoma. The occurrence of NAFLD and the association with its known risk factors were studied. The risk factors considered were diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, body mass index, dyslipidemia, and arterial hypertension. Presence of reticulin fibers in the hepatic neoplasms was assessed by histological analysis using slide-mounted specimens stained with either hematoxylin and eosin or Masson's trichrome and silver impregnation. Analysis of tumor-free liver parenchyma was carried out to determine the association between NAFLD and its histological grade. RESULTS: No difference was found in the association of NAFLD with the general population (34.2% and 30.0% respectively, 95%CI: 25.8-43.4). Evaluation by cancer type showed that NAFLD was more prevalent in patients with liver metastasis of colorectal cancer than in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma (OR = 3.99, 95%CI: 1.78-8.94, P < 0.001 vs OR = 0.60, 95%CI: 0.18-2.01, P = 0.406 and OR = 0.70, 95%CI: 0.18-2.80, P = 0.613, respectively). There was a higher prevalence of liver fibrosis in patients with hepatocellular carcinoma (OR = 3.50, 95%CI: 1.06-11.57, P = 0.032). Evaluation of the relationship between the presence of NAFLD, nonalcoholic steatohepatitis, and liver fibrosis, and their risk factors, showed no significant statistical association for any of the tumors studied. CONCLUSION: NAFLD is more common in patients with liver metastases caused by colorectal cancer.

TGF-ß1 expression is associated with invasion and metastasis of intrahepatic cholangiocarcinoma

BACKGROUND: Transforming growth factor (TGF)-ß is involved in many physiologic processes, it often promotes metastasis, and its high expression is correlated with poor prognosis. In the present study, we analyzed the correlation between transforming growth factor beta 1 (TGF-ß1) expression and prognosis in intrahepatic cholangiocarcinoma RESULTS: We examined the expression of TGF-ß1 in 78 intrahepatic cholangiocarcinomas by immunohistochemistry and correlated the expression with clinicopathological parameters. TGF-ß1 was expressed in 37 of 78 (47.4 %) intrahepatic cholangiocarcinomas. The expression of TGF-ß1 was significantly correlated with lymph node metastasis, distant metastasis, and tumour recurrence. Patients with TGF-ß1-positive tumours had significantly shorter survival time. In a multivariant analysis, the expression of TGF-ß1 and the tumour stage were independent prognostic factors CONCLUSIONS: Our data suggest that expression of TGF-ß1 is a novel prognostic marker for intrahepatic cholangiocarcinoma.

Seleccionando candidatos para tratamiento quirúrgico de las neoplasias hepáticas primarias malignas, riesgos y resultados / Selecting candidates for surgical treatment of malignant primary liver tumors: risks and results

Surgical resection is the treatment of choice in patients with primary liver neoplasm, both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Results for surgical morbidity, mortality, overall survival and recurrence are better if the correct protocols are implemented for the selection of patients. The surgical goal of this modality of treatment is based in a complete excision of the tumor with free resection margins, associated with a preservation of liver functionality. Due to the association between HCC and liver cirrhosis, is critical to establish surveillance protocols in those patients who are at high risk of developing HCC. Once the diagnosis of HCC is confirmed, patient selection is made according to the characteristics of the tumor, hepatic function and performance status. In patients who are not candidates for hepatic resection, liver transplantation offers a treatment alternative. Selection criteria are based principally on size and number of lesions. ICC is a bad prognosis disease, due to late diagnosis. Surgical resection represents the main therapeutic option. Patient selection is based on imaging findings. ICC staging is made based on the number of lesions and the presence of vascular invasion, but not tumor size. In contrast with HCC, liver transplantation in patients with ICC is a controversial alternative.

El tratamiento quirúrgico es actualmente la modalidad terapéutica de elección para las neoplasias primarias hepáticas, tanto para el carcinoma hepatocelular (CHC) como para el colangiocarcinoma intrahepático (CCI). Los resultados en cuanto a morbilidad quirúrgica, sobrevida global y recidiva tumoral mejoran cuando se establecen correctos protocolos de selección de pacientes. El objetivo quirúrgico en el tratamiento de estas neoplasias se basa en la erradicación completa de la masa tumoral, con márgenes quirúrgicos adecuados, asociado a la preservación de la funcionalidad hepática. En el caso del CHC, debido a su asociación con cirrosis hepática es fundamental establecer protocolos de vigilancia en pacientes susceptibles. Una vez que se establece el diagnóstico, la selección de los pacientes se realiza en base a las características del tumor, la funcionalidad hepática y la capacidad funcional. En aquellos pacientes que no son candidatos a resección quirúrgica, el trasplante hepático representa una alternativa de tratamiento, para lo que se han establecido criterios que se basan principalmente en el tamaño y número de lesiones. El CCI es una enfermedad de mal pronóstico, debido a que el diagnóstico se realiza generalmente en etapas avanzadas. El tratamiento quirúrgico es la principal alternativa terapéutica. La selección de los pacientes se basa en los hallazgos imagenológicos. La etapificación se realiza de acuerdo al número de lesiones y la invasión vascular, pero no el tamaño tumoral. A diferencia del CHC, el trasplante hepático en pacientes con CCI es una alternativa controversial.