Combination of CRAFITY score with Alpha-fetoprotein response predicts a favorable outcome of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma

Immune checkpoint inhibitors (ICIs) with atezolizumab plus bevacizumab are promising agents for unresectable hepatocellular carcinoma (HCC). We tried to guide the treatment based on recent developed CRAFITY score combining with on-treatment AFP response. Eighty-nine patients who received atezolizumab plus bevacizumab regardless of as a first-line therapy or not for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). The objective response rate (ORR) and disease control rate (DCR) were 25.0% and 65.5%, respectively. Multivariate analysis showed that low CRAFITY score (AFP<100 ng/ml or CRP<10 mg/l) and satisfactory AFP response at 6 weeks (≥75% decrease or ≤10% increase from baseline) were independent factors determining good overall survival (OS) (hazard ratio [HR]=0.143, P=0.002 & HR=0.337, P=0.031), progression-free survival (PFS) (HR=0.419, P=0.022 & HR=0.429, P=0.025) and good responder (odds ratio [OR]=1.763, P=0.044 & OR=3.881, P=0.011). Patients were further divided into three classes by combination of CRAFITY score and AFP response at 6 weeks [The CAR (CRAFITY score and AFP-Response) classification)]: low CRAFITY score with satisfactory AFP response at 6 weeks (class I), either high CRAFITY score or unsatisfactory AFP response at 6 weeks (class II) and high CRAFITY score together with unsatisfactory AFP response at 6 weeks (class III). ORR was 35.0%, 18.2%, and 0% in class I, II and III patients, respectively (overall P=0.034). Patients in the class I had the best OS and PFS, followed by class II and class III (median OS: not reached vs. 11.1 vs. 4.3 months, log-rank P<0.001; median PFS: 7.9 vs. 6.6 vs. 2.6 months, log-rank P=0.001). Combination CRAFITY score and AFP response at 6 weeks with AUROC predicts OS and tumor response to be 0.809 and 0.798, respectively, better than either CRAFITY score (0.771 & 0.750) or AFP response at 6 weeks (0.725 & 0.680) alone. In conclusions, the CAR classification which combining CRAFITY score and AFP response at 6 weeks provides a practical guidance for atezolizumab plus bevacizumab therapy in unresectable HCC patients.     

Alpha-fetoprotein response predicts treatment outcomes in patients with unresectable hepatocellular carcinoma receiving immune checkpoint inhibitors with or without tyrosine kinase inhibitors or locoregional therapies

Combined immune checkpoint inhibitors (ICIs) along with tyrosine kinase inhibitors (TKIs) and locoregional therapies have been used increasingly to treat hepatocellular carcinoma (HCC). Biomarkers are required to predict the treatment efficacy of ICIs with or without combination therapies in patients with unresectable HCC. This study enrolled 95 consecutive patients with unresectable HCC from May 2017 to June 2021 from two hospitals retrospectively. Of the 95 patients, 15 and 80 had Barcelona Clinic Liver Cancer stages B and C, respectively. The median ICI treatment duration was 3.43 (1.87-7.87) months, and 77 patients received combination therapies. Radiological imaging was not performed in 13 patients. Objective response and disease control rates were 27.4% and 53.7%, respectively. The duration of progression-free survival (PFS) and overall survival (OS) was 4.07 (1.59-6.54) months and 14.53 (6.93-22.14) months, respectively. Alpha-fetoprotein (AFP) response was defined as a decline of >15% in the serum AFP level within the initial 3 months of ICI therapy according to Youden’s index. AFP response was determined to be a predictor of disease control (odds ratio: 11.657, 95% confidence interval [CI]: 2.834-47.941, P=.001). Macrovascular invasion (MVI), AFP response (hazard ratio [HR]: 0.488, 95% CI: 0.255-0.934, P=.030), combination therapy, and disease control were predictors of PFS, and MVI, AFP response (HR: 0.344, 95% CI: 0.160-0.737, P=.006), and disease control were predictors of OS. AFP response was a predictor of disease control, PFS, and OS. These findings indicate that AFP response can serve as a biomarker to predict treatment outcomes in patients with unresectable HCC receiving ICIs with or without TKIs or locoregional therapies.     

Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma

Nivolumab monotherapy has a modest objective response rate (ORR) in hepatocellular carcinoma (HCC). To overcome the lack of biomarkers that predict delayed alpha-fetoprotein (AFP) response beyond 4 weeks, we applied a novel 50-10 rule of AFP response for unresectable HCC patients under nivolumab monotherapy and proposed an algorithm based on on-treatment AFP reduction at different time-points. Ninety unresectable HCC patients who underwent nivolumab monotherapy in 2015-2019 were retrospectively recruited and divided into four classes: rapid AFP decrease of ≥ 50% of baseline at week 4 (class I), AFP changes within ± 50% of baseline at week 4 that later decreased to ≥ 10% of baseline (class II) or not (class III) at week 12, and rapid AFP increase of ≥ 50% of baseline at week 4 (class IV). ORR was 47.4%, 36.0%, 7.7%, and 5.0% in class I-IV patients, respectively. Rapid (class I) and delayed (class II) AFP responders had significantly higher ORR, overall survival (OS) and progression-free survival (PFS) than non-responders (class III and IV) (ORR: 40.9% vs. 6.5%, P<0.001; median OS: not reached vs. 9.6 months, log-rank P<0.001; median PFS: 9.6 vs. 2.8 months, log-rank P<0.001). In multivariate analysis, AFP response was an independent factor associated with good OS (hazard ratio [HR]=0.301, P=0.001) and PFS (HR=0.332, P<0.001). Moreover, AFP responders had higher ORR and better OS as well as PFS than non-responders, regardless of nivolumab as a first- or more than a second-line therapy (all P<0.05). In conclusion, the novel 50-10 rule of AFP response provides practical guidance for nivolumab monotherapy in unresectable HCC patients. However, this algorithm remains to be verified in a large prospective cohort.     

Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China

BackgroundRegorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear.MethodsThis was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4–6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS).ResultsA total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8–16.2] months, and the median OS was 17.0 (95% CI: 12.8–21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3–4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073–0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051–0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063–0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009–0.608; P=0.015) before 2nd-line treatment were independently associated with PFS.ConclusionsThe sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.     

Comparable benefits of HCV eradication by direct acting antivirals and interferon-based therapy in patients with hepatocellular carcinoma undergoing surgical resection

Whether direct-acting antivirals (DAA) provide comparable survival benefit with interferon (IFN)-based therapy remains unclear. The aim of this study was to compare the outcomes after achieving SVR by IFN-based and DAA therapy after resection of HCV-related hepatocellular carcinoma (HCC). Consecutive 285 patients receiving curative resection for HCV-related HCC were retrospectively enrolled, including 103 (36.1%) and 69 (24.2%) patients with IFN-based and DAA therapy, respectively. Factors associated with recurrence, overall survival (OS) and hepatic decompensation-free survival were evaluated. The SVR rate of DAA was 95.7% in HCC patients. During a median follow-up period of 49.6 months, 102 (35.8%) patients died and 63 (24%) developed hepatic decompensation. By multivariate analysis, SVR by DAA or IFN-based therapy was not associated with early or late HCC recurrence. Achieving SVR (by IFN-based therapy: HR=0.321, P<0.001; by DAA: HR=0.396, P=0.011), BCLC stage B-C (HR=1.914, P=0.024), FIB-4 score >3.25 (HR=1.664, P=0.016) and microvascular invasion (HR=1.603, P=0.048) were independent predictors of OS. Achieving SVR (by IFN-based therapy: HR=0.295, P<0.001; by DAA: HR=0.193, P=0.002), BCLC stage B-C (HR=2.975, P=0.001), GGT >70 U/L (HR=1.931, P=0.015) and cirrhosis (HR=2.035, P=0.007) were independent predictors of decompensation-free survival. The benefit of achieving SVR was consistently observed in cirrhotic and non-cirrhotic patients, and in patients with and without HCC recurrence. In conclusion, achieving SVR by either DAA or IFN-based therapy provide comparable and significant reduction of mortality and hepatic decompensation after surgical resection of HCV-related HCC. DAA therapy should be prescribed for all HCC patients after curative surgical resection.     

Adjuvant transarterial chemoembolization improves survival outcomes in hepatocellular carcinoma with microvascular invasion: A systematic review and meta-analysis

BackgroundThe benefits of adjuvant transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) remain controversial. We compared the efficacy and safety of adjuvant TACE and hepatic resection (HR) alone for HCC patients with MVI.MethodsThe PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched to compare adjuvant TACE and HR alone for the treatment of HCC with MVI from inception to January 1, 2019. The study outcomes, including overall survival (OS) and disease-free survival (DFS), were extracted independently by two authors.Results12 trials involving 2190 patients were evaluated. A meta-analysis of 11 studies suggested that the 1-, 3-, and 5-year overall survival (OS) rates (OR = 0.33, P < 0.001; OR = 0.49, P < 0.001; and OR = 0.59, P < 0.01; respectively), favored adjuvant TACE over HR alone. 11 studies were included in the meta-analysis of DFS, and adjuvant TACE showed better 1-, 3-, and 5-DFS (OR = 0.45, P < 0.001; OR = 0.50, P < 0.001; and OR = 0.58, P < 0.001; respectively) compared to HR alone. Subgroup analysis demonstrated that adjuvant TACE could benefit HCC patients with MVI with tumor diameter >5 cm or multinodular tumors.ConclusionAdjuvant TACE may improve OS and DFS for HCC patients with MVI compared to HR alone and should be recommended for selected HCC patients with MVI. However, these results need to be validated through further high-quality clinical studies.Lay summaryThe benefits of adjuvant TACE in HCC patients with microvascular invasion remain controversial. Twelve studies involving 2190 patients were include in our meta-analysis. Adjuvant TACE may improve OS and DFS for HCC patients with MVI compared to HR alone and should be recommended for selected HCC patients with MVI.     

ALBI grade in dialysis patients with hepatocellular carcinoma: prognostic impact and staging strategy

BackgroundPatients with hepatocellular carcinoma (HCC) may develop end-stage renal disease and receive dialysis, but the impact of dialysis on the prognosis is unclear. This study aimed to evaluate the outcome of dialysis HCC patients and the prognostic role of albumin-bilirubin (ALBI) grade in these patients.MethodsAmong the consecutive 3,794 HCC patients between 2002–2017, 43 patients undergoing dialysis, and 129 age, sex-matched controls were analyzed. Multivariate Cox hazards model was used to identify independent prognostic predictors.ResultsDialysis patients had decreased overall survival when compared with non-dialysis patients (n=3,751) and matched controls (n=129; each P=0.004). Patients with ALBI grade 1 had the best survival in the pooled cohort of dialysis and matched controls (n=172). In the Cox model, total tumor volume >33 cm³ [hazard ratio (HR): 6.763, P<0.001], presence of ascites (HR: 6.168, P<0.001), dialysis duration less than 24 months (HR: 3.144, P=0.006), diabetes-related dialysis (HR: 9.366, P=0.001) and non-curative treatments (HR: 9.220, P<0.001) were poor prognosis factors associated with increase mortality among dialysis patients. Of the 9 currently-used HCC staging systems, the CLIP score was the optimal cancer staging for dialysis patients.ConclusionsPatients receiving dialysis had decreased overall survival compared with non-dialysis patients. Longer duration of dialysis, non-diabetes related dialysis, absence of ascites, and curative treatments were associated with improved survival in these patients. The ALBI grade is a feasible prognostic model to evaluate liver functional reserve, and the CLIP model is the best staging system for dialysis patients with HCC.     

High KIF18A expression correlates with unfavorable prognosis in primary hepatocellular carcinoma

This study aimed to investigate KIF18A expression in hepatocellular carcinoma (HCC) and to determine the possibility of KIF18A expression being a biomarker in HCC diagnosis or being an independent predictor of disease-free survival (DFS) and overall survival (OS) in HCC patients underwent surgical resection. KIF18AmRNA was detected in 216 cases of HCC tissues by quantitative real-time PCR (qRT-PCR) and in 20 cases of HCC tissues by semi-quantitative RT-PCR. KIF18A protein was determined in 32 cases of HCC tissues by immunohistochemistry (IHC). The survival probability was analyzed by Kaplan-Meier method, and survival curves between groups were obtained by using the log-rank test. Independent predictors associated with DFS were analyzed with Stepwise Cox proportional hazard models. High KIF18A mRNA level was detected in 154 out of 216 (71.3%) cases of HCC. The positive rate of KIF18A expression was significantly higher in liver cancer tissues than that in adjacent normal liver tissues (ANLT) from HCC patients [65.6% (21 of 32) vs. 25.0% (8 of 32), P=0.001]. The KIF18A expression level had positive relevance to the alpha-fetoprotein (AFP) (≥200 ng/ml), tumor size (≥5cm), clinical tumor-node-metastasis (TNM) stage and portal vein tumor thrombus (PVTT) in HCC (all P <0.05). A survival analysis indicated that HCC patients with higher KIF18A expression had a significantly shorter DFS and OS after resection. A multivariate analysis suggested that KIF18A upregualtion was an independent factor for DFS [hazard risk (HR)=1.602; 95% confidence interval (CI), 1.029-2.579; P=0.031] and OS (HR=1.682; 95% CI, 1.089-2.600; P=0.019). KIF18A might be a biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection.     

Sarcopenia with systemic inflammation can predict survival in patients with hepatocellular carcinoma undergoing curative resection

BackgroundThis study aimed to examine the prognostic significance of sarcopenia combined with systemic inflammation in patients who underwent curative hepatectomy for hepatocellular carcinoma (HCC).MethodsBetween January 2010 and July 2019, we identified 159 patients with HCC who underwent curative hepatectomy at three institutional centers. We retrospectively analyzed clinicopathological outcomes, surgical outcomes, platelet lymphocyte ratio (PLR) as a systemic inflammatory marker, and computed tomography (CT)-assessed sarcopenia at the third lumbar vertebra level (L3).ResultsSarcopenia was noted in 74 (46.5%) of 159 patients and was significantly associated with male sex, low body mass index (BMI), and high PLR. In the multivariate analysis, sarcopenia [hazard ratio (HR): 2.127, P=0.026] and high PLR (HR: 1.971, P=0.038) were associated with a decrease in overall survival (OS) but not in recurrence-free survival (RFS). The combination of sarcopenia and PLR status stratified the 5-year OS into 82.0% (non-sarcopenia and a low PLR), 68.3% (sarcopenia or a high PLR), and 44.4% (sarcopenia and a high PLR) (P=0.001). In the multivariate analysis, “sarcopenia and a high PLR” and “sarcopenia or a high PLR” were revealed to be significant predictors of OS (HR: 4.300, P=0.001 and HR: 2.723, P=0.010, respectively).ConclusionsSarcopenia and high PLR were significantly associated with poor OS. The combination of these two factors may be useful for predicting survival of patients with HCC undergoing curative hepatectomy.     

Modified CLIP using PIVKA-II for evaluating prognosis after hepatectomy for hepatocellular carcinoma.

AIMS: The new staging system proposed by the Cancer of the Liver Italian Program (CLIP) for hepatocellular carcinoma (HCC) accounts for both liver dysfunction and tumour characteristics. The present study was designed to analyze UICC TNM stage, CLIP and modified CLIP in 91 patients who underwent hepatic resection for HCC. METHODS: In the modified CLIP, scoring of AFP was replaced by that of protein induced by vitamin K absence or antagonist II (PIVKA-II; predictive value, > or = 400 mAU/ml). RESULTS: After hepatic resection, 54 patients developed recurrent tumours. High PIVKA-II was a significant determinant of recurrence (p<0.05). However, a high score of the modified CLIP as well as those other staging systems did not correlate with tumour-recurrence rate. Univariate analysis showed that high TNM score, CLIP score and our modified CLIP score were significant predictors of poor prognosis. Multivariate Cox's analysis revealed that high PIVKA-II and high modified CLIP score were associated with higher risk for disease-free and overall survival as well as high TNM stage. CONCLUSIONS: Compared with the original CLIP, our modified CLIP was a better predictor of prognosis of HCC patients who underwent hepatic resection.     

Ablative radiation therapy for hepatocellular carcinoma is associated with reduced treatment- and tumor-related liver failure and improved survival

BackgroundMore than 70% of patients with hepatocellular carcinoma (HCC) are not candidates for curative therapy or recur after curative-intent therapy. There is growing evidence on the use of ablative radiation therapy (RT) for liver tumors. We aimed to analyze outcomes of HCC patients treated with conventional versus ablative RT.MethodsWe retrospectively analyzed medical records of HCC patients treated with liver RT from 2001 to 2019. We defined ablative RT as biologically effective dose (BED) ≥80 Gy. RECIST 1.1 was used to define early responses at 3–6 months after RT, and local control (LC) at last follow-up (FU). Data was analyzed using Fisher exact test, Kaplan-Meier, cumulative incidence rates, Cox proportional hazards model and Fine-Gray competing risks.ResultsForty-five patients were identified, of whom 14 (31.1%) received ablative RT using a stereotactic technique. With median FU of survivors of 10.1 months, 1-year cumulative incidence of LC was 91.7% for ablative and 75.2% for BED <80 Gy. At early FU, patients treated with ablative RT had better responses compared to BED <80 Gy, with 7% progressing versus 19%, and 21.4% with complete response versus none (P=0.038). On univariate analysis (UVA), Child-Pugh (CP) score [hazard ratio (HR): 3 for CP-B, HR: 16 for CP-C] and BED (HR: 7.69 for BED <80 Gy) correlated with deterioration of liver function, leading to liver failure. Most liver failure cases were due to disease progression. No RT-related liver failure occurred in the ablative RT group. On UVA, only BED ≥80 Gy was associated with improved overall survival (OS) (HR: 0.4; P=0.044). Median OS (mOS) and 1-year OS were 7 months and 35% respectively for BED <80 Gy compared to 28 months and 66% for BED ≥80 Gy. No grade 3+ bowel toxicity was reported in either group.ConclusionsGreater than 90% LC was achieved after stereotactic ablative RT, which was associated with minimized tumor- and treatment-related liver failure and improved survival for highly selected inoperable HCC patients.     

Risk Factors for Early Recurrence of HBV-related Hepatocellular Carcinoma Meeting Milan Criteria after Curative Resection

Background: The prognosis of patients with hepatocellular carcinoma (HCC) after curative resection variesgreatly. Few studies had investigated the risk factors for early recurrence (recurrence-free time ≤ 1 year) ofhepatitis B virus (HBV)-related HCCs meeting Milan criteria. Methods: A retrospective analysis was performedon the 224 patients with HCC meeting Milan criteria who underwent curative liver resection in our center betweenFebruary 2007 and March 2012. The overall survival (OS) rate, recurrence-free survival (RFS) rate and riskfactors for early recurrence were analyzed. Results: After a median follow-up of 33.3 months, HCC reoccurredin 105 of 224 patients and 32 died during the period. The 1-, 3- and 5-year OS rates were 97.3%, 81.6% and75.6% respectively, and the 1-, 3- and 5-year RFS rates were 73.2%, 53.7% and 41.6%. Cox regression showedalpha-fetoprotein (AFP) > 800 ng/ml (HR 2.538, 95% CI 1.464-4.401, P=0.001), multiple tumors (HR 2.286, 95%CI 1.123-4.246, P=0.009) and microvascular invasion (HR 2.518, 95% CI 1.475-4.298, P=0.001) to be associatedwith early recurrence (recurrence-free time ≤ 1-year) of HCC meeting Milan criteria. Conclusions: AFP > 800ng/ml, multiple tumors and microvascular invasion are independent risk factors affecting early postoperativerecurrence of HCC. In addition resection appears capable of replacing liver transplantation in some situationswith safety and a better outcome.     

Therapeutic efficacy of transcatheter arterial chemoembolization as compared with hepatic resection in hepatocellular carcinoma patients with compensated liver function in a hepatitis B virus-endemic area: a prospective cohort study.

PURPOSE: Identifying a special subgroup of hepatocellular carcinoma (HCC) patients who may benefit from transcatheter arterial chemoembolization (TACE) when compared with the standard treatment of hepatic resection (HR) warrants research in Asian countries. PATIENTS AND METHODS: From January 1993 to December 1994, 182 patients with operable HCC (Child-Pugh class A and International Union Against Cancer [UICC] stage T1-3N0M0) were enrolled. After initial TACE and lipiodol computed tomography, 91 received HR and 91, who refused the operation, received repeated sessions of TACE. After stratification according to the tumor stage (UICC and Cancer of the Liver Italian Program [CLIP]) and lipiodol retention pattern, the survival rates of the two treatment groups were compared. The median follow-up period was 83 months. RESULTS: As of December 31, 2000, 48 patients who underwent HR and 68 patients who underwent TACE had died. In a subgroup analysis according to tumor stage, the HR group survival rate was significantly higher than the TACE group in both UICC T1-2N0M0 (P =.0058) and CLIP 0 (P =.0027) subgroups. However, there was no significant difference in either UICC T3N0M0 (P =.7512) or CLIP 1-2 (P =.5366) subgroups. Even in patients with UICC T1-2N0M0 HCC, when lipiodol was compactly retained, the survival rate of the HR group was comparable to that of the TACE group (P =.0596). CONCLUSION: TACE proved to be as effective as HR in the subpopulations with UICC T3N0M0 or CLIP 1-2 HCC and adequate liver function, and even with UICC T1-2N0M0 HCC when lipiodol was compactly retained in the tumor. In such cases, the choice of treatment modality between TACE and HR may be left to the patient's preference.     

High neutrophil-to-lymphocyte ratio following stereotactic body radiation therapy is associated with poor clinical outcomes in patients with borderline resectable and locally advanced pancreatic cancer

BackgroundThe purpose of this study is to report on the prognostic role of pre- and post-stereotactic body radiation therapy (SBRT) neutrophil-to-lymphocyte ratio (NLR) in a cohort of patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) who was treated with multi-agent induction chemotherapy followed by five-fraction SBRT.MethodsPatients treated with multi-agent induction chemotherapy followed by SBRT from August 2016 to January 2019 and who had laboratory values available for review were included in the study. Univariate (UVA) and multivariate analyses (MVA) were performed to determine associations between pre-/post-SBRT NLR and overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS).ResultsA total of 156 patients were treated with multi-agent induction chemotherapy followed by SBRT and had laboratory values available for review. On UVA, chemotherapy duration ≥4 months, poorly differentiated disease, inability to undergo resection, pre-SBRT ANC ≥3.7 No./µL, pre-SBRT NLR ≥2.3, and post-SBRT NLR ≥2.6 were associated with worse OS. Patients with post-SBRT NLR ≥2.6 had a median OS of 16.7 months versus median OS not yet reached in patients with post-SBRT <2.6 (P=0.009). On MVA, poorly differentiated disease [hazard ratio (HR) =1.82, 95% CI: 1.04–3.18, P=0.035], inability to undergo resection (HR =2.17, 95% CI: 1.25–3.70, P=0.006), and post-SBRT NLR ≥2.6 (HR =2.55, 95% CI: 1.20–5.45, P=0.015) were associated with inferior OS. On UVA, baseline CA 19-9 ≥219 U/mL, pre-SBRT platelet count ≥157×1,000/µL, and post-SBRT NLR ≥2.6 were associated with inferior LPFS. Patients with post-SBRT NLR ≥2.6 had a median LPFS of 18.3 months versus median LPFS not yet reached in patients with post-SBRT <2.6 (P=0.028). On MVA, only post-SBRT NLR ≥2.6 was associated with worse LPFS (HR =3.22, 95% CI: 1.04–9.98, P=0.043).ConclusionsPost-SBRT NLR ≥2.6 predicted for inferior OS and LPFS in BRPC/LAPC patients treated with multi-agent chemotherapy and SBRT. These findings highlight the importance of further elucidating the immunologic effects of radiation therapy in this setting, which may have significant implications on both radiation design as well as combination strategies.     

Development of a prognostic score for recommended transarterial chemoembolization candidates with spontaneous rupture of hepatocellular carcinoma

BackgroundAlthough transarterial chemoembolization (TACE) has been widely used for treating the spontaneous rupture of hepatocellular carcinoma (HCC), no existing model exists for predicting survival. The aim of this study was thus to develop and validate a nomogram for estimating the prognosis in patients with ruptured HCC upon undergoing TACE treatment.MethodsThis study included 55 patients with spontaneously ruptured HCC who underwent TACE treatment between January 2015 and April 2019. The diagnosis of spontaneous HCC rupture was based on the disruption of the peritumoral liver capsule with surrounding fluid in the perihepatic region. The prognostic nomogram was constructed using the independent predictors assessed by the multivariate Cox proportional hazards model.ResultsThe median overall survival (OS) was 6.4 months, with 6-month and 1-year survival rates of 52.7% and 41.8%, respectively. In the univariate analysis, the size of the largest tumor, total bilirubin (TBIL) levels, and aspartate aminotransferase (AST) levels were associated with the OS of patients. Multivariate analysis suggested that TBIL levels (HR =0.358, P=0.036) and diameter of the largest tumor (HR =1.012, P=0.044) were independent prognostic factors for predicting the OS. Based on these variables, we developed and validated a nomogram for the risk stratification of HCC rupture after TACE treatment for individual patients. According to the nomogram risk assessment, we were able to evaluate the approximate 1- and 2-year survival rates based on patients’ tumor diameter and TBIL level after TACE treatment of ruptured HCC. The concordance index for the OS prediction was 0.748 (95% CI: 0.691–0.805). This newly developed nomogram represents an intuitive tool for predicting the OS of patients with ruptured HCC.ConclusionsThis study indicated that TBIL levels and diameter of the largest tumor were independent prognostic factors for predicting the OS of ruptured HCC. This study may help maximize favorable TACE treatment outcomes.     

Predictive effects of preoperative serum CA125 and AFP levels on post-hepatectomy survival in patients with hepatitis B-related hepatocellular carcinoma

The association between the serum levels of cancer antigen 125 (CA125; also termed MUC16) and the prognosis of patients with hepatocellular carcinoma (HCC) has not been widely reported to date. The aim of the present study was to determine the association between preoperative serum CA125 levels and prognosis of patients with hepatitis B virus (HBV)-related HCC after hepatectomy. The study included 306 patients with HBV-related HCC who underwent liver resection and were classified into four subgroups based on their baseline CA125 and α-fetoprotein (AFP) levels. The perioperative clinical data were compared and analyzed. Kaplan-Meier and Cox regression analyses were performed to determine the associations between patient clinicopathological characteristics and survival. The results revealed that the median follow-up time was 35 months. Patients with low preoperative serum CA125 levels presented with improved 3-year disease-free survival (DFS) (79.3 vs. 75.7%; P=0.278) and overall survival (OS) (84.4 vs. 77.1%; P=0.001) rates compared with those among patients with high preoperative serum CA125 levels. High preoperative serum CA125 levels were a risk factor associated with short DFS and OS rates in all patients. In patients with baseline AFP levels >100 ng/ml, low preoperative serum CA125 levels were significantly associated with prolonged DFS and OS rates (log-rank test P=0.002 and P=0.005, respectively). In patients with AFP levels ≤100 ng/ml, no significant differences were observed in DFS or OS rates between the high and low preoperative serum CA125 groups. Patients with high preoperative serum CA125 and AFP levels exhibited the worst prognosis (low DFS and OS rates). In conclusion, high baseline CA125 levels may be associated with a poor prognosis in patients with HBV-related HCC.     

Prognostic Significance of Preoperative Serum Alphafetoprotein in Hepatocellular Carcinoma and Correlation with Clinicopathological Factors: a Single-center Experience from China

Objectives: To investigate the prognosis significance of preoperative serum alpha-fetoprotein (AFP) andthe correlation with clinicopathological factors of hepatocellular carcinoma (HCC) patients who underwenthepatectomy. Materials and Methods: Clinicopathological data of retrospective analysis were collected for251 HCC patients undergoing hepatectomy in this study. According to preoperative AFP level, patients werecategorized into AFP-negative (0-20ng/mL) and AFP-positive (>20 ng/mL) groups for Kaplan-Meier analysisand Cox proportional hazard regression modeling. Results: The results demonstrated that increased AFPwas associated with longer prothrombin time (PTs), liver capsule invasion, low grade differentiation, and lateBarcelona Clinic Liver Center (BCLC) stage. Moreover, the female patients had a greater prevalence of increasedpreoperative AFP than male patients [284.8 (3.975-3167.5) vs (3.653-140.65); Z-2.895, p=0.004]. The 1-, 3-, and5-year recurrence-free survival (RFS) rates were 78.1, 57.5, and 40.6 % in the AFP-negative group and 61.8,37.7, and 31.4 %, respectively, in the AFP-positive group (log-rank test 8.312, p=0.004). The 1-, 3-, and 5-yearoverall survival (OS) rates were 94.4, 83.8, and 62.3% in the AFP-negative group and 87.2, 60.0, and 36.7%,respectively, in the AFP-positive group. The difference was statistically significant (log-rank test, 16.884, p=0.000).Cox proportional-hazards model identified preoperative AFP to be an independent prognostic predictor of overallsurvival. Conclusions: Preoperative serum AFP is an independent predictor of prognosis among HCC patientsfollowing surgical resection. Female patients have a higher preoperative AFP than their male counterparts.     

Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma

BackgroundEmbolizing branches of the hepatic artery lengthens survival for patients with unresectable hepatocellular carcinoma (HCC), but the benefit of combining chemotherapy with the embolizing particles remains controversial.MethodsA retrospective review was undertaken of sequential patients with advanced HCC undergoing embolization in the past 10 years at 2 neighboring institutions and with 2 years of follow-up data. TACE was generally performed with doxorubicin plus mitomycin C. Results: One hundred twenty-four patients were included; 77 received TACE and 47 received TAE. On multivariable analysis stratified by institution, type of embolization and CLIP score significantly predicted PFS and time to progression (TTP), whereas CLIP score and AFP independently predicted overall survival (OS). TACE significantly prolonged PFS and TTP (P = .0004 and P = .001, respectively), but not OS (P = .83).ConclusionsThe addition of chemotherapy to TAE prolongs PFS and TTP. Future efforts should focus on adjunctive therapies after the embolization to increase survival.     

Outcomes of curative liver resection for hepatocellular carcinoma in patients with cirrhosis

BACKGROUNDGiven the poor synthetic function of cirrhotic liver, successful resection for patients with hepatocellular carcinoma (HCC) necessitates the ability to achieve resections with tumor free margins.AIMTo validate post hepatectomy liver failure score (PHLF), compare it to other established systems and to stratify risks in patients with cirrhosis who underwent curative liver resection for HCC. METHODSBetween December 2010 and January 2017, 120 patients underwent curative resection for HCC in patients with cirrhosis were included, the pre-operative, operative and post-operative factors were recorded to stratify patients'' risks of decompensation, survival, and PHLF.RESULTSThe preoperative model for end-stage liver disease (MELD) score [odds ratio (OR) = 2.7, 95%CI: 1.2-5.7, P = 0.013], tumor diameter (OR = 5.4, 95%CI: 2-14.8, P = 0.001) and duration of hospital stay (OR = 2.5, 95%CI: 1.5-4.2, P = 0.001) were significant independent predictors of hepatic decompensation after resection. While the preoperative MELD score [hazard ratio (HR) = 1.37, 95%CI: 1.16-1.62, P < 0.001] and different grades of PHLF (grade A: HR = 2.33, 95%CI: 0.59-9.24; Grade B: HR = 3.15, 95%CI: 1.11-8.95; Grade C: HR = 373.41, 95%CI: 66.23-2105.43; P < 0.001) and HCC recurrence (HR = 11.67, 95%CI: 4.19-32.52, P < 0.001) were significant independent predictors for survival.CONCLUSIONPreoperative MELD score and tumor diameter can independently predict hepatic decompensation. While, preoperative MELD score, different grades of PHLF and HCC recurrence can precisely predict survival.     

Postoperative adjuvant transarterial chemoembolization for intrahepatic cholangiocarcinoma patients with microvascular invasion: a propensity score analysis

BackgroundMicrovascular invasion (MVI) is an independent risk factor associated with tumor recurrence and poor survival in patients with intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy (PH). The potential impact of adjuvant TACE on the prognosis of patients with ICC involving MVI (ICC-MVI) remains uncertain. Our aim was to investigate the effectiveness of postoperative adjuvant transarterial chemoembolization (TACE) on ICC involving MVI.MethodsMulticentric data consisted of 223 patients who underwent curative-intent PH for ICC-MVI from 2002–2015 were retrospectively analyzed. The impact of adjuvant TACE was evaluated using inverse probability of treatment weighting (IPTW) and propensity-score matched (PSM) analyses.ResultsNo association between the TACE and the overall survival (OS) and recurrence rates was observed among the overall ICC-MVI patients. However, subgroup analyses revealed that adjuvant TACE favored OS (HR, 0.62; 95% CI, 0.39–0.99; P=0.047) and time to recurrence (TTR) (HR, 0.59; 95% CI, 0.36–0.97; P=0.037) among patients with elevated CA19-9 and those without lymphadenectomy (HR, 0.53; 95% CI, 0.30–0.93; P=0.027 for OS, and HR, 0.49; 95% CI, 0.28–0.87; P=0.015 for TTR, respectively). In the CA19-9 ≥39 U/L subgroup and Nx subgroup, adjuvant TACE was associated with higher 1-, 3-, and 5-year OS rates (P=0.033 and P=0.034, respectively) and lower corresponding recurrence rates (P=0.024 and P=0.023, respectively).ConclusionsAmong the ICC-MVI patients undergoing curative-intent PH, only those have elevated CA19-9 or who did not undergo lymphadenectomy might be suitable for adjuvant TACE.