Necrosis Of Hepatocellular Carcinoma Research Articles

Multiparametric MRI manifestations of the spontaneous intratumoral coagulative necrosis in HCC.

To investigate the MRI manifestations of the spontaneous intratumoral coagulative necrosis (iCN) in patients with hepatocellular carcinoma (HCC) and its value in predicting the postoperative early recurrence (≤ 2years). Patients with HCC who underwent preoperative multiparametric MRI between January 2015 and February 2019 were enrolled in this retrospective study. The MRI manifestations of iCNs on TIWI, T2WI, and ADC were recorded. The sensitivity and specificity of MRI for the detection of iCNs were also evaluated. A multivariable Cox proportional hazards model and the Kaplan-Meier method were used to verify the value of histologically-confirmed and MRI-identified iCNs, respectively, in predicting early recurrence. A total of 163 patients (median age, 56years; interquartile range, 49-64years; 139 men) with HCCs were evaluated, of whom 27(16.6%) had histologically-confirmed iCNs. MRI identified 92.6% (25 of 27; 95% confidence interval [CI] 74.2%, 98.7%) of iCNs (sensitivity), with a specificity of 79.4% (78 of 136; 95% CI 71.4%, 85.7%), based on non-enhancement on post-contrast MRI. And the MRI-identified iCNs were characterized by a similar appearance to surrounding tumour tissue shown on pre-contrast MRI but not enhanced on post-contrast MRI. The multivariable Cox proportional hazards model revealed that only the presence of histologically-confirmed iCN was independently associated with early HCC recurrence (hazard ratio = 2.73; 95% CI 1.20, 6.21; P = 0.017). The Kaplan-Meier curve showed that the presence of MRI-identified iCN was also associated with early recurrence (P < 0.001). Multiparametric MRI identified iCNs with high sensitivity and modest specificity. The presence of iCNs is associated with early HCC recurrence.

Local Recurrence following Radiological Complete Response in Patients Treated with Subsegmental Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma.

The aim of this study was to determine the local recurrence (LR) rate and identify factors associated with LR in patients who achieve a radiological complete response (CR) after undergoing balloon-occluded transcatheter arterial chemoembolization (B-TACE) for hepatocellular carcinoma (HCC). From November 2017 to September 2021, 60 patients (44 men, 16 women; mean age, 63.5 years; range, 39-82 years) with 72 HCCs (mean diameter, 31 mm; range, 10-50 mm) who underwent subsegmental B-TACE were included in this retrospective study. Radiological and clinical evaluation of oily subsegmentectomy, defined as radiological CR of the HCC and peritumoral parenchymal necrosis, was performed. The CR rate was 97.2% (70 of 72 HCCs) at first follow-up (mean, 41 days; range, 14-110 days). Overall, 13 HCCs (19.7%) demonstrated LR at a mean of 29.8 months (range, 3-63 months) and cumulative LR rates were 1.5% 14.2% 21%, 21%, and 21% at 6, 12, 24, 36, and 48 months, respectively. In 28 (38.9%) of 72 HCCs, oily subsegmentectomy was achieved, tumor markers were normalized, and LR did not occur. The oily subsegmentectomy-positive group had a significantly lower LR rate than the oily subsegmentectomy-negative group (p = 0.001). Age ≥65 years (adjusted hazard ration (HR), 0.124; 95% confidence interval (CI), 0.037-0.412; p < 0.001) and peripheral location (adjusted HR, 0.112; 95% CI, 0.046-0.272; p < 0.001) were independent predictive factors of LR. Subsegmental B-TACE can be an effective method with a high initial CR rate and low LR incidence. Oily subsegmentectomy can be considered as an index of successful treatment because it did not demonstrate any LR.

Longitudinal assessment of hepatocellular carcinoma response to stereotactic body radiation using gadoxetate-enhanced MRI: A case series

PurposeTo describe the longitudinal response in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) and who underwent liver transplant (LT) using gadoxetate-enhanced MRI. MethodsFive men (median age 61y, range 57–64y) with 6 HCCs treated with SBRT (median dose 50 Gy) who subsequently underwent LT were included in this retrospective study. Patients underwent gadoxetate-enhanced MRI before and after SBRT over a period of 3–18 months. Response was assessed using RECIST1.1, mRECIST, LI-RADS and image subtraction, by 2 observers in consensus. Percentage of pathologic tumor necrosis was evaluated. ResultsLT was performed 278 days (IQR, 148–418d) after completion of SBRT and 48d after the last MRI. Histopathology demonstrated tumor necrosis of 48 ± 42% (range, 10–100%). Mean tumor size at baseline and last post-treatment MRIs pre-LT were 2.6 ± 0.8 cm and 2.4 ± 0.9 cm. Enhancing tumor component size at baseline MRI and last post-treatment MRI pre-LT were 1.6 ± 0.8 cm and 0.9 ± 1.0 cm. Responses assessed at the last LRI pre-LT were: partial response (PR, n = 3), stable disease (SD, n = 3) using RECIST1.1; complete response (CR, n = 2), partial response (PR, n = 2), stable disease (SD, n = 2) using mRECIST; and LR-TR viable (n = 4), LR-TR non-viable (n = 2) using LI-RADS. At the last MRI pre-LT, per-lesion features of arterial phase hyperenhancement (APHE, 4/6), portal venous washout (3/6) and capsule (3/6) were observed. 5/6 lesions displayed a hypointense perilesional halo on hepatobiliary phase with a mean delay of 3.1 months post-SBRT. ConclusionsThis case-series showed decreased size, persistent APHE, and incomplete pathologic necrosis in most HCCs treated with SBRT undergoing transplant.

Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.

Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.

Recurrence in patients with totally necrotic nodules of hepatocellular carcinoma after liver transplantation: "totally" an inaccurate description.

Total necrosis of hepatocellular carcinoma (HCC) achieved via locoregional treatment (LRT) is considered to indicate a lack of tumor viability. Nonetheless, there is insufficient evidence of recurrence after liver transplantation (LT) in patients with such a status. The aim of this study was to investigate the prognosis of patients diagnosed with totally necrotic nodules upon explant hepatectomy after LT. We conducted a retrospective study of patients diagnosed with totally necrotic nodules after LT for HCC. A total of 165 patients with HCC who underwent living- or deceased-donor LT from 2000 to 2020 in our hospital were included. A total of 5 patients (3.0%) exhibited HCC recurrence during a median follow-up of 84 months (range, 4-243 months) after LT. The 5-year overall and recurrence-free survival rates of these patients were 92.8% and 92.2%, respectively. Four patients in the HCC-recurrence group (80.0%) died even after further treatment, including transarterial chemoembolization, surgery, and systemic treatment. Both univariate and multivariate analyses of clinicopathological factors identified a maximum diameter of the totally necrotic nodules of >5 cm as the only factor associated with tumor recurrence following LT (P = 0.005 and P = 0.009, respectively). Total necrosis of HCC via LRT yielded excellent survival outcomes for patients undergoing LT. Nevertheless, patients with large tumors should be considered at high risk of recurrence after LT, suggesting the need for their active surveillance during the follow-up period.

Gundelia tournefortii inhibits hepatocellular carcinoma progression by lowering gene expression of the cell cycle and hepatocyte proliferation in immunodeficient mice

Gundelia (G.) tournefortii has antibacterial, anti-inflammatory, and hypolipemic effects. We evaluated the anticancer effect of G. tournefortii in an hepatocellular carcinoma (HCC) mouse model of an HCC cell line (Hep3B) injected into NOD.CB17-Prkdc-SCID/NCrHsD male mice. Tumorigenicity was assessed by tumor size, histology, serum α-fetoprotein (αFP), and glypican 3 (GPC3). HCC-related gene expression of the cell cycle (Cyclin-dependent kinase inhibitor 2A (CDNK2A)), proliferation (MKI67), and platelet-derived growth factor receptor α (PDGFA) were measured. HCC cell cycle alterations, apoptosis, and antioxidant markers in serum and liver following treatment with G. tournefortii were determined. Signaling pathways of liver p53 and phosphorylated PI3K, AKT, and mTOR were also evaluated. Results indicate a significant increase in tumor size in HCC animals associated with elevated αFP, GPC3, and MKI67. Tumor markers of p53 and phosphorylated AKT/PI3K/mTOR signaling pathway were diminished, with less proliferating cells and reduced PDGFRA gene expression following G. tournefortii infection. H&E staining showed a remarkable reduction in inflammatory lesions in HCC mice treated with G. tournefortii. This result was in line with a significant delay in the G2/M phase of HCC-primary hepatocytes by 1.39- to 2.4-fold and reduced HCC necrosis associated with inhibited CDNK2A gene expression. Antioxidant activity was significantly lower in the HCC mice than in the control group. Moreover, G. tournefortii inhibited the HCC formation of 3D MCTS spheroids. G. tournefortii treatment markedly restored antioxidant levels and displayed anticancer and antiproliferative effects and could be a promising cancer therapy.

Abstract No. 197 Predictors of complete pathologic necrosis in hepatocellular carcinoma treated with yttrium-90 radiation segmentectomy prior to liver transplantation: an explant analysis of 75 tumors

To analyze yttrium-90 glass microsphere radiation segmentectomy treatment parameters predictive of complete pathological necrosis (CPN) in patients with hepatocellular carcinoma (HCC) prior to liver transplantation.

Identification of CT Values That Could Be Predictive of Necrosis (N-CTav) in Hepatocellular Carcinoma after Lenvatinib Treatment.

Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e., the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (≥30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (<30.6%) N30-CTav group (p < 0.001, 61.5% at 1 year). Conclusion: The cut-off value of 30.2 HU for CTav (N30-CTav) might be appropriate for identifying post-lenvatinib necrosis in HCC, and an N30-CTav occupancy rate of >30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

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

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. 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. 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. EASLand percentage of tumor necrosis on subtraction at the AP/PVP were independent predictorsof 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). 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. • Percentage of tumor necrosis onimage 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.

LI-RADS Treatment Response Algorithm: Performance and Diagnostic Accuracy With Radiologic-Pathologic Explant Correlation in Patients With SBRT-Treated Hepatocellular Carcinoma

Our purpose was to evaluate the accuracy of LI-RADS Treatment Response Algorithm (LR-TRA) for assessing the viability of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT), using explant pathology as the gold standard. This retrospective study included patients who underwent SBRT for locoregional treatment of HCC between 2008 and 2019 with subsequent liver transplantation. Five radiologists independently assessed all treated lesions by using the LR-TRA. Imaging and posttransplant histopathology were compared. Lesions were categorized as either completely (100%) or incompletely (<100%) necrotic, and performance characteristics and predictive values for the LR-TR viable and nonviable categories were calculated for each reader. Interreader reliability was calculated using the Fleiss kappa test. A total of 40 treated lesions in 26 patients (median age, 63 years [interquartile range, 59.4-65.5]; 23 men) were included. For lesions treated with SBRT, sensitivity for incomplete tumor necrosis across readers ranged between 71% and 86%, specificity between 85% and 96%, and positive predictive value between 86% and 92%, when the LR-TR equivocal category was treated as nonviable, accounting for subject clustering. When the LR-TR equivocal category was treated as viable, sensitivity of complete tumor necrosis for lesions treated with SBRT ranged from 88% to 96%, specificity from 71% to 93%, and negative predictive value from 85% to 96%. Interreader reliability was fair (k=0.22; 95% confidence interval, 0.13-0.33). Although a loss of arterial phase hyperenhancement (APHE) was highly correlated with pathologically nonviable tumor on explant, almost half of the patients with APHE had pathologically nonviable tumor on explant. LR-TRA v2018 performs well for predicting complete and incomplete necrosis in HCC treated with SBRT. In contrast to other locoregional therapies, the presence of APHE after SBRT does not always indicate viable tumor and suggests that observation may be an appropriate strategy for these patients.

To turn weakness into a strength-preoperative future liver remnant (FLR) augmentation with special focus on local tumor control and in-situ immunization for patients with advanced hepatocellular carcinoma (HCC) and liver cirrhosis (LC)

Portal vein embolization (PVE) provokes tumor progression. LC decreases FLR regeneration capacity doubling the risk for patient dropout. Our aim was to develop method of FLR augmentation that convert aggressive tumor into safe vaccine and prolonged waiting period for FLR regeneration into effective In situ immunization period. 3 initially unresectable patients due to small FLR with advanced hepatocellular carcinoma (HCC) and LC were treated. Selective transarterial chemoembolization with short term biodegradable starch microspheres (DSM-TACE), into tumor bearing liver to be resected, was followed by simultaneous PVE of latter. Upon completion of PVE selective intratumoral immunotherapy (HIT-IT) with antiPD-L1 (atezolizumab 1,200 mg) into restored after DSM-TACE tumor arterial feeders (for selective connection with PD-L1 ligands located on tumor cells but not on normal human tissues) was done. DSM-TACE and HIT-IT was repeated one more time in all patients after postzenith decrease of T-cytotoxic cells. Predominantly T and NK cells response was observed. All patients had successfully underwent major liver resection upon sufficient FLR regeneration. In all 3 cases we had achieved effective local tumor control via total or subtotal HCC necrosis, even more, in 1 (33%) case planned amount of liver resection was decreased due to achieved tumor downsizing. There were no severe morbidity or Immune-related adverse events (irAEs). Herein we had proposed new aggressive but safe method of FLR augmentation for patients with HCC and LC that could potentially preclude drop out of patients during anticipated prolonged waiting period of FLR augmentation and possible improves long-term outcomes by means of tumor downsizing and HCC immunoscore conversion.

LI-RADS treatment response algorithm for detecting incomplete necrosis in hepatocellular carcinoma after locoregional treatment: a systematic review and meta-analysis using individual patient data.

To perform a systematic review and meta-analysis using individual patient data to investigate the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) Treatment Response (TR) algorithm for detecting incomplete necrosis on pathology. PubMed and EMBASE were searched from Jan 1, 2017 until October 14, 2020. Studies reporting diagnostic accuracy of LI-RADS TR algorithm on CT or MRI for detecting incomplete necrosis on pathology as a reference standard were included. Sensitivity and specificity were pooled using random-effects model. Subgroup analyses were performed for locoregional treatment (LRT) type and imaging modality. Six studies (393 patients, 534 lesions) were included. Pooled sensitivity was 0.56 (95% confidence interval [CI] 0.43-0.69) and specificity was 0.91 (95%CI 0.84-0.96). Pooled sensitivity was highest using arterial phase hyperenhancement (APHE) (0.67 [95%CI 0.51-0.81]), followed by washout (0.43 [95%CI 0.26-0.62]) and enhancement similar to pretreatment (0.24 [95%CI 0.15-0.36]). Among lesions with incomplete necrosis, 2% (95%CI 0.00-0.05) manifested as washout but no APHE; 0% (95% CI 0.00-0.02) as enhancement similar to pretreatment without both APHE and washout. Pooled sensitivity was lower after ablation than embolization (0.42 [95%CI, 0.28-0.57] vs. 0.65 [95%CI, 0.53-0.77], p = 0.033). MRI and CT were comparable (p = 0.783 and 0.290 for sensitivity and specificity). LI-RADS TR algorithm shows moderate sensitivity and high specificity for detecting incomplete necrosis after LRT. APHE is the dominant criterion, a washout contributes to small but meaningful extent, while the contribution of enhancement similar to pretreatment may be negligible. LRT type may affect performance of the algorithm.

Preoperative future liver remnant(FLR) augmentation with local tumor control and in-situ immunization for patients with advanced hepatocellular carcinoma (HCC)

Purpose: Portal vein embolization(PVE) provokes tumor progression. Liver Cirrhosis(LC) decreases FLR regeneration capacity doubling the risk for patient dropout. Our aim was to turn weakness into a strength- develop method of FLR augmentation that converts aggressive tumor into a safe vaccine and prolonged waiting period for FLR regeneration into effective In situ immunization period Method: 3 initially unresectable patients due to small FLR with advanced hepatocellular carcinoma(HCC) and liver cirrhosis were treated. Selective transarterial chemoembolization with short term biodegradable starch microspheres(DSM-TACE), into tumor bearing liver to be resected, was followed by simultaneous PVE of latter. Upon completion of PVE selective intratumoral immunotherapy(HIT-IT) with antiPD-L1(atezolizumab 1200mg) into restored after DSM-TACE tumor arterial feeders (for selective connection with PD-L1 ligands located on tumor cells but not on normal human tissues) was done. DSM-TACE and HIT-IT was repeated one more time in all patients after postzenith decrease of T-cytotoxic cells level in peripheral blood had started. Anticancer immune response was investigated by comparison of initial histopathology specimen with specimens obtained just before second DSM-TACE+ HIT-IT and finally with specimen of resected tumor bearing liver. Latter were analyzed along with peripheral blood flow cytometry. Results: Predominantly T and NK cells response was observed. All patients had successfully underwent extended liver resection upon sufficient FLR regeneration. In all 3 cases we had achieved effective local tumor control via total or subtotal HCC necrosis, even more, in 1(33%) case planned amount of liver resection was decreased due to achieved tumor downsizing. There were no severe morbidity or Immune-related adverse events (irAEs). Conclusion: Herein we had proposed new aggressive but safe method of FLR augmentation for patients with HCC and liver cirrhosis that could potentially preclude drop out of patients during anticipated prolonged waiting period of FLR augmentation and possible improves long-term outcomes by means of tumor downsizing and HCC immunoscore conversion.

Tumor Necrosis Impacts Prognosis of Patients Undergoing Curative-Intent Hepatocellular Carcinoma.

The impact of tumor necrosis relative to prognosis among patients undergoing curative-intent resection for hepatocellular carcinoma (HCC) remains ill-defined. Patients who underwent curative-intent resection for HCC without any prior treatment between 2000 and 2017 were identified from an international multi-institutional database. Tumor necrosis was graded as absent, moderate (< 50% area), or extensive (≥ 50% area) on histological examination. The relationship between tumor necrosis, clinicopathologic characteristics, and long-term survival were analyzed. Among 919 patients who underwent curative-intent resection for HCC, the median tumor size was 5.0cm (IQR, 3.0-8.5). Tumor necrosis was present in 367 (39.9%) patients (no necrosis: n = 552, 60.1% vs < 50% necrosis: n = 256, 27.9% vs ≥ 50% necrosis: n = 111, 12.1%). Extent of tumor necrosis was also associated with more advanced tumor characteristics. HCC necrosis was associated with OS (median OS: no necrosis, 84.0months vs < 50% necrosis, 73.6months vs ≥ 50% necrosis: 59.3months; p < 0.001) and RFS (median RFS: no necrosis, 49.6months vs < 50% necrosis, 38.3months vs ≥ 50% necrosis: 26.5months; p < 0.05). Patients with T1 tumors with extensive ≥ 50% necrosis had an OS comparable to patients with T2 tumors (median OS, 62.9 vs 61.8months; p = 0.645). In addition, patients with T2 disease with necrosis had long-term outcomes comparable to patients with T3 disease (median OS, 61.8 vs 62.4months; p = 0.713). Tumor necrosis was associated with worse OS and RFS, as well as T-category upstaging of patients. A modified AJCC T classification that incorporates tumor necrosis should be considered in prognostic stratification of HCC patients.

Correlation of tumor response on CT with pathologically proven necrosis in hepatocellular carcinoma treated by conventional transcatheter arterial chemoembolization: threshold value of intratumoral Lipiodol accumulation predicting tumor necrosis.

To evaluate associations between pathology and CT assessments made according to the mRECIST in HCC treated by conventional TACE (cTACE), and to identify predictors of complete tumor necrosis. From March 2016 to July 2018, 83 patients with a total of 100 masses were retrospectively included. Patients underwent sequential cTACE and portal vein embolization, and later hepatic surgery. Evaluation of treatment response and measurement of baseline lipiodol accumulation as mean HU was performed on CT at the time point closest to the time of operation (mean, 54.5days after cTACE). Significant predictors associated with complete necrosis were identified by multivariate analysis. The optimal cut-off HU value of lipiodol accumulation for prediction of complete necrosis was determined using a ROC analysis. According to mRECIST, complete response (CR, n = 70) and partial response (n = 30) were classified. 34.3% (24/70) masses classified as CR according to mRECIST were found to have viable lesions on pathology. On multivariate analysis, mean HU of lipiodol accumulation was the only significant predictor of complete necrosis (p = .003, odds ratio 1.746, 95% CI 1.201-2.539). On ROC analysis, 460 HU as a cut-off value was significantly associated with complete necrosis (67.4% sensitivity, 75.0% specificity). A threshold value for lipiodol accumulation > 460 HU was highly sensitive and specific for complete necrosis, even in complete response according to mRECIST. Therefore, if lipiodol accumulation is insufficient in post-TACE CT, recurrence should be monitored more sensitively.

Impact of intraoperative blood salvage and autologous transfusion during liver transplantation for hepatocellular carcinoma.

Intraoperative blood salvage (IBS) with autologous blood transfusion is controversial in liver transplantation (LT) for hepatocellular carcinoma (HCC). This study evaluated the role of IBS usage in LT for HCC. In a retrospective cohort study at a single center from 2002 to 2018, the outcomes of LT surgery for HCC were analyzed. Overall survival and disease-free survival of patients who received IBS were compared with those who did not receive IBS. Cancer recurrence, length of hospital stay, post-transplant complications, and blood loss also were evaluated. The primary aim of this study was to evaluate overall mid-term and long-term survival (4 and 6years, respectively). Of the total 163 patients who underwent LT for HCC in the study period, 156 had complete demographic and clinical data and were included in the study. IBS was used in 122 and not used in 34 patients. Ninety-five (60.9%) patients were men, and the mean patient age was 58.5 ± 7.6years. The overall 1-year, 5-year, and 7-year survival in the IBS group was 84.2%, 67.7%, and 56.8% vs. 85.3%, 67.5%, and 67.5% in the non-IBS group (p = 0.77). The 1-year, 5-year, and 7-year disease-free survival in the IBS group was 81.6%, 66.5%, and 55.4% vs. 85.3%, 64.1%, and 64.1% in the non-IBS group (p = 0.74). For patients without complete HCC necrosis (n = 121), the 1-year, 5-year, and 7-year overall survival rates for those who received IBS (n = 95) were 86.2%, 67.7%, and 49.6% vs. 84.6%, 70.0%, and 70.0% for 26 patients without IBS (p = 0.857). For the same patients, the 1-year, 5-year, and 7-year disease-free survival in the IBS group was 84.0%, 66.8%, and 64.0% vs. 88.0%, 72.8%, and 72.8% in the non-IBS group (p = 0.690). IBS does not appear to be associated with worse outcomes in patients undergoing LT for HCC, even in the presence of viable HCC in the explant. There seems to be no reason to contraindicate the use of IBS in LT for HCC.

Effect of sarcopenia on systemic targeted therapy response in patients with advanced hepatocellular carcinoma.

Sarcopenia is an independent prognostic indicator for hepatocellular carcinoma (HCC). Our objective was to determine the effect of sarcopenia on response to systemic targeted therapy in patients with advanced HCC. This was a retrospective, Institutional Review Board approved study of 36 patients on systemic targeted therapy with immune checkpoint blockade (n = 25) or tyrosine kinase inhibitor (n = 11) for biopsy-proven advanced HCC. Skeletal muscle index (SMI) was calculated from erector spinae muscle area (SMA) at the level of T12 on pretreatment CT: [SMI = SMA (cm2)/height (m2)]. SMI was compared to treatment response defined as overall survival ≥ 1year (nonsurgical patients) or > 50% HCC necrosis (surgical patients). Receiver operating characteristic curve and area under the curve was used for analysis with p < 0.05 for statistical significance. Median age of men and women was 66.5years (range 32-83) and 70years (range 54-78), respectively. Liver disease etiology was nonalcoholic steatohepatitis (n = 9), hepatitis C (n = 10), hepatitis B (n = 5), alcohol (n = 3) and unknown (n = 9). Mean (± SD) height and SMI for men were 1.7m (± 0.1) and 11.4 (± 3.6); values for women were 1.7m (± 0.1) and 8.2 (± 1.9). Treatment was withdrawn in five patients due to treatment intolerance. Response occurred in 10/31 (32.3%) patients (23 men, 8 women). T12SMI correlated with treatment response using a threshold of 7.21-8.23 for women (AUC = 1; p = 0.037), and 11.47 for men (AUC = 0.83; p = 0.015); correlation was increased for men ≥ 60years, (AUC = 0.87; p = 0.023). Sarcopenia was associated with reduced survival and HCC necrosis in patients treated with systemic targeted therapy. Sarcopenia may help in predicting outcomes to targeted therapy in advanced HCC.

Correlation of Y90-absorbed radiation dose to pathological necrosis in hepatocellular carcinoma: confirmatory multicenter analysis in 45 explants.

To study the correlation between absorbed perfused liver dose using Y90 radioembolization and degree of hepatocellular carcinoma (HCC) necrosis in liver explants in a multicenter cohort analysis METHODS: A retrospective analysis of 45 HCC patients treated between 2014 and 2017 is presented. Inclusion criteria were treatment-naïve solitary HCC ≤ 8cm and Child-Pugh A liver status using the radiation segmentectomy approach. All patients underwent liver resection or transplantation (LT). Liver explants were examined per institutional routine protocols to assess histopathological viability of HCC. Tumor pathological necrosis was classified into complete (100% necrosis), extensive (> 50% and ≤ 99%) necrosis, and partial (< 50%) necrosis. Absorbed perfused liver doses were estimated using MIRD calculations. Associations between dose and degree of necrosis were studied. Thirty-four (76%) patients underwent LT, and 11 (24%) patients underwent hepatic resection. Median radiation dose was 240 (IQR: 136-387) Gy. Thirty (67%) patients had complete pathologic necrosis (CPN) at explant, while 10 (22%) and 5 (11%) had extensive and partial necrosis, respectively. There were significant differences among perfused liver doses that exhibited partial, extensive, and complete necrosis (p = 0.001). Twenty-four out of twenty-eight (86%) patients who had dose > 190Gy achieved CPN, while 11/17 (65%) who had < 190Gy did not (Fisher's exact test; p = 0.001). Using binary logistic regression, only absorbed radiation dose was significantly associated with CPN (p = 0.01), while tumor size was not (p = 0.35). All patients receiving > 400Gy exhibited CPN. Radiation segmentectomy for early HCC with ablative dosing > 400Gy results in CPN. This represents the new standard target dose for radiation segmentectomy.

A murine cellular model of necroinflammation displays RAGE-dependent cytokine induction that connects to hepatoma cell injury.

Unresolved inflammation maintained by release of danger‐associated molecular patterns, particularly high‐mobility group box‐1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N‐lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N‐lys from hepatoma cells were highly active—inducing in macrophages efficient expression of inflammatory cytokines like C‐X‐C motif ligand‐2 , tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐23‐p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen‐activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N‐lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N‐lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL‐17, IL‐22 or interferon‐γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.

Role of Dynamic Contrast Enhanced MRI and Diffusion Weighted Imaging in Evaluation of H.C.C after Chemo-Embolization

AbstractBackground: Hepatocellular Carcinoma (HCC) is the most common primary malignant disease of the liver and is the third leading cause of death from cancer worldwide. Dynamic Contrast-Enhanced MRI (DCE MRI) can play a significant role as an imaging of H.C.C, especially in the detection of viable tumor foci, the differentiation between necrosis and viable tumor after TACE and early prediction of response. Diffusion-weighted MRI shall be more frequently used for tumor response evaluation to TACE because they provide detailed anatomic and functional or metabolic change information during tumor treatment, particularly during tar-geted chemotherapy.Aim of Study: Detection of the value of DCE (Dynamic contrast enhanced) MRI and DWI (Diffusion Weighted Imag-ing) in evaluation of HCC (Hepatocellular Carcinoma) necrosis after TACE (Trans-Arterial Chemo-Embolization).Material and Methods: Pre-contrast T1 and T2 WIs fol-lowed by diffusion weighted MR images (several b factors 20, 500, 800s/mm2) then DCE MRI study using a 3 Telsa scanner followed by measuring different ADC values obtained in 30 patients underwent TACE for treatment of 40 HCC lesions for assessment of tumoral necrosis. ADC cut-off number was estimated using the ROC curve after measuring ADC values for all cases.Results: Statistical analysis demonstrated that Dynamic MRI had sensitivity of about 100% and 95.24% for specificity, While DWI has level of sensitivity of about 52.63% and 90.5% as a degree of specificity.The difference between well-ablated and residual/newly developed groups'.ADC values was found to be significant statistically (p-value <0.001) and best cut-off variable that maximize specif-icity and sensitivity is 1.35, where sensitivity level reaches about 78.9% and specificity level reaches about 85.7%.Conclusions: Depending on our study, dynamic MRI showed very high sensitivity while DWI with ADC mapping series alone have low level of sensitivity so it promotes reader confidence and might be used in case of gadolinium contra-indications or in case of incapability of breath holding ade-quately.