Case Report: Successful Surgical Resection of PVTT Vp4 Hepatocellular Carcinoma Following Hepatic Arterial Infusion Chemotherapy Combined with Cadonilimab Plus Donafenib

In this study, we evaluate the effectiveness and safety of conventional transcatheter arterial chemoembolization (C-TACE) and drug-loaded microsphere-based TACE (DEB-TACE) in patients with hepatocellular carcinoma (HCC) accompanied by portal vein tumor thrombus (PVTT). A total of 51 HCC patients with PVTT treated at our hospital between August 2016 and December 2021 were collected and retrospectively analyzed. 39 patients were in the DEB-TACE group and 9 patients were in the C-TACE group, after excluding 3 patients. Serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels were assessed using magnetic nanoparticle-based chemiluminescence immunoassay. The liver function was evaluated before TACE, at 1 month, and at 3 months after treatment. The therapeutic response and intraoperative and postoperative adverse events were analyzed in two groups. Both TACE treatments effectively reduced tumor thrombus size, tumor count, and PVTT classification, with DEB-TACE demonstrating superior efficacy. The median survival time was slightly longer in the DEB-TACE group (14 months) compared to the c-TACE group (11 months), but there were no significant differences in the survival curves. Both groups experienced decreased postoperative AFP levels, while PIVKA-II levels remained stable without significant differences between the two groups. The PIVKA-II index exhibited no significant alteration, and there was no notable disparity observed between the two groups. There were no statistically significant differences observed in liver function and postoperative adverse reactions between the two groups after the operation. In conclusion, the therapeutic effect and safety of DEB-TACE are found to be equivalent to those of C-TACE.

The treatment efficacy of transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) for huge single hepatocellular carcinoma (HCC) has not been fully documented. The aim of this study was to compare TACE and HAIC for patients with solitary nodular HCCs greater than or equal to 10cm without vascular invasion and metastasis. From July 2015 to June 2020, a total of 147 patients with single nodular HCC greater than or equal to 10cm without vascular invasion and metastasis receiving TACE ( n =77) or HAIC ( n =70) were retrospectively enrolled. The tumor response, overall survival (OS), and progression-free survival (PFS) were investigated and compared. The treatment outcome of two transarterial interventional therapies was explored. The objective response rate and PFS were higher in patients who received HAIC than in those who received TACE (44.3 vs. 10.4% and 8.9 vs. 4.2 months, respectively; P =0.001 and P =0.030), whereas the disease control rate and OS were not significantly different (92.9 vs. 84.4% and 21.3 vs. 26.6 months, respectively; P =0.798 and P =0.749). The decreased levels of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in patients treated with HAIC were significantly higher than those treated with TACE ( P =0.038 and P <0.001). Multivariable analysis showed that the aspartate aminotransferase/platelet ratio index was associated with OS, whereas albumin-bilirubin grade and PIVKA-II were associated with PFS. HAIC has better potential than TACE to control local tumors for huge single HCC without vascular invasion and metastasis and thus may be the preferred conversion therapy for these tumors.

Preoperative prediction score of hepatocellular carcinoma recurrence in living donor liver transplantation: Validation of SNAPP score developed at Asan Medical Center

BackgroundLiver cancers are common malignancies that primarily include hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Currently, the most commonly used serum markers for HCC are alpha fetoprotein (AFP), AFP-L3% and protein induced by vitamin K absence or antagonist-II (PIVKA-II), while the most commonly used serum markers for CCA are carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). In recent years, many HCC diagnostic models using the combined detection of serum AFP, AFP-L3% and PIVKA-II have been established. For serum AFP, AFP-L3%, PIVKA-II and their many diagnostic models, there has been no clear guidance on the selection of these markers and their various combinations in the diagnosis of liver cancers. The aim of this study was to evaluate and compare the efficacy of these markers and the models that incorporate them in diagnosing HCC and CCA. This could assist in identifying the optimal patterns of serum AFP, AFP-L3% and PIVKA-II for the diagnosis of liver cancers.MethodsClinical data and the results of serum AFP, AFP-L3%, PIVKA-II, CEA and CA19-9 were collected from 117 patients with HCC, 28 patients with CCA and 101 patients with benign liver diseases. Laboratory tests and detection of serum tumor markers in liver cancer patients were conducted prior to treatments. Recently published diagnostic models for AFP, AFP-L3% and PIVKA-II detection were collected; these included GALAD, ASAP, GALAD-C, GAAP, C-GALAD, C-GALAD II and GAP-TALAD.ResultsLevels of AFP-L3%, PIVKA-II, GALAD, ASAP, GALAD-C, GAAP, C-GALAD and C-GALAD II significantly differed between the patient cohorts, with the highest levels seen in HCC, followed by CCA and with the lowest levels seen in benign liver diseases (p < 0.05). Levels of CEA and CA19-9 significantly differed between cohorts, with the highest levels seen in CCA, followed by HCC and with the lowest levels seen in benign liver diseases (p < 0.05). Levels of AFP and GAP-TALAD in HCC patients were significantly higher than those in patients with CCA and patients with benign liver diseases (p < 0.05), but there were no significant differences in levels of AFP and GAP-TALAD between patients with CCA and benign liver diseases (p > 0.05). In the diagnosis of HCC, GAP-TALAD, GALAD, C-GALAD, ASAP and GALAD-C showed the highest efficacy. In the diagnosis of overall liver cancers (HCC and CCA), GALAD-C, GAAP, GALAD, ASAP and C-GALAD showed the highest efficacy. In the diagnosis of early liver cancers (early HCC and CCA), GALAD, GALAD-C, GAAP, C-GALAD and ASAP showed the highest efficacy.ConclusionsFor serum AFP, AFP-L3% and PIVKA-II, diagnostic models of combined marker detection improved efficacy in the diagnosis of liver cancers. Diagnostic models GALAD, ASAP, GALAD-C and C-GALAD showed the highest efficacy in the diagnosis of HCC, overall liver cancers (HCC + CCA) and early liver cancers, and can be used preferentially in clinical practice.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) was widely used as a diagnostic marker for hepatocellular carcinoma (HCC), however, its prognostic value is unclear. The authors evaluated PIVKA-II clinicopathologically as a prognostic marker for HCC. The relationship between pathologic prognostic factors and plasma PIVKA-II and alpha-fetoprotein (AFP) was investigated in 72 patients with resectable HCC measuring less than 6 cm in greatest dimension. PIVKA-II shows significantly lower sensitivity, but higher specificity than AFP, and the use of these two complementary markers appears to be useful in the diagnosis of HCC. The frequencies of intrahepatic metastasis, portal vein tumor thrombus, hepatic vein tumor thrombus, and capsular infiltration were significantly higher in patients with positive PIVKA-II than in those with negative-PIVKA-II, and the recurrence-free rate was significantly lower in patients with positive rather than with negative PIVKA-II. However, there were no significant differences between the patients who were AFP positive and those who were AFP negative in pathologic prognostic factors and the recurrence-free rate. From univariate and multivariate analyses, the authors find that PIVKA-II is one of the risk factors for recurrence of HCC after hepatectomy. PIVKA-II may be a useful marker for the prediction of intrahepatic spread and for the prognosis of HCC. In addition, PIVKA-II-positive patients, thus, need aggressive postoperative adjuvant therapy for undetectable residual tumors and careful postoperative monitoring to enable the early recognition of recurrence.

We report a successfully managed case of far-advanced hepatocellular carcinoma (HCC) by intraarterial infusion therapy. A 55-year-old man was admitted to our hospital with abdominal pain and subileus. Abdominal ultrasonography, computed tomography, and angiography revealed HCC with obstruction of the main portal vein due to tumor thrombus. Serum levels of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were elevated. Neoadjuvant chemotherapy was tried with a course of low-dose cisplatin (CDDP) +5-fluorouracil (5-FU) intrahepatic arterial infusion through the indwelling catheter via the subcutaneous reservoir port. After 7 weeks of administration (total dose CDDP 370 mg/5-FU 18.5 mg), the main tumor size was effectively reduced. Serum levels of AFP and PIVKA-II decreased markedly. Adverse effects were tolerated. Following the chemoinfusion therapy, posterior segmentectomy and thrombectomy were performed. Reconstruction of the portal vein was not necessary because we removed the tumor thrombus without resecting the portal vein. The postoperative course was uneventful, and the patient has been doing well more than 2 years after surgery, with no evidence of recurrence or metastasis. Preoperative low-dose CDDP +5-FU intrahepatic arterial infusion therapy in combination with hepatic resection may be an effective treatment for advanced HCC with portal vein tumor thrombus.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a possible hepatocellular carcinoma (HCC) specific marker, however it may also be generated by a limited number of stomach malignancies. PIVKA-II-producing stomach cancer has been recorded in 16 instances so far, two of which were reported by us and all of which were found in Japan. In virtually all instances, serum alpha-fetoprotein (AFP) levels are also elevated. In roughly 80% of instances, liver metastasis is found, and portal vein tumor thrombus is detected in roughly 20% of cases. It's often difficult to tell the difference between a metastatic liver tumor and HCC. Almost all cases appear to be advanced stomach cancer macroscopically. In many cases, a hepatoid pattern is present, as well as a moderately to poorly differentiated adenocarcinoma component. Immunohistochemical staining is frequently used to confirm the generation of PIVKA-II and AFP. The presence of liver metastasis influences treatment and prognosis, and individuals with liver metastasis have a poor prognosis. PIVKA-II may be generated by tumor cells during hepatocellular metaplasia.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a putative specific marker of hepatocellular carcinoma (HCC), but it may also be produced by a small number of gastric cancers. To date, 16 cases of PIVKA-II-producing gastric cancer have been reported, 2 of which were reported by us and all of which were identified in Japan. There are no symptoms specific to PIVKA-II-producing gastric cancer, and the representative clinical symptoms are general fatigue, appetite loss, and upper abdominal pain. Serum alpha-fetoprotein (AFP) levels are also increased in almost all cases. Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is observed in approximately 20% of cases. Differential diagnosis between metastatic liver tumor and HCC is often difficult. Grossly, almost all cases appear as advanced gastric cancer. Histologically, a hepatoid pattern is observed in many cases, in addition to a moderately to poorly differentiated adenocarcinoma component. The production of PIVKA-II and AFP is usually confirmed using immunohistochemical staining. Treatment and prognosis largely depends on the existence of liver metastasis, and the prognosis of patients with liver metastasis is very poor. PIVKA-II may be produced during the hepatocellularmetaplasia of the tumor cells.

Conversion resection for patients with hepatocellular carcinoma and inferior vena cava tumor thrombus: a consecutive case series

The prognosis of hepatocellular carcinoma (HCC)is poor,and tumor thrombus in the portal vein or in the bile duct is an important influencing factor.Approximately 30%of HCC patients are found to have portal vein tumor thrombus (PVTT)when diagnosed,and their median survival time is about 2.7-4.0 months if they do not receive any treatment.The incidence of HCC complicated with bile duct tumor thrombus (BDTT)is less than 10%,while the prognosis is dismal.Once tumor thrombus extends to the major bile ducts,obstructive jaundice and subsequent hepatic dysfunction are inevitable.The survival time of patients with HCC complicated with BDTT is less than 4 months if they only receive palliative biliary stenting.The management of HCC complicated with PVTT or BDTT is challenging with controversy at present.Different treatment approaches and their benefits for patients with HCC complicated with PVTT or BDTT are introduced in this paper. Key words: Liver neoplasms; Portal vein tumor thrombus; Bile duct tumor thrombus; Treatment

Hepatocellular carcinoma with portal vein tumor thrombus has a high incidence rate and rapid progression,and there are limited therapies with a poor clinical effect. Although sorafenib is recommended as the sole therapy for such patients in foreign guidelines,studies have shown that some patients may achieve a better outcome via surgical treatment,especially those with tumor thrombus in the first-or second-order branches of the portal vein( type Ⅰ/Ⅱ thrombus according to Cheng's classification). However in clinical practice,a large proportion of patients cannot undergo radical resection due to extensive lesions,or there may be a high possibility of residual tumor thrombus after surgery due to the presence of tumor thrombus in the main portal vein( type Ⅲ according to Cheng's classification),and therefore,downstaging resection is needed to improve prognosis. Studies have shown that with the help of palliative therapies including neoadjuvant three-dimensional conformal radiotherapy,( 90) Y-loaded microsphere radioembolization,and hepatic arterial infusion chemotherapy,some patients may achieve regression or disappearance of portal vein tumor thrombus,tumor shrinkage,and disappearance of satellite lesions,which helps to achieve tumor downstaging,increase surgical resection rate,and prolong survival time. Multidisciplinary therapy is of vital importance in improving downstaging resection rate in patients with hepatocellular carcinoma and portal vein tumor thrombus.

Background: Hepatocellular carcinoma (HCC) frequently develops in patients with chronic hepatitis B and C. Early detection is critical, but current methods, including ultrasound and AFP, have suboptimal accuracy. Objectives: This study aimed to evaluate the predictive performance of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) testing, alone and in combination, for HCC development. Methods: A retrospective cohort study at a single university center included 242 CHB and 181 CHC patients. Data on demographics, clinical status, laboratory parameters, and imaging were collected, with fibrosis and steatosis assessed by FibroScan®. Serum AFP and PIVKA-II were measured, but measurements of PIVKA-II in patients receiving vitamin K antagonists were excluded from the analysis. HCC diagnosis and staging followed clinical guidelines. Cox regression and ROC analyses identified independent predictors and evaluated biomarker accuracy for HCC detection. Results: HCC incidence was comparable between cohorts (5.0% in CHB vs. 5.5% in CHC). Both AFP and PIVKA-II independently predicted HCC development in multivariate models adjusted for age and sex. The combined biomarker score (AFP × PIVKA-II) showed superior predictive accuracy with hazard ratios of 1.38 (CHB) and 1.36 (CHC). ROC analyses demonstrated high discriminative ability for PIVKA-II (AUC ~0.81) and AFP (AUC ~0.83) in both cohorts. Additional independent predictors were chronic alcohol abuse, cirrhosis, and higher liver stiffness measurements. Specific viral factors such as HBeAg positivity and HCV subgenotype 1b were also associated with increased HCC risk. Conclusions: AFP and PIVKA-II are independent, valuable biomarkers for HCC risk in chronic hepatitis B and C. Combined use improves early detection, aiding timely treatment. These results support adding PIVKA-II to AFP in surveillance, but larger studies are needed to confirm the findings and refine cut-off values.

The prognosis of hepatocellular carcinoma (HCC) combined with portal and hepatic vein cancerous thrombosis is poor, for unresectable patients the combination of targeted therapy and immune therapy was the first-line recommended treatment for advanced HCC, with a median survival time of only about 2.7-6 months. In this case report, we present the case of a patient with portal and hepatic vein cancerous thrombosis who achieved pathologic complete response after conversion therapy. In our center, a patient with giant HCC combined with portal vein tumor thrombus and hepatic vein tumor thrombus was treated with transcatheter arterial chemoembolization (TACE), radiotherapy, targeted therapy and immunotherapy, and was continuously given icaritin soft capsules for oral regulation. After 7 months of conversion therapy, the patient's tumor shrank and the tumor thrombus subsided significantly. The pathology of surgical resection was in complete remission, and there was no progression in the postoperative follow-up for 7 months, which provided a basis for the future strategy of combined conversion therapy. In this case, atezolizumab, bevacizumab, icaritin soft capsules combined with radiotherapy and TACE had a good effect. For patients with hepatocellular carcinoma combined with hepatic vein/inferior vena cava tumor thrombus, adopting a high-intensity, multimodal proactive strategy under the guidance of multidisciplinary team (MDT) is an important attempt to break through the current treatment dilemma.

Chapter 4: Chemotherapy and radiotherapy

Simple SummaryCirculating biomarkers for the early detection and prediction of hepatocellular carcinoma development are an unmet need. In the present study, we observed that serum values of three biomarkers (namely AFP, PIVKA-II and GPC-3) were significantly different between patients with cirrhosis and those with hepatocellular carcinoma; the best accuracy for the detection of tumors was achieved by a combination of AFP + PIVKA-II. However, PIVKA-II resulted as the only biomarker able to identify patients with cirrhosis at increased risk of hepatocellular carcinoma development. The measurement of PIVKA-II in patients with cirrhosis at risk of tumor development may be useful to tailor personalized surveillance strategies and thus to improve patients’ survival.International guidelines recommend the use of ultrasound as a surveillance tool for hepatocellular carcinoma (HCC) in patients with cirrhosis, while the role of serum biomarkers is still debated. We investigated serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II) and glypican-3 (GPC-3) diagnostic accuracy for HCC detection and prediction in patients with liver cirrhosis of viral etiology under surveillance. A total of 349 patients (200 cirrhosis and 149 HCC) were enrolled. The 200 patients with cirrhosis consisted of 114 patients still HCC-free after 36 months of follow-up and 86 patients that developed HCC after 13.8 (11.0–19.8) months. AFP, PIVKA-II and GPC-3 were measured in serum samples collected at tumor diagnosis in the 149 patients with HCC, and at the beginning of follow-up in the 200 patients with cirrhosis. The higher performance for HCC detection was observed for PIVKA-II (area under the curve (AUC) = 0.790), followed by AFP (AUC = 0.737) and GPC-3 (AUC = 0.637); the combination of AFP + PIVKA-II improved the diagnostic accuracy to AUC = 0.822. Serum PIVKA-II values, but not AFP and GPC-3, were significantly higher in the 86 cirrhotics that developed HCC compared with the 114 cirrhotics still HCC-free after 36 months of follow-up (p = 0.020). PIVKA-II ≥ 55 mAU/mL allowed to identify patients with cirrhosis at higher risk of HCC development (Log-rank test, p < 0.001; adjusted Hazard Ratio = 1.99, p = 0.001). In conclusion, the measurement of PIVKA-II in patients with cirrhosis may be useful to tailor personalized surveillance strategies.