Efficacy of Lenvatinib Combined with Transcatheter Intra-Arterial Therapies for Patients with Advanced-Stage of Hepatocellular Carcinoma: A Propensity Score Matching.

This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized into the LEN combined with TIT group (n = 30) or the LEN monotherapy group (n = 85). After PSM, 38 patients (LEN + TIT group, n = 19; LEN monotherapy group, n = 19) were analyzed. The median overall survival (OS) in the LEN + TIT group was significantly higher than that in the LEN monotherapy group (median survival time (MST): 28.1 months vs. 11.6 months, p = 0.014). The OS in the LEN combined with transcatheter arterial chemoembolization and LEN combined with hepatic arterial infusion chemotherapy groups was significantly higher than that in the LEN monotherapy group (MST 20.0 vs. 11.6 months, 30.2 vs. 11.6 months, p = 0.048, and p = 0.029, respectively). Independent factors associated with OS were alpha-fetoprotein and LEN combined with TIT. The indications for LEN combined with TIT were age <75 years and modified albumin bilirubin (m-ALBI) grade 1. We concluded that LEN combined with TIT may improve prognosis compared with LEN monotherapy in patients with advanced-stage HCC.

The beneficial impact of metabolic dysfunction-associated fatty liver disease on lenvatinib treatment in patients with non-viral hepatocellular carcinoma.

AIM: Lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming a major etiology of HCC. We aimed to evaluate the impact of MAFLD on the efficacy of lenvatinib. METHODS: We enrolled 320 patients with HCC who were treated with lenvatinib. All patients were classified into the MAFLD (n = 155) and non-MAFLD (n = 165) groups. Independent factors for overall survival (OS) were analyzed. In the stratification analysis, HCC was categorized as non-viral (n = 115) or viral HCC (n = 205). RESULTS: The OS rate was significantly higher in the MAFLD group than in the non-MAFLD group (median 21.1 vs. 15.1 months, p = 0.002). Multivariate analysis demonstrated that, in addition to albumin-bilirubin grade and Barcelona Clinic Liver Cancer stage, MAFLD was identified as an independent factor for OS (HR 0.722, 95% CI 0.539-0.966, p = 0.028). In the stratification analysis, the OS rate was significantly higher in the MAFLD group than in the non-MAFLD group among patients with non-viral HCC (median 21.1 vs. 15.1 months, p = 0.002), but not in patients with viral HCC. Furthermore, MAFLD was an independent negative risk factor for OS in patients with non-viral HCC (HR 0.506, 95% CI 0.297-0.864, P < 0.01). However, MAFLD was not an independent factor for OS in patients with viral HCC. CONCLUSIONS: MAFLD was a beneficial factor for survival in patients with HCC treated with lenvatinib. Moreover, the better OS of the MAFLD group was more pronounced in patients with non-viral HCC. Lenvatinib may be a suitable agent for patients with non-viral HCC and MAFLD.

Deterioration of liver function and aging disturb sequential systemic therapy for unresectable hepatocellular carcinoma.

This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p < 0.001; 6.7% vs. 58.3%; p < 0.001, respectively). In the decision tree analysis, m-ALBI grade 1 or 2a and non-advanced age were selected splitting variables, respectively, for sequential systemic therapy. In conclusion, sequential therapy prolonged the OS of unresectable HCC. Additionally, good hepatic function and non-advanced age were clinically eligible characteristics for sequential systemic therapy.

First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study.

BACKGROUND AND AIMS: Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC. METHODS: We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2). RESULTS: Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. CONCLUSIONS: Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.

A phase II study of gemcitabine plus nab-paclitaxel as first-line therapy for locally advanced pancreatic cancer.

ABSTRACT: Gemcitabine plus nab-paclitaxel (GnP) is widely used in clinical practice, despite a lack of prospective data to validate its efficacy in locally advanced pancreatic cancer (LAPC). We conducted a phase II study of GnP for LAPC to assess its efficacy and safety.We performed a single-arm, single-institution study with GnP in 24 patients with LAPC. The treatment protocol included successive administration of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2). The primary endpoint was the tumor overall response rate (ORR), and secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse events (AEs).The median PFS was 11.0 months, median OS was 21.2 months, ORR was 62.5%, and 37.5% of the patients had stable disease. Four (16.7%) of the patients were converted to surgical resection; 3 of these achieved R0 resection. Grade 3 to 4 AEs included hematological (neutropenia, 64%; thrombocytopenia, 12%), nonhematological (cholangitis, 16%), and sensory neuropathy (4%). These AEs were manageable and tolerable.The GnP treatment in patients with LAPC showed favorable tumor shrinkage, good toxicity profile, and enabled conversion to surgical resection in a subset of patients; therefore, GnP is an option for first-line chemotherapy in patients with LAPC.

Alternating Lenvatinib and Trans-Arterial Therapy Prolongs Overall Survival in Patients with Inter-Mediate Stage HepatoCellular Carcinoma: A Propensity Score Matching Study.

We aimed to evaluate the impact of alternating lenvatinib (LEN) and trans-arterial therapy (AT) in patients with intermediate-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 113 patients with intermediate-stage HCC treated LEN. Patients were classified into the AT (n = 41) or non-AT group (n = 72) according to the post LEN treatment. Overall survival (OS) was calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Factors associated with AT were evaluated using a decision tree analysis. After PSM, there were no significant differences in age, sex, etiology, or albumin-bilirubin (ALBI) score/grade between groups. The survival rate of the AT group was significantly higher than that of the non-AT group (median survival time; not reached vs. 16.3 months, P = 0.01). Independent factors associated with OS were AT and ALBI grade 1 in the Cox regression analysis. In the decision tree analysis, age and ALBI were the first and second splitting variables for AT. In this study, we show that AT may improve prognosis in patients with intermediate-stage HCC. Moreover, alternating LEN and trans-arterial therapy may be recommended for patients below 70 years of age with ALBI grade 1.

Lenvatinib prolongs the progression-free survival time of patients with intermediate-stage hepatocellular carcinoma refractory to transarterial chemoembolization: A multicenter cohort study using data mining analysis.

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression-free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate-stage HCC refractory to TACE using a data-mining analysis. A total of 171 patients with intermediate-stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan-Meier method and analyzed using a log-rank test. Factors associated with PFS time were evaluated using multivariate and decision-tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up-to-seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up-to-seven, P=0.001). The decision-tree analysis revealed that patients beyond the up-to-seven criteria, treated with lenvatinib and with albumin-bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up-to-seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate-stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate-stage HCC refractory to TACE, ALBI grade 1 and who are within the up-to-seven criteria.

Clinical Significance of Adverse Events for Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study.

We sought to investigate the clinical profile(s) associated with the discontinuation of lenvatinib (LEN) due to severe adverse events (DLSAE) in patients with unresectable hepatocellular carcinoma (HCC). This retrospective study enrolled 177 patients with HCC treated with LEN. Independent factors associated with DLSAE were advanced age, albumin-bilirubin (ALBI) grade 2, fatigue grade ≥ 3, and appetite loss ≥ 2. The overall survival (OS) in the group that did not require DLSAE was significantly longer compared to the group that did require DLSAE (median survival time (MST): not reached vs. 12.8 months, p < 0.001). Moreover, advanced age was the most important variable for DLSAE in a decision tree analysis. Hypertension and hand-foot-skin-reaction (HFSR) were also significantly associated with longer survival, and the occurrence of hypertension was the earliest predictor for improved prognosis, while appetite loss and development of grade ≥ 3 fatigue were predictive of a poor prognosis. We concluded that the appearance of hypertension has potential as an early surrogate marker to predict improved prognosis. Moreover, careful management to avoid discontinuation of treatment leads to longer survival in patients receiving LEN.

Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Cohort Study.

We aimed to investigate the impact of the controlling nutritional status (CONUT) score, an immuno-nutritional biomarker, on the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). This retrospective study enrolled 164 patients with HCC and treated with LEN (median age 73 years, Barcelona Clinic Liver Cancer (BCLC) stage B/C 93/71). Factors associated with overall survival (OS) were evaluated using multivariate and decision tree analyses. OS was calculated using the Kaplan-Meier method and analyzed using the log-rank test. Independent factors for OS were albumin-bilirubin grade 1, BCLC stage B, and CONUT score <5 (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.58-5.31, p < 0.001). The CONUT score was the most important variable for OS, with OS rates of 70.0% and 29.0% in the low and high CONUT groups, respectively. Additionally, the median survival time was longer in the low CONUT group than in the high CONUT group (median survival time not reached vs. 11.3 months, p < 0.001). The CONUT score was the most important prognostic variable, rather than albumin-bilirubin grade and BCLC stage, in patients with HCC treated with LEN. Accordingly, immuno-nutritional status may be an important factor in the management of patients with HCC treated with LEN.

[Gemcitabine in Combination with Cisplatin in Patients with Unresectable Advanced or Recurrent Biliary Tract Cancer--A Multicenter Prospective Observational Study in Fukuoka].

The standard chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers is considered gemcitabine plus cisplatin (GC) on the basis of favorable results reported in the ABC-02 study from the UK and the BT22 study from Japan. However, the GC cohort of the BT22 study consisted of only 42 patients, and we considered it necessary to confirm the effectiveness and safety of GC chemotherapy in a multicenter prospective observational study in Fukuoka. Thirty-seven patients were enrolled in this study, including two patients with recurrent disease. The median patient age was 67.5 years (range, 43-84 years). Twelve patients had intrahepatic cholangiocarcinoma, 13 patients had extrahepatic cholangiocarcinoma, and 12 patients had gallbladder cancer. The median survival time (MST) was 14.9 months, the 1-year survival rate was 54.5%, and the median progression free survival (PFS) was 7.7 months. No chemotherapy-related deaths occurred, and Grade 3/4 adverse events were mainly hematological events including leucopenia in 13 (35.1%) patients and neutropenia in 12 (32.4%). The MST, 1-year survival rate, median PFS, and rate of Grade 3/4 adverse events in our study were similar to those of the BT22 study. In conclusion, this multicenter prospective observational study confirms the effectiveness and safety of GC chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers.

Contrast-enhanced ultrasonograpic studies on pancreatic carcinoma with special reference to staining and muscular arterial vessels.

Comparative study of contrast-enhanced ultrasonography (CE-US) and histopathology of surgically resected specimens in 13 patients with pancreatic carcinoma. A time intensity curve was used to determine the percentage brightness increase in cancerous and normal regions and the patients were divided into two groups, hyperperfusion, with a percentage brightness increase over 80% (n=6) and hypoperfusion, with an increase of less than 80% (n=7) on CE-US. The hyperperfusion group included well-differentiated tubular adenocarcinoma, adenosquamous cell carcinoma and acinar cell carcinoma, while all 7 patients in the hypoperfusion group had moderately differentiated tubular adenocarcinoma. Immunological staining (α-SMA and anti-CD34) of the resected specimens showed significantly higher microartery count (MAC) in the hyperperfusion group (p<0.005) than in the hypoperfusion group or normal pancreas. In the normal pancreas, the mean vessel diameter was significantly higher (over 100 µm) than in the hyperperfusion group (30 µm; p<0.005). It was concluded that a muscular arterial vessel density of less than 30 µm is an important factor in determining staining degree and carcinoma progression by CE-US in pancreatic carcinoma.

Utility of multidetector row CT in diagnosing branch duct IPMNs of the pancreas compared with MR cholangiopancreatography and endoscopic ultrasonography.

This study aimed to compare the usefulness of multidetector row CT (MDCT), MR cholangiopancreatography (MRCP), and endoscopic ultrasonography (EUS) in diagnosing branch duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Imaging and pathological findings were retrospectively evaluated for 25 patients with branch duct IPMNs of the pancreas who underwent surgical resection (13 adenomas, 4 borderline lesions, and 8 carcinomas). MDCT and MRCP were performed on all 25 patients, whereas EUS was performed on 22 patients. MDCT and MRCP were used to identify features predictive of malignancy, including carcinoma, borderline lesions, and the presence of thickened irregular walls/septa or a solid mass. EUS was used to identify the presence of intramural nodules or a solid mass. Correlations between histopathology and maximum diameter of the main pancreatic duct (MPD) or cyst size detected by MDCT and MRCP were also examined. Presence of a solid mass was highly correlated with malignancy with all imaging methods (MDCT; P=0.001, MRCP; P=0.008, EUS; P<0.001, respectively). Presence of thickened irregular walls/septa on MDCT correlated well with malignancy (P=0.019). In contrast, presence of thickened irregular walls/septa on MRCP and intramural nodules on EUS did not correlate with malignancy. No significant correlation was found between malignancy and average maximum MPD diameter or cyst size (P>0.05), though values tended to be larger in malignant tumors. Our results suggest that the presence of thickened irregular walls/septa or a solid mass on MDCT are highly correlated with malignancy, and that MDCT is useful for diagnosis of branch duct IPMNs of the pancreas.

Endoscopic retrieval of migrated plastic stent into bile duct or pancreatic pseudocyst.

Proximally migrated biliary plastic stent and migrated stent in the pancreatic pseudocyst are relatively rare complications. A migrated stent causes poor drainage conditions, which leads to secondary complications such as infection, abscess, perforation and, moreover, becomes a foreign object in the body, and retrieval or re-stenting is therefore necessary. The retrieval of a migrated stent includes surgical, percutaneous and endoscopic approaches, and the most non-invasive method is endoscopic retrieval. However, because very few devices are exclusively designed for retrieval, the current situation is that the available devices are used while taking advantage of various ideas and techniques. From previously reported cases and our experiences of such cases, we herein describe the methods of endoscopic retrieval for stents that have migrated into a bile duct or pancreatic pseudocysts.

Leukocytapheresis Therapy Improved Cholestasis in a Patient Suffering from Primary Sclerosing Cholangitis with Ulcerative Colitis.

Primary sclerosing cholangitis (PSC) is an autoimmune disease of the hepatobiliary system for which effective therapy has not been established. Leukocytapheresis (LCAP) therapy is known to effective in patients with ulcerative colitis (UC). In addition, effects of LCAP therapy were reported on some autoimmune diseases such as Crohn's disease, rheumatoid arthritis and rapidly progressive glomerulonephritis. Here we report the case of a 29-year-old man with PSC associated with UC who was treated with LCAP therapy. He had a 16-year history of UC and a 12-year history of PSC. Although he was under treatment with prednisolone and ursodeoxycholic acid, exacerbation of UC and PSC-associated cholestasis were seen. Since he showed side effects of prednisolone, he was treated with LCAP. Not only improvement of UC, but also decreased serum alkaline phosphatase, gamma-guanosine triphosphate and total bile acids, suggesting improvement of PSC-associated cholestaisis, were seen after treatment with LCAP. Our experience with this case suggests that LCAP therapy could be a new effective therapeutic strategy for patients with PSC associated with UC.

[A case of hepatic eosinophilic granuloma, which needs distinction with metastatic liver cancer].

A 68-year-old man was referred to our hospital because of eosinophilia in peripheral blood and pancreatic tumor on abdominal US. He was accustomed to eating the raw flesh of wild boar and keeping wild boar, and under medical treatment for Diabetes. Pancreatic tumor was diagnosed to the pancreatic ductal cancer by the imaging examination and endoscopic transpapillary brushing cytology for pancreatic duct. The diagnosis of hepatic eosinophilic granuloma was done by aspiration biopsy for hepatic multiple small nodules. Because of the strong positive finding for nematose in the assay of multi dot-ELISA for parasite, hepatic eosinophilic granuloma caused by visceral larva migrans was accidentally complicated by pancreatic cancer, and operation for the pancreatic cancer was done. To bear this disease in mind and to research his life history, is important to diagnose hepatic multiple nodules with eosinophilia.

[The role of multi-detector-row computed tomograph in the diagnosis of intraductal papillary-mucinous tumors of the pancreas in comparison to endoscopic retrograde pancreatography, endoscopic ultrasonography, magnetic resonance cholangiopancreatography].

Thirty patients with intraductal papillary-mucinous tumor (IPMT) of the pancreas underwent multidetector-row CT (MD-CT) in addition to endoscopic retrograde pancreatography (ERP), and, in 27 cases magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography (EUS). The usefulness of MD-CT was investigated by comparing various imaging methods of the communication from the main pancreatic duct (MPD) to patulous/bulging papilla in addition to the indices for benign or malignant disease, the degree of dilation of the MPD, localization and size of cystic lesions, and presence or absence of neoplastic lesions, such as thickened walls and septa, intramural nodule, solid mass. With MD-CT, dilation of the MPD and localization and size of cystic lesions were accurately assessed, even in patients with obstruction of the main pancreatic duct in whom ERP was difficult to perform regardless of the presence or absence of massive amount of mucus. MD-CT with reconstructive imaging, such as MPR imaging and CPR imaging, allowed us to assess communication with the MPD and patulous/bulging papilla easier than MRCP. In our study, MD-CT was useful in the evaluation of thickened walls and septa that are predictive factors of malignancy in IPMT.

[Arterial infusion chemotherapy for patients with advanced pancreatic cancer].

Although various therapies have been tried to improve advanced nonresectable pancreatic cancer, a sufficient consensus has not yet been obtained about the treatment. We have performed arterial infusion chemotherapy for pancreatic cancer in order to maintain QOL. The response rate was 17.3%, the mean survival time 282.1+/-204.7 days, median survival time 243.0+/-84.7 days, and many patients were continuously treated on an outpatient basis. It is thus expected that survival time and maintenance of QOL can be extended by self-sustaining arterial infusion chemotherapy.

CD56 (NCAM) expression in pancreatic carcinoma and the surrounding pancreatic tissue.

Expression of CD56, also known as the neural cell adhesion molecule (NCAM), in the pancreatic ducts of chronic pancreatitis is considered to represent a regenerative process of the pancreatic duct system. CD56 expression was analyzed in 25 tissue samples of invasive ductal carcinoma without mixed ductal-endocrine carcinoma of the pancreas, and in the surrounding non-cancerous pancreatic tissue. CD56 expression was detected in intercalated ducts (ICDs) of lobules in the pancreatic parenchyma showing chronic inflammation close to the carcinoma, but not in the carcinoma itself, in all cases. CD56 showed strong, diffuse expression in the areas with severe inflammation, but expression was weak in ICDs where the inflammation was mild. We suggested that CD56 expression is degenerative process in pancreatic tissue with chronic inflammation, and that examination of CD56 expression may be helpful in the differentiation of atypical degenerative ducts from cancerous ducts.

Endoscopic ultrasonography-guided cystogastrostomy for large pancreatic pseudocyst with obstructive jaundice--a case report.

The patient was a 45-year-old man with a history of heavy drinking. A pseudocyst about 30 mm in diameter was found in the head of his pancreas. About four weeks later an upper abdominal mass, abdominal pain and obstructive jaundice were confirmed. Abdominal CT revealed that the cyst had increased in size to about 60 mm, compressing the lower common bile duct and the surrounding digestive tract. Therefore endoscopic ultrasonography-guided cystogastrostomy following percutaneous transhepatic biliary drainage (PTBD) was performed. Postoperatively, the cyst quickly decreased in size and jaundice improved. Because of persistent common bile duct stenosis, an endoscopic retrograde biliary stent was implanted. There has been no recurrence at ten months after the endoscopic therapy. While invasive surgery is generally employed in the treatment of pancreatic pseudocyst complicated by obstructive jaundice, EUS-guided cystogastrostomy appears to be a useful procedure, particularly when considering the relatively minor degree of surgical invasion.