Two cases of severe oral mucositis caused by atezolizumab plus bevacizumab combination therapy for hepatocellular carcinoma.

Atezolizumab is an immune checkpoint inhibitor specific for the programmed death-1 (PD-1) receptor. In this case report, we describe two cases of oral mucositis that developed following the initiation of a systemic chemotherapy regimen comprising atezolizumab and bevacizumab for recurrent hepatocellular carcinoma. After 2 or 3 cycles of treatment, each patient presented with mucosal ulcers in the mouth, oral pain, difficulty in speech and oral intake, and both were admitted to our hospital for management. Following rule out of other conditions such as pharyngeal ulcers, herpetic mucositis, denture or oral trauma, or necrotizing mucositis, both patients were diagnosed with oral mucositis as a severe immune-related adverse event. Oral candidiasis was observed in both cases and should be considered a risk factor for the development of oral mucositis. Chemotherapy was discontinued and treatment with prednisolone was started, along with supportive care. The oral mucositis improved, and prednisolone was gradually reduced; however, in one patient, discontinuation of chemotherapy led to a recurrence of hepatocellular carcinoma. The other patient was lost to follow-up. In patients with risk factors, attention must be paid to the development of oral mucositis during immune checkpoint inhibitor treatment.

Partial splenic embolization improved stomal varices in patient with decompensated liver cirrhosis: a case report.

A 63-year-old man with decompensated liver cirrhosis was admitted for treatment of stomal hemorrhage. Eighteen months earlier, he was diagnosed with rectal and sigmoid colon cancer with multiple lymph node metastases, and he underwent colostomy surgery and postoperative chemotherapy. Sixteen months after the surgery, his stoma began to bleed repeatedly, and he required frequent blood transfusions. A contrast-enhanced computed tomography revealed ectopic varices around the stoma. We considered surgical or endoscopic treatment; however, these approaches would have been technically difficult in this patient. The patient was treated with partial splenic embolization to improve thrombocytopenia and portal hypertension. After two-stage partial splenic embolization, the platelet counts increased, and the concentration of the liver fibrosis marker, Mac-2 binding protein, decreased. In addition, blood flow in the stomal varices decreased, with no recurrence of bleeding. This is a case of recurrent hemorrhage from stomal varices that was successfully treated with partial splenic embolization in a patient with liver cirrhosis. There are no guidelines for hemorrhage from ectopic varices. PSE may present potential utility as a treatment for ectopic variceal bleeding, such as stomal varices.

Disappearance of Hepatocellular Adenoma in a Patient with Cornelia de Lange Syndrome after Treatment with Transcatheter Arterial Embolization.

Cornelia de Lange syndrome (CdLS) is a congenital disorder occasionally associated with congenital portosystemic shunt (CPSSs). We herein report a patient with CdLS and CPSS who developed hepatocellular adenomas (HCAs). The patient presented to our hospital for the further investigation of newly diagnosed liver tumors. Imaging findings and pathological examination results indicated that the liver tumors were inflammatory HCAs that subsequently shrank following transcatheter arterial embolization (TAE). Patients with CdLS and CPSS are at risk of developing HCAs, and TAE may be an effective management strategy for HCA in these patients.

Long-term outcome and eligibility of radiofrequency ablation for hepatocellular carcinoma over 3.0 cm in diameter.

Percutaneous radiofrequency ablation (RFA) is effective for the treatment of small hepatocellular carcinoma (HCC) with a diameter ≤ 3.0 cm. The present study aimed to elucidate the prognostic factors and clarify the indication of treatment for RFA outcomes in patients with HCC with a diameter > 3.0 cm. Among 2188 patients with HCC who underwent RFA, 100 patients with HCC with a diameter > 3.0 cm were enrolled in this study between August, 2000 and August, 2021. We analyzed local therapeutic efficacy, long-term outcomes, and prognostic factors in patients with HCC with a diameter > 3.0 cm. Among all patients, 77 patients achieved complete ablation in one session. There were no treatment-related deaths or major complications. Local tumor recurrence occurred in 48% (n = 48) of the patients, and distant tumor recurrence occurred in 82% (n = 82) of the patients during the study period. The survival rates at 1-, 3-, 5-, 10-, and 15- years were 93.0%, 66.0%, 40.0%, 15.5%, and 10.2%, respectively. Cox proportional hazards regression analysis confirmed that distant tumor recurrence, Child-Pugh class B, and pre-ablation des-γ-carboxy prothrombin (DCP) levels ≥ 200 mAU/mL were independent unfavorable prognostic factors with a hazard ratio of 3.34 (95% CI, 1.57-7.11; P = 0.002), 2.43 (95% CI, 1.35-4.37; P = 0.003), and 1.83 (95% CI, 1.14-2.93; P = 0.012), respectively. In conclusion, patients with HCC with a diameter > 3.0 cm with Child-Pugh class A and DCP levels < 200 mAU/mL might be eligible for RFA treatment.

Hepatitis C Virus-associated Cryoglobulinemic Livedo Reticularis Improved with Direct-acting Antivirals.

We herein report a case of hepatitis C virus (HCV)-associated cryoglobulinemic livedo reticularis in a woman in her 60s that improved with direct-acting antivirals (DAAs). Hyperpigmentation was observed in both lower legs, and a skin biopsy confirmed livedo reticularis, suggesting a relationship with cryoglobulinemia and HCV infection. DAAs with an NS5A inhibitor+NS3/4A protease inhibitor (glecaprevir/pibrentasvir) were administered for eight weeks, and a sustained virological response (SVR) was obtained. The disappearance of serum cryoglobulin was confirmed approximately two years after an SVR was obtained and livedo reticularis was improved. DAA therapy can be an effective therapeutic option for extrahepatic complications associated with HCV infection.

Two Cases of Rapidly Progressive Fatty Liver Disease due to Pancreatic Exocrine Insufficiency without a History of Surgery.

We herein report two cases of rapidly progressive fatty liver (FL) disease due to pancreatic exocrine insufficiency (PEI) without a surgical history. Two women, 59 and 72 years old, with no history of abdominal surgery presented to our hospital with severe anorexia and nausea persisting for one week. Examinations revealed progressive, marked FL disease with hepatomegaly and PEI, for which pancreatic enzyme replacement therapy was effective. Commonly known causes of PEI include chronic pancreatitis, abdominal surgery (e.g. pancreaticoduodenectomy), pancreatic cancer, and obstruction of the pancreatic duct, none of which were present in either of these two cases.

Complete tumor necrosis confirmed by conversion hepatectomy after atezolizumab-bevacizumab treatment for advanced-stage hepatocellular carcinoma with lung metastasis.

A combined therapy of atezolizumab and bevacizumab (atezo/bev) is used as the first-line treatment for unresectable hepatocellular carcinoma (HCC). In this study, we report the case of curative hepatic resection in a 77-year-old man who initially had unresectable advanced-stage HCC with lung metastases. This rare hepatectomy conversion was owing to the administration of atezo/bev. Notwithstanding the side effects of immune-related adverse event hepatitis and intratumoral hemorrhage developed during atezo/bev treatment; after seven treatment cycles, the patient's tumor markers normalized, the tumor shrank markedly, and the metastasis disappeared. Subsequently, conversion therapy with hepatic resection was performed, and pathology confirmed complete tumor necrosis. No cancer recurrence was observed at the 8-month postoperative follow-up, and the patient remained drug free.

Multipolar radiofrequency ablation via three bipolar electrodes with C-arm type X-ray fluoroscopy assistance for hepatocellular carcinoma: An observational study.

The present study aimed to investigate the therapeutic efficacy and safety of the insertion technique of 3 bipolar electrodes in patients with hepatocellular carcinoma (HCC), using C-arm type X-ray fluoroscopy-assisted ultrasonography (US) in guiding a multipolar radiofrequency ablation (RFA) system. Seventy-three patients with HCC treated with a multipolar RFA system (1 electrode, n = 2; 2 electrodes, n = 56; 3 electrodes, n = 17) were enrolled in this retrospective cohort study. To analyze their therapeutic outcome in this study, we divided among 17 patients using 3 electrodes into 2 subgroups: the C-arm type X-ray fluoroscopy-assisted (n = 7) and the US-guided alone groups (n = 10). Therapeutic efficacy and safety were analyzed between the 2 groups. Multipolar RFA treatment was performed safely in all cases, and no severe adverse events occurred. Comparing the patient background of the group treated using 1 or 2 electrodes with that treated using 3 electrodes, larger-sized HCC was treated using 3 electrodes (P < .001). The differences in overall and recurrence-free survival rates between the 1- or 2-electrode and the 3-electrode groups were not significantly different (P = .843 and P = .891). Comparing the C-arm type X-ray fluoroscopy-assisted and the US-guided alone groups among patients treated using 3 electrodes, technical factors such as total ablation time and the number of sessions were not significantly different between the 2 groups. The local tumor progression rate was not significantly different between the 2 groups (P = .942). Multipolar RFA treatment was effective for the treating HCC; using 3 electrodes was suitable for larger-sized HCCs. The technical approach with C-arm type X-ray fluoroscopy assistance using 3 electrodes was useful for operators to perform safe and appropriate insertion techniques by synchronizing the US and X-ray fluoroscopy images.

Improvement of vanishing bile duct syndrome with hyperlipidemia.

A 75-year-old man was admitted to our hospital with acute onset of marked jaundice, elevated liver enzymes, and hyperlipidemia. He had been taking clopidogrel and pemafibrate for 3 months. He tested negative for autoantibodies and hepatitis-causing viruses. Gadoxetate-enhanced magnetic resonance imaging showed diffusely hypointense liver parenchyma in the hepatobiliary phase, with no appreciable excretion of gadoxetate into the biliary system. Histological examination of a liver specimen revealed disappearance of the bile ducts in the portal area and decreased expression of organic transporting polypeptide 1B3 on immunostaining. The patient was diagnosed with drug-induced vanishing bile duct syndrome and treated with ursodeoxycholic acid. The signs of liver dysfunction shown on blood chemistry tests improved spontaneously. After the acute hepatitis and lipid abnormalities had improved, repeat liver biopsy and gadoxetate-enhanced magnetic resonance imaging revealed improvement of the vanishing bile duct syndrome and recovery of the expression of organic transporting polypeptide 1B3. The reduction of OATP1B3 expression might be involved in the development of vanishing bile duct syndrome.

Pretreatment Modified Albumin-Bilirubin Grade Is an Important Predictive Factor Associated with the Therapeutic Response and the Continuation of Atezolizumab plus Bevacizumab Combination Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (ATZ + BV) treatment is recommended as the first-line systemic therapy for patients with unresectable hepatocellular carcinoma (u-HCC). This study aimed to investigate the predictive factors of therapeutic response and the continuation of ATZ + BV treatment for u-HCC in a real-world setting. METHODS: This retrospective study was conducted between January 2021 and April 2022. Twenty-eight patients with u-HCC, who were treated with ATZ + BV, were assessed for their treatment response, continuation, and adverse events (AEs). RESULTS: Among the 28 patients, 24 were evaluated at the first imaging. The objective response rate (ORR) was 29.2% (n = 7), and 54.2% (n = 13) on the response evaluation criteria in solid tumors (RECIST 1.1) and in the modified RECIST (mRECIST) guidelines, respectively. Comparing the objective response (OR) group (n = 13) and the non-OR group (n = 11), the modified albumin-bilirubin (mALBI) grades 1 and 2a were found to be significant predictive factors for OR (p = 0.021) in the mRECIST guidelines. Among the 28 patients, 17 discontinued their treatment due to AEs. Comparing the treatment continuation (n = 11) and discontinuation groups (n = 17), a Child-Pugh score of five points (p = 0.009) and mALBI grades 1 and 2a (p = 0.020) were predictive factors with significant differences. CONCLUSIONS: Pretreatment mALBI grades 1 and 2a were the important predictive factors associated with the therapeutic response and the therapeutic continuation of ATZ + BV for patients with u-HCC.

Clinical Utility of Ultrasound-Guided Attenuation Parameter for the Detection and Quantification of Hepatic Steatosis in Patients with Fatty Liver Diagnosed by Computed Tomography.

This retrospective study was aimed (i) at elucidating the correlation between fatty liver diagnoses based on the plain computed tomography (CT) value and those based on the attenuation coefficient (AC) value determined with the ultrasound-guided attenuation parameter (UGAP) and (ii) at evaluating the diagnostic power of AC values. We included 125 patients who underwent blood tests, abdominal ultrasonography and abdominal CT at our department between April 2020 and March 2021. Hepatic fat infiltration was categorized as S0 (<5%), S1 (≥5 and 30<%), S2 (≥30 and <50%) or S3 (≥50%). The diagnostic ability of UGAP-determined AC was evaluated using receiver operating characteristic (ROC) curve analysis, and the correlation between AC value and fatty liver grade by CT value. The coefficient of correlation (r) between the AC value and plain CT value was -0.6188, indicating a moderate relationship. For diagnosing grade ≥S1 (n = 44), the area under the ROC curve (AUROC) was 0.8541, sensitivity 84.1%, specificity 81.5% and cutoff value 0.676 dB/cm/MHz. In diagnosing grade ≥S2 (n = 35), the AUROC was 0.8603, sensitivity 88.6%, specificity 81.1% and cutoff value 0.694 dB/cm/MHz. In diagnosing grade = S3 (n = 18), the AUROC was 0.9016, sensitivity 94.5%, specificity 81.9% and cutoff value, 0.704 dB/cm/MHz. The AC value is useful in diagnosing fatty liver.

Suppression of Local Tumor Progression in Perivascular Hepatocellular Carcinoma by Combination Therapy with Radiofrequency Ablation and Percutaneous Ethanol Injection: A Propensity Score Matching Analysis.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) has replaced percutaneous ethanol injection (PEI) as the treatment of choice for hepatocellular carcinoma (HCC); however, control of local tumor progression (LTP) remains a challenge in perivascular HCC. The aim of this study was to determine whether PEI added to RFA can reduce the LTP rate in perivascular HCC patients. METHODS: We retrospectively analyzed 167 patients, with 197 newly diagnosed HCC nodules with peritumoral vessels, who underwent either RFA plus PEI or RFA monotherapy as the first-line treatment between June 2001 and April 2015. Ethanol was injected inside the tumor close to the peritumoral vessels in the combination therapy group. Patients were matched 1:1 according to their propensity scores to reduce selection bias; cumulative LTP was then analyzed using log-rank tests and Cox proportional hazard regression analyses. RESULTS: The two matched groups comprised 62 tumors each. The overall median follow-up period was 34 months (range, 1-140 months). In the RFA plus PEI group, the cumulative LTP rates were 5.7%, 15.5%, and 20.4% at 1, 3, and 5 years, respectively; in the RFA monotherapy group, the rates were 13.2%, 32.0%, and 40.2%, respectively. The rates were significantly lower in the RFA plus PEI group (p = 0.032). Cox proportional hazard regression analysis showed that PEI combination treatment was significantly associated with a reduced risk of local HCC recurrence (hazard ratio, 0.44; 95% confidence interval, 0.19-0.93; p = 0.031). DISCUSSION/CONCLUSION: The risk of LTP after RFA for perivascular HCC can be significantly reduced by injecting ethanol close to the peritumoral vessels.

Eosinophilic Granuloma of the Liver Mimicking Metastatic Liver Tumor.

We herein report a case of coagulation necrosis with granulation and eosinophilic infiltration of the liver. A 37-year-old woman was diagnosed with a new mass lesion in the liver 1 month after breast cancer surgery and admitted for a further examination. Because the tumor occurred immediately after surgery, it was considered essential to determine whether or not it was a metastatic liver tumor from breast cancer. A percutaneous liver tumor biopsy revealed eosinophilic granuloma of the liver, which is considered to have a high possibility of visceral larva migrans with suspected gnathostomiasis infection. A detailed medical history and histological diagnosis are important for making a differential diagnosis.

Male-specific Association between Iron and Lipid Metabolism Changes and Erythroferrone after Hepatitis C Virus Eradication.

Objective Hepatitis C virus (HCV) eradication is associated with decreased serum ferritin and increased serum low-density lipoprotein-cholesterol (LDL-C) levels, although the mechanisms underlying these changes remain unclear. This study aimed to identify the mechanisms underlying the changes in iron and lipid metabolism after HCV eradication. Methods We retrospectively investigated iron and lipid metabolism changes in 22 patients with chronic hepatitis or compensated liver cirrhosis with HCV genotype 1b infection after HCV eradication. We measured the serum erythroferrone (ERFE) levels to assess the association with these metabolic changes. Patients were administered ledipasvir 90 mg and sofosbuvir 400 mg once daily for 12 weeks and were observed for 12 more weeks to evaluate the sustained virological response. Results Half of the patients were men. At baseline, the serum ferritin and ERFE levels were elevated, while the serum LDL-C levels were within the normal range. All patients achieved a sustained virological response at 24 weeks; furthermore, the serum ferritin and ERFE levels were significantly decreased, and the serum LDL-C levels were significantly increased at 24 weeks from baseline (p<0.001, all). In men, a decrease in serum ERFE levels was correlated with changes in the serum ferritin and LDL-C levels (r=0.78, p<0.01; r=-0.76, p<0.01, respectively). In addition, a decrease in the serum ferritin levels was correlated with an increase in the serum LDL-C levels (r=-0.89, p<0.001). These correlations were not observed in women. Conclusion Our results suggest a possible association between iron and lipid metabolism changes and the involvement of ERFE after HCV eradication in men as well as potential sex-related differences.

Multiple focal fatty changes in the liver in patients with porphyria cutanea tarda: A case series and review of the literature.

Porphyria cutanea tarda (PCT) is commonly diagnosed in cases where multiple hyperechoic nodules are observed in the liver. Pathologically, these nodules associated with PCT are focal fatty deposits. We report here, seven cases of PCT with fatty changes over multiple foci in the liver. Furthermore, the characteristics of ultrasonography (US) findings of 32 previously reported cases are summarized. The US features of these nodules showed a homogenous hyperechoic or hyperechoic rim pattern, partial confluence, and no mass effect in the vascular structures. Because multiple hyperechoic liver nodules occasionally mimic malignancies, and because their diagnosis can be challenging, clinicians should consider checking urine porphyrin levels to rule out PCT when such nodules are observed on US.

Gastroesophageal Varices and Hyperplastic Nodules of the Liver in a Patient with Anorexia Nervosa.

We report a case of anorexia nervosa (AN) with gastroesophageal varices (GEV) in a 36-year-old woman. The patient presented to our hospital with progressive bloating due to severe ascites. She had no history of alcohol intake. Esophagogastroduodenoscopy and enhanced computed tomography revealed GEV and multiple hepatic nodules, respectively. The histological examination of a liver biopsy specimen revealed similar features to nonalcoholic fatty liver disease and showed hyperplastic nodules that were suspected to be related to the uneven distribution of portal blood flow in the liver. In conclusion, patients with long-term AN should undergo abdominal imaging to detect signs of portal hypertension.

Hepatitis B virus core-related antigen is useful for surveillance of hepatocellular carcinoma recurrence in a patient with occult hepatitis B virus infection: Case report.

Serum HBV core-related antigen (HBcrAg) is useful for detecting HCC in patients with occult HBV infection. Surveillance for HCC is needed in patients who are positive for HBcrAg, even if they are negative for HBsAg and HBV DNA.

Reduction in Tumor Stain at 2 Weeks after Treatment Initiation Is a Predictor of the Efficacy of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Lenvatinib is an oral anticancer drug for patients with unresectable advanced hepatocellular carcinoma (HCC). We evaluated whether a reduction in tumor stain at 2 weeks after lenvatinib treatment in patients with unresectable HCC is a predictor of early treatment efficacy at 12 weeks. PATIENTS AND METHODS: Of the 23 patients who initiated lenvatinib treatment between April 2018 and January 2019, treatment efficacy was measured in 15 patients for more than 12 weeks after treatment. Changes in tumor stain, tumor size on contrast-enhanced computed tomography (CT), and serum levels of tumor markers were evaluated 2 weeks after lenvatinib treatment. Therapeutic efficacy was assessed by tumor stain and tumor size by contrast-enhanced CT within the first 12 weeks, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. RESULTS: At 12 weeks, efficacy evaluation of 15 patients revealed that 11 of them experienced partial responses, for a response rate of 73.3%. In the first 2 weeks, 13 patients (86.7%) experienced a decreased tumor stain, including 10 responders (90.9%) and 3 non-responders (75.0%). All patients in the non-responder group had required a lenvatinib dose reduction due to adverse events within 12 weeks. On contrast-enhanced CT, the change rate of tumor stain to HCC at 2 weeks after treatment was <0.8 among 10 responders (90.9%) and 1 non-responder (25.0%; p = 0.033). No significant differences between responders and non-responders were observed with regard to most characteristics at baseline and at 2 weeks after treatment initiation. However, significant differences were observed between groups in the presence or absence of a dose suspension period, the presence or absence of lenvatinib dose reduction from the maximum value during the first 2 weeks, and decreased tumor stain at 2 weeks after treatment initiation. CONCLUSION: Reduction in tumor stain at 2 weeks after lenvatinib treatment may be an early biomarker of efficacy at 12 weeks in patients with unresectable HCC.

The Efficacy and Therapeutic Outcome of Bipolar Radiofrequency Ablation for the Treatment for Hepatocellular Carcinoma in the Real-World Setting, Compared with Monopolar Radiofrequency Ablation Conducted during the Same Period.

BACKGROUND: Several reports have suggested that the bipolar radiofrequency ablation (RFA) system is useful for the treatment of hepatocellular carcinoma (HCC). We evaluated the efficacy and safety of the bipolar RFA system for HCC treatment in the real-world setting. METHODS: A total of 155 patients with 224 HCC tumors were enrolled. First, we examined the characteristics and outcomes of two RFA systems, monopolar and bipolar. Second, we identified the factors associated with local tumor progression in 72 patients with 104 HCC tumors, who could be followed up for at least 3 months after treatment and had been treated with the bipolar RFA system. RESULTS: Of the baseline characteristics, tumor size and location were associated with the selection of the bipolar RFA system. A sufficient ablative zone margin (≥5 mm) was obtained by bipolar RFA in 81 of 94 (86.1%). The 1- and 2-year local tumor progression rates were 15.6 and 26.3%, respectively. An alpha-fetoprotein-L3 (AFP-L3) ratio >10% (HR: 7.64; 95% CI: 1.7-39.8, p = 0.007) and an insufficient ablative zone margin (<5 mm) (HR: 4.53; 95% CI: 1.02-20.3, p = 0.047) were related to local tumor progression in Cox regression analysis. Although severe adverse events were not observed in most cases, severe hepatic infarction occurred in 1 patient. CONCLUSIONS: The bipolar RFA system is safe and effective for HCC treatment. Tumor localization within the liver is an important factor associated with bipolar RFA. Careful follow-up or reconsideration of treatment is necessary for cases with AFP-L3 ratio >10% or insufficient ablative zone margin (<5 mm), which were associated with local tumor progression.

Unresectable Ectopic Hepatocellular Carcinoma Treated with Sorafenib.

Ectopic hepatocellular carcinoma (HCC) is a rare malignancy, which manifests similar morphology and immunohistochemistry to intrahepatic HCC. Herein, we report a case of ectopic HCC in a 73-year-old male. The patient presented to our hospital with gradually progressing right lower abdominal pain, and enhanced computed tomography revealed multiple nodules in the peritoneum without intrahepatic mass. A diagnostic laparoscopy was performed, and the final pathology result confirmed that it was HCC. Additional laboratory tests showed elevated serum alpha-fetoprotein and protein induced by vitamin K absence-II (PIVKA-II) levels, suggesting our diagnosis. The patient received sorafenib, a tyrosine kinase inhibitor (TKI), for unresectable ectopic HCC. However, the tumor progressed, and because of tarry stools and hemorrhagic anemia, sorafenib was ceased after 7 months of therapy. One month after the cessation of sorafenib, the PIVKA-II level increased abruptly, and the patient died 1 year after diagnosis. The effective treatment for unresectable ectopic HCC is still unknown. Additional cases should be accumulated to determine the effect of TKI on ectopic HCC.