Pulmonary Metastasectomy after Radiofrequency Ablation of Hepatocellular Carcinoma.

Introduction: Single distant metastases after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) are rare. There are no guidelines for treating patients without liver tumors after resecting lung metastases. Case Presentation: Here, we report a patient with HCC recurring as a single lung metastasis 14 months after RFA. A 76-year-old woman with primary biliary cholangitis without hepatitis B virus or hepatitis C virus infection had been treated by RFA for a single 16-mm-sized HCC lesion in liver S8. Fourteen months thereafter, despite lack of intrahepatic recurrence, a single new 26-mm-sized mass was found in S10 of the right lung. The patient underwent right lower lobectomy. The histopathological diagnosis was HCC metastasis. Because no residual disease could be found, she was followed up without any additional treatment after surgery. She remains alive with no signs of recurrence 3 years later. Conclusion: HCC patients who relapse with lung metastases but without intrahepatic recurrence after RFA are extremely rare, especially when RFA is used to treat HCC lesions <30 mm. However, it should be noted that, although rare, HCC may recur in the form of extrahepatic metastases after RFA. Furthermore, it is suggested that, as in the presently-described case, at least some patients without intrahepatic recurrence whose lung metastases are completely resected have a good prognosis even without additional treatment for HCC.

Sotrovimab Treatment for COVID-19 Effective in a B-Cell-Depleted Patient After Anti-CD20 Treatment.

Patients with hematologic malignancies are well known to have prolonged COVID-19 pneumonia. The cause has been reported to be B cell depletion after administration of anti-CD20 antibodies. Here, we report a case of COVID-19 pneumonia due to prolonged B-cell depletion after anti-CD20 antibody therapy for malignant lymphoma two years before. Sotrovimab, a neutralizing antibody that was designed to prevent the progression of COVID-19, was successful in preventing the progression to severe disease in this B-cell-depleted patient.

Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma.

BACKGROUND: Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC. METHODS AND RESULT: Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive. CONCLUSION: Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.

Consensus Statement on the definition and classification of metabolic hyperferritinaemia.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

Achievement of a durable response with eribulin for relapsed cardiac metastasis of uterine leiomyosarcoma after surgery: a case report and literature review.

BACKGROUND: Uterine leiomyosarcoma (U-LMS) is an aggressive malignancy linked to a high risk of metastasis to distant major organs. Although cardiac metastasis of U-LMS is extremely rare, it is often associated with life-threatening conditions, leading to dismal prognosis. Currently, there is no established therapy for patients with unresectable/relapsed cardiac metastasis of U-LMS. In this article, we report a case of locally relapsed cardiac metastasis of U-LMS, which occurred 3 years after surgical resection, successfully treated with eribulin. CASE DESCRIPTION: A 69-year-old female with cardiac symptoms (e.g., dyspnea, tachycardia, and easy fatigability) was sequentially treated with doxorubicin plus ifosfamide, gemcitabine plus docetaxel, and pazopanib. However, cardiac metastasis continued to grow despite treatment. Hence, eribulin was administered as fourth-line therapy. Exceptionally, eribulin markedly improved cardiac symptoms, and the patient achieved a durable response for 17 months without the development of severe adverse events. Moreover, the volume of the metastatic cardiac tumor was decreased by 70%. Despite the poor prognosis of this condition, the patient survived for 8 years from the diagnosis of cardiac metastasis due to surgery and the continuous administration of chemotherapies. CONCLUSIONS: Eribulin may be an effective and accessible treatment option for cardiac metastasis of U-LMS in patients with life-threatening conditions for whom surgery is not indicated. Additionally, the expression levels of phosphorylated AKT (p-AKT) may be a predictive biomarker for the sensitivity of patients with U-LMS to treatment with eribulin.

Current standard values of health utility scores for evaluating cost-effectiveness in liver disease: A meta-analysis.

BACKGROUND: Health utility assessments have been developed for various conditions, including chronic liver disease. Health utility scores are required for socio-economic evaluations, which can aid the distribution of national budgets. However, the standard health utility assessment scores for specific health conditions are largely unknown. AIM: To summarize the health utility scores, including the EuroQOL 5-dimensions 5-levels (EQ-5D-5L), EuroQol-visual analogue scale, short from-36 (SF-36), RAND-36, and Health Utilities Index (HUI)-Mark2/Mark3 scores, for the normal population and chronic liver disease patients. METHODS: A systematic literature search of PubMed and MEDLINE, including the Cochrane Library, was performed. Meta-analysis was performed using the RevMan software. Multiple means and standard deviations were combined using the StatsToDo online web program. RESULTS: The EQ-5D-5L and SF-36 can be used for health utility evaluations during antiviral therapy for hepatitis C. HUI-Mark2/Mark3 indicated that the health utility scores of hepatitis B patients are roughly 30% better than those of hepatitis C patients. CONCLUSION: The EQ-5D-5L is the most popular questionnaire for health utility assessments. Health assessments that allow free registration would be useful for evaluating health utility in patients with liver disease.

Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/ß-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma.

We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/ß-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the 'high RER' group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with "serum ferritin levels above the upper limits or iron staining-positive" and '8-oxo-dG high' cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/ß-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/ß-catenin signaling and trigger carcinogenesis.

A Case of Unresectable Combined Hepatocellular-Cholangiocarcinoma Successfully Treated with Lenvatinib.

A 77-year-old man was referred to our hospital because of a hepatic tumor. Blood biochemistry showed elevated serum alfa-fetoprotein, protein induced by vitamin K absence-II, and carbohydrate antigen 19-9 levels. Gd-EOB-DTPA-enhanced magnetic resonance imaging revealed a 95-mm-sized tumor in liver S7. The tumor showed heterogeneous hyperintensity in the arterial phase, slightly washed out from the portal vein phase, and hypointensity in the hepatocellular phase. Post-enlargement segmental resection was performed, and the pathological diagnosis was combined hepatocellular cholangiocarcinoma. Seven months after surgery, multiple liver tumors were found, and biopsy revealed combined hepatocellular-cholangiocarcinoma. Hepatic arterial infusion chemotherapy with cisplatin was initiated. However, the patient developed a pulmonary abscess, which was treated with antibiotics. He then underwent treatment with lenvatinib, 11 months after surgery. At 8 weeks follow-up, a complete response (according to the modified Response Evaluation Criteria in Solid Tumors [RECIST]) and a partial response (RECIST version 1.1) was noted. To the best of our knowledge, thus far, only a single case of lenvatinib treatment of unresectable mixed liver cancer has been reported. In that case, lenvatinib was used as a third-line treatment. The present report is the first to describe lenvatinib as a first-line therapy for unresectable combined hepatocellular-cholangiocarcinoma, which resulted in a meaningful response. This case provides useful insights into the choice of appropriate drug treatment in this disease in the absence of randomized controlled trials of drug treatment.

A case of acute exacerbation of chronic hepatitis C during the course of adrenal Cushing's syndrome.

A 50-year-old woman with adrenal Cushing's syndrome and chronic hepatitis C developed an acute exacerbation of chronic hepatitis C before adrenectomy. After administration of glecaprevir/pibrentasvir was started, her transaminase levels normalized promptly and a rapid virological response also was achieved. Laparoscopic left adrenectomy was then performed safely.

Complete Response Induced by Concurrent Chemoradiotherapy in a Patient with NUT Carcinoma.

An 18-year-old man presented with sudden vision loss in his left eye. Magnetic resonance imaging revealed a tumor that had invaded the left optic nerve, originating from the left posterior ethmoid sinus. Immunohistochemical analyses identified positive staining for NUT protein in the nuclei of tumor cells. We diagnosed locally advanced NUT carcinoma (NC) and initiated concurrent chemoradiotherapy (CCRT), consisting of chemotherapy with vincristine, doxorubicin, and cyclophosphamide, alternating with ifosphamide and etoposide, plus radiation therapy. The patient achieved a complete response. CCRT can be a useful treatment option for adolescent and young-adult patients with locally advanced unresectable NC.

Nature of the liver volume depending on the gender and age assessing volumetry from a reconstruction of the computed tomography.

Although the liver is a regenerating organ, excessive loss of liver volume (LV) can cause fatal liver failure. It is unclear whether LV is correlated with age; however, it is known that liver function decreases with age. In addition, the gender-related role of LV remains unclear. This study aimed to investigate the changes in LV by age and gender. Between January and December 2018, 374 consecutive patients who underwent abdominal multidetector computed tomography (MDCT) for any abdominal examinations were enrolled. LV was evaluated using MDCT. The relationship between the LV and body mass index (BMI), body surface area (BSA), age, and gender was investigated. The modified LV (mLV) was calculated by a formula measured LV × 1.5/BSA. LV correlated to BSA more than to BMI in both the males (R: 0.559 vs. 0.416) and females (R: 0.479 vs. 0.300) in our study. Age was negatively correlated to LV and BSA, and correlated to LV more than to BSA in males (R: 0.546 vs. 0.393) and females (R: 0.506 vs. 0.385). In addition, the absolute slope between age and LV in the males was higher than that in the females (14.1 vs. 10.2, respectively). Furthermore, the absolute slope of age and mLV in the males was slightly higher than in the females (9.1 vs. 7.3, respectively). In conclusion, LV in the normal liver is correlated to age rather than the one in the diseased liver. Liver volume in the males decreased more with age than LV in the females.

Combination of psoas muscle mass index and neutrophil/lymphocyte ratio as a prognostic predictor for patients undergoing nonsurgical hepatocellular carcinoma therapy.

BACKGROUND AND AIM: Reliable predictors for hepatocellular carcinoma (HCC) are urgently needed. The psoas muscle index (PMI) is a simple and rapid method for evaluating muscle atrophy. Furthermore, the neutrophil/lymphocyte ratio (NLR) is a prognostic factor that is easy to calculate in everyday clinical practice. We aimed to investigate the value of the PMI and NLR as prognostic factors for patients receiving nonsurgical HCC therapy, hepatic arterial infusion chemotherapy (HAIC), transcatheter arterial chemoembolization (TACE), or molecular targeted drugs such as sorafenib (SOR) and lenvatinib (LEN). METHODS: We enrolled 87 patients with HCC who were treated with HAIC, TACE, SOR, or LEN. The primary endpoint was overall survival (OS) with variable PMI or NLR status. For Barcelona Clinic Liver Cancer (BCLC)-B patients, useful prognostic factors were examined by comparing the OS between stratified groups. Prognostic factors including PMI and NLR were evaluated by univariate and multivariate analysis. RESULTS: Analysis of HAIC or TACE (HAIC/TACE) and SOR or LEN (SOR/LEN) patients showed significant differences in OS between low and high PMI. In patients treated with TACE, there was a significant difference in OS between low and high NLR. For BCLC-B and low PMI, the prognosis was significantly worse for SOR/LEN than for TACE, although there was no difference for high PMI, suggesting that PMI may be useful for treatment selection. In addition, the prognostic formula composed of PMI, NLR, and up-to-seven criteria developed in the present study may be useful. CONCLUSION: PMI and NLR are considered to be independent prognostic factors for HCC.

[A case of intraductal tubulopapillary adenocarcinoma with bone metastases].

A woman in her 70s with main pancreatic duct dilatation was referred to our hospital. Various imaging examinations showed an extensive mass within the lumen of the main pancreatic duct in the head and body of the pancreas. The microscopic examination of a biopsy specimen revealed an adenocarcinoma. She was diagnosed with intraductal tubulopapillary adenocarcinoma of the pancreas;a pylorus-preserving total pancreatectomy was subsequently performed. However, 30 days after surgery, the patient presented with neck pain and left upper arm numbness. Results of magnetic resonance imaging and bone scintigraphy revealed a cervical spinal tumor that was subsequently biopsied. The patient was diagnosed with intraductal tubulopapillary adenocarcinoma with bone metastasis.

Programmed cell death ligand 1 expression in a case of poorly differentiated lymphocyte-rich hepatocellular carcinoma.

Our pathological study of a case of poorly differentiated lymphocyte-rich hepatocellular carcinoma suggested that immune checkpoint inhibitor may be an effective therapy. The histological type is an important factor in determining treatment choices.

Six-transmembrane epithelial antigen of the prostate 1 accelerates cell proliferation by targeting c-Myc in liver cancer cells.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has emerged as an ideal target in cancer therapeutics. However, the functions of STEAP1 in liver cancer remain unexplored. The current study aimed to characterize the biological roles of STEAP1 in liver cancer. STEAP1 expression was upregulated in tumor tissues, and high STEAP1 expression was associated with poor clinical outcomes in patients with liver cancer, according to several publicly available datasets. STEAP1 silencing using small interfering RNA inhibited cell proliferation and was accompanied by G1 arrest induced by the suppression of cyclin D1 and the promotion of p27. STEAP1 silencing suppressed c-Myc expression, which was identified as a component in STEAP1 signal transduction by mining publicly available datasets and was then confirmed by PCR array. In conclusion, the knockdown of STEAP1 in liver cancer cell lines led to inhibition of cell proliferation involving G1 arrest by suppressing c-Myc. The present study provides a preclinical concept for STEAP1 as a druggable target in liver cancer.

Determination of reactivation rate and risk factors for Hepatitis B virus reactivation in low-positive cases: A retrospective cohort study.

INTRODUCTION: In quantitative assays for hepatitis B virus (HBV) DNA, although the amplification reaction signal is detected for low-positive cases, quantification remains challenging. HBV reactivation has been reported in many studies, but only a few have focused on HBV low-positive cases. This study aimed to determine the reactivation rate and risk factors for HBV reactivation in low-positive cases. METHODS: In this retrospective cohort study, we analyzed 7498 patients who had their HBV DNA measured at Sapporo Medical University Hospital between April 2008 and November 2020. Patient selection criteria were defined as follows: hepatitis B surface antigen was negative; HBV DNA was detectable but not quantifiable at least once. HBV DNA was monitored according to the guidelines for HBV reactivation. RESULTS: In total, 49,086 HBV DNA quantitative tests were performed. HBV DNA levels of 2578 tests were detectable but not quantifiable. Eighty patients met the criteria in this study. The median observation period was 497 days, and the 2-year reactivation rate was 15%. Ten patients had low HBV DNA positivity at baseline. Malignant lymphoma was observed in 15 patients; chemotherapy was used to treat other solid tumors in 35 patients, and immunosuppressive therapy was used in 30 patients. Multivariate analysis revealed that HBV DNA detected below the quantification level at baseline was an independent risk factor for HBV reactivation (adjusted hazard ratio 5.82; P = 0.010). CONCLUSIONS: Patients with low HBV DNA positivity, especially at baseline, are at high risk for HBV reactivation and therefore require closer monitoring.

Survival benefit of conversion surgery after intensive chemotherapy for unresectable metastatic gastric cancer: a propensity score-matching analysis.

PURPOSE: The clinical benefit of conversion surgery (CS) for unresectable gastric cancer (GC), whereby unresectable GC responds to chemotherapy and subsequently receives curative-intent surgery, remains unclear. Here, we aimed to clarify the clinical value of CS. METHODS: In this retrospective cohort study, we analyzed 175 unresectable GC, who received triple combined chemotherapy between 2004 and 2019. We divided patients into two groups: those who underwent CS and those receiving chemotherapy only (CS and C groups, respectively). Propensity score matching was used to minimize confounding bias. RESULTS: Of 175 cases, 61 (34.9%) underwent CS. R0 resection was obtained in 85.2%. After matching, 44 pairs were selected; there were no significant differences in baseline covariants. Group CS had a significantly better median overall survival (OS) (18.8 vs. 46.0 months, p < 0.001), and prolonged progression-free survival (7.4 vs. 25.8 months, p < 0.001). Subgroup analysis of OS showed a favorable trend for CS for almost all subgroups. Multivariate analysis revealed that good ECOG performance status and CS were associated with a longer OS. CONCLUSION: The survival benefit of CS was consistently demonstrated in the univariate and multivariate analysis, even in the matched cohort. Additional large-scale trials are needed for further validation.

Successful mycophenolate mofetil treatment of a patient with severe steroid-refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer.

Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis, induced by nivolumab plus ipilimumab.

A case of hypervascular tumors in the liver and pancreas: synchronous hepatocellular carcinoma and pancreatic metastasis from renal cell carcinoma 36 years after nephrectomy.

It is sometimes difficult to distinguish between multiple cancers and metastases using only diagnostic imaging, particularly when multiple hypervascular tumors are found in multiple organs. We present a case in which the preoperative histological evaluation was essential to determine the management of a hypervascular pancreatic tumor and liver tumor.