Simultaneous occurrence of autoimmune hepatitis and autoimmune hemolytic anemia after COVID-19 infection: case report and literature review.

Various autoimmune diseases have been reported to develop as a result of a coronavirus disease 19 (COVID-19) infection. There have been some reports of COVID-19-triggered autoimmune hepatitis and autoimmune hemolytic anemia infection, but none have reported simultaneous onset of these diseases. A 15-year-old girl was admitted to our hospital with severe liver injury and anemia. Three weeks before admission, her father was diagnosed with COVID-19, after which she became aware of a sore throat. Two weeks later, she visited her doctor for malaise. She was referred to our hospital due to severe anemia, elevated hepatobiliary enzymes, and jaundice. A COVID-19 polymerase chain reaction test was positive at the time of referral. She was diagnosed with autoimmune hemolytic anemia based on decreased hemoglobin and haptoglobin, positive direct Coombs test, and increased urinary urobilinogen. Blood tests were positive for antinuclear antibodies, and a liver biopsy revealed interface hepatitis and plasma cell infiltration, consistent with autoimmune hepatitis. Based on these findings, a diagnosis of autoimmune hepatitis and autoimmune hemolytic anemia triggered by COVID-19 infection was made. Steroid therapy was initiated, which resulted in rapid improvement of blood markers and symptoms.

Shrinkage of Enlarged Hepatic Nodules by an Embolizing Congenital Extrahepatic Portosystemic Shunt.

A 38-year-old woman was admitted to our university hospital with loss of muscle strength. She was diagnosed with dermatomyositis and underwent contrast-enhanced computed tomography of the entire body to check for malignant tumors. Computed tomography revealed multiple enhanced hepatic nodules and an extrahepatic portosystemic shunt. Although a needle biopsy of the nodule could not diagnose definitive hepatocellular carcinoma, some nodules increased in size after three months. Because of the inconclusive results of the second biopsy, we performed shunt embolization using a vascular plug. After another three months, the hepatic nodules shrank markedly, as expected.

Proton beam therapy for hepatocellular carcinoma with bile duct invasion.

AIM: Hepatocellular carcinoma (HCC) with bile duct invasion (BDI) (BDIHCC) has a poor prognosis. Moreover, due to the paucity of reports, there is no consensus regarding optimal management of this clinical condition yet. The aim of this study was to clarify the efficacy and safety of proton beam therapy (PBT) for BDIHCC. METHODS: Between 2009 and 2018, 15 patients with BDIHCC underwent PBT at our institution. The overall survival (OS), local control (LC), and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria of Adverse Events version 4.0. RESULTS: The median follow-up time was 23.4 months (range, 7.9-54.3). The median age was 71 years (range, 58-90 years). Many patients were Child A (n = 8, 53.3%) and most had solitary tumors (n = 11, 73.3%). Additionally, most patients had central type BDI (n = 11, 73%). The median tumor size was 4.0 cm (range, 1.5-8.0 cm). The 1-, 2-, and 3-year OS rates were 80.0%, 58.7% and 40.2%, respectively, and the corresponding LC and PFS rates were 93.3%, 93.3%, and 74.7% and 72.7%, 9.7%, and 0.0%, respectively. Acute grade 1/2 dermatitis (n = 7, 46.7%), and grades 2 (n = 1, 6.7%) and 3 (n = 1, 6.7%) cholangitis were observed. Late toxicities such as grade 3 gastric hemorrhage and pleural effusion were observed. No toxicities of grade 4 or higher were observed. CONCLUSIONS: PBT was feasible with tolerable toxicities for the treatment of BDIHCC.

Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial).

BACKGROUND: Locally advanced pancreatic ductal adenocarcinoma (PDAC), accounting for about 30% of PDAC patients, is difficult to cure by radical resection or systemic chemotherapy alone. A multidisciplinary strategy is required and our TT-LAP trial aims to evaluate whether triple-modal treatment with proton beam therapy (PBT), hyperthermia, and gemcitabine plus nab-paclitaxel is a safe and synergistically effective treatment for patients with locally advanced PDAC. METHODS: This trial is an interventional, open-label, non-randomized, single-center, single-arm phase I/II clinical trial organized and sponsored by the University of Tsukuba. Eligible patients who are diagnosed with locally advanced pancreatic cancer, including both borderline resectable (BR) and unresectable locally advanced (UR-LA) patients, and selected according to the inclusion and exclusion criteria will receive triple-modal treatment consisting of chemotherapy, hyperthermia, and proton beam radiation. Treatment induction will include 2 cycles of chemotherapy (gemcitabine plus nab-paclitaxel), proton beam therapy, and 6 total sessions of hyperthermia therapy. The initial 5 patients will move to phase II after adverse events are verified by a monitoring committee and safety is ensured. The primary endpoint is 2-year survival rate while secondary endpoints include adverse event rate, treatment completion rate, response rate, progression-free survival, overall survival, resection rate, pathologic response rate, and R0 (no pathologic cancer remnants) rate. The target sample size is set at 30 cases. DISCUSSION: The TT-LAP trial is the first to evaluate the safety and effectiveness (phases1/2) of triple-modal treatment comprised of proton beam therapy, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer. ETHICS AND DISSEMINATION: This protocol was approved by the Tsukuba University Clinical Research Review Board (reference number TCRB22-007). Results will be analyzed after study recruitment and follow-up are completed. Results will be presented at international meetings of interest in pancreatic cancer plus gastrointestinal, hepatobiliary, and pancreatic surgeries and published in peer-reviewed journals. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031220160. Registered 24 th June 2022, https://jrct.niph.go.jp/en-latest-detail/jRCTs031220160 .

Survey of Dietary Habits and Physical Activity in Japanese Patients with Non-Obese Non-Alcoholic Fatty Liver Disease.

The incidence of non-obese non-alcoholic fatty liver disease (NAFLD), characterized by the presence of a fatty liver in individuals with a normal body mass index, is on the rise globally. Effective management strategies, including lifestyle interventions such as diet and exercise therapy, are urgently needed to address this growing public health concern. The aim of this study was to investigate the association between non-obese NAFLD, dietary habits, and physical activity levels. By elucidating these relationships, this research may contribute to the development of evidence-based recommendations for the management of non-obese NAFLD. The study had a single-center retrospective cross-sectional design and compared clinical data and dietary and physical activity habits between patients with and without non-obese NAFLD. Logistic regression analysis was utilized to investigate the relationship between food intake frequency and the development of NAFLD. Among the 455 patients who visited the clinic during the study period, 169 were selected for analysis, including 74 with non-obese NAFLD and 95 without NAFLD. The non-obese NAFLD group showed a less-frequent consumption of fish and fish products as well as olive oil and canola/rapeseed oil, while they showed more frequent consumption of pastries and cake, snack foods and fried sweets, candy and caramels, salty foods, and pickles compared to the non-NAFLD group. Logistic regression analysis revealed that NAFLD was significantly associated with the consumption of fish, fish products, and pickles at least four times a week. The physical activity level was lower and the exercise frequency was lower in patients with non-obese NAFLD compared to those without NAFLD. The results of this study suggest that a low consumption of fish and fish products and high consumption of pickles may be associated with a higher risk of non-obese NAFLD. Moreover, dietary habits and physical activity status should be taken into consideration for the management of patients with non-obese NAFLD. It is important to develop effective management strategies, such as dietary and exercise interventions, to prevent and treat NAFLD in this patient population.

Usefulness of argon plasma coagulation for bleeding around hepaticojejunal anastomosis.

Ectopic varices due to extrahepatic portal vein obstruction (EHO) after hepaticojejunostomy have been previously reported. However, few case reports have described angiodysplasia-like lesions due to EHO around the hepaticojejunal anastomosis because they comprise small vessels in the mucosal surface and cannot be detected by contrast-enhanced computed tomography. Physicians need to insert the endoscope into the long afferent limb to diagnose angiodysplasia-like lesions around the hepaticojejunal anastomosis. Some reports have described that endoscopy stops bleeding from angiodysplasia-like lesions around the hepaticojejunal anastomosis; however, a standard methodology remains to be established. We present three cases of bleeding from an angiodysplasia-like lesion around the hepaticojejunal anastomosis that were successfully treated using argon plasma coagulation (APC) with balloon-assisted enteroscopy. Although one patient died owing to cancer progression 3 months after APC hemostasis, the hemostatic effect persisted for >2 years in the remaining two patients. These results suggest that APC is a good treatment option to stop bleeding from angiodysplasia-like lesions at hepaticojejunal anastomosis.

A Transarterial Chemoembolization of Balloon-Occluded Alternate Infusions of Cisplatin and Gelatin Particles for Hepatocellular Carcinoma: A Phase I/II Multicenter Prospective Study of Safety and Efficacy.

PURPOSE: To evaluate the safety and efficacy of a newly developed technique of balloon-occluded alternate infusions of cisplatin and gelatin particles in transarterial chemoembolization in hepatocellular carcinoma (HCC) and to evaluate the liver damage following the procedure. MATERIALS AND METHODS: Forty-three patients with HCC from 4 medical centers were enrolled in this multicenter prospective study. Of these, 41 patients were observed for 6 months following balloon-occluded alternate infusion transarterial chemoembolization. The primary endpoint was the safety of the procedure, and the secondary endpoint was the objective response rate (ORR) of the HCCs at 2 months following treatment. RESULTS: Three patients experienced adverse events, including 1 patient with facial swelling and skin rash, dissection of the celiac artery, and bland portal vein thrombus. No major adverse events were identified. Two (5.3%) patients regressed from a Child-Pugh classification of A to B. The balloon-occluded alternate infusion transarterial chemoembolization treatment achieved a 22.0% complete response (CR) rate and a 73.2% ORR (95% confidence interval [CI], 57.9%-84.4%). In a retrospective analysis of 23 patients with HCCs above the up-to-7 criteria, the CR rate and ORR of the balloon-occluded alternate infusion transarterial chemoembolization were 21.7% and 82.6% (95% CI, 62.3%-93.6%), respectively. CONCLUSIONS: Balloon-occluded alternate infusion transarterial chemoembolization is safe and effective for achieving a high ORR while preserving liver function.

Percutaneous transhepatic obliteration-related procedures for isolated gastric varices: experience of three cases.

Percutaneous transhepatic obliteration (PTO) can facilitate antegrade embolization of variceal veins. We herein report three patients who underwent percutaneous transhepatic sclerotherapy (PTS) or percutaneous transportal outflow-vessel-occluded sclerotherapy (PTOS) for isolated gastric varices. PTS was performed in Cases 1 and 2, and PTOS was performed in Case 3. Technical success was achieved in all patients without a decline in liver function; however, lack of a therapeutic benefit with rupture of esophageal varices occurred in Case 3. Case 3 had a history of pylorus gastrectomy plus Billroth-I reconstruction for gastric cancer and multiple feeding veins existed. PTO-related procedures are good treatment options for isolated gastric varices, but clinicians should be aware of the risk of treatment failure, especially the cases which have multiple feeding veins.

Relationships of Dietary Habits and Physical Activity Status with Non-Alcoholic Fatty Liver Disease Featuring Advanced Fibrosis.

(1) Aim: Hepatic fibrosis is a prognostic factor for disease progression in non-alcoholic fatty liver disease (NAFLD). We aimed to determine the relationships between diet, physical activity, and the progression of liver fibrosis. (2) Methods: The 349 participants were categorized by their FibroScan-aspartate aminotransferase score, and they completed a questionnaire regarding their diet and physical activity. (3) Results: There were 233 patients in the negative-on-screening group, 78 in the gray zone group, and 38 in the positive-on-screening group. The frequencies of consumption of soybeans and soybean products and of light-colored vegetables were lower in the positive group; whereas the frequencies of consumption of snack food and fried sweets, jelly and pudding, fried food, and butter, lard, and beef tallow were higher. The odds ratios for the fibrosis progression in patients who consumed fried food ≥4 times/week was 2.21. The positive group also showed lower physical activity level (PAL) and exercise (Ex, metabolic equivalents for tasks (METs)/hour/week). The patients who undertook Ex at >7.5 had an odds ratio of 0.21 for the fibrosis progression. (4) Conclusion: High consumption of fried food and low Ex are risk factors for the fibrosis progression in NAFLD.

Mediastinal Neuroendocrine Carcinoma Slowly Growing for 8 Years after Surgical Resection of Esophageal Squamous Cell Carcinoma.

A 70-year-old woman was referred to our department due to a solitary mediastinal tumor which gradually grew near the site of anastomosis for 8 years after radical surgery of esophageal squamous cell carcinoma. It was difficult to distinguish the lymph node recurrence of esophageal cancer from another tumor of unknown primary origin. Endoscopic ultrasound-guided fine-needle aspiration was performed, and the tumor was diagnosed to be neuroendocrine carcinoma. She received concurrent chemoradiotherapy with etoposide plus cisplatin. After the completion of chemoradiotherapy, the tumor disappeared. A solitary growing tumor which develops after radical resection of cancer would be better to be examined histologically in order to make an accurate diagnosis and select the most appropriate treatment.

Splenic rupture caused by pancreatic pseudocyst successfully treated by endoscopic ultrasound-guided drainage.

A 43-year-old man was admitted to a local hospital because of acute left abdominal pain. Chronic alcoholic pancreatitis and a 10-cm pancreatic pseudocyst in the tail of the pancreas had been found 5 years previously. He had not stopped drinking alcohol since then. On admission, laboratory tests revealed severe anemia, and contrast-enhanced computed tomography showed extravasation in the pancreatic pseudocyst. The spleen was retracted by the pancreatic pseudocyst, and its configuration was indistinct. The patient was diagnosed with acute bleeding within the pancreatic pseudocyst and splenic rupture. He was transferred to our university hospital on an emergency basis. Abdominal angiography of the splenic artery was immediately performed, but the bleeding point was not found. Although the bleeding stopped spontaneously, an infection of the pancreatic pseudocyst and a splenic hematoma subsequently developed. Endoscopic ultrasound-guided pseudocyst drainage was performed. The infection improved after the drainage, and the size of the pancreatic pseudocyst and splenic hematoma decreased. Five months later, the pancreatic pseudocyst had almost disappeared, and the splenic hematoma was even smaller. We herein report a rare case of splenic rupture caused by a pancreatic pseudocyst. Although the patient's condition became complicated by severe infection, treatment by endoscopic ultrasound-guided drainage was successful.

A case report: Long-term complete response of metastatic hepatocellular carcinoma obtained after discontinuation of 2-month sorafenib monotherapy.

A 69-year-old woman who had a history of chronic hepatitis C, autoimmune hemolytic anemia and myelodysplastic syndrome was treated with sorafenib at a daily dose of 400 mg for HCC with multiple lung metastases. Nonetheless, elevated serum tumor markers further increased (alpha fetoprotein from 121,100 to 348,660 ng/ml and protein induced by vitamin K absence/antagonist-II from 3435 to 29,357 mAU/ml), and lung metastatic lesions on chest X-ray showed no improvement after 2 months of sorafenib treatment. Sorafenib was discontinued because of adverse events with diarrhea, fatigue, and severe anemia due to bleeding from stomach telangiectasia. Hand-foot syndrome was mild. Thereafter, the tumor markers rapidly decreased to almost normal range, and the lung and liver tumors markedly shrunk and disappeared without any other cancer treatments. Her tumors remained in complete remission for 17 months until an intrahepatic recurrence occurred. This unique course of metastatic HCC indicated that antitumor mechanisms other than the direct anticancer effect of sorafenib contributed to tumor shrinkage.

Indicator for local recurrence of hepatocellular carcinoma after proton beam therapy: analysis of attenuation difference between the irradiated tumor and liver parenchyma on contrast enhancement CT.

OBJECTIVES: We aimed to identify dynamic CT features that can be used for prediction of local recurrence of hepatocellular carcinoma (HCC) after proton beam therapy (PBT). METHODS: We retrospectively retrieved CT scans of patients with PBT-treated HCC, taken between January 2004 and December 2016. 17 recurrent lesions and 34 non-recurrent lesions were retrieved. The attenuation difference between irradiated tumor and irradiated parenchyma (ADHCC-IP) was compared in the two groups by using the Mann-Whitney U test. Cut-off value of ADHCC-IP was estimated by using the Youden index. RESULTS: The follow-up time after PBT initiation ranged from 374 to 2402 days (median, 1069 days) in recurrent lesions, and 418 to 2923 days (median, 1091.5 days) in non-recurrent lesions (p = 0.892). The time until appearance of local recurrence after PBT initiation ranged from 189 to 2270 days (median, 497 days). ADHCC-IP of recurrent lesions [mean, -21.8 Hounsfield units (HU); from -95 to -31 HU] was significantly greater than that of non-recurrent lesions (mean, -51.7 HU; from -117 to -12 HU) at 1-2 years in portal venous phase (p = 0.039). 5-year local tumor control rates were 0.93 and 0.56 in lesions with ADHCC-IP at 1-2 years in PVP < -55 and ≥ -55 HU, respectively. CONCLUSION: The attenuation difference between irradiated HCC and irradiated liver parenchyma in portal venous phase at 1-2 years after PBT can predict long-term local recurrence of HCC after treatment. ADVANCES IN KNOWLEDGE: We identified a cut-off value for contrast enhancement of HCC after PBT that could predict future local recurrence.

Clinical outcomes of previously untreated patients with unresectable intrahepatic cholangiocarcinoma following proton beam therapy.

BACKGROUND: The effectiveness of proton beam therapy (PBT) as initial treatment for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is unclear, particularly as related to ICC histological subtypes. We performed this study to address this gap in knowledge. METHODS: Thirty-seven patients with unresectable ICC who underwent PBT as their initial treatment were evaluated. Twenty-seven patients had Child-Pugh class A liver function, 11 exhibited jaundice, and 10 had multiple tumors. Nineteen, 7, and 11 tumors were classified as mass forming (MF), periductal infiltrating (PI), and intraductal growth (IG) types, respectively, based on gross appearance in imaging studies. Patients were classified into the curative group (n = 25) and palliative group (n = 12) depending on whether the planning target volume covered all the macroscopic tumors. RESULTS: The 1- and 2-year overall survival rates were 60.3, and 41.4%, respectively; the median survival time (MST) was 15 months for all patients. The MSTs for curative and palliative groups were 25 and 7 months, respectively. Curative treatment and adjuvant chemotherapy significantly improved overall survival, while the presence of periductal infiltrating type tumors was a negative prognostic factor. In the curative group, the 1- and 2-year local control rates were 100 and 71.5%, respectively, while the 1-, and 2-year progression-free survival rates were 58.5, and 37.6%, respectively. No severe acute toxicities were observed. Three patients experienced grade 3 biliary tract infection, although it was unclear whether this was radiotherapy-related. CONCLUSION: PBT may yield to improve survival and local tumor control among patients with unresectable ICC.

Angiographic Findings in Patients with Hepatocellular Carcinoma Previously Treated Using Proton Beam Therapy.

Given the growing interest in using proton beam therapy (PBT) for hepatocellular carcinoma (HCC), it is possible that transarterial chemoembolization (TACE) could be used for selected patients who have previously undergone PBT. However, these cases can be technically challenging to treat and require appropriate preparation. Thus, we aimed to identify angiographic findings in this setting. We retrospectively identified 31 patients (28 men and 3 women, mean age: 69 years, range: 43-84 years) who underwent hepatic angiography plus TACE or transarterial infusion chemotherapy (TAI) for HCC that recurred after PBT (July 2007 to June 2018). We discovered four angiographic findings, which we speculate were related to the previous PBT. 18 patients experienced recurrence in the irradiated field, and 13 patients experienced recurrence outside the irradiated field. 29 patients underwent TACE and only 2 patients underwent TAI. The mean number of previous PBT treatments was 1.3 ± 0.6 (range: 1-4). The median interval from the earliest PBT treatment to hepatic angiography was 559 days (range: 34-5,383 days), and the median interval from the latest PBT treatment to hepatic angiography was 464 days (range: 34-5,383 days). Abnormal staining of the irradiated liver parenchyma was observed in 22 patients, which obscured the angiographic tumor staining in 4 patients. Development of a tortuous tumor feeder vessel was observed in 13 patients. Development of an extrahepatic collateral pathway was observed in 7 patients. Development of an arterioportal or arteriovenous shunt was observed in 4 patients. Based on these findings, we conclude that PBT was associated with various angiographic findings during subsequent transarterial chemotherapy for recurrent HCC, and familiarity with these findings will be important in developing appropriate treatment plans.

Safety margin of radiofrequency ablation for hepatocellular carcinoma: a prospective study using magnetic resonance imaging with superparamagnetic iron oxide.

PURPOSE: In radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), it is difficult to assess the ablative margin (AM) precisely by comparing pre- and post-RFA CT images. We prospectively studied the AMs using magnetic resonance imaging (MRI) with pre-administered superparamagnetic iron oxide (SPIO). SPIO is safe for kidney disease patients. MATERIALS AND METHODS: Hepatocellular carcinoma patients were treated with RFA within 8 h of SPIO administration. On T2*-weighted MRI performed 4-7 days later, AM was visualized as a hypointense rim. The ablation status was classified as AM(+) if the rim completely surrounded the tumor, AM(0) if the rim was partly discontinuous without tumor protrusion, and AM(-) if the rim was partly discontinuous with tumor protrusion. The minimal thickness of AM was measured. AM(-) tumors were re-treated consecutively. RESULTS: In total, 85 HCCs ablated in 76 patients were evaluated. The local recurrence rate at 3 years was 2% for AM(+) tumors and 34% for AM(0) tumors (p < 0.01). In addition, no local recurrence was seen in the tumors with an AM of ≥ 2 mm. CONCLUSION: MRI with pre-administered SPIO is useful for determining the AM precisely, and an AM of ≥ 2 mm is recommended for curative RFA. TRIAL REGISTRATION NUMBER: This study was registered with UMIN Clinical Trials Registry (UMIN 000025406).

A robust culture method for maintaining tumorigenic cancer stem cells in the hepatocellular carcinoma cell line Li-7.

Cancer tissues contain small populations of highly tumorigenic cells termed cancer stem cells (CSCs). Immortalized cell lines containing CSCs are valuable and powerful experimental tools for research into the characteristics of these stem cells. We previously reported that the hepatocellular carcinoma cell line Li-7 includes abundant CD13+ CD166- CSCs; however, the number of these cells decreases after long-term culture as a result of differentiation to non-CSC populations. To ensure consistent and reproducible results in experiments using Li-7 cells, it is important that the CSC population is maintained stably regardless of culture duration and passage. In the present study, we found that a commercially available culture medium for maintenance of embryonic stem cells and induced pluripotent stem cells, mTeSR1, effectively prevented spontaneous differentiation by CD13+ CD166- cells to CD13- CD166+ cells and therefore maintained the CSC population in Li-7 cell cultures. CD13+ CD166- CSCs maintained using this culture medium retained high tumorigenicity after transplantation into mice; they also showed the ability to differentiate in vitro into non-CSC populations in RPMI-1640 with 10% FBS medium. We analyzed gene expression profiles of CSC and non-CSC populations in Li-7 cultures using an RNA sequencing method. Genes such as FGFR, NOTCH1, and JAG1, that are associated with tumorigenicity and stemness, were upregulated in the CSC population. Our results suggest that CSCs can be maintained in immortalized cancer cell lines cultured over an extended period using a medium developed for culture of embryonic/induced pluripotent stem cells.

Oncolytic Virotherapy and Gene Therapy Strategies for Hepatobiliary Cancers.

Advanced liver cancers and biliary cancers represent diseases with dismal prognosis because of frequent local invasion and metastasis. Effective therapeutic agents for these cancers have not been established. Oncolytic viruses (OVs) constitute a novel class of promising, selective anticancer agents and recent studies have elucidated their unique features. Moreover, clinical trials are demonstrating promising results. Numerous OVs are being tested in preclinical models of hepatocellular carcinoma (HCC). The lead agent Pexa-Vec (pexastimogene devacirepvec, JX-594), a recombinant Wyeth strain vaccinia virus, has demonstrated preliminary evidence of safety and efficacy for HCC in clinical trials. Few other OVs have entered clinical testing. Relatively few preclinical studies and clinical trials exist for biliary cancers. In this review, we introduce various approaches using OVs to treat the intractable hepatobiliary cancers.