Clinicopathological Findings and Treatment Outcomes of Patients with Primary Hepatobiliary Neuroendocrine Neoplasms: A Retrospective Single-institution Analysis.

Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.

Combination Therapy With Lenvatinib and Radiofrequency Ablation for Patients With Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh Class A Liver function: A Pilot Study.

Background: The present study aimed to evaluate the efficacy and safety of combined lenvatinib (first-line systemic therapy) and radiofrequency ablation (RFA) therapy in patients with intermediate-stage hepatocellular carcinoma with beyond up-to-seven criteria and Child-Pugh Class A liver function (CP A B2-HCC). Methods: Twenty-two patients with CP A B2-HCC were enrolled in the study. The patients had no history of systemic treatment. For the initial lenvatinib administration in this study, all of the patients had an adequate course of treatment (no less than two weeks) and were administered the recommended dose. Of them, 13 were treated by means of lenvatinib monotherapy (monotherapy group), while the 9 patients with no contraindication to RFA operation and who had consented to RFA received initial lenvatinib plus subsequent RFA (combination group). The clinical outcomes that were considered to evaluate the treatments included tumor response, prognosis (recurrence and survivals), and possible adverse events (serum liver enzymes and clinically visible complications). Results: The combination group exhibited a higher object response rate (9/9, 100%) as best tumor response than the monotherapy group (10/13, 76.9%). Longer progression-free survival (PFS) (12.5 months) and overall survival (OS) (21.3) were demonstrated in the combination group than in the monotherapy group (PFS: 5.5 months; OS:17.1 months). The combination group achieved a higher PFS rate (1-year: 74.1%) and OS rate (2-year: 80%) than the monotherapy group (1-year PFS rate: 0%; 2-year OS rate: 25.6%; for PFS, p<0.001; for OS, p=0.022). The treatment strategy was the independent factor for PFS (HR: 18.215 for monotherapy, p =0.010), which was determined by Cox regression analysis, suggesting that a combination strategy may reduce tumor progression when compared to the use of lenvatinib alone. There were no statistically significant intergroup differences that were observed in terms of adverse events, with the exception of ALT elevation (p=0.007) in the combination group. Conclusion: Our newly proposed combination therapy may potentially be effective and safe for CP A B2-HCC beyond up-to-seven criteria. A larger scale, multicenter, prospective study is warranted to confirm our findings.

Novel clip device for prevention of bleeding after endoscopic papillectomy.

Objectives: Recently, a novel clip device, SureClip® (Micro-Tech Co. Ltd., Nanjing, China), has been developed, which improved rotation and reopening performance. We aimed to assess the efficacy of the SureClip® in prophylactic closure of the mucosal break after endoscopic papillectomy (EP) for ampullary neoplasm. Methods: We retrospectively reviewed the medical records of 40 patients who underwent EP for ampullary neoplasms between October 2009 and March 2020. Prophylactic closure after resection was performed using the conventional clip between 2014 and 2018, and with the SureClip® after 2019. The baseline characteristics, techniques, outcomes, and complications of EP were analyzed. Results: The median age of the patients (25 males and 15 females) was 70 years. The en block resection rate was 82.5% and the curative resection rate was 80.0%. Histologically, 11 (27.5%) patients had malignancy. Prophylactic closure was performed in 29 (72.5%) patients (17 conventional clips, 12 SureClip®). Complications occurred in 18 (45.0%) patients, including postprocedure bleeding in 9 (22.5%) patients. However, no postprocedure bleeding was observed in the patients who received prophylactic closure using the SureClip® (p = 0.038). All other factors were not significantly correlated with postprocedure bleeding. The duration of hospital stay after EP was significantly shorter in patients treated with the SureClip® compared to those treated with a conventional clip or without clips (p < 0.05). Conclusions: In the present study, prophylactic clipping of the mucosal break using the SureClip® was effective in preventing bleeding after EP.

Liver Injury and Use of Contrast-Enhanced Ultrasound for Evaluating Intrahepatic Recurrence in a Case of TACE-Refractory Hepatocellular Carcinoma Receiving Atezolizumab-Bevacizumab Combination Therapy: A Case Report.

A 67-year-old male with type 2 diabetes (T2DM) was diagnosed with postoperative intrahepatic recurrence for hepatocellular carcinoma (HCC). Nine sessions of transarterial chemoembolization (TACE) proved ineffective, and the patient was diagnosed as having TACE-refractory disease and received seven cycles of atezolizumab-bevacizumab combination therapy. After that, the patient developed hyperglycemia with the HbA1c elevation and the marked fasting serum C-peptide reduction and was diagnosed with developed immune-mediated diabetes (IMD) (T2DM exacerbation with insulin-dependent diabetes development). Subsequently, the hepatobiliary enzyme levels, which were high before the systemic therapy, worsened. Thus, we clinically diagnosed an exacerbation of liver injury due to TACE-induced liver injury complicated by drug-induced liver injury such as immune-mediated hepatotoxicity (IMH). Meanwhile, after contrast-enhanced computed tomography revealed complete response, contrast-enhanced ultrasound was performed to assess intrahepatic recurrence. We found that the latter modality allowed earlier and more definitive diagnosis of intrahepatic recurrence of HCC. Subsequently, despite systemic therapy discontinuation and steroids administration, the liver injury worsened, and the patient died. The autopsy revealed intrahepatic recurrence of HCC and extensive arterial obstruction by the beads used for TACE within the liver, which indicated that disturbed circulation was the primary cause of the liver injury and histopathologically confirmed IMD, but not IMH.

Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.

A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.

Clinical outcome of a highly flexible duodenal stent for gastric outlet obstruction: A multicenter prospective study.

BACKGROUND AND AIM: Endoscopic duodenal stenting for patients with malignant gastric outlet obstruction (GOO) has been widespread; however, clinical trials evaluating the structures of duodenal stents are lacking. Thus, we aimed to investigate the clinical outcomes of a highly flexible duodenal stent for GOO patients. METHODS: A prospective study of duodenal stenting for GOO patients from five hospitals between August 2017 and August 2018 was performed. WallFlex Duodenal Soft were used in all procedures. The primary endpoint was clinical success, defined as an improvement in the GOO scoring system. RESULTS: The study enrolled 31 patients (12 women, 19 men) with GOO, with a median age of 70 (range 52-90) years. Primary diseases were pancreatic cancer, gastric cancer, biliary tract cancer, and others in 14, 10, 3, and 4 patients, respectively. The technical success rate was 97%, and the clinical success rate was 87%. Simultaneous biliary drainage was performed in 19% of patients. Adverse events occurred in three patients. Chemotherapy was given in 41% of clinically successful cases, and the median overall survival time after stent placement was 82 days (range, 30-341 days), and. Stent dysfunction occurred in 30% of clinically successful cases (stent ingrowth in seven and stent overgrowth in one patient). The median time to stent dysfunction was 157 days (range, 11-183 days). Six patients were treated with additional stent placement after dysfunction. CONCLUSION: Placement of a highly flexible duodenal stent is an effective and safe treatment for patients with GOO (UMIN-CTR 000028783).

Therapeutic effects of regorafenib after sorafenib monotherapy with advanced hepatocellular carcinoma including Child-Pugh classification B: A retrospective observational study.

The therapeutic effect of regorafenib was previously demonstrated in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh classification A (CP-A) whose disease progressed during sorafenib treatment in a phase III trial. However, treatment options are limited for patients with advanced HCC other than CP-A. In this study, we aimed to evaluate the therapeutic effect of regorafenib on advanced HCC patients including those with Child-Pugh classification B (CP-B).We retrospectively analyzed the medical records of 21 patients with advanced HCC who were treated with regorafenib after sorafenib monotherapy at our hospital from July 2017 to April 2018 and were followed up until September 2019. Patients were classified according to liver function and adverse events experienced during sorafenib treatment and were started on regorafenib with a pre-defined reduced starting dose along with a dose reduction and schedule change based on the judgement of the attending physician.At regorafenib initiation, 13 and 8 patients were classified as CP-A and CP-B, respectively. In all patients with CP-B, the starting dose of regorafenib was reduced, and the pre-defined starting-dose sets were applied to 17 (81%) patients. The median duration of regorafenib treatment in patients with CP-A and CP-B were 4.1 months and 2.0 months, respectively, with no significant difference. The median overall survival from regorafenib initiation (OS-r) and sorafenib initiation (OS-s) was 13.2 months and 30.9 months, respectively. In subgroup analysis, OS-r was 16.3 months in patients with CP-A and 10.1 months with CP-B with no significant difference (P = .44), whereas OS-r was 16.3 months in patients with modified albumin-bilirubin Grade 1/2a and 13.2 months in patients with Grade 2b, with no significant difference. There was no clear difference in the incidence rate of ≥grade 3 adverse events between CP-A and CP-B. OS-r and OS-s were significantly correlated.Even patients with impaired liver function achieved the desired therapeutic effects by safely reducing the starting dose of regorafenib according to both impaired liver function and adverse events during pretreatment. Regorafenib may be considered to be an effective treatment after sorafenib monotherapy in patients with impaired liver function.

Lenvatinib for large hepatocellular carcinomas with portal trunk invasion: Two case reports.

BACKGROUND: In a phase III trial of lenvatinib as first-line treatment for advanced unresectable hepatocellular carcinoma (uHCC), the drug proved non-inferior to sorafenib in terms of the overall survival, but offered better progression-free survival. However, the effects of lenvatinib in uHCC patients with a tumor thrombus in the main portal vein and/or a high tumor burden (tumor occupancy more than 50% of the total liver volume), remain unclear, because these were set as exclusion criteria in the aforementioned trial. CASE SUMMARY: A 53-year-old man (case 1) and 66-year-old woman (case 2) with uHCC presented to us with a tumor thrombus in both the main portal vein and inferior vena cava, a high tumor burden accompanied by a tumor diameter greater than > 100 mm, and distant metastasis, with the residual liver function classified as grade 2A according to the modified Albumin-Bilirubin grading. We started both patients on lenvatinib. The therapeutic effect, as evaluated by the modified Response Evaluation Criteria in Solid Tumors, was rated as partial response in both case 1 and case 2 (at 8 wk and 4 wk after the start of lenvatinib administration, respectively). The therapeutic effect was sustained for 6 mo in case 1 and 20 mo in case 2. Fever occurred as an adverse event in both case 1 and 2, and hyperthyroidism and thrombocytopenia in only case 2, neither of which, however, necessitated treatment discontinuation. CONCLUSION: Even in hepatocellular carcinoma patients with poor prognostic factors, if the liver function is well-preserved, lenvatinib is effective and safe.

Surgical intervention for portal hypertension caused by oxaliplatin-based chemotherapy: a case report and a review of literature regarding radiological and/or surgical interventions for oxaliplatin-associated portal hypertension.

A 63-year-old man showed massive ascites, massive pleural effusion, severe lower-extremity edema, and repeated esophageal variceal bleeding. Two-year previously, he received 13-courses of oxaliplatin-based chemotherapy (OBC) followed by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for multiple colorectal cancer liver metastases but developed a solitary remaining liver metastasis and multiple lung metastases 2 months after the ALPPS, for which multiple regimens of chemotherapy were conducted. The symptoms were considered attributable to the OBC-associated portal-hypertension. Water-retention symptoms were mitigated by the use of tolvaptan but the variceal bleeding necessitated frequent endoscopic treatments and disallowed restarting antineoplastic treatment. Transjugular intrahepatic portosystemic shunt (TIPS) was considered undesirable because TIPS in this patient might have prohibited future repeat hepatectomy. Thus, the patient underwent splenectomy and surgical portosystemic shunting. Since then, the portal-hypertension symptoms were completely resolved. Thereafter, chemotherapy was able to be recommenced. Moreover, repeat hepatectomy was performed. A literature review demonstrated that radiological and/or surgical interventions for the OBC-associated portal-hypertension have been reported in 31 cases to date. However, this report is the first to show a case of successful treatment of the OBC-associated portal-hypertension with splenectomy and surgical portosystemic shunting, which allowed subsequent chemotherapy followed by repeat hepatectomy.

Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy.

According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct-DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue- and ct-DNA samples. The 21 patients were subjected to quantitative ct-DNA monitoring at 4 to 8-week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation-negative cases, next-generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct-DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%-31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%-0.2%]). In the ct-DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression-free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P < .001). Therefore, ct-DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.

Diffuse fatty metamorphosis of a large, well-differentiated hepatocellular carcinoma originating in the normal liver: a case report and literature review.

Fatty changes are frequently observed in small, well-differentiated hepatocellular carcinomas (HCCs), but are rarely observed in large (over 30 mm in diameter) lesions. Here, we report a 76-year-old man who developed a large (58 mm in diameter), well-differentiated HCC with diffuse extensive fatty changes in the right lobe of the liver. He had no history of alcohol abuse, obesity, or hepatitis B or C infection, and no autoantibodies, but he did have type 2 diabetes. The serum alpha-fetoprotein level was within the normal range, and ultrasonography showed a round hyperechoic lesion. Dynamic contrast-enhanced computed tomography revealed a tumor with inhomogeneous low attenuation in the arterial, portal, and venous phases, mimicking an angiomyolipoma. The patient underwent central bisegmentectomy of the liver, and the histological diagnosis was well-differentiated HCC with diffuse extensive fatty changes. The surrounding non-cancerous area was normal. A review of the published literature found six published cases of large, well-differentiated HCC with extensive fatty changes. Unlike the patients in most previous reports, our patient did not have any underlying liver disease and had no history of alcohol abuse.