Treatment strategy changes for inflammatory bowel diseases in biologic era: results from a multicenter cohort in Japan, Far East 1000.

Many molecular targeted agents, including biologics, have emerged for inflammatory bowel diseases (IBD), but their high prices have prevented their widespread use. This study aimed to reveal the changes in patient characteristics and the therapeutic strategies of IBD before and after the implementation of biologics in Japan, where the unique health insurance system allows patients with IBD and physicians to select drugs with minimum patient expenses. The analysis was performed using a prospective cohort, including IBD expert and nonexpert hospitals in Japan. In this study, patients were classified into two groups according to the year of diagnosis based on infliximab implementation as the prebiologic and biologic era groups. The characteristics of therapeutic strategies in both groups were evaluated using association analysis. This study analyzed 542 ulcerative colitis (UC) and 186 Crohn's disease (CD). The biologic era included 53.3% of patients with UC and 76.2% with CD, respectively. The age of UC (33.9 years vs. 38.8 years, P < 0.001) or CD diagnosis (24.3 years vs. 31.9 years, P < 0.001) was significantly higher in the biologic era group. The association analysis of patients with multiple drug usage histories revealed that patients in the prebiologic era group selected anti-tumor necrosis factor (TNF)-α agents, whereas those in the biologic era group preferred biologic agents with different mechanisms other than anti-TNF-α. In conclusion, this study demonstrated that both patient characteristics and treatment preferences in IBD have changed before and after biologic implementation.

Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma from Japanese real-world practice.

BACKGROUND: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics. METHODS: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGKR) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed. RESULTS: A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGKR, 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGKR. No significant difference was observed in the baseline characteristics between HPD and non-HPD. CONCLUSION: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated.

Clinical effects and emerging issues of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma from Japanese real-world practice.

BACKGROUND: Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long-term efficacy and association with adverse events in real-world practice are unknown. This study was designed to shed light on these issues. METHODS: In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition. RESULTS: A total of 123 patients were enrolled in this study. The median progression-free survival (PFS) for the first-line treatment group was 8.0 months (95% confidence interval [CI], 6.1-9.9), whereas the median PFS for the second- or later-line treatment group was 4.1 months (95% CI, 2.6-5.7), which was significantly worse than that of the first-line treatment group (p = .005). Twenty-seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p = .026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p = .013). CONCLUSIONS: The PFS of atezolizumab plus bevacizumab as first-line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long-term PFS. PLAIN LANGUAGE SUMMARY: Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma. With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly. The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus. The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma.

Six autoantibodies as potential differential biomarkers of hepatocellular carcinoma vs. liver cirrhosis and chronic hepatitis: A prospective multi-institutional study.

Serum autoantibodies respond not only to tumor-associated antigens of hepatocellular carcinoma (HCC) but also to those of liver cirrhosis (LC) and chronic hepatitis (CH). The present prospective multi-institutional study evaluated the diagnostic properties of six autoantibodies in distinguishing HCC from LC and CH. A total of 416 participants were enrolled: 149 With HCC, 76 with LC, 103 with CH and 88 healthy controls. Titers of serum autoantibodies to Sui1, RalA, p62, p53, c-myc and NY-ESO-1 were determined using enzyme-linked immunosorbent assays. All six antibodies were positive for HCC: s-Sui1-Abs (44%), s-RalA-Abs (23%), s-p62-Abs (21%), s-p53-Abs (13%), s-c-myc-Abs (11%) and s-NY-ESO-1-Abs (6%). The positivity rates of all six antibodies combined were 5% for healthy controls, 52% for CH, 58% for LC and 66% for HCC. The positivity rates of s-Sui1-Abs, s-RalA-Abs and s-p53-Abs were higher for HCC compared with those of LC and CH. However, the positivity rates of s-p62-Abs, s-c-myc-Abs and s-NY-ESO-1-Abs for HCC were not higher compared with those for LC and CH. Overall, autoantibodies were useful in differentiating patients with HCC from healthy individuals. However, they were not specific to HCC and were also present in the sera of individuals with CH and LC. These autoantibodies may be induced during the development of HCC. Clinical trial registration number: UMIN000014530 (date of registration 2011/07/11).

Posttreatment after Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy. METHODS: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. RESULTS: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively. CONCLUSION: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.

Potential of Lenvatinib for an Expanded Indication from the REFLECT Trial in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial. METHODS: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan. RESULTS: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7-6.9 for first line, 4.8 months; 95% CI 3.8-5.9 for second or later line, p = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin - bilirubin scores. CONCLUSION: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.

Safety and Efficacy of Early Tube Removal Following Percutaneous Transhepatic Gallbladder Drainage: an Observational Study.

BACKGROUND: There are currently no guidelines concerning the advisability and timing of tube removal following percutaneous transhepatic gallbladder drainage (PTGBD). The present study aimed to assess the feasibility and risks of early removal of the PTGBD tube under the scenario of subsiding inflammation, patent cystic and common bile ducts, and absence of intraperitoneal leakage. METHODS: Patient background and outcomes were assessed retrospectively in 701 cases of acute cholecystitis treated with PTGBD. The median times until tube removal and tube dislodgement and the cumulative rates of tube dislodgement were calculated. RESULTS: Tube removal was performed in 275 patients after a median time of 16 days (range: 6 to 213 d); biliary peritonitis was observed in 2 patients following tube removal. Tubes were removed in 8 and 35 patients within 7 and 10 days, respectively. Tube dislodgement was observed in 82 patients after a median time of 12 days (range: 1 to 125 d). CONCLUSION: The present study suggests that drainage tube removal is safe and effective when performed after a short drainage period of 7 to 10 days if the criteria for the removal of the drainage tube were met.

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

[A Case of Boderline Resectable Pancreatic Cancer Curatively Resected after Chemotherapy with Gemcitabine and Nab-Paclitaxel].

Combination therapy containingnab -paclitaxel(nab-PTX)and gemcitabine(GEM)is widely administered for metastatic pancreatic cancer. Recently, this regimen is likely to be applied for treatment in patients with locally advanced disease or for neoadjuvant chemotherapy(NAC)in patients with borderline resectable(BR)pancreatic cancer. We report a case of BR pancreatic cancer in a patient who was eligible for comparison of the imaging findings with the microscopic findings of the resected specimen. A 72-year-old woman was admitted to our hospital with a complaint of jaundice. Enhanced CT showed a 35mm tumor at the head of the pancreas involvingthe portal vein and in contact with the superior mesenteric artery(SMA). After 4 courses of chemotherapy containinga combination of nab-PTX and GEM, the tumor reduced in size, but was still in contact with the portal vein and SMA on imaging. The level of tumor marker CA19-9 was remarkably reduced. Subtotal stomach-preservingpancreaticoduodenectomy with portal vein reconstruction was performed. Macroscopic findings of the cut surface of the resected specimen showed that a white nodule at the pancreas head involved the portal vein and was in contact with the close-cut margin from the SMA; however, microscopic findings revealed that tumor cells had disappeared in the plexus around the SMA. R0 resection was achieved. The histological treatment effect based on Evans' classification and TNM classification were GradeⅡ and pT3N1aM0(pStage ⅡB), respectively. There has been no recurrence 15 months after the surgery. Based on the abovementioned findings, chemotherapy containing a combination of nab-PTX and GEM can be an effective option of NAC for BR-A pancreatic cancer. Even if the tumor is in contact with the SMA on imaging, when the CA19- 9 level is markedly reduced, there is a possibility of achievingR0 surgery.

To-and-fro waveforms in the left gastric vein in portal hypertension.

Unusual to-and-fro waveforms were demonstrated in the left gastric vein on Doppler sonograms in four patients with liver cirrhosis. The patterns of the to-and-fro waveforms were diverse in each of the patients: both hepatopetal and hepatofugal flow occurred in a single waveform in case 1, changes in the flow direction with flow interruption were noted in case 2, and changes in flow direction without observation of flow interruption and changes after meals were noted in cases 3 and 4, respectively. These waveforms may represent a transitional phase during the development of a portal systemic shunt in patients with portal hypertension.

Safety and tolerance of sorafenib in Japanese patients with advanced hepatocellular carcinoma.

PURPOSE: Sorafenib provides a survival benefit for patients with advanced hepatocellular carcinoma (HCC). However, there has been little experience with it in Japan. This study evaluated the safety and tolerance of sorafenib in Japanese patients with HCC. METHODS: Clinical data for patients given sorafenib for advanced HCC were captured from eight institutions. All patients were classified as Child-Pugh A and the treatment was started at 400 mg twice daily. We recorded adverse events, treatment duration, and survival retrospectively. Adverse events were graded using Common Terminology Criteria, version 3.0; tumor response was assessed according to Response Evaluation Criteria in Solid Tumor, version 1.1. RESULTS: Of the 54 patients treated, their median age was 69 years (range 48-82), 91% were males, 52% had HCV infection, and 22% had HBV infection. The most common drug-related adverse events were hand-foot skin reactions (HFSR) (72%), aspartate transaminase elevation (55%), alanine aminotransferase elevation (52%), rash (50%), fatigue (41%), and diarrhea (32%). Liver failure occurred in 19%. The median time to treatment failure was 2 months. Dose reduction was required in 83% of the patients, and this occurred within 2 weeks in 44%. The median overall survival was 6.9 months. CONCLUSIONS: These data suggest that sorafenib is generally tolerated in Japanese patients with HCC. Nevertheless, the majority needed a dose reduction. Adverse events including HFSR, rash, and liver failure occurred more frequently in our patients than those reported elsewhere. Careful attention must be paid to these adverse events during sorafenib administration.

Portal vein thrombosis associated with ischemic colitis.

We report the case of a 52-year-old male who was admitted for sudden abdominal pain and hematochezia. Colonoscopy showed erosion and edema in the mucosa of the descending colon, leading to a diagnosis of ischemic colitis. Blood tests revealed hepatic dysfunctions. Using abdominal ultrasonography (US), thrombus was observed in the left branch of the portal vein and a part of the right branch. Although the Doppler method detected blood flow in the right branch, no blood flow signal was observed in the left branch. Since coagulation examinations were almost normal, and there was no past history of liver cirrhosis or malignancy, it was diagnosed to be portal vein thrombosis (PVT) associated with ischemic colitis. Anticoagulation therapy was initiated for PVT. According to the results of the US and abdominal computed tomography performed 3 months after starting the treatment, thrombus in the right branch had diminished but remained in the umbilical region of the left branch. Due to atrophy of the lateral segment of the liver, we terminated the treatment. Ischemic colitis is not a rare disease; however, when accompanying hepatic dysfunction, it is necessary to take the complications associated with PVT into consideration.

Portal hemodynamics and clinical outcomes of patients with gastric varices after balloon-occluded retrograde transvenous obliteration.

BACKGROUND: Long-term hemodynamic effects and clinical outcomes after balloon-occluded retrograde transvenous obliteration (B-RTO) remain unclear. The purpose of this study was to evaluate long-term clinical results and effects on portal hemodynamics after B-RTO for the treatment of gastric varices with spontaneous gastrorenal shunt. METHODS: A total of 21 patients with cirrhosis and gastric varices treated by B-RTO were evaluated. The cumulative survival rate was calculated, portal blood flow was measured by Doppler ultrasonography, and liver function was estimated on the basis of Child-Pugh classification before and 1 year after B-RTO. RESULTS: Gastric varices disappeared or decreased markedly in size in all patients. Overall cumulative survival rates at 1, 3 and 5 years were 90.48, 71.11 and 53.71%, respectively. Portal blood flow increased significantly from 681.9 +/- 294.9 to 837.0 +/- 279.1 ml/min (P = 0.0125) after B-RTO. Child-Pugh score was not significantly changed (P = 0.755) after obliteration, but serum albumin was elevated significantly from 3.49 +/- 0.49 to 3.75 +/- 0.53 g/dl (P = 0.0459). The ascites score was significantly increased (P = 0.0455) after B-RTO, but all cases of ascites could be controlled with medication. CONCLUSIONS: Balloon-occluded retrograde transvenous obliteration is a safe and effective treatment for gastric varices with gastrorenal shunt. Portal blood flow and serum albumin parameters are increased, and liver function is unchanged after B-RTO.

Study of hemodynamic changes in portal systemic shunts and their relation to variceal relapse after endoscopic variceal ligation combined with ethanol sclerotherapy.

BACKGROUND: Among the factors influencing variceal relapse after endoscopic treatment, portal hemodynamic changes, especially in portal systemic shunts, could be the most important factor because hemodynamics are directly related to the development of esophageal varices. We aimed to clarify the influence of endoscopic treatment for esophageal varices on portal systemic shunts as well as its predictive value for variceal relapse. METHODS: Fifty patients who underwent combined endoscopic variceal ligation and injection sclerotherapy were examined with sonography and portography. RESULTS: Decrease of diameter, hepatopetal flow direction in the left gastric vein, or the presence of non-varices portal systemic shunt were sonographic findings related to a low incidence of variceal relapse. The presence of blood flow in and around the esophagus on venograms was highly predictive for variceal relapse. In patients with such venograms, non-varices portal systemic shunts did not develop. CONCLUSIONS: Sonographic assessment of hemodynamic changes in portal systemic shunt could be useful for estimating the results of endoscopic treatment for esophageal varices.

Hemodynamic response of the left gastric vein to glucagon in patients with portal hypertension and esophageal varices.

Flow direction and flow velocity of the left gastric vein (LGV) and the portal vein (PV) were examined by a Doppler sonographic machine in 33 patients with esophageal varices, before and after venous injection of glucagon (1 mg). In two patients with hepatopetal blood flow in the LGV, the flow direction changed to hepatofugal after injection of glucagon. In 31 patients with hepatofugal blood flow in the LGV, a significant increase of flow velocity was observed in the LGV in 18 patients (58.1%) and the changes (26.4 +/- 24.6%) were significantly larger than those in the PV (7.9 +/- 16.0%). The changes in flow velocity decreased in the LGV as the diameter of the LGV and the size of varices increased. In conclusion, glucagon increased collateral blood flow in the LGV in portal hypertension. However, the grade of the response decreased as the grade of portal hypertension increased.