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The preferred regimen for unresectable pancreatic cancer following gemcitabine-based chemotherapy is not well-established. This study compared the efficacy of (ⅰ) liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/leucovorin (LV) (nal-IRI/5-FU/LV) versus modified FOLFIRINOX (mFFX) and (ⅱ) nal-IRI/5-FU/LV versus FOLFIRI, respectively, and the safety of the three regimens each other, as second-line chemotherapies for unresectable pancreatic cancer.This was a retrospective single-center analysis of all patients who were administered nal-IRI/5-FU/LV, mFFX, or FOLFIRI from December 2014 to July 2021 as second-line chemotherapy for pancreatic cancer. The primary endpoint was the overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. Regarding safety, we assessed the incidence of grade ≥3 adverse events of interest in all patients.A total of 137 patients (nal-IRI/5-FU/LV, n = 55; mFFX, n = 39; FOLFIRI, n = 43) were included. The median OS in the nal-IRI/5-FU/LV group, the mFFX group, and the FOLFIRI group was 7.4, 11.8, and 8.4 months, respectively. Compared with the nal-IRI/5-FU/LV group, the mFFX and FOLFIRI groups displayed a hazard ratio of 0.66 [95% confidence interval 0.40-1.08] and 0.87 [95% confidence interval 0.55-1.39], respectively. In the FOLFIRI group, the incidence of grade ≥3 treatment-related adverse events tended to be low among all three groups.Given the trend toward longer OS in the mFFX group and the lower incidence of adverse events in the FOLFIRI group, both mFFX and FOLFIRI, as well as nal-IRI/5-FU/LV, can be treatment options for second-line chemotherapy for unresectable pancreatic cancer.

Background Immune checkpoint inhibitors (ICIs) are effective for advanced hepatocellular carcinoma (HCC). However, there are few reports on the correlation between the clinical efficacy of ICIs and the development of immune-related adverse events (irAEs) in patients with HCC. The aim of this study was to investigate the association between irAE development and survival in patients with HCC treated with atezolizumab plus bevacizumab. Patients and Methods We enrolled 150 patients with advanced HCC treated with atezolizumab plus bevacizumab between October 2020 and October 2021 at 5 territorial institutions. We compared the efficacy of atezolizumab plus bevacizumab between patients who experienced irAEs (irAE group) and those who did not (non-irAE group). Results Thirty-two patients (21.3%) developed irAEs of any grade. Grade 3/4 irAEs were observed in 9 patients (6.0%). The median progression-free survivals (PFS) in the irAE and non-irAE groups were 273 and 189 days, respectively (P = .055). The median overall survivals (OS) in the irAE and non-irAE groups were not reached and 458 days, respectively (P = .036). Grade 1/2 irAEs significantly prolonged PFS (P = .014) and OS (P = .003). Grade 1/2 irAEs were significantly associated with PFS (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.166-0.691; P = .003) and OS (HR, 0.086; 95% CI, 0.012-0.641; P = .017) on multivariate analysis. Conclusion The development of irAEs was associated with increased survival in a real-world population of patients with advanced HCC treated with atezolizumab plus bevacizumab. Grade 1/2 irAEs were strongly correlated with PFS and OS.

Pancreatic cancer frequently involves cancer‐associated thromboembolism, which is strongly associated with poor prognosis. Tissue factor, a blood coagulation factor largely produced in cancer patients as a component of extracellular vesicles, plays a key role in the incidence of cancer‐associated thromboembolism in patients with pancreatic cancer. However, no prospective studies have been published on the relationship between tissue factor and cancer‐associated thromboembolism or patient clinical characteristics, including recent chemotherapy regimens. Thus, we aimed to address this in a Japanese cohort of 197 patients and 41 healthy volunteers. Plasma tissue factor levels were measured by ELISAs preevaluated by tissue factor specificity. Multivariable analysis was used to identify independent predictors of cancer‐associated thromboembolism. We found that the cancer‐associated thromboembolism rate in the patient cohort was 6.6% (4.6%, venous thromboembolism; 2.0%, arterial thromboembolism). Tissue factor levels of 100 pg/mL or higher at patient registration were predictive of cancer‐associated thromboembolism, with positive and negative predictive values of 23.1% and 94.6%, respectively. Multivariable analysis showed that plasma tissue factor levels were an independent predictive factor for cancer‐associated thromboembolism, with a risk ratio of 5.54 (95% confidence interval, 1.02‐30.09). Unlike in healthy volunteers and patients without cancer‐associated thromboembolism, tissue factor levels were highly correlated with extracellular vesicles’ procoagulant activity in patients developing cancer‐associated thromboembolism. Taken together, our data show that the tissue factor levels at patient registration were a predictive factor for cancer‐associated thromboembolism in this cohort of patients with pancreatic cancer., Tissue factor levels were highly correlated with extracellular vesicles’ procoagulant activity in patients with pancreatic cancer who developed cancer‐associated thromboembolism. Tissue factor levels before the start of systemic chemotherapy were a predictive factor of cancer‐associated thromboembolism in a Japanese cohort of patients with pancreatic cancer.

Sarcopenia often affects patients with various types of cancer, and has been reported to affect patient prognosis and therapeutic effects. However, to the best of our knowledge, there are no reports on the relationship between gemcitabine plus nab-paclitaxel combination therapy (GnP) and sarcopenia in patients with unresectable pancreatic cancer. The present study analyzed the relationship between overall survival (OS), progression-free survival (PFS), response rate, disease control rate, adverse events (AEs) and sarcopenia in patients with pancreatic cancer treated with GnP. A total of 121 consecutive patients with advanced pancreatic cancer who received GnP as first-line chemotherapy between January 2015 and December 2017 were retrospectively analyzed. GnP consisted of 1,000 mg/m

Background Malignant gastric outlet obstruction (MGOO) occasionally occurs due to pancreaticobiliary cancer. Endoscopic duodenal stenting (DS) is a common treatment for MGOO. However, it has been reported that DS does not have sufficient patency time for it to be used in patients who have a potentially increased lifespan. Nowadays, systemic chemotherapy for pancreaticobiliary cancer has developed, and its anti-tumour effect would make time to stent dysfunction longer. Therefore, we retrospectively evaluated the association between objective response to systemic chemotherapy, followed by DS and time to stent dysfunction in patients with advanced pancreaticobiliary cancer. Methods This retrospective study included 109 patients with advanced pancreaticobiliary cancer who received systemic chemotherapy after DS. Patients who showed complete or partial response were defined as responders. The rest were defined as non-responders. Time to stent dysfunction was compared between responders and non-responders using the landmark analysis at 2 months after DS. Death without recurrence of MGOO was considered as a competing risk for time to stent dysfunction. Results Combination and monotherapy regimens were adopted for 46 and 63 patients, respectively. Median progression-free survival and overall survival were 3.2 months (95% confidence interval [CI], 2.4–4.0) and 6.0 months (95% CI, 4.6–7.3). Objective response was observed in 21 patients (19.3%). Median time to stent dysfunction was 12.5 months (95% CI, 8.4–16.5) in the entire cohort. In 89 patients, responders had a lower cumulative incidence of stent dysfunction than non-responders: 9.5 and 19.1% at 6 months, and 19.0 and 27.9% at 1-year, respectively. There was difference of time to stent dysfunction between responders and non-responders among patients who received combination regimen as the first-line treatment with p-value of 0.009: cumulative incidence was 0 and 42.9% at 6 months, and 9.3 and 57.1% at 1-year, respectively. Conclusions Longer time to stent dysfunction is expected when systemic chemotherapy following DS suppresses tumour progression; DS is slated to be a standard treatment for MGOO even in patients with pancreaticobiliary cancer and a long lifespan.

The aim of the study was to clarify the association of skeletal muscle mass and the prognosis of unresectable pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine plus nab-paclitaxel (GnP).We included 124 unresectable PDAC patients who received GnP chemotherapy. Skeletal muscle mass of the third lumbar vertebrae (L3) level was measured by computed tomography immediately before GnP initiation, and the skeletal muscle index (L3-SMI) was calculated. Sarcopenia was defined as L3-SMI less than 42 cm2/m2 in male patients and less than 38 cm2/m2 in female patients.Sarcopenia was found in 63 patients (50.8%). There was no significant difference in overall survival (OS) between sarcopenia and nonsarcopenia patients; however, in elderly patients (70 years), the OS of sarcopenia patients was significantly poorer than that of nonsarcopenia patients (390 vs 631 days, respectively; hazard ratio, 2.64; 95% confidence interval, 1.33-5.23). Multivariate analyses in elderly patients revealed that sarcopenia and tumor stage were independent poor prognostic factors. Despite the short OS of elderly sarcopenia patients, there were no significant differences in progression-free survival or response rate.Sarcopenia diagnosed by L3-SMI is a prognostic factor in elderly patients who receive GnP for unresectable PDAC. However, GnP exhibits a certain efficacy in sarcopenia and nonsarcopenia patients.

Mucinous cystadenocarcinoma (MCAC) with malignant ascites is rare. We report a case of a 28-year-old woman who presented with epigastric pain. The ascites in the Douglas fossa was identified at a nearby gynecology clinic. Computed tomography showed a multiloculated cystic lesion (9.5 × 6.4 cm) in the tail of the pancreas, which was diagnosed as mucinous cystic neoplasm on imaging. Staging laparoscopy was performed, and rapid cytology of ascites revealed adenocarcinoma, leading to a diagnosis of unresectable MCAC. Subsequently, combination chemotherapy with gemcitabine plus S-1 was initiated. Although there were no remarkable changes in the imaging findings, the peritoneal dissemination node was not consistently recognized in any of the imaging findings, and distal pancreatectomy was performed. A peritoneal dissemination node was not observed in the laparotomy findings, but the peritoneal lavage cytology was positive. The postoperative pathological result was non-invasive MCAC, and the ascites was suspected to be caused by cyst rupture. The patient has been recurrence-free, including the reappearance of ascites, for > 8 years after adjuvant therapy with S-1. Although careful follow-up will be required in the future, the very good prognosis in this case suggests that MCAC with malignant ascites without obvious peritoneal dissemination should be considered for surgical resection.

Katsuaki Ogushi,1,* Makoto Chuma,1,* Haruki Uojima,2 Hisashi Hidaka,2 Kazushi Numata,1 Satoshi Kobayashi,3 Shunji Hirose,4 Nobuhiro Hattori,5 Tomoaki Fujikawa,6 Takahide Nakazawa,2 Naohisa Wada,2 Shuitirou Iwasaki,2 Taito Fukushima,3 Yusuke Sano,3 Makoto Ueno,3 Kuniyuki Kawano,3 Kota Tsuruya,4 Masako Shomura,4 Tsunamasa Watanabe,5 Kotaro Matsunaga,5 Yosuke Kunishi,7 Yusuke Saigusa,8 Kuniyasu Irie,9 Shogo Iwabuchi,6 Makoto Kako,10 Manabu Morimoto,3 Tatehiro Kagawa,4 Katsuaki Tanaka,11 Shin Maeda9 1Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan; 2Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan; 3Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan; 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; 6Department of Gastroenterology, Shonan Fujisawa General Hospital, Fujisawa, Japan; 7Department of Gastroenterology, Kanagawa Prefectural Ashigarakami Hospital, Kanagawa, Japan; 8Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 9Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan; 10Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Japan; 11Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan*These authors contributed equally to this workCorrespondence: Makoto Chuma Gastroenterological CenterYokohama City University Medical Center, 4-57 Urafune-Cho, Minami-Ku, Yokohama, Kanagawa 2320024, JapanTel +81 45 261 5656Fax +81 45 253 9955Email chuma@yokohama-cu.ac.jpPurpose: To assess the safety, efficacy and prognostic impact of clinical factors related to lenvatinib treatment in Child-Pugh class A (CP-A) and class B (CP-B) patients with unresectable hepatocellular carcinoma (u-HCC).Methods: Patients with u-HCC who were treated with lenvatinib at multiple centers in Japan were retrospectively analyzed for treatment outcomes according to their respective CP status. Radiological objective response (OR) was assessed using modified response evaluation criteria in solid tumors (mRECIST) guidelines.Results: Baseline demographic parameters were comparable between 126 (69.6%) patients with CP-A disease and 55 patients (30.4%) with CP-B disease. Frequency of lenvatinib-related adverse events, including decreased appetite (P=0.034), diarrhea (P=0.040), elevated serum bilirubin (P=0.016) and vomiting (P=0.009), were higher in CP-B than in CP-A patients. Relative dose intensity (RDI) was significantly higher in CP-A (0.69) than CP-B patients (0.50, P < 0.001). Furthermore, OR rate (44.0%) was markedly higher in CP-A5 patients as compared to CP-A6 (25.5%), CP-B7 (22.2%), and CP-B8 patients (5.3%), respectively (P=0.002). In multivariable analysis, performance status (0 vs 1, 2, P=0.026), CP class (A vs B, P=0.045) and RDI (≥ 0.7 vs < 0.7, P=0.034) were identified as factors associated with response to lenvatinib treatment. Overall survival (OS) at 12 months was significantly different between CP-A (66.3%) and CP-B patients (30.0%, P=0.002), and between CP 5– 7 (59.2%) and CP 8 patients (34.8%, P=0.003). In multivariable analysis, CP class (A vs B, P=0.007) and Barcelona clinic liver cancer (BCLC) stage (B vs C, P=0.002) were associated with OS following lenvatinib treatment.Conclusion: Lenvatinib treatment offers significant benefits in patients with good liver function in real-world practice. The various characteristics identified in this study might be helpful as clinical predictors of response to lenvatinib and survival in clinical practice. Further studies are required to address eligibility for lenvatinib treatment in CP 7 patients.Keywords: lenvatinib, tyrosine kinase inhibitor, hepatocellular carcinoma, Child-Pugh, adverse events, overall survival

Background/Aims: Lusutrombopag, a small-molecule thrombopoietin receptor agonist, is used to treat thrombocytopenia based on the results of a phase 3 trial, including data for single-use administration in patients with chronic liver disease (CLD) undergoing invasive procedures. We aimed to evaluate the efficacy and safety of repeated lusutrombopag use. Methods: Lusutrombopag was administered repeatedly in patients undergoing multi-cycle invasive procedures at intervals >1 month. Results: Data from 8 patients (median platelet count at baseline, 44.0 [range, 35–49] × 109/L) and 25 cycles of invasive procedures, including 2 cycles in 3 patients, 3 cycles in 4 patients, and 7 cycles in 1 patient, were retrospectively evaluated. The procedures included 18 transarterial chemoembolizations, 5 radiofrequency ablations, and 2 liver needle biopsies. Platelet counts increased significantly compared with baseline, and median changes in platelet counts were 46.0 × 109/L (p = 0.012) in cycle 1, 44.0 × 109/L (p = 0.012) in cycle 2, and 42.0 × 109/L (p = 0.008) in cycles 3–7. No severe adverse events, including portal vein thrombus or bleeding, were observed. Conclusions: Repeated use of lusutrombopag might be safe and effective against thrombocytopenia in patients with CLD undergoing multi-cycle invasive procedures, although long-term data from more patients are required.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P, Previous genome-wide association studies have identified risk loci for pancreatic cancer but were centered on individuals of European ancestry. Here the authors identify GP2 gene variants associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Background Although second‐line treatment for pancreatic cancer has been proven to have survival benefit, it is not clear which is the most preferred regimen. This study compared the efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) and sequential chemotherapy (FOLFIRI/FOLFOX) as a second‐line treatment regimen for unresectable pancreatic cancer. Method This was a retrospective single‐center analysis of all patients who initiated treatment with mFOLFIRINOX or sequential chemotherapy from December 2014 to May 2019 as a second‐line treatment for unresectable pancreatic cancer. The sequential chemotherapy group included all patients who initiated sequential chemotherapy. For efficacy analysis, the primary endpoint was overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. For safety analysis, we assessed the incidence of grade ≥3 adverse events in all patients. Results Seventy‐four patients (mFOLFIRINOX group, n = 44; sequential chemotherapy group, n = 30) were included. OS tended to be slightly prolonged in the mFOLFIRINOX group than in the sequential chemotherapy group (median 10.6 [95% confidence interval {CI} 5.9–13.8] vs. 8.5 [95% CI 5.0–12.2] months; hazard ratio 1.40 [95% CI 0.71–2.71]). The objective response rate and disease control rate were 8.1% and 64.9%, respectively, in the mFOLFIRINOX group and 3.8% and 42.3%, respectively, in the sequential chemotherapy group. In safety analysis, the grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 40.9%, 6.8%, and 18.2%, respectively, in the mFOLFIRINOX group and 3.3%, 0%, and 3.3%, respectively, in the sequential chemotherapy group. Conclusions Whereas efficacy tended to be slightly better in the mFOLFIRINOX group than in the sequential chemotherapy group, given the higher incidence of grade ≥3 adverse events with mFOLFIRINOX than with sequential chemotherapy, sequential chemotherapy is a regimen with better risk–benefit balance than mFOLFIRINOX, and can be considered a second‐line treatment option for patients with unresectable pancreatic cancer.

Purpose To assess the impact of clinical factors on the safety and efficacy of atezolizumab plus bevacizumab (ATZ+BV) treatment in patients with unresectable hepatocellular carcinoma (u-HCC). Method Ninety-four u-HCC patients who were treated with ATZ+BV at multiple centers were enrolled. We defined Child-Pugh (CP)-A patients who received ATZ+BV treatment as a 1st line therapy as the 'meets the broad sense of the IMbrave150 criteria' group (B-IMbrave150-in, n=46), and patients who received ATZ+BV treatment as a later line therapy or CP-B patients (regardless of whether ATZ+BV was a 1st line or later line therapy) as the B-IMbrave150-out group (n=48). Patients were retrospectively analyzed for adverse events (AEs) and treatment outcomes according to their clinical status characteristics, including neutrophil lymphocyte ratio (NLR) at baseline. Results The overall incidence of AEs was 87.2% (82/94 patients). The frequency of interruption of ATZ+BV treatment due to fatigue was higher in CP-B than CP-A patients (P=0.030). Objective response (OR) rates of the B-IMbrave150-in group (28.3%, 39.1%) were significantly higher than those of the B-IMbrave150-out group (8.3%, 18.8%; P=0.0157, 0.0401) using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST, respectively. In multivariate analysis, neutrophil lymphocyte ratio (NLR) (hazard ratio (HR), 4.591; P=0.0160) and B-IMbrave150 criteria (HR, 4.108; P=0.0261) were independent factors associated with the OR of ATZ+BV treatment using RECIST. Conclusion In real-world practice, ATZ+BV treatment might offer significant benefits in patients who meet B-IMbrave150 criteria or have low NLR. This article is protected by copyright. All rights reserved.

In cancer patients, impairment of kidney function is not uncommon. Recently, the efficacy of the combination of gemcitabine and nab-paclitaxel for pancreatic ductal adenocarcinoma (PDAC) patients has been reported, however, there is no recommendation for dose and administration to patients undergoing hemodialysis (HD). A 66-year-old man began receiving HD for chronic renal failure 4 years previously. He suffered from diarrhea, back pain, and loss of appetite, and his weight gradually decreased. Abdominal dynamic computed tomography showed a 45-mm hypodense mass in the pancreatic body and a 30-mm hypodense mass in the liver. The patient was diagnosed with metastatic PDAC. He started combination chemotherapy of gemcitabine and nab-paclitaxel without dose modification. He developed pneumonia and neutropenia in the first and second courses, so we modified to a 60% dose of gemcitabine and nab-paclitaxel on day 1 every 2 weeks. After dose modification, he continued combination chemotherapy for over 7 months without severe adverse events or tumor progression. Combination chemotherapy using gemcitabine and nab-paclitaxel was effective in a PDAC patient undergoing HD. While it is possible to originally administer these drugs with no dose modification, early dose modification was needed for our patient because of severe adverse events.

412 Background: The standard treatment for intermediate stage hepatocellular carcinoma (HCC) has been transarterial chemoembolization (TACE); however, it might not be suitable for patients (pts) beyond the up-to-7 criteria because of its insufficient efficacy and decline of liver function. Conversely, lenvatinib has shown a good response rate in the phase III trial REFLECT and was considered promising as an initial treatment for patients with BCLC stage B2 HCC. Methods: We conducted a multicenter prospective observational study to evaluate the efficacy of lenvatinib as an initial treatment for pts aged 20 years or older, diagnosed with BCLC stage B2 HCC, naive to TACE, and with preserved organ function. The primary endpoint was a 1-year survival rate, with a threshold of 60% and an expected survival rate of 78% based on previous reports of TACE. With a one-sided alpha error of 5% and a power of 70%, 25 pts were recruited over an enrollment period of 2 years and a follow-up period of 10 months. Results: Enrollment began in June 2018 and was closed with 31 eligible pts enrolled by June 2020. Data cut-off was done in April 2021. Patient characteristics are as follows: the median age was 77 years (range: 57–86); 94% of the pts were male; the etiology of chronic liver disease was hepatitis B virus, hepatitis C virus, alcohol abuse, and others in 3, 6, 9, and 10 pts, respectively; 20 and 11 pts had a Child-Pugh score of 5 and 6 points, respectively; the median maximum tumor diameter was 36 mm (range: 10–135); the number of pts with a tumor number of ≥10 was 8; and the median AFP level was 52.1 ng/mL (range: 2.4–49800). The 1-year survival rate was 71.0% (90% confidence interval [CI]: 68.4–73.6) and the primary endpoint was met. The median overall and progression-free survival was 17.0 months (95% CI, 15.3–19.2) and 10.4 months (95% CI, 6.6–13.8), respectively; the 2-year survival rate was 32.3%. The objective response rate according to RECIT1.1 and mRECIST was 22.6% and 70.0%, respectively. The common adverse events (AEs) were fatigue (68%), hypertension (65%), and anorexia (61%) in any grade, AST increased (23%), ALT increased (16%), and proteinuria (13%) in grade 3 or worse. Treatment interruption and dose reduction was required in 61% and 81% of the pts, respectively. The median relative dose intensity was 61.8% (range: 7.5–100). At the time of analysis, out of 24 pts, 17 (55%), nine (29%), and two (6%) discontinued lenvatinib due to disease progression, AEs, and conversion to curative treatments, respectively. One patient who showed partial response suddenly died during treatment due to unknown reasons. Systemic chemotherapy, TACE, and transarterial infusion therapy was administered in 11 (38%), six (21%) and one (3%) as a post study treatment, respectively. Conclusions: Our study indicates that initial treatment using lenvatinib prolongs the survival of pts with BCLC stage B2 HCC.

The aim of the present study was to evaluate the long-term outcomes and the impact of repeated conventional transarterial chemoembolization (C-TACE) and transarterial chemoembolization with epirubicin-loaded superabsorbent polymer embolics (SAP-TACE) on liver function in TACE-naive patients with unresectable hepatocellular carcinoma (HCC). Overall, 155 consecutive patients with HCC received either C-TACE or SAP-TACE. The first cohort (n=71), treated between 2011 and 2014, received C-TACE; the second cohort (n=84), treated between 2014 and 2016, received SAP-TACE. Overall survival and deterioration of liver function were compared between the two cohorts. The 1-, 2- and 3-year overall survival rates and median survival times were 74, 50, 35% and 26 months in the C-TACE cohort and 75, 60, 39% and 28 months in the SAP-TACE cohort, respectively. There were no significant differences between the two groups (P=0.289). Age

Aims To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). Methods A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. Results The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462). Conclusions Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.

OBJECTIVES This study aimed to assess the lesser known therapeutic benefit, particularly safety and effectiveness of gemcitabine plus nab-paclitaxel (GnP) treatment in elderly patients with advanced pancreatic cancer. METHODS We retrospectively enrolled advanced pancreatic cancer patients aged ≥75 years who received GnP as first-line treatment between December 2014 and December 2016. We assessed survival, adverse events, and early treatment discontinuation. RESULTS The cohort comprised 116 patients (median age, 77 [range, 75-84] years). The overall survival and progression-free survival were 21.8 and 12.1 months in patients with locally advanced cancer and 13.3 and 5.9 months, in patients with metastasis, respectively. The response and disease control rates were 31% and 81%, respectively. Within the first 2 months of treatment, grade 4 hematological and grade 3-4 nonhematological toxicities occurred in 10 and 23 patients, respectively. Early discontinuation due to adverse events occurred in 12 patients; the associated risk factors were age ≥80 years (odds ratio, 9.43) and serum albumin level

The initial symptoms of Crohn's disease (CD) sometimes present as extraintestinal lesions, which can be a diagnostic challenge for physicians. Painful legs, known as "gastrocnemius myalgia syndrome", are rare complications that often precede abdominal manifestations. We herein report the case of a 38-year-old man who presented with bilateral leg myalgia lasting for 4 months. Magnetic resonance imaging showed abnormal intensity, and a muscle biopsy revealed inflammatory cell infiltration. Abdominal symptoms appeared three months after the myalgia onset, and the diagnosis of CD was confirmed later by endoscopic and radiological findings. To our knowledge, this is the first description of gastrocnemius myalgia syndrome in Japan.

The etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P-8) and 4 suggestive loci (P-6) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28×10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus.

711 Background: Therapy options for second-line treatment of advanced pancreatic adenocarcinoma (PDAC) are limited and preferred regimens have not been established. This study compared the efficacy and safety of modified FOLFIRINOX (mFFX) and sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced PDAC. Methods: This was a retrospective single-center analysis of all patients who received mFFX or sequential chemotherapy between December 2014 and May 2019 as second-line treatment for advanced PDAC. The sequential arm included all patients intended to be treated with sequential chemotherapy even if finished with either FOLFIRI or FOLFOX. For efficacy analysis, progression-free survival (PFS), overall survival (OS), and response rate (RR)of all the patients, excluding those with locally advanced pancreatic cancer (LAPC), were evaluated. For safety analysis, we evaluated the incidence of grade ≥3 adverse events in all the patients. Results: Seventy-four patients (mFFX 44; sequential 30) were included.The patients characteristics (mFFX/sequential) are as follows:median age 64/67 years, performance status (ECOG) 0 50%/53%, and LAPC 16%/13%. In contrast to sequential therapy, the mFFX group showed better OS and RR. However, there was no significant difference between mFFX and sequential therapy in PFS (median 4.4 [95% confidence interval (CI) 1.8-7.9] vs. 4.6 [95% CI 2.0-6.2] months; hazard ratio [HR] 0.88 [95% CI 0.51-1.56]; p = 0.657), OS (median 10.6 [95% CI 5.9-13.8] vs. 8.5 [95% CI 5.0-12.2] months; HR 0.71 [95% CI 0.37-1.41]; p = 0.318), and RR (8.1% vs. 3.8%; odds ratio 1.94 [95% CI 0.19-19.87]; p = 1.000). In the safety analysis, grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 36.4%, 6.8%, and 16.0%, respectively, with mFFX and 0%, 0% and 3.3%, respectively, with sequential chemotherapy. Conclusions: Whereas certain trends were observed, there were no significant differences in efficacy between mFFX and sequential chemotherapy. Considering the incidence of grade ≥3 adverse events with mFFX, sequential chemotherapy could be considered as one of the second-line treatment options for advanced PDAC.

Background and aim Currently, non-alcoholic steatohepatitis (NASH) can only be diagnosed histopathologically. Our objective was to establish a new scoring system for the fibrotic stage of NASH. Methods We enrolled 139 patients with histologically proven NASH and divided them into two groups to construct (n = 90) and validate (n = 49) a fibrotic score for NASH (FSN). We used 17 variables and their natural logarithmic transformations in the multivariate analysis. To assess the accuracy of the FSN in determining NASH advanced fibrosis (stages 3–4), we compared various fibrotic scores for NASH. Results In the construct group, multivariate regression analysis ultimately obtained the following function: z = 1.022 × ln (type IV collagen 7S) (ng/mL) − 0.00680 × (platelet count) (×109/L) + 1.925 × ln (AST) (IU/L) − 1.239 × ln (ALT) (IU/L) + 0.249. Median values of the FSN for stages 1, 2, 3 and 4 were 1.87, 2.14, 3.26 and 3.89, respectively. The multiple regression coefficient and coefficient of determination were 0.70 and 0.46, respectively. In the validation group, the median value was 2.00, 2.83, 3.08 and 4.37 in each stage. With regard to the utility of the FSN for predicting advanced fibrosis of NASH (stage ≥3), the area under the receiver operating characteristic curves (AUROC), 0.909 (95 % CI 0.847–0.970, p

Aim Tolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites. Methods Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, five) after adding tolvaptan (3.75–11.25 mg/day) to conventional diuretics. Bodyweights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 days (range, 28–56). Results In the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P

Aim To compare the early virological effectiveness, sustained virological response and safety of telaprevir 1500 mg/day with telaprevir 2250 mg/day, when combined in triple therapy with pegylated interferon and ribavirin in Japanese patients with high viral loads of genotype 1 hepatitis C virus. Methods The telaprevir 2250 mg/day and 1500 mg/day groups each contained 60 patients matched by age, sex and history of previous interferon-based treatment. Serum levels of genotype 1 hepatitis C virus RNA, hemoglobin levels, drug adherence and drug discontinuation rates were monitored during and after triple therapy. Results Patients receiving telaprevir 1500 mg/day had significantly lower telaprevir adherence and lower initial ribavirin dose but similar or superior pegylated interferon and ribavirin adherence and a lower rate of telaprevir discontinuation than did those receiving telaprevir 2250 mg/day. The early virological responses and sustained virological response rates were similar in both groups. Hemoglobin levels decreased to a greater extent in patients treated with telaprevir 2250 mg/day. Conclusion Compared to triple therapy including telaprevir 2250 mg/day, that including telaprevir at a reduced dose of 1500 mg/day was associated with lower rates of anemia and similar antiviral efficacy. Such a regimen may meaningfully improve sustained virological response rates, especially among female and elderly Japanese patients.

AIM Treatment of hepatocellular carcinoma located on the liver surface is frequently difficult because direct puncture of the tumor must be avoided during needle insertion. The aim of this study was to investigate the utility of a no-touch pincer ablation procedure that uses a multipolar radiofrequency ablation (RFA) system for a tumor located on the liver surface. METHODS The experimental animals were three pigs, and RFA was performed with two internally cooled bipolar electrodes. Three ablative procedures were compared: linear insertion at regular 13-mm intervals (pattern 1; virtual target tumor size

The clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir–peginterferon (PEG-IFN)–ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis identified a PEG-IFN dose of IL28B rs8099917 genotype (genotype non-TT), detection of telaprevir-resistant variants of amino acid (aa) 54 at baseline, nonresponse to prior treatment, and a leukocyte count of 3 as significant pretreatment factors for detection of telaprevir-resistant variants at the time of reelevation of the viral load. In 63 patients who showed nonresponse to prior treatment, a higher proportion of patients with no detected telaprevir-resistant variants at baseline (54%) achieved a sustained virological response than did patients with detected telaprevir-resistant variants at baseline (0%). Furthermore, 2 patients who did not have a sustained virological response from the first course of triple therapy with telaprevir received a second course of triple therapy with telaprevir. These patients achieved a sustained virological response by the second course despite the persistence of very-high-frequency variants (98.1% for V36C) or a history of the emergence of variants (0.2% for R155Q and 0.2% for A156T) by ultradeep sequencing. In conclusion, this study indicates that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors. The presence of resistant variants at baseline might partly affect treatment efficacy, especially in those with nonresponse to prior treatment.

Background: The significance of anti-inflammatory therapy has not been fully evaluated in hepatitis C virus (HCV)-related cirrhosis. Patients and Methods: We analyzed stepwise progression rates from cirrhosis to hepatocellular carcinoma (HCC) and to death using a Markov model in 1,280 patients with HCV-related cirrhosis. During the observation period, 303 patients received interferon and 736 received glycyrrhizin injections as anti-inflammatory therapy. Results: In the entire group, annual progression rates from cirrhosis to HCC and from cirrhosis to death were 6.8 and 1.9%, and the rate from HCC to death was 19.0%. When sustained virological response (SVR) or biochemical response (BR) was attained with interferon, the annual rate to HCC decreased to 2.6%. On the contrary, the progression rates to HCC and to death in the patients without SVR and BR were 7.2 and 2.0%, respectively (p < 0.0001). Continuous interferon administration significantly decreased the carcinogenesis rate to 5.5% (p = 0.0087). In the analysis of the remaining patients with high alanine transaminase of 75 IU/l or more but without interferon response or without interferon administration, glycyrrhizin injection significantly decreased annual non-progression probability (no glycyrrhizin 88.0% vs. glycyrrhizin therapy 92.3%, p = 0.00055). Conclusion: Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis.

Background/Aims: The aim of this study was to determine the pharmacodynamics of cisplatin following three different treatment procedures for intrahepatic arterial infusion therapy for hepatocellular carcinoma (HCC). Methods: We divided 13 HCC patients into the following three groups: group A, lone injection of cisplatin (n=3); group B, combined injection of cisplatin and lipiodol, with embolization using small gelatin cubes (GCs) (n=5); and group C, injection of suspended lipiodol with cisplatin powder, with embolization using small GCs (n=5). In each group, the free cisplatin concentration in the hepatic vein was measured at 0, 5, 10, and 30 minutes. Results: The mean free cisplatin concentrations were as follows. For group A, the mean was 48.58 mg/mL at 0 minute, 7.31 mg/mL at 5 minutes, 5.70 mg/mL at 10 minutes, and 7.15 mg/mL at 30 minutes. For the same time points, for group B, the concentrations were 8.66, 4.23, 3.22, and 1.65 mg/mL, respectively, and for group C, the concentrations were 4.81, 2.61, 2.52, and 1.75 mg/mL, respectively. The mean area under the curve (AUC)0-infinity for the free cisplatin concentration was 7.80 in group A, 2.48 in group B, and 2.27 in group C. The AUC0-infinity for the free cisplatin concentration gradually decreased, from group A to group C. Conclusions: These results indicate that the combination of lipiodol and small GCs may be useful for delaying cisplatin drainage from the liver. (Gut Liver 2013;7:576-584)

We report on two cases of hepatocellular carcinoma (HCC) with metastasis to the cavernous sinus and sphenoid sinus. Both cases presented with diplopia and retro-orbital headache and both underwent surgery for a primary pituitary gland tumor. After surgery, both cases were diagnosed with metastases from HCC. Case 1 was a 67-year-old male with a history of HCC who was referred to our hospital for pituitary tumor surgery. The tumor appeared to be in the sella turcica and to invade the sphenoid sinus and right cavernous sinus. Transnasal transsphenoidal surgery (TSS) was performed. The tumor was postoperatively diagnosed by histology to be a metastatic pituitary tumor from HCC. Radiotherapy was administered to the metastatic site. Case 2 was a 58-year-old male with a history of TSS for a pituitary tumor 16 years previously. He was referred to our hospital for TSS for a recurrent pituitary adenoma. TSS was performed twice in 3 months. During a preoperative general examination, HCC and chronic hepatitis B were revealed. TSS was performed initially, followed by arterial infusion chemotherapy. After TSS, the pituitary tumor was diagnosed by histology to be a metastasis from HCC. As with Case 1, radiotherapy was administered to the metastasis. Most tumors in the sella turcica are pituitary adenomas, although some cases of metastatic pituitary tumors and skull base metastases have been reported. Distant metastases generally have a poor prognosis; however, surgery to the metastatic site can effectively control symptoms caused by the metastatic tumor.

The definitive diagnosis of nonalcoholic steatohepatitis (NASH) is currently based on histopathological assessment. This study aimed to elucidate the utility of a novel noninvasive method, three-dimensional magnetic resonance imaging (3D-MRI), for diagnosing advanced fibrosis in patients with NASH, using histopathological diagnosis as the reference standard.This retrospective study included 30 consecutive patients who had been diagnosed with NASH by histopathology and had undergone 3D-MRI before biopsy. 3D-MRI provided a three-dimensional reconstruction of the liver from contrast-enhanced hepatobiliary phase MR images. In the present study, histopathological advanced fibrosis was defined as stage 3 and 4 NASH. Advanced fibrosis, diagnosed by 3D-MRI, was considered to be diffuse irregularity of the entire surface of the liver. The diagnostic features of 3D-MRI and the noninvasive evaluation systems (APRI, FIB-4 index, and BARD score) for identifying advanced and nonadvanced fibrosis of NASH were determined and compared.Nine (30 %) of the 30 study patients were diagnosed histopathologically with advanced fibrosis, and 11 (37 %) of 30 patients were diagnosed with advanced fibrosis using 3D-MRI. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 3D-MRI for diagnosing advanced fibrosis were 100, 90, 82, and 100 %, respectively. The sensitivities of APRI, the FIB-4 index, and BARD score ranged from 78 to 89 %, the specificities from 71 to 90 %, the PPVs from 54 to 78 %, and the NPVs from 88 to 94 %.Compared with the common noninvasive methods for diagnosing advanced fibrosis associated with NASH, 3D-MRI was more accurate.

Aim Patients with unresectable hepatocellular carcinoma (HCC) often undergo transcatheter arterial chemoembolization (TACE). Miriplatin is a lipophilic cisplatin derivative used in TACE that is effective in HCC. However, the difference in antitumor efficacy between warmed versus room temperature miriplatin is unclear. Methods Chemotherapy efficacy was evaluated by dynamic computed tomography 1–3 months after TACE, according to the Modified Response Evaluation Criteria in Solid Tumors. A total of 203 patients with HCC who received TACE with miriplatin for the first time were included in a follow-up study to retrospectively investigate its efficacy and safety. Overall, 45 patients underwent TACE with warmed (40°C) miriplatin and 158 patients received TACE with room temperature miriplatin. Results Seventy patients (44.3%) treated with room temperature miriplatin and 32 patients (71.1%) who received warmed miriplatin experienced complete or partial responses. Multivariate analysis identified miriplatin temperature (warmed miriplatin, risk ratio (RR) = 2.26, P = 0.047), tumor number (solitary, RR = 3.48, P = 0.007), α-fetoprotein (AFP) level (

Objectives: The aim of this study was to generate three-dimensional (3D) images of the ablative zone in patients with hepatocellular carcinoma (HCC) treated with multipolar radiofrequency ablation (RFA) using contrast-enhanced ultrasound (CEUS) and 3DUS and to investigate the shape of the ablative zone among several patterns after insertion of two or three electrodes. Methods: This study included 16 patients and 20 HCCs treated with a multipolar RFA system. All patients underwent CEUS within 14 days after multipolar RFA therapy. The 3D scanning functionality of the LOGIQ E9 US imaging system (GE Healthcare, Milwaukee, Wis., USA), which acquires volume data using a manually controlled sweep on perfusion defects of CEUS, was used in this study to acquire CEUS/3DUS data. The ablative-area shapes resulting from three insertion patterns were investigated, using two electrodes (T20-T20 and T30-T30) or three electrodes (T30-T30-T30). Results: The resulting shapes using two electrodes were globule-like (T20-T20) or elliptical (T30-T30). The shape using three electrodes (T30-T30-T30) was almost ellipse-like but slightly irregular. Conclusions: Generating 3D images using CEUS/3DUS techniques is simple and useful for evaluating the shape of the ablative area, and these images provide informational or educational tools for patients and medical staff associated with multipolar RFA procedures.

Background: Although DC Bead has been useful in treatment of multiple and large hepatocellular carcinoma, loading time of doxorubicin into the DC Bead takes a long time of 30-120 minutes. Epirubicin is also used as an antitumor agent together with DC Bead, but its loading efficiency was not sufficiently elucidated. Methods: To shorten loading time of epirubicin into DC Bead (100-300µm, 300-500µm, 500-700µm), we examined the following three methods after mixing the drug: (a) let stand in room temperature, (b) agitated for 30 seconds with Vortex mixer, and (c) sonicated for 30 seconds with ultrasonic cleaner. After loading of epirubicin by each method, supernatant concentration for epirubicin was assayed at 5, 10, 30, 60, and 120 minutes. Results: Epirubicin loading rates for small bead (100-300µm) at 5 minutes were 82.9 % in group a, 93.8% in group b, and 79.9 % in group c. Similarly, medium bead (300-500µm), 40.1% in group a, 65.7% in group b and 45.5% in group c, respectively. In large-sized bead (500-700µm), loaded rates of epirubicin were 38.8% in group a, 59.0% in group b and 48.0% in group c. Agitation of mixture of epirubicin and DC Bead with Vortex mixer significantly shortened the loading time, but sonication did not affect the time required. Microscopic examination did not lead to any morphological change of microspheres in all the methods. Conclusions: Short time of agitation with Vortex mixer reduced the necessary time for loading of epirubicin in every standard of DC Bead.

Objectives: A randomized controlled trial was conducted to evaluate the efficacy of impedance control of a radiofrequency interstitial thermal ablation system (RITA) used to treat hepatocellular carcinoma (HCC). Methods: Fifteen patients with hypervascular HCCs Results: The median long and short diameters of the axial cross sections of radiofrequency-induced necrotic areas visualized by CT were 32 mm (range, 26-36) and 25 mm (20-31) in group A and 32 mm (28-40) and 31 mm (24-37) in group B, respectively. The short diameter of group B patients was significantly greater than that of group A patients (p = 0.029). The median ablation time was 18.8 min in group A and 13.4 min in group B, thus significantly shorter in group B (p = 0.001). The energy requirement did not differ significantly between the groups. Conclusions: Impedance control of the RITA system resulted in an increased size of the ablation zone and a decreased ablation time.

Tolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites.Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, five) after adding tolvaptan (3.75-11.25 mg/day) to conventional diuretics. Bodyweights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 days (range, 28-56).In the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P 0.004). The numbers of good responders (≥3 kg reduction in 4 days), responders (3 kg weight reduction) and non-responders (no weight reduction) were seven (46.7%), six (40.0%) and two of the 15 (13.3%), respectively. The two non-responders had concomitant chylous pleural effusion or spontaneous bacterial peritonitis. All patients continued tolvaptan for 2 weeks or longer and six (40%, three good responders and three responders) were treated for a median of 42 days without additional intervention. During this intermediate-term administration of tolvaptan, the median weight reduction was statistically significant (65.4, 61.9 and 56.9 kg on days 0, 7 and 42, respectively; P 0.030) and there was no serum sodium imbalance or renal dysfunction; but two of these six developed hepatic coma.Tolvaptan safely alleviated fluid retention caused by hepatic cirrhosis. Intermediate-term administration of tolvaptan apparently helped maintain weight reduction achieved during the introduction phase.

Background & Aims Genome-wide association studies (GWAS) recently indicated that polymorphisms in the human leucocyte antigen (HLA)-DP genes were associated with risk of persistent hepatitis B virus (HBV) infection and clearance of HBV, but the effect of HLA-DP gene polymorphisms on the effect of antiviral therapy was unknown. We here investigated whether such polymorphisms were associated with decreases in HBsAg levels and seroclearance in patients who received long-term lamivudine (LAM) treatment. Methods Japanese patients (202) who were hepatitis B e antigen positive at baseline, received LAM as first-line treatment, and consented to HLA-DP genotyping (HLA-DPA1 rs3077 and HLA-DPB1 rs9277535) were categorized into two cohorts, viz., a cohort who achieved virological response without rescue therapy (cohort 1) and those who did so with rescue therapy (cohort 2). Results Serum HBsAg levels declined significantly between year 3 and 9 from baseline among cohort 1 patients possessing ≥2 A-alleles at rs3077 and rs9277535. The percentages of such patients in cohort 1 patients with decreases in HBsAg ≥0.5 log IU/ml were higher than those with

To compare the early virological effectiveness, sustained virological response and safety of telaprevir 1500 mg/day with telaprevir 2250 mg/day, when combined in triple therapy with pegylated interferon and ribavirin in Japanese patients with high viral loads of genotype 1 hepatitis C virus.The telaprevir 2250 mg/day and 1500 mg/day groups each contained 60 patients matched by age, sex and history of previous interferon-based treatment. Serum levels of genotype 1 hepatitis C virus RNA, hemoglobin levels, drug adherence and drug discontinuation rates were monitored during and after triple therapy.Patients receiving telaprevir 1500 mg/day had significantly lower telaprevir adherence and lower initial ribavirin dose but similar or superior pegylated interferon and ribavirin adherence and a lower rate of telaprevir discontinuation than did those receiving telaprevir 2250 mg/day. The early virological responses and sustained virological response rates were similar in both groups. Hemoglobin levels decreased to a greater extent in patients treated with telaprevir 2250 mg/day.Compared to triple therapy including telaprevir 2250 mg/day, that including telaprevir at a reduced dose of 1500 mg/day was associated with lower rates of anemia and similar antiviral efficacy. Such a regimen may meaningfully improve sustained virological response rates, especially among female and elderly Japanese patients.

It is often difficult to predict the response to telaprevir-pegylated interferon (PEG-IFN)-ribavirin triple therapy and the appearance of telaprevir-resistant variants. The present study determined the predictive factors of a sustained virological response (SVR) to 12- or 24-week triple therapy (T12PR12 or T12PR24, respectively) in 194 Japanese patients infected with hepatitis C virus genotype 1b (HCV-1b). The study also evaluated whether ultradeep sequencing technology can predict at baseline the emergence of resistant variants after the start of therapy. Analysis of the data of the entire group indicated that an SVR was achieved in 78% of the patients. Multivariate analysis identified IL28B rs8099917 (genotype TT), the substitution of amino acid (aa) 70 (Arg70), response to prior treatment (naive or relapse), PEG-IFN dose (≥1.3 μg/kg of body weight), and treatment regimen (T12PR24) as significant determinants of SVR. Among patients of the T12PR24 group, 92% with genotype TT achieved an SVR, irrespective of a substitution at aa 70. In patients with the non-TT genotype, an SVR was achieved in 76% of those with Arg70, while only 14% of patients with the non-TT genotype, Gln70(His70), and nonresponse to ribavirin combination therapy achieved an SVR. Ultradeep sequencing was conducted for 17 patients who did not achieve an SVR to determine the emergence of resistant variants during therapy. De novo resistant variants were detected in 16 of 17 patients (94%), regardless of the variant frequencies detected at baseline. In conclusion, the results indicate that the response to triple therapy can be predicted by the combination of host, viral, and treatment factors and that it is difficult to predict at baseline the telaprevir-resistant variants that emerge during triple therapy, even with the use of ultradeep sequencing.