Lenvatinib radiofrequency ablation sequential therapy offers survival benefits for patients with unresectable hepatocellular carcinoma at intermediate stage and the liver reserve of Child-Pugh A category: A multicenter study.

AIM: This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients. METHODS: One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child-Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy. RESULTS: After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin-bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186-0.782), 2.220 (95% CI, 1.410-3.493), and 0.982 (95% CI, 0.966-0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176-0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215-0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p < 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed. CONCLUSION: Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.

Risk assessment of metachronous gastric cancer after endoscopic submucosal dissection based on endoscopic intestinal metaplasia.

Background and Aim: The incidence of metachronous gastric cancer (MGC) after endoscopic treatment for early gastric cancer (EGC) is high, but a method of risk assessment for MGC based on endoscopic findings has not been established. In this study, we focused on endoscopic intestinal metaplasia (IM) and investigated the risk for MGC after endoscopic submucosal dissection (ESD) for EGC. Methods: This retrospective observational study involved patients who underwent curative ESD for EGC from April 2015 to January 2021. We assessed endoscopic IM using the pretreatment endoscopic examination images. The severity of endoscopic IM was classified into four levels: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Four different gastric areas were evaluated. We divided the patients into a low-score group and a high-score group, and compared the cumulative incidence of MGC. Results: In total, 156 patients who met the inclusion criteria were followed up for at least 12 months after ESD, and MGC developed in 14 patients during a mean period oof 41.5 months. The endoscopic IM scores in the lesser curvature of the antrum, lesser curvature of the corpus, and greater curvature of the corpus were higher in patients with MGC than in those without MGC. In the corpus, the 5-year cumulative incidence of MGC was significantly higher in the high-score group than in the low-score group (29.8% vs 10.0%, P = 0.004). Conclusion: The severity of endoscopic corpus IM was associated with MGC. Thus, patients with severe corpus IM at the time of ESD require careful examination and intensive follow-up.

The Origin of Epithelium with Low-Grade Atypia in Early Gastric Cancer.

INTRODUCTION: Helicobacter pylori (HP) infection causes chronic inflammation and atrophy of the gastric mucosa and thus a high risk of gastric cancer (GC). With the increasing success of HP infection treatment, a larger number of GCs that develop after eradication can be assessed. Several studies have shown that epithelium with low-grade atypia (ELA) is a frequent characteristic of these GCs, but the origin of this condition is unknown. In this study, we compared the mucin phenotype, cellular proliferation, and p53 staining in ELA and cancerous tissues obtained from patients with GC with and without HP eradication. METHODS: The study population consisted of 23 patients with GC that developed after successful HP eradication therapy (eradicated group) and 24 patients with GC and HP infection (infected group). The prevalence of ELA was determined by hematoxylin and eosin staining. Tumor tissue and ELA samples were further analyzed by immunohistochemical staining for Muc5AC, Muc2, p53, and Ki-67. RESULTS: The ELA coverage rate was significantly higher in the eradicated group than in the infected group. Gastric-type mucin was frequently expressed by the ELA, and the mucin phenotypes of ELA and cancerous areas differed in 75% of cases. The Ki-67 labeling index was consistently lower in ELA than in the cancerous mucosa. Fourteen of 21 (66.7%) cancerous lesions, but only 3 ELA samples, were p53-positive. CONCLUSION: In most cases, ELA on the surfaces of GCs seems to have originated from normal gastric cells, not from cancer cells.

Severe anaphylaxis caused by intravenous anti-cancer drugs.

BACKGROUND: The incidence and risk factors of severe anaphylaxis by intravenous anti-cancer drugs are unclear, whereas those of milder reactions have been reported. STUDY DESIGN: Electronic medical charts of cancer patients who have undergone intravenous chemotherapy between January 2013 and October 2020 in a university hospital were retrospectively reviewed. Non-epithelial malignancies were also included in the analysis. "Severe anaphylaxis" was judged using Brown's criteria: typical presentation of anaphylaxis and one or more of hypoxia, shock, and neurologic compromise. (UMIN000042887). RESULTS: Among 5584 patients (2964 males [53.1%], 2620 females [46.9%], median age 66 years), 88,200 person-day anti-cancer drug administrations were performed intravenously, and 27 severe anaphylaxes were observed. The causative drugs included carboplatin (14 cases), paclitaxel (9 cases), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each). The person-based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%-0.67%) and the administration-based incidence was 0.031% (27/88,200, 95% CI 0.019%-0.043%). Among 124 patients who received at least 10 carboplatin administrations, 10 patients experienced carboplatin-induced severe anaphylaxis (10/124, 8.1%, 95% CI 3.0%-13.1%). Carboplatin caused severe anaphylaxis after at least 9-min interval since the drip started. Thirteen out of 14 patients experienced carboplatin-induced severe anaphylaxis within a 75-day interval from the previous treatment. Paclitaxel infusion caused severe anaphylaxis after a median of 5 min after the first drip of the day at a life-long incidence of 0.93% (9/968, 95% CI 0.27%-1.59%). CONCLUSION: We elucidated the high-risk settings of chemotherapy-induced severe anaphylaxis.

NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition, affecting up to 25% of the population worldwide. NAFLD has been linked to several conditions, including hepatic inflammation, fibrosis, and hepatocellular carcinoma (HCC), however the role of NAFLD in cholangitis and the development of cholangiocellular carcinoma (CCC) remains poorly understood. This study investigated whether a high-fat diet (HFD) promotes cholangitis and the development of CCC in mice. We used liver-specific E-cadherin gene (CDH1) knockout mice, CDH1∆Liv , which develop spontaneous inflammation in the portal areas along with periductal onion skin-like fibrosis, similar to that of primary sclerosing cholangitis (PSC). An HFD or normal diet (ND) was fed to CDH1∆Liv mice for 7 mo. In addition, CDH1∆Liv mice were crossed with LSL-KrasG12D mice, fed an HFD, and assessed in terms of liver tumor development. The extent of cholangitis and number of bile ductules significantly increased in mice fed an HFD compared with ND-administered CDH1∆Liv mice. The numbers of Sox9 and CD44-positive stem cell-like cells were significantly increased in HFD mice. LSL-KrasG12D /CDH1∆Liv HFD mice exhibited increased aggressiveness along with the development of numerous HCC and CCC, whereas LSL-KrasG12D /CDH1∆Liv ND mice showed several macroscopic tumors with both HCC and CCC components. In conclusion, NAFLD exacerbates cholangitis and promotes the development of both HCC and CCC in mice.

Safety and Efficacy of Lenvatinib Treatment in Child-Pugh A and B Patients with Unresectable Hepatocellular Carcinoma in Clinical Practice: A Multicenter Analysis.

PURPOSE: 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.

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).

Pembrolizumab-induced secondary sclerosing cholangitis in a non-small cell lung cancer patient.

A 50-year-old woman with stage IV lung adenocarcinoma received seven cycles of pembrolizumab as third-line chemotherapy. Following the failure of pembrolizumab, she commenced fourth-line chemotherapy of docetaxel and ramucirumab. The patient complained of epigastric pain and a computed tomography (CT) scan revealed oedema-like thickening of the gallbladder wall, dilation of the bile ducts from the common to the intrahepatic bile ducts, and thickening of the common bile duct wall without any visible obstructions. Accumulation of fluorodeoxyglucose (FDG) in the gallbladder wall and bile duct was also detected with positron emission tomography (PET)-CT. A biopsy of the extrahepatic bile duct showed non-specific inflammation. Antibiotic treatment was not effective and pathogens were not detected. The patient was diagnosed with secondary sclerosing cholangitis (SSC) by pembrolizumab. She received 80 mg/day of prednisolone (PSL); however, SSC recurred with tapering of PSL. SSC then improved with steroid pulse therapy and subsequently 50 mg/day azathioprine and 80 mg/day PSL.

Loss of Pancreatic E-Cadherin Causes Pancreatitis-Like Changes and Contributes to Carcinogenesis.

BACKGROUND & AIMS: E-cadherin (Cdh1) is a key molecule for adherence required for maintenance of structural homeostasis. Loss of E-cadherin leads to poor prognosis and the development of resistance to chemotherapy in pancreatic cancer. Here, we evaluated the physiological and pathologic roles of E-cadherin in the pancreas. METHODS: We crossbred Ptf1a-Cre mice with Cdh1f/f mice to examine the physiological roles of E-cadherin in the pancreas. In addition, we crossbred these mice with LSL-KrasG12D/+ mice (PKC) to investigate the pathologic roles of E-cadherin. We also generated a tamoxifen-inducible system (Ptf1a-CreERT model). Organoids derived from these models using lentiviral transduction were analyzed for immunohistochemical features. Established cell lines from these organoids were analyzed for migratory and invasive activities as well as gene expression by complementary DNA microarray analyses. RESULTS: None of the Ptf1a-Cre mice crossbred with Cdh1f/f mice survived for more than 28 days. We observed aberrant epithelial tubules that resembled the structure of acinar-to-ductal metaplasia after postnatal day 6, showing features of pancreatitis. All of the PKC mice died within 10 days. We observed tumorigenicity with increasing stroma-like aggressive tumors. Ptf1a-CreERT models showed that deletion of E-cadherin led to earlier pancreatic intraepithelial neoplasm formation. Cells established from PKC organoids had greater migratory and invasive activities, and these allograft tumors showed a poorly differentiated phenotype. Gene expression analysis indicated that Hdac1 was up-regulated in PKC cell lines and a histone deacetylase 1 inhibitor suppressed PKC cell proliferation. CONCLUSIONS: Under physiological conditions, E-cadherin is important for maintaining the tissue homeostasis of the pancreas. Under pathologic conditions with mutational Kras activation, E-cadherin plays an important role in tumor formation via the acquisition of tumorigenic activity.

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.

Differential diagnosis of gallbladder polypoid lesions using contrast-enhanced ultrasound.

PURPOSE: The purpose of the study is to evaluate the utility of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of gallbladder polypoid lesions (GPLs). METHODS: Thirty-six patients with GPLs (17 with gallbladder cancer, 19 with benign polyps) who underwent CEUS were enrolled in the study. The mean age of patients was 65.7 ± 12.6 years. Perflubutane-based contrast agent and high-mechanical index mode, which can eliminate the background B-mode and provide precise visualization of tumor vessels, were used for CEUS, and two blinded readers evaluated the images, retrospectively. RESULTS: Patient age and size of malignant GPLs (72.4 ± 9.4 years and 23.4 ± 7.5 mm) were significantly greater than those for benign lesions (59.6 ± 12.3 years and 12.4 ± 2.9 mm) (P < 0.01, respectively), and the receiver operating characteristic analysis showed the cut-off value as over 65 years and 16 mm. Univariate analysis showed that heterogeneity in B-mode (80% [12/15]), sessile shape (76% [13/17]), dilated vessel (71% [12/17]), irregular vessel (82% [14/17]), and heterogeneous enhancement (59% [10/17]) on CEUS were significantly correlated with malignant GPLs (P < 0.01, respectively). On CEUS, the diagnostic criterion for malignant GPLs was defined as having one or more of the above four features because of the highest accuracy. Sensitivity, specificity, and accuracy for malignant GBLs were 88%, 68%, and 78% for patient age; 76%, 89%, and 83% for size of GPLs; 80%, 68%, and 74% for B-mode; and 94%, 89%, and 92% for CEUS, respectively. CONCLUSIONS: CEUS is useful for the differential diagnosis of malignant and benign GPLs.

Activation of Signal Transduction and Activator of Transcription 3 Signaling Contributes to Helicobacter-Associated Gastric Epithelial Proliferation and Inflammation.

BACKGROUND/AIM: Although IL-6-mediated activation of the signal transduction and activator of transcription 3 (STAT3) axis is involved in inflammation and cancer, the role of STAT3 in Helicobacter-associated gastric inflammation and carcinogenesis is unclear. This study investigated the role of STAT3 in gastric inflammation and carcinogenesis and examined the molecular mechanism of Helicobacter-induced gastric phenotypes. METHODS: To evaluate the contribution of STAT3 to gastric inflammation and carcinogenesis, we used wild-type (WT) and gastric epithelial conditional Stat3-knockout (Stat3Δgec ) mice. Mice were infected with Helicobacter felis and euthanized at 18 months postinfection. Mouse gastric organoids were treated with recombinant IL-6 (rIL-6) or rIL-11 and a JAK inhibitor (JAKi) to assess the role of IL-6/STAT3 signaling in vitro. RESULTS: Inflammation and mucous metaplasia were more severe in WT mice than in Stat3Δgec mice. The epithelial cell proliferation rate and STAT3 activation were increased in WT mice. Application of rIL-6 and rIL-11 induced expression of intestinal metaplasia-associated genes, such as Tff2; this induction was suppressed by JAKi administration. CONCLUSIONS: Loss of STAT3 signaling in the gastric mucosa leads to decreased epithelial cell proliferation, atrophy, and metaplasia in the setting of Helicobacter infection. Therefore, activation of STAT3 signaling may play a key role in Helicobacter-associated gastric carcinogenesis.

Fusion imaging with contrast-enhanced ultrasonography for evaluating the early therapeutic efficacy of radiofrequency ablation for small hypervascular hepatocellular carcinomas with iso-echoic or unclear margins on conventional ultrasonography.

PURPOSE: We evaluated the efficacy of fusion imaging combining contrast-enhanced ultrasonography (CEUS) images and arterial phase contrast-enhanced CT (CECT) or hepatobiliary phase magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (EOB-MRI) images for the early evaluation of the effectiveness of radiofrequency ablation (RFA) for small hypervascular hepatocellular carcinoma (HCC) with iso-echoic or unclear margins on conventional US. METHODS: Forty HCCs (22 iso-echoic and 18 unclear margin lesions) with mean diameters of 13.7 mm were treated using RFA under the guidance of fusion imaging with CEUS. The adequacy of RFA was evaluated using fusion imaging with CEUS 1 day after RFA. CECT or EOB-MRI was performed 1 month after RFA. We reviewed the images obtained using both modalities. RESULTS: When the 1-month CECT or EOB-MRI scans were used as the reference standard, the sensitivity, specificity, and accuracy of the 1-day fusion imaging for the diagnosis of the adequate ablation of these HCCs were 97, 100, and 98%, respectively; the kappa value for the agreement between the findings using the two modalities was 0.655. CONCLUSION: Fusion imaging with CEUS appears to be a useful method for the early evaluation of the efficacy of RFA for the treatment of HCCs with iso-echoic or unclear margins on conventional US.

Phase II study of fixed dose-rate gemcitabine plus S-1 as a second-line treatment for advanced biliary tract cancer.

PURPOSE: Gemcitabine plus platinum is considered standard first-line chemotherapy for patients with advanced biliary tract cancer. However, no standard second-line therapy has been established for this disease. According to reports, S-1 exerts anti-tumor effects on advanced biliary tract cancer and gemcitabine is more effective via fixed dose-rate administration. We evaluated the efficacy and safety of a combination of fixed dose-rate gemcitabine and S-1 after failure of gemcitabine or gemcitabine plus cisplatin therapy. METHODS: This single-arm phase II study (clinical trial number: UMIN000005918) set the response rate as the primary endpoint and used a MiniMax two-stage design with a null hypothesis < 7% and alternative hypothesis ≥ 25%. Thirty-five patients were needed to yield a power of 90% and α value of 0.05. Patients received gemcitabine (1000 mg/m2, div, 100-min period, day 1) and S-1 (40 mg/m2 twice daily, oral, days 1-7), every 2 weeks until disease progression or intolerable adverse events were observed. RESULTS: Forty-one patients were enrolled, and 3 of 23 first-stage patients responded. The overall response rate was 9.8% [95% confidence interval (CI): 2.7-19.2%]. The median overall and progression-free survival were 7.0 [95% CI: 5.3-8.6] and 2.6 months (95% CI: 1.6-3.5), respectively. The most common grade 3-4 adverse events were leukopenia (19.5%), neutropenia (19.5%), anemia (14.6%), thrombocytopenia (7.3%), and anorexia (4.8%). CONCLUSION: Second-line fixed dose-rate gemcitabine plus S-1 was not sufficiently effective and tolerable in patients with advanced biliary tract cancer refractory to gemcitabine or gemcitabine plus cisplatin.

Switch to miriplatin for multinodular hepatocellular carcinoma unresponsive to transarterial chemoembolization with epirubicin: a prospective study.

OBJECTIVE: The aim of this prospective study was to evaluate the efficacy of transarterial chemoembolization using miriplatin, a platinum-based anticancer drug, as a retreatment regimen for hepatocellular carcinoma (HCC) unresponsive to chemoembolization using epirubicin. METHODS: Between April 2013 and December 2014, we enrolled 57 consecutive chamoembolization-naïve patients with unresectable HCC, and performed chemoembolization with epirubicin. Treatment effect, necrotizing rate of the target nodules, was evaluated at 1-3 months after treatment using contrast-enhanced CT or MRI. We subsequently included retreatment chemoembolization with miriplatin for patients whose treatment effect was <50% after chemoembolization with epirubicin. The treatment effect after chemoembolization with miriplatin and the liver function before and after chemoembolization were evaluated. RESULTS: Eighteen patients of the 57 showed a treatment effect <50% after chemoembolization with epirubicin, and were switched to chemoembolization with miriplatin. The treatment effect after chemoembolization with miriplatin was ≥50% in four (22%) patients. Four of the remaining 14 (78%) patients who had <50% necrosis exhibited deterioration of the liver function after chemoembolization with miriplatin. Univariate analysis indicated that an alpha-fetprotein-L3 level <10% and a serum albumin level ≥3.6 g/dl were predictive factors of therapeutic response after chemoembolization with miriplatin (P < 0.05). However, there was no predictive factor regarding the deterioration of liver function after chemoembolization with miriplatin. CONCLUSIONS: In unresectable HCC patients who were unresponsive to chemoembolization with epirubicin, switching the chemotherapeutic regimen to a platinum-based anticancer drug in retreatment chemoembolization should be considered as a treatment option. Trial registration: UMIN 000015887.

Short-term efficacy of transarterial chemoembolization with epirubicin-loaded superabsorbent polymer microspheres for hepatocellular carcinoma: comparison with conventional transarterial chemoembolization.

PURPOSE: This study aimed to compare the short-term efficacy of transarterial chemoembolization (TACE) with epirubicin-loaded superabsorbent polymer embolics (SAP) and conventional TACE in TACE-naïve patients with unresectable hepatocellular carcinoma (HCC). METHODS: Fifty consecutive patients (mean age, 72.8 years; hepatitis C, 46%; BCLC-A or B, 52% or 48%) treated with TACE with SAP during 2013-2015 and 55 consecutive patients (mean age, 71.8 years; hepatitis C, 40%; BCLC-A or B, 51% or 49%) treated with conventional TACE during 2011-2013 were evaluated. Safety evaluations were based on CTCAE ver. 4.0. Short-term efficacies, i.e., at 1 month after TACE, were assessed using the European Association for the Study of the Liver criteria. Overall survival rates were calculated using the Kaplan-Meier method. Short-term response markers were analyzed by univariate and multivariate analyses. RESULTS: There was no significant difference in the incidence of any grade of adverse events. The objective response rates were 50% and 62% in patients treated with TACE with SAP and with conventional TACE, respectively (P = 0.358). The overall survival rates were not significantly different (P = 0.810); the 1-year survival rates and the median survival time of the patients treated with TACE with SAP and with conventional TACE were 76% and 74%, and 18 months and 21 months, respectively. Overall survival was related to the short-term response. An alpha-fetoprotein level <1,000 ng/mL was a significant short-term response marker on multivariate analysis. CONCLUSIONS: For TACE-naïve patients, TACE with SAP and conventional TACE had comparable safety and short-term efficacies.

Duodenal stenting followed by systemic chemotherapy for patients with pancreatic cancer and gastric outlet obstruction.

OBJECTIVES: Endoscopic duodenal stenting has recently been proposed as a substitute for surgical gastrojejunostomy for the treatment of gastric outlet obstruction. We aimed to evaluate the efficacy and safety of duodenal stenting followed by systemic chemotherapy for patients with advanced pancreatic cancer with gastric outlet obstruction. METHODS: This was a single-center, retrospective cohort study, conducted at an academic medical center, of 71 patients with advanced pancreatic cancer and gastric outlet obstruction (mean age: 67.6 years; range: 31-92 years) who underwent duodenal stenting with or without subsequent chemotherapy. Overall survival, duration of oral intake of foods, the rate of introduction of chemotherapy, progression-free survival, and adverse events were evaluated. RESULTS: Stent placement was technically successful in 69 (97%) patients. Thirty-six (51%) patients were treated with chemotherapy: 17 with gemcitabine alone, 15 with S-1 alone, 3 with FOLFIRINOX, and 1 with paclitaxel. Median progression-free survival and overall survival after chemotherapy were 2.6 months (95% confidence interval: 1.3-3.9 months) and 4.7 months (95% confidence interval: 2.6-6.8 months), respectively. Cases of grade 3 anemia were frequently observed during chemotherapies following duodenal stenting (32%). Tumor stage, performance status, neutrophil-to-lymphocyte ratio, and introduction of chemotherapy were independent prognostic factors for survival (hazard ratios of 3.73, 2.21, 2.69, and 1.85 with p-values of <0.001, 0.010, <0.001, and 0.045, respectively). CONCLUSIONS: The findings of this study suggest that endoscopic duodenal stenting is an advantageous treatment in advanced pancreatic cancer patients with gastric outlet obstruction regarding its safety and smooth conduction of subsequent chemotherapies.

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer.

OBJECTIVE: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated. METHODS: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m2/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m2/day (n = 27 vs. 28) in the GS arm. RESULTS: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively. CONCLUSIONS: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

Potential prognostic significance of a new proteomic profile in patients with advanced pancreatic adenocarcinoma.

OBJECTIVES: Seven-signal proteomic approach has recently been developed as a new proteomic profile measured by matrix-assisted laser desorption/ionization mass spectrometry. The aim of this study was to evaluate prognostic significance of this proteomic value in patients with pancreatic adenocarcinoma. METHODS: Blood samples from the patients with pancreatic adenocarcinoma were prospectively collected before treatments including surgical resection and systemic chemotherapies. The seven-signal proteomic profiles of the samples were measured, and the prognostic significance of the proteomic value was evaluated through comparison with other existing prognostic markers. RESULTS: Cut-off value of the proteomic profiles at 52 stratified overall prognosis of the patients (6.5 months vs. 10.9 months with the values ≥52 vs. <52, p = 0.020). In subgroup analyses of inoperable cases with carcinoembryonic antigen level of <5 ng/ml or performance status of 0-1, the proteomic value at 52 stratified their prognosis (p = 0.002 and p = 0.006, respectively). CONCLUSIONS: The new seven-signal proteomics showed useful prognostic significance for patients with pancreatic adenocarcinoma. Further studies with a large sample size would be required to evaluate whether this proteomic approach possibly complements the existing parameters, such as carcinoembryonic antigen and performance status.