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Background: Chemotherapy-induced nausea and vomiting (CINV) are common side effects, classified according to timing and severity. Conventional agents such as dexamethasone are effective but have various side effects. For moderately emetogenic chemotherapy, dexamethasone-sparing antiemetic therapies have been developed to minimize these side effects. This systematic review evaluated the efficacy and safety of dexamethasone-sparing antiemetic therapy for highly emetogenic chemotherapy (HEC)., Methods: We performed a thorough literature search for studies related to dexamethasone-sparing antiemetic therapy with neurokinin-1 antagonists (NK 1 RA) for HEC using the PubMed, Cochrane Library, and Ichushi-Web databases. A qualitative analysis of the combined data was performed and risk differences with confidence intervals were calculated., Results: Two reviewers independently assessed the 425 records and 12 full-text articles were evaluated for eligibility. Two studies were included in the qualitative and meta-analyses. These studies included anthracycline-cyclophosphamide (AC) regimens and cisplatin-based regimens, with palonosetron as the serotonin receptor antagonist. In the two studies, no difference was found in the prevention of vomiting (delayed complete response). However, non-inferiority was not demonstrated in the subgroup that received cisplatin-containing regimens. Delayed complete control showed different results for nausea prevention; however, there was no significant difference in the meta-analysis. Only one report has shown non-inferiority for delayed total control. Although the strength of evidence for individual outcomes varied, there was no difference in the duration of dexamethasone administration., Conclusions: This systematic review and meta-analysis revealed that dexamethasone-sparing antiemetic therapy with NK 1 RA and palonosetron can be used to prevent CINV in HEC, limited to AC combination therapy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Chemotherapy-induced nausea and vomiting (CINV) commonly affects patient quality of life and the overall effectiveness of chemotherapy. This study aimed to evaluate whether adding neurokinin-1 receptor antagonists (NK1RAs) to 5-hydroxytryptamine-3 receptor antagonists (5-HT 3 RAs) and corticosteroids provides clinically meaningful benefits in preventing CINV in patients receiving moderately emetogenic chemotherapy (MEC)., Methods: We conducted a systematic review of PubMed, Cochrane Library, and Ichushi-Web to identify clinical studies evaluating NK1RAs combined with 5-HT 3 RAs and dexamethasone for managing CINV in MEC. The endpoints were complete response (CR), complete control (CC), total control (TC), adverse events, and costs. The data were analyzed using a random effects model., Results: From 142 articles identified, 15 randomized controlled trials (RCTs), involving 4,405 patients, were included in the meta-analysis. Approximately 60% of the patients received carboplatin (CBDCA)-based chemotherapy. The meta-analysis showed that triplet antiemetic prophylaxis with NK1RA was significantly more effective for achieving CR than doublet prophylaxis in each phase. Regarding CC, the triplet antiemetic prophylaxis was significantly more effective than the doublet in the overall (risk difference [RD]: 0.11, 95% confidence interval [CI]: 0.06-0.17) and delayed (RD: 0.08, 95% CI: 0.02-0.13) phases. For TC, no significant differences were observed in any phase. Adding NK1RA did not cause adverse events., Conclusions: Adding NK1RA to CBDCA-based chemotherapy has shown clinical benefits. However, the clinical benefits of NK1RA-containing regimens for overall MEC have not yet been established and require RCTs that exclusively evaluate MEC regimens other than CBDCA-based chemotherapy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Anticipatory chemotherapy-induced nausea and vomiting (CINV) is a conditioned response influenced by the severity and duration of previous emetic responses to chemotherapy. We aimed to evaluate the efficacy of non-pharmacologic interventions for anticipatory CINV among patients with cancer., Methods: We conducted a systematic search in databases, including PubMed, the Cochrane Library, CINAHL, and Ichushi-Web, from January 1, 1990, to December 31, 2020. Randomized controlled trials, non-randomized designs, observational studies, or case-control studies that utilized non-pharmacological therapies were included. The primary outcomes were anticipatory CINV, with an additional investigation into adverse events and the costs of therapies. The risk-of-bias for each study was assessed using the Cochrane risk-of-bias tool, and meta-analysis was performed using Revman 5.4 software., Results: Of the 107 studies identified, six met the inclusion criteria. Three types of non-pharmacological treatments were identified: systematic desensitization (n = 2), hypnotherapy (n = 2), and yoga therapy (n = 2). Among them, systematic desensitization significantly improved anticipatory CINV as compared to that in the control group (nausea: risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.49-0.72, p < 0.00001; vomiting: RR = 0.54, 95% CI = 0.32-0.91, p = 0.02). However, heterogeneity in outcome measures precluded meta-analysis for hypnotherapy and yoga. Additionally, most selected studies had a high or unclear risk of bias, and adverse events were not consistently reported., Conclusions: Our findings suggest that systematic desensitization may effectively reduce anticipatory CINV. However, further research is warranted before implementation in clinical settings., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: The Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis 2023 was extensively revised to reflect the latest advances in antineoplastic agents, antiemetics, and antineoplastic regimens. This update provides new evidence on the efficacy of antiemetic regimens., Methods: Guided by the Minds Clinical Practice Guideline Development Manual of 2017, a rigorous approach was used to update the guidelines; a thorough literature search was conducted from January 1, 1990, to December 31, 2020., Results: Comprehensive process resulted in the creation of 13 background questions (BQs), 12 clinical questions (CQs), and three future research questions (FQs). Moreover, the emetic risk classification was also updated., Conclusions: The primary goal of the present guidelines is to provide comprehensive information and facilitate informed decision-making, regarding antiemetic therapy, for both patients and healthcare providers., (© 2024. The Author(s).)

Aim: Patients with cancer experience various forms of psychological distress, including depressive symptoms, which can impact quality of life, elevate morbidity risk, and increase medical costs. Psychotherapy and pharmacotherapy are effective for reducing depressive symptoms among patients with cancer, but most patients prefer psychotherapy. This study aimed to develop an efficient and effective smartphone psychotherapy component to address depressive symptom., Methods: This was a decentralized, parallel-group, multicenter, open, individually randomized, fully factorial trial. Patients aged ≥20 years with cancer were randomized by the presence/absence of three cognitive-behavioral therapy (CBT) skills (behavioral activation [BA], assertiveness training [AT], and problem-solving [PS]) on a smartphone app. All participants received psychoeducation (PE). The primary outcome was change in the patient health questionnaire-9 (PHQ-9) total score between baseline and week 8. Secondary outcomes included anxiety., Results: In total, 359 participants were randomized. Primary outcome data at week 8 were obtained for 355 participants (99%). The week 8 PHQ-9 total score was significantly reduced from baseline for all participants by -1.41 points (95% confidence interval [CI] -1.89, -0.92), but between-group differences in change scores were not significant (BA: -0.04, 95% CI -0.75, 0.67; AT: -0.16, 95% CI -0.87, 0.55; PS: -0.19, 95% CI -0.90, 0.52)., Conclusion: As the presence of any of the three intervention components did not contribute to a significant additive reduction of depressive symptoms, we cannot make evidence-based recommendations regarding the use of specific smartphone psychotherapy., (© 2024 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

The aim of this study was to evaluate the clinical validity of monitoring urine pellet DNA (upDNA) of bladder cancer (BC) by digital PCR (dPCR) as a biomarker for early recurrence prediction, treatment efficacy evaluation, and no-recurrence corroboration. Tumor panel sequencing was first performed to select patient-unique somatic mutations to monitor both upDNA and circulating tumor DNA (ctDNA) by dPCR. For longitudinal monitoring using upDNA as well as plasma ctDNA, an average of 7.2 (range, 2 to 12) time points per case were performed with the dPCR assay for 32 previously treated and untreated patients with BC. Clinical recurrence based on imaging and urine cytology was compared using upDNA variant allele frequency (VAF) dynamics. A continuous increasing trend of upDNA VAF ≥1% was considered to indicate molecular recurrence. Most (30/32; 93.8%) cases showed at least one traceable somatic mutation. In 5 of 7 cases (71.4%) with clinical recurrence, upDNA VAF >1% was detected 7 to 15 months earlier than the imaging diagnosis. The upDNA VAF remained high after initial treatment for locally recurrent cases. The clinical validity of upDNA monitoring was confirmed with the observation that 26 of 30 cases (86.7%) were traceable. Local recurrences were not indicated by ctDNA alone. The results support the clinical validity of upDNA monitoring in the management of recurrent BC., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Biomarkers that could detect the postoperative recurrence of upper tract urothelial carcinoma (UTUC) have not been established. In this prospective study, we aim to evaluate the utility of individualized circulating tumor DNA (ctDNA) monitoring using digital PCR (dPCR) as a tumor recurrence biomarker for UTUC in the perioperative period. Twenty-three patients who underwent radical nephroureterectomy (RNU) were included. In each patient, whole exome sequencing by next-generation sequencing and TERT promoter sequencing of tumor DNA were carried out. Case-specific gene mutations were selected from sequencing analysis to examine ctDNA by dPCR analysis. We also prospectively collected plasma and urine ctDNA from each patient. The longitudinal variant allele frequencies of ctDNA during the perioperative period were plotted. Case-specific gene mutations were detected in 22 cases (96%) from ctDNA in the preoperative samples. Frequently detected genes were TERT (39%), FGFR3 (26%), TP53 (22%), and HRAS (13%). In all cases, we obtained plasma and urine samples for 241 time points and undertook individualized ctDNA monitoring for 2 years after RNU. Ten patients with intravesical recurrence had case-specific ctDNA detected in urine at the time of recurrence. The mean lead time of urinary ctDNA in intravesical recurrence was 60 days (range, 0-202 days). Two patients with distal metastasis had case-specific ctDNA in plasma at the time of metastasis. In UTUC, tumor-specific gene mutations can be monitored postoperatively as ctDNA in plasma and urine. Individualized ctDNA might be a minimally invasive biomarker for the early detection of postoperative recurrence., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary., Competing Interests: Competing Interests: Ms. Yamamoto received personal fees from Chugai outside of the submitted work. Dr. Tsuchiya received personal fees from Chugai, Taiho, Ono, Sun Pharma, Kyowa-Kirin, Pfizer, Eizai, and Daiichi Sankyo outside the submitted work. Dr. Iihara received personal fees from Taiho, Chugai, Yakult, Astellas, Eli Lilly, Daiichi Sankyo, AstraZeneca, Nippon Kayaku, Ono, and Nippon Boehringer Ingelheim and consulting fees for their institution from Taiho and Eisai outside the submitted work. Dr. Suzuki received personal fees from Takeda and AstraZeneca outside of the submitted work. Mr. Watanabe received personal fees from Chugai outside of the submitted work. Dr. Suzuki A received personal fees from Toa Eiyo, Asahi Kasei, Daiichi Sankyo, Pfizer, Eisai, Nippon Shinyaku, Celltrion Healthcare Japan, Otsuka, Sandoz, Tsumura, Nipro, Taiho, Kyowa-Kirin, Nippon Chemiphar, Japan Blood Products Organization, Takeda, and Nippon Boehringer Ingelheim and grants for their institution from Nippon Kayaku, Asahi Kasei, Chugai, Taiho, Daiichi Sankyo, Japan Blood Products Organization, Mochida, and Sun Pharma outside the submitted work. Dr. Abe received personal fees from Taiho, Chugai, AstraZeneca, and Takeda outside the submitted work., (© The author(s).)

Background and Aims: Bilioenteric anastomotic stricture (BES) is a well-known adverse event after bilioenterostomy. Recently, EUS-guided antegrade intervention (EUS-AI) has been developed for cases that are difficult to treat by balloon enteroscopy-assisted ERCP. However, no data are available on the long-term outcomes after EUS-AI. The main goal of the present study was to clarify the long-term outcomes of EUS-AI in such patients., Methods: Between November 2013 and November 2021, 34 patients who were followed for more than 1 year after EUS-AI for BES were identified. The primary endpoint was the rate of stricture resolution. Secondary endpoints were factors associated with stricture resolution, rate of BES recurrence, rate of conversion to surgery, and rate of hepatic fibrosis progression during follow-up., Results: The median follow-up period was 56.7 months. Stricture resolution was achieved in 17 of 34 patients (50%). A multivariate analysis confirmed that the presence of bile duct stones (odds ratio, 9.473; 95% confidence interval, 1.66-53.98; P = .01) was significantly associated with stricture resolution. The stricture recurrence rate was 33%, and the median time from stent removal to recurrence was 31.2 months. Four patients underwent surgery because of recurrent cholangitis. During the median follow-up period of 56.7 months, 25% progressed to hepatic fibrosis based on the Fibrosis-4 index grade. Interestingly, patients without cholangitis during follow-up did not show progression of hepatic fibrosis., Conclusions: EUS-AI has achieved acceptable long-term clinical outcomes. EUS-AI can be a viable alternative treatment of choice before surgical treatment in patients who are difficult to treat by conventional approaches., Competing Interests: Disclosure The following authors disclosed financial relationships: T. Tsuchiya, T. Itoi: Consultants for Gadelius Medical Corporation. All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Prostate cancer in the anterior region may be missed on a transrectal systematic biopsy (SBx). Therefore, this study aimed to evaluate the performance of magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion targeted biopsy (TBx) in detecting anterior region cancer in patients with a history of SBxs., Methods: Prostate biopsies were performed in 224 patients after multiparametric MRI, among whom 119 patients with prostate imaging reporting and data system (PI-RADS version 2) scores of 3 to 5 underwent MRI-TRUS fusion TBxs. Afterward, cancer detection rates (CDRs) and TBx-positive core regions were compared by categorizing patients into those with or without a history of SBxs., Results: Total CDR was 68.8% (44/64 cases) in the initial biopsy group (Initial-Bx group) and 47.3% (26/55 cases) in the previous-negative-systematic biopsy group (Pre-Neg-SBx group) ( P  = 0.018). Interestingly, both TBx- and SBx-core positive cases were more common in the Initial-Bx group than in the Pre-Neg-SBx group (Initial-Bx group: 75% [33/44 cases] vs. Pre-Neg-SBx group: 42.3% [11/26 cases], P  = 0.006). However, only TBx-core positive cases were more common in the Pre-Neg-SBx group than in the Initial-Bx group (Initial-Bx group: 11.4% [5/44 cases] vs. Pre-Neg-SBx group: 30.8% [8/26 cases], P  = 0.043). In addition, the proportion of anterior lesions detected by TBx cores was higher in the Pre-Neg-SBx group than in the Initial-Bx group (Initial-Bx group: 26.3% [10/38 cases] vs. Pre-Neg-SBx group: 52.6% [10/19 cases], P  = 0.049)., Conclusion: Using MRI-TRUS fusion TBx in the evaluation of previously negative SBx cases improved the detection rate of anterior lesions, which might have been missed in previous SBxs. Especially in patients with a history of SBxs mpMRI should be performed to screen for anterior lesions., (© 2023 The Asian Pacific Prostate Society. Published by Elsevier B.V.)

Aim: The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy., Methods: Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0-1500 s/mm 2 ), and other clinicopathologic factors were analyzed., Results: Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/β-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS., Conclusions: The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC., (© 2023 Japan Society of Hepatology.)

Background: Early monitoring and feedback on the treatment of infectious diseases are some of the methods for optimising antimicrobial treatment throughout the treatment period. Prospective audits and feedback interventions have also been shown to improve antimicrobial use and reduce antimicrobial resistance. We examined the appropriate use of antimicrobials by focusing on the initial timing for audits and feedback intervention of antimicrobial prescription by Infection Control Team pharmacists., Methods: We conducted a retrospective observational study in a university hospital in Tokyo, Japan from 1 January 2019 to 31 May 2021. We retrospectively enrolled patients with infections and those patients suspected of having an infection, who were administered vancomycin and assessed at our hospital. The definition of primary outcome was the maintenance of target vancomycin trough blood concentrations of 10-20 μg/ml during treatment. Multivariable logistic regression and multivariate linear regression analyses were performed to test the effectiveness of the initial timing of the intervention by Infection Control Team pharmacists as the explanatory variable., Results: A total of 638 patients were included in this study, with a median age of 69 years (interquartile range: 54-78 years). Multivariable logistic regression revealed that the maintenance of target vancomycin trough concentrations was not associated with the timing of the audit and the initiation of monitoring by Infection Control Team pharmacists (adjusted odds ratio: 0.99, 95% confidence interval: 0.99-1.00, p = 0.990). Multivariate linear regression revealed that the duration of vancomycin administration was significantly correlated with the timing of initiation of monitoring by Infection Control Team pharmacists (adjusted estimate: 0.0227, standard error: 0.0051, p = 0.012)., Conclusions: Our study showed that early initiation of a comprehensive audit and monitoring by Infection Control Team pharmacists did not affect the maintenance of the target vancomycin trough blood concentration. However, it reduced the duration of vancomycin administration., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EI received lecture fees from Pfizer Japan Inc., Bristol-Myers Squibb Co., and Eisai Co., Ltd., and consulting fees from Nippontect Systems Co., Ltd., and Cyberdine, Inc. The other authors declare no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Sugita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This review outlines several modified versions of the contrast-enhanced ultrasonography Liver Imaging Reporting and Data System (CEUS LI-RADS) that utilize Sonazoid. Furthermore, it discusses the advantages and challenges of diagnosing hepatocellular carcinoma using these guidelines, as well as the authors' expectations and opinions regarding the next CEUS LI-RADS version. It is possible that Sonazoid could be incorporated into the next version of CEUS LI-RADS.

Background: Cancer patients experience various forms of psychological distress. Their distress, mainly in the form of depression and anxiety, leads to poor quality of life, increased medical spending due to frequent visits, and decrease in treatment adherence. It is estimated that 30-50% among them would require support from mental health professionals: in reality, much less actually receive such support partly due to a shortage of qualified professionals and also due to psychological barriers in seeking such help. The purpose of the present study is to develop the easily accessible and the most efficient and effective smartphone psychotherapy package to alleviate depression and anxiety in cancer patients., Methods: Based on the multiphase optimization strategy (MOST) framework, the SMartphone Intervention to LEssen depression/Anxiety and GAIN resilience project (SMILE-AGAIN project) is a parallel-group, multicenter, open, stratified block randomized, fully factorial trial with four experimental components: psychosocial education (PE), behavioral activation (BA), assertion training (AT), and problem-solving therapy (PS). The allocation sequences are maintained centrally. All participants receive PE and then are randomized to the presence/absence of the remaining three components. The primary outcome of this study is the Patient Health Questionnaire-9 (PHQ-9) total score, which will be administered as an electronic patient-reported outcome on the patients' smartphones after 8 weeks. The protocol was approved by the Institutional Review Board of Nagoya City University on July 15, 2020 (ID: 46-20-0005). The randomized trial, which commenced in March 2021, is currently enrolling participants. The estimated end date for this study is March 2023., Discussion: The highly efficient experimental design will allow for the identification of the most effective components and the most efficient combinations among the four components of the smartphone psychotherapy package for cancer patients. Given that many cancer patients face significant psychological hurdles in seeing mental health professionals, easily accessible therapeutic interventions without hospital visits may offer benefits. If an effective combination of psychotherapy is determined in this study, it can be provided using smartphones to patients who cannot easily access hospitals or clinics., Trial Registration: UMIN000041536, CTR. Registered on 1 November 2020  https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000047301 ., (© 2023. The Author(s).)

Chemotherapy-induced nausea and vomiting (CINV) is often ranked by patients as one of the most distressing and feared consequences of chemotherapy. The novel neurokinin-1 (NK 1 ) receptor antagonist fosnetupitant, a phosphorylated prodrug formulation of netupitant, was approved in Japan in 2022. Fosnetupitant is one of the standard treatments for the prevention of CINV in patients who are receiving highly (any treatment where CINV occurs in more than 90% of patients) or moderately (where CINV occurs in 30-90% of patients) emetogenic chemotherapies. The aim of this commentary is to describe the mechanism of action, tolerability, and antiemetic efficacy of single-agent fosnetupitant in the prevention of CINV, and to discuss its clinical application, in order to aid optimal use., (© 2023. The Author(s).)

Importance: It is unknown whether olanzapine combined with triplet antemetic therapy is effective for all patients undergoing highly emetogenic chemotherapy. A secondary analysis of randomized clinical trials using olanzapine may provide insight into the effectiveness of olanzapine for chemotherapy-induced nausea and vomiting (CINV), including cisplatin., Objective: To examine the add-on effect of olanzapine according to risk factors for CINV., Design, Setting, and Participants: This preplanned secondary analysis evaluated results of the J-FORCE trial, a large double-blind, placebo-controlled phase 3 randomized clinical trial conducted in Japan from February 9, 2017, to July 18, 2018. Participants were enrolled from 26 participating hospitals across Japan and included patients aged 20 to 75 years who had a malignant tumor and were cisplatin-naive. The efficacy analysis population of the J-FORCE trial was analyzed according to allocation adjustment factors (sex [male or female], age [≥55 years or <55 years], and cisplatin dose [≥70 mg/m2 or <70 mg/m2]) and patient-related risk factors (history of motion sickness, drinking habit [defined as alcoholic drinks consumption in excess of occasional drinking], and history of morning sickness during pregnancy). Statistical analysis was performed from February 18 to April 18, 2020., Interventions: Patients were randomized 1:1 to receive 5 mg of olanzapine or placebo combined with standard triplet antiemetic therapy., Main Outcomes and Measures: The primary end point was complete response (CR, defined as no vomiting and no use of rescue medication) in the delayed phase (24-120 hours after cisplatin-based chemotherapy administration). Secondary end points were CR, complete control, and total control in the acute, delayed, and overall phases for 6 CINV risk factors as well as time to treatment failure. The CR point estimates and 95% CIs of the differences between groups were calculated, and a Mantel-Haenszel test was performed., Results: Of the 705 patients (mean [SD] age, 63.0 [9.2] years; 471 males [66.8%]) included in the efficacy analysis population; 581 patients (82.4%) were 55 years or older, and 526 (74.6%) were treated with a cisplatin dose of 70 mg/m2 or more. Risk difference (RD) for a CR in the delayed phase was significantly greater in the olanzapine group than the placebo group in males (RD, 12.6% [95% CI, 5.0%-20.1%]; P = .001); in females (RD, 14.5% [95% CI, 2.2%-26.3%]; P = .02); in those 55 years or older (RD, 11.1% [95% CI, 3.9%-18.2%]; P = .003) or younger than 55 years (RD, 23.6% [95% CI, 7.3%-38.3%]; P = .005); for a cisplatin dose of 70 mg/m2 or more (RD, 13.5% [95% CI, 5.9%-21.0%]; P < .001); for those without a history of motion sickness (RD, 13.9% [95% CI, 6.9%-20.6%]; P < .001); for those with a drinking habit (RD, 14.9% [95% CI, 6.1%-23.4%]; P = .001) or without a drinking habit (RD, 12.0% [95% CI, 2.5%-21.3%]; P = .01); and for those with a history of morning sickness during pregnancy (RD, 27.2% [9.7%-42.6%]; P = .002). In other subgroups, a delayed CR was higher in the olanzapine group than the placebo group, although not significantly higher., Conclusions and Relevance: Results of this study suggest a benefit of using 5 mg of olanzapine plus triplet antiemetic therapy to counter CINV regardless of the presence or absence of risk factors., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000024676.

Aim: To evaluate the usefulness and safety of a newly developed full-core biopsy needle., Methods: We selected 149 patients who underwent percutaneous liver biopsy at our institution from February 2019 to April 2021. We excluded 35 patients with hepatic fibrosis stage F3 or higher, which made it histopathologically difficult to measure the number of complete portal triads. The patients were divided into two groups as follows: 62 cases with the 18-G conventional automated needle (TruCore needle: T needle), and 52 cases with the 18-G full-core needle (CorVocet needle: C needle). We measured the number of complete portal triads in the liver tissue specimens, and the sum of the length and width of the collected tissues. Moreover, we compared the number of session counts, fragmentations, and complications., Results: The sum of the length and the width was 12.8 mm (11.2-14.3) and 15.9 mm (13.1-17.3; p < 0.001), and 0.68 mm (0.63-0.74) and 0.82 mm (0.78-0.90; p < 0.001) for the T needle and C needle, respectively. The number of complete portal triads and fragmentation was six (3-8) and 10 (6-13; p < 0.001), and one (1-10) and one (1-3; p < 0.001), for the T needle and C needle, respectively. There was one session count (1-2) in both groups; however, there were significantly higher cases of two sessions with the T needle than that with the C needle (p = 0.018). There were no serious adverse events., Conclusions: Compared with the conventional needles, the newly developed full-core needles enabled the acquisition of a larger amount of tissue sample in liver biopsy., (© 2022 Japan Society of Hepatology.)

Background: Despite the diversity of thermal ablations, such as radiofrequency ablation (RFA) and microwave ablation (MWA), and non-thermal ablation, such as irreversible electroporation (IRE) cross-comparisons of multiple ablative modalities for hepatocellular carcinoma (HCC) treatment remain scarce. Thus, we investigated the therapeutic outcomes of different three ablation modalities in the treatment of early stage HCC., Methods: A total of 322 consecutive patients with 366 HCCs (mean tumor size ± standard deviation: 1.7 ± 0.9 cm) who underwent RFA (n = 216, 59.0%), MWA (n = 91, 28.3%), or IRE (n = 15, 4.7%) were included. Local tumor progression (LTP) rates for LTP were compared among the three modalities. Propensity score-matched analysis was used to reduce selection bias., Results: A significant difference in 2-year LTP rates between the IRE and RFA groups (IRE, 0.0% vs. RFA, 45.0%; p = 0.005) was found. There was no significant difference in 2-year LTP rates between the IRE and MWA groups (IRE, 0.0% vs. MWA, 25.0%; p = 0.103) as well as between the RFA and MWA groups (RFA, 18.2% vs. MWA, 20.6%; p = 0.586)., Conclusion: IRE provides better local tumor control than RFA as a first-line therapeutic option for small perivascular HCC.

Aim: To compare the diagnostic performance based on the modified CEUS Liver Imaging Reporting and Data System (LI-RADS), which includes Kupffer-phase findings as a major imaging feature, with that of CT and MRI (CT/MRI) LI-RADS for liver nodules in patients at high risk of HCC., Methods: A total of 120 patients with 120 nodules were included in this retrospective study. The median size of the lesions was 20.0 mm (interquartile range, 14.0-30.8 mm). Of these lesions, 90.0% (108 of 120) were confirmed as HCCs, 6.7% (8 of 120) were intrahepatic cholangiocarcinomas, 1.7% (2 of 120) were metastases, and 1.7% (2 of 120) were dysplastic nodules. All nodules were diagnosed histopathologically. Each nodule was categorized according to the modified CEUS LI-RADS and CT/MRI LI-RADS version 2018. The diagnostic performance and inter-modality agreement of each criterion was compared., Results: The inter-modality agreement for the modified CEUS LI-RADS and CT/MRI LI-RADS was slight agreement (kappa = 0.139, p = 0.015). The diagnostic accuracies of HCCs for the modified CEUS LR-5 and CT/MRI LR-5 were 70.0% (95% confidence interval [CI]: 61.0%, 78.0%) versus 70.8% (95% CI: 61.8%, 78.8%) (p = 0.876), respectively. The diagnostic accuracies of non-HCC malignancies for the modified CEUS LR-M and CT/MRI LR-M were 84.2% (95% CI: 76.4%, 90.2%) versus 96.7% (95% CI: 91.7%, 99.1%) (p = 0.002), respectively., Conclusions: The diagnostic performance for HCCs on the modified CEUS LR-5 and CT/MRI LR-5 are comparable. In contrast, CT/MRI LR-M has better diagnostic performance for non-HCC malignancy than that of the modified CEUS LR-M., (© 2022 Japan Society of Hepatology.)

Objectives: The aim of this study was to investigate postoperative conduction disorder differences between continuous and interrupted suturing techniques for the closure of perimembranous outlet-type ventricular septal defects (VSDs) in both tetralogy of Fallot (ToF) and isolated VSD cases., Methods: Patients aged 4 years or younger who underwent VSD closure for ToF (n = 112) or isolated perimembranous outlet-type VSD (n = 73) from April 2010 to December 2018 at 3 centres were reviewed. Patients either received continuous suturing for ToF (C-ToF, n = 58) or isolated VSD (C-VSD, n = 50), or interrupted suturing for ToF (I-ToF, n = 54) or isolated VSD (I-VSD, n = 23). Cohorts did not differ in preoperative characteristics. Postoperative conduction disorder differences upon discharge and postoperative year 1 (POY1) were evaluated by electrocardiography., Results: The C-ToF group showed significantly shorter PQ intervals (124.0 vs 133.5 ms; P = 0.042 upon discharge, 125.3 vs 133.5 ms; P = 0.045 at POY1) and QRS durations (98.0 vs 106.2 ms; P = 0.031 upon discharge, 97.3 vs 102.5 ms; P = 0.040 at POY1) than the I-ToF group. Right bundle branch block incidence was significantly lower in the C-ToF versus I-ToF groups (56.8 vs 75.9; P = 0.045 upon discharge, 56.8 vs 75.9; P = 0.045 at POY1). Heart rates were significantly lower in the C-ToF versus I-ToF groups at POY1 (109.2 vs 119.3 bpm; P < 0.001). No parameters significantly differed between C-VSD and I-VSD groups. Multivariable analyses confirmed the group (C-ToF versus I-ToF) as a significant covariate in postoperative heart rate, PQ interval, QRS duration and right bundle branch block outcomes at POY1 (P = 0.013, 0.027, 0.013 and 0.014, respectively)., Conclusions: A continuous suturing technique for the closure of outlet-type VSD in ToF could reduce the incidence of postoperative right bundle branch block, shorten the PQ interval and lower heart rate., Subject Collection: 110, 138, 139., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Balloon-occluded retrograde transvenous obliteration (BRTO) is an effective treatment for gastric varices, but predictors associated with overall survival rate (OS) and occurrence of esophagogastric varices (EGV) have not yet been clarified. In this study, we clarified these predictors by performing ultrasound elastography and blood tests at various time points., Methods: A total of 34 patients were enrolled. The primary endpoint was to identify predictors associated with OS and EGV occurrence by univariate and multivariate analyses. Secondary endpoints were to extract the cut-off values for OS and EGV occurrence, and to clarify chronological changes in liver stiffness (LS), spleen stiffness (SS), spleen index (SI), and portal vein flow volume (PVF). Time points were set as before BRTO (Bf), and 1 day (D1), 7 days (D7), 1 month (1M), 3 months (3M), and 6 months (6M) after BRTO., Results: Albumin-bilirubin score Bf, fibrin-4 index change 6M, and branched chain amino acids tyrosine molar ratio (BTR) 1M were predictors of OS on univariate analysis (P = .021, .033, and .019, respectively) but were not extracted by multivariate analysis. The factors of LS 6M > 19.9 kPa and SS D7 > 21.7 kPa were predictors of the occurrence of EGV on multivariate analysis (P = .029 and .025, respectively). PVF significantly increased with time after BRTO., Conclusion: Albumin-bilirubin score and BTR had the possibility to associate with OS, and the predictors of reduced occurrence of EGV were LS < 19.9 and SS < 21.7., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK 1 RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT 3 RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK 1 RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy., Methods: Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK 1 RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK 1 RA (non-NK 1 RA group: 31 patients) and with NK 1 RA (NK 1 RA group: 31 patients). The patients were selected using propensity score matching., Results: The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0-120 h post carboplatin administration) was 93.5% in the non-NK 1 RA group and 96.8% in the NK 1 RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine., Conclusions: The findings suggest that antiemetic regimens consisting of olanzapine, 5HT 3 RA, and DEX without NK 1 RA may be a treatment option for patients receiving carboplatin-based chemotherapy., (© 2022. The Author(s).)

Introduction: Triple antiemetic therapy with neurokinin-1 receptor antagonist, 5-hydroxytryptamine type 3 receptor antagonist, and dexamethasone has been widely recommended for high emetogenic chemotherapeutic (HEC) agents and regimens, including anthracycline combined with cyclophosphamide (AC). The addition of olanzapine (OLZ) 5 mg or 10 mg to the recommended triple antiemetic therapy has demonstrated superiority in antiemetic efficacy compared with the standard triplet therapy for a cisplatin-based HEC regimen. Although OLZ plus the triple antiemetic treatment may also be effective for patients on an AC-based HEC regimen, no study has investigated its efficacy at a lower dose of 5 mg., Methods and Analysis: To assess whether 5 mg OLZ, as compared with placebo, in combination with triple combination therapy, significantly improves nausea and vomiting, we are conducting a randomised, parallel-group controlled clinical trial with a total of 500 patients at 15 study centres in Japan. The primary outcome is the complete response rate, defined as no emetic episodes and no use of rescue medication during 120 hours after the initiation of chemotherapy. Treatment group comparison for the primary endpoint will be done by using the Cochran-Mantel-Haenszel test., Ethics and Dissemination: The study was approved by the institutional review board of Juntendo University Hospital and relevant approval was obtained from all participating centres. All participants will be required to provide written informed consent. The trial results will be reported at conferences and in peer-reviewed journals., Trial Registration Number: Japan Registry of Clinical Trials (jRCT) jRCT1031200134; protocol date: 30 July 2020, version: 1.3, approval: 25 August 2020., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this study was to compare the diagnostic performance of Contrast-Enhanced US Liver Imaging Reporting and Data System (CEUS LI-RADS) version 2017, which includes portal- and late-phase washout as a major imaging feature, with that of modified CEUS LI-RADS, which includes Kupffer-phase findings as a major imaging feature. Participants at risk of hepatocellular carcinoma (HCC) with treatment-naïve hepatic lesions (≥1 cm) were recruited and underwent Sonazoid-enhanced US. Arterial phase hyperenhancement (APHE), washout time, and echogenicity in the Kupffer phase were evaluated using both criteria. The diagnostic performance of both criteria was analyzed using the McNemar test. The evaluation was performed on 102 participants with 102 lesions (HCCs ( n = 52), non-HCC malignancies ( n = 36), and benign ( n = 14)). Among 52 HCCs, non-rim APHE was observed in 92.3% (48 of 52). By 5 min, 73.1% (38 of 52) of HCCs showed mild washout, while by 10 min or in the Kupffer phase, 90.4% (47 of 52) of HCCs showed hypoenhancement. The sensitivity (67.3%; 35 of 52; 95% CI: 52.9%, 79.7%) of modified CEUS LI-RADS criteria was higher than that of CEUS LI-RADS criteria (51.9%; 27 of 52; 95% CI: 37.6%, 66.0%) ( p = 0.0047). In conclusion, non-rim APHE with hypoenhancement in the Kupffer phase on Sonazoid-enhanced US is a feasible criterion for diagnosing HCC.

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open-label, phase II trial (JGOG3023), patients were randomized 1:1 to a single-agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m 2 administered intravenously], topotecan [1.25 mg/m 2 intravenously], paclitaxel [80 mg/m 2 intravenously], or gemcitabine [1000 mg/m 2 intravenously]) or single-agent chemotherapy + bevacizumab (15 mg/m 2 intravenously). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator-assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32-0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38-1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment-related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Peri-esophageal collateral veins have been reported to be associated with the recurrence of esophageal varices (EVs). In this study, we retrospectively analyzed whether endoscopic ultrasonography (EUS) findings obtained just before endoscopic injection sclerotherapy (EIS) are associated with the success rate of intravariceal injection, recurrence rate of EVs, and overall survival rate (OS) of patients. Furthermore, we investigated the independent predictors associated with these factors by multivariate analysis., Methods: A total of 91 patients with risky EVs treated by EIS were analyzed. The primary endpoint was to identify independent predictors associated with the success rate of intravariceal injection, recurrence rate, and OS by multivariate analysis, to confirm the usefulness of EUS examination. The secondary endpoint was to clarify differences in recurrence rate and OS between patients who underwent additional argon plasma coagulation (APC) and those who did not, by the propensity score matching method., Results: Luminal diameter of EVs and F factor were predictors of the success rate of intravariceal injection. APC was predictor of OS and recurrence of EVs. EUS findings were not associated with these factors. Propensity score matching (APC, 23; without APC, 23) showed that recurrence rate was significantly improved in the APC group (P = 0.050) and that OS had the tendency to be higher in the APC group (P = 0.068)., Conclusion: Endoscopic ultrasonography findings before EIS were associated with successful intravariceal injection but were not associated with recurrence rate or OS. Additional APC could improve OS and reduce the recurrence of EVs., (© 2021 Japan Gastroenterological Endoscopy Society.)

Background: Red dichromatic imaging (RDI) is a novel image-enhanced endoscopy released in 2020, which increases the visibility of deeper vessels. In this study, we retrospectively investigated whether RDI can shorten treatment times of endoscopic injection sclerotherapy (EIS), and which operational procedure times are affected compared with white light imaging (WLI)., Methods: A total of 155 patients (RDI, 70; WLI, 85) with risky esophageal varices (EV), who were treated with EIS were analyzed. Treatment times were compared, and predictors associated with treatment time were analyzed by multivariate analysis. For 24 cases (RDI, 12; WLI, 12) in which treatment videos were recorded, the procedure times of each step (observation of EV, needle flush, positioning, puncture, observation of bleeding, hemostasis, observation after hemostasis) were measured. Regarding the seven patients with EV bleeding, color differences were calculated between the bleeding point and the blood pool using the CIE (L*a*b*) color measurement method, and results were compared between using RDI and WLI., Results: Treatment times were shorter in the RDI group (RDI vs. WLI = 35.1 vs. 42.2 min; P < 0.01). 'RDI function' and 'amount of sclerosant' were extracted as independent predictors of treatment time. Times for 'observation of EV' and 'observation of bleeding' were shorter in the RDI group (P = 0.01 and <0.01, respectively). Regarding the color difference, RDI significantly increased bleeding point visibility (RDI vs. WLI = 31.4 ± 11.8 vs. 8.6 ± 6.2, P < 0.001)., Conclusion: Red dichromatic imaging can shorten the treatment time of EIS by increasing bleeding point visibility., (© 2021 Japan Gastroenterological Endoscopy Society.)

Background Nonalcoholic fatty liver disease (NAFLD) is common in the general population but identifying patients with high-risk nonalcoholic steatohepatitis (NASH) who are candidates for pharmacologic therapy remains a challenge. Purpose To develop a score to identify patients with high-risk NASH, defined as NASH with an NAFLD activity score (NAS) of 4 or greater and clinically significant fibrosis (stage 2 [F2] or higher). Materials and Methods This was a cross-sectional secondary analysis of data prospectively collected between April 2017 and March 2019 for a group of patients with NAFLD in Japan (Japan NAFLD, the derivation data set) with contemporaneous two-dimensional shear-wave elastography and biopsy-proven NAFLD (age range, 20-89 years). Three US markers (liver stiffness [LS, measured in kilopascals], attenuation coefficient [AC, measured in decibels per centimeter per megahertz], and dispersion slope [DS, measured in meters per second per kilohertz]) were determined, together with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and the AST-to-ALT ratio. The best-fit multivariate logistic regression model for identifying patients with high-risk NASH was determined. Diagnostic performance was assessed by using the area under the receiver operating characteristic curve (AUC). The findings were validated in an independent data set (Korea NAFLD; age range, 20-78 years). Results The Japan NAFLD data set included 111 patients (mean age, 53 years ± 18 [standard deviation]; 57 men), 84 (76%) with NASH. The Korea NAFLD data set included 102 patients (mean age, 48 years ± 18; 43 men), 55 (36%) with NASH. The most predictive model (LAD NASH score) combined LS, AC, and DS. Performance was satisfactory in both the derivation sample (AUC, 0.86; 95% CI: 0.79, 0.93) and the validation sample (AUC, 0.88; 95% CI: 0.80, 0.95). The LAD NASH score showed a positive predictive value of 86.5% and a negative predictive value of 87.5% for high-risk NASH in the derivation sample. Conclusion A score combining three US markers may be useful for noninvasive identification of patients with high-risk nonalcoholic steatohepatitis for inclusion in clinical trials and pharmacologic therapy. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lockhart in this issue.

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses was evaluated by the ratio of the variant allele frequency of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50 or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 versus 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Attenuation imaging (ATI) is a new noninvasive ultrasound technique for assessing steatosis grade (S). However, validated region-of-interest (ROI) sampling strategies are not currently available. We investigated the diagnostic performance of various ATI-ROI positions for determining histopathologic S in patients with nonalcoholic fatty liver disease (NAFLD)., Methods: This retrospective study included 105 patients with biopsy-proven NAFLD. All attenuation coefficient (AC, dB/cm/MHz) measurements were obtained by the same hepatologist using a commercially available ultrasound system on the same day as liver biopsy. Mean (± standard deviation) age and body mass index of the patients were 53 (± 18) years and 27.1 (± 4.1) kg/m 2 , respectively. The numbers of patients with steatosis affecting < 5%, 5-33%, 33-66%, and > 66% of hepatocytes were 8, 50, 29, and 18, respectively. The ATI-ROI was placed at three different positions for AC measurement using a dedicated workstation: the upper edge of the area ROI, twice the depth of the liver capsule, and the lower edge of the area ROI. Diagnostic performance was evaluated using the area under the receiver-operating characteristic curve (AUC)., Results: The AUCs of AC at the three ATI-ROI positions were 0.734 (95% confidence interval [CI]: 0.470-0.998), 0.750 (0.639-0.861), and 0.878 (0.788-0.968) for S ≥ 1; 0.503 (0.392-0.615), 0.824 (0.741-0.907), and 0.809 (0.724-0.895) for S ≥ 2; and 0.606 (0.486-0.726), 0.849 (0.767-0.932), and 0.737 (0.626-0.848) for S = 3, respectively., Conclusion: For accurate steatosis grade assessment, the ATI-ROI should not be placed at the upper edge of the area ROI., (© 2021. The Japan Society of Ultrasonics in Medicine.)

Purpose: Measurement of spleen stiffness (SS) using ultrasound (US) elastography is useful for predicting portal hypertension. However, the mechanism leading to increased SS remains unclear. We jointly developed a new US elastography system (Aplio i-series, Canon Medical Systems) that can easily measure organ viscosity (dispersion slope: DS). We analyzed the cause of increased SS by calculating the shear wave speed (SWs, which reflects fibrosis) and DS of the spleen in carbon tetrachloride (CCL 4 ) rat liver cirrhosis models., Methods: A total of 13 Sprague-Dawley rats were randomly divided into four groups (C group: 3 rats as control, 2D group: 3 rats injected with CCL 4 twice in 1 week, 4D group: 4 rats injected 4 times in 1 week, 6W group: 3 rats injected twice a week for 6 weeks). The SWs and the DS of each group were calculated, and histopathological analysis was performed., Results: The spleen SWs of the 6W group was significantly higher than that of the C group (p = 0.044). The spleen DS did not change after CCL 4 . The liver SWs of the 4D and 6W groups was significantly higher than that of the C group (p = 0.012 and 0.007, respectively) with fibrosis change on histopathology, and the DS of the 4D group was significantly higher than that of the C group (p = 0.033). Splenic fibrosis was confirmed in the 6W group, but inflammation and necrosis were not seen., Conclusion: SS increased due to fibrosis and can be predicted based on SWs and DS values., (© 2021. The Japan Society of Ultrasonics in Medicine.)

Background: The efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine's efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine., Methods: Data were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors., Results: Regarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist., Conclusions: The findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy., (© 2021. The Author(s).)

Background: Red dichromatic imaging (RDI) is next-generation image-enhanced endoscopy technique released in July 2020. We previously reported that RDI can predict esophageal varices (EV) depth and decrease their recurrence rate by accurate intravariceal injections during endoscopic injection sclerotherapy (EIS) using unreleased prototype RDI endoscope. In this study, we analyzed whether RDI improves the overall survival (OS) rate and whether it is more accurate independent predictor of EV recurrence than white light imaging (WLI), using propensity score matching., Methods: A total of 179 patients were enrolled. Patients were matched for age, platelet count, liver function, EV size, luminal diameter, and EV depth using propensity score matching, and 78 patients (RDI, 39; WLI, 39) were finally matched. Primary endpoints were OS and recurrence rates. Secondary endpoints were success rate of intravariceal injection, operating time, incidence of adverse events (AEs), and predictors associated with OS and recurrence rates., Results: There was no difference in OS (P = .193), but the cumulative recurrence rate in the RDI group was significantly lower than in the WLI group (P = .002). Success rates of intrainjection, operating time, and incidence of AEs were better in the RDI group (p = 0.035, .026, and .0019, respectively). Independent predictors associated with recurrence rate by Cox proportional regression were RDI function and luminal diameter (P < .001 and .017, respectively)., Conclusion: RDI did not improve OS but decreased the recurrence rate. Independent predictors of recurrence rate were RDI and luminal diameter, resulting from secure intravariceal injections in EIS., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Venous thromboembolism (VTE) is frequently observed in patients with advanced cancer. The objective of this prospective observational study was to estimate, based on intensive screening, using computed tomography, lower-extremity ultrasonography, and D-dimer testing, the prevalence of VTE in patients with advanced cancer. Patients with metastatic or locally advanced cancer without anticoagulant therapy, who were planning to receive chemotherapy during 4 weeks, were eligible. Evaluations of VTE were performed at pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy. Primary endpoint was cumulative incidence of VTE for 24 weeks. Secondary endpoints included incidence of VTE (pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy), VTE according to primary cancer site, symptomatic VTE, pulmonary thromboembolism (PE), and treatment of VTE. We enrolled 860 patients with a median age of 68 years, including 34% female and 71% lung cancer. Cumulative incidence of VTE for 24 weeks was 22.6% (95% confidence interval: 19.8%-25.5%) (194 of 860 patients). Incidence of VTE was 11.3% pretreatment, 16.8% 12 weeks, and 14.1% 24 weeks. Symptomatic VTE was observed in 4.0% and PE in 1.0% of patients. By multivariate analysis, sex, D-dimer level, and platelet count were independent risk factors of VTE for 24 weeks. This large prospective observational study showed that cumulative incidence of VTE was high in advanced cancer patients, mainly lung cancer. Although most patients showed asymptomatic VTE, intensive screening of VTE may be considered in advanced cancer patients, especially in women with high level of D-dimer and decreased platelet count (UMIN000015243)., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Cancer patients are regarded as highly vulnerable to severe acute respiratory syndrome coronavirus (SARS-CoV)-2. However, little is known regarding how cancer treatments should be restarted for cancer patients after coronavirus disease (COVID)-19. We herein report a pancreatic cancer case in which chemotherapy was able to be reinstituted after COVID-19. The patient was a 67-year-old man diagnosed with pancreatic cancer. On day 7 after first chemotherapy, he was infected with COVID-19. A SARS-CoV-2 test was negative after one month of treatment, and we reinstituted chemotherapy. The patient has received three cycles of chemotherapy without recurrence of COVID-19. It may be feasible to reinstitute chemotherapy for cancer patients after a negative SARS-CoV-2 test.

Background: The thrombopoietin (TPO) receptor agonist lusutrombopag was developed to treat thrombocytopenia in chronic liver disease (CLD). However, its effectiveness remains unclear. The purpose of this study was to assess the efficacy of lusutrombopag and identify predictors associated with increase in platelet count., Methods: Eighty CLD patients with thrombocytopenia were enrolled. The primary endpoint was a satisfactory increase in platelets (greater than 1.0 × 10 4 /μL from baseline) in the absence of platelet transfusion. The secondary endpoints were response rate (an increase of greater than 1.0 × 10 4 /μL from baseline), independent predictors of increase in platelets, and the superiority of lusutrombopag over platelet transfusion., Results: The primary endpoint was achieved in 93.8% (75 of 80) patients. The response rate was 96.2% (77 of 80). Renal function parameters (blood urea nitrogen, creatinine, eGFR) were significantly negatively associated with platelet count (p = 0.033, 0.049, and 0.0014, respectively) and were identified as independent predictors by multiple regression analysis (p = 0.049, 0.0023, and 0.0016, respectively). The median increase in platelet count was significantly higher after lusutrombopag than after platelet transfusion (41,000 vs. 12,000/μL, p = 0.015)., Conclusion: Lusutrombopag was more effective than platelet transfusion for CLD patients, and renal function independently predicted increase in platelet count. Renal function parameters were significantly associated with platelet count.

The Contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) was introduced for classifying suspected hepatocellular carcinoma (HCC). However, it cannot be applied to Sonazoid. We assessed the diagnostic usefulness of a modified CEUS LI-RADS for HCC and non-HCC malignancies based on sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Patients with chronic liver disease at risk for HCC were evaluated retrospectively. Nodules ≥1 cm with arterial phase hyperenhancement, no early washout (within 60 s), and contrast defects in the Kupffer phase were classified as LR-5. Nodules showing early washout, contrast defects in the Kupffer phase, and/or rim enhancement were classified as LR-M. A total of 104 nodules in 104 patients (median age: 70.0 years; interquartile range: 54.5-78.0 years; 74 men) were evaluated. The 48 (46.2%) LR-5 lesions included 45 HCCs, 2 high-flow hemangiomas, and 1 adrenal rest tumor. The PPV of LR-5 for HCC was 93.8% (95% confidence interval (CI): 82.8-98.7%). The 22 (21.2%) LR-M lesions included 16 non-HCC malignancies and 6 HCCs. The PPV of LR-M for non-HCC malignancies, including six intrahepatic cholangiocarcinomas, was 100% (95% CI: 69.8-100%). In conclusion, in the modified CEUS LI-RADS for Sonazoid, LR-5 and LR-M are good predictors of HCC and non-HCC malignancies, respectively.

Background: Very rarely does a splenic solitary metastasis arise from a gastric carcinoma because splenic metastasis is usually seen in association with widespread visceral metastasis. Splenectomy is considered to be a curative treatment; however, long-term prognosis after splenectomy has scarcely been reported. We report a case of a metachronous and solitary metastasis to the spleen from gastric cancer in which the patient achieved 5-year recurrence-free survival after splenectomy., Case Presentation: An 84-year-old man underwent an open total gastrectomy involving D1+ lymph nodes dissection for gastric cancer located in the cardia (pT3N1M0, pStage IIB). Eighteen months later, a 2-cm solitary hypodense lesion was detected in the spleen by computed tomography (CT). Twenty-three months later, the serum carcinoembryonic antigen (CEA) value elevated to 19.9 ng/ml, and abdominal CT revealed an increase in tumor size to 5 cm. Positron-emission tomography (PET)-CT revealed intense 18 F-2-deoxy-2-fluoro-glucose (FDG) uptake in the spleen without the involvement of other organs and lymph nodes. We diagnosed him with solitary splenic metastasis from gastric cancer and performed a splenectomy 26 months after the first surgery. Histological examination revealed that the splenic tumor was a moderately differentiated adenocarcinoma, which was very similar to the primary gastric tumor; the lesion was diagnosed as a metastatic tumor from the previous gastric carcinoma. The patient remains healthy to date without recurrence, 5 years after the splenectomy., Conclusion: We experienced a case of a solitary splenic metastasis from gastric cancer in which 5-year recurrence-free survival was achieved after splenectomy. To determine the surgical indication in patients with splenic metastasis, it is important to differentiate between a solitary lesion or multiple metastasis. Especially, occult metastasis should be excluded by means of several months of follow-up with imaging tests and systemic FDG-PET surveys before splenectomy.

Background Nonalcoholic steatohepatitis (NASH) is diagnosed with histopathologic testing, but noninvasive surrogate markers are desirable for screening patients who are at high risk of NASH. Purpose To investigate the diagnostic performance of dispersion slope, attenuation coefficient, and shear-wave speed measurements obtained using two-dimensional (2D) shear-wave elastography (SWE) in assessing inflammation, steatosis, and fibrosis and in the noninvasive diagnosis of NASH in patients suspected of having nonalcoholic fatty liver disease (NAFLD). Materials and Methods This prospective study collected data from 120 consecutive adults who underwent liver biopsy for suspected NAFLD and were enrolled between April 2017 and March 2019. Three US parameters (dispersion slope [(m/sec)/kHz], attenuation coefficient [dB/cm/MHz], and shear-wave speed [in meters per second]) were measured using a 2D SWE system immediately before biopsy. The biopsy specimens were scored by one expert pathologist according to the Nonalcoholic Steatohepatitis Clinical Research Network criteria (119 participants underwent a histologic examination). Diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUC) for the categories of inflammation, steatosis, and fibrosis. Results One hundred eleven adults (mean age, 53 years ± 18 [standard deviation]; 57 men) underwent a US examination. Dispersion slope enabled the identification of lobular inflammation, with an AUC of 0.95 (95% confidence interval [CI]: 0.91, 0.10) for an inflammation grade greater than or equal to A1 (mild), 0.81 (95% CI: 0.72, 0.89) for an inflammation grade greater than or equal to A2 (moderate), and 0.85 (95% CI: 0.74, 0.97) for an inflammation grade equal to A3 (marked). Attenuation coefficient enabled the identification of steatosis, with an AUC of 0.88 (95% CI: 0.80, 0.97) for steatosis grade greater than or equal to S1 (mild), 0.86 (95% CI: 0.79, 0.93) for steatosis grade greater than or equal to S2 (moderate), and 0.79 (95% CI: 0.68, 0.89) for steatosis grade equal to S3 (severe). Shear-wave speed enabled the identification of fibrosis, with an AUC of 0.79 (95% CI: 0.69, 0.88) for fibrosis stage greater than or equal to F1 (portal fibrosis), 0.88 (95% CI: 0.82, 0.94) for fibrosis stage greater than or equal to F2 (periportal fibrosis), 0.90 (95% CI: 0.84, 0.96) for fibrosis stage greater than or equal to F3 (septal fibrosis), and 0.95 (95% CI: 0.91, 0.99) for fibrosis stage equal to F4 (cirrhosis). The combination of dispersion slope, attenuation coefficient, and shear-wave speed showed an AUC of 0.81 (95% CI: 0.71, 0.91) for the diagnosis of NASH. Conclusion Dispersion slope, attenuation coefficient, and shear-wave speed were found to be useful for assessing lobular inflammation, steatosis, and fibrosis, respectively, in participants with biopsy-proven nonalcoholic fatty liver disease. © RSNA, 2020 Online supplemental material is available for this article .

Aim: The thrombopoietin receptor agonist, lusutrombopag, was recently adapted for treatment of thrombocytopenia in chronic liver disease. However, no studies have compared the effects of lusutorombopag and platelet transfusion. Therefore, we aimed to clarify the efficacy and proportion of responders of lusutrombopag compared with platelet transfusion, by propensity score matching., Methods: A total of 200 patients (90 lusutrombopag, 110 platelet transfusion) with thrombocytopenia were enrolled, and matched for age, liver function, renal function, platelet count, peripheral blood count, and spleen size, using the propensity score-matching method. Finally, 52 patients (26 lusutrombopag, 26 platelet transfusion) were included. The primary end-point was an increase in platelet count. Secondary end-points were the proportion of responders, duration of the sustained effect, incidence of adverse events, and predictors associated with an increase in platelet count., Results: The median increase in platelets from baseline was 48 × 10 3 /μL versus 9.5 × 10 3 /μL (lusutrombopag vs. transfusion, P < 0.0001). The proportion of responders (increase of >10 × 10 3 /μL) was 100% versus 50.0% (P < 0.0001). Median duration of the sustained effect (increase of >50 × 10 3 /μL) was 10 versus 2 days (P < 0.0001). The incidence of adverse events was 7.7% versus 50.0% (P = 0.036). Predictors associated with an increase in platelets were hemoglobin and spleen size by multiple regression analysis., Conclusion: Lusutrombopag was more effective in chronic liver disease patients than platelet transfusion. The proportion of responders, effect duration, and non-incidence rate of adverse events were higher in the lusutrombopag group., (© 2020 The Japan Society of Hepatology.)

Irreversible electroporation (IRE) is a novel form of soft tissue ablation therapy that uses highcurrent electrical pulses to induce the formation of pores in the cell membrane, leading to cell death. Although outcome data for the ablation of hepatocellular carcinoma (HCC) by IRE are limited, early results are encouraging and may suggest equivalency to the outcomes achieved by thermal ablation methods such as radiofrequency ablation (RFA) and microwave ablation (MWA). However, IRE can be a challenging and very time-consuming procedure compared to RFA and MWA. In this review article, we not only evaluate the efficacy and safety of IRE for the treatment of HCC, but also discuss imaging guidance, ablation monitoring, and endpoint assessment, with a particular focus on ultrasonography.

Background: Prognostic outcomes and safety following treatment with pembrolizumab in patients with advanced urothelial carcinoma (UC) have not been fully elucidated in clinical practice. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in a routine clinical setting., Methods: This retrospective study included 41 consecutive Japanese patients with advanced UC treated with pembrolizumab as second-line or greater therapy at Iwate Medical University Hospital from January 2018 to April 2019., Results: The mean follow-up period was 6.2 months. The objective response rate, median progression-free survival, and median overall survival were 15%, 2.5 months, and 11.9 months, respectively. Univariate analysis identified poor performance status (> 1), liver metastasis, two or more metastatic organs, low hemoglobin levels, two or more prior regimens, high baseline C-reactive protein levels, higher relative C-reactive protein level change after 6 weeks, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks as significant predictors of overall survival. Among these factors, poor performance status (> 1), two or more metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks were identified as independent predictors of overall survival in multivariate analysis., Conclusions: The introduction of pembrolizumab can result in favorable cancer control outcomes in Japanese patients with advanced UC, and the prognosis of these patients can be stratified according to three potential parameters, including poor performance status, high number of metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change.

Purpose: The aim of this study was to investigate the efficacy and safety of prophylactic administration of 5 mg olanzapine (OLZ) combined with neurokinin 1 receptor antagonist (NK 1 RA), 5-hydroxytryptamine type-3 receptor antagonist (5-HT 3 RA), and dexamethasone (DEX) to prevent nausea and vomiting in carboplatin (CBDCA) combination therapy for patients with gynecological cancer., Methods: We conducted a single-arm, multi-institution, phase II study. Gynecological cancer patients scheduled to receive AUC ≥4 mg/mL/min CBDCA were enrolled. All patients received 5 mg OLZ (once daily after supper on days 1-4) combined with NK 1 RA, 5-HT 3 RA, and DEX. The primary end point was complete response (CR; no emesis and rescue therapy) during overall phase (120 h after the start of carboplatin administration)., Results: Between May 2018 and June 2019, 60 patients were enrolled from 3 institutions in Japan. A total of 57 patients who met the criteria were included in the efficacy and safety analysis. The CR rate for the overall phase was 78.9%. Acute (0-24 h) and delayed phases (24-120 h) were 96.5% and 80.7%, respectively. Somnolence was observed in 73.7% patients. However, somnolence of grade 2 or higher was observed in only 3.5% of cases. There were no grade 3 or 4 toxicities associated with OLZ., Conclusions: Preventive use of OLZ combined with standard triplet therapy had promising activity with manageable safety, suggesting that this combination could be an effective standard treatment option for patients with AUC ≥4 mg/mL/min CBDCA combination therapy., Competing Interests: Declaration of competing interest No conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy., Methods: This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m 2 ) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0-2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1-4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24-120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m 2 or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676., Findings: Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75-83] of 354 patients in the olanzapine group and 231 (66% [61-71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group., Interpretation: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy., Funding: Japan Agency for Medical Research and Development., (Copyright © 2020 Elsevier Ltd. All rights reserved.)