Publications by authors named "Tomoko Saito"

132 Publications

Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring Mutation in Early Clinical Experience.

J Cancer 2022 16;13(8):2656-2661. Epub 2022 May 16.

Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of locus. A total of eight patients (24.2%) exhibited at least one mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT was comparable to those patients with WT . These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by mutation.
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http://dx.doi.org/10.7150/jca.71494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174847PMC
May 2022

Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis.

Int J Clin Oncol 2022 Jun 15. Epub 2022 Jun 15.

Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles.

Methods: Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation CDx was investigated.

Results: In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion.

Conclusions: Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.
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http://dx.doi.org/10.1007/s10147-022-02195-9DOI Listing
June 2022

A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis.

Lab Invest 2022 May 28. Epub 2022 May 28.

Department of Gastroenterology, Chiba University, Graduate School of Medicine, Chiba, 260-8677, Japan.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-A mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-A mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.
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http://dx.doi.org/10.1038/s41374-022-00807-6DOI Listing
May 2022

Changes in regional oxygen saturation of the kidney and brain of infants during hospitalization.

J Clin Monit Comput 2022 Apr 20. Epub 2022 Apr 20.

Department of Neonatology, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa, Minami-ku, 232-8555, Yokohama, Japan.

Background: In pre-term infants, the postnatal changes in the regional oxygen saturation (rSO) of the brain and kidney are unclear.

Methods: We performed a prospective observational study. We measured the cerebral/renal rSO ratio and recorded the associated clinical features of infants born at 23 to 41 weeks of gestation weekly from the early postnatal period to discharge.

Results: The median cerebral/renal rSO ratios (interquartile ranges) between birth and the expected date of birth were 1.13 (1.06-1.26) at 23-24 weeks (n = 7), 1.18 (1.10-1.32) at 25-26 weeks (n = 11), 1.24 (1.11-1.37) at 27-28 weeks (n = 9), 1.12 (1.05-1.19) at 29-30 weeks (n = 4), 1.11 (1.03-1.15) at 31-32 weeks (n = 5), 1.02 (0.98-1.06) at 33-34 weeks (n = 9), 0.98 (0.94-1.06) at 35-36 weeks (n = 19), and 0.95 (0.86-0.99) at 37-41 weeks of gestation (n = 22). The median cerebral/renal rSO ratio did not significantly change after birth, but with increasing gestational age, the cerebral/renal rSO ratio at the expected date of birth decreased (r = - 0.74, p < 0.001). Nephrotoxic drugs did not affect cerebral/renal rSO at the expected date of birth, after adjustment for clinical factors.

Conclusions: Unlike in most infants born after the late pre-term period, the renal rSO remained lower than the cerebral rSO on the expected date of birth in infants born very pre-term.
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http://dx.doi.org/10.1007/s10877-022-00836-yDOI Listing
April 2022

Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial.

BMJ Open 2022 04 8;12(4):e059779. Epub 2022 Apr 8.

National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Introduction: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI.

Methods And Analysis: This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B.

Ethics And Dissemination: This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication.

Trial Registration Number: jRCT2031210046.
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http://dx.doi.org/10.1136/bmjopen-2021-059779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995959PMC
April 2022

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2022 Jan 6;11(1):48-60. Epub 2021 Dec 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet.

Approach And Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, = 267; period 2: 2013-2016, = 352; period 3: 2017-2019, = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively ( = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC.

Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
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http://dx.doi.org/10.1159/000519868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820147PMC
January 2022

Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma.

PLoS One 2022 27;17(1):e0261619. Epub 2022 Jan 27.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background/aims: Organ failure in patients with acute decompensation (AD) is a defining characteristic of acute-on-chronic liver failure (ACLF). However, the clinical features of AD during the long-term clinical course of hepatocellular carcinoma (HCC) are still poorly understood. This study aimed to clarify features and impact of AD/ACLF on the prognosis of patients after treatment for HCC.

Methods: This retrospective study enrolled 556 consecutive patients who were initially diagnosed with HCC, and analyses were conducted taking into account HCC treatment type, HCC stage, and presence or absence of cirrhosis.

Results: During follow-up, 299 patients with AD were hospitalized. AD occurrence is closely related to prognosis, regardless of the presence or absence of cirrhosis and HCC stage, and early-onset AD (within 90 days after HCC treatment) has negative impact on prognosis. In the intermediate-advanced-stage group, surgical resection had a positive impact on AD incidence post-treatment. After systemic therapy for HCC, renal impairment was the predictive factors for AD development. The 28/90-day mortality rate was higher among 41 cases (13.7%) with AD who exhibited ACLF as compared with cases without ACLF. AD without cirrhosis had similar ACLF incidence and short-term mortality, compared to AD with cirrhosis. The prognostic model using a decision-tree-based approach, which includes ACLF, bilirubin level, HCC progression, and MELD score is useful for predicting 90- or 28-day mortality after AD diagnosis.

Conclusions: Careful management of patients with HCC who are hospitalized with AD is necessary, considering ACLF, HCC progression, and liver function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794202PMC
February 2022

Prostaglandin E-major urinary metabolite diagnoses mucosal healing in patients with ulcerative colitis in remission phase.

J Gastroenterol Hepatol 2022 May 14;37(5):847-854. Epub 2022 Feb 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.

Background And Aim: Ulcerative colitis (UC) is usually detected by clinical symptoms, such as bleeding and diarrhea; however, it is rather difficult to assess during asymptomatic clinical remission (CR). Hence, there is a need for a biomarker that can reliably detect UC during remission. We previously reported on the utility of the prostaglandin E-major urinary metabolite (PGE-MUM) as a biomarker reflecting UC activity. In this study, we evaluated the effectiveness of the PGE-MUM in the diagnosis of endoscopic, histological, and histo-endoscopic mucosal remission of UC, comparing with fecal tests.

Methods: This prospective study was conducted at the Jikei University Hospital between August 2017 and January 2021. Patients with UC in CR scheduled to undergo colonoscopy were included. The association between the PGE-MUM with endoscopic remission (ER), histological remission (HR), and complete mucosal healing (CMH, defined as histo-endoscopic remission) was analyzed. We also compared the area under the curve (AUC) for the receiver operating characteristic curves between PGE-MUM, fecal calprotectin (FC), and fecal immunochemical test (FIT).

Results: In total, 128 patients were analyzed. PGE-MUM differed significantly in ER versus non-ER (14.5 vs 16.7, P = 0.028), HR versus non-HR (14.2 vs 17.4, P = 0.004), and CMH versus non-CMH (14.3 vs 16.7, P = 0.021). There were no significant differences between the AUCs for PGE-MUM, FC, and FIT for ER, HR, or CMH.

Conclusions: The PGE-MUM can determine CMH in UC even during CR, regardless of the disease phenotype, indicating its clinical benefit for non-invasive monitoring.
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http://dx.doi.org/10.1111/jgh.15782DOI Listing
May 2022

Exploring microsatellite instability in patients with advanced hepatocellular carcinoma and its tumor microenvironment.

JGH Open 2021 Nov 1;5(11):1266-1274. Epub 2021 Oct 1.

Department of Diagnostic Pathology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Immune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability-high (MSI-H) by using tumor samples from advanced HCC patients eligible for systemic therapy.

Methods: MSI-H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD-L1, CD8, VEGF, and HLA-class1 was evaluated by immunohistochemistry. Whole-exome sequencing was performed for MSI-H tumor samples.

Results: Of 50 patients, one (2.0%) was confirmed with MSI-H. In the MSI-H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8 lymphocytes, and low expression of VEGF were identified. Although PD-L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR-21 and miR-155 overexpression and hypermethylation of the gene.

Conclusion: We identified a very small number of MSI-H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI-H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI-H in HCC and to analyze tumor microenvironments.
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http://dx.doi.org/10.1002/jgh3.12660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593775PMC
November 2021

Maximum Plasma Concentration of Lenvatinib Is Useful for Predicting Thrombocytopenia in Patients Treated for Hepatocellular Carcinoma.

World J Oncol 2021 Oct 5;12(5):165-172. Epub 2021 Oct 5.

Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan.

Background: Although lenvatinib treatment has a favorable efficacy for unresectable hepatocellular carcinoma (HCC), it is associated with adverse events (AEs) that must be closely monitored and managed. Thrombocytopenia is one of the major AEs. The aim of this study was to clarify whether thrombocytopenia can be predicted by the plasma concentration of lenvatinib.

Methods: This was a single-center retrospective observational study. Twenty-three patients with unresectable HCC and pharmacokinetics data at the initial lenvatinib administration between May 2018 and September 2020 at Oita University Hospital were enrolled. The AEs during the 4 weeks after the initiation of treatment were evaluated, and the correlations between the thrombocytopenia and the plasma concentration of lenvatinib were examined. Spearman's correlation was used to evaluate the correlation between two continuous variables.

Results: The rate of platelet count decrease correlated with the maximum plasma concentration (C) (r = 0.65, P = 0.001), whereas it did not with the minimum plasma concentration (C) (r = 0.29, P = 0.206). After stepwise multiple linear regression analysis, the starting dose of lenvatinib and the serum albumin concentration were identified as independent explanatory variables. Next, a formula for predicting the C using these two variables was created. The predicted C was strongly correlated with the C (r = 0.87, P < 0.0001) and the rate of platelet count decrease (r = 0.67, P = 0.001).

Conclusions: This study identified the usefulness of the drug C to predict the rate of platelet count decrease within 4 weeks after the initiation of treatment. Although it is difficult to measure the plasma concentration of lenvatinib in community hospitals, the predicted C is useful for predicting the rate of platelet count decrease with this treatment.
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http://dx.doi.org/10.14740/wjon1399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577601PMC
October 2021

Changes in therapeutic options for hepatocellular carcinoma in Asia.

Liver Int 2021 Nov 15. Epub 2021 Nov 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

The incidence rate of hepatocellular carcinoma (HCC) is expected to increase, with most cases occurring in Asia. In some parts of Asia, the occurrence of HCC developing from metabolic-related liver disease has markedly increased in recent years, whereas the occurrence of HCC developing from viral-hepatitis-related liver disease has decreased. Advancements in the treatment of HCC over the past few decades has been remarkable, with most treatment strategies to remove or control liver tumours (hepatic resection, local ablation, radiation therapy, transarterial chemoembolisation, hepatic arterial infusion chemotherapy) primarily developing in Asia. In addition, recent progress in systemic therapies has prolonged the prognosis of advanced HCC. Nowadays, six regimens of systemic therapies have become available in most countries, according to phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). In a global randomised phase III trial (IMbrave 150 trial), the most effective of the latest drug designs was newly emerged combination immunotherapy (atezolizumab plus bevacizumab), which has shown significantly prolonged overall survival compared with sorafenib, which was the first-line systemic therapy for more than a decade. Now, the treatment dynamics for HCC are undergoing a major transition as a result of two important changes: the replacement of viral-related HCC by metabolic-related HCC and the emergence of combination immune therapy.
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http://dx.doi.org/10.1111/liv.15101DOI Listing
November 2021

Pan-cancer methylome analysis for cancer diagnosis and classification of cancer cell of origin.

Cancer Gene Ther 2022 05 8;29(5):428-436. Epub 2021 Nov 8.

Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.

The accurate and early diagnosis and classification of cancer origin from either tissue or liquid biopsy is crucial for selecting the appropriate treatment and reducing cancer-related mortality. Here, we established the CAncer Cell-of-Origin (CACO) methylation panel using the methylation data of the 28 types of cancer in The Cancer Genome Atlas (7950 patients and 707 normal controls) as well as healthy whole blood samples (95 subjects). We showed that the CACO methylation panel had high diagnostic potential with high sensitivity and specificity in the discovery (maximum AUC = 0.998) and validation (maximum AUC = 1.000) cohorts. Moreover, we confirmed that the CACO methylation panel could identify the cancer cell type of origin using the methylation profile from liquid as well as tissue biopsy, including primary, metastatic, and multiregional cancer samples and cancer of unknown primary, independent of the methylation analysis platform and specimen preparation method. Together, the CACO methylation panel can be a powerful tool for the classification and diagnosis of cancer.
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http://dx.doi.org/10.1038/s41417-021-00401-wDOI Listing
May 2022

EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma.

Sci Rep 2021 11 1;11(1):21396. Epub 2021 Nov 1.

Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2H3K27me3 cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
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http://dx.doi.org/10.1038/s41598-021-00889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560765PMC
November 2021

Posttreatment after Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2021 Sep 20;10(5):473-484. Epub 2021 Apr 20.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy.

Methods: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions.

Results: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively.

Conclusion: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.
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http://dx.doi.org/10.1159/000515552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527907PMC
September 2021

A Broad Range High-Throughput Assay for Lenvatinib Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry With Clinical Application in Patients With Hepatocellular Carcinoma.

Ther Drug Monit 2021 10;43(5):664-671

Department of Clinical Pharmacy, Oita University Hospital; and.

Background: Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future.

Methods: After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode.

Results: The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2-1000 ng/mL concentration range. The average recovery rate was 98.63 ± 4.55% (mean ± SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib.

Conclusions: A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting.
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http://dx.doi.org/10.1097/FTD.0000000000000872DOI Listing
October 2021

The Evolving Genomic Landscape of Esophageal Squamous Cell Carcinoma Under Chemoradiotherapy.

Cancer Res 2021 10 19;81(19):4926-4938. Epub 2021 Aug 19.

Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Esophageal squamous cell carcinoma (ESCC) often recurs after chemoradiotherapy, and the prognosis of ESCC after chemoradiotherapy has not improved over the past few decades. The mutation process in chemoradiotherapy-resistant clones and the functional relevance of genetic alterations remain unclear. To address these problems, we performed whole-exome sequencing of 52 tumor samples from 33 patients with ESCC who received radiotherapy combined with 5-fluorouracil/platinum. In multiregion analyses of pretreatment and locally recurrent lesions from five cases, most driver gene-altered clones remained under chemoradiotherapy selection pressure, while few driver gene alterations were acquired at recurrence. The mutation signatures of recurrent ESCC, including increased deletion frequency and platinum dose-dependent base substitution signatures, were substantially different from those of primary ESCC and reflected the iatrogenic impacts of chemoradiotherapy. Single-region analysis of 28 pretreatment tumors indicated that focal copy-number gain at the locus was significantly associated with poor progression-free survival and overall survival after chemoradiotherapy. gain remained throughout the chemoradiotherapy course and potentially contributes to intrinsic resistance to chemoradiotherapy. Consistent with these findings, copy number and mRNA and protein levels in ESCC cell lines correlated positively with resistance to radiotherapy, and knockdown improved sensitivity to radiotherapy. Overall, these data characterize the clonal evolution process induced by chemoradiotherapy and clinically relevant associations for genetic alterations in ESCC. These findings increase our understanding of therapeutic resistance and support the rationale for precision chemoradiotherapy. SIGNIFICANCE: Whole-exome sequencing reveals the genetic evolution of ESCC during chemoradiotherapy, highlighting gain in pretreatment tumors as a potential marker of therapy resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0653DOI Listing
October 2021

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.

J Neurol 2022 Feb 30;269(2):885-896. Epub 2021 Jun 30.

Central Coordinating Unit, Clinical Research Support Center, The University of Tokyo Hospital, Tokyo, Japan.

Objective: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS).

Methods: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment.

Results: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483).

Conclusions: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.
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http://dx.doi.org/10.1007/s00415-021-10670-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782807PMC
February 2022

Serum Angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma.

J Cancer 2021 5;12(9):2694-2701. Epub 2021 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Hepatocellular carcinoma (HCC) is typically accompanied by abundant arterial blood flow. Although angiogenic growth factors such as Angiopoietin 2 (Ang2) play a central role in tumor angiogenesis in HCC, the role of serum Ang2 as a biomarker in HCC remains unclear. In this study, we aimed to investigate the potential of Ang2 as a diagnostic and prognostic biomarker in HCC using a sandwich enzyme-linked immunosorbent assay (ELISA). The median Ang2 levels in controls (n=20), chronic liver disease patients (n=98), and HCC patients (n=275) were 1.58, 2.33, and 3.53 ng/mL, respectively. The optimal cut-off value of Ang2 was determined as 3.5 ng/mL by receiver operating curve analysis. The sensitivity, specificity, and accuracy of Ang2 for HCC detection were 50.9, 83.7, and 59.5%, respectively. Spearman's rank correlation coefficient analysis demonstrated only a weak correlation between Ang2 serum levels and alpha-fetoprotein (AFP) or des-gamma-carboxy prothrombin (DCP) serum levels. The diagnostic value of Ang2 was comparable to those of other existing markers. In addition, 24 out of 73 patients with normal AFP and DCP levels (32.9%) demonstrated abnormally high Ang2 levels (≥3.5 ng/mL). Although no significant difference in overall survival was found between Ang2 and Ang2 patients with curative ablation therapy, recurrence-free survival (RFS) in Ang2 patients was observed to be significantly shorter than those in Ang2 patients. Multivariate analysis demonstrated that high serum Ang2 levels (≥3.5 ng/mL) and the presence of multiple tumors were poor prognostic factors. In conclusion, our findings indicate that serum Ang2 is a potential novel biomarker for both diagnosis and prognosis in HCC.
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http://dx.doi.org/10.7150/jca.56436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040723PMC
March 2021

Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Biochem Biophys Res Commun 2021 04 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.097DOI Listing
April 2021

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

Sci Rep 2021 03 5;11(1):5303. Epub 2021 Mar 5.

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19 (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 (n = 105) patients, there were no significant differences between FGF19 (n = 21) and FGF19 (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
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http://dx.doi.org/10.1038/s41598-021-84117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935880PMC
March 2021

Propofol midazolam for sedation during radiofrequency ablation in patients with hepatocellular carcinoma.

JGH Open 2021 Feb 22;5(2):273-279. Epub 2020 Dec 22.

Departmetn of Anesthesiology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Standardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single-blind, investigator-initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.

Methods: Few- and small-nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100-mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5.

Results: Between July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups.

Conclusion: Patient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable.
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http://dx.doi.org/10.1002/jgh3.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857294PMC
February 2021

Acute effect of hydrocortisone for respiratory deterioration in preterm infants: Oxygenation, ventilation, vital signs, and electrolytes.

Early Hum Dev 2021 03 26;154:105320. Epub 2021 Jan 26.

Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Japan.

Background: Preterm infants with severe bronchopulmonary dysplasia require rescue therapy with glucocorticoids, and hydrocortisone is increasingly replacing dexamethasone. The standard for rescue therapy is unclear.

Aim: To quantify the short-term effects of respiratory rescue hydrocortisone of 4 mg/kg/day for 3 days.

Study Design: Retrospective single-center study.

Subjects: Ventilator-dependent infants born at <28 weeks of gestation with an increased oxygen demand to maintain the target oxygen saturation at 88% to 95% >1 week after birth.

Outcome Measures: Ventilator settings, SpO/FiO ratio, heart rate, and blood parameters within 24 h before and 228 h after starting hydrocortisone.

Results: Twenty-five infants (median gestational age, 25.1 weeks) received hydrocortisone at a median age of 16 days. The median pre-therapy SpO/FiO was 297 (interquartile range, 265-320) and began to rise after 12 h of administration, reaching 307 (interquartile range, 278-335). The increase in SpO/FiO peaked from the third day to 3 days after therapy (median range, 341-356). SpO/FiO decreased thereafter and remained unchanged from 6 and 7 days after therapy (median range, 304-314). The pCO level (median range, 49-53 mmHg) did not change significantly. The heart rate significantly decreased from -4 to -6 beats/min from the first day to 1 day after therapy. Systolic blood pressure increased by a median of 4 to 8 mmHg after therapy. Blood electrolytes and glucose were similar after therapy.

Conclusion: Rescue hydrocortisone administration improved oxygenation without particular adverse effects at the stage of respiratory deterioration in preterm infants.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105320DOI Listing
March 2021

Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases.

PLoS Genet 2021 01 21;17(1):e1009113. Epub 2021 Jan 21.

Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.

A Darwinian evolutionary shift occurs early in the neutral evolution of advanced colorectal carcinoma (CRC), and copy number aberrations (CNA) are essential in the transition from adenoma to carcinoma. In light of this primary evolution, we investigated the evolutionary principles of the genome that foster postoperative recurrence of CRC. CNA and neoantigens (NAG) were compared between early primary tumors with recurrence (CRCR) and early primary tumors without recurrence (precancerous and early; PCRC). We compared CNA, single nucleotide variance (SNV), RNA sequences, and T-cell receptor (TCR) repertoire between 9 primary and 10 metastatic sites from 10 CRCR cases. We found that NAG in primary sites were fewer in CRCR than in PCRC, while the arm level CNA were significantly higher in primary sites in CRCR than in PCRC. Further, a comparison of genomic aberrations of primary and metastatic conditions revealed no significant differences in CNA. The driver mutations in recurrence were the trunk of the evolutionary phylogenic tree from primary sites to recurrence sites. Notably, PD-1 and TIM3, T cell exhaustion-related molecules of the tumor immune response, were abundantly expressed in metastatic sites compared to primary sites along with the increased number of CD8 expressing cells. The postoperative recurrence-free survival period was only significantly associated with the NAG levels and TCR repertoire diversity in metastatic sites. Therefore, CNA with diminished NAG and diverse TCR repertoire in pre-metastatic sites may determine postoperative recurrence of CRC.
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http://dx.doi.org/10.1371/journal.pgen.1009113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864431PMC
January 2021

[Posterior reversible encephalopathy syndrome during intravenous immunoglobulin therapy in Guillain-Barré syndrome].

Rinsho Shinkeigaku 2021 Jan 15;61(1):12-17. Epub 2020 Dec 15.

Department of Neurology, Tokyo Medical University.

A 63-year-old woman was diagnosed with Guillain-Barré syndrome (GBS), and intravenous immunoglobulin (IVIg) therapy was initiated. On the second day of IVIg therapy, she became less alert (JCS III-200) and had hyponatremia. Brain MRI showed vasogenic edema in bilateral occipital lobes, which disappeared afterwards. Her clinical course and MRI findings were consistent with those of posterior reversible encephalopathy syndrome (PRES). As a result of considering the timing of the onset of GBS and PRES and the degree of hyponatremia and hypertension in some documented patients, the cause of PRES onset in this case is considered to be IVIg therapy itself and IVIg therapy-induced hyponatremia.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001461DOI Listing
January 2021

Acute respiratory effect of transpyloric feeding for respiratory exacerbation in preterm infants.

J Perinat Med 2021 Mar 11;49(3):383-387. Epub 2020 Nov 11.

Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Japan.

Objectives: Gastroesophageal reflux may exacerbate chronic lung disease in preterm infants. We evaluated the short-term effects of transpyloric feeding on respiratory status in preterm infants during mechanical ventilation.

Methods: We retrospectively collected data from the hospital information management system. To evaluate the effect of transpyloric feeding on oxygenation, we compared changes in SpO/FiO ratios before and after commencing transpyloric feeding by a piecewise linear regression model.

Results: We examined 33 infants (median gestational age, 25.4 weeks; median birth weight, 656 g) who underwent transpyloric feeding. All tubes were placed at the bedside without fluoroscopy. No cases of unsuccessful placement, gastroduodenal perforation, or tracheal misinsertion occurred. Transpyloric feeding began at a median age of 18 (interquartile range, 15-23) days. Mean SpO/FiO (±SD) ratios were 391 (±49), 371 (±51), 365 (±56), and 366 (±53) 72-96 h before, 0-24 h before, 48-72 h after, and 96-120 h after starting transpyloric feeding, respectively. The rate of change per hour of SpO/FiO ratios increased 48-120 h after compared with 0-96 h before transpyloric feeding (0.03 [95% confidence interval, -0.10 to 0.17] vs. -0.29 [-0.47 to -0.12]) (p=0.007). No apparent changes occurred in the mean airway pressure, amplitude pressure, or pCO.

Conclusions: Transpyloric feeding during mechanical ventilation can prevent the deterioration of oxygenation without major complications at the stage of respiratory exacerbation in preterm infants.
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http://dx.doi.org/10.1515/jpm-2020-0243DOI Listing
March 2021

Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

Liver Cancer 2020 Sep 22;9(5):596-612. Epub 2020 Jul 22.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden.

Aims: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs.

Methods: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC.

Results: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC.

Conclusions: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.
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http://dx.doi.org/10.1159/000508809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548915PMC
September 2020

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

Liver Cancer 2020 Aug 5;9(4):382-396. Epub 2020 May 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial.

Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan.

Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7-6.9 for first line, 4.8 months; 95% CI 3.8-5.9 for second or later line, = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin - bilirubin scores.

Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.
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http://dx.doi.org/10.1159/000507022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506220PMC
August 2020

Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.

Oncol Lett 2020 Sep 19;20(3):2161-2168. Epub 2020 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-γ treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-α treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-γ in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-γ treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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http://dx.doi.org/10.3892/ol.2020.11757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400993PMC
September 2020

Long-term administration of Tolvaptan to patients with decompensated cirrhosis.

Int J Med Sci 2020 15;17(7):874-880. Epub 2020 Mar 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. : A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. : Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. : A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.
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http://dx.doi.org/10.7150/ijms.41454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163362PMC
February 2021

Switching to systemic therapy after locoregional treatment failure: Definition and best timing.

Clin Mol Hepatol 2020 04 15;26(2):155-162. Epub 2020 Jan 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients' survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.
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http://dx.doi.org/10.3350/cmh.2019.0021nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160341PMC
April 2020
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