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FUNAKOSHI YouheiGraduate School of Medicine / Faculty of Medical SciencesAssociate Professor
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■ Paper- AIM: Although immune checkpoint inhibitors (ICPi) for salivary gland cancer (SGC) have been investigated in clinical trials, details of the tumor immune microenvironment (TIME) remain unclear. This research aimed to elucidate the TIME of SGC and its relationship with tumor mutation burden (TMB) and to explore the rationale for the applicability of ICPi. MATERIALS AND METHODS: We selected five pathological types, namely adenoid cystic carcinoma (ACC); adenocarcinoma, not otherwise specified (ANOS); salivary duct carcinoma (SDC); and low/high-grade mucoepidermoid carcinoma (MEClow/high). We investigated the TIME and TMB of each pathological type. TIME was evaluated by multiplexed fluorescent immunohistochemistry. TMB was measured by next-generation sequencing. RESULTS: ACC and MEChigh showed the lowest and highest infiltration of immune effector and suppressor cells in both tumor and stroma. ANOS, SDC, and MEClow showed modest infiltration of immune effector cells in tumors. Correlation analysis showed a positive correlation between CD3+CD8+ T cells in tumor and TMB (r = 0.647). CD3+CD8+ T cells in tumors showed a positive correlation with programmed cell death-ligand 1 expression in tumor cells (r = 0.513) and a weak positive correlation with CD3+CD4+Foxp3+ cells in tumors (r = 0.399). However, no correlation was observed between CD3+CD8+ T cells and CD204+ cells in tumors (r = -0.049). CONCLUSION: The TIME of ACC was the so-called immune desert type, which may explain the mechanisms of the poor response to ICPi in previous clinical trials. On the other hand, MEChigh was the immune-inflamed type, and this may support the rationale of ICPi for this pathological subtype.Sep. 2024, Asia-Pacific journal of clinical oncology, English, International magazineScientific journal
- Aug. 2024, ESMO Open, 9(8) (8)Scientific journal
- Monovalent Omicron XBB.1.5 mRNA vaccines were newly developed and approved by the FDA in Autumn 2023 for preventing COVID-19. However, clinical efficacy for these vaccines is currently lacking. We previously established the quantification of antigen-specific antibody sequence (QASAS) method to assess the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the coronavirus antibody database (CoV-AbDab). Here, we used this method to evaluate the immunogenicity of monovalent XBB.1.5 vaccines. We analyzed repeated blood samples of healthy volunteers before and after monovalent XBB.1.5 vaccination (BNT162b2 XBB.1.5 or mRNA-1273.815) for the BCR repertoire to assess BCR/antibody sequences that matched SARS-CoV-2-specific sequences in the database. The number of matched unique sequences and their total reads quickly increased 1 week after vaccination. Matched sequences included those bound to the Omicron strain and Omicron XBB sublineage. The antibody sequences that can bind to the Omicron strain and XBB sublineage revealed that the monovalent XBB.1.5 vaccines showed a stronger response than previous vaccines or SARS-CoV-2 infection before the emergence of XBB sublineage. The QASAS method was able to demonstrate the immunogenic effect of monovalent XBB.1.5 vaccines for the 2023-2024 COVID-19 vaccination campaign.Aug. 2024, EJHaem, 5(4) (4), 661 - 668, English, International magazineScientific journal
- (一社)日本血栓止血学会, May 2024, 日本血栓止血学会誌, 35(2) (2), 336 - 336, Japanese進行・再発・転移の固形腫瘍における血栓塞栓症と出血リスク PROVE-emboli試験post-hoc解析
- Background In Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. Methods This study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4–16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events. Discussion To our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.Public Library of Science (PLoS), Apr. 2024, PLOS ONE, 19(4) (4), e0299742 - e0299742Scientific journal
- (一財)日本消化器病学会, Mar. 2024, 日本消化器病学会雑誌, 121(臨増総会) (臨増総会), A51 - A51, Japanese
- A monovalent Omicron XBB.1.5 mRNA RBD analogue vaccine, MAFB-7256a (DS-5670d), was newly developed and approved in Japan in the Spring of 2024 for the prevention of COVID-19. However, clinical efficacy data for this vaccine are currently lacking. We previously established the Quantification of Antigen-specific Antibody Sequence (QASAS) method to assess the response to SARS-CoV-2 vaccination at the mRNA level using B-cell receptor (BCR) repertoire assays and the Coronavirus Antibody Database (CoV-AbDab). Here, we used this method to evaluate the immunogenicity of MAFB-7256a. We analyzed repeated blood samples using the QASAS method from three healthy volunteers before and after MAFB-7256a vaccination. BCR response increased rapidly one week post-vaccination and then decreased, as with conventional vaccine. Notably, the matched sequences after MAFB-7256a vaccination specifically bound to the receptor-binding domain (RBD), with no sequences binding to other epitopes. These results validate that MAFB-7256a is an effective vaccine that exclusively induces antibodies specific for the RBD, demonstrating its targeted immunogenic effect.2024, Frontiers in immunology, 15, 1468760 - 1468760, English, International magazineScientific journal
- The use of anti-SARS-CoV-2 antibody products like tixagevimab/cilgavimab represents an important strategy to protect immunocompromised patients with haematological malignancies from COVID-19. Although patients who receive these agents should still be vaccinated, the use of tixagevimab/cilgavimab can mask the production of anti-spike antibody after vaccination, making it hard to assess vaccine response. We have newly established a quantification method to assess the response to SARS-CoV-2 vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the Coronavirus Antibody Database (CoV-AbDab). Repeated blood samples before and after vaccination were analysed for the BCR repertoire, and BCR sequences were searched in the database. We analysed the number and percentage frequency of matched sequences. We found that the number of matched sequences increased 2 weeks after the first vaccination and quickly decreased. Meanwhile, the number of matched sequences more rapidly increased after the second vaccination. These results show that the postvaccine immune response can be assessed at the mRNA level by analysing the fluctuation in matching sequences. Finally, BCR repertoire analysis with CoV-AbDab clearly demonstrated the response to mRNA SARS-CoV-2 vaccination even after tixagevimab/cilgavimab administration in haematological malignancy patients who underwent allogeneic haematopoietic stem cell transplantation.2024, 日本臨床腫瘍学会学術集会(CD-ROM), 21st(3) (3), 504 - 516, English, International magazine
- Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34+ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)– and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor–mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.Frontiers Media SA, Dec. 2023, Frontiers in Immunology, 14Scientific journal
- Oct. 2023, Annals of surgical oncology, 30(11) (11), 6613 - 6614, English, International magazineScientific journal
- BACKGROUND: Few reports have discussed the association between total tumor volume (TTV) and prognosis in patients with colorectal liver metastases (CRLM). The present study aimed to evaluate the usefulness of TTV for predicting recurrence-free survival and overall survival (OS) in patients receiving initial hepatic resection or chemotherapy, and to investigate the value of TTV as an indicator for optimal treatment selection for patients with CRLM. PATIENTS AND METHODS: This retrospective cohort study included patients with CRLM who underwent hepatic resection (n = 93) or chemotherapy (n = 78) at the Kobe University Hospital. TTV was measured using 3D construction software and computed tomography images. RESULTS: A TTV of 100 cm3 has been previously reported as a significant cut-off value for predicting OS of CRLM patients receiving initial hepatic resection. For patients receiving hepatic resection, the OS for those with a TTV ≥ 100 cm3 was significantly reduced compared with those with a TTV < 100 cm3. For patients receiving initial chemotherapy, there were no significant differences between the groups divided according to TTV cut-offs. Regarding OS of patients with TTV ≥ 100 cm3, there was no significant difference between hepatic resection and chemotherapy (p = 0.160). CONCLUSIONS: TTV can be a predictive factor of OS for hepatic resection, unlike for initial chemotherapy treatment. The lack of significant difference in OS for CRLM patients with TTV ≥ 100 cm3, regardless of initial treatment, suggests that chemotherapeutic intervention preceding hepatic resection may be indicated for such patients.Jun. 2023, Annals of surgical oncology, 30(11) (11), 6603 - 6610, English, International magazineScientific journal
- PURPOSE: Many effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed, but a weaker response in individuals undergoing anticancer treatment has been reported. This study evaluates the immunogenic status and safety of SARS-CoV-2 vaccines for patients with non-small-cell lung cancer (NSCLC), receiving tegafur-uracil (UFT) as postoperative adjuvant chemotherapy. METHODS: The subjects of this prospective study were 40 patients who underwent surgery for NSCLC and received SARS-CoV-2 vaccines postoperatively. We compared the antibody titers of SARS-CoV-2 vaccines and the adverse events between patients who received adjuvant UFT and patients who did not. RESULTS: The mean anti-S1 IgG titers were not significantly different between the UFT and without-UFT groups (mean optimal density, 0.194 vs. 0.205; P = 0.76). Multivariate analysis identified the period after the second vaccination as an independent predictor of anti-S1 IgG titer (P = 0.049), but not the UFT status (with or without-UFT treatment; P = 0.47). The prevalence of adverse events did not differ significantly between the groups, and no severe adverse events occurred. CONCLUSIONS: The efficacy and safety of the SARS-CoV-2 vaccines for NSCLC patients who received postoperative adjuvant UFT chemotherapy were comparable to those for NSCLC patients who did not receive postoperative adjuvant UFT chemotherapy. CLINICAL TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (UMIN) in Japan (UMIN000047380).Feb. 2023, Surgery today, 1 - 7, English, Domestic magazineScientific journal
- CONTEXT: The occurrence of multiple endocrinopathies due to immune checkpoint inhibitors (ICIs) is a relatively common adverse event. However, the occurrence of a combination of hypophysitis and type 1 diabetes mellitus (T1DM) is extremely rare, and its clinical features are unclear. OBJECTIVE: We comparatively analyzed the clinical features of this combination and each individual ICI-induced endocrinopathy. METHODS: We reported 3 cases that we encountered and reviewed previously reported cases of patients with combined hypophysitis and T1DM due to ICIs. RESULTS: Anti-programmed cell death-1 (anti-PD-1) antibodies were prescribed to all 3 cases. The duration from ICI initiation to the onset of endocrine disease was 12 to 48 weeks. Several human leukocyte antigen (HLA) haplotypes that have disease susceptibility to hypophysitis were detected in all 3 patients. With the 17 previously reported cases, combined endocrinopathies were more common in men (85%). The onset age was in the 60s for both combined and single endocrinopathies. Anti-PD-1 antibodies were used in most of the cases (90%). The time from ICI initiation to the onset of endocrinopathies was 24 (8-76) weeks for hypophysitis and 32 (8-76) weeks for T1DM in patients with combined endocrinopathies, which was not significantly different from that for each single endocrinopathy. CONCLUSION: We presented 3 cases of patients with combined endocrinopathies of hypophysitis and T1DM that may have been caused by anti-PD-1 antibodies. There was no difference in the time from ICI initiation to the onset of endocrinopathies between combined and single endocrinopathies. Further case accumulation and pathogenic investigations are required.Jan. 2023, Journal of the Endocrine Society, 7(3) (3), bvad002, English, International magazineScientific journal
- We previously reported that a second dose of BNT162b2 was safe and effective for allogeneic hematopoietic stem cell transplantation (HSCT) patients. Here, we investigated the safety and efficacy of a third dose of COVID-19 mRNA vaccine in allogeneic HSCT patients. Antibody titers against the S1 spike protein were measured using the QuaResearch COVID-19 Human IgM IgG ELISA kit. The previous study included 25 allogeneic HSCT patients who received two doses of BNT162b2. Following the exclusion of three patients because of the development of COVID-19 (n = 2) and loss to follow-up (n = 1), the study evaluated 22 allogeneic HSCT patients who received a third dose of COVID-19 mRNA vaccine (BNT162b2 [n = 15] and mRNA-1273 [n = 7]). Median age at the time of the first vaccination was 56 (range, 23-71) years. Five patients were receiving immunosuppressants at the third vaccination, namely calcineurin inhibitors (CI) alone (n = 1), steroids alone (n = 2), or CI combined with steroids (n = 2). Twenty-one patients (95%) seroconverted after the third dose. None of our patients had serious adverse events, new-onset graft-versus-host disease (GVHD), or GVHD exacerbation after vaccination. A third dose of the BNT162b2 and mRNA-1273 COVID-19 vaccines was safe and effective for allogeneic HSCT patients.Oct. 2022, 日本造血・免疫細胞療法学会総会プログラム・抄録集, 45th(11) (11), English, International magazine
- OBJECTIVES: Oral corticosteroids reduce the antibody titer of the BNT162b2 mRNA vaccine against SARS-CoV-2. To date, the effect of inhaled corticosteroids on antibody titers is unknown. STUDY DESIGN: The design of this study is retrospective study. METHODS: We analyzed the relationship between the clinical features and total antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in 320 subjects who had never been infected with Coronavirus disease 2019 (COVID-19) and were vaccinated the second time with the BNT162b2 mRNA vaccine between October 1 to December 28, 2021. RESULTS: Of the 320 subjects, 205 were treated with inhaled corticosteroids. The median antibody titer of patients treated with inhaled corticosteroids was 572 U/mL, which was significantly higher than that of patients treated without inhaled corticosteroids (454U/mL, P = 0.00258). The median antibody titers of smokers, men, and patients aged 65 years and over, were 315.5 U/mL, 385 U/mL, and 425.5 U/mL, respectively. These results are significantly lower than those of patients who never smoked, women, and patients aged less than 64 years (582 U/mL [P < 0.0001], 682.5 U/mL [P < 0.0001], and 717 U/mL [P < 0.0001], respectively). The multivariate analysis revealed that females and age were independent antibody titer-reducing factors (P = 0.0001 and P < 0.0001, respectively). CONCLUSIONS: The use of inhaled corticosteroids did not reduce the antibody titer against SARS-CoV-2 spike protein. Clinicians should continue treatment with inhaled corticosteroids if indicated.Aug. 2022, Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, 18(1) (1), 78 - 78, English, International magazineScientific journal
- Anti-CD20 antibodies react with CD20 expressed not only on malignant B cells, but also on normal B cells. It has been reported that patients treated with anti-CD20 antibodies had an insufficient response to two-dose mRNA SARS-CoV-2 vaccination. To investigate the efficacy of a third dose in these patients, we investigated serum IgG antibody titers for the S1 protein after a third vaccination in 22 patients treated with the anti-CD20 antibody who failed two-dose vaccination. Results showed that overall, 50% of patients seroconverted. Although no patient who received the third dose within 1 year of the last anti-CD20 antibody administration showed an increase in S1 antibody titer, 69% of patients who received the third dose more than 1 year after the last anti-CD20 antibody administration seroconverted. Our data show that a third dose of vaccination is effective in improving the seroconversion rate in patients treated with the anti-CD20 antibody who failed standard two-dose vaccination.Jun. 2022, Vaccines, 10(6) (6), English, International magazineScientific journal
- Although nivolumab is administered every two or four weeks, high programmed cell death-1 (PD-1) binding of nivolumab on T cells lasting for several months has been reported. A relationship between the PD-1 occupancy rate on T-cells and the efficacy of nivolumab is not yet fully understood. The present study used flow cytometric analyses to determine the time-dependence of PD-1 occupancy in five patients who discontinued nivolumab. The relationship between PD-1 occupancy at relapse and the efficacy of re-challenge was also studied. Occupancies after discontinuation were measured at a total of 32 points. The data indicated that it took 32.4 and 48.9 weeks to decrease occupancy by 50 and 70%, respectively. Subsequently, two patients had recurrence and were re-challenged with nivolumab. At that time, one patient had 70.8% occupancy while the other had 6.6%. Treatment was effective only for the patient with lower occupancy. Overall, the present study suggests that re-challenge with nivolumab may be efficacious in patients with low occupancy at recurrence.Corresponding, May 2022, Molecular and clinical oncology, 16(5) (5), 104 - 104, English, International magazineScientific journal
- BACKGROUND: Recent pivotal phase III trials involving direct oral anticoagulant (DOAC) versus low molecular weight heparin have demonstrated the utility of DOACs in Western patients with cancer-associated venous thromboembolism (VTE). However, these trials did not include Japanese patients. This phase II trial evaluated the safety and efficacy of apixaban in Japanese patients with cancer-associated VTE (UMIN000028447). METHOD AND RESULTS: Apixaban was initiated at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 23 weeks. The primary endpoint was the incidence of major or clinically relevant non-major (CRNM) bleeding events during the treatment period. The study was terminated due to safety concerns after enrolling 27 patients. Median age was 71 years; median body weight was 51.3 kg; and major primary tumor sites were the gastrointestinal tract (26%) and lung (19%). During the median follow-up period of 5.4 months, major or CRNM bleeding occurred in in 26% of patients (major, n = 5; CRNM, n = 2; 95% confidence interval, 11-46%). No recurrent VTE or VTE-related death occurred. Estimated overall survival at 6 months was 68%. CONCLUSION: This study demonstrated the excessive bleeding risk of apixaban at the standard dose in Japanese patients with cancer-associated VTE.Apr. 2022, International journal of hematology, 115(4) (4), 499 - 507, English, Domestic magazineScientific journal
- BACKGROUND/AIM: Aldehyde dehydrogenase (ALDH) 1A1 is a well-known marker for cancer stem cells (CSCs), characterized by self-renewal capacity and multidrug resistance in breast cancer. We developed a near-infrared turn-on fluorescence probe for ALDH1A1, C5S-A, which is suitable for observing and analyzing viable cells. Here, we demonstrated the utility of C5S-A in CSC research using breast cancer cell lines. MATERIALS AND METHODS: To evaluate concordance between C5S-A and conventional stem cell markers, breast cancer cells sorted for ALDEFLUOR-positive cells and for CD44+/CD24- cell populations were stained with C5S-A. Tumorigenicity of C5S-A-positive cells was examined by mammosphere formation assay and subcutaneous transplantation to immunodeficient mice. Additionally, to determine how long fluorescence from a single staining remained observable, we cultured breast cancer cells for 5 days after C5S-A staining. We then evaluated whether C5S-A-positive cells possessed resistance to cytotoxic drugs by chronological imaging. RESULTS: C5S-A staining showed good concordance with conventional breast CSC markers, and good utility for research into CSC characteristics in breast cancer cell lines, including tumorigenesis. Additionally, C5S-A was observable for more than 3 days with a single staining. Using this property, we then confirmed that C5S-A-positive cells possessed resistance to cytotoxic drugs, which is one of the characteristics of CSCs. CONCLUSION: We showed that C5S-A is suitable for CSC research using breast cancer cell lines, and confirmed its utility in observing cells over time.Corresponding, Mar. 2022, Anticancer research, 42(3) (3), 1199 - 1205, English, International magazineScientific journal
- Patients who have undergone hematopoietic stem cell transplantation (HSCT) for hematological disease experience high mortality when infected by coronavirus disease 2019 (COVID-19). However, the safety and efficacy of the COVID-19 vaccine in HSCT patients remain to be investigated. We prospectively evaluated the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine (Pfizer BioNTech) in 25 Japanese allogeneic HSCT patients in comparison with 19 healthy volunteers. While anti-S1 antibody titers in almost all healthy volunteers after the second dose were higher than the cut-off value reported previously, levels in HSCT patients after the second dose were diverse. Nineteen patients (76%) had seroconversion of anti-S1 IgG. The median optical density of antibody levels in HSCT patients with low IgG levels (<600 mg/dL), steroid treatment, or low lymphocytes (<1000/μL) was significantly lower than that in the other HSCT patients. There were no serious adverse events (>Grade 3) and no new development or exacerbation of graft-versus-host disease after vaccination. We concluded that the BNT162b2 mRNA vaccine is safe and effective in Japanese allogeneic HSCT patients.Jan. 2022, Vaccines, 10(2) (2), English, International magazineScientific journal
- We investigated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody. Although T-cell-mediated immune responses were detected even in patients receiving R-CHOP treatment, the S1 antibody titer following BNT162b2 vaccination remained only marginally increased for more than 3 years after the final dose of anti-CD20 antibody. We found no relationship between the percent of B-cells and S1 antibody titer. The duration of this suppression was much longer than we anticipated. Further protection and treatment strategies against COVID-19 for these patients are warranted.Jan. 2022, International journal of hematology, 115(1) (1), 7 - 10, English, Domestic magazineScientific journal
- BACKGROUND: Although COVID-19 severity in cancer patients is high, the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing chemotherapy for solid cancers in Japan have not been reported. METHODS: We investigated the safety and immunogenicity of BNT162b2 in 41 patients undergoing chemotherapy for solid cancers and in healthy volunteers who received 2 doses of BNT162b2. We evaluated serum IgG antibody titers for S1 protein by ELISA at pre-vaccination, prior to the second dose and 14 days after the second vaccination in 24 cancer patients undergoing cytotoxic chemotherapy (CC group), 17 cancer patients undergoing immune checkpoint inhibitor therapy (ICI group) and 12 age-matched healthy volunteers (HV group). Additionally, inflammatory cytokine levels were compared between the HV and ICI groups at pre and the next day of each vaccination. RESULTS: Anti-S1 antibody levels were significantly lower in the ICI and CC groups than in the HV group after the second dose (median optimal density: 0.241 [0.063-1.205] and 0.161 [0.07-0.857] vs 0.644 [0.259-1.498], p = 0.0024 and p < 0.0001, respectively). Adverse effect profile did not differ among the three groups, and no serious adverse event occurred. There were no differences in vaccine-induced inflammatory cytokines between the HV and ICI groups. CONCLUSION: Although there were no significant differences in adverse events in three groups, antibody titers were significantly lower in the ICI and CC groups than in the HV group. Further protection strategies should be considered in cancer patients undergoing CC or ICI.Dec. 2021, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 28(4) (4), 516 - 520, English, International magazineScientific journal
- BACKGROUND: Although rare, cytomegalovirus (CMV) reactivation can be lethal in patients with cancer. However, the criteria for the prevention of cytomegalovirus reactivation during cancer treatment are unclear. This study aimed to identify factors associated with CMV reactivation in patients with esophageal cancer who were receiving chemoradiotherapy. METHODS: This retrospective study included esophageal cancer patients receiving definitive or palliative chemoradiotherapy during April 2013-March 2020. Patients with fever during chemoradiotherapy underwent a systemic work-up to detect the primary focus of infection, and CMV antigenemia was assessed in cases of unidentifiable infection. RESULTS: Among 132 patients (80.3% male, median age 69 years [range, 39-86 years]), 124 received 5-fluorouracil plus cisplatin and 8 received oxaliplatin-5-fluorouracil-levofolinate chemotherapy. Overall, 19 patients had CMV reactivation, 37 had other infections, and 76 had no identified infection (groups 1, 2, and 3, respectively). Median minimum lymphocyte counts were 81.0/µl (interquartile range: 52.0-144.0/µl), 120.0/µl (81.0-162.5/µl), and 185.5/µl (120.5-328.0/µl) in groups 1, 2, and 3, respectively, with counts being significantly lower in groups 1 and 2 than in group 3 (p < 0.001). In multiple logistic regression analysis, the minimum lymphocyte count was associated with CMV reactivation (odds ratio 0.983, 95% confidence interval: 0.973-0.994, p = 0.002). CONCLUSION: CMV reactivation is not rare in patients with esophageal cancer who were receiving chemoradiotherapy and is associated with the minimum lymphocyte counts. CMV reactivation should be considered during differential diagnosis for patients with a severe decline in lymphocyte counts when receiving chemoradiotherapy.Nov. 2021, Cancer medicine, 10(21) (21), 7525 - 7533, English, International magazineScientific journal
- Treatment with anti-programmed cell death-1 (PD-1) antibodies improves the anti-cancer immune response and can provide a meaningful clinical benefit to cancer patients. However, this treatment can result in specific autoimmune toxicities, termed immune-related adverse events (irAEs). Although irAEs are well recognized, the development of infectious diseases due to this treatment is not often observed. Some recent reports have indicated that patients who receive anti-PD-1 antibodies are at a higher risk for tuberculosis than others. However, reports on nontuberculous mycobacterial infection during anti-PD-1 antibody treatment are still rare. We herein report the first case of Mycobacterium mageritense infection during anti-PD-1 antibody treatment.Corresponding, Nov. 2021, Internal medicine (Tokyo, Japan), 60(21) (21), 3485 - 3488, English, Domestic magazineScientific journal
- Serum Cytokine Profiles of Rapid Recovery Patients with COVID-19: Series of 6 Cases.COVID-19 patients reveal various clinical manifestations; however, the specific mechanisms and factors contributing to rapid recovery remain unclear. We performed serum cytokine profiling using a bead-based immunoassay in six COVID-19 patients with mild symptoms who experienced rapid recovery. All patients had fever that resolved within 4 days. During the study, the interferon gamma-related protein 10 (IP-10) level rapidly increased initially, and then rapidly decreased in all six patients. Similarly, the interferon (IFN)-λ 2/3 levels rapidly increased initially, and then decreased in five of the six patients. IP-10 and IFN-λ2/3 may play a key role in the rapid recovery of mild COVID-19.Oct. 2021, The Kobe journal of medical sciences, 67(2) (2), E55-E60, English, Domestic magazineScientific journal
- Accumulating evidence supports that cancer stem cells (CSCs) are responsible for cancer proliferation, metastasis, and therapy resistance; therefore, an effective strategy to identify and isolate CSCs is required urgently. Because of their low invasiveness and high signal/noise ratio, "turn-on" fluorescence probes working in the deep-red/near-infrared (DR/NIR) region are one of the most attractive yet undeveloped tools for CSC detection. Herein, we report DR/NIR turn-on fluorescence probes, CS5-A and CS7-A, targeted to aldehyde dehydrogenase 1A1 as an intracellular CSC marker. In contrast to the conventional "always-on" green-fluorescent ALDEFLUOR, we succeeded in generating high-contrast (signal/noise ratio > 8.3) and wash-free in vitro CSC imaging with the DR probe C5S-A. This probe can facilitate CSC isolation with minimal contamination by autofluorescence from other tissues through fluorescence-activated cell sorting. Furthermore, the NIR absorbance/emission and turn-on properties of C7S-A allow simple and rapid CSC detection in vivo within 15 min.Sep. 2021, ACS sensors, 6(9) (9), 3320 - 3329, English, International magazineScientific journal
- BACKGROUND: The incidence of cancer-associated venous thromboembolism (CA-VTE) in Japan has not been fully investigated. METHODS AND RESULTS: Clinicopathological information from patients with solid malignancies who first visited our department between November 2011 and March 2018 were retrospectively reviewed from medical records. The primary outcome was incidence of CA-VTE, defined as deep-vein thrombosis (DVT) and/or pulmonary embolism (PE). On median follow-up of 187 days, 91 of 2735 patients (3.3%) developed CA-VTE during their clinical course, giving an incidence rate of 40.7 per 1000 person-years. Of the 91 patients, 75 (82%) were diagnosed with DVT alone, 6 (7%) with PE alone, and 10 (11%) with both DVT and PE. CA-VTE was most frequent in non-small cell lung cancer (10.8%), followed by cancer of unknown origin (5.8%). Forty-four patients (48%) had one or more symptoms at the initial diagnosis of VTE. Five patients (6%) had a normal D-dimer level (≤ 1.0 µg/mL); of these, 2 were asymptomatic. CONCLUSIONS: In this retrospective study, the incidence of CA-VTE in Japanese patients with cancer was equivalent to that in Western populations. Approximately half of CA-VTE patients were asymptomatic and 6% had normal D-dimer levels, indicating the need for closer attention to occult CA-VTE.Sep. 2021, International journal of hematology, 114(3) (3), 319 - 324, English, Domestic magazineScientific journal
- (一社)日本医療検査科学会, Aug. 2021, 医療検査と自動化, 46(4) (4), 416 - 416, Japaneseマイクロ流路を用いた新型コロナウイルスの新規抗体検査キット
- Background: Antibody production is one of the primary mechanisms for recovery from coronavirus disease 2019 (COVID-19). It is speculated that massive clonal expansion of B cells, which can produce clinically meaningful neutralizing antibodies, occurs in patients who recover on the timing of acquiring adaptive immunity. Methods: To evaluate fluctuations in clonal B cells and the size of the clones, we chronologically assessed the B-cell receptor (BCR) repertoire in three patients with COVID-19 who recovered around 10 days after symptom onset. Results: We focused on the three dominant clonotypes (top 3) in each individual. The percentage frequencies of the top 3 clonotypes increased rapidly and accounted for 27.8 % on day 9 in patient 1, 10.4 % on day 12 in patient 2, and 10.8 % on day 11 in patient 3, respectively. The frequencies of these top 3 clonotypes rapidly decreased as the patients' clinical symptoms improved. Furthermore, BCR network analysis revealed that accumulation of clusters composed of similar complementarity-determining region 3 (CDR3) sequences were rapidly formed, grew, and reached their maximum size around 10 days after symptom onset. Conclusions: BCR repertoire analysis revealed that a massive surge of some unique BCRs occurs during the acquisition of adaptive immunity and recovery. The peaks were more prominent than expected. These results provide insight into the important role of BCRs in the recovery from COVID-19 and raise the possibility of developing neutralizing antibodies as COVID-19 immunotherapy.Aug. 2021, Heliyon, 7(8) (8), e07748, English, International magazineScientific journal
- Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.Apr. 2021, Molecular and clinical oncology, 14(4) (4), 68 - 68, English, International magazineScientific journal
- Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.Feb. 2021, Molecular and clinical oncology, 14(2) (2), 30 - 30, English, International magazineScientific journal
- BACKGROUND/AIM: Biomarkers for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) are required. We encountered a patient whose skin irAE fluctuated in parallel with serum soluble interleukin-2 receptor (sIL-2R). PATIENTS AND METHODS: We examined 15 patients with cancer who received ICIs. Serum sIL-2R levels before and during ICI treatment were measured. The sIL-2R levels of preserved serum samples from another five patients who developed grade 3 irAEs were measured. RESULTS: Twelve patients showed no significant changes in sIL-2R levels during ICI treatment. Baseline serum sIL-2R levels in three patients increased beyond the normal range before the second cycle. These three patients had grade ≥2 irAEs at the second cycle treatment visit, supporting our hypothesis. Furthermore, at diagnosis of irAEs, the sIL-2R levels of all preserved samples from patients with grade 3 irAEs were significantly elevated. CONCLUSION: Serum sIL-2R is a promising biomarker for the diagnosis of irAEs.Corresponding, Feb. 2021, Anticancer research, 41(2) (2), 1021 - 1026, English, International magazineScientific journal
- CONTEXT: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immune cells of myeloid lineage. Recent reports have suggested that human MDSC are divided into three subsets: monocytic MDSC (M-MDSC), granulocytic MDSC (G-MDSC), and immature MDSC (I-MDSC). However, the characteristics of each human MDSC subset still remain unclear. MATERIALS AND METHODS: To evaluate the immunosuppressive effects and mechanisms, we first performed a T-cell suppression assay using cells obtained from healthy donor peripheral blood samples. The levels of immune inhibitory molecules in the culture supernatant of each MDSC subset were measured to reveal the T-cell suppressive mechanisms. Then, we compared these results with the results from cells obtained from cancer patient blood samples. Finally, we investigated the difference in the frequency of each MDSC subset between the healthy donors and the cancer patients. RESULTS: Although M-MDSC and G-MDSC suppressed T-cell activation, I-MDSC had no T-cell suppressive effect. We found that the culture supernatant of M-MDSC and G-MDSC contained high levels of interleukin-1 receptor antagonist (IL-1RA) and arginase, respectively, in both healthy donors and cancer patients. No inhibitory molecules were detected in the culture supernatant of I-MDSC. The population of functional MDSC (M-MDSC and G-MDSC) in the total MDSC was significantly increased in cancer patients compared with that in healthy donors. CONCLUSIONS: Although M-MDSC and G-MDSC, which released IL-1RA and arginase, respectively, suppressed T-cell activation, I-MDSC did not have an immunosuppressive effect. The population of functional MDSC was increased in cancer patients compared with that in healthy donors.Corresponding, 2021, Journal of cancer research and therapeutics, 17(4) (4), 1093 - 1100, English, International magazineScientific journal
- CONTEXT: There is an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies. AIMS: Therefore, we established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived peripheral blood mononuclear cells (PBMCs). SUBJECTS AND METHODS: The CRC tissues of patients scheduled for surgery were tested for MSI status, and CRC tumors were transplanted into NOD/LtSz-scid/IL-2Rg-/-(NSG) mice to establish MSI-H PDX models. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. To humanize the immune system of MSI-H PDX models, patient PBMCs were injected through the tail vein. RESULTS: PDX models were established from two patients with MSI-H CRC; one patient had a germline mutation in MLH1 (c.1990-2A > G), and the other patient had MLH1 promoter hypermethylation. PDX with the germline mutation was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H, deficient mismatch repair (dMMR), and MLH1 mutation. In contrast, the histological features of the other PDX from a tumor with MLH1 promoter hypermethylation were clearly different from those of the original tumor, and MLH1 promoter hypermethylation and MSI-H/dMMR were lost in the PDX. When T cells from the same patient with MLH1 mutation were injected into the PDX through the tail vein, they were detected in the PDX tumor. CONCLUSIONS: The MSI-H tumor with an MMR mutation is suitable for MSI-H PDX model generation. The PBMC humanized MSI-H PDX has the potential to be used as an efficient model for cancer immunotherapy research.Corresponding, 2021, Journal of cancer research and therapeutics, 17(6) (6), 1358 - 1369, English, International magazineScientific journal
- PURPOSE: We conducted a phase 1 study to determine the maximum tolerated dose and the recommended dose of gemcitabine/nab-paclitaxel/S-1 combination chemotherapy in patients with unresectable pancreatic cancer. METHODS: We enrolled patients aged 20 years or older with unresectable pancreatic cancer and who had not been treated with chemotherapy or radiation therapy. Gemcitabine and nab-paclitaxel were administered on days 1 and 8, and S-1 was administered orally twice daily for 2 weeks, repeated every 3 weeks. The starting dose was level 0 [gemcitabine 700 mg/m2, nab-paclitaxel 90 mg/m2, S-1 60/80/100 mg/day (< 1.25 m2/1.25-1.50 m2/ > 1.5 m2)]. Dose-limiting toxicities were determined during the first course, and a classical 3 + 3 dose finding design was planned. RESULTS: From March 2018 to October 2019, 20 patients were enrolled. At dose level 0, three of six patients experienced dose-limiting toxicities; one grade 3 skin rash on day 8, and two grade 3 or 4 neutropenia on day 8. At dose level-1 (gemcitabine 600 mg/m2, nab-paclitaxel 90 mg/m2, and S-1 50/70/80 mg/day), two of twelve patients experienced dose-limiting toxicities, all of which were grade 3 neutropenia on day 8. The most frequently observed toxicity during eight courses was neutropenia. Other treatment-related adverse events were mild. Eleven out of 19 (58%) patients achieved partial response. CONCLUSION: We defined the maximum tolerated dose and the recommended dose for combination therapy with gemcitabine/nab-paclitaxel/S-1 as dose level-1. Considering the observed response rate, further studies are warranted in order to determine the efficacy of this regimen (UMIN-CTR 000030007).Jan. 2021, Cancer chemotherapy and pharmacology, 87(1) (1), 65 - 71, English, International magazineScientific journal
- Intimal sarcoma of the pulmonary artery (PAIS) is a rare disease with a poor prognosis. Pazopanib, which has been indicated in metastatic non-adipocytic soft-tissue sarcomas and is expected to be active in PAIS, is a multi-kinase inhibitor that targets the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor. The present study reports findings related to two cases of PAIS with PDGF and VEGF expression following treatment with pazopanib. A case with a moderate to strong expression of PDGFR-α and -β presented a long-term stable disease when treated with pazopanib (progression-free survival, 5.8 months). In a second case with a weak expression of PDGFR-α and -β, the disease progressed rapidly on pazopanib (progression-free survival, 1.1 months). VEGFR-2 was not expressed in the tumors of both cases. The level of PDGFR expression in the tumor tissue may therefore be predictive of pazopanib efficacy.Jan. 2021, Molecular and clinical oncology, 14(1) (1), 6 - 6, English, International magazineScientific journal
- BACKGROUND: Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. METHODS: We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4 weeks. RESULTS: Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). CONCLUSIONS: These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.Springer Science and Business Media LLC, Jul. 2020, International Journal of Clinical Oncology, 25(7) (7), 1270 - 1277, English, Domestic magazineScientific journal
- (一社)日本循環器学会, Jul. 2020, 日本循環器学会学術集会抄録集, 84回, PE52 - 6, EnglishBleeding Events Associated with Anticoagulant Therapy; Apixaban in Japanese Patients with Cancer-associated Venous Thromboembolism: A Multicenter Phase II Trial(J-CAV)(和訳中)
- (一社)日本内科学会, Feb. 2020, 日本内科学会雑誌, 109(臨増) (臨増), 186 - 186, Japaneseがん免疫療法時代の再発・転移頭頸部扁平上皮癌における全身性炎症スコアの予後予測性
- (一社)日本内科学会, Feb. 2020, 日本内科学会雑誌, 109(臨増) (臨増), 226 - 226, Japanese2735人を対象とした悪性腫瘍関連静脈血栓塞栓症の合併率に関する後ろ向きコホート研究 甲状腺癌に対するチロシンキナーゼ阻害薬と血栓の関係
- (一社)日本内科学会, Feb. 2020, 日本内科学会雑誌, 109(臨増) (臨増), 259 - 259, Japanese当院における頭頸部がんに対する3-weekly高用量シスプラチン併用化学放射線療法の臨床的忍容性の検討
- {ClinMed} International Library, Sep. 2019, International Journal of Oncology Research, 2(2) (2)Scientific journal
- Tumor microenvironment plays a key role for tumor development and progression. Although adipose tissue is a predominant component of stroma in mammary tissues and secretes various cytokines, chemokines and growth factors, roles of adipocytes in breast cancers remain to be elucidated. In this study, we found that adipsin, an adipokine secreted from mammary adipose tissues, enhanced proliferation and cancer stem cell (CSC)-like properties of human breast cancer patient-derived xenograft (PDX) cells. Adipsin was predominantly expressed in both adipose tissues of the surgical specimens of breast cancer patients and adipose-derived stem cells (ADSCs) isolated from them, and its expression level was significantly higher in obese patients. ADSCs significantly enhanced the sphere-forming ability of breast cancer PDX cells derived from both estrogen receptor-positive and -negative breast cancer PDX cells. Suppression of adipsin-mediated signaling by a specific inhibitor or adipsin knockdown in ADSCs significantly decreased the sphere-forming ability and the expression of CSC markers in co-cultured breast cancer PDX cells. Growth of breast cancer PDX tumors was significantly enhanced by co-transplantation with ADSCs in vivo, and it was weakened when co-transplanted with the adipsin knocked-down ADSCs. These results suggest that adipsin is an important adipokine secreted from mammary adipose tissue that functions as a component of tumor microenvironment and a CSC niche in breast cancers.Feb. 2019, Oncogene, 38(6) (6), 767 - 779, English, International magazineScientific journal
- (一社)日本内科学会, Feb. 2019, 日本内科学会雑誌, 108(臨増) (臨増), 284 - 284, Japanese甲状腺癌に対するレンバチニブ治療中の観血的処置の安全性・予後への影響に関する遡及的検討[Refereed]
- (一社)日本がん看護学会, Jan. 2019, 日本がん看護学会誌, 33(Suppl.) (Suppl.), 214 - 214, Japanese生活支援における効果的な多職種連携 経口抗がん薬服用患者への介入
- BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer. The triple-negative subtype of IBC (TN-IBC) is particularly aggressive. Identification of molecular differences between TN-IBC and TN-non-IBC may help clarify the unique clinical behaviors of TN-IBC. However, our previous study comparing gene expression between TN-IBC and TN-non-IBC did not identify any TN-IBC-specific molecular signature. Lehmann et al recently reported that the mesenchymal stem-like (MSL) TNBC subtype consisted of infiltrating tumor-associated stromal cells but not cancer cells. Therefore, we compared the gene expression profiles between TN-IBC and TN-non-IBC patient samples not of the MSL subtype. METHODS: We classified 88 TNBC samples from the World IBC Consortium into subtypes according to the Vanderbilt classification and Insight TNBCtype, removed samples of MSL and unstable subtype, and compared gene expression profiles between the remaining TN-IBC and TN-non-IBC samples. RESULTS: In the Vanderbilt analysis, we identified 75 genes significantly differentially expressed between TN-IBC and TN-non-IBC at an FDR of 0.2. In the Insight TNBCtype analysis, we identified 81 genes significantly differentially expressed between TN-IBC and TN-non-IBC at an FDR of 0.4. In both analyses, the top canonical pathway was "Fc Receptor-mediated Phagocytosis in Macrophages and Monocytes", and the top 10 differentially regulated genes included PADI3 and MCTP1, which were up-regulated, and CDC42EP3, SSR1, RSBN1, and ZC3H13, which were downregulated. CONCLUSIONS: Our data suggest that the activity of macrophages might be enhanced in TN-IBC compared with TN-non-IBC. Further clinical and preclinical studies are needed to determine the cross-talk between macrophages and IBC cells.Lead, 2019, PloS one, 14(9) (9), e0222336, English, International magazineScientific journal
- (一社)日本癌学会, Sep. 2018, 日本癌学会総会記事, 77回, 1910 - 1910, English脂肪細胞は補体活性化経路を介して腫瘍増殖とがん幹細胞性を促進する(Adipocytes enhance tumor growth and cancer stem cell-like properties through the complement activation pathway)
- Jul. 2018, CANCER RESEARCH, 78(13) (13), English
- BACKGROUND AND OBJECTIVES: To explore whether lymphocytes in sentinel lymph nodes (SLNs) are highly exposed to tumor neoantigens and thus express high level of programmed death 1 (PD-1), we examined PD-1 expression in SLNs and non-sentinel regional lymph nodes (non-SLNs) in breast cancer. METHODS: We performed PD-1 immunohistochemistry in two cohorts: 40 metastasis-negative SLNs including 10 patients for each subtype (luminal A-like, luminal B-like, HER2, and triple negative breast cancer [TNBC]); and 25 pairs of metastasis-positive SLNs and non-SLNs (10 luminal A-like, 10 luminal B-like, and 5 TNBC). RESULTS: Among 40 metastasis-negative SLNs, 34 and 6 samples were PD-1 intensity grade 1 (low) and 2 (high), respectively. PD-1 intensity correlated with PD-1-positive lymphocyte numbers (P = 0.005); TNBC had the highest PD-1 lymphocyte numbers among all subtypes. The median PD-1-positive lymphocyte number was higher in SLNs than non-SLNs. In most cases, more lymphocytes in SLNs expressed PD-1 than those in non-SLNs (P < 0.0001). CONCLUSIONS: TNBC had the greatest PD-1 expression among all subtypes, and metastasis-positive SLNs had more PD-1-positive lymphocytes than downstream non-SLNs. These data suggested that lymphocytes in SLNs are activated following exposure to tumor neoantigens and thus tumor specific, and could be utilized as a biomarker platform.May 2018, Journal of surgical oncology, 117(6) (6), 1131 - 1136, English, International magazineScientific journal
- 3D Culture Represents Apoptosis Induced by Trastuzumab Better than 2D Monolayer Culture.BACKGROUND: Our hypothesis was that three-dimensional (3D) culture better represents differential in vivo responses to trastuzumab between PIK3CA-wild-type (wt) and mutant (mt) cell lines than does two-dimensional (2D) culture. MATERIALS AND METHODS: Apoptosis and cell signaling proteins were evaluated in response to trastuzumab with and without BKM120, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, using western blot analysis of four breast cancer cell lines with human epidermal growth factor receptor 2 (HER2) amplification. RESULTS: Increased expression of cleaved poly (ADP-ribose) polymerase (PARP) was observed only in 3D-cultured PIK3CA-wt lines in response to trastuzumab, but not in 2D-cultured PIK3CA-wt or PIK3CA-mt lines. Decrease in the ratio of phosphorylated (p-)AKT to AKT in response to trastuzumab was more profound in PIK3CA-wt cells than in PIK3CA-mt cells in 3D culture, while the difference between PIK3CA genotypes was less apparent in 2D culture. Treatment with BKM120 and trastuzumab resulted in a stronger increase in cleaved PARP than either treatment alone. CONCLUSION: 3D Culture appears to better represent trastuzumab-induced apoptosis and resistance to trastuzumab associated with PIK3CA mutation.May 2018, Anticancer research, 38(5) (5), 2831 - 2839, English, International magazineScientific journal
- (一社)日本内科学会, Feb. 2018, 日本内科学会雑誌, 107(臨増) (臨増), 189 - 189, Japanese次世代シークエンサーを用いた唾液腺導管癌・腺癌NOSの新規治療標的遺伝子の同定[Refereed]
- (一社)日本内科学会, Feb. 2018, 日本内科学会雑誌, 107(臨増) (臨増), 189 - 189, Japaneseがんクリニカルシークエンスと遺伝性腫瘍の関係[Refereed]
- Inflammatory breast cancer (IBC) is the most lethal and aggressive type of breast cancer, with a strong proclivity to metastasize, and IBC-specific targeted therapies have not yet been developed. Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in IBC. However, the mechanism behind the therapeutic effect of EGFR targeted therapy is not well defined. Here, we report that EGFR regulates the IBC cell population that expresses cancer stem-like cell (CSC) markers through COX-2, a key mediator of inflammation whose expression correlates with worse outcome in IBC. The COX-2 pathway promoted IBC cell migration and invasion and the CSC marker-bearing population in vitro, and the inhibition of this pathway reduced IBC tumor growth in vivo. Mechanistically, we identified Nodal, a member of the TGFβ superfamily, as a potential driver of COX-2-regulated invasive capacity and the CSC phenotype of IBC cells. Our data indicate that the EGFR pathway regulates the expression of COX-2, which in turn regulates the expression of Nodal and the activation of Nodal signaling. Together, our findings demonstrate a novel connection between the EGFR/COX-2/Nodal signaling axis and CSC regulation in IBC, which has potential implications for new combination approaches with EGFR targeted therapy for patients with IBC.Sep. 2017, Oncotarget, 8(40) (40), 67904 - 67917, English, International magazineScientific journal
- OBJECTIVE: Radiation-induced mucositis (RIM) in chemoradiotherapy (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance, QOL and outcome. Following retrospective reports, we conducted a randomized trial of the safety and efficacy of gabapentin for RIM-associated pain during CRT. METHODS: HNC patients (pts) receiving CRT were randomized to standard pain control (SPC) with acetaminophen and opioids, or SPC plus gabapentin (SPC+G). Gabapentin was maintained at 900mg/day for 4 weeks after CRT. Primary endpoint was maximum visual analogue scale (VAS) score during CRT, and secondary endpoints were total opioid dose, changes in QOL (EORTC QLQ-C30 and QLQ-HN 35) from baseline to 4 weeks after CRT, and adverse events. RESULTS: Twenty-two eligible Stage III or IV pts were randomly assigned to SPC or SPC+G (n=11 each). Twelve were treated in a locally advanced setting and 10 in a postoperative setting. Median maximum VAS scores, median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT tended to be higher in the SPC+G arm (47 in SPC vs. 74 in SPC+G, p=0.517; 215mg vs. 745.3mg, p=0.880; and 1260mg vs. 1537.5mg, p=0.9438, respectively), without significance. QOL analysis showed significantly worse scores in the SPC+G arm for weight gain (p=0.005). Adverse events related to gabapentin were manageable. CONCLUSIONS: This pilot study is the first prospective randomized trial of gabapentin for RIM-related pain. Gabapentin had no apparent beneficial effect. Further research into agents for RIM-related pain is warranted.Dec. 2016, Auris, nasus, larynx, 43(6) (6), 677 - 84, English, International magazineScientific journal
- PURPOSE: Creatinine clearance (Ccr) is used as a marker of renal function in cancer chemotherapy, but it is not correlated with glomerular filtration rate (GFR) after high-dose cisplatin treatment. In addition to Ccr, measured using 24-h urine collection (24-h Ccr) or Cockcroft-Gault formula (CGF), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Japanese GFR estimation equation (the Japanese equation) have been recently developed to estimate GFR for predicting renal function. However, these equations remain to be evaluated, particularly in cancer patients treated with cisplatin. Therefore, we investigated the validity of these equations for predicting the GFR in cancer patients treated with cisplatin. METHODS: GFR was measured by inulin clearance (Cin) in 50 cancer patients and compared with GFR estimated by the CKD-EPI equation, the Japanese equation, and Ccr estimated by CGF or measured by 24-h Ccr before the first and third cisplatin-containing chemotherapy cycles (considered pretreatment and posttreatment, respectively). RESULTS: Before treatment, the CKD-EPI and the Japanese equations estimated GFR with higher accuracy than Ccr. Posttreatment bias values for GFR estimation using the CKD-EPI and the Japanese equations were lower than those for Ccr. The CKD-EPI and the Japanese equations were also more precise than Ccr. However, for patients with low renal function, these equations still overestimated Cin. CONCLUSION: The CKD-EPI and the Japanese equations estimated GFR with lower bias and higher precision than Ccr pre- and postcisplatin treatment. This study is registered at UMIN: 000002167.Lead, Feb. 2016, Cancer chemotherapy and pharmacology, 77(2) (2), 281 - 8, English, International magazineScientific journal
- (一社)日本癌学会, Oct. 2015, 日本癌学会総会記事, 74回, P - 3067, Englishヒト大腸直腸がん幹細胞のマイクロRNA発現に異種移植部位がおよぼす影響
- Effect of Natural Killer Cell Infiltration on the Growth of Breast Cancer Patient-Derived Tumor XenograftsNatural killer (NK) cells, a component of the innate immunity, play important roles in tumor suppression. In this study, three human breast cancer patient-derived tumor xenografts (PDXs), established by the transplantation of surgical specimens, were passaged in immunodeficient NOD/SCID mice or NSG mice, that further lacks NK cell activity. The intensity of the relative growth suppression between NOD/SCID and NSG mice was clearly different depending on the PDX lines, and it was associated with the intensities of the CD49b-positive NK cell infiltration in the PDX tumor tissues. However, no obvious association was observed between the mRNA expression levels of the NK cell ligands in the PDX tumor cells and the intensity of NK cell infiltration into the PDX tumors. These results suggest that the suppressive effect of NK cells on the growth of breast cancer PDX is highly variable depending on the PDX lines. Further studies are needed to elucidate the molecular mechanism of NK cell infiltration in PDX tumors.Oct. 2015, 癌と化学療法, 42(10) (10), 1252 - 5, Japanese, Domestic magazine
- (株)癌と化学療法社, Oct. 2015, 癌と化学療法, 42(10) (10), 1252 - 1255, Japanese[Refereed]
- We report a mediastinal germ cell tumor (GCT) that exhibited a discrepancy between the time course of serum human chorionic gonadotropin (hCG) levels and clinical consequences. An otherwise healthy man, aged 34 years, was diagnosed with a nonseminomatous GCT, most likely embryonal carcinoma (EC), based on a mediastinal tumor biopsy. Standard chemotherapy resulted in an optimal decrease in serum hCG levels. However, multiple lesions in the liver continued to enlarge, which led to his death. Autopsy revealed few viable tumor cells in the liver, with the great majority of the tumor cells appearing to have undergone necrosis, suggesting that they responded to the chemotherapy. The residual tumor cells in the mediastinum and the liver were similar to syncytiotrophoblast cells, suggesting a choriocarcinoma (CC). On immunohistochemical analysis, the mediastinal tumor cells in the diagnostic biopsy specimen expressed both CD30 and hCG, whereas residual mediastinal and hepatic tumor cells in the autopsy specimen after chemotherapy also expressed hCG, but not CD30. These findings suggested that the patient suffered from a primary mixed GCT consisting of an EC and a CC. Both pre- and postchemotherapy tumors strongly expressed matrix metalloproteinase-2, supporting the aggressive and invasive features of the tumor phenotype. We speculate that the extremely invasive tumor destroyed normal liver structure, whereas chemotherapy and central necrosis reduced the number of viable cells themselves, causing a discordant decrease in serum hCG levels.S. Karger AG, Aug. 2015, Case Reports in Oncology, 8(2) (2), 323 - 331Scientific journal
- It is becoming recognized that screening of oncology drugs on a platform using two-dimensionally (2D)-cultured cell lines is unable to precisely select clinically active drugs; therefore three-dimensional (3D)-culture systems are emerging and show potential for better simulating the in vivo tumor microenvironment. The purpose of this study was to reveal the differential effects of chemotherapeutic drugs between 2D- and 3D-cultures and to explore their underlying mechanisms. We evaluated differences between 2D- and 3D-cultured breast cancer cell lines by assessing drug sensitivity, oxygen status and expression of Ki-67 and caspases. Three cell lines (BT-549, BT-474 and T-47D) developed dense multicellular spheroids (MCSs) in 3D-culture, and showed greater resistance to paclitaxel and doxorubicin compared to the 2D-cultured cells. An additional three cell lines (MCF-7, HCC-1954, and MDA-MB‑231) developed only loose MCSs in 3D, and showed drug sensitivities similar to those found in the 2D-culture. Treatment with paclitaxel resulted in greater increases in cleaved-PARP expression in the 2D-culture compared with the 3D-culture, but only in cell lines forming dense 3D-MCSs, suggesting that MCS formation protected the cells from paclitaxel-induced apoptosis. Hypoxia was observed only in the dense 3D-MCSs. BT-549 had fewer cells positive for Ki-67 in 3D- than in 2D-culture, suggesting that the greater G0-dormant subpopulation was responsible for its drug resistance in the 3D-culture. BT-474 had a lower level of caspase-3 in the 3D- than in the 2D-culture, suggesting that the 3D-environment was anti-apoptotic. Finally, we compared staining for Ki-67 and caspases in the 2D- and 3D-primary‑cultured cells originating from a patient-derived xenograft (PDX), fresh PDX tumor, and the patient's original tumor; 2D-cultured cells showed greater proportions of Ki-67-positive and caspase-3-positive cells, in agreement with the view that 3D-primary culture better represents characteristics of tumors in vivo. In conclusion, 3D-cultured cells forming dense MCSs may be better than 2D-cultured cells in simulating important tumor characteristics in vivo, namely hypoxia, dormancy, anti-apoptotic features and their resulting drug resistance.Apr. 2015, Oncology reports, 33(4) (4), 1837 - 43, English, International magazineScientific journal
- (一社)日本癌学会, Sep. 2014, 日本癌学会総会記事, 73回, P - 2060, EnglishNK細胞浸潤がヒト乳がん異種移植マウスの腫瘍増殖に与える影響(Effect of natural killer cell infiltration on the growth of the mouse xenografts tumors of human breast cancers)
- TYRO3 as a potential therapeutic target in breast cancer.AIM: We evaluated the potential of TYRO3 as a therapeutic target in various types of breast cancer cell lines. MATERIALS AND METHODS: The effects of TYRO3-knockdown by small interfering RNA (siRNA) on proliferation, cell-cycle distribution, and cell signaling in four estrogen receptor (ER)-positive/HER2-non-amplified (luminal-type), two ER-negative/HER2-amplified (HER2-type), and two ER-negative/HER2-non-amplified (triple negative [TN]-type) cell lines were compared. RESULTS: Whereas TYRO3 knockdown induced the greatest proliferation suppression in luminal-type cells, and to a lesser extent in HER2-type cells, no proliferation inhibition was observed in TN-type cells. The TYRO3 siRNA-induced proliferation inhibition in luminal-type cells was observed in both estradiol (E2)-rich and -null conditions. The proliferation suppression was correlated with G0-G1/S cell-cycle arrest. Western blot analysis showed a decrease in phosphorylation of ERK1/2 or STAT3, and in cyclin D1 only in cell lines sensitive to TYRO3-knockdown. CONCLUSION: TYRO3 is a potential therapeutic target in breast cancer, particularly in luminal-type cells.Jul. 2014, Anticancer research, 34(7) (7), 3337 - 45, English, International magazineScientific journal
- 2014, Journal of clinical and experimental hematopathology : JCEH, 54(2) (2), 167 - 70, English, Domestic magazineA new complex translocation t(8;11;21)(q22;q24;q22) in acute myeloid leukemia with RUNX1/RUNX1T1.
- The clinical efficacy of MET tyrosine kinase inhibitors (MET-TKIs) is hindered by the emergence of acquired resistance, presenting an obstacle to drug discovery. To clarify the mechanisms underlying acquired resistance to MET-TKIs, we established resistance models by continuous exposure of the MET-amplified gastric cancer cell line MKN45 to MET-TKIs, PHA665752 (MKN45-PR) and GSK1363089 (MKN45-GR). Baseline expression and phosphorylation of MET were elevated in MKN45-PR and MKN45-GR compared to MKN45 cells, and higher concentrations of MET-TKIs were required to inhibit MET phosphorylation compared to parental cells. Alterations in MET previously associated with resistance to MET-TKIs were observed in resistant cells, including elevated MET copy number, observed in both resistant lines compared to MKN45 cells, and the Y1230H mutation, detected in MKN45-PR cells. Notably, the growth of resistant lines was lower in the absence of MET-TKIs, suggesting "addiction" to inhibitors. While MKN45-PR cells exhibited a higher S-phase fraction in the absence of PHA665752, bromodeoxyuridine (BrdU) uptake was identical. Baseline phosphorylation of ATR, Chk1 and p53 and p21(waf1/Cip1) expression was higher in MKN45-PR compared to MKN45 cells, and levels were reduced to those observed in untreated MKN45 cells following PHA665752 treatment. Furthermore, targeted knockdown of MET enhanced the growth of MKN45-PR cells. These findings suggest that alterations in MET leading to acquired MET-TKI resistance, may cause excessive MET signaling, subsequent replication stress and DNA damage response, and intra-S-phase arrest in the absence of MET-TKIs. Thus, partial MET inhibition is necessary for resistant cells to proliferate, a phenomenon we refer to as MET-TKI "addiction".Lead, Oct. 2013, Investigational new drugs, 31(5) (5), 1158 - 68, English, International magazineScientific journal
- Targeted therapy with tyrosine kinase inhibitors, including vascular endothelial growth factor receptors, has been demonstrated to induce hypothyroidism and thyroid dysfunction. Cancer patients with thyroid dysfunction may be underdiagnosed and undertreated. Thyroid function in colorectal cancer patients receiving fluoropyrimidine-based chemotherapy with or without bevacizumab was evaluated at baseline and monthly. In the present study, 3 of 27 (11.1%) patients who received fluoropyrimidine-based chemotherapy developed a thyroid-stimulating hormone (TSH) level >10 µU/ml, and 13 (48.1%) developed an elevation above the upper limit of the normal range. No difference in TSH elevation was noted between the bevacizumab and chemotherapy-alone group (50 vs. 45%; P=1.00, respectively). Three (11.1%) patients developed a TSH level >10 µU/ml and 2 with hypothyroidism were treated with thyroid hormone replacement therapy. We demonstrated that bevacizumab does not affect thyroid function but fluoropyrimidines may induce thyroid dysfunction in patients with colorectal cancer. Further investigation is required to clarify the mechanism of fluoropyrimidine-induced thyroid dysfunction.Oct. 2013, Oncology reports, 30(4) (4), 1802 - 6, English, International magazineScientific journal
- (一社)日本リンパ網内系学会, Apr. 2013, 日本リンパ網内系学会会誌, 53, 109 - 109, English
- The purpose of this study was to clarify the mechanism of acquired resistance to the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor NVP-AEW541. We developed an acquired resistant model by continuously exposing MCF-7 breast cancer cells to NVP-AEW541 (MCF-7-NR). MCF-7 and MCF-7-NR were comparatively analyzed for cell signaling and cell growth. While phosphorylation of Akt was completely inhibited by 3 μM NVP-AEW541 in both MCF-7 and MCF-7-NR, phosphorylation of S6K remained high only in MCF-7-NR, suggesting a disconnection between Akt and S6K in MCF-7-NR. Consistently, the mTOR inhibitor everolimus inhibited phosphorylation of S6K and cell growth equally in both lines. Screening of both lines for phosphorylation of 42 receptor tyrosine kinases with and without NVP-AEW541 showed that Tyro3 phosphorylation remained high only in MCF-7-NR. Protein expression of Tyro3 was found to be higher in MCF-7-NR than in MCF-7. Gene silencing of Tyro3 using siRNA resulted in reduced cell growth and cyclin D1 expression in both lines. While Tyro3 expression was inhibited by NVP-AEW541 and everolimus in MCF-7, it was reduced only by everolimus in MCF-7-NR. These findings suggested that cyclin D1 expression was regulated in a S6K/Tyro3-dependent manner in both MCF-7 and MCF-7-NR, and that the disconnection between IGF-1R/Akt and S6K may enable MCF-7-NR to keep cyclin D1 high in the presence of NVP-AEW541. In summary, acquired resistance to NVP-AEW541 appears to result from IGF-1R/Akt-independent activation of S6K and expression of Tyro3 and cyclin D1.Apr. 2013, Investigational new drugs, 31(2) (2), 293 - 303, English, International magazineScientific journal
- BACKGROUND: Assessment of renal function is important for safe cancer chemotherapy, and eligibility criteria for clinical trials often include creatinine clearance. However, creatinine clearance overestimates glomerular filtration rate, and various new formulae have been proposed to estimate glomerular filtration rate. Because these were developed mostly in patients with chronic kidney disease, we evaluated their validity in cancer patients without kidney disease. METHODS: Glomerular filtration rate was measured by inulin clearance in 45 Japanese cancer patients, and compared with creatinine clearance measured by 24-h urine collection as well as that estimated by the Cockcroft-Gault formula, Japanese estimated glomerular filtration rate developed in chronic kidney disease patients, the Modification of Diet in Renal Disease study equation and the Chronic Kidney Disease Epidemiology Collaboration equation. The Modification of Diet in Renal Disease study and Chronic Kidney Disease Epidemiology Collaboration equations were adjusted for the Japanese population by multiplying by 0.808 and 0.813, respectively. RESULTS: The mean inulin clearance was 79.2 ± 18.7 ml/min/1.73 m(2). Bias values to estimate glomerular filtration rate for Japanese estimated glomerular filtration rate, the Cockcroft-Gault formula, creatinine clearance measured by 24-h urine collection, the 0.808 × Modification of Diet in Renal Disease study equation and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation were 0.94, 9.75, 29.67, 5.26 and -0.92 ml/min/1.73 m(2), respectively. Precision (root-mean square error) was 14.7, 22.4, 39.8, 16.0 and 14.1 ml/min, respectively. Of the scatter plots of inulin clearance versus each estimation formula, the Japanese estimated glomerular filtration rate correlated most accurately with actual measured inulin clearance. CONCLUSION: The Japanese estimated glomerular filtration rate and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation estimated glomerular filtration rate with lower bias and higher precision than the other formulae. We therefore propose Japanese estimated glomerular filtration rate for the estimation of glomerular filtration rate in Japanese cancer patients.Lead, Mar. 2013, Japanese journal of clinical oncology, 43(3) (3), 271 - 7, English, International magazineScientific journal
- We previously established acquired resistant models for MET-tyrosine kinase inhibitors (TKIs) by continuously exposing the MET-amplified gastric cancer cell line MKN45 to MET-TKIs, PHA665752 (MKN45-PR), or GSK1363089 (MKN45-GR). We found resistant mechanisms caused by increased copy number of MET in both lines and Y1230H mutation in MKN45-PR. We also found that excessive MET signaling caused by these MET alterations resulted in intra-S-phase arrest in the absence of MET-TKIs, so that cells grew faster in the presence of MET-TKIs, a phenomenon referred to as "addiction." In this study, to investigate reversibility of the acquired resistance and "addiction" to MET-TKIs and their causative MET alterations, we sequentially cultured MKN45-PR and MKN45-GR in decreasing concentrations of MET-TKIs until they were able to grow in a drug-free condition. These "revertant" cell lines (designated MKN45-PR-RE and MKN45-GR-RE) were comparatively analyzed. Growth assay showed that both MKN45-PR-RE and MKN45-GR-RE partially lost the property of "addiction" to MET-TKIs. MKN45-GR-RE lost the property of resistance to GSK1363089, but MKN45-PR-RE retained resistance to PHA665752. Copy numbers and expression and phosphorylation of MET protein reduced in both MKN45-PR-RE and MKN45-GR-RE compared with MKN45-PR and MKN45-GR, respectively, but Y1230H mutation and biochemical resistance to PHA665752 remained in MKN45-PR-RE. The "addiction" to MET-TKIs appeared attributable to increased copy number, and the property and the MET alteration were reversible. The Y1230H mutation appeared enough in itself to keep cells resistant to MET-TKIs and was irreversible.2013, Oncology research, 21(6) (6), 287 - 93, English, International magazineScientific journal
- To explore the mechanism of action of foretinib (GSK1363089), an oral multi-kinase inhibitor known to target MET, RON, AXL, and vascular endothelial growth factor receptors (VEGFRs), in gastric cancer, we evaluated the effects of the agent on cell growth and cell signaling in the following panel of gastric cancer cell lines: KATO-III, MKN-1, MKN-7, MKN-45, and MKN-74. Of these, only MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib. In MKN-45, 1 μM of foretinib or PHA665752, another MET kinase inhibitor, inhibited phosphorylation of MET and downstream signaling molecules as expected. In KATO-III, however, PHA665752 inhibited phosphorylation of MET independently of downstream molecules. Further, 1 μM of foretinib or PD173074, a selective FGFR kinase inhibitor, inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III. We confirmed this novel activity of foretinib against FGFR2 in OCUM-2M, another FGFR2-amplified gastric cancer cell line. Using a phospho-receptor tyrosine kinase array, we found that foretinib inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. Knockdown of HER3 and FGFR3 in MKN-45 with siRNA resulted in the partial inhibition of cell signaling and cell growth. In conclusion, foretinib appears effective against gastric cancer cells harboring not only MET but also FGFR2 amplification, and exerts its inhibitory effects by blocking inter-RTK signaling networks with MET or FGFR2 at their core.Aug. 2012, Investigational new drugs, 30(4) (4), 1352 - 60, English, International magazineScientific journal
- The purpose of this study was to explore the effect of trastuzumab in enhancing the activity of chemotherapeutic agents and the molecular basis of this effect. Two gastric cancer cell types with HER2 amplification, one sensitive (NCI‑N87) and one insensitive (MKN-7) to trastuzumab, were tested for the effects of trastuzumab on cell growth and cell signaling using MTS assay and western blotting, respectively. Interaction between trastuzumab and chemotherapeutic agents (fluorouracil, doxorubicin, cisplatin and paclitaxel) was evaluated by the combination index (CI). Fluorouracil-induced apoptosis was evaluated using western blot for poly (ADP-ribose) polymerase (PARP). Trastuzumab decreased phosphorylation of S6K, showed synergistic effect with fluorouracil or doxorubicin, and increased fluorouracil-induced apoptosis in NCI-N87 cells, but not in MKN-7 cells. While the mTOR inhibitor everolimus enhanced fluorouracil-induced apoptosis in both HER2-amplified cell lines, this was not the case in the gastric cancer cell lines without HER2 amplification. Consistently, while the EGFR/HER2 inhibitor Cl-387,785 inhibited cell growth of MKN-7, this growth inhibition did not accompany decrease in phosphorylation of S6K, and the compound did not enhance fluorouracil-induced apoptosis. In summary, inhibition of the mTOR/S6K signal may be a key molecular event in enhancing fluorouracil-induced apoptosis specifically in gastric cancer cells with HER2 amplification. mTOR inhibitors may therefore be attractive alternative drugs in gastric cancers with HER2 amplification regardless of their sensitivity to trastuzumab.Aug. 2012, International journal of oncology, 41(2) (2), 551 - 8, English, International magazineScientific journal
- OBJECTIVES: The t(9;11)(p22;p15) is a very rare but recurrent translocation in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) blast crisis. The translocation results in a fusion gene between NUP98 at 11p15 and PSIP1 encoding two transcriptional coactivators, p52 and p75, at 9p22. Here, we describe the first case of myelodysplastic syndrome (MDS) with t(9;11)(p22;p15). PATIENT: A 64-yr-old woman presented pancytopenia, trilineage dysplasia, and 9.2% blasts in the bone marrow, indicating the diagnosis of MDS. RESULTS: G-banding and spectral karyotyping showed 46,XX,t(9;11)(p22;p15)[20]. Reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing detected four types of NUP98/PSIP1-p52 and two types of NUP98/PSIP1-p75 fusion transcripts. Essentially, the NUP98 exon 12 or exon 11 by alternative splicing was fused in-frame with the PSIP1 exon 8. Real-time quantitative (RQ) PCR for NUP98/PSIP1/GAPDH demonstrated a 4-log decrease after cord blood transplantation and a 2-log increase at relapse. CONCLUSIONS: The fusion genes combining NUP98 exon 11/12 with PSIP1 exon 8, which have never been detected in other AML/CML cases, may be implicated in the pathogenesis of MDS. Furthermore, RQ-PCR for NUP98/PSIP1 could be useful to monitor minimal residual disease.Mar. 2012, European journal of haematology, 88(3) (3), 244 - 8, English, International magazineScientific journal
- (一社)日本内科学会, Feb. 2012, 日本内科学会雑誌, 101(Suppl.) (Suppl.), 174 - 174, Japanese切除不能高分化神経内分泌腫瘍に対するダカルバジン療法
- (一社)日本血液学会-東京事務局, Jan. 2012, 臨床血液, 53(1) (1), 118 - 119, JapaneseSMILE療法及び同種骨髄移植によって良好な経過が得られた再発・難治性NK/T細胞リンパ腫の1例
- Nov. 2011, Leukemia research, 35(11) (11), e212-4, English, International magazine
- Chromosomal translocations involving MYC at 8q24 are found in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU). Here, we describe a novel five-way translocation, t(3;9;13;8;14)(q27;p13;q32;q24;q32), involving MYC, BCL6, and the immunoglobulin heavy locus (IGH@) in a 73-year-old man with BCLU. The bone marrow was massively infiltrated with 95.6% abnormal medium- to large-sized lymphoid cells without vacuoles. Flow cytometric analyses indicated that the infiltrating cells were positive for CD10, CD19, CD20, CD25, HLA-DR, and κ chain. Immunohistochemistry revealed that they were also positive for BCL2 and CD10, and weakly positive for BCL6. The MIB1 index was approximately 99%. G-banding and spectral karyotyping demonstrated the presence of a t(3;9;13;8;14)(q27;p13;q32;q24;q32). Fluorescence in situ hybridization detected an IGH/MYC fusion signal on the der(14)t(8;14)(q24;q32). In addition, 5' and 3'BCL6 signals were separated onto the der(9)t(3;9)(q27;p13) and the der(3)t(3;14)(q27;q32), respectively. Unexpectedly, no BCL6 signal was found on the non-translocated chromosome 3. Finally, the revised karyotype was as follows: 49,XY,del(3)(q27q27),t(3;9;13;8;14)(q27;p13;q32;q24;q32), +der(6)t(6;13)(q13;q32)t(9;13)(p13;q32),+7,+12,i(18)(q10)[2]/50,sl,+7[2]/50,sl,+2[1]. These results suggest that this five-way translocation could bring about the deregulated expression of MYC on the der(14)t(8;14) and BCL6 on the der(3)t(3;14) by the IGH@ enhancer/promoter in a single event and may have contributed to the development of this BCLU.Sep. 2011, Cancer genetics, 204(9) (9), 501 - 6, English, International magazineScientific journal
- Jul. 2011, Leukemia research, 35(7) (7), e100-3, English, International magazine
- In allogeneic hematopoietic stem cell transplantation (allo-SCT), most physicians in Japan utilize granulocyte colony-stimulating factor (G-CSF) at a high dose (HD) of 300 μg/m(2) per day for filgrastim to promote faster neutrophil engraftment. However, the necessity of the HD has not been validated under graft-versus-host disease (GVHD) prophylaxis by mycophenolate mofetil (MMF), which can also be expected to facilitate engraftment. In a total of 51 patients, we compared the clinical outcomes between a standard dose (SD) fixed at 300 μg per day and a HD of G-CSF. While time to neutrophil engraftment was not different in the HD and SD groups in patients receiving cord blood transplantation (CBT, 20 vs. 17.5 days, P = 0.243) or bone marrow transplantation (BMT, 11 vs. 10 days, P = 0.227), there seemed to be an increased risk of developing acute GVHD in the HD group with CBT (20 vs. 0%, P = 0.073) and BMT (57 vs. 24%, P = 0.165). Progression-free survival of patients in the HD group was likely to be worse compared with that of the SD group with CBT (P = 0.099). In this study, the clinical benefits of a HD of G-CSF could not be documented, and we find that the use of G-CSF at a SD after allo-SCT with MMF should be prospectively evaluated.Jun. 2011, International journal of hematology, 93(6) (6), 765 - 770, English, Domestic magazineScientific journal
- Lead, 2011, Internal medicine (Tokyo, Japan), 50(8) (8), 941 - 941, English, Domestic magazineFungal endophthalmitis successfully treated with intravitreal voriconazole injection.Scientific journal
- Therapy-related pure erythroid leukemia with hepatic infiltration and hemophagocytic syndrome.Pure erythroid leukemia (PEL) is an extremely rare disorder characterized by neoplastic proliferation of immature erythroblasts. A 66-year-old man, who had received chemoradiotherapy for hypopharyngeal cancer, was admitted because of pancytopenia. Bone marrow was infiltrated with 81% proerythroblasts positive for CD71 and CD235a. An increased number of macrophages with active hemophagocytosis was also present. Chromosome analysis showed hypodiploid complex abnormalities. The patient died of progressive disease despite induction chemotherapy. Erythroblastic infiltration into the liver and hemophagocytosis in the spleen were found at autopsy. Therapy-related PEL with hemophagocytic syndrome and hepatic infiltration of PEL has never been reported.Lead, 2011, Internal medicine (Tokyo, Japan), 50(24) (24), 3031 - 5, English, Domestic magazineScientific journal
- Extension of metastatic lung tumors into the left atrium via pulmonary veins is rare. Here, we report the first case of Ewing sarcoma exhibiting such extension. A 31-year-old man with pulmonary metastasis from Ewing sarcoma presented with a mass in the left lung, extending to the left atrium through the left inferior pulmonary vein. As the patient was considered to be at risk of tumor embolism, the mass was excised surgically.Lead, Sep. 2010, Rare tumors, 2(3) (3), e53, English, International magazine
- (一社)日本血液学会-東京事務局, Sep. 2008, 臨床血液, 49(9) (9), 1034 - 1034, Japanese原発性硬化胆肝炎(PSC)経過中に発症し、生体肝移植後に貧血の改善を示した赤芽球癆(PRCA)の一例
- (一社)日本血液学会-東京事務局, Sep. 2008, 臨床血液, 49(9) (9), 1054 - 1054, Japanese成人寛解期急性リンパ芽球性白血病における臍帯血移植の有用性
- (一社)日本血液学会-東京事務局, Sep. 2007, 臨床血液, 48(9) (9), 927 - 927, Japanese類洞閉塞症候群(SOS)発症予測因子としての血小板凝集能検査の有用性
- (一社)日本血栓止血学会, May 2024, 日本血栓止血学会誌, 35(2) (2), 336 - 336, Japanese進行・再発・転移の固形腫瘍における血栓塞栓症と出血リスク PROVE-emboli試験post-hoc解析
- (一財)日本消化器病学会, Mar. 2024, 日本消化器病学会雑誌, 121(臨増総会) (臨増総会), A51 - A51, Japanese
- 2024, 日本消化器病学会雑誌(Web), 121びまん性胃癌における遺伝子変異と腫瘍免疫微小環境から考える複合免疫療法
- 泌尿器科紀要刊行会, Jul. 2023, 泌尿器科紀要, 69(7) (7), 179 - 182, JapaneseA CASE OF INFLAMMATORY MYOFIBROBLASTIC TUMOR OF THE BLADDER TREATED WITH PARTIAL CYSTECTOMY
- (一社)日本血栓止血学会, May 2023, 日本血栓止血学会誌, 34(2) (2), 195 - 195, Japanese進行・再発・転移の未治療固形がん患者における静脈血栓塞栓症の前向き観察研究の統合解析
- (一社)日本内科学会, Feb. 2023, 日本内科学会雑誌, 112(臨増) (臨増), 163 - 163, Japaneseがん関連静脈血栓塞栓症に対するアピキサバン療法の出血リスク予測 多施設共同第2相臨床試験副次的解析
- 2023, 日本腫瘍循環器学会学術集会抄録集(Web), 6th小児がん経験者の移行期医療の現状およびがん治療歴と心機能に関する解析
- 2023, 日本腫瘍循環器学会学術集会抄録集(Web), 6thがん治療前の悪性腫瘍関連下肢静脈血栓塞栓症のリスク因子に関する検討:PROVE-emboli study
- (公社)日本分析化学会, Sep. 2022, 日本分析化学会講演要旨集, 71年会, H1002 - H1002, Japanese新規マイクロ流路技術による迅速・多項目・高度な抗SARS-CoV-2抗体検査キットの開発と実証試験
- 日本分子イメージング学会, Apr. 2022, JSMI Report, 15(2) (2), 77 - 77, Japaneseアルデヒド脱水素酵素応答性turn-on型蛍光プローブを用いるがん幹細胞の可視化
- 日本分子イメージング学会, Apr. 2022, JSMI Report, 15(2) (2), 126 - 126, Japaneseアルデヒド脱水素酵素応答性turn-on型蛍光プローブを用いるがん幹細胞の可視化
- 2022, 臨床血液, 63(2) (2)SARS-CoV-2PCRが持続陽性となったDLBCLの1症例
- 2022, 日本造血・免疫細胞療法学会総会プログラム・抄録集, 44thSafety and Efficacy of SARS-CoV-2 Vaccine (BNT162b2) in Allogeneic HSCT Patients
- 2021, 医療検査と自動化(Web), 46(4) (4)マイクロ流路を用いた新型コロナウイルスの新規抗体検査キット
- 2021, 日本泌尿器科学会総会(Web), 109th前立腺生検におけるMRI検査の有用性に関する検討
- (一社)日本皮膚悪性腫瘍学会, Dec. 2020, 日本皮膚悪性腫瘍学会学術大会プログラム・抄録集, 36回, 129 - 129, JapaneseCTにて両肺野すりガラス状陰影を呈した悪性黒色腫肺転移の1例
- 2020, 日本血液学会学術集会抄録(Web), 82nd日本人悪性腫瘍関連静脈血栓塞栓症に対するapixaban療法の第II相臨床試験
- 2019, 日本がん看護学会誌(Web), 33生活支援における効果的な多職種連携~経口抗がん薬服用患者への介入~
- 2019, 日本消化器癌発生学会総会プログラム・抄録集, 30th当院における高頻度マイクロサテライト不安定性大腸癌のスクリーニング方法の検討
- 2019, 日本家族性腫瘍学会学術集会プログラム・抄録集, 25th本邦における高頻度マイクロサテライト不安定性大腸癌のスクリーニング方法の検討
- (一社)日本癌学会, Sep. 2018, 日本癌学会総会記事, 77回, 2402 - 2402, English本邦での大腸癌患者におけるマイクロサテライト不安定性検査の有用性についての検討(Universal screening with microsatellite instability testing in Japanese patients with colorectal cancer)
- 2018, 日本臨床腫瘍学会学術集会(CD-ROM), 16thPazopanibにより長期病勢安定が得られた肺動脈原発血管内膜肉腫の一例
- 2017, 日本造血細胞移植学会総会プログラム・抄録集, 40th自家末梢血幹細胞移植における栄養状態と予後に関する後方視的解析
- 2016, 日本医療薬学会年会講演要旨集(Web), 26頭頸部がん患者に対するCDDP+RT療法の腎機能による減量基準に関する検討-Cockcroft-Gault式に代入するCr値の+0.2補正について-
- (NPO)日本気管食道科学会, Apr. 2015, 日本気管食道科学会会報, 66(2) (2), s17 - s17, Japanese60
- (NPO)日本肺癌学会, Feb. 2015, 肺癌, 55(1) (1), 72 - 72, Japaneseクリゾチニブ抵抗性のALK陽性肺癌に対してアレクチニブが奏効した1例
- (一社)日本内科学会, Feb. 2015, 日本内科学会雑誌, 104(臨増) (臨増), 282 - 282, Japanese再発・転移粘膜悪性黒色腫に対するダカルバジン単剤療法の後方視的検討
- 2015, 日本臨床腫瘍学会学術集会(CD-ROM), 13th薬物療法における口腔管理と口腔有害事象の検討
- 2015, 日本臨床腫瘍学会学術集会(CD-ROM), 13th当院における前腕留置埋め込み型中心静脈ポートの合併症に関する検討
- 2015, 肺癌(Web), 55(1) (1)クリゾチニブ抵抗性のALK陽性肺癌に対してアレクチニブが奏効した1例
- Dec. 2014, BLOOD, 124(21) (21), EnglishEfficacy of the Two-Dose Influenza Vaccine in Cancer Patients Receiving Chemotherapy: A Prospective StudySummary international conference
- Oct. 2014, ANNALS OF ONCOLOGY, 25, EnglishSummary international conference
- Oct. 2014, ANNALS OF ONCOLOGY, 25, EnglishSummary international conference
- (一社)日本内科学会, Feb. 2014, 日本内科学会雑誌, 103(Suppl.) (Suppl.), 253 - 253, Japanese当院における唾液腺導管癌15例の臨床病理学的検討
- 2014, 日本臨床腫瘍学会学術集会(CD-ROM), 12th気道狭窄を伴う異なる頸部悪性腫瘍の2例
- (一社)日本癌学会, Oct. 2013, 日本癌学会総会記事, 72回, 484 - 484, English乳癌における新規治療標的としてのTyro3(Tyro3 as a potential therapeutic target in breast cancer)
- Sep. 2013, EUROPEAN JOURNAL OF CANCER, 49, S753 - S753, English25-year experience with primary major salivary gland carcinoma at a single institution in JapanSummary international conference
- 2013, 日本臨床腫瘍学会学術集会(CD-ROM), 11th再発・転移頭頸部がんに対するドセタキセル・シスプラチン併用(DC)療法
- 2013, 日本臨床腫瘍学会学術集会(CD-ROM), 11thsunitinibを使用し腸管壊死をきたしたACTH産生神経内分泌腫瘍
- Oct. 2012, ANNALS OF ONCOLOGY, 23, 161 - 161, EnglishDACARBAZINE MONO-THERAPY FOR UNRESECTABLE NEUROENDOCRINE TUMOR: A RETROSPECTIVE ANALYSISSummary international conference
- Oct. 2012, ANNALS OF ONCOLOGY, 23, 91 - 91, EnglishA PILOT RANDOMIZED TRIAL COMPARING STANDARD PAIN CONTROL WITH OR WITHOUT GABAPENTIN FOR THE TREATMENT OF PAIN RELATED TO RADIATION-INDUCED MUCOSITIS IN HEAD AND NECK CANCERSummary international conference
- (一社)日本癌学会, Aug. 2012, 日本癌学会総会記事, 71回, 335 - 335, EnglishMCF-7乳癌細胞株におけるinsulin-like growth factor 1 receptor阻害薬に対する獲得耐性機構(Mechanisms of acquired resistance to insulin-like growth factor 1 receptor inhibitor in MCF-7 breast cancer cell line)
- (一社)日本頭頸部癌学会, May 2012, 頭頸部癌, 38(2) (2), 188 - 188, Japanese頭頸部癌患者における放射線性粘膜炎による疼痛に対するガバペンチンのパイロット・ランダム化比較試験
- (一社)日本内科学会, Feb. 2012, 日本内科学会雑誌, 101(Suppl.) (Suppl.), 192 - 192, Japanese抗がん薬投与におけるeGFRの有用性の検討
- (一社)日本内科学会, Feb. 2012, 日本内科学会雑誌, 101(Suppl.) (Suppl.), 241 - 241, JapaneseExtra-Pulmonary Neuroendocrine Carcinoma(EP-NEC)に対する救済化学療法としてのアムルビシン(AMR)の効果
- 2012, 日本造血細胞移植学会総会プログラム・抄録集, 34th造血幹細胞移植前の眼科受診の意義
- 2012, 日本造血細胞移植学会総会プログラム・抄録集, 34thSMILE療法及び末梢血幹細胞移植によって良好な経過が得られた再発・難治性NK/T細胞リンパ腫の一例
- 2012, 日本内科学会雑誌, 101切除不能高分化神経内分泌腫瘍に対するダカルバジン療法
- (一社)日本検査血液学会, Jun. 2011, 日本検査血液学会雑誌, 12(学術集会) (学術集会), S79 - S79, JapaneseNPM/RARαキメラ遺伝子を認めた急性前骨髄性白血病の一例
- 2011, 日本造血細胞移植学会総会プログラム・抄録集, 33rd急性GVHD予防薬ミコフェノール酸モフェチル(MMF)使用下における移植後G-CSF至適投与量の検討
- 2011, 日本造血細胞移植学会総会プログラム・抄録集, 33rd臍帯血移植前にボリコナゾール水晶体内投与が有効であった真菌性眼内炎
- 2011, 人工知能学会言語・音声理解と対話処理研究会資料, 61st音声対話システムによる意思決定を促す発話がユーザに与える影響の分析
- (公社)日本皮膚科学会, Feb. 2010, 日本皮膚科学会雑誌, 120(2) (2), 260 - 260, Japanese歯科治療により誘発を繰り返し、気管内挿管を要した遺伝性血管浮腫(HAE)の1例
- (一社)日本内科学会, Feb. 2010, 日本内科学会雑誌, 99(Suppl.) (Suppl.), 162 - 162, Japanese結腸直腸がんに対するmFOLFOX6/FOLFIRI±Bevacizumab療法における甲状腺機能の評価
- 2010, 人工知能学会言語・音声理解と対話処理研究会資料, 58th非対称な3人会話における合意形成場面の収録と予備的分析
- (一社)日本内分泌学会, Sep. 2009, 日本内分泌学会雑誌, 85(2) (2), 512 - 512, Japanese偶発性低体温症にて救急搬送された高齢者特発性粘液水腫性昏睡の1例
- (一社)日本糖尿病学会, May 2009, 糖尿病, 52(5) (5), 386 - 386, Japanese糖尿病教育入院中、腹部エコーを契機にPreclinical Cushing症候群と診断した1例
- (一社)日本糖尿病学会, May 2009, 糖尿病, 52(5) (5), 366 - 366, JapaneseCastleman病と同時期に発症した抗インスリン抗体陽性、1型糖尿病が疑われた1例
- The Japanese Society of Hematology, Jan. 2009, 臨床血液, 50(1) (1), 3 - 8, Japanese, Domestic magazineDefibrotide therapy for patients with sinusoidal obstruction syndrome after hematopoietic stem cell transplantation
- (一社)日本内分泌学会, Dec. 2008, 日本内分泌学会雑誌, 84(3) (3), 873 - 873, Japanese下垂体機能不全を契機に診断されたTolosa-Hunt症候群の1例
- (株)南江堂, Aug. 2008, 内科, 102(2) (2), 409 - 412, JapaneseA case of successful treatment with intrahepatic arterial infusion of liposomal amphotericin-B for multiple fungal liver abscesses
- (一社)日本血液学会-東京事務局, Sep. 2007, 臨床血液, 48(9) (9), 975 - 975, Japanese多発性肝膿瘍に対し肝動脈留置カテーテルからのアムホテリシンBリポソーム製剤が奏功した急性白血病
- 63rd ASH Annual Meeting, Dec. 2021, EnglishIncrease in Antibody Titers Following Sars-Cov-2 Vaccination Remains Limited for More Than 3 Years after Final Dose of Anti-CD20 AntibodyOral presentation
- ASCO-SITC, Jan. 2019, English, サンフランシスコ, International conferenceRelationship between tumor burden to growth rate and treatment outcomes of nivolumab for patients with head and neck squamous carcinoma.Poster presentation
- 2018San Antonio Breast Cancer Symposium, Dec. 2018, English, サンディエゴ, International conferenceTP-0903, a multikinase inhibitor of AXL/JAK2/Aurora B, reduces inflammatory breastPoster presentation
- 第1回日本腫瘍循環器学会学術集会, Nov. 2018, Japanese, 日本腫瘍循環器学会, 東京, Domestic conference肺動脈原発内膜肉腫の3例Poster presentation
- 第77回日本癌学会学術集会, Sep. 2018, Japanese, 日本癌学会, 大阪, Domestic conference本邦での大腸癌患者におけるマイクロサテライト不安定性検査の有用性についての検討Poster presentation
- 第77回日本癌学会学術総会, Sep. 2018, Japanese, 日本癌学会, 大阪, Domestic conference脂肪細胞は補体活性化経路を介して腫瘍増殖とがん幹細胞性を促進するOral presentation
- 第77回日本癌学会学術集会, Sep. 2018, English, 日本癌学会, 大阪, Domestic conference脂肪細胞は補体活性化経路を介して腫瘍増殖とがん幹細胞性を促進するOthers
- 第77回日本癌学会学術総会, Sep. 2018, English, 日本癌学会, 大阪, Domestic conferenceUniversal screening with microsatellite instability testing in Japanese patients with colorectal cancerPoster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 日本臨床腫瘍学会, 神戸, Domestic conference透析中の大腸癌患者におけるオキサリプラチンのPKおよび安全性の評価Poster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 日本臨床腫瘍学会, 神戸, Domestic conference脂肪幹細胞によるアディプシンを介したヒト乳がん細胞の増殖促進Oral presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 第16回日本臨床腫瘍学会, 神戸, Domestic conferenceプラチナ抵抗性舌扁平上皮癌に対してニボルマブ投与後にStevens-Johson syndromeを発症した一例Poster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, English, 日本臨床腫瘍学会, 神戸, Domestic conferenceSynchronous esophageal cancer and multiple myeloma: a report of two casesPoster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 日本臨床腫瘍学会, 神戸, Domestic conferencePazopanibにより長期病勢安定が得られた肺動脈原発血管内膜肉腫の一例Poster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 日本臨床腫瘍学会, 神戸, Domestic conferenceEfficacy and Safety of Nivolumab for Previously Treated Non-squamous Cell Carcinoma of the Head and NeckPoster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 日本臨床腫瘍学会, 神戸, Domestic conferenceA Retrospective Analysis of Extra-pulmonary Small Cell Carcinoma Treated with Chemotherapy Concurrent with or without RadiotherapyPoster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 第16回日本臨床腫瘍学会, 神戸, Domestic conferenceA Case of Stevens-Johnson Syndrome After Administration of Nivolumab for Platinum-refractory Tongue CancerPoster presentation
- 第16回日本臨床腫瘍学会, Jul. 2018, Japanese, 日本臨床腫瘍学会, 神戸, Domestic conferenceA case of intimal sarcoma of pulmonary artery with long-term disease stabilization by pazopanibPoster presentation
- 第115回内科学会総会, Apr. 2018, Japanese, 日本内科学会, 京都, Domestic conferenceがんクリニカルシークエンスと遺伝性腫瘍の関係Poster presentation
- AACR Annual Meeting 2018, Apr. 2018, English, American Association for Cancer research, シカゴ, International conferenceアディプシンによるヒト乳がん患者由来細胞のがん幹細胞性と増殖促進Poster presentation
- 第51回制癌剤適応研究会, Mar. 2018, Japanese, 制癌剤適応研究会, 下呂, Domestic conference乳癌センチネルリンパ節におけるprogrammed death-1発現に関する検討Oral presentation
- 第40回日本造血細胞移植学会総会, Feb. 2018, Japanese, 日本造血細胞移植学会, 札幌, Domestic conference自家末梢血幹細胞移植における栄養状態と予後に関する方視的解析Poster presentation
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 01 Apr. 2024 - 31 Mar. 2027BCRレパトア解析を用いた造血幹移植後免疫再構築の解明
- 日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 01 Apr. 2023 - 31 Mar. 2027B細胞を軸とした免疫チェックポイント阻害の有害事象の包括的機序解明と効果の推定
- 公益財団法人 上原記念生命科学財団, 研究助成金, Apr. 2025 - Mar. 2026, Principal investigator抗原受容体をバイオセンサとする網羅的免疫反応評価
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), Kobe University, 30 Jun. 2023 - 31 Mar. 2025Establishment of a platform for high-throughput CAR-T cell generation for gastric cancer
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2022 - 31 Mar. 2025Development of novel cancer immunotherapies targeting functional MDSCsMDSCはがん免疫を抑制することより、がん治療の標的となると考えている。MDSCはM-MDSC、G-MDSC、I-MDSCの３つの集団に分類されるが、我々は、M-及びG-MDSCはT細胞活性を強く抑制するが、I-MDSCは抑制を示さないことを明らかにしている。よって、MDSCを一つの集団として治療標的にせず、「機能性MDSCを標的とすること」また、「抑制機構が異なるG-及びM-MDSCに対する個別の治療を開発すること」が必要である。 本年はM-MDSCがどのようにして免疫抑制作用を発揮するのか、そのメカニズムを解明することで、M-MDSCの標的分子を同定することを試みた。まず、我々は「MDSCは、免疫の活性化に反応し、その活性を抑制するために機能を発揮する」と仮説を立てた。この仮説に基づき、“通常の培養液”、“T細胞培養上清液”、“活性化T細胞培養上清液”でMDSCを培養しMDSCの変化を確認した。具体的には、MDSC培養液中に放出されるサイトカイン(IL-1RA、IL-4 、IL-5、IL-10。IL-11、IL-13、CLL17、GM-CSF)の測定をした。まず、M-MDSCを前述の３つの上清により培養した。我々はM-MDSCがIL-1RAを放出し免疫抑制機能を発揮していることを見出していたので、予測として、活性化T細胞培養上清液によってより多くのIL-1RAが放出されることを予測した。しかし、IL-1RAの放出に違いは認めなかった。一方、活性化T細胞培養上清液でM-MDSCを培養すると、その他の上清での培養と比較し、大量のCCL-17を放出することが明らかになった。我々はM-MDSCがCCL-17のレセプターであるCCR4を発現していることを確認しており、CCL-17/CCR4がM-MDSCの免疫抑制能の発揮に必要であり、CCR4は有望な治療標的候補と位置付けている。
- 神戸大学, 神戸大学GAPファンドプログラム, Apr. 2024 - Mar. 2025, Principal investigator画期的な免疫反応の評価法「QASAS法」の事業化に向けた検証~ワクチン評価から網羅的免疫センシングまで~
- 公益財団法人 ひょうご科学技術協会, 学術研究助成, Apr. 2024 - Mar. 2025, Principal investigatorレパトア解析を用いた新規抗原反応評価法による「真のネオアンチゲン」の同定
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2020 - 31 Mar. 2023Investigating whether antibody production contributes to immune-related adverse events using an acellular protein synthesis systemTo determine whether antigen-antibody reactions contribute to immune-related adverse events (irAE), B cell kinetics were analyzed in patients receiving a combination therapy of anti-CTLA-4 and anti-PD-1 antibodies. Compared to patients who did not develop irAE, CD21LowB cells, plasmablasts, and plasma cells were significantly increased in 5 patients who experienced grade 3 irAE. The BCR repertoire was analyzed in a patient who developed irAE hepatitis together with a dramatic increase in the number of activated B cells. BCR gene sequences of CD21LowB cells were ranked according to copy number, and 20 unique sequences with high copy numbers were selected for further analysis. However, single cell analysis did not detect these sequences in CD21LowB cells.
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), Kobe University, 29 Jun. 2018 - 31 Mar. 2021This study aimed to clarify the physiological significance of the CD28 IS formation rate of T cells and its relationship to cancer. First, we established a system to measure IS formation rate and compared IS formation rate between cancer patients and healthy subjects, but there was no significant difference. However, there was a significant difference in the expression of CD28 on T cells. Next, the T-cell CD28 IS formation rate and CD28 positivity rate in cancer patients did not correlate with their stage of the disease. In preoperative chemotherapy cases, there was a correlation between histological response and CD28 IS formation rate. More cases are being collected. In addition, immune checkpoint inhibitors are under investigation.Competitive research funding
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, Kobe University, 01 Apr. 2018 - 31 Mar. 2021, Principal investigatorThere has been an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies. Because conventional mouse models have limitations in cancer immunity research, we newly established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived PBMCs.
PDX models were established from three patients with MSI-H CRC. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. PDX with the germline mutation (PDX1) was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H. When T cells from the same patient with MLH1 mutation were injected into the PDX1 through the tail vein, they were detected in the PDX tumor. Finally, we performed drug (anti PD-1 antibody) test by using humanized PDX1, and we found tendency for the increased number of infiltrating T cells.Competitive research funding - 公益財団法人 伊藤忠兵衛基金, 学術研究助成金, Apr. 2019 - Mar. 2020, Principal investigator前臨床試験モデルとしての免疫ヒト化MSI-H大腸がん異種移植マウスモデルの開発