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Development of a novel microRNA-based signature for prediction of rectal neuroendocrine tumor invasion and metastasis
abstracts
Annals of Oncology
MO2 9 3
The bacteria which were detected by blood culture of 20152017: Mouth care and bacteremia during anticancer therapy
Yumi Jo1, Junji Suzumiya2, Fumiyoshi Ikejiri2, Fumimasa Takahashi2, Takahiro Okada2, Masaya Inoue2, Ichiro Moriyama2, Tsutomu Takahashi2, Takaaki Miyake2, Ritsuro Suzuki2 1 Shimane University Hospital, infection control division, 2Shimane University Hospital, Innovative Cancer Center Introduction: Recent evidence demonstrates that gram-positive bacteria are commonly found in patients with febrile neutropenia, and that this is caused by translocation of the bacteria from the intestinal tract. At the Innovative Cancer Center of our institution, we found that Escherichia coli and Streptococcus mitis/Streptococcus oralis are commonly found in blood cultures, in addition to Staphylococcus epidermidis. Objective: Our aim was to determine the types of bacteria found in blood cultures of patients receiving anti-cancer treatments in order to better define strategies for infection prevention and for selecting appropriate antibiotics. Methods: Blood cultures collected from inpatients at our hospital between April 2015 and March 2018 were analyzed to determine the presence of bacterial species. Results: E. coli was the most common bacteria found in patients with solid cancers. On the other hand, S. epidermidis was the most common bacteria in patients with hematologic cancer, followed by E. coli and S. mitis/S. oralis. S. mitis and S. oralis were detected on and after the day of oral care in these patients. Discussion: There was a difference in the prevalence of the types of bacterial species found in patients with solid cancers compared with those with hematologic cancers. Specifically, S. epidermidis was more prevalent in patients with hematologic cancers than those admitted within other departments of our institution. These findings suggest that infection in these patients may have occurred due to contamination of a sample and/or via the infusion site. We also demonstrated that the prevalence of oral bacteria was high in patients with hematologic cancers. Thus, it is necessary to re-examine the practice of antibiotic prophylaxis during oral care, especially the type of antibiotics and the duration of the treatment.
MO2 9 4
Incidence, risk factors and clinical features of febrile neutropenia in malignant lymphoma patients in our institution
Ai Mogi, Yuta Nakashima, Naoko Kunami, Maki Goto, Atsushi Togawa, Hidenori Sasaki, Toshihiro Tanaka, Toru Takata, Kazuo Tamura, Yasushi Takamatsu Division of Medical Oncology, Hematology and Infectious Disease, Department of Internal medicin, Fukuoka University Background: Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the standard treatment regimen for malignant lymphoma. CHOP-induced neutropenia is a common clinical complication that often develops into life-threatening febrile neutropenia (FN). The incidence rate of FN in malignant lymphoma patients receiving a CHOP þ rituximab regimen is approximately 10%–20% in clinical trials. Assessing FN-related factors in an individual hospital is an important step towards ensuring appropriate treatment. Therefore, we aimed to evaluate the incidence, risk factors, and clinical features related to FN in our institution and to determine the rate of treatment success in FN patients receiving antibiotics. Methods: FN-related characteristics were investigated in 182 malignant lymphoma patients who were treated with the CHOP regimen between January 2013 and December 2018. All data were retrospectively collected from the electronic medical record system. Categorical factors were compared using the Fisher’s exact test and Mann-Whitney U test. Logistic regression analysis was used to analyze FN-related risk factors. Results: Among 182 patients, 79 (43.4%) were men. Median age was 67 years. Most patients (90.7%) had an Eastern Cooperative Oncology Group performance status (PS) of 0–2. We noted 80 FN episodes in 60 patients (33.0%). On multivariate analysis, lack of granulocyte colony stimulating factor (G-CSF) prophylaxis in cycle 1 and poor PS were significantly associated with FN occurrence. Documented infections were observed in case of 35 FN episodes (43.8%), and median fever duration was 3 days. Treatment was successful without any modifications in case of 64 episodes (80%). No deaths were observed.
Volume 30 | Supplement 6 | October 2019
Conclusion: FN incidence was 33.3% at our institution. Lack of G-CSF prophylaxis and poor performance status were risk factors for FN in this setting. Use of G-CSF prophylaxis in patients with poor PS may help in decreasing FN incidence.
MO2 10 1
Development of a novel microRNA-based signature for prediction of rectal neuroendocrine tumor invasion and metastasis
Jinsei Miyoshi1, Noriaki Murayama1, Satoshi Teramae1, Yoshihiko Miyamoto1, Hironori Tanaka1, Yasuyuki Okada1, Yasuhiro Mitsui1, Yasuteru Fujino1, Takahiro Tanaka1, Kumiko Tanaka1, Keiichiro Matsumura1, Miwako Kagawa1, Tetsu Tomonari1, Shinji Kitamura1, Koichi Okamoto1, Hiroshi Miyamoto1, Yasushi Sato2, Naoki Muguruma1, Tetsuji Takayama1 1 Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 2Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences Background: Rectal neuroendocrine tumors (NETs) are the most common of GI NETs, growing in incidence. Though NETs are capable of invasion and metastasis regardless of size, currently there is no molecular marker to predict them. Accumulating evidence indicates that miRNAs have been implicated as key regulators of carcinogenesis. Aim: We sought to develop a miRNA-based signature to predict rectal NETs invasion and metastasis using comprehensive miRNA-based analysis and examined its performance. We also analyzed associated mechanisms. Methods: We performed miRNA microarray using small (1cm) rectal NETs tissues resected endoscopically to compare lymphovascular invasion (LVI)(þ) (n ¼ 7) vs. LVI(-) (n ¼ 7). Candidate miRNAs were assessed by qRT-PCR in an independent cohort (n ¼ 10). We then evaluated the diagnostic performance of the marker by qRT-PCR for the other independent cohort (n ¼ 22). Finally, we examined its metastasis-promoting mechanisms by pathway analysis program and in-vitro experiments using NET cell line H727. Results: Initially, we identified 5 most over-expressed miRNAs in LVI, of which miR144/451 were successfully validated in an alternative cohort. The miRNA signature (miR-144/451) was able to accurately discriminate LVI patients (AUC¼0.75; Sens:80%, Spec:82%). Mechanistically, we revealed miR-144/451 directly targeted PTEN/p19 and validated by immunohistochemistry. Transfection of miR-144/451 mimics into NET cells significantly increased invasion and migration. Similarly, knockdown of PTEN/p19 with siRNAs in NET cells significantly increased them. Conclusion: Using systematic and comprehensive biomarker discovery approach, we have developed and successfully validated the first novel and robust miRNA signature to detect rectal NETs invasion and metastasis and demonstrated the underlying mechanisms for invasion and metastasis. These data highlights great potential for not only the biomarker-guided treatment strategy, but therapeutic targets for rectal NET.
MO2 10 2
Aged donor derived CAR-T exhibits enhanced effector functions but shorter persistence and less memory-like phenotypes
Hiroshi Kotani1, Gongbo Li1, Jiqiang Yao2, Tania E. Mesa3, Jon Chen4, Bin Yu1, Justin C. Boucher1, Sean J. Yoder3, Jing Zhou4, Marco L. Davila5,6,7 1 Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 2Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, 3Molecular Genomics Core, H. Lee Moffitt Cancer Center and Research Institute, 4IsoPlexis Corporation, 5Morsani College of Medicine, University of South Florida, 6Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 7Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute Background: CD19 chimeric antigen receptor (CAR) T cell therapies have been successful in B cell malignancies. Recent reports about CD19 CAR T cell therapy in B-cell acute lymphoblastic leukemia suggest that the median event-free survival of children and young adult patients is longer than that of adult patients. Since the reason is unclear, we compared the functions of CAR-T derived from young or aged mice and also healthy human donors. Methods: Young and aged B6 mice spleens (6-12 vs. 72 weeks) or young and aged human PBMCs (20-26 vs. 53-60 years) were used for mouse or human CAR-T preparation. 4 types of mouse CD19 CAR and 2 types of human CD19 CAR were evaluated in T cells. Results: Aged mouse CAR-T predominates with CD8þ and effector-like phenotypes at the expense of CD4þ and memory-like phenotypes. Compared to young mouse CART, aged mouse CAR-T exhibited superior cytotoxicity for mouse CD19þ artificial antigen presenting cell (aAPC). Using our immune competent in vivo murine model, aged mouse CAR-T was short-lived and expanded poorly despite superior in vitro cytotoxicity. RNA-Seq suggestes that young mouse CAR-T is advantageous for cell proliferation and regulation of cell differentiation whereas aged mouse CAR-T up-regulates gene expression pathways that regulate responses to stimulus and exocytosis. Furthermore, compared to mouse CAR-T, human CAR-T is complementary with immune phenotypes after human CD19þ aAPC stimulation.
doi:10.1093/annonc/mdz338 | vi105
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.066/5582814 by Goteborgs Universitet user on 24 November 2019
administration. The pharmacokinetics of edoxaban was analyzed by a noncompartment and compartment model. Results: Twelve patients were enrolled from May 2016 to August 2018, and the data from 10 were able to be examined. The patients were a median 77 years of age (range: 59-91), male/female: 3/7, PS 0/1/2/3: 4/5/0/1, IIIA/IIIB/ IV (TNM 7th edition): 1/2/7, and gefitinib/erlotinib/afatinib (EGFR-TKI): 3/6/1. The PK analysis showed that there were no marked differences before and after combination administration of EGFR-TKI. The mean clearance was as follows: before, 11.7963.92 mL/min; after, 10.2462.86 mL/min. The mean half-life was as follows: before, 5.3361.75 h; after, 6.3161.07 h. Conclusions: The PK of edoxaban were not markedly influenced by the combined administration with EGFR-TKI. Funding: Daiichi Sankyo Co.,Ltd
Annals of Oncology
MO2 9 3
The bacteria which were detected by blood culture of 20152017: Mouth care and bacteremia during anticancer therapy
Yumi Jo1, Junji Suzumiya2, Fumiyoshi Ikejiri2, Fumimasa Takahashi2, Takahiro Okada2, Masaya Inoue2, Ichiro Moriyama2, Tsutomu Takahashi2, Takaaki Miyake2, Ritsuro Suzuki2 1 Shimane University Hospital, infection control division, 2Shimane University Hospital, Innovative Cancer Center Introduction: Recent evidence demonstrates that gram-positive bacteria are commonly found in patients with febrile neutropenia, and that this is caused by translocation of the bacteria from the intestinal tract. At the Innovative Cancer Center of our institution, we found that Escherichia coli and Streptococcus mitis/Streptococcus oralis are commonly found in blood cultures, in addition to Staphylococcus epidermidis. Objective: Our aim was to determine the types of bacteria found in blood cultures of patients receiving anti-cancer treatments in order to better define strategies for infection prevention and for selecting appropriate antibiotics. Methods: Blood cultures collected from inpatients at our hospital between April 2015 and March 2018 were analyzed to determine the presence of bacterial species. Results: E. coli was the most common bacteria found in patients with solid cancers. On the other hand, S. epidermidis was the most common bacteria in patients with hematologic cancer, followed by E. coli and S. mitis/S. oralis. S. mitis and S. oralis were detected on and after the day of oral care in these patients. Discussion: There was a difference in the prevalence of the types of bacterial species found in patients with solid cancers compared with those with hematologic cancers. Specifically, S. epidermidis was more prevalent in patients with hematologic cancers than those admitted within other departments of our institution. These findings suggest that infection in these patients may have occurred due to contamination of a sample and/or via the infusion site. We also demonstrated that the prevalence of oral bacteria was high in patients with hematologic cancers. Thus, it is necessary to re-examine the practice of antibiotic prophylaxis during oral care, especially the type of antibiotics and the duration of the treatment.
MO2 9 4
Incidence, risk factors and clinical features of febrile neutropenia in malignant lymphoma patients in our institution
Ai Mogi, Yuta Nakashima, Naoko Kunami, Maki Goto, Atsushi Togawa, Hidenori Sasaki, Toshihiro Tanaka, Toru Takata, Kazuo Tamura, Yasushi Takamatsu Division of Medical Oncology, Hematology and Infectious Disease, Department of Internal medicin, Fukuoka University Background: Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the standard treatment regimen for malignant lymphoma. CHOP-induced neutropenia is a common clinical complication that often develops into life-threatening febrile neutropenia (FN). The incidence rate of FN in malignant lymphoma patients receiving a CHOP þ rituximab regimen is approximately 10%–20% in clinical trials. Assessing FN-related factors in an individual hospital is an important step towards ensuring appropriate treatment. Therefore, we aimed to evaluate the incidence, risk factors, and clinical features related to FN in our institution and to determine the rate of treatment success in FN patients receiving antibiotics. Methods: FN-related characteristics were investigated in 182 malignant lymphoma patients who were treated with the CHOP regimen between January 2013 and December 2018. All data were retrospectively collected from the electronic medical record system. Categorical factors were compared using the Fisher’s exact test and Mann-Whitney U test. Logistic regression analysis was used to analyze FN-related risk factors. Results: Among 182 patients, 79 (43.4%) were men. Median age was 67 years. Most patients (90.7%) had an Eastern Cooperative Oncology Group performance status (PS) of 0–2. We noted 80 FN episodes in 60 patients (33.0%). On multivariate analysis, lack of granulocyte colony stimulating factor (G-CSF) prophylaxis in cycle 1 and poor PS were significantly associated with FN occurrence. Documented infections were observed in case of 35 FN episodes (43.8%), and median fever duration was 3 days. Treatment was successful without any modifications in case of 64 episodes (80%). No deaths were observed.
Volume 30 | Supplement 6 | October 2019
Conclusion: FN incidence was 33.3% at our institution. Lack of G-CSF prophylaxis and poor performance status were risk factors for FN in this setting. Use of G-CSF prophylaxis in patients with poor PS may help in decreasing FN incidence.
MO2 10 1
Development of a novel microRNA-based signature for prediction of rectal neuroendocrine tumor invasion and metastasis
Jinsei Miyoshi1, Noriaki Murayama1, Satoshi Teramae1, Yoshihiko Miyamoto1, Hironori Tanaka1, Yasuyuki Okada1, Yasuhiro Mitsui1, Yasuteru Fujino1, Takahiro Tanaka1, Kumiko Tanaka1, Keiichiro Matsumura1, Miwako Kagawa1, Tetsu Tomonari1, Shinji Kitamura1, Koichi Okamoto1, Hiroshi Miyamoto1, Yasushi Sato2, Naoki Muguruma1, Tetsuji Takayama1 1 Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 2Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences Background: Rectal neuroendocrine tumors (NETs) are the most common of GI NETs, growing in incidence. Though NETs are capable of invasion and metastasis regardless of size, currently there is no molecular marker to predict them. Accumulating evidence indicates that miRNAs have been implicated as key regulators of carcinogenesis. Aim: We sought to develop a miRNA-based signature to predict rectal NETs invasion and metastasis using comprehensive miRNA-based analysis and examined its performance. We also analyzed associated mechanisms. Methods: We performed miRNA microarray using small (1cm) rectal NETs tissues resected endoscopically to compare lymphovascular invasion (LVI)(þ) (n ¼ 7) vs. LVI(-) (n ¼ 7). Candidate miRNAs were assessed by qRT-PCR in an independent cohort (n ¼ 10). We then evaluated the diagnostic performance of the marker by qRT-PCR for the other independent cohort (n ¼ 22). Finally, we examined its metastasis-promoting mechanisms by pathway analysis program and in-vitro experiments using NET cell line H727. Results: Initially, we identified 5 most over-expressed miRNAs in LVI, of which miR144/451 were successfully validated in an alternative cohort. The miRNA signature (miR-144/451) was able to accurately discriminate LVI patients (AUC¼0.75; Sens:80%, Spec:82%). Mechanistically, we revealed miR-144/451 directly targeted PTEN/p19 and validated by immunohistochemistry. Transfection of miR-144/451 mimics into NET cells significantly increased invasion and migration. Similarly, knockdown of PTEN/p19 with siRNAs in NET cells significantly increased them. Conclusion: Using systematic and comprehensive biomarker discovery approach, we have developed and successfully validated the first novel and robust miRNA signature to detect rectal NETs invasion and metastasis and demonstrated the underlying mechanisms for invasion and metastasis. These data highlights great potential for not only the biomarker-guided treatment strategy, but therapeutic targets for rectal NET.
MO2 10 2
Aged donor derived CAR-T exhibits enhanced effector functions but shorter persistence and less memory-like phenotypes
Hiroshi Kotani1, Gongbo Li1, Jiqiang Yao2, Tania E. Mesa3, Jon Chen4, Bin Yu1, Justin C. Boucher1, Sean J. Yoder3, Jing Zhou4, Marco L. Davila5,6,7 1 Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 2Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, 3Molecular Genomics Core, H. Lee Moffitt Cancer Center and Research Institute, 4IsoPlexis Corporation, 5Morsani College of Medicine, University of South Florida, 6Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 7Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute Background: CD19 chimeric antigen receptor (CAR) T cell therapies have been successful in B cell malignancies. Recent reports about CD19 CAR T cell therapy in B-cell acute lymphoblastic leukemia suggest that the median event-free survival of children and young adult patients is longer than that of adult patients. Since the reason is unclear, we compared the functions of CAR-T derived from young or aged mice and also healthy human donors. Methods: Young and aged B6 mice spleens (6-12 vs. 72 weeks) or young and aged human PBMCs (20-26 vs. 53-60 years) were used for mouse or human CAR-T preparation. 4 types of mouse CD19 CAR and 2 types of human CD19 CAR were evaluated in T cells. Results: Aged mouse CAR-T predominates with CD8þ and effector-like phenotypes at the expense of CD4þ and memory-like phenotypes. Compared to young mouse CART, aged mouse CAR-T exhibited superior cytotoxicity for mouse CD19þ artificial antigen presenting cell (aAPC). Using our immune competent in vivo murine model, aged mouse CAR-T was short-lived and expanded poorly despite superior in vitro cytotoxicity. RNA-Seq suggestes that young mouse CAR-T is advantageous for cell proliferation and regulation of cell differentiation whereas aged mouse CAR-T up-regulates gene expression pathways that regulate responses to stimulus and exocytosis. Furthermore, compared to mouse CAR-T, human CAR-T is complementary with immune phenotypes after human CD19þ aAPC stimulation.
doi:10.1093/annonc/mdz338 | vi105
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.066/5582814 by Goteborgs Universitet user on 24 November 2019
administration. The pharmacokinetics of edoxaban was analyzed by a noncompartment and compartment model. Results: Twelve patients were enrolled from May 2016 to August 2018, and the data from 10 were able to be examined. The patients were a median 77 years of age (range: 59-91), male/female: 3/7, PS 0/1/2/3: 4/5/0/1, IIIA/IIIB/ IV (TNM 7th edition): 1/2/7, and gefitinib/erlotinib/afatinib (EGFR-TKI): 3/6/1. The PK analysis showed that there were no marked differences before and after combination administration of EGFR-TKI. The mean clearance was as follows: before, 11.7963.92 mL/min; after, 10.2462.86 mL/min. The mean half-life was as follows: before, 5.3361.75 h; after, 6.3161.07 h. Conclusions: The PK of edoxaban were not markedly influenced by the combined administration with EGFR-TKI. Funding: Daiichi Sankyo Co.,Ltd