Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.pan.2024.05.530

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Colorectal cancer liver metastasis (CCLM) is the most frequent cause of death of colorectal cancer. Development of novel new effective therapy is needed for CCLM patients to improve outcome. The aim of the present study was to investigate the efficacy of recombinant methioninase (rMETase) on a CCLM orthotopic mouse model of liver metastasis established using the human colon cancer cell line HT29 expressing red fluorescent protein (RFP). MATERIALS AND METHODS: Orthotopic CCLM nude mouse models were randomized into two groups: control group (n = 6, PBS 200 µl, i.p., daily); rMETase group (n = 6, 100 units/200 µl, i.p., daily). Tumor volume was measured on day 0 and day 15. Body weight was measured twice a week. All mice were sacrificed on day 15. RESULTS: rMETase significantly inhibited the increase of the liver metastasis as determined by RFP fluorescence area and intensity (p = 0.016 and 0.015, respectively). There was no significant difference of body weight between either group on any day. CONCLUSIONS: The present study suggests that rMETase has future potential therapy for CCLM in the clinic.

DOI： 10.1016/j.tice.2023.102125

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Language：Japanese   Publisher：(一社)日本胆道学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although previous studies have noted the potential benefit of early drain removal (EDR) after pancreatoduodenectomy (PD), there is a paucity of data on the timing of drain removal utilizing a national database that reflect the "real world" setting. Given the ongoing controversy related to PD drain use and management, we sought to define trends in drain use among a large national cohort, as well as identify factors associated with EDR following PD. METHODS: The ACS NSQIP targeted pancreatectomy database was used to identify patients who underwent PD between 2014 and 2020. The trend in proportion of patients with EDR (removal ≤ POD3) as well as predictors of EDR were assessed. Risk-adjusted postoperative outcomes were evaluated by multivariable regression analysis. RESULTS: Among 14,356 patients, 16.2% of patients (N = 2324) experienced EDR, and the proportion of patients with EDR increased by 68% over the study period (2014: 10.9% vs. 2020: 18.3%, p < 0.001). Higher drain fluid amylase on POD1-3 [LogWorth (LW) = 44.3], operative time (LW = 33.2), and use of minimally invasive surgery (LW = 14.0) were associated with EDR. Additionally, EDR was associated with decreased risk of overall and serious morbidity, PD-related morbidity (e.g., pancreatic fistula), reoperation, prolonged length of stay and readmission (all p < 0.05). CONCLUSIONS: Routine drain placement remains a common practice among most surgeons. EDR following PD increased over time was associated with lower post-operative complications and shorter LOS. Despite evidence that EDR was safe and may even be associated with lower complications, only 1 in 6 patients were managed with EDR.

DOI： 10.1007/s00268-023-06966-x

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Language：Japanese   Publisher：医学図書出版(株)  

胆道癌における遠隔転移はStage IVに分類され,たとえそれが限局,少数個の転移であっても積極的な切除の対象とされてこなかった。実際これまでのStage IV胆道癌の切除成績は現在行われている胆道癌化学療法の治療効果と同等であり,あえて高侵襲の胆道癌外科切除を選択するメリットは全くなかったと言える。一方で近年,乳癌などの領域では少数の遠隔転移の切除成績が良好であることから"oligometastases"という概念が広まり,乳癌を含めた一部の癌腫領域では少数の遠隔転移であれば切除が行われている。今回教室で経験した胆道癌遠隔転移症例の切除例について検討すると,1臓器5個以内のいわゆるoligometastases状態であっても一期的に転移巣と原発巣を切除した症例の予後は非常に不良であった。一方,down staging chemotherapyを行いconversion surgeryが施行できた症例の予後は良好であり,現時点で胆道癌の少数遠隔転移に対する切除術はdown staging chemotherapyを前提とすれば,その意義は高いと思われる。一方oligometastases状態は原発巣の癌悪性度の表現型とも言われており,実際には数だけで規定できるものではない。悪性度の高い胆道癌でoligometastases状態を定義するためには原発巣の病理学的因子や転移巣の数だけでなく,より癌の性質を特定するバイオマーカーの探索が必要である。(著者抄録)

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Background: Although surgery is the mainstay of curative-intent treatment for extrahepatic biliary tract cancer (EBTC), recurrence following surgery can be high and prognosis poor. The impact of neoadjuvant therapy (NAT) relative to upfront surgery (US) among patients with EBTC remains unclear. Methods: The Surveillance, Epidemiology, and End Results (SEER) databases was utilized to identify patients who underwent surgery from 2006 to 2017 for EBTC, including gallbladder cancer (GBC) and extrahepatic cholangiocarcinoma (ECC). Trends in NAT utilization were investigated, and the impact of NAT on prognosis was compared with US using a propensity score-matched (PSM) analysis. Results: Among 6582 EBTC patients (GBC, n = 4467, ECC, n = 2215), 1.6% received NAT; the utilization of NAT for EBTC increased over time (Ptrend = 0.03). Among patients with lymph node metastasis, the lymph node ratio was lower among patients with NAT (0.18 vs. 0.40, p < 0.01). After PSM, there was no difference in overall survival (OS) and cancer-specific survival (CSS) among patients treated with NAT versus US (5-year OS: 24.0% vs. 24.6%, p = 0.14, 5-year CSS: 38.0% vs. 36.1%, p = 0.21). A subgroup analysis revealed that NAT was associated with improved OS and CSS among patients with stages III-IVA of the disease (OS: HR 0.65, 95%CI 0.46-0.92, p = 0.02, CSS: HR 0.62, 95%CI 0.41-0.92, p = 0.01). Conclusions: While NAT did not provide an overall benefit to patients undergoing surgery for EBTC, individuals with advanced-stage disease had improved OS and CSS with NAT. An individualized approach to NAT use among patients with EBTC may provide a survival benefit.

DOI： 10.3390/jcm12072654

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：医学図書出版(株)  

膵癌の随伴徴候である耐糖能低下,凝固能亢進を惹起する因子について述べる。糖尿病は膵癌のリスクファクターとして広く知られているが,新規発症の糖尿病の膵癌に対する相対的リスクの高さや,膵切除後に糖尿病が改善する例があることから,膵癌自体が耐糖能低下を引き起こすことが指摘されている。その中でadrenomedullinは膵癌患者で多く発現し,インスリン分泌を抑制するとされ,注目を集めている。がん関連血栓症(cancer associated thrombosis:CAT)の中でも膵癌はとくにリスクの高い癌腫とされ,凝固能亢進においては,外因系凝固カスケードのinitiation factorである組織因子(tissue factor:TF)が膵癌患者で多く発現し,血栓形成を促す重要な役割を担っているとされる。(著者抄録)

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.

DOI： 10.1016/j.bbrc.2022.12.062

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞肝門部胆管癌に対する肝右三区域+尾状葉切除術は,もっとも大量の肝切除を伴う術式である.肝右三区域切除は肝不全をはじめとした術後合併症発生率が非常に高率であり,血行再建を伴う場合その手術難易度はさらに高度となるため,慎重な症例選択のもとに限られた専門施設で施行されるべき術式である.本稿では,肝門部胆管癌に対する肝右三区域+尾状葉切除術の適応,周術期管理,手術手技に関して,当科で経験した症例を提示しながら概説する.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00393&link_issn=&doc_id=20230302110006&doc_link_id=10.15106%2Fj_geka85_135&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_geka85_135&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: This study aimed to analyze treatment outcomes and prognostic markers, including immune and inflammatory factors, of postoperative radiation therapy (RT) administered to patients with cholangiocarcinoma (CCA). METHODS: We retrospectively included 59 patients with CCA who underwent surgery and postoperative RT with curative intent from 2004 to 2019. Patients received external irradiation (50 Gy in 25 fractions) using three-dimensional RT. We analyzed prognostic factors of inflammation, such as pre-RT platelet count, hemoglobin, lymphocyte count ratio (LCR) of the leukocyte count, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). RESULTS: Tumor stages were distributed as follows: I (n = 8), II (n = 25), III (n = 15), and IVA (n = 11). The median follow-up was 24 months. Two-year overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and locoregional control (LRC) rates were 59.5%, 62.0%, 40.1%, and 66.7%, respectively. Univariate analysis revealed that lower LCR was significantly associated with shorter PFS (p = 0.0446). There was no significant difference between the median baseline values of PLR and NLR; and age ≥75, positive regional lymph node metastases (N+), and chemotherapy after RT were significantly associated with poor OS. Multivariate analysis revealed a significant association of N+ with worse OS, PFS, and CSS and that lower LCR was significantly associated with better PFS (p = 0.0234). Among late toxicity events, two patients (3.38%) were suspected with therapy-related liver toxicity. CONCLUSIONS: Lower LCR before RT was a better prognostic factor for postoperative RT of patients with CCA.

DOI： 10.1111/ajco.13809

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Language：Japanese   Publisher：(株)へるす出版  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：医学図書出版(株)  

高齢化社会が進むにつれ,高齢胆管癌患者の数も増加傾向である。胆管癌に対する外科的切除術は,肝門部領域胆管癌に対する肝切除術と遠位胆管癌に対する膵頭十二指腸切除術に大別され,いずれも複雑で高侵襲,術後合併症も多い術式である。これまでの報告では,高齢者に対する膵頭十二指腸切除術は非高齢者と比べても,同等の安全性で施行できるとの報告が多い。しかし,高齢者肝門部領域胆管癌に対する肝切除術の安全性に関する報告は少ない。限られた報告の中でも,高齢者と非高齢者で短期・長期成績で差がないとする報告もあれば,その真逆の報告もあり,手術適応に対する客観的指標や医学的根拠が存在しない。本稿ではこれまでの報告と自施設の成績を交えて,肝門部領域胆管癌を中心に高齢者胆管癌に対する手術について概説した。高齢者であっても慎重に評価した上で手術を行えば,非高齢者と同等の予後を期待できることから,手術の意義が大きいと考える。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The efficacy of multidisciplinary treatment, including neoadjuvant treatment, in borderline resectable pancreatic cancer (BRPC) remains unclear. We assessed the efficacy of neoadjuvant chemoradiotherapy with gemcitabine and tegafu/gimearcil/oteracil (S-1) for BRPC. METHODS: In a single-center, non-randomized prospective study, neoadjuvant chemoradiotherapy (NACRT) with gemcitabine plus S-1 was administered for BRPC (no. B090312028) in 122 patients enrolled between 2009-2015. Gemcitabine plus S-1 comprised gemcitabine on days 8 and 15, and daily S-1 on days 1-14. After two courses of gemcitabine plus S-1, 30 Gy radiotherapy was administered in 10 fractions with S-1. RESULTS: Eighty-four and 38 patients had BR-PV and BR-A, respectively. No deaths occurred during NACRT. Ninety-four patients (77%) underwent resection with curative intent. R0 resection was performed in 91% of resected cases. Patients who underwent post-NACRT resection had better overall survival than did patients without resection (mean survival time [MST]: 24.7 vs. 9.6 months, 5-year-survival rate (5ysr): 30.3% vs. 0%, p<0.001). Adjuvant chemotherapy was administered in 73% of patients. MST and 5ysr of the patients treated with NACRT followed by resection and adjuvant chemotherapy were 29.6 months and 34.3%, respectively. CONCLUSIONS: Neoadjuvant chemoradiotherapy with gemcitabine and S-1 can be safely administered in BRPC and may require adjuvant chemotherapy.

DOI： 10.1002/jhbp.1245

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：医学図書出版(株)  

胆道再建を伴う肝切除術後の胆汁漏は、本術式の約1/3の症例に発症し、比較的多く遭遇する術後合併症である。胆汁漏そのものが致死的になることは少ないものの、感染のフォーカスとなり、コントロールできない場合には出血や、肝不全などの致死的合併症の引き金となることがあるため、早期に適切な対応が必要である。胆道再建を伴う肝切除術後の胆汁漏は肝切離面もしくは胆管空腸吻合の縫合不全が原因となる。いずれの場合においてもドレナージが基本治療となる。適切なドレナージを継続することでcavityの縮小をはかり、治癒をめざす。肝切離面からの非交通型胆汁漏は難治性となることもあるため、予防には術前の胆管走行の理解などの注意も必要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

Methionine addiction, found in all types of cancer investigated, is because of the overuse of methionine by cancer cells for excess transmethylation reactions. In the present study, we compared the histone H3 lysine-methylation status and degree of malignancy between methionine-addicted cancer cells and their isogenic methionine-independent revertants, selected by their growth in low concentration of methionine. The methionine-independent revertans can grow on low levels of methionine or independently of exogenous methionine using methionine precursors, as do normal cells. In the methionine-independent revertants, the excess levels of trimethylated histone H3 lysine marks found in the methionine-addicted parental cancer cells were reduced or lost, and their tumorigenicity and experimental metastatic potential in nude mice were also highly reduced. Methionine addiction of cancer is linked with malignancy and hypermethylation of histone H3 lysines. The results of the present study thus provide a unique framework to further understand a fundamental basis of malignancy.

DOI： 10.1016/j.isci.2022.104162

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) model. An important goal of PDOX-model development is facile visualization of metastasis in live mice. In the present report we evaluated tumor growth and metastasis in pancreatic cancer PDOX NOG [Non-obese diabetes (NOD)/Scid/IL2Rγnull]-and nude-mouse models using red fluorescent protein (RFP)-expressing tumor stroma to visualize the primary tumor and metastasis. MATERIALS AND METHODS: A patient-derived pancreatic cancer was initially implanted in transgenic RFP-expressing nude mice. Then, tumor fragments, which acquired RFP expressing stroma while growing in RFP-expressing nude mice were orthotopically implanted in nude and NOG mice. The primary pancreatic tumor and metastasis were observed 8 weeks after implantation. RESULTS: Lymph-node metastases expressing red fluorescence were detected only in NOG mice. Significantly faster growth of primary pancreatic tumors and a higher incidence of lymph-node metastasis occurred in NOG mice compared to nude mice. CONCLUSION: RFP-expressing tumor stroma, which traffics together with cancer cells to lymph nodes, is useful to observe tumor behavior, such as lymph-node metastasis in a PDOX NOG-mouse model which can be used for evaluation of novel anti-metastatic agents, as well as personalized therapy to identify effective drugs.

DOI： 10.21873/anticanres.15532

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/cgp.20299

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Pancreatectomy is the main curative therapeutic option for pancreatic neuroendocrine tumors (pNETs). Given the indolent behavior of pNETs and the relatively limited lifetime of elderly patients, the impact of primary site surgery (PSS) of pNETs on long-term outcomes among older patients has been a topic of debate. METHODS: Patients aged 70 or older with pNETs were identified in the Surveillance, Epidemiology and the End Results (SEER) database from 1998 to 2016. Propensity score matching was used to compare overall (OS) and cancer-specific survival (CSS) of patients who did versus did not undergo PSS. RESULTS: Among 2,319 elderly patients with pNETs, 942 patients (40.6%) underwent PSS, while 1,377 (59.4%) did not undergo PSS (non-PSS: NPSS). After propensity score matching (n = 433 in each group), PSS group had improved survival compared with the NPSS group (5-year OS: 53.4% vs. 37.3%; 5-year CSS: 77.2% vs. 58.1%, both p < 0.001). In contrast, subgroup analysis of individuals aged ≥ 80 revealed no difference in 5-year CSS (PSS: 69.2% vs. NPSS: 67.4%, p = 0.27). A subgroup analysis among patients who had small (≤ 2 cm) non-functional (NF) pNETs noted comparable long-term outcomes among patients who underwent PSS versus NPSS patients (5-year OS: 73.1% vs. 66.5%, p = 0.19; 5-year CSS: 98.5% vs. 95.2%, p = 0.14). CONCLUSIONS: Approximately 2 in 5 elderly patients with pNETs underwent PSS. While PSS was generally associated with prolonged OS and CSS among older patients, PSS was not associated with improved CSS among a subset of patients aged 80 or older, as well as among patients age ≥ 70 years with NF-pNET less than 2 cm.

DOI： 10.1007/s00268-021-06281-3

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p &lt; 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.

DOI： 10.1038/s41598-021-87553-9

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Other Link： http://www.nature.com/articles/s41598-021-87553-9

Language：Japanese   Publisher：(一社)日本消化器外科学会  

症例は55歳の男性で,肝腫瘍精査にて前医を受診し,経皮肝生検でadenocarcinomaを認め肝内胆管癌の診断となった.ERCPでは右肝管から肝門部に至る狭窄を認めた.CTでは肝右葉に45mm大の不整形な乏血性腫瘤を認め,右肝動脈を含めた右グリソン鞘への浸潤を認めた.また,肝門リンパ節腫大を認めた.以上より,肝内胆管癌(T3N1M0 cStage IVA)と診断され,前医では切除不能と判断された.GEM+CDDP療法を計10コース施行したところ治療効果判定SDであったため切除の可否を含め当科紹介となった.当科では治癒切除可能と判断し,肝右葉尾状葉切除,肝外胆管切除,胆嚢摘出術,D2郭清を施行した.病理学的には腫瘤形成型の中分化型腺癌であり,門脈浸潤・右肝管浸潤を認め,傍大動脈リンパ節を含めリンパ節転移を認めた.また,胆嚢粘膜にも癌を認め,肝内胆管癌の胆嚢転移と診断した.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although multidisciplinary treatments including the use of adjuvant therapy (AT) have been adopted for biliary tract cancers, patients with distal cholangiocarcinoma (DCC) can still experience recurrence. We sought to characterize the incidence and predictors of early recurrence (ER) that occurred within 12 months following surgery for DCC. PATIENTS AND METHODS: Patients who underwent resection for DCC between 2000 and 2015 were identified from the US multi-institutional database. Cox regression analysis was used to identify clinicopathological factors to develop an ER risk score, and the predictive model was validated in an external dataset. RESULTS: Among 245 patients included in the analysis, 67 patients (27.3%) developed ER. No difference was noted in ER rates between patients who did and did not receive AT (28.7% vs. 25.0%, p = 0.55). Multivariable analysis revealed that neutrophil-to-lymphocyte ratio (NLR), peak total bilirubin (T-Bil), major vascular resection (MVR), lymphovascular invasion, and R1 surgical margin status were associated with a higher ER risk. A DIstal Cholangiocarcinoma Early Recurrence Score was developed according to each factor available prior to surgery [NLR > 9.0 (2 points); peak T-bil > 1.5 mg/dL (1 points); MVR (2 points)]. Cumulative ER rates incrementally increased among patients who were low (0 points; 10.6%), intermediate (1-2 points; 26.8%), or high (3-5 points; 57.6%) risk (p < 0.001) in the training dataset, as well as in the validation dataset [low (0 points); 3.4%, intermediate (1-2 points); 32.7%, or high risk (3-5 points); 55.6% (p < 0.001)]. CONCLUSIONS: Among patients undergoing resection for DCC, 1 in 4 patients experienced an ER. Alternative treatment strategies such as neoadjuvant chemotherapy may be considered especially among individuals deemed to be at high risk for ER.

DOI： 10.1245/s10434-021-09811-4

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/anticanres.15115

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/anticanres.14814

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: Methionine addiction, a fundamental and general hallmark of cancer, is due to the excess use of methionine for transmethylation, and is described as the Hoffman-effect. Methionine-addicted cancer cells can revert at low frequency to methionine independence when selected under methionine-restriction. We report here that highly-malignant methionine-addicted H460 human lung-cancer cells, when selected for methionine independence, have greatly-reduced tumorigenic potential. MATERIALS AND METHODS: Methionine-addicted H460 parental cancer cells and methionine-independent revertant H460-R1 cells were injected in nude mice subcutaneously. RESULTS: When the parental H460 methionine-addicted cells were injected in nude mice at 2.5×105, 1×105 and 5×104, the cells could form tumors. In contrast, the H460-R1 methionine-independent revertant cells could not form tumors when the above-listed cell numbers were injected in nude mice. CONCLUSION: There is a tight linkage between methionine addiction and malignancy.

DOI： 10.21873/anticanres.14815

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Gastroenterological Surgery  

An 80-year-old man visited another doctor with a complaint of fever. A blood test showed hepatic dysfunction and abdominal contrast-enhanced CT revealed dilatation of the common bile duct and intrahepatic bile ducts and a poorly contrasted mass in the distal bile duct. He was referred to our department for surgical treatment. Endoscopic retrograde cholangiography revealed a 5 cm stenosis in the distal bile duct and bile juice cytology showed class IV. The patient was diagnosed with distal cholangiocarcinoma cT2N0M0 cStage IB and underwent pancreaticoduodenectomy and regional lymph node dissection. Histopathological findings revealed a spindle cell-dominated, circumferential tumor in the distal bile duct. Immunohistological staining showed that the tumor cells were positive for epithelial markers (CK and CAM5.2) and a mesenchymal marker (vimentin), and the final diagnosis was “socalled sarcomatoid carcinoma”. The patient received gemcitabine as adjuvant chemotherapy for six months and has been alive without recurrence for one year postoperatively.

DOI： 10.5833/jjgs.2020.0061

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PURPOSE: This study aimed to investigate gender-dependent antitumor immune response to neoadjuvant chemoradiotherapy (NACRT) in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: This study enrolled 58 patients (25 females and 33 males) with borderline resectable PDAC who underwent R0 surgical resection after NACRT. The resected tumor specimens were analyzed for tumor-associated macrophages (TAMs); tumor-infiltrating lymphocytes (CD8+ and CD4+ T cells); regulatory T cells; and IRF-5-expressing cells using immunohistochemical staining for CD163, CD204, CD8, CD4, Foxp3, and IRF-5 antigen. The relationship between clinicopathological features and clinical outcomes was evaluated using multivariate Cox proportional hazard analysis. RESULTS: Females had longer overall survival (P = .044) and relapse-free survival (P = .044) than males. The CD204+ TAM number was significantly lower in females than in males (P = .009). No significant difference occurred between female and male patients in other tumor-infiltrating immune cells. IRF-5+ cell number was significantly higher in female patients (P = .002). Negative correlation occurred between CD204+ cells and IRF-5-positive cells (P = .003, r = -.385). CONCLUSIONS: Female gender was an independent prognostic factor possibly due to the greater reduction in CD204+ TAM infiltration in tumors after NACRT. The beneficial effects of NACRT on TAMs' infiltration might be associated with gender-dependent IRF-5 expression.

DOI： 10.1002/jhbp.883

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BACKGROUND/AIM: The direct placement of patient tumors in 2-D culture on plastic or glass surfaces has inhibited the establishment of patient-derived cancer cells (PDCCs). The aim of the present study was to develop universal and efficient methods to prepare PDCCs. MATERIALS AND METHODS: Fragments of patient-derived xenograft (PDX) tumors established form colon cancer liver metastasis (1 mm3) were placed on Gelfoam and cultured in DMEM. RESULTS: PDX tumor fragments were cultured on Gelfoam. Cancer cells migrated from the explant and formed distinct 3-D structures in the Gelfoam. Each of the three PDCCs showed a distinct morphology. The cultures were essentially all cancer cells without fibroblasts, the opposite of what usually occurs in 2-D culture on plastic or glass. Gelfoam cultures could be readily passaged from one Gelfoam cube to anothers suggesting indefinite culture potential. CONCLUSION: A potentially universal method to establish PDCC using PDX tumors and 3-D Gelfoam histoculture was developed.

DOI： 10.21873/anticanres.14699

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Liver metastasis is a recalcitrant disease that usually leads to death of the patient. The present study established a unique patient-derived orthotopic xenograft (PDOX) nude mouse model of a highly aggressive liver metastasis of colon cancer. The aim of the present study was to demonstrate proof-of-concept that candidate drug combinations could significantly inhibit growth and re-metastasis of this recalcitrant tumor. The patient's liver metastasis was initially established subcutaneously in nude mice and the subcutaneous tumor tissue was then orthotopically implanted in the liver of nude mice to establish a PDOX model. Two studies were performed to test different drugs or drug combination, indicating that 5-fluorouracil (5-FU) + irinotecan (IRI) + bevacizumab (BEV) and regorafenib (REG) + selumetinib (SEL) had significantly inhibited liver metastasis growth (p = 0.013 and p = 0.035, respectively), and prevented liver satellite metastasis. This study is proof of concept that a PDOX model of highly aggressive colon-cancer metastasis can identify effective drug combinations and that the model has future clinical potential.

DOI： 10.1038/s41598-020-76708-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE RESEARCH  

Liver metastasis is a recalcitrant disease that usually leads to death of the patient. The present study established a unique patient-derived orthotopic xenograft (PDOX) nude mouse model of a highly aggressive liver metastasis of colon cancer. The aim of the present study was to demonstrate proof-of-concept that candidate drug combinations could significantly inhibit growth and re-metastasis of this recalcitrant tumor. The patient's liver metastasis was initially established subcutaneously in nude mice and the subcutaneous tumor tissue was then orthotopically implanted in the liver of nude mice to establish a PDOX model. Two studies were performed to test different drugs or drug combination, indicating that 5-fluorouracil (5-FU)+irinotecan (IRI)+bevacizumab (BEV) and regorafenib (REG)+selumetinib (SEL) had significantly inhibited liver metastasis growth (p=0.013 and p=0.035, respectively), and prevented liver satellite metastasis. This study is proof of concept that a PDOX model of highly aggressive colon-cancer metastasis can identify effective drug combinations and that the model has future clinical potential.

DOI： 10.1038/s41598-020-76708-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background/Aim: A more realistic mouse model of bladder cancer is necessary to develop effective drugs for the disease. Tumor models enhanced by bright fluorescent-reporter genes to follow the disease in real-time would enhance the ability to accurately predict the efficacy of various therapeutics on this particularly-malignant human cancer. Materials and Methods: A highly-fluorescent green fluorescent protein (GFP)-expressing bladder cancer model was orthotopically established in nude mice using the UM-UC-3 human bladder-cancer cell line (UM-UC-3-GFP). Fragments from a subcutaneous tumor of UM-UC-3-GFP were surgically implanted into the nude mouse bladder. Non-invasive and intra-vital fluorescence imaging was obtained with a simple imaging box. Results: The GFP-expressing orthotopic bladder tumor was imaged in realtime non-invasively as well as intra-vitally, with the two methods correlating at r=0.99. Conclusion: This is the first noninvasive-fluorescence-imaging orthotopic model of bladder cancer and can be used for rapidly screening novel effective agents for this recalcitrant disease.

DOI： 10.21873/invivo.12158

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

Background/Aim: Dedifferentiated liposarcoma (DDLPS) is recalcitrant type of sarcoma. DDLPS has a low survival rate with high recurrence and metastasis. In the present study, we evaluated the efficacy of several drugs against doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model for precision oncology. To establish the PDOX model, a tumor from a patient who had recurrent high-grade DDLPS from the retroperitoneum was previously grown orthotopically in the retroperitoneum of nude mice. Materials and Methods: We randomized DDLPS PDOX models into 8 treatment groups when tumor volume became approximately 100 mm3: Control, no treatment
G2, doxorubicin (DOX)
G3, pazopanib (PAZ)
G4, gemcitabine (GEM) combined with docetaxel (DOC)
G5, trabectedin (YON)
G6, temozolomide (TEM)
G7, palbociclib (PAL)
G8, eribulin (ERB). Tumor length and width were measured both at the beginning and at the end of treatment. Results: At the end of treatment (day 14), all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control, except DOX. ERB was significantly more effective and regressed tumor volume compared to other treatments on day 14 after initiation of treatment. No significant differences were found in the relative body weight on day 14 compared to day 0 in any group. Conclusion: The clinical potential of ERB against DDLPS is herein presented in a PDOX model.

DOI： 10.21873/cgp.20194

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Methionine addiction is a fundamental and general hallmark of cancer. Gene expression analysis showed that methionine restriction (MR) of methionine-addicted cancer cell increases TNF-related apoptosis-induced ligand receptor-2 (TRAIL-R2) expression. Here, we determined the effects of MR on TRAIL-R2 targeted therapy in pancreatic cancer by the TRAIL-R2 agonist tigatuzumab. Human pancreatic cancer cell lines were cultured in control or methionine-free medium. The effects of MR on TRAIL-R2 expression and sensitivity to tigatuzumab were evaluated in vitro. An orthotopic pancreatic cancer mouse model was established to evaluate the efficacy of MR using oral recombinant methioninase (o-rMETase), and the efficacy of tigatuzumab and their combination. MR enabled tigatuzumab-induced apoptosis, by increasing TRAIL-R2 expression in pancreatic cancer cells in vitro. The protein expression level of the melanoma-associated antigen MAGED2, which reduces TRAIL-R2 expression, was decreased by MR. In the orthotopic pancreatic cancer mouse model, o-rMETase increased TRAIL-R2 expression level in the tumors and enabled the antitumor efficacy of tigatuzumab. MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic cancer.

DOI： 10.1016/j.canlet.2020.07.034

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

Background/Aim: Brain metastases are found in approximately 30% of patients with epidermal-growth-factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We compared the efficacy of two EGFR-tyrosine kinase inhibitors (TKIs), erlotinib and osimertinib on a PC-9-GFP EGFR mutant NSCLC growing in the brain of nude mice. Materials and Methods: The brain metastasis models were randomized into five groups and treated for 15 days: Control
5 mg/kg erlotinib
50 mg/kg erlotinib
0.5 mg/kg osimertinib
5 mg/kg osimertinib. Tumor volume was evaluated by non-invasive fluorescence imaging. Results: Only 5 mg/kg osimertinib, a low-dose compared to the clinically-equivalent dose, showed significant tumor regression compared to the control. Conclusion: This study strongly supports the high activity of osimertinib for intracranial lesions of EGFR-mutant NSCLC.

DOI： 10.21873/invivo.11871

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BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In this study, we determined drug sensitivity for a triple-negative MPBC, without BRCA mutations, in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The MPBC PDOX model was established in the left 2nd mammary gland of nude mouse by implantation of the patient tumor using surgical orthotopic implantation (SOI). We randomized MPBC PDOX mice into 5 groups (n=5 mice/per treatment group) when the tumor volume reached 80 mm3: G1, control-no treatment; G2, bevacizumab [intra-peritoneal (i.p.), weekly, for 2 weeks]; G3, vinorelbine (i.p., weekly, for 2 weeks); G4, olaparib (oral., daily, for 2 weeks); G5, eribulin [intravenous (i.v.), weekly, for 2 weeks]. The mice in each treatment group were sacrificed on day 15. Tumor volume and body weight were measured once/week. RESULTS: The MPBC PDOX model was resistant to olaparib (p=0.22). The MPBC PDOX model treated with bevacizumab and vinorelbine showed significantly suppressed tumor growth compared to the untreated group (p=0.005 and 0.002, respectively). However, only eribulin regressed the tumor (p=0.0001). Eribulin was more effective than olaparib (p=0.0001), bevacizumab (p=0.0025) and vinorelbine (p=0.0061). CONCLUSION: Eribulin has clinical potential as treatment for triple-negative MPBC patients that are resistant to a PARP inhibitor such as olaparib.

DOI： 10.21873/anticanres.14221

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BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. RESULTS: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). CONCLUSION: Eribulin has clinical potential for triple-negative MPBC patients.

DOI： 10.21873/anticanres.14217

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BACKGROUND/AIM: Dedifferentiated liposarcoma (DDLPS) is associated with a poor survival rate even with multi-modality treatment. In the present study, we evaluated the efficacy of recombinant methioninase (rMETase) combined with tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R against a doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: A recurrent high-grade DDLPS from the right retroperitoneum of a patient was grown orthotopically in the retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomly divided into the following groups: Control, no treatment; doxorubicin monotherapy; rMETase monotherapy; S. typhimurium A1-R monotherapy; S. typhimurium A1-R and rMETase combination therapy. Tumor length and width were measured before and after treatment. RESULTS: On day 14 after treatment, all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control except for doxorubicin monotherapy. rMETase combined with S. typhimurium A1-R was significantly more effective and regressed tumor volume compared to either rMETase or S. typhimurium A1-R alone. The relative body weight did not significantly differ between days 0 and 14 for individual groups. CONCLUSION: The combination of rMETase and S. typhimurium A1-R has important clinical potential for this recalcitrant sarcoma.

DOI： 10.21873/anticanres.14222

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Cancer cells are methionine (MET) and methylation addicted and are highly sensitive to MET restriction. The present study determined the efficacy of oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, decitabine (DAC) on restricting MET in an undifferentiated-soft tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) nude-mouse model. The USTS PDOX models were randomized into five treatment groups of six mice: Control; doxorubicin (DOX) alone; DAC alone; o-rMETase alone; and o-rMETase-DAC combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only in the o-rMETase-DAC condition. Tumors treated with the o-rMETase-DAC combination exhibited tumor necrosis with degenerative changes. This study demonstrates that the o-rMETase-DAC combination could arrest the USTS PDOX tumor suggesting clinical promise.

DOI： 10.1016/j.bbrc.2019.12.024

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Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.

DOI： 10.1016/j.tranon.2019.10.005

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Sarcoma is a rare and recalcitrant malignancy. Although immune and novel targeted therapies have been tested on many cancer types, few sarcoma patients have had durable responses with such therapy. Doxorubicin and cisplatinum are still first-line chemotherapy after four decades. Our laboratory has established the patient-derived orthotopic xenograft (PDOX) model using surgical orthotopic implantation (SOI). Many promising results have been obtained using the sarcoma PDOX model for identifying effective approved drugs and experimental therapeutics, as well as combinations of them for individual patients. In this review, we present our laboratory's experience with PDOX models of sarcoma, and the ability of the PDOX models to identify effective approved agents, as well as experimental therapeutics.

DOI： 10.1016/j.canlet.2019.10.028

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© 2020 Elsevier Inc. Methionine addiction is a fundamental and general hallmark of cancer. Methionine addiction prevents cancer cells, but not normal cells from proliferation under methionine restriction (MR). Previous studies reported that MR altered the histone methylation levels in methionine-addicted cancer cells. However, no study has yet compared the status of histone methylation status, under MR, between cancer cells and normal cells. In the present study, we compared the histone methylation status between cancer cells and normal fibroblasts of H3K4me3 and H3K9me3, using recombinant methioninase (rMETase) to effect MR. Human lung and colon cancer cell lines and human normal foreskin fibroblasts were cultured in control medium or medium with rMETase. The viability of foreskin fibroblasts was approximately 10 times more resistant to rMETase than the cancer cells in vitro. Proliferation only of the cancer cells ceased under MR. The histone methylation status of H3K4me3 and H3K9me3 under MR was evaluated by immunoblotting. The levels of the H3K4me3 and H3K9me3 were strongly decreased by MR in the cancer cells. In contrast, the levels of H3K4me3 and H3K9me3 were not altered by MR in normal fibroblasts. The present results suggest that histone methylation status of H3K4me3 and H3K9me3 under MR was unstable in cancer cells but stable in normal cells and the instability of histone methylation status under MR may determine the high methionine dependency of cancer cells to survive and proliferate.

DOI： 10.1016/j.bbrc.2020.09.108

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DOI： 10.1016/j.clnesp.2019.07.017

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Multidrug resistance (MDR) which results in chemoresistance is a major problem in osteosarcoma. P-glycoprotein (P-gp) plays a critical role in MDR by pumping out chemotherapy agents. Peroxisome proliferator activated receptor gamma (PPARγ) is a nuclear receptor involved in cellular differentiation and proliferation. Recently, a correlation between the expression and activity of PPARγ and the expression of P-gp-associated with MDR, has been reported in several human cancers. The present study determined if pioglitazone (PIO), a PPARγ agonist, could modulate P-gp and overcome doxorubicin (DOX)-resistance in a patient-derived orthotopic xenograft (PDOX) model of osteosarcoma. P-gp mRNA expression was quantified in 143B human osteosarcoma cells treated with DOX with/without PIO. The osteosarcoma PDOX models were randomized into four treatment groups of six mice: Control; PIO alone; DOX alone; DOX and PIO combination. Tumor size and body weight were measured during the 14 days of treatment. DOX significantly induced P-gp mRNA in a dose-dependent manner in 143B cells. PIO inhibited the increase of P-gp mRNA induced by DOX treatment when co-administrated with DOX. Tumor growth was inhibited the most by the DOX-PIO combination. Tumors treated with the DOX-PIO combination also had the most tumor necrosis. This study suggests that the DOX-PIO combination could be used in the clinic for osteosarcoma patients who develop DOX-resistance.

DOI： 10.1016/j.biopha.2019.109356

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BACKGROUND/AIM: Gemcitabine is standard first-line treatment for patients with advanced pancreatic cancer, however the efficacy is limited. Although acquired drug resistance and side-effects are known to limit efficacy, opposite effects of a drug, which enhance the malignancy of treated cancer, have been observed but are not well understood. The aim of the present study was to determine whether gemcitabine has such opposite effects on the BxPC-3 human pancreatic cancer cell line expressing green fluorescent protein (BxPC-3-GFP) in an orthotopic mouse model. MATERIALS AND METHODS: BxPC-3-GFP tumors grown subcutaneously in nude mice were harvested. Tumor fragments were orthotopically implanted in the tail of the pancreas of nude mice using the technique of surgical orthotopic implantation. The BxPC-3-GFP orthotopic models were divided randomly into three groups: Group 1: untreated control; Group 2: low-dose gemcitabine (weekly intraperitoneal injection at 25 mg/kg for 6 weeks); Group 3: high-dose gemcitabine (weekly intraperitoneal injection at 125 mg/kg for 6 weeks). Each group comprised eight mice. Tumor size, fluorescent area of metastases, and body weight were measured. RESULTS: Low- and high-dose gemcitabine inhibited primary tumor growth in a dose-dependent manner, and to the greatest extent by high-dose gemcitabine compared to the untreated control (p=0.0134). In contrast, the extent of metastasis on the peritoneum was significantly increased by low-dose gemcitabine compared to the untreated control (p=0.0112). The extent of metastasis showed no significant difference between the untreated control and mice treated with high-dose gemcitabine. Body weight of the treated mice was not significantly different from that of the untreated mice. CONCLUSION: The use of very bright GFP expressing of BxPC-3 cells and the orthotopic model demonstrated an unexpected increase in metastasis by low-dose gemcitabine. Future experiments will investigate the mechanism of this phenomenon.

DOI： 10.21873/anticanres.13726

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BACKGROUND: Osteosarcoma is a recalcitrant disease treated with surgery and intensive chemotherapy as standard. The 5-year survival rate of patients with relapsed and lung metastatic osteosarcoma is as low as 20%. MATERIALS AND METHODS: A 16-year-old patient developed left distal femoral high-grade osteosarcoma and underwent cisplatinum-based neoadjuvant chemotherapy and surgery. From the resected tumor, a patient-derived orthotopic xenograft (PDOX) model was established in the femur of nude mice. PDOX models were randomized into the following groups: untreated control, or treatment with doxorubicin (3 mg/kg, i.p., weekly for 14 days), sunitinib (40 mg/kg, oral gavage, daily for 14 days), pazopanib (100 mg/kg, oral gavage, daily for 14 days), temozolomide(25 mg/kg, oral gavage, daily for 14 days), and eribulin (1.5 mg/kg, i.p., daily for 14 days). Tumor volume and body weight were monitored twice a week. RESULTS: The osteosarcoma PDOX was resistant to doxorubicin, sunitinib, and pazopanib. In contrast, eribulin and temozolomide arrested tumor growth. CONCLUSION: This study demonstrated the utility of the PDOX model in allowing effective from non-effective drugs to be distinguished in a model in which the tumor was growing on the organ corresponding to that of the patient.

DOI： 10.21873/anticanres.13661

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BACKGROUND/AIM: Osteosarcoma is a rare but recalcitrant type of bone cancer. To discover an effective therapy for osteosarcoma, we used a patient-derived orthotopic xenograft (PDOX) mouse model. A PDOX mouse model has been established for all major cancer types. Strong synergistic efficacy of sorafenib (SFN) and everolimus (EVL) has been demonstrated in several cancers. In the present study, we examined the efficacy of a SFN and EVL combination on a doxorubicin (DOX)-resistant osteosarcoma PDOX. MATERIALS AND METHODS: The osteosarcoma PDOX models were randomly divided into five treatment groups, each containing six mice: Control; DOX; SFN; EVL; and a combination of SFN and EVL. Mice were treated for 14 days. To observe the efficacy of these treatments, tumor size and body weight were measured, and histological sections were analyzed. RESULTS: Tumor growth regression was observed only in the mice treated with the combination of SFN-EVL. Histological analysis revealed necrosis with degenerative changes in tumors treated with a combination of SFN-EVL. CONCLUSION: A SFN-EVL combination could be a novel effective treatment option for osteosarcoma.

DOI： 10.21873/anticanres.13662

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BACKGROUND/AIM: Osteosarcoma is a recalcitrant neoplasm which occurs predominantly in adolescents and young adults. Recently, using a patient-derived orthotopic xenograft (PDOX) model of malignant soft-tissue sarcoma (STS), we showed that oral recombinant methioninase (o-rMETase), in combination with caffeine, was more efficacious than o-rMETase alone in inhibiting STS tumor growth. In the present report, we determined the efficacy of o-rMETase combined with oral caffeine on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into seven treatment groups (6 mice in each group): untreated control; CDDP alone; o-rMETase alone; o-rMETase with caffeine; CDDP plus o-rMETase; CDDP plus caffeine; and CDDP plus o-rMETase with caffeine. Tumor size and body weight were measured throughout the treatment. RESULTS: Tumors regressed after treatment with CDDP plus o-rMETase with caffeine. Tumors treated with CDDP plus o-rMETase with caffeine also had the most necrosis. CONCLUSION: The combination of o-rMETase and caffeine together with first-line chemotherapy was efficacious for drug-resistant osteosarcoma and has clinical potential in the treatment of this highly-resistant neoplasm.

DOI： 10.21873/anticanres.13646

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BACKGROUND/AIM: Liver metastasis in colorectal-cancer is a recalcitrant disease. To develop precision individualized therapy of this disease, we developed a patient-derived orthotopic xenograft (PDOX) model of colorectal-cancer liver metastasis. In the present report, we evaluated the efficacy of oral recombinant methioninase (o-rMETase) in combination with 5-fluorouracil (5-FU) and oxaliplatinum (OXA) on the colorectal-cancer liver metastasis PDOX mouse model. MATERIALS AND METHODS: Colorectal-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Group 1, untreated control with phosphate buffered saline (PBS); Group 2, treated with 5-FU + OXA; and Group 3, treated with 5-FU + OXA + o-rMETase. RESULTS: The colorectal-cancer liver metastasis PDOX model was resistant to 5-FU + OXA (p=0.83 at day 15 of treatment, Group 2). In contrast, the colorectal-cancer liver metastasis PDOX model was arrested by o-rMETase combined with 5-FU + OXA (p<0.01 at day 15, Group 3). No significant body-weight differences were observed among the groups. CONCLUSION: The combination therapy of 5-FU and OXA with o-rMETase can overcome the resistance of first line drugs for colorectal-cancer liver metastasis.

DOI： 10.21873/anticanres.13648

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Liposarcoma (LS) is a chemotherapy-resistant disease. The aim of the present study was to find precise therapy for a recurrent dedifferentiated liposarcoma (DDLS) in a patient-derived orthotopic xenograft (PDOX) model. The DDLS PDOX models were established orthotopically in the right inguinal area of nude mice. The DDLS PDOX models were randomized into five groups: untreated; doxorubicin (DOX); gemcitabine (GEM) combined with docetaxel (DOC); pazopanib (PAZ); and yondelis (YON). On day 15, all mice were sacrificed. Measurement of tumor volume and body weight were done two times a week. The DDLS PDOX was resistant to DOX (P > 0.184). YON suppressed tumor growth significantly compared to control group (P < 0.027). However, only GEM combined with DOC arrested the tumor growth (P < 0.001). These findings suggest that GEM combined with DOC has clinical potential for this and possibly other DDLS patients.

DOI： 10.1016/j.biopha.2019.109093

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Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of the present study was to determine the efficacy of the combination of olaratumab (OLA), doxorubicin (DOX), and cisplatinum (CDDP) on osteosarcoma, which is resistant to first-line therapy, in a patient-derived orthotopic xenograft (PDOX) model. The osteosarcoma PDOX model was randomized into six treatment groups of six mice: control; CDDP alone; DOX and CDDP; OLA + DOX; OLA + CDDP; and OLA + DOX and CDDP. Tumor size and body weight were measured during 14 days of treatment. Tumor growth was regressed only by the treatment with a combination of OLA + DOX and CDDP. Tumors treated with this three-drug combination had the most tumor necrosis and the lowest Ki-67 index. The present study demonstrates the power of the PDOX model to identify novel effective treatment strategy for chemotherapy-resistant osteosarcoma.

DOI： 10.1016/j.tranon.2019.06.002

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BACKGROUND/AIM: Recurrent osteosarcoma is a recalcitrant disease; therefore, an improved strategy is urgently needed to provide therapy. In order to develop a novel strategy for this disease, our lab has developed a patient-derived orthotopic xenograft (PDOX) mouse model for osteosarcoma. The combination of sorafenib (SFN) and palbociclib (PAL) was shown to be effective of hepatocellular carcinoma. However, whether this combination is efficacious on osteosarcoma has not been reported. The aim of this study was to determine the efficacy of the SFN and PAL combination on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into five treatment groups: untreated-control, CDDP, SFN, PAL and the combination of SFN and PAL. RESULTS: Of these agents, the SFN-PAL combination significantly regressed tumor growth, and enhanced tumor necrosis with degenerative changes in the osteosarcoma PDOX. CONCLUSION: The SFN-PAL combination is an effective treatment strategy for osteosarcoma and therefore holds promise for clinical efficacy.

DOI： 10.21873/anticanres.13565

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DOI： 10.21873/anticanres.13563

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BACKGROUND/AIM: Patient-derived orthotopic xenograft (PDOX) models have patient-like clinical features and may be imaged, in case of some cancers, by passaging of the tumors through transgenic nude mice expressing red-fluorescent protein (RFP) where they stably acquire RFP expressing stroma. The aim of the present study was to quantify red fluorescent area and intensity in colon-cancer peritoneal metastases in PDOX models in non-transgenic nude mice after passage in RFP transgenic nude mice by non-invasive external fluorescence imaging. MATERIALS AND METHODS: Tumor fragments originating from a colon cancer patient with peritoneal metastases were implanted in transgenic RFP nude mice. Resultant tumors were harvested, and fragments were implanted in the same strain a second time. Passaged tumors stably acquired RFP-expressing stroma from their transgenic hosts. The tumor with RFP-expressing stromal cells were harvested and implanted orthotopically in non-transgenic nude mice. At eight weeks post-implantation, non-invasive external RFP images were obtained. RFP area and intensity were measured and correlated with tumor weight and volume. RESULTS: Metastatic patient colon cancer can be stably and brightly labeled by passage in transgenic RFP-expressing nude mice such that tumor growth could be non-invasively imaged. Tumor growing could be non-invasively imaged when passaged to non-transgenic nude mice. A strong correlation between fluorescence intensity and area values with tumor weight and volume were established by external fluorescence imaging. CONCLUSION: This new tumor model of metastatic colon cancer can be used to evaluate novel therapeutics in real time for this recalcitrant disease.

DOI： 10.21873/anticanres.13492

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Olaratumab (OLA), a monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα), has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), with limited efficacy. The goal of the present study was to determine the efficacy of OLA in combination with DOX and ifosfamide (IFO) on STS. Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish USTS patient-derived orthotopic xenograft (PDOX) model. USTS PDOX tumors were treated with OLA alone, DOX alone, DOX combined with IFO, OLA combined with DOX or IFO, and OLA combined with DOX and IFO. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested by OLA combined with DOX and IFO. Tumors treated with OLA combined with DOX and IFO had the most necrosis. The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, DOX and IFO for soft-tissue sarcomas.

DOI： 10.1016/j.canlet.2019.03.003

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PURPOSE: Olaratumab (OLA) is a monoclonal antibody against platelet-derived growth factor receptor alpha. OLA has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), but with limited efficacy. The goal of present study was to determine the efficacy of OLA combined with gemcitabine (GEM) and docetaxel (DOC) on a chemotherapy-resistant STS patient-derived orthotopic xenograft (PDOX). METHODS: Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The USTS PDOX was treated with GEM alone, GEM combined with DOC, OLA combined with DOX or GEM, and OLA combined with GEM and DOC. Tumor size and body weight were measured during the 14 days of treatment. RESULTS: Tumor growth was arrested only by OLA combined with GEM and DOC. Tumors treated with OLA combined with GEM and DOC also had the most necrosis. CONCLUSIONS: The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, GEM and DOC for drug-resistant soft-tissue sarcoma.

DOI： 10.1007/s00280-019-03824-3

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Follicular dendritic cell sarcoma (FDCS) is a very rare and highly recalcitrant disease. A patient's doxorubicin-resistant FDCS was previously established orthotopically on the right high thigh into the biceps femoris of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present manuscript was to identify an effective drug for this recalcitrant tumor. Here, we evaluated the efficacy of temozolomide (TMZ), trabectedin (TRAB) and pazopanib (PAZ) on the FDCS PDOX model. PDOX mouse models were randomized into five groups of eight to nine mice, respectively. Group 1, untreated control with PBS, i.p.; Group 2, treated with doxorubicin (DOX), 2.4 mg/kg, i.p., weekly for 3 weeks; Group 3, treated with PAZ, 50 mg/kg, oral gavage, daily for 3 weeks; Group 4, treated with TMZ, 25 mg/kg, oral gavage, daily for 3 weeks; Group 5, treated with TRAB, 0.15 mg/kg, i.v., weekly for 3 weeks. Body weight and tumor volume were assessed 2 times per week. TMZ arrested the FDCS PDOX model compared to the control group (p < 0.05). PAZ and TRAB did not have significant efficacy compared to the control group (p = 0.99, p = 0.69 respectively). The PDOX tumor was resistant to DOX (p= 0.99). as was the patient. The present study demonstrates that TMZ is effective for a PDOX model of FDCS established from a patient who failed DOX treatment, further demonstrating the power of PDOX to identify effective therapy including for tumors that failed first line therapy.

DOI： 10.1016/j.tice.2019.04.002

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DOI： 10.3390/cells8060599

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DOI： 10.1007/s00404-019-05147-3

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Synovial sarcoma (SS) is an aggressive subgroup of soft tissue sarcoma (STS) with high grade and high risk of metastasis. However, there are no systemic therapies available that target SS. Therefore, transformative therapy is needed for SS. To establish a patient-derived orthotopic xenograft (PDOX) model, a patient tumor with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of mice. To test the efficacy of drugs, the PDOX models were randomized into five groups: Group 1 (G1), control-without treatment; Group 2 (G2), doxorubicin (DOX); Group 3 (G3), temozolomide (TEM); Group 4 (G4), gemcitabine (GEM) combined with docetaxel (DOC); and Group 5 (G5), pazopanib (PAZ). Tumor size and body weight were measured twice a week for each treatment group. A significant growth inhibition was found on day 14 in each treatment group compared to the untreated control, except for DOX. However, PAZ was significantly more effective than both TEM and GEM + DOC. In addition, PAZ significantly regressed the tumor volume on day 14 compared to day 0. No change was found in body weight on day 14 compared to day 0 in any treatment group. The present study demonstrated the precision of the SS PDOX models for individualizing SS therapy.

DOI： 10.1016/j.tice.2019.04.010

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Recurrent osteosarcoma is a chemotherapy-resistant disease. Individualized precision therapy is needed for this disease. Toward this goal, we have developed the patient-derived othotopic xenograft (PDOX) mouse model of all major cancer types including osteosarcoma. Synergistic efficacy of trabectedin (TRAB) and irinotecan (IRT) has been reported in Ewing's sarcoma, soft-tissue sarcoma, and ovarian cancer. However, the efficacy of this combination on osteosarcoma is not known. The goal of present study was to determine the efficacy of the TRAB and IRT combination on cisplatinum (CDDP)-resistant osteosarcoma PDOX. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: Untreated control; CDDP alone; TRAB alone; IRT alone; and TRAB and the IRT combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was regressed only by the TRAB-IRT combination. Tumors treated with the TRAB-IRT combination had the most tumor necrosis with degenerative change. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the TRAB and IRT combination for chemotherapy-resistant osteosarcoma.

DOI： 10.1016/j.bbrc.2019.03.191

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DOI： 10.1007/s00280-019-03782-w

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The goal of the present study was to determine the efficacy of osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor for the treatment of aggressive EGFR-mutant non-small cell lung cancer (NSCLC), compared to cisplatinum (CDDP) + pemetrexed (PEM). The NSCLC cell line PC-9 expressing green fluorescence protein (PC-9-GFP) was implanted in the brain of nude mice and was treated with CDDP + PEM or AZD9291. Tumors were observed by non-invasive fluorescence imaging. AZD9291 treatment caused tumor regression in contrast to CDDP + PEM which had only a slight inhibitory effect. These results suggest that AZD9291 is a promising clinical option for NSCLC patients with brain metastasis.

DOI： 10.1016/j.tranon.2019.01.007

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DOI： 10.1016/j.phrs.2019.02.021

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Undifferentiated/unclassified soft-tissue sarcomas (USTS) is recalcitrant neoplasms that is usually treated with doxorubicin (DOX)-containing regimens as first-line therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a nanotechnology-based drug and is widely used in pancreatic cancer in combination with gemcitabine (GEM). The major goal of the present study was to determine the efficacy of nab-PTX in combination with GEM, compared to conventional drugs such as docetaxel (DOC), GEM combined with DOC, or first-line drug DOX on a USTS not-otherwise specified (USTS/NOS) from a striated muscle implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. USTS PDOX models were randomized into six groups: untreated control; DOX; DOC; nab-PTX; GEM combined with DOC; and GEM combined with nab-PTX. Tumor size and body weight were measured. Tumor growth was inhibited to the greatest extent by GEM combined with nab-PTX. Tumors treated with GEM combined with nab-PTX had the most necrosis. Body weight of the treated mice was not significantly different from the untreated controls. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the combination of GEM and nab-PTX for recalcitrant soft-tissue sarcomas. These results suggest that combination of GEM and nab-PTX could be a promising therapeutic strategy for USTS.

DOI： 10.1016/j.biopha.2018.12.110

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DOI： 10.1186/s40792-019-0585-x

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DOI： 10.1016/j.bbrc.2019.01.046

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BACKGROUND/AIM: Undifferentiated pleomorphic sarcoma (UPS) is a common soft tissue sarcoma and highly recalcitrant. We have previously developed patient-derived orthotopic xenograft (PDOX) mouse models of UPS and other major sarcoma types. Unlike PDOX models of other cancer types, it has been difficult to demonstrate metastasis in the sarcoma PDOX models. MATERIALS AND METHODS: To visualize metastasis at high resolution in the UPS PDOX model, established tumor fragments were implanted in transgenic nude mice expressing red fluorescent protein (RFP) for one passage. The tumors acquired RFP-expressing stroma from transgenic host. UPS tumor with RFP stromal cells were harvested and implanted orthotopically in non-transgenic nude mice. After six weeks of UPS tumor growth in the PDOX model, the primary tumor was imaged non-invasively and lung, liver, and spleen were resected and imaged ex-vivo in order to visualize the presence of RFP, with a FluorVivo® imaging system and FV1000® confocal laser microscope, respectively. RESULTS: The primary tumor was imaged non-invasively. Confocal microscopy visualized the presence of RFP in the lung and liver indicating metastases in these organs. This is the first report of metastasis in a sarcoma PDOX model. CONCLUSION: This study should prove very useful to screen for anti-metastatic drugs for the PDOX donor patients and to understand the metastatic process in sarcoma.

DOI： 10.21873/anticanres.13082

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

Pancreatic cancer is a highly lethal disease in part due to incomplete tumor resection. Targeting by tumor-specific antibodies conjugated with a fluorescent label can result in selective labeling of cancer in vivo for surgical navigation. In the present study, we describe a patient-derived orthotopic model of pancreatic cancer that recapitulated the disease on a gross and microscopic level, along with physiologic clinical manifestations. We additionally show that the use of an anti-CEA antibody conjugated to the near-infrared (NIR) fluorescent dye, IRDye800CW, can selectively highlight the pancreatic cancer and its metastases in this model with a tumor-to-background ratio of 3.5 (SEM 0.9). The present results demonstrate the clinical potential of this labeling technique for fluorescence-guided surgery of pancreatic cancer.

DOI： 10.18632/oncotarget.26484

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Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future.

DOI： 10.1016/j.bbrc.2018.10.119

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Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS.

DOI： 10.1016/j.bbrc.2018.09.106

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BACKGROUND/AIM: Synovial sarcoma (SS) is a recalcitrant neoplasm with low chemosensitivity. We recently reported that recombinant methioninase (rMETase) inhibited SS growth in a patient-derived orthotopic xenograft (PDOX) mouse model and was more effective when administered in combination with the first-line drug doxorubicin (DOX). Caffeine enhances the efficacy of anticancer drugs by overcoming drug-induced cell-cycle arrest and increasing subsequent apoptosis. Here, we determined the efficacy of oral recombinant methioninase (o-rMETase) in combined with caffeine on an SS-PDOX model. MATERIALS AND METHODS: Mice bearing SS-PDOX tumors were randomized into four treatment groups of six: Untreated control; o-rMETase alone; o-rMETase with caffeine; DOX plus o-rMETase with caffeine. Tumor size and body weight were measured during the treatment and plasma L-methionine (MET) levels were measured at the end of treatment. RESULTS: All treatments significantly inhibited SS-PDOX tumor growth. Combining caffeine with o-rMETase was more effective than o-rMETase alone. DOX combined with o-rMETase and caffeine led to regression of SS-PDOX. Plasma MET levels were reduced with o-rMETase treatment. CONCLUSION: These results suggest that combining o-rMETase and caffeine along with first-line chemotherapy can be highly effective for SS and has clinical potential for this recalcitrant disease.

DOI： 10.21873/anticanres.12899

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DOI： 10.1016/j.tice.2018.09.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

Recombinant methioninase (rMETase) was previously administered as an injectable drug to target methionine dependence of cancer. Recently, we observed that rMETase could be administered orally (o-rMETase) in a patient-derived orthotopic xenograft (PDOX) mouse model of melanoma. Here, we determined the efficacy of o-rMETase on a pancreatic cancer PDOX model. Forty pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each. o-rMETase was significantly more effective than i.p.-rMETase, but the combination of both was significantly more effective than either alone. Acquired gemcitabine resistance is a major factor in the recalcitrance of pancreatic cancer. We tested a human pancreatic cancer cell line, which has acquired &gt
100-fold GEM-resistance (PK-9R) than its parental cell line PK-9. In contrast to GEM, both cell lines were very sensitive to rMETase. In orthotopic nude mouse models of PK-9 and PK-9R, GEM inhibited tumor growth in PK-9 but not PK-9R. In contrast, o-rMETase could inhibit both tumors. The combination of GEM + o-rMETase could regress the PK-9 tumor and inhibit PK-9R tumor growth. The present study shows that o-rMETase is effective and overcomes acquired GEM resistance in pancreatic cancer and demonstrates the clinical potential of this strategy.

DOI： 10.1016/j.canlet.2018.06.016

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Melanoma is a recalcitrant cancer. To improve and individualize treatment for this disease, we previously developed a patient-derived orthotopic xenograft (PDOX) model for melanoma. We previously reported the individual efficacy of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and recombinant methioninase (rMETase) for melanoma in the PDOX models of this disease. In the present study, we evaluated the efficacy of the combination of S. typhimurium A1-R with orally-administered rMETase (o-rMETase) for BRAF-V600E-negative melanoma in a PDOX model. Three weeks after implantation, 60 PDOX mouse models were randomized into six groups of 10 mice each: untreated control, temozolomide (TEM); o-rMETase; S. typhimurium A1-R; TEM + rMETase, S. typhimurium A1-R + rMETase. All treatments inhibited tumor growth compared to untreated control (TEM: p < 0.0001, rMETase: p < 0.0001, S. typhimurium A1-R: p < 0.0001, TEM + rMETase: p < 0.0001, S. typhimurium A1-R + rMETase: p < 0.0001). The most effective was the combination of S. typhimurium A1-R + o-rMETase which regressed this melanoma PDOX, thereby indicating a new paradigm for treatment of metastatic melanoma.

DOI： 10.1016/j.bbrc.2018.08.097

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Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1-R. There was no significant body-weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1-R-GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first-line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1-R.

DOI： 10.1002/jcb.27183

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BACKGROUND: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS. METHODS: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight. RESULTS: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight. CONCLUSIONS: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.

DOI： 10.1186/s12885-018-4703-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Liss Inc.  

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer, resistant to conventional chemotherapy. A patient with high-grade USCS from a striated muscle was implanted orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment
G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks)
G3, temozolomide (TEM) (25 mg/kg, p.o., daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance twice a week. TEM significantly inhibited tumor volume growth compared to the untreated control and the DOX-treated group on day 14 after treatment initiation: control (G1): 343 ± 78 mm3
DOX (G2): 308 ± 31 mm3, P = 0.272
TEM (G3): 85 ± 21 mm3, P &lt
0.0001. TEM significantly regressed the tumor volume compared to day 0 (P = 0.019). There were no animal deaths in any group. The body weight of treated mice was not significantly different in any group. Tumors treated with DOX were comprised of spindle-shaped viable cells without apparent necrosis or inflammatory changes. In contrast, tumors treated with TEM showed extensive tumor necrosis. The present study demonstrates the potential power of matching the patient with an effective drug and saving the patient needless toxicity from ineffective drugs.

DOI： 10.1002/jcb.26792

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Undifferentiated/unclassified soft tissue sarcoma (USTS) is a recalcitrant disease; therefore, precise individualised therapy is needed. Toward this goal, we previously established patient-derived orthotopic xenograft (PDOX) models of USTS in nude mice. Here, we determined the extent of uniqueness of drug response in a panel on USTS PDOX models from 5 different patients. We previously showed that 3 of the 5 patients were resistant to doxorubicin (DOX) despite DOX being first-line therapy. Two weeks after orthotopic tumour implantation, PDOX mouse models were randomised into five groups: untreated control, DOX, gem-citabine/docetaxel (GEM/DOC), pazopanib (PAZ), temozolomide (TEM). Three PDOX cases were completely resistant to DOX. TEM had high efficacy for 4 USTS PDOX models, including DOX-resistant cases. GEM/DOC and PAZ were effective in three USTS PDOX. One case was completely resistant to TEM. Two cases were completely resistant to PAZ. The results showed the drug sensitivity pattern for each USTS PDOX was highly individualised and that at least one effective drug could be found for each. The PDOX model could be effective in precise individualised drug sensitivity testing which is especially important for heterogeneous cancers such as USTS, and can give the patient a greater chance to be treated with an effective drug.

DOI： 10.1080/1061186X.2018.1499748

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Pleomorphic liposarcoma (PLPS) is a heterogeneous resistant group of tumors. Complete surgical resection is the only known way to treat PLPS. PLPS is reristant to both radiation and chemotherapy. Therefore, precise individualized therapy is needed to improve outcome of advanced PLPS patients. In this study, a patient-derived orthotopic xenograft (PDOX) model of a PDGFRA-amplified PLPS was established in the biceps femoris of nude mice by surgical orthotopic implantation (SOI) in order to match the patient. The PLPS PDOX was treated with pazopanib (PAZ) which targets PDGFRA, as well as with temozolomide (TEM) and first-line therapy doxorubicin (DOX). The PLPS PDOX was resistant to DOX and responded very well to PAZ as well as TEM. The tumor volume on treatment day-14 relative to day-1 was as follows: DOX (4.50 ± 2.6, p = 0.8087); PAZ (1.29 ± 0.9, p = 0.0008 compared to the control, p = 0.0167 compared to DOX); TEM (1.07 ± 0.8, p = 0.0079 compared to the control, p = 0.0079 compared to DOX). There was no significant difference in body weight between any treated group or control. The PAZ- and TEM-treated tumors showed extensive necrosis compared to the DOX-treated and untreated PDOX tumors. The present study showed that PDGFRA amplification could be effectively targeted by PAZ. The PLPS PDOX model also identified the efficacy of TEM which does not target PDGFRA, indicating that the PDOX model can identify effective targeted therapy as well as standard therapy and at the same time, identify ineffective drugs, even if they are first-line.

DOI： 10.1016/j.tice.2018.05.010

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Gastrointestinal stromal tumor (GIST) is a refractory disease in need of novel efficacious therapy. The aim of our study was to evaluate the effectiveness of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) using on a patient derived orthotopic xenograft (PDOX) model of imatinib-resistant GIST. The GIST was obtained from a patient with regional recurrence, and implanted in the anterior gastric wall of nude mice. The GIST PDOX mice were randomized into 3 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group
G2, imatinib group (oral administration [p.o.], daily, for 3 weeks)
G3, S. typhimurium A1-R group (intravenous [i.v.] injection, weekly, for 3 weeks). All mice from each group were sacrificed on day 22. Relative tumor volume was estimated by laparotomy on day 0 and day 22. Body weight of the mouse was evaluated 2 times per week. We found that S. typhimurium A1-R significantly reduced tumor growth in contrast to the untreated group (P = 0.001). In addition, we found that S. typhimurium A1-R was more effective compared to imatinib (P = 0.013). Furthermore, Imatinib was not significantly effective compared to the control group (P = 0.462). These results indicate that S. typhimurium A1-R may be new effective therapy for imatinib-resistant GIST and therefore a good candidate for clinical development of this disease.

DOI： 10.1016/j.heliyon.2018.e00643

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Pancreatic cancer is resistant to treatment and needs precision individualized therapy to improve the outcome of this disease. Previously, we demonstrated that trametinib (TRA), a MEK inhibitor, could inhibit a pancreatic cancer patient-derived orthotopic xenograft (PDOX). In the present study, we show that gemcitabine (GEM) in combination with TRA was more effective than TRA alone. We implanted a patient pancreatic cancer orthotopically in the pancreatic tail of nude mice to establish the PDOX model. After seven weeks of tumor growth, we divided 32 pancreatic-cancer PDOX nude mice into 4 groups of eight: untreated control
GEM (once a week for 2 weeks)
TRA (14 consecutive days)
GEM + TRA (GEM: once a week for 2 weeks, TRA:14 consecutive days). We found that treated mice on day 14 had significantly reduced tumor volume in comparison to untreated control. TRA and the combination of GEM + TRA therapy significantly inhibited tumor development in comparison to GEM alone. However, GEM + TRA inhibited the PDOX tumor growth significantly greater than TRA alone. These results suggest the clinical potential of the combination of TRA and GEM for pancreatic cancer.

DOI： 10.1016/j.tice.2018.05.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patientderived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment
G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks
G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks)
G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/ mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48
rMETase: p &lt
0.005
DOX combined with rMETase &lt
0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p &lt
0.001) and rMETase alone (p &lt
0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease.

DOI： 10.18632/oncotarget.24996

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer New York LLC  

Background/Purpose: Development of a humanized fluorophore-conjugated antibody that can improve contrast for fluorescence-guided oncologic surgeries. Methods: BxPC-3-GFP pancreatic cancer cells were injected into flanks of nude mice. Fragments of subcutaneous tumors were grafted onto the pancreatic tail of recipient mice to create orthotopic xenograft models of pancreatic cancer. After tumors developed for 4 weeks, a humanized anti-carcinoembryonic antigen antibody conjugated to an 800 nm near-infrared fluorescent dye (hM5A-IR800) was injected intravenously. Mice were imaged at 6, 12, 24, 48, and 72 h after injection. Results: Fluorescence imaging showed that hM5A-IR800 specifically localized to BxPC-3 human pancreatic cancer cells. The fluorescent probe localized to cell surfaces in vitro and specifically co-localized with green fluorescent protein-labeled tumors in an orthotopic pancreatic xenograft model in vivo. Serial imaging at specific time points showed peak signal intensity of the orthotopic pancreatic tumor at 48 h
this time point corresponded with a maximal tumor-to-background ratio (TBR) of 16.6 at 48 h. Discussion: hM5A-IR800 was successfully able to specifically label orthotopic pancreatic tumors in situ. The longer wavelength allowed deeper tissue penetration, particularly in tumor areas covered by normal pancreatic parenchyma. The probe had expected kinetics for an antibody-fluorophore conjugate, with the peak signal intensity reached at 48 h. A clear tumor signal was observed with a TBR CloseSPigtSPi 5 at all time points, with high contrast (TBR of 16.6) at 48 h. Conclusion: hM5A-IR800 demonstrated excellent tumor localization and a very bright signal. It is a promising agent for future clinical fluorescence-guided surgery applications.

DOI： 10.1245/s10434-018-6344-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Liss Inc.  

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant ­cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3: G1, untreated control without treatment
G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks)
G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3
DOX (G2): 329.5 ± 79 mm3, P = 0.670
rMETase (G3): 162.6 ± 51 mm3, P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.

DOI： 10.1002/jcb.26527

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Publisher：Springer Nature  

DOI： 10.1038/s41392-018-0016-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

We have previously established a patient-derived orthotopic xenograft (PDOX) model of undifferentiated spindle cell sarcoma (USCS). Recombinant methioninase (rMETase) has previously demonstrated efficacy in PDOX mouse models of human cancers. In the present study, we determined if rMETase in combination with doxorubicin (DOX) can overcome first-line DOX resistance in a PDOX models of USCS. The USCS PDOX mouse models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment
G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks)
G3, rMETase (100 units/mouse, i.p., daily, for 2 weeks)
G4, DOX (3 mg/kg, i.p., weekly, for 2 weeks) combined with rMETase (100 units/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured twice a week. On day 14 after initiation, the USCS PDOX tumor sizes were (G1): 360 ± 85 mm3
DOX (G2): 355 ± 111 mm3, p =.927
rMETase (G3): 182 ± 57 mm3, p =.0003
DOX + rMETase (G4): 134 ± 29 mm3, p =.00001. These results indicate that rMETase can overcome USCS resistance to DOX, which is first line therapy for this disease. The body weight of treated mice was not significantly different in any group. The present results demonstrate the power of the PDOX model to identify effective therapy for recalcitrant cancer and the potential of rMETase to overcome DOX resistance.

DOI： 10.1016/j.canlet.2017.12.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Inc.  

In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G2, and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment
G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks)
G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks)
G5, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks)
G6, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586
rMETase: p = 0.002
S. typhimurium A1-R: p = 0.002
S. typhimurium A1-R combined with rMETase: p = 0.0004
rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

DOI： 10.1080/15384101.2018.1431596

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Inc.  

Gastrointestinal stromal tumor (GIST) with a mutation in exons 11 and 17 of c-kit is a rare type of sarcoma. The aim of this study was to determine drug sensitivity for a regionally-recurrent case of GIST using a patient-derived orthotopic xenograft (PDOX) model. The PDOX model was established in the anterior wall of the stomach. GIST PDOX models were randomized into 5 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group
G2, imatinib group (oral administration (p.o.), daily, for 3 weeks)
G3, sunitinib group (p.o., daily, for 3 weeks)
G4, regorafenib (p.o., daily, for 3 weeks)
G5, pazopanib (p.o., daily, for 3 weeks). All mice were sacrificed on day 22. Tumor volume was evaluated on day 0 and day 22 by laparotomy. Body weight were measured 2 times per week. Though regorafenib is third-line therapy for GIST, it was the most effective drug and regressed the tumor significantly (p &lt
0.001). Sunitinib suppressed tumor growth compared to the control group (p = 0.002). Imatinib, first-line therapy for GIST, and pazopanib did not have significant efficacy compared to the control group (p = 0.886, p = 0.766). The implications of this result is discussed for GIST patients.

DOI： 10.1080/15384101.2017.1423223

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general.

DOI： 10.1016/j.bbrc.2018.02.174

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Inc.  

Doxorubicin (DOX) is often first-line treatment of undifferentiated/unclassified soft tissue sarcoma (USTS). However, the DOX response rate for USTS patients is low. Individualized precision-medicine technology that could identify DOX responders as well as non-responders would be of high value to cancer patients. In the present study, we established 5 patient-derived orthotopic xenograft (PDOX) nude mouse models from 5 USTS patients and evaluated the efficacy of DOX in each PDOX model. USTS's were grown orthotopically in the right thigh of nude mice to establish the PDOX models. Two weeks after implantation, the mouse models were randomized into two groups of 8 mice each: untreated control
and DOX (3 mg/kg, i.p., once a week for 2 weeks). DOX showed significant growth inhibition in only 2 USTS PDOX models out of 5 (p = 0.0054, p = 0.0055, respectively) on day 14 after initiation. DOX was ineffective in the other 3 PDOX models. However, even in the DOX-sensitive cases, DOX could not regress the PDOX tumors responding to treatment. The present study has important implications since this is the first in vivo study to compare the DOX sensitivity for USTS on multiple patient tumors. We showed that only two of five USTS were responsive to DOX, despite DOX being first line chemotherapy for USTS. The 3 resistant cases should not be treated with DOX clinically, in order to spare the patients' unnecessary toxicity. This PDOX model is useful for precise individualized drug sensitivity testing, especially for rare heterogeneous recalcitrant sarcomas such as USTS.

DOI： 10.1080/15384101.2017.1421876

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Inc.  

The elevated methionine (MET) use by cancer cells is termed MET dependence and may be the only known general metabolic defect in cancer. Targeting MET by recombinant methioninase (rMETase) can arrest the growth of cancer cells in vitro and in vivo. We previously reported that rMETase, administrated by intra-peritoneal injection (ip-rMETase), could inhibit tumor growth in a patient-derived orthotopic xenograft (PDOX) model of a BRAF-V600E mutant melanoma. In the present study, we compared ip-rMETase and oral rMETase (o-rMETase) for efficacy on the melanoma PDOX. Melanoma PDOX nude mice were randomized into four groups of 5 mice each: untreated control
ip-rMETase (100 units, i.p., 14 consecutive days)
o-rMETase (100 units, p.o., 14 consecutive days)
o-rMETase+ip-rMETase (100 units, p.o.+100 units, i.p., 14 consecutive days). All treatments inhibited tumor growth on day 14 after treatment initiation, compared to untreated control (ip-rMETase, p&lt
0.0001
o-rMETase, p&lt
0.0001
o-rMETase+ip-rMETase, p&lt
0.0001). o-rMETase was significantly more effective than ip-rMETase (p = 0.0086). o-rMETase+ip-rMETase was significantly more effective than either mono-therapy: ip-rMETase, p = 0.0005
or o-rMETase, p = 0.0367. The present study is the first demonstrating that o-rMETase is effective as an anticancer agent. The results of the present study indicate the potential of clinical development of o-rMETase as an agent for chronic cancer therapy and for cancer prevention and possibly for life extension since dietary MET reduction extends life span in many animal models.

DOI： 10.1080/15384101.2017.1405195

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Ewing's sarcoma is a recalcitrant tumor greatly in need of more effective therapy. The aim of this study was to determine the efficacy of eribulin on a doxorubicin (DOX)-resistant Ewing's sarcoma patient derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma PDOX model was previously established in the right chest wall of nude mice from tumor resected form the patient's right chest wall. In the previous study, the Ewing's sarcoma PDOX was resistant to doxorubicin (DOX) and sensitive to palbociclib and linsitinib. In the present study, the PDOX models were randomized into three groups when the tumor volume reached 60mm(3): G1, untreated control (n=6); G2, DOX treated (n=6), intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, Eribulin treated (n=6, intravenous (i.v.) injection, weekly for 2 weeks). All mice were sacrificed on day 15. Changes in body weight and tumor volume were assessed two times per week. Tumor weight was measured after sacrifice. DOX did not suppress tumor growth compared to the control group (P=0.589), consistent with the previous results in the patient and PDOX. Eribulin regressed tumor size significantly compared to G1 and G2 (P=0.006, P=0.017) respectively. No significant difference was observed in body weight among any group. Our results demonstrate that eribulin is a promising novel therapeutic agent for Ewing's sarcoma.

DOI： 10.1002/jcb.26263

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8(+) tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8(+) TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n=8); and G2: S. typhimurium A1-R-treatment group (n=8, 1x10(7) colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 +/- 2.8) than the untreated control (G1) (39.9 +/- 30.7, P&lt;0.01). Hematoxylin and easin (H&E) staining on tumor sections was performed to evaluate tumor destruction which was classified according to the Evans grading system and found to be much greater in the S. typhimurium A1-R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P&lt;0.01). Immunohistochemical staining with anti-mouse CD8(+) antibody was performed in order to detect TILs determined by calculating the average number of CD8(+) cells in three high power fields (200x) in the treated and untreated tumors. The TIL score was significantly higher in G2 (133.5 +/- 32.2) than G1 (45.1 +/- 19.4, P&lt;0.001). The present study demonstrates that S. typhimurium A1-R promotes CD8(+) T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. (c) 2017 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.26224

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DOI： 10.1038/s41392-018-0016-7

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：SPIE  

Specific tumor targeting can result in selective labeling of cancer in vivo for surgical navigation. In the present study, we show that the use of an anti-CEA antibody conjugated to the near-infrared (NIR) fluorescent dye, IRDye800CW, can selectively target and label pancreatic cancer and its metastases in a clinically relevant patient derived xenograft mouse model.

DOI： 10.1117/12.2292546

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Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.

DOI： 10.1080/15384101.2018.1445907

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Gemcitabine (GEM) is first-line therapy for pancreatic cancer but has limited efficacy in most cases. Nanoparticle-albumin bound (nab)-paclitaxel is becoming first-line therapy for pancreatic cancer, but also has limited efficacy for pancreatic cancer. Our goal was to improve the treatment outcome in patient-like models of pancreatic cancer. We previously established patient-derived orthotopic xenografts (PDOX) pancreatic cancers from two patients. The pancreatic tumor was implanted orthotopically in the pancreatic tail of nude mice to establish the PDOX models. Five weeks after implantation, 50 PDOX mouse models were randomized into five groups of 10 mice for each pancreatic cancer PDOX: untreated control; GEM (100 mg/kg, i.p., once a week for 2 weeks); GEM + nab-PTX (GEM: 100 mg/kg, i.p., once a week for 2 weeks, nab-PTX: 10 mg/kg, i.v., twice a week for 2 weeks); S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks); GEM + S. typhimurium A1-R (GEM: 100 mg/kg, i.p., once a week for 2 weeks, S. typhimurium A1-R; 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks). GEM + nab-PTX was significantly more effective than GEM alone in one PDOX model (p = 0.0004), but there was no significant difference in the other PDOX model. The combination of GEM + S. typhimurium A1-R regressed both PDOX models. These results show S. typhimurium A1-R can overcome the ineffectiveness or partial effectiveness of GEM in patient-like models of pancreatic cancer and demonstrate clinical potential for this combination.

DOI： 10.1080/15384101.2018.1480223

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

Relapsed osteosarcoma is a recalcitrant tumor. A patient's cisplatinum (CDDP)- resistant relapsed osteosarcoma lung metastasis was previously established orthotopically in the distal femur of mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment
G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks)
gemcitabine (GEM) (100 mg/kg, i.p., weekly, for 2 weeks) combined with docetaxel (DOC) (20 mg/kg, i.p., once)
temozolomide (TEM) (25 mg/kg, p.o., daily, for 2 weeks) combined with irinotecan (IRN) (4 mg/kg i.p., daily for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. After 2 weeks, all treatments significantly inhibited tumor growth except CDDP compared to the untreated control: CDDP: p = 0.093
GEM+DOC: p = 0.0002, TEM+IRN: p &lt
0.0001. TEM combined with IRN was significantly more effective than either CDDP (p = 0.0001) or GEM combined with DOC (p = 0.0003) and significantly regressed the tumor volume compared to day 0 (p = 0.003). Thus the PDOX model precisely identified the combination of TEM-IRN that could regress the CDDP-resistant relapsed metastatic osteosarcoma PDOX.

DOI： 10.18632/oncotarget.22892

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An excessive requirement for methionine (MET) for growth, termed MET dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by MET restriction such as with recombinant methioninase (rMETase). In the present study, we utilized patient-derived orthotopic xenograft (PDOX) nude mouse models with pancreatic cancer or melanoma to determine the relationship between intra-tumor MET level and tumor size. After the tumors grew to 100 mm3, the PDOX nude mice were divided into two groups: untreated control and treated with rMETase (100 units, i.p., 14 consecutive days). On day 14 from initiation of treatment, intra-tumor MET levels were measured and found to highly correlate with tumor volume, both in the pancreatic cancer PDOX (p &lt
0.0001, R2=0.89016) and melanoma PDOX (p &lt
0.0001, R2=0.88114). Tumors with low concentration of MET were smaller. The present results demonstrates that patient tumors are highly dependent on MET for growth and that rMETase effectively lowers tumor MET.

DOI： 10.18632/oncotarget.24264

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

Melanoma is a recalcitrant disease. Melanoma patients with the BRAF-V600E mutation have been treated with the drug vemurafenib (VEM) which targets this mutation. However, we previously showed that VEM is not very effective against a BRAF-V600E melanoma mutant in a patient-derived orthotopic xenograft (PDOX) model. In contrast, we demonstrated that recombinant methioninase (rMETase) which targets the general metabolic defect in cancer of methionine dependence, was effective against the BRAF-V600E mutant melanoma PDOX model. In the present study, we demonstrate that rMETase is effective against a BRAF-V600E-negative melanoma PDOX which we established. Forty BRAF-V600E-negative melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10)
temozolomide (TEM) (25 mg/kg, p.o., 14 consecutive days, n = 10)
rMETase (100 units, i.p., 14 consecutive days, n = 10)
TEM + rMETase (TEM: 25 mg/kg, p.o., rMETase: 100 units, i.p., 14 consecutive days, n = 10). All treatments inhibited tumor growth compared to untreated control (TEM: p = 0.0003, rMETase: p = 0.0006, TEM/ rMETase: p = 0.0002) on day 14 after initiation. Combination therapy of TEM and rMETase was significantly more effective than either mono-therapy (TEM: p = 0.0113, rMETase: p = 0.0173). The present study shows that TEM combined with rMETase is effective for BRAF-V600E-negative melanoma PDOX similar to the BRAF-V600Epositive mutation melanoma. These results suggest rMETase in combination with firstline chemotherapy can be highly effective in both BRAF-V600E-negative as well as BRAF-V600E-positive melanoma and has clinical potential for this recalcitrant disease.

DOI： 10.18632/oncotarget.23185

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DOI： 10.1159/000495574

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Background: A high accumulation of CD8(+) tumor- infiltrating lymphocytes (TILs) induced by neoadjuvant chemoradiotherapy (NACRT) is associated with a favorable prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). However, the correlation between a high accumulation of CD8(+) TILs and a favorable prognosis has yet to be fully clarified. The aim of this study was to determine predictive markers of a high accumulation of CD8(+) TILs, with a favorable prognosis, using proteomic analysis.
Materials and methods: We studied 72 resected borderline resectable PDAC patients treated with NACRT between April 2009 and March 2014. Three matched pairs of high CD8(+) TIL patients with a favorable prognosis and low CD8(+) TIL patients with a poor prognosis were selected. Shotgun proteomics of the stroma and cancerous lesion was performed using formalin- fixed, paraffin- embedded tissue. Validation of the identified proteins was performed using immunohistochemical staining. Relationships between the identified proteins and TILs and clinical outcomes were assessed.
Results: Marginal zone B- and B1- cell- specific protein (MZB1) was detected in the tumor stroma. MZB1 expression was positively correlated with a high accumulation of CD8_ TILs. High stromal MZB1 expression also correlated with disease- free and overall survival. In a subgroup analysis of CD8(+) expression, there was a significant association between stromal MZB1 expression and disease- free and overall survival in the high CD8(+) TIL group.
Conclusions: MZB1 is a potential marker of a high accumulation of CD8(+) TILs in borderline resectable PDACs resected after NACRT. Combination of CD8(+) TILs with MZB1 may be a new biomarker of resected cases after NACRT. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jss.2017.07.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

A patient-derived orthotopic xenograft (PDOX) model of undifferentiated pleomorphic sarcoma (UPS) was previously established that acquired red fluorescent protein (RFP)-expressing stroma by growth in an RFP transgenic nude mouse. In the present study, an imageable PDOX model (iPDOX) of UPS was established by orthotopic implantation in the biceps femoris of transgenic RFP nude mice. After the tumors grew to a diameter of 10mm, they were harvested and the brightest portion of the tumors were subsequently orthotopically transplanted to both RFP and non-colored nude mice. The UPS PDOX tumor was again transplanted to RFP transgenic and non-colored nude mice, and finally a 3rd passage was made in the same manner. Five UPS tumors from each passage in both RFP and non-colored mouse models were harvested. The FV1,000 confocal microscope was used to visualize and quantitate the RFP area of the resected tumors. The average percent fluorescent area in the first passage of RFP mice was 34 +/- 22%; in the second passage, 34 +/- 20%; and 36 +/- 11% in the third passage of RFP transgenic nude mice. The average tumor RFP area in the first passage from RFP mice to non-colored mice was 20 +/- 7%; in the second passage, 28 +/- 11%; in the third passage was 27 +/- 13%. The present results demonstrate the extensive and stable acquisition of stroma by the UPS-tumor growing orthotopically in transgenic RFP nude mice (iPDOX). This model can be used for screening for effective drugs for individual patients and drug discovery. (C) 2017 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.25991

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

An excessive requirement for methionine termed methionine dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by methionine deprivation such as with recombinant methioninase (rMETase). The present study used a previously-established patient-derived orthotopic xenograft (PDOX) nude mouse model of BRAF V600E-mutant melanoma to determine the efficacy of rMETase in combination with a first-line melanoma drug, temozolomide (TEM). In the present study 40 melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); TEM (25 mg/kg, oral 14 consecutive days, n = 10); rMETase (100 units, intraperitoneal 14 consecutive days, n = 10); combination TEM + rMETase (TEM: 25 mg/kg, oral rMETase: 100 units, intraperitoneal 14 consecutive days, n = 10). All treatments inhibited tumor growth compared to untreated control (TEM: p = 0.0081, rMETase: p = 0.0037, TEM-rMETase: p = 0.0024) on day 14 after initiation. However, the combination therapy of TEM and rMETase was significantly more efficacious than either mono-therapy (TEM: p = 0.0051, rMETase: p = 0.0051). The present study is the first demonstrating the efficacy of rMETase combination therapy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as melanoma, where rMETase may enhance first-line therapy.

DOI： 10.18632/oncotarget.20231

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). In the present study, we evaluated the efficacy of standard first-line chemistry of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. A high-grade USCS from a striated muscle of the patients was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100mm(3): G1, control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, GEM (100 mg/kg, i.p., weekly, for 2 weeks) combined with DOC (20 mg/kg, i.p., once); G4, PAZ (100 mg/kg, p.o., daily, for 14 days). All treatments except DOX significantly inhibited tumor growth compared to untreated control on day 14 after treatment initiation. Tumor sizes were as fallows: control (G1): 332.0 +/- 58.7mm(3); DOX (G2): 316.9 +/- 55.9mm(3), P = 0.605; GEM+DOC (G3): 228.9 +/- 39.8mm(3), P = 0.001; PAZ (G4): 173.8 +/- 23.3mm(3), P &lt; 0.0001. PAZ showed significantly more efficacy compared to other therapies evaluated: DOX (P &lt; 0.0001), GEM + DOC (P = 0.006). There were no animal deaths in any group and body weight of treated mice was not significantly different in each group. The present results demonstrate that the PDOX model of USCS can identify a promising novel agent with significantly greater efficacy than first-line therapy for this recalcitrant disease. (c) 2017 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.25923

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

A patient high-grade undifferentiated pleomorphic soft-tissue sarcoma (UPS) from a striated muscle was previously orthotopically implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) nude-mouse model. In the present study, two weeks after orthotopic transplantation of the UPS, mice were treated intraperitoneally with cisplatinum (CDDP), doxorubicin (DOX) or a novel anionic-phosphate-platinum compound 3Pt. Treatments were repeated weekly for a total of 3 times. Six weeks after transplantation, all mice were sacrificed and evaluated. After two weeks treatment, tumor sizes were as follows: control (G1): 2208.3 mm(3); CDDP (G2): 841.8 +/- 3 mm(3), p=0.0001; DOX (G3): 693.1 +/- 3 mm(3), p=6.56E-7; 3Pt (G4): 333.7 +/- 1 mm(3), p=4.8E-8. 3Pt showed significantly more efficacy compared to other therapy drugs tested: CDDP (p=0.0002), DOX (p=0.001). There were no animal deaths in any of the four groups. The present results suggest 3Pt is a promising new candidate for UPS since it was demonstrated to be effective in a PDOX model.

DOI： 10.18632/oncotarget.18806

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm(3): G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance, respectively, twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5 +/- 258.8 mm(3); CDDP (G2): 608.6 +/- 126.9 mm(3); TRAB (G3): 286.6 +/- 133.0 mm(3); TEM (G4): 182.9 +/- 69.1 mm(3). CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p=0.0002; TRAB vs. CDDP, p=0.0002; TEM vs. CDDP, p=0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while accurately maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.

DOI： 10.18632/oncotarget.19095

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background: Damage-associated molecular patterns (DAMPs) are related to immune responses in malignant tumors including tumor-infiltrating lymphocytes (TILs). The aim of the present study was to determine the relationship between expression of components of DAMPs and TILs in pancreatic cancer patients who underwent neoadjuvant chemoradiotherapy (NACRT) versus those who did not.
Methods: NACRT was administered to 51 patients with borderline-resectable pancreatic cancer and not to 33 patients with resectable pancreatic cancer. Resected specimens were analyzed for the presence of DAMPs, major histocompatibility complex class I-related chain A/B (MICA/B), and CD8(+) TILs, CD4(+) TILs, and forkhead box P3 positive (Foxp3(+)) TILs. The Treg/TIL ratio was obtained by dividing the number of Foxp3(+) TILs, a surrogate for regulatory T cells, by the sum of CD8(+) and CD4(+) TILs.
Results: Overexpression of calreticulin, Hsp70, and MICA/B were all significantly correlated with NACRT administration. In the NACRT group, high MICA/B expression was associated with a low Treg/TIL ratio, indicating a favorable immunogenic tumor microenvironment. Patients with a lower Treg/TIL ratio had longer survival.
Conclusions: Overexpression of MICA/B, a component of DAMPs induced by NACRT, may play an important role in acquiring a favorable immune response for pancreatic cancer which contributes to longer survival, suggesting the potential of immunotherapy of this recalcitrant disease, especially for patients with overexpression of DAMPs.

DOI： 10.1002/jso.24681

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background: Methionine dependence may be the only known general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine alpha-deamino-gamma-mercaptomethane lyase [EC 4.4.1.11]) (recombinant methioninase [rMETase]), which was subsequently tested in mouse models of various types of human tumors. The present study aimed to investigate the efficacy of rMETase on human osteosarcoma cells in vitro and in vivo. Materials and Methods: Human osteosarcoma cell lines 143B, HOS and SOSN2 were tested in vitro for survival during a 72-h exposure to rMETase using the WST-8 assay. Half-maximal inhibitory concentrations were calculated for in vitro efficacy experiments. 143B cells were orthotopically transplanted into the tibia of nude mice. Mouse models were randomized into the following groups 1 week after transplantation: Group 1, untreated control; Group 2, cisplatinum (CDDP) [intraperitoneal (i.p.) injection at 6 mg/kg weekly, for 3 weeks], positive control; Group 3, rMETase, 100 units/mouse i.p. daily, for 21 days. Tumor sizes and body weight were measured with calipers and a digital balance once per week, respectively. Results: rMETase significantly inhibited osteosarcoma cell growth, in a dose-dependent manner, in vitro. Both CDDP and rMETase treatment significantly inhibited tumor volume compared to untreated control mice at 5 weeks after initiation. Tumor volumes were as follows: Group 1, untreated, control: 1808.2 +/- 344 mm(3); Group 2, CDDP: 1102.2 +/- 316 mm(3), p = 0.0008 compared to untreated control; Group 3, rMETase: 884.8 +/- 361 mm(3), p = 0.0001 compared to untreated control. There were no animal deaths in any group. The body weight of mice was not significantly different between any group. Conclusion: rMETase showed promising efficacy against osteosarcoma, a recalcitrant tumor type. Future studies will investigate the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) models of osteosarcoma as a bridge to testing rMETase in the clinic.

DOI： 10.21873/anticanres.11887

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DOI： 10.1158/1538-7445.AM2017-5900

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine alpha-deamino-gamma-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.

DOI： 10.18632/oncotarget.15823

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background: Cervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective. Materials and Methods: Cervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX. Results: H&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42+/-0.36) than the control group (tumor volume ratio: 3.47+/-1.66) (p&lt;0.01). In contrast, NAB-PTX did not show significant efficacy on the cervical cancer PDOX model (tumor volume ratio: 2.85+/-1.45) (p=0.47). CDDP-treated tumor weight (50+/-50 mg) was significantly less than control (238+/-114 mg) (p&lt;0.01). NAB-PTX-treated tumors were not reduced in weight (246+/-136 mg) compared to control (p=0.91). There were no significant differences in mouse body weight between groups. Histological evaluation demonstrated that CDDP-treated tumors were fibrotic with scattered squamous cell nests compared to control or NAB-PTX-treated tumors. Conclusion: The results of the present study demonstrate the power of PDOX models of cervical cancer to distinguish efficacy of potential therapeutics for individual patients with this disease.

DOI： 10.21873/anticanres.11289

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Pancreatic cancer is a recalcitrant malignancy, partly due to desmoplastic stroma which stimulates tumor growth, invasion, and metastasis, and inhibits chemotherapeutic drug delivery. Transforming growth factor- (TGF-) has an important role in the formation of stromal desmoplasia. The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF- inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The BxPC-3 human pancreatic adenocarcinoma cell line expressing green fluorescent protein (GFP), which also has a high TGF- expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3weeks) and a treated group (n = 7, SB431542 [TGF- receptor type I inhibitor] 0.3mg, i.p., weekly, for 3weeks). Stromal cells expressing RFP and cancer cells expressing GFP were observed weekly for 3weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells, relative to the GFP fluorescence area of the cancer cells, was significantly decreased in the TGF--inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in an orthotopic pancreatic-cancer cell-line mouse model can readily detect the selective anti-stromal-cell targeting of a TGF- inhibitor.

DOI： 10.1080/15384101.2017.1315489

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

William B. Coley developed bacterial therapy of cancer more than 100years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimurium A1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimurium A1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimurium A1-R and DOX significantly reduced tumor weight (37.8 +/- 15.6 mg) compared to the untreated control (73.8 +/- 10.1mg, P &lt; 0.01). S. typhimurium A1-R monotherapy-treated tumors tended to be smaller (50.9 +/- 17.8mg, P = 0.051). DOX monotherapy did not show efficacy (66.3 +/- 26.4mg, P = 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient. S. typhimurium A1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80years if Ewing did not stop Coley.

DOI： 10.1080/15384101.2017.1304340

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Previously, a patient-derived orthotopic xenograft (PDOX) model was established with a lung metastasis from an osteosarcoma patient which developed after adjuvant cisplatinum (CDDP) treatment. In this model, we previously demonstrated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared with CDDP. In the present report, osteosarcoma tissue was implanted orthotopically in the distal femur of mice which were randomized into the following groups when tumor volume reached approximately 100 mm(3); On day 14 after initiation of treatment, all but CDDP significantly inhibited tumor volume growth compared with untreated controls. Control (G1): 793.7 perpendicular to 215.0 mm(3); CDDP (G2): 588.1 perpendicular to 176.9 mm(3); Salmonella typhimurium A1-R (S. typhimurium A1-R) intravenous (i.v.) (G3): 269.7 perpendicular to 72.7 mm(3); S. typhimurium A1-R intra-arterial (i.a.) (G4): 70.2 perpendicular to 18.9 mm(3) (CDDP: p = 0.056; S. typhimurium A1-R i.v.: p = 0.0001; S. typhimurium A1-R i.a.: p = 0.00003, all vs. untreated controls). i.a. administration of S. typhimurium A1-R was significantly more effective than either CDDP (p = 0.00007), or i.v. administration of S. typhimurium A1-R (p = 0.00007) and significantly regressed the tumor volume compared with day 0 (p = 0.001). The new model of i.a. administration of S. typhimurium A1-R has great promise for the treatment of recalcitrant osteosarcoma.

DOI： 10.1080/15384101.2017.1317417

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

The aim of the present study was to determine the usefulness of a patientderived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm3: untreated control
gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks)
irinotecan combined with temozolomide (irinotecan: i.p. injection
temozolomide: oral administration, daily, for 2 weeks)
pazopanib (oral administration, daily, for 2 weeks)
yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient.

DOI： 10.18632/oncotarget.20789

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Gastroenterological Surgery  

An 80-year-old man underwent right hemicolectomy for ascending colon cancer. The histopathological diagnosis was pSSpN1M0, pStage IIIa. After six months, abdominal enhanced CT showed a mass measuring 13 mm at the pancreatic head, and FDG-PET/CT detected intense FDG uptake in the region (early phase: SUVmax=5.8, late phase: SUVmax=6.9). Recurrence of colon cancer was suspected, therefore subsequent pancreatoduodenectomy was performed. The resected specimen revealed foreign body granuloma (FBG) due to a surgical suture. A case of FBG with false positive FDG-PET/CT delayed imaging findings is rare. Surgeons should be aware that FBG could be a possible differential diagnosis of disease recurrence after surgical resection.

DOI： 10.5833/jjgs.2015.0014

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：医学図書出版(株)  

肝門部領域胆管癌において大動脈周囲リンパ節転移症例の切除後予後は極めて不良であり、現在では同部への転移は遠隔転移に分類されガイドライン上も切除不能因子の一つとされている。したがって大動脈周囲リンパ節への癌転移を正確に診断することが治療方針決定のために重要である。術前画像診断モダリティとしてのMDCTやFDG18-PET/CTは簡便にリンパ節腫大の診断が可能であるが質的診断としては診断精度が低く、切除の可否を決めるためにはリンパ節のサンプリングによる術中病理診断が必須である。今日では肝門部領域胆管癌を含む胆道癌でも非切除症例を対象とした化学療法施行後のconversion surgeryや癌検体を用いたMSI highなどの遺伝子ステータス、クリニカルシークエンスによる遺伝子変異情報に基づいた免疫、分子標的治療が行われつつある。大動脈周囲リンパ節サンプリングは単に切除の可否を決めるだけでなく、これら新規治療法を行うための情報提供手段として今後もますます重要になってくると思われる。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：Japanese   Publisher：医学図書出版(株)  

術前治療は1960年代から諸臓器の癌腫に対して行われてきた。新規薬剤の開発や放射線照射法の進歩によりその治療成績は向上しつつある。膵癌においては初診時局所進行膵癌に対してconversionを目的として行われてきたが、徐々に適応が拡大されborderline resectableや切除可能膵癌まで施行されるようになりつつある。治療成績の適正な評価のためにはユニバーサルな効果判定法の確立が必要である。組織学的効果判定、画像による判定、血液検体による判定などさまざまな可能性が試されてきた。今後、より信頼できる効果判定法が開発されれば、効果に応じて補助治療の追加や手術の中止を選択できるようになり、より適正な治療を実現することが可能になると思われる。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.e23164

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Language：Japanese   Publisher：(一社)日本外科感染症学会  

はじめに:膵頭部癌や遠位胆管癌切除例における術中胆汁培養陽性はsurgical site infection(以下、SSI)発生に関連があるとされてきた。近年、肝門部領域胆管癌切除例に対する術前ドレナージは大きく変化しており、胆汁感染とSSIとの関連は明らかではない。目的:肝門部領域胆管癌切除例における胆汁感染と術後合併症、特にSSIとの関連を明らかにする。対象と方法:2008年1月から2012年12月に切除した肝門部領域胆管癌51例を対象とした。術中胆汁培養と術後合併症、SSI発生率、SSI起因菌との関連について検討した。結果:術中胆汁培養陽性率は62.7%(32/51例)であった。陽性群32例と陰性群19例に分け比較すると、術後全合併症発生率、在院日数、死亡率に差を認めず、SSI発生率にも差はなかった(陽性群vs陰性群:34.4% vs 31.6%)。しかし、陽性群でSSIを生じた11例中9例(81.8%)のSSI起因菌が術中胆汁培養検出菌と同一であった。結語:術中胆汁培養検出菌は、SSI起因菌と高率に一致するため術後早期の治療抗菌薬選択に有用である。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2015321664

Language：Japanese   Publisher：日本臨床外科学会  

症例は37歳,男性.統合失調症のため精神科入院中であった.外出時に自殺企図により酸性液体洗剤(サンポール)を服用し,誤嚥性肺炎を発症したため,前医で人工呼吸器管理の下に抗生剤治療を行った.服用2ヵ月後から経口摂取後に嘔吐を繰り返すようになり,腐食性幽門狭窄が疑われたため精査加療目的に当院当科紹介受診となった.透視下上部消化管内視鏡検査では,幽門前庭部の狭窄を認め,内視鏡は通過不能であった.酸性洗剤による腐食性幽門狭窄と診断し,手術加療の方針とした.術中所見では狭窄が広範囲であり,膵臓との癒着も疑われたため空置的胃空腸吻合術を施行した.酸性洗剤の服用による消化管の遅発性瘢痕狭窄は外科治療を要することがあり,文献的考察を加えて報告する.(著者抄録)

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Language：Japanese   Publisher：日本外科系連合学会  

症例は67歳男性.急性胆嚢炎に対して腹腔鏡下胆嚢摘出術を施行し,その際胆嚢壁を損傷し腹腔内に小結石が落下したため可能な限り回収した.半年後の造影MRI検査で肝右葉辺縁にT1,T2共に内部に淡いhigh intensity areaが混在した38mm大の腫瘤を認めた.肉芽腫やSFT,血腫などの良性病変を疑い経過観察としたが,さらに半年後のMRI検査では52mm大と増大傾向にあることから悪性腫瘍の可能性も考慮し手術加療の方針とした.腫瘤は右横隔膜下にあり,肝臓,横隔膜との境界が不明瞭であったため腫瘤とともに横隔膜,肝臓を合併切除した.病理組織学的検査では悪性所見は認めず,腹腔内落下結石を核とした右横隔膜下肉芽腫の診断であった.腹腔内落下結石を核とした腹腔内肉芽腫を形成した稀な1例を経験したため,文献的考察を加え報告する.(著者抄録)

DOI： 10.4030/jjcs.40.116

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Other Link： http://search.jamas.or.jp/link/ui/2015308090

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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Language：Japanese   Publisher：日本外科系連合学会  

はじめに:術後の段階食は慣習として行われてきたものであり,味の満足度も高くないため必ずしも必要ではないとされているが,胃切除後の症例を検討した報告は少ない.目的:食事内容の満足度向上と,在院日数短縮のために導入した幽門側胃切除後に全粥で開始するパスの有用性を明らかにする.対象と方法:幽門側胃切除術を行った204症例を段階食群(A群)104例と全粥開始群(B群)100例に分け,A群は術後5日目に3分粥,B群は術後5日目に全粥で開始し,2群間の術後在院日数,合併症などを比較検討した.結果:術後合併症発生率に有意差は認めず(A群vsB群:19%vs20%,p=0.889),短期の予後栄養指数では有意差を認めなかったが,アンケート調査の満足度も高く術後在院日数はB群で2日短縮した(12日vs10日,p&lt;0.01).結語:幽門側胃切除術後に全粥で経口摂取を開始することは,安全であり,患者満足度の向上,在院日数短縮に寄与すると考えられた.(著者抄録)

DOI： 10.4030/jjcs.39.827

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Other Link： http://search.jamas.or.jp/link/ui/2015248373

Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Books

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：国家公務員共済組合連合会  

東日本大震災で被災した福島県に平成23年3月16日から4月15日まで1ヵ月間にわたり計8班、延べ39名の医療者を派遣した。前半は福島県災害対策本部の基で放射線測定、避難所での診療、域外搬送支援および福島県避難所救護災害対策本部設置支援を行い、後半は新地町で救護所の設置・運営、避難所の巡回、関係組織との折衝、他の医療チームとの協働や引き継ぎ、福島県避難所救護災害対策本部との密な連携を行った。これらは未だ確立されていない、災害の超急性期を担うDMATの後を引き継ぎ、被災地の希望に沿った医療救護活動であったと考える。(著者抄録)

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2014107734

Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：日本臨床外科学会  

症例は72歳,男性.上行結腸癌S状結腸癌同時多発肝転移左肺転移腹膜播種転移に対し,S状結腸切除術,結腸右半切除術施行した.se,ssn3M1H2P3,stage IVの診断で,術後FOLFOX4療法を3クール.その後,内服化学療法を施行するもCEA29.5ng/mlとなり,mFOLFOX6療法を開始した.開始24時間後嘔気,投与終了1時間後意識消失JCS III-300となった.画像検査,腰椎穿刺では異常を認めず,血中アンモニア濃度は339μg/dlで意識障害の原因は高アンモニア血症によるものと診断した.肝不全用アミノ酸輸液,肝不全治療薬使用し,意識消失後21時間で意識状態は改善した.その1ヵ月後,FOLFOX4療法を開始した.FOLFOX4療法再開後は8クール施行したが高アンモニア血症認めることなく施行できた.今回臨床上まれである5FUによる意識障害を経験したので,文献的考察を加えて報告する.(著者抄録)

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Books

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：国家公務員共済組合連合会共済医学会  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2011298763

Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Books

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