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Because active-targeted liposomes are very complex formulations, quality characteristics of functional lipids have not been defined yet, and this is a major obstacle in clinical application of active targeted liposomes. We have developed high functionality and quality (HFQ) lipids, which define quality characteristics of functional lipids for clinical drug delivery system (DDS) applications. Because HFQ lipids are designed to enable facile and rapid functionalization of DDS carrier by simple and one-step mixing, we are expanding applications for not only liposomes but also exosomes and cells. Recently, we developed multi-color deep imaging by tissue clearing for analysis of spatial distribution of DDS in various tissues. Nanocarriers are usually non-uniformly distributed in solid tumors because of their heterogeneity. Especially, in refractory cancer such as pancreatic cancer, the presence of collagen and blood vessels greatly affects intra-tumor distribution of DDS carrier. Therefore information on spatial relations between the tissue structure and DDS carrier is important to regulate precisely intra-tumor distribution of DDS carrier. Recently, our group has established multicolor deep imaging to analyze spatial distribution of stromal collagen, liposomes, and blood vessels in pancreatic tumor tissue. In this review, we present recent research in developing HFQ lipids. Moreover, current status of research on DDS for pancreatic cancer treatment is reviewed., Yakugaku Zasshi, 140(5), pp.633-640; 2020

放射線療法は, ほぼすべての臓器がんに対し対応可能な低侵襲性治療である. 特に, この30年間は放射線照射技術の進歩が目覚ましく, 腫瘍と正常臓器との位置関係を3次元的に把握し線量分布を評価することのできる3次元治療が主流となった. さらに, 腫瘍への選択性を高める技術として, 定位放射線照射(定位放射線治療, 定位手術的照射)や強度変調放射線治療, 画像誘導放射線治療といった高精度放射線治療が日常臨床として普及しつつある. しかし, 肝癌や胆管癌, 膵癌などの腹部難治がんに対しては, これまで, 根治的な役割を十分に果たすことができていない. 腹部臓器は常に呼吸により動きを伴っており, 腫瘍制御に必要な高線量を安全に投与することが困難であったことが, その大きな要因として挙げられる. この問題に対応するために, 近年, 放射線療法では, 三次元空間に時間的要素を加えた四次元化治療に向けての研究開発が進められており, 臨床への展開が始まっている. 本稿では, これまでの研究成果と課題について概説する., Radiation therapy is a minimally invasive treatment that is indicated for almost any organ cancer irrespective of its location. There have been remarkable advances in irradiation technology over the past 30 years, and three-dimensional conformal radiotherapy (3D-CRT) has now become mainstream. With 3D-CRT, it is possible to understand the positional relationship between tumors and normal organs in three dimensions, and evaluate the dose distribution as a volume. Furthermore, use of high-precision radiotherapy, such as stereotactic radiation therapy (stereotactic radiotherapy, stereotactic radiosurgery), intensity-modulated radiotherapy, and image-guided radiotherapy, is becoming widespread indaily clinical practice as a technique for enhancing the selectivity of tumors....

Aim: The current study aims at visualizing the nursing care for patients diagnosed with pancreatic cancer (PC) at a PC specialty hospital in Japan.Methods: A qualitative approach was taken to carry out the study. 10 nurses caring for patients diagnosed with PC at the specialty hospital were interviewed after obtaining signed consents. Notes of interview were analyzed using qualitative descriptive research.Results: 3 categories and 12 sub-categories about nursing cares were found. 【Care of symptom】 was consist of〈 Observation of complications/side effects accompanying treatment/detailed examination〉,〈 Attention of advancer symptom〉,〈Cooperation with professional and family〉 and〈Treatment of refractory diarrhea〉.【 Support of willow-like heart】 was consist of〈 Careful thought for heart〉, 〈Guess of timing〉, 〈manipulation of information volume for anxiety alleviation〉 and 〈Setting a short term goal〉.【 Consideration for refractory cancer】 was consist of〈 Listening closelyas best care〉,〈 Direction of decision〉 and〈Support for surgical decisions not directly touched〉.Conclusion: It was suggested that nursing care at a PC specialty hospital may lead to better nursing care by involved in patient decision making and snuggled with patients can achieve their life goals., 《目的》本研究の目的は，精査から手術治療終了までの入院中の膵臓がん患者に対して膵臓がん専門病院の看護師がどのような看護ケアを行っているのかを語りから明らかにすることである．《方法》年間30 例以上の手術を行う膵臓がん専門病院である肝胆膵外科病棟で働いている看護師10 名を対象に半構成的面接を行い，質的記述的方法を用いて分析した．《結果》膵臓がん患者に対する看護は，3 つのカテゴリーと11 のサブカテゴリーから構成された．【症状への対応】は，〈治療・検査に伴う合併症・副作用の観察〉，〈進行症状への注意〉，〈専門家や家族との協力〉，〈どうしようもない下痢への試行錯誤〉から構成された．【柳ようのこころの支持】は，〈こころへの顧慮〉，〈タイミングの推察〉，〈不安を増長させない為の情報量操作〉，〈今を乗り越える目標設定〉から構成された．【難治性がんへの配慮】は〈最善策としての傾聴〉，〈病識の確認〉，〈直接触れられない手術決断への支持〉から構成された．《考察》膵臓がん専門病院における看護ケアは，患者の意思決定に関わり，人生の目標を達成できるように寄り添うことで，より良い看護ケアにつながる可能性が示された．

Early and accurate diagnosis is essential for improving the efficacy of treatment in patients with pancreatic cancer. The aim of this study was to evaluate the usefulness of cytological examination during retrograde cholangiopancreatography (ERCP) and tissue diagnosis by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in our hospital. Between April 2011 and April 2016, 70 patients (58 cases in invasive ductal carcinoma) were performed pancreatic surgery for pancreatic solid tumor. Sensitivity and specificity were 89 and 67% of the ERCP cytology, 80% and 75% of the EUS-FNA, respectively. Post-ERCP pancreatitis occurred in 2 of 33 (6%) patients. The tumors less than 2cm in diameter accounted for 12% of the invasive ductal carcinomas examined, and all of them were greater than 10 mm in diameter. In the present study, high-sensitivity cancer detection was limited to larger-sized, advanced-stage cancers in ERCP cytology, whereas the sensitivity was commonly high irrespective of tumor sizes or stages in EUS-FNA method. In conclusion, preoperative cytological and histological diagnosis using ERCP and EUS were performed safety and effectively in our hospital. Higher-sensitivity diagnosis of small pancreatic cancer, especially of less than 10 mm in diameter may be a future challenge.

甲医博第917号

膵臓癌の剖検は，最終的かつ組織学的に膵臓癌を確定診断する。さらに，剖検により，臨床経過と照らし合わせて，治療効果，その生存期間延長への寄与，死亡時の病勢進行度と死因との関係等様々な情報を得ることが可能となる。しかし，膵臓癌に関しては，病理学的のみならず臨床分野からもまとまった剖検症例の検討は少ない。今回，切除不能膵臓癌に限定して，当院で経験した48剖検症例を検討したので報告する。

A 58-year-old man complaining of jaundice was diagnosed with advanced cancer in the head of the pancreas and pancreatic pseudocyst. After the placement of a 7Fr plastic biliary stent, endoscopic ultrasonography-guided pseudocyst drainage was successfully performed. The cytology of pseudocyst fluid was class V. The jaundice and abdominal pain improved. The patient underwent FOLFILINOX chemotherapy without major complaints. Here, we report a case of pancreatic pseudocyst associated with pancreatic cancer that was successfully treated with endoscopic pseudocyst drainage, and chemotherapy.

Pancreatic cancer is the fourth leading cause of cancer death in Japan and the incidence and mortality rates have been increasing year by year. Despite the significant progress has been made in management of pancreatic cancer, further preclinical and clinical research studies are needed to advance our clinical approach to this aggressive cancer. Recent advance in diagnostic modalities including MDCT, MRCP and EUS-FNA allow early detection and accurate preoperative staging of the disease. Although surgery remains the only curative treatment for pancreatic cancer, increasing evidence now suggest that further significant improvements to overall survival can be achieved via new chemotherapeutic options such as FOLFIRINOX and gemcitabine/nabpaclitaxel regimen. This review will provide an overview of clinical practice for pancreatic cancer.

膵癌は難治癌の一つであり，5 年生存率が10％ 未満と予後不良の疾患である．一方，最大径2cm 以下で膵内に限局し転移を伴わない症例では，5 年生存率が50％ 以上と報告されており，予後の改善には小膵癌の段階での早期診断が不可欠である． 現在の膵癌診断の手順は，以下の通りである．急激な糖尿病発症や腹痛など膵癌を疑う症状を認めるものの，他に原因を指摘出来ない場合や，複数の危険因子を有する症例では，膵癌発生の可能性を考慮する．スクリーニング検査法としての膵酵素・腫瘍マーカー測定やUS で異常を認めた場合は，MDCT を行う．また，適宜EUS やMRCP も併用し，必要によりERCP やPET も考慮するが，画像診断により膵癌が疑われた場合には積極的に病理学的な確定診断を行う． 膵癌の早期診断には，腫瘤描出能が優れているEUS の積極的な施行や，ERCP 下膵液細胞診が効果的であるが，対象症例の設定には更なる検討が必要である．

Article, 信州医学雑誌. 58(3): 95-102 (2010)

We review the pathological diagnosis of general pancreatic disease, which is divided into three categories; solid lesions, cystic lesions and strictures of the pancreatic duct. Pathological examinations include cytology of the pancreatic juice, histological biopsy and histological examination of the resected specimen. These pathological examinations are performed before, during and after surgery. Therefore, pathological diagnosis of pancreatic disease plays an important role in the differential diagnosis between benign lesions and malignant lesions, grading of intraepithelial lesions in the pancreatic duct and staging of malignant tumors.

HER2(human epidermal growth factor receptor 2)は細胞膜貫通型チロシンキナーゼ受容体であり細胞の増殖,分化に関与している.膵癌の19.6～47.6%にHER2過剰発現が認められるがHerceptin(trastuzumab)の有効性や化学療法との併用効果に関しては不明である.今回,ヒト膵癌培養細胞株TRGを用いてHerceptinと5-FU(5-fluorouracil)の細胞傷害効果および併用効果をin vitroで検討した.TRG細胞はRT-PCR,Flow cytometryでHER2過剰発現が認められた.TRG細胞にHerceptinまたは5-FUを処理するとそれぞれ濃度依存性の細胞傷害効果が認められた.Herceptinと5-FUを併用処理するとそれぞれ単独処理よりも強い細胞傷害効果が認められた.Herceptinの抗体依存性細胞傷害活性(ADCC)を分析するためにTRG細胞にHerceptinまたは5-FUを処理した後,末梢血単核球(PBMC)を作用させた.PBMCの添加によりHerceptin,5-FUの細胞傷害効果は増強されたがHerceptinの方が増強効果が強く,ADCCの関与が示唆された.TRG細胞に5-FUを処理するとTRG細胞のHER2発現量が増加した.その結果Herceptinの細胞傷害効果が増強され5-FUとHerceptinの併用効果が得られたと考えられた.今回の研究でHerceptinと5-FUの併用療法はHER2を過剰発現する膵癌に対して有効な治療法となりうる可能性が示唆された., HER2, a transmembrane growth factor receptor, is overexpressed in 21 - 48% of pancreatic cancer. However, the efficacy of anti-HER2 antibody, Herceptin (trastuzumab), for pancreatic cancer patients has not been fully evaluated. In this study, the cytotoxic effect of Herceptin in combination with 5-FU (5-fluorouracil) for HER2 overexpressing human pancreatic cancer in vitro was investigated, using the human pancreatic adenocarcinoma cell line, TRG. The TRG cell line was positive for HER2 mRNA in RT-PCR analyses and overexpressed HER2 protein in flow cytomerty analyses. Either Herceptin or 5-FU concentration-dependently inhibited the growth of TRG cells. Combination of Herceptin and 5-FU resulted in significant inhibition of growth of TRG cells compared to either agent alone. We added peripheral blood mononuclear cells (PBMC) to TRG cells after treatment with Herceptin or 5-FU in order to analyze the effect of antibody-dependent cellular cytotoxicity (ADCC) by the chemotherapeutics. Incubation with PBMC enhanced the antiproliferative effect of Herceptin more than that of 5-FU, which could be the result of ADCC induced by Herceptin. This study showed that combination therapy with Herceptin and 5-FU could be effective for HER2 overexpressing pancreatic cancer patients.

2001年4月より新規抗癌剤gemcitabineの保険認可以後, 外来にて浸潤性膵管癌切除後, 全身補助化学療法を35例(男:女, 19:16)に行ってきた。平均年齢62.8歳(38歳〜84歳)。副作用は白血球減少26例(74.3%), 食欲不振・悪心等消化器症状13例(37.1%)にみられた。しかし, いずれもGrade 2以下の軽微なものであり, 入院加療を要した副作用はなかった。局所癌遺残度R0とR1の症例に対するgemcitabine総投与量および, 生存期間は同等であったのに対し, R2症例に対する総投与量は有意に少なく(P=0.0215).生存期間も短かった(P=0.004)。以上より, 浸潤性膵管癌切除後の患者に対し, gremcitabineは膵癌術後補助化学療法として, 外来において安全に投与が可能であった。R1症例でも繰り返し投与を行うことにより, R0と同等の生存期間を得る可能性が示され、補助化学療法の併用することにより, 積極的膵切除の意義も増すものと考えられた。, Post-operative adjuvant chemotherapy using gemcitabine has been performed for 35 patients who underwent pancreatectomy at our department. All patients were administrated intravenously gemcitabine (1000mg/m^2 weekly×7 followed by 1 week of rest, then weekly×3 every 4 weeks thereafter as outpatients. Grade 1 or 2 leucopenia was found in twenty-six patients (74.3%). Thirteen patients complained of appetite loss and/or nausea. All toxicities were grade 1 or 2, and then no patient needed admission for its side effect. Median survival was 16.2 months. There was no significant difference of total gemcitabine doses and survival rates between residual tumor 0 patients (n=25) and 1 (n=6). In contrast, macroscopically non-curative patients (n=4) had low doses of gemcitabine and short survival, compare with microscopically curative patients. In conclusion, gemcitabine as adjuvant chemotherapy could be administrated safely in outpatients with post-operative pancreatic cancer.

We performed clinical and immunohistochemicalstudies on MOS-1antigen,a newmarker for pancreatic cancers.The antigen was detected by a new monoclonal antibody,MOS-1,An enzyme immunoassay was devised to measure the value of the MOS-1antigen in serum. Serum Values of MOS-1antigen exceedingthe mean plus three standard deviations for 134 healthy control blood samples were found in a high proportion of patients with pancreatic cancer （71%）. The MOS-1antigen values in serum from patients with benign diseases,including chronic pancreatitis,were within the normal range in 95% of the cases. Furthermore,imunohistochemical analysis indicated that MOS-1 antigen was detected in pancreas cancer,bile duct cancer,and colon cancer. However,it was seldom detected in esophagus cancer,stomach cancer,lumg cancer nor in normal cells. Our data suggested that MOS-1antigen maybe useful in the diagnosis,management,and prognosis of patients with panecreatic cancer.

1～2cmの小膵癌は, EUSで尾側膵管の急激な拡張を伴う比較的境界明瞭な円形低エコー腫瘤として描出される場合が多い. 上皮内癌など1cm以下の場合には分枝の嚢状拡張が唯一の所見となる可能性もあり, 主膵管および分枝の系統的スキャンが膵癌の早期発見につながると思われる. 小膵癌と炎症性膵腫瘤との鑑別では, 尾側膵管の形状を加味して腫瘤の形態や内部エコーの性状を評価することが重要だが, 腫瘤が小さくなればなる程両者の鑑別は困難となる. 診断能の向上を図るため膵液の遺伝子診断を組み合わせている. PCR-RFLP法では, 全膵管癌の81%(21/26)にK-rasコドン12の点突然変異が検出されたが, 慢性膵炎でも9%(5/53)に検出された. しかし, HPA法の開発によりK-rasコドン12の簡便な定量的測定が可能となり癌特異性が向上した. 膵液の遺伝子診断は, EUSにて検出された小腫瘍性病変や実質内の嚢胞状変化の質的診断に有用であり, これら内視鏡を応用した一連の検査は, 膵癌の早期診断法として大いに期待される.

This study was undertaken to determine whether or not intraportal and intrahepatic arterial one-shot infusion chemotherapy can prevent hepatic metastasis after resection of pancreatic cancer. Eight patients received 20 mg of mitomycin C in the portal vein during the operation and postoperatively they received 20 mg of mitomysin C in the hepatic artery by Seldinger's method at three-month intervals(Group A). Fifteen patients received no chemotherapy before or after the operation (Group B). The histological type and size of the tumor , nodular involvement and the degree of surrounding tissue invasion did not differ significantly between the two groups. The cumulative survival rates at 1, 2 and 3 years were 100%, 60% and 20% respectively after resection in Group A. On the other hand, in Group B, the cumulative survival rates 1, 2 and 3 years after resection were 44%, 17% and 7% respectively. There was no statistically significant difference between Group A and Group B. But in Group A, no patient died from recurrence of cancer with in one year and 8 patients died of cancer recurrence in Group B. The recurrent forms of cancer in Group B were liver metastasis in 6 patients and local recurrence in 2 patients. Therefore, our method seems beneficial for preventing hepatic metastasis for patients who have received resection of pancreatic cancer.

ヒト膵癌細胞3株 (Capan-1, BxPC-3, MIAPaCa-2) における serine protease の発現からみた肝転移能並びに protease inhibitor である FOY-305 投与による肝転移抑制効果をヌードマウスを用いた脾内移植法による肝転移モデル実験で評価した. さらに, vacuolar type proton pump (V-type ATPase)発現の有無を検索し, その inhibitor である bafilomycin A_1 による浸潤抑制効果を matrigel invasion chamber を用いた chemoinvasion assay 法で評価した. その結果, 膵癌の転移能は trypsinogen 1(cationic type) の発現とよく相関し, その転移発生率は FOY-305 投与で有意に抑制された. さらに, 膵癌の浸潤能は bafilomycin A_1 によって有意に抑制された. 以上の成績より, ヒト膵癌の浸潤・転移に際し trypsinogen 1 と V-type ATPase 発現が重要な役割を演じていること, さらに浸潤・転移の制御法として protease および proton pumpのinhibitor を用いた治療法の有用性が示唆された. The potential for hepatic metastasis in nude mice was studied by the intrasplenic implatation method with three human pancreatic cancer cell lines, Capan-1, BxPC-3, and MIAPaCa-2, especially in relation to serine protease expression. The inhibitory effect of a protease inhibitor agent, FOY-305, on hepatic metastasis was also assessed. In addition, we examined these cell lines, for expression of he vacuolar type proton pump (V-type ATPase), and determined the effect of its inhibitor agent, bafilomycin A1, on the cancer cell invasion in vitro by chemoinvasion assay using a MATRIGEL invasion chamber.The potential for hepatic metastasis was well correlated with expression of trypsinogen l (cationic isoform) in these cell lines, and the incidence of metastasis was significantly decreased by FOY-305. In addition, the potential for invasion in vitro in these cell lines was also siginificantly suppressed by bafilomycin A1. These finding suggest that pharmacologic inhibition of the activity of serine protease and V-type ATPase may be a new strategy for the therapy of pancreatic cancer invasion and metastasis.

Article, 信州医学雑誌 41(3): 205-210(1993)

Article, 信州医学雑誌 41(3): 211-215(1993)

69才の女性で癌性腹膜炎, 胆管拡張およぴ胆嚢腫大などが認められ, 剖検時まで確定診断の困難であった膵摘の1例を報告した. 腹水の細胞診ではclass V(adenocardnoma)であったが, 画像診断では原発巣を特走し得なかった. 剖検時の肉眼的所見でも膵臓に腫瘍塊を認めなかったが, 組織学的検索により膵体部より高分化型腺癌(duct cell carcinoma)がみられ, これが肝内胆管を這うような形で肝内に転移していた.(1987年2月10日 受付), Presented here is the case of a 69-year-old woman with pancreatic cancer, Efforts were made to discover the origin of the cancer but without success. Tumor nodules were scarcely observed in the pancreas macroscopically at autopsy, while histological examination of the pancreas revealed the presence of a well-differentiated adenocarcinoma (duct cell carcioma). The invasion to the wall of the intrahepatic bile duct was also observed microscopically.

Among the secondary ureteral tumors, there have been a few true metastases to the ureters. We report a case of metastatic ureteral tumor from the pancreas, and review and discuss 60 cases collected from the Japanese literature.

Article, 信州医学雑誌 37(5): 433-443(1989)

We have detected two novel antigens of human pancreatic cancer cells by the use of murine monoclonal antibodies. Mouse myeloma cells, NS-1, were fused with spleen cells from BALB/C mice immunized with human pancreatic cancer cells, HGC-25. These antigens, provisionally named HC-1 and HC-2, were not present on human hematopoietic cells. HC-1 was expressed on a variety of human tissue culture cell lines which originated from cancer cells. Immunoperoxidase studies failed to demonstrate HC-1 in frozen sections of normal pancreatic and fresh turor tissues other than pancreatic cancer tissues that were so far tested. In consideration of these findings, HC-1 appeared to be a cancer associated antigen. On the other hand, HC-2 was only present on pancreatic cancer cells in both immunofluorescence on tumor cell lines and immnoperoxidase studies on fresh tumor tissues. In the enzyme immunoassays used with anti-HC-2 antibody, however, HC-2 was also demonstrable on normal pancreatic tissue and pancreatic juice from patients with chronic pancreatitis and patients with pancreatic cancer. We can not precisely document the reason for the descrepancy at present. Enzyme immunoassay proved that HC-2 was detectable as a soluble antigen in the culture supernatant of HGC-25 cells. We have already established an enzyme immunoassay for HC -2 and have detected the antigen in pancreatic juice from patients with pancreatic and bile duct cancer. Immunochemical analysis revealed that HC-1 was a glycoprotein with a molecular weight of 130 K daltons which consisted of two subunit components with a molecular weight of 95 K- and 28 K- daltons. The combined study of gel filtration with enzyme immunoassay demonstrated an antigen activity in the region of elution profile with a molecular weight of 360 K daltons for HC-2. From these dat HC-1 and HC-2 are different antigens from the other tumor markers reported elsewhere, and moreover, the two monoclonal antibodies demonstrated here may be useful in the diagnosis for pancreatic cancer.

Article, 信州医学雑誌 26(1): 43-53(1978)

Article, 信州医学雑誌 32(4): 326-333(1984)

Article, 信州医学雑誌 30(2): 253-258(1982)

Article, 信州医学雑誌 32(5): 389-401(1984)