Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402

<p>Abstract</p> <p>Background</p> <p>The tumor associated antigen (TAA) gp100 was one of the first identified and has been used in clinical trials to treat melanoma patients. However, the gp100 epitope peptide restricted to HLA-A*2402 has not been extensively examined clinically due to the ethnic variations. Since it is the most common HLA Class I allele in the Japanese population, we performed a phase I clinical trial of cancer vaccination using the HLA-A*2402 gp100 peptide to treat patients with metastatic melanoma.</p> <p>Methods</p> <p>The phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80°C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-γ- ELISPOT and MHC-Dextramer assays.</p> <p>Results</p> <p>No related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8⁺gp100-in4⁺CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4.</p> <p>Conclusion</p> <p>Our results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications.</p

決定木学習を利用したビジネスプロセス実行ログ検証のための論理式の生成

情報システムによって記録されたビジネスプロセスの実行履歴を分析することはプロセスマイニングと呼ばれ，実際に行われたビジネスプロセスの問題を把握して改善へ繋げるための重要な手段である．LTL checkerは線形時相論理(LTL)をベースにした形式的な言語を利用してビジネスプロセスにおいて成り立つべき性質を記述し，検証を行うためのツールであり，ビジネスプロセスの分析を行うための有力な手段として知られている．しかし，多くのビジネスアナリストはLTLのような数学的な記法に精通していないため，ビジネスプロセスにおいて検証したい性質を記述する際に，真に検証すべき性質を正確に記述することは困難である．論理式を誤って記述した場合は当然のことながら本来意図していた検証を行うことはできない．そこで本研究では教師あり機械学習手法の一種である決定木を用いてビジネスプロセス実行ログからイベントの実行順序関係に着目して抽出した特徴量に基づいて学習を行い，論理式を自動生成することで検証したい性質を記述する手法を提案する．本手法を用いることで，数学的な手法に精通していない者でも検証すべき性質を記述することができる．本手法の妥当性を示すために，電話修理プロセスに対し提案手法を適用し，有効性を確認した．Process mining is a important means for analyzing business process and LTL checker is a famous tool for process mining. However, since many business analysts are not familiar with mathematical notation like LTL, it is difficult to describe exactly the property to be verified when describing the property to be verified in the business process is there. Therefore, in this study, learning is performed based on feature quantities extracted from the business process execution log using a decision tree, and a logical expression is automatically generated. We propose a method to describe properties to be verified

Two-photon excitable boron complex based on tridentate imidazo[1,5-a]pyridine ligand for heavy-atom-free mitochondria-targeted photodynamic therapy

We have synthesized a cyan fluorescent boron complex based on a tridentate imidazo[1,5-a]pyridine ligand. The boron complex was found to have potential applications as not only a chiroptical material but also a heavy-atom-free mitochondria-targeted photosensitizer for cancer treatment

NK cells control tumor-promoting function of neutrophils in mice

Although NK cells are recognized as direct antitumor effectors, the ability of NK cells to control cancer-associated inflammation, which facilitates tumor progression, remains unknown. In this study, we demonstrate that NK cells control tumor-promoting inflammation through functional modification of neutrophils. NK cells control the tumor-promoting function of neutrophils through an IFNgamma-dependent mechanism. Tumor progression in an NK cell-depleted host is diminished when the IL17A-neutrophil axis is absent. In NK cell-depleted mice, neutrophils acquire a tumor-promoting phenotype, characterized by up-regulation of VEGF-A expression, which promotes tumor growth and angiogenesis. A VEGFR inhibitor which preferentially suppressed tumor growth in NK cell-depleted mice was dependent on neutrophils. Furthermore, the systemic neutropenia caused by an anti-metabolite treatment showed an anti-cancer effect only in mice lacking NK cells. Thus, NK cells likely control the tumor-promoting and angiogenic function of neutrophils

Total Skin Electron Beam Therapy

The peripherally T-cell lymphoma; Mycosis fungoides etc, has the good radiation sensitivity, and has been adapted for total skin electron beam therapy. In this study the pendular irradiation method was used for the purpose of total skin electron beam therapy in Mycosis fungoides, and physical data on the radiation field and the electron beam energy were useful clinically.皮膚に限局した一連の末梢型T細胞リンパ腫は放射線に対する感受性が高く、電子線治療の適応となる疾患である。こららの疾患は一般的に全身の皮膚に浸潤するため、治療に際してはTarget Volumeの深さに合わせた最小限のエネルギーで全身隈なく照射する必要がある。筆者等は最近臨床で遭遇した菌状息肉症の患者を治療するため、その患者に合った物理的なデータを測定した。照射野の拡大には振子照射法を用い、エネルギー低減方法は装置に装備されている鉛のスキャタラーを低原子番号で、しかも加工のしやすい塩化Vinyl板に交換する方法を工夫した。データとして治療効果、副作用に関係する線量率、エネルギー、及び照射野内平坦度について測定した結果、距離が長くなる関係から線量率が低下する全身照射法の欠点は解消できなかったが、エネルギー及び平坦度については使用可能なデータを得ることができた

Photon background caused by the reduction of the electron beam energy - Materials of scattering foil -

The total skin electron beam therapy has been one of the clinical treatment for peripherally T-cell lymphoma; Mycosis fungoides, adult T-cell lymphoma, and so on. The crucial points in this treatment are not only having an optimum energy level of electron beam for a target volume (a tissue) but also keeping the photon back ground low. It is not easy to regulate those points by the control panel, however, for the equipment that is conventinally used for electron beam, theoretically, is to exchange lead (Pb), which is ordinarily used, to a low atomic number material as a scattering foil. We examined several different kinds and / or various thickness as a scattering foil material that can make the electron beam lower without an increase of the contaminant as X-ray. We hereby reported the results, and strongly suggested the following two materials in use; acrylic plate, carbon board, and so on, which are easily available and worked, would be practically useful for the total skin electron beam therapy

The Role of Optical Coherence Tomography in Coronary Intervention

Optical coherence tomography (OCT) is an optical analog of intravascular ultrasound (IVUS) that can be used to examine the coronary arteries and has 10-fold higher resolution than IVUS. Based on polarization properties, OCT can differentiate tissue characteristics (fibrous, calcified, or lipid-rich plaque) and identify thin-cap fibroatheroma. Because of the strong attenuation of light by blood, OCT systems required the removal of blood during OCT examinations. A recently developed frequency-domain OCT system has a faster frame rate and pullback speed, making the OCT procedure more user-friendly and not requiring proximal balloon occlusion. During percutaneous coronary intervention (PCI), OCT can provide detailed information (dissection, tissue prolapse, thrombi, and incomplete stent apposition [ISA]). At follow-up examinations after stent implantation, stent strut coverage and ISA can be assessed. Several OCT studies have demonstrated delayed neointimal coverage following drug-eluting stent (DES) implantation vs. bare metal stent (BMS) placement. While newer DESs promote more favorable vascular healing, the clinical implications remain unknown. Recent OCT studies have provided insights into restenotic tissue characteristics; DES restenotic morphologies differ from those with BMSs. OCT is a novel, promising imaging modality; with more in-depth assessments of its use, it may impact clinical outcomes in patients with symptomatic coronary artery disease

ゴール指向洗練パターン駆動によるユースケースモデリング

ゴール指向要求分析手法KAOSは，要求を系統的，論理的にモデリングできる要求分析手法である．本論文では，ゴール指向要求分析の成果をオブジェクト指向設計プロセスに組込むことを意図して，KAOSモデルをユースケースモデルに変換するアプローチを提案する．この変換は洗練パターンを媒体としている．提案アプローチにより作成したユースケースモデルとあらかじめ用意された基準モデルを比較し，提案アプローチ適用の効果を評価するために，米国ATMシステムを事例とするユースケースモデリングに提案アプローチを適用した．この結果，提案アプローチは効果的に適用され，モデル変換における洗練パターンの意味（シナリオ）の継承と属人性の排除について効果を確認できた．We propose a practical and semi-formal transformation procedure from KAOS model to use case model. KAOS goal-oriented requirements methodology is useful for requirements engineering and well-established to model requirements systematically and logically. Proposed approach aims at reflecting artifact of KAOS modeling to an object-oriented design process as much as possible. It is based on that a use case model is positioned at requirements model of object-oriented design processes. We confirmed that our proposed approach was effective one through evaluating a case study on ATM system in United States

Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma

Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3–4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy