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Regenerative medicine is a medical treatment that aims to restore lost human body functions by regenerating missing or dysfunctional organs and tissues using stem cells, etc. There are three major types of stem cells used in regenerative medicine: induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), and mesenchymal stem cells (MSCs). MSCs are expected to be widely applied to regenerative medicine because of their ability to differentiate into various types of cells, repair cells and tissues; anti-inflammatory effects; secretion of various growth factors; and resolution of abnormally accumulated protein amyloid. MSCs can be derived from bone marrow, dental pulp, and other sources, but adipose tissue-derived stem cells (ADSCs) may be superior in that they can be harvested with the least amount of invasion, and therefore, a sufficient amount of stem cells can be cultured relatively easily. When MSCs are administered systemically by intravenous infusion, they tend to accumulate at the site of disease, a property known as "homing," which is extremely advantageous for clinical applications. In Japan, stem cell therapy can be performed only after the research or treatment plan has been reviewed and approved by the "Committee for Specific Approval of Regenerative Medicine" and submitted to the Ministry of Health, Labor and Welfare for approval in accordance with the "Act on Securing the Safety of Regenerative Medicine" and after approval by the ethics committee of the facility where the therapy is performed. In this review, the characteristics of MSCs, the actual status of their clinical application, and their future prospects are presented.

Objective This study aimed to evaluate in situ tissue-engineered esophagus in a canine model after experimental resection and replacement of a full circumferential defect of the intrathoracic esophagus. Methods Two types of scaffolding were fabricated. In the KF(+) group (n = 6), oral keratinocytes and fibroblasts cultured on human amniotic membrane were sheeted on polyglycolic acid felt with smooth muscle tissue and were then rolled around tubes. In the KF(−) group (n = 6), the same procedure was followed, but the keratinocytes and fibroblasts were omitted. Both scaffolds were wrapped in omentum and implanted in the abdomen. In the KF(+) group, at 3 weeks after implantation, the scaffold developed into a tube with a well-differentiated lumen of stratified squamous cells surrounded by a thick smooth muscle-like tissue (in situ tissue-engineered esophagus). A part of the esophagus was resected and replaced by the graft in the same dogs. Results In the KF(−) group, strictures developed after esophageal replacement, with almost complete obstruction within 2 to 3 weeks. In contrast, in the KF(+) group, the in situ tissue-engineered esophagus showed good distensibility and the dogs remained without feeding problems through 420 days. Esophageal peristalsis transferred food to the stomach, despite the absence of peristaltic activity in the in situ tissue-engineered esophagus itself. The thickness of the squamous epithelial layer and the smooth muscle layer of the in situ tissue-engineered esophagus were similar to that of the adjacent native esophagus. Conclusion The in situ tissue-engineered esophagus can successfully replace the intrathoracic esophagus, and this procedure may offer a promising surgical approach to esophageal diseases.

Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. RUNX3, a novel tumor suppressor of gastric cancer, functions in transforming growth factor (TGF)-beta-dependent apoptosis. We obtained paired samples from 62 patients with advanced esophageal cancers diagnosed initially as T3 or T4 with image diagnosis; one sample was obtained from a biopsy before presurgical radiotherapy, and the other was resected in surgical specimens after radiotherapy. RUNX3 was repressed in 67.7% cases of the pretreatment biopsy samples and 96.7% cases of the irradiated, resected samples. The nuclear expression of RUNX3 was associated with radiosensitivity and a better prognosis than cytoplasmic or no RUNX3 expression (P0.003); cytoplasmic RUNX3 expression was strictly associated with radioresistance. RUNX3 was downregulated and its promoter was hypermethylated in all radioresistant esophageal cancer cell lines examined. Stable transfection of esophageal cancer cells with RUNX3 slightly inhibited cell proliferation in vitro, enhanced the antiproliferative and apoptotic effects of TGF-beta and increased radiosensitivity in conjunction with Bim induction. In contrast, transfection of RUNX3-expressing cells with a RUNX3 antisense construct or a Bim-specific small interfering RNA induced radioresistance. Treatment with 5-aza-2'-deoxycytidine restored RUNX3 expression, increased radiosensitivity and induced Bim in both control and radioresistant cells. These results suggest that RUNX3 silencing promotes radioresistance in esophageal cancers. Examination of RUNX3 expression in pretreatment specimens may predict radiosensitivity, and induction of RUNX3 expression may increase tumor radiosensitivity.

ERM (ezrin/radixin/moesin) proteins are organizers of apical actin cortical layer in general. We previously reported that the knockout of radixin resulted in Rdx − / − mice with displacement/loss of the canalicular transporter Mrp2, giving rise to Dubin–Johnson syndrome-like conjugated hyperbilirubinemia in the mixed genetic background (C57BL/6-129/Sv) (Kikuchi, et al. (2002) Nature Genetics 31, 320–325). However, when these mice were kept under mixed genetic background for years (late mixed backgrounds; LMB), the conjugated hyperbilirubinemia gradually became inconspicuous, while evidence of liver injury increased. We examined the effect of genetic background by backcrossing LMB Rdx − / − mice to C57BL/6 and 129/Sv wild type mice with the result that the Rdx − / − congenic mice regained hyperbilirubinemia with reduced hepatocellular damage. As revealed by immunofluorescence and western blots, the localization/expression of apical transporters, Mrp2, CD26, P-gps, and Bsep were not influenced by backcrossing, though those of a basolateral transporter, Mrp3, were strikingly increased by backcrossing.

症例は76歳, 男性. 検診でCA19-9高値 (486.6U/ml) を指摘されて当院を受診した. 腹部造影CT検査で腹部傍大動脈領域に8×3cmの腫瘤を認め, 上・下部消化管内視鏡・MRI・FDG-PETも行ったが, 原発巣となりうる病変を同定することはできなかった. 病理組織診断のために試験開腹を行い, 診断は高度の線維化を伴う膵外発育型膵癌であった. 7病日目に突然の腹痛・39度台の発熱とともに敗血症性ショックとなり, 腹部造影CT検査を行ったところ, 腸間膜脂肪織炎, 横行結腸壁肥厚および腸間膜静脈・門脈ガス血症を認めた. 発症後8時間で緊急開腹手術を行い, 横行結腸切除術・上行結腸人工肛門造設術を行った. 術後は急速に敗血症を離脱して, 軽快退院した. 腸間膜脂肪織炎による門脈ガス血症の報告はこれまでにないが, 早期の診断と迅速な原因の除去によって軽快することを示した.

The first randomized controlled trial in medicine was an investigation of streptomycin in 1948.1 Since then, randomized controlled trials have been widely recognized as offering the gold standard for evaluating treatment efficacy and effectiveness and are classified as providing the highest grade of evidence in the hierarchy of research designs.2 Evaluations in the 1970s and 1980s suggested that observational studies may spuriously overestimate treatment benefits, yielding misleading conclusions.3–6 In recent years, this debate has resurfaced. Some reports have suggested that for selected medical topics, both randomized and observational studies, may yield very similar results.7,8 Conversely, opposing results have been reported from a large number of diverse medical topics.9 Although these previous studies have contained some surgical topics, most have assessed topics involving pharmacotherapies. However, pharmacologic and surgical therapies differ in clinical nature, and results for pharmacologic investigations may therefore not apply to surgical fields. This issue warrants investigation with a focus on the surgical area, and no previous studies appear to have undertaken an exhaustive assessment of a single clinical field. The present study investigated digestive surgery, allowing a systematic search and evaluation. This systematic and exhaustive search of a large number of diverse articles on digestive surgery seeks to answer the following question: Do observational studies in digestive surgery tend to produce the same results as randomized controlled trials?

In this randomized multicenter Phase III study, patients with curatively resected Stage II/IIIA gastric cancer were assigned to postoperative adjuvant therapy with an oral fluoropyrimidine S-1 alone (2 weeks of treatment and 1 week of rest for 6 months, followed by 2 weeks of treatment and 2 weeks of rest for 6 months) or S-1 combined with an oral biological response modifier PSK (the same regimen of S-1 plus daily PSK for 12 months). The main objective was to evaluate the survival benefit and quality of life (QOL) of combined therapy. The primary end points were the time to relapse and the duration of survival after surgery, i.e. the rates of disease-free survival and overall survival at 3 and 5 years. The secondary end points were the relations of survival rates to drug compliance, QOL, adverse events, postoperative complications, relapse status, and the preoperative expression of immune or tumor markers. The sample size was 140 per treatment arm.

症例は80歳の女性で, 平成16年5月に軽度の下痢・腹痛・右下腹部腫瘤のために近医を受診した. 腹部CT, X線検査にて右下腹部に手拳大の腹壁浸潤を疑う嚢胞性腫瘤を認めた. 腫瘤は充実性成分を持ち, CT・MRI・FDG-PET・腫瘍マーカーなどより「虫垂癌・腹膜播種」と考えた. 手術時診断も同様であったが, 病理組織学的診断は乳頭状腺癌がclear cell carcinoma成分を持つ非常にまれな原発性腹膜嚢胞性腺癌であり, 中腎傍管 (paramesonephric duct/mullerian) 由来であると考えられた. 文献的には非常に予後の悪い癌であるが, 本症例においては外科的切除に加えてCDDP+TS-1の術後化学療法にて再発腫瘍の縮小を認め, 手術後17か月で外来通院治療中である.

Background: Local recurrence, the most frequent pattern of recurrence of rectal carcinoma, is almost always fatal. The difficulty of diagnosing local recurrence contributes importantly to the poor prognosis. Methods: We coupled monoclonal antibody (Mab) A7, which reacts specifically with human colorectal carcinoma, to ferromagnetic lignosite (FML) particles to distinguish rectal carcinoma from other tissues by magnetic resonance (MR) imaging. We examined retention of immunoreactivity by the A7-FML complexes in vitro, and also their distribution in vivo according to radiolabeling and MR imaging when injected into nude mice bearing human colorectal carcinoma xenografts. Results: A7-FML retained binding activity nearly identical to that of Mab A7. Significantly more 125I-labeled A7-FML accumulated in engrafted tumors than did 125I-labeled normal mouse IgG-FML complexes (P

A series of molecular pathological investigations of the molecules that stimulate the cyclin dependent kinases (CDK1, 2, 4, and 6) have led to enormous accumulation of knowledge of the clinical significance of these molecules for cancer diagnosis. However, the molecules have yet to be applied to clinical cancer diagnosis, as there is no available technology for application of the knowledge in a clinical setting. We hypothesized that the direct measurement of CDK activities and expressions (CDK profiling) might produce clinically relevant values for the diagnosis. This study investigated the clinical relevance of CDK profiling in gastrointestinal carcinoma tissues by using originally developed expression and activity analysis methods. We have established novel methods and an apparatus for analyzing the expression and activities of the CDK molecules in lysate of tumor tissue in a clinical setting, and examined 30 surgically dissected gastrointestinal carcinomas and corresponding normal mucosal specimens. We demonstrate here that remarkably elevated CDK2 activity is evident in more than 70% of carcinoma tissues. Moreover, a G1-CDK activity profiling accurately mirrored the differences in proliferation between tumor and normal colonic tissues. Our results suggest that CDK profiling is a potent molecular–clinical approach to complement the conventional pathological diagnosis, and to further assist in the individualized medications.

Superparamagnetic iron oxide (SPIO)-based colloid has been used clinically as a tissue-specific magnetic resonance contrast agent. We coupled monoclonal antibody A7 (Mab A7), which reacts specifically with human colorectal carcinoma, to Ferumoxides (SPIO) and examined the accumulation of this conjugate in xenografted tumours in nude mice. We examined in vitro immunoreactivity of Mab A7 coupled to Ferumoxides and its in vivo distribution in nude mice with human colorectal carcinoma. Magnetic resonance imaging of tumour-bearing nude mice was performed 72 h after injection of A7-Ferumoxides. A7-Ferumoxides retained binding activities that were nearly identical to intact Mab A7. More of the radiolabelled A7-Ferumoxides accumulated in the tumour than normal mouse IgG-Ferumoxides from 12 h onwards after injection (P

Our previous studies suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. This study was conducted to determine whether alteration of RUNX3 gene expression could be detected in the normal-looking gastric remnant mucosa, and to ascertain any difference in the potential of gastric carcinogenesis between the anastomotic site and other areas in the remnant stomach after distal gastrectomy for peptic ulcer (RB group) or gastric cancer (RM group), by analysing RUNX3 expression with special reference to topography. A total of 89 patients underwent distal gastrectomy for gastric cancer from the intact stomach (GCI group) and 58 patients underwent resection of the remnant stomach for gastric cancer (RB group: 34 cases, RM group: 24 cases). We detected RUNX3 and gene promoter methylation by in situ hybridisation, quantitative reverse transcriptase–polymerase chain reaction (RT–PCR), and methylation-specific PCR. The interval between the initial surgery and surgery for remnant gastric cancer (interval time) was 10.4 years in the RM group, and 27.5 years in the RB group. Cancers in the RB group were significantly more predominant in the anastomosis area (P

今回, 我々は先天性無フィブリノゲン (以下, Fbgと略記) 血症患者に対し, Fbg製剤補充下に回盲部切除術を施行し, 良好な経過を得たので報告する. 症例は36歳の男性で, 主訴は右下腹部痛. 以前より先天性無Fbg 血症と診断されていた. 急性虫垂炎による限局性腹膜炎と診断し手術を行った. 入院時の血漿Fbg値は50mg/dl (基準値200～400mg/dl) であった. 手術直前にFbg製剤10gを静注し, 執刀直前の血漿Fbg 値は198mg/dlであった. 開腹所見より憩室炎と診断し, 回盲部切除術を施行した. 術中出血傾向は認めなかった. 術後もFbg製剤を血漿Fbg値を目安に静注投与し, 血漿Fbg値は術後8日目まで100～199mg/dlで推移した. 術後は特に合併症なく経過した. 本症例においてはFbg製剤補充療法が有用と考えられた. また, 血漿Fbg値は100mg/dl以上に維持することが望ましいと考えられた.

今回, 我々は肺癌術後に腸重積で発症した多形癌の小腸転移の1例を経験したので報告する. 症例は75歳の男性で, 2003年4月上旬に肺癌に対して胸腔鏡下左上葉切除術を受けた. 病理組織学的には新WHO分類の扁平上皮癌の関連組織型であるpleomorphic carcinoma (多形癌) の診断を得た. 術後3か月から貧血が出現し, 腹部X線検査で鏡面像を認め腸閉塞と診断した. イレウス管からの小腸造影でTreitz 靭帯から50cmの空腸に狭窄部を認め, CTで層状の腹腔内腫瘤を認めた. 以上から, 肺癌の小腸転移による腸重積を疑い, 開腹術を施行した. 開腹するとTreitz靭帯より50cmに重積を起こした空腸を認め小児手拳大の腫瘤を形成していたため, 小腸部分切除術を施行した. 病理組織学的には肺癌の小腸転移であった. 術後16か月を経過した現在, 再発は認められていない.

全内臓逆位を伴った巨大腹腔内遊離体の1例を経験したので,文献的考察を加えて報告した.症例は75歳,全内臓逆位を伴った男性で, 2002年10月に肝S5に径15mmの肝細胞癌を指摘され,ラジオ波焼灼療法 (radio-frequency ablation; RFA) 目的にて入院中,頻尿を主訴に当院泌尿器科を受診.精査にて膀胱を圧迫する後腹膜腫瘍を認めた. 2003年1月,再入院し摘出術を施行した.病理組織検査では腹腔内遊離体の診断を得た.術後経過は良好で10日目に退院,現在外来通院中である.本症例のような全内臓逆位を伴った腹腔内遊離体の本邦での報告例は,われわれが調べた限りではなかった.

Peritoneal dissemination is the most common mode of metastasis in gastric cancer. We previously reported the importance of milky spots (MS), peritoneal lymphoid tissues, as selective sites of cancer implantation in peritoneal dissemination. In the present study, we first demonstrated that intraperitoneal injection of adenovirus vector encoding the GFP gene into tumor-free nude mice resulted in GFP expression at omental and mesenteric MS; MS macrophages were target cells for adenovirus infection. We confirmed that intraperitoneal injection of adenovirus vector encoding the NK4 gene (AdNK4) resulted in NK4 production localized to the peritoneal cavity, especially the omentum. Adenovirus vector-mediated MS-selective transgene expression was markedly impaired in tumor-bearing mice whose MS had already been replaced by infiltrating cancer cells. However, prior injection of AdNK4 successfully inhibited MS-selective cancer cell implantation, resulting in suppression of peritoneal dissemination and prolongation of survival. Adenovirus vector-mediated MS-selective delivery of a therapeutic gene may prevent peritoneal dissemination of gastric cancer.

Radiation therapy is a powerful tool for the treatment of oesophageal cancer. We established radioresistant cell lines by applying fractionated irradiation in order to identify differentially expressed genes between parent and radioresistant cells. Six oesophageal cancer cell lines (TE-2, TE-5, TE-9, TE-13, KYSE170, and KYSE180) were treated with continuous 2 Gy fractionated irradiation (total dose 60 Gy). We compared expression profiles of each parent and radioresistant lines on a cDNA microarray consisting of 21168 genes. In the fractionated irradiation trial, four radioresistant sublines (TE-2R, TE-9R, TE-13R, KYSE170R) were established successfully, and we identified 19 upregulated and 28 downregulated genes common to radioresistant sublines. Upregulated genes were associated with apoptosis and inflammatory response (BIRC2 and COX-2), DNA metabolism (CD73), and cell growth (PLAU). Downregulated genes were associated with apoptosis (CASP6), cell adhesion (CDH1 and CDH3), transcription (MLL3), and cell cycle (CDK6). Some of these genes were known to be associated with radiation response, such as COX-2, but others were novel. Reverse transcription-polymerase chain reaction confirmed that genes selected by cDNA microarray were overexpressed in clinical specimens of radioresistant cases. Global gene analysis of radioresistant sublines may provide new insight into mechanisms of radioresistance and effective radiation therapy.

We previously performed a global analysis of the gene expression of gastric cancer cell lines established from metastases to the peritoneal cavity with the cDNA microarray method, which made it possible to analyse the expression of approximately 21168 genes for the identification of novel markers for the detection of micrometastases in the peritoneal cavity. One of the upregulated genes is dopa decarboxylase (DDC), which is responsible for the synthesis of the key neurotransmitters dopamine and serotonine. We have examined its potential as a novel marker for the detection of peritoneal micrometastases of gastric cancer.DDC mRNA in the peritoneal wash from 112 gastric cancer patients was quantified for comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time reverse transcriptase-polymerase chain reaction (RT-PCR) with a fluorescently labelled probe to predict peritoneal recurrence. The quantity of DDC and CEA correlated with wall penetration. Real-time RT-PCR could quantitate 10-10(6) DDC-expressing gastric cancer cells per 10(7) mesothelial cells. The cutoff value was set at the upper limit of the quantitative value for noncancer patients, and those above this cutoff value constituted the micrometastasis (MM+) group. Of 15 cases with peritoneal dissemination, 13 were MM+DDC (87% sensitivity), and one of 48 t1 cases was MM+ (98% specificity). DDC levels in peritoneal washes from patients with synchronous peritoneal metastases were more than 50 times higher than in those from patients without metastasis (P

症例は56歳,女性.主訴は右側腹部腫瘤.平成9年7月3日胃癌(占拠部位AM)に対し,胃全摘・脾合併切除術, D2郭清, Roux-Y再建術を施行された.病理組織所見は, signet ring cell carcinoma, m, (broad), ly0, v0, aw (-), ow (-), n0, P0, H0, M0, stage Iaであった.その後,再発なく内科外来通院中であった.平成14年8月頃より右側腹部の腫瘤を自覚するも放置していた.その後増大傾向がみられたため,平成14年9月19日に当科を受診した.摘出生検の結果,胃癌の皮膚転移と診断された.早期胃癌の中でも深達度m癌の根治術後に緩徐な経過をたどり,他臓器転移なく複数個の皮膚転移のみをきたした極めて稀な症例であると考えられた.

To treat established melanoma in mice, intratumoral transfer of bleomycin and/or an interleukin (IL)-12 expression vector was performed by means of electroporation. Although either bleomycin alone or the IL12 gene alone significantly suppressed the subcutaneous tumors, the combination therapy drastically improved the therapeutic outcome. Three of eight mice (37.5%) that received both bleomycin and the IL12 gene showed complete remission of the preestablished tumors and rejected subsequent rechallenge with the tumor cells. We also examined whether electrochemo-gene therapy for subcutaneous tumor mass induced suppression of pulmonary metastasis that had been established by intravenous inoculation of the melanoma cells. Although metastatic foci were significantly reduced in number in groups that were given IL12 gene alone or bleomycin plus IL12 gene, it was only the combination therapy that significantly prolonged the mean survival period of the tumor-bearing animals. Natural killer (NK) and cytotoxic T lymphocyte cytolytic activities were markedly enhanced in the mice that received the chemo-gene therapy, while IL12 gene therapy alone partially elevated the NK cytotoxicity. The present study suggests that the electroporation-mediated delivery of the IL12 gene and bleomycin synergistically elicits innate and adaptive anti-melanoma immune responses, resulting in marked suppression of the treated tumors as well as bystander metastatic lesions.

IL-21 supports proliferation of mature T and B cells and facilitates expansion and maturation of natural killer (NK) cells in synergy with IL-15. However, the biological implications of IL-21 in vivo have not been fully elucidated. IL-21 and IL-15 expression plasmids were intravenously injected under high pressure into the tail veins of mice, which were subsequently challenged by an intravenous injection of RLmale1 lymphoma cells. The IL15 gene transfection significantly reduced the numbers of metastatic tumor foci in the liver. In contrast, when IL21 and IL15 genes were cotransfected, complete regression was achieved in 80% of the mice. The cytokine gene therapy was also performed in mice that had been intravenously inoculated with the tumor cells. Forty percent of mice that received a single injection of a mixture of cytokine genes successfully rejected the preestablished metastatic lymphoma and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte activity in the spleens of tumor-inoculated mice, while the two cytokines augmented NK killing activity in a synergistic manner. These results strongly suggest that the codelivery of IL-21 and IL-15 elicits powerful antitumor immune responses, resulting in marked therapeutic efficacy against metastatic tumors.

Biodegradability of new types of polyglycolic acid (PGA)-collagen composite tubes for nerve regeneration was evaluated in the peritoneal cavity. Hollow PGA mesh tubes were coated with atelocollagen solution, dried at room temperature, and then subjected to dehydrothermal treatment (hollow composite tubes). Hollow composite tubes filled with collagen sponge were also investigated in this study (sponge tubes). Tubes were fixed at the parietal peritoneum of BALB/c mice, and excised 0.5, 1, 2 and 3 months after the insertion. The inner areas of the excised tubes were measured microscopically. The rate of remained inner areas were calculated and analyzed statistically by one-way ANOVA and Fisher's PLSD test. 1 month after the insertion, the inner areas of the sponge tubes were well maintained, though they were not maintained in the hollow composite tubes. The rate of remained inner areas of the sponge tubes was significantly larger than that of the hollow composite tubes until 2 months after insertion. These results suggest that sponge tubes are more suitable than hollow composite tubes for nerve regeneration in the peritoneal cavity.

膵頭十二指腸切除術後の膵空腸吻合縫合不全,膵液瘻は今日においても治療に難渋する合併症である.今回,われわれは膵頭十二指腸切除術後の難治性膵液瘻に対して非観血的に内瘻化し,良好な結果を得たので報告する.症例は71歳の男性.下部胆管癌の診断で膵頭十二指腸切除術を施行.膵管チューブ抜去後に,膵空腸吻合部ドレーン孔より膵液瘻を生じたが,自然治癒し退院した.退院後1週間目に膵液瘻が再燃し,再入院となった.瘻孔より膵管と対側腸管内にカニュレーションできたことより,局所麻酔下に瘻孔を通してendoprosthesisを両者間に橋渡しする形で留置し内瘻化した.難治性膵液瘻の治療として,非観血的内瘻術は低侵襲で非常に有効な治療法であると考えられた.

Advanced gastric cancer is often accompanied by metastasis to the peritoneum, resulting in a high mortality rate. Mechanisms involved in gastric cancer metastasis have not been fully clarified because metastasis involves multiple steps and requires a combination of altered expressions of many different genes. Thus, independent analysis of any single gene would be insufficient to understand all of the aspects of gastric cancer peritoneal dissemination. In this study, we performed a global analysis of the differential gene expression of a gastric cancer cell line established from a primary main tumour (SNU-1) and of other cell lines established from the metastasis to the peritoneal cavity (SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB). The application of a high-density cDNA microarray method made it possible to analyse the expression of approximately 21 168 genes. Our examinations of SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB showed that 24 genes were up-regulated and 17 genes down-regulated besides expression sequence tags. The analysis revealed the following altered expression such as: (a) up-regulation of CD44 (cell adhesion), keratins 7, 8, and 14 (epitherial marker), aldehyde dehydrogenase (drug metabolism), CD9 and IP3 receptor type3 (signal transduction); (b) down-regulation of IL2 receptor γ, IL4-Stat (immune response), p27 (cell cycle) and integrin β4 (adhesion) in gastric cancer cells from malignant ascites. We then analysed eight gastric cancer cell lines with Northern blot and observed preferential up-regulation and down-regulation of these selected genes in cells prone to peritoneal dissemination. Reverse transcriptase–polymerase chain reaction confirmed that several genes selected by DNA microarray were also overexpressed in clinical samples of malignant ascites. It is therefore considered that these genes may be related to the peritoneal dissemination of gastric cancers. The results of this global gene expression analysis of gastric cancer cells with peritoneal dissemination, promise to provide a new insight into the study of human gastric cancer peritoneal dissemination. British Journal of Cancer (2002) 87, 1153–1161. doi:10.1038/sj.bjc.6600580 www.bjcancer.com © 2002 Cancer Research UK

Carcinoembryonic antigen (CEA), an oncofetal glycoprotein overexpressed in most gastrointestinal and lung cancers, is a candidate molecule for cancer immunotherapy. Recently, a CEA-derived 9-mer peptide, CEA652 (TYACFVSNL), has been identified as the epitope of cytotoxic T lymphocytes restricted with human leukocyte antigen (HLA)-A24, which is present in 60% of the Japanese population and in some Caucasians. The authors performed a clinical study of a vaccine using autologous dendritic cells (DCs) pulsed with CEA652 and adjuvant cytokines, natural human interferon alpha (nhuIFN-alpha), and natural human tumor necrosis factor alpha (nhuTNF-alpha), for the treatment of patients with CEA-expressing advanced metastatic malignancies. Ten HLA-A24 patients with advanced digestive tract or lung cancer were enrolled in the study to assess toxicity, tolerability and immune responses to the vaccine. DCs were generated from plastic adherent monocytes of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMCs) in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). Generated DCs showing an immature phenotype were loaded with CEA652 and injected into patients intradermally and subcutaneously with 50% of the dose administered by each route every 2 weeks for a total of ten vaccinations. The total dose of administered DCs ranged from 2.7x10(7)cells to 1.6x10(8)cells. Adjuvant cytokines, i.e., 1x10(6) U/body of nhuIFN-alpha and nhuTNF-alpha, were administered to patients twice a week during the vaccination period. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. In the delayed-type hypersensitivity (DTH) skin test, two patients showed a positive skin response to peptide-pulsed DCs after vaccination, although none of the patients tested positive prior to vaccination. In the two patients who showed a positive skin response disease remained stable for 6 and 9 months respectively. These results suggest that active immunization using DCs pulsed with CEA652 peptide in combination with the administration of adjuvant cytokines is a safe and feasible treatment procedure.

膵浸潤した十二指腸癌症例に対する新しい術式として,下部十二指腸と膵鉤部後ろ半分を一塊として切除する手術を施行したので報告する.症例は69歳女性,嘔吐を主訴に近医で精査の結果,肝転移を伴い膵鉤部へ直接浸潤する十二指腸癌と診断され当科紹介となった.術前に膵鉤部の画像診断を十分に行いSantorini管の欠損を認めた.本症例に対し腫瘍の主栄養血管である下膵十二指腸動脈を根部で処理し十二指腸を完全に脱転した.術中エコーで主病巣とリンパ節から十分距離を取り膵切除面を決定した.十二指腸肛門側半分と膵鉤部後ろ半分の切除を行った.肝転移に対する切除は2期的とした.術後合併症なく2年6カ月現在生存中である.膵頭十二指腸切除術に比して手術侵襲も小さく,過不足ない郭清が行え有望な手術法と思われた.膵の切除区域の境界決定は困難であるがエコー等併用することにより膵鉤部背側半切除を行えた.

子宮広間膜異常裂孔ヘルニアは稀な疾患であるが,今回われわれは腹腔鏡下にイレウス解除後,開腹にて確定診断した1症例を経験した.症例は33歳,女性.卵巣出血疑いで婦人科入院し,保存的治療を行っていたが, 2日後にイレウス症状を呈したため当科に紹介となった.小腸捻転による絞扼性イレウスを疑い緊急手術を施行した.腹腔鏡にて観察したところ,回盲部より約10cm口側の回腸にcaliber changeを認め,腹腔鏡下に嵌入腸管を引き出しイレウスを解除することができた.右骨盤底内にヘルニア門を認めたが原因検索のため開腹術へ移行した.その結果ヘルニア門が右子宮広間膜に生じた異常裂孔であったことが判明した.腸管壊死には陥っていなかったため異常裂孔を縫合閉鎖するのみで腸切除は行っていない.診断が困難であり,腸切除の頻度は高い本疾患において腹腔鏡下手術は有用であると考えられた.

症例は61歳の女性. 主訴は右下腹部痛. 虫垂切除の既往有り. 大腸憩室炎の疑いで抗生剤投与を行うも改善せず, 汎発性腹膜炎となり手術目的で緊急入院となった. 腹部CTで上行結腸の近傍に卵円形の薄いリング状のheperdensityな層を伴った脂肪組織濃度の上昇領域を認めた. 開腹所見は, 上行結腸の腹膜垂の1つが茎部で360度捻転して鶏卵大に腫大し, 暗赤褐色を呈していた. 表面は顆粒状で一部壊死に陥り右側腹壁に癒着していた. これを上行結腸付着部で切除した. 病理組織で脂肪織の出血性梗塞壊死を認め, 上行結腸腹膜垂炎と診断した. 腹膜垂炎はまれな疾患で, 急性虫垂炎や大腸憩室炎などと鑑別が極めて難しいが, CTでの卵円形の薄いhyperdensityなリング層を伴う脂肪組織濃度上昇は, 腹膜垂炎の画像診断に有用であると考えられた.

Cimetidine, a H2 receptor antagonist, has been reported to improve survival in gastrointestinal cancer patients. These effects have largely been attributed to the enhancing effects of cimetidine on the host's antitumour cell-mediated immune response, such as inhibition of suppressor T lymphocyte activity, stimulation of natural killer cell activity and increase of interleukin-2 production from helper T lymphocytes. We conducted an in vitro study on the effects of cimetidine on differentiation and antigen presenting capacity of monocyte-derived dendritic cells from advanced colorectal cancer patients and normal controls. As a result, an investigation of expression of surface molecules associated with dendritic cells by flow cytometric analyses showed that cimetidine had no enhancing effect on differentiation of dendritic cells from cancer patients and normal controls. An investigation of [3H]thymidine incorporation by allogeneic mixed lymphocyte reactions revealed that cimetidine increased the antigen presenting capacity of dendritic cells from both materials. Moreover, a higher antigen presenting capacity was observed in advanced cancer patients compared to normal controls. These effects might be mediated via specific action of cimetidine and not via H2 receptors because famotidine did not show similar effects. Our results suggest that cimetidine may enhance the host's antitumour cell-mediated immunity by improving the suppressed dendritic cells function of advanced cancer patients. British Journal of Cancer (2002) 86, 1257–1261. DOI: 10.1038/sj/bjc/6600233 www.bjcancer.com © 2002 Cancer Research UK

症例は69歳の女性. 右下腹部腫瘤を主訴に受診し, 同部位に圧痛を伴う小児頭大の腫瘤を触知した. 下部消化管造影検査では横行結腸に圧排像と腫瘍内腔と思われる壁外腔への造影剤の流出を認めた. 内視鏡検査では横行結腸に腸管腔の狭小化と瘻孔を認めたが瘻孔開口部周囲粘膜は正常であった. 開口部より腫瘍内腔へと内視鏡を挿入すると多量の便塊が認められ, 内腔壁よりの生検はmucinous car-cinomaであった. 手術所見では腫瘍は回腸瘻を形成しており, 回盲部から40cmにわたる小腸合併切除を伴う右半結腸切除術を行った. 病理組織学的検査にて横行結腸原発と診断された. 他臓器浸潤を伴う大腸粘液癌では腫瘍径が大きく腸管腔内への腫瘍の発育も顕著であることが多い. 本例の如く壁外性にのみ著明に発育する例は特異的であった. また, 瘻孔形成も十二指腸瘻もしくは空腸瘻のことがほとんどであり, 回腸瘻はまれであった.

Our recent analysis of gastric cancers using comparative genomic hybridization (CGH) revealed a novel high frequent copy number increase in the long arm of chromosome 20. Tumour-amplified kinase BTAK was recently cloned from breast cancers and mapped on 20q13 as a target gene for this amplification in human breast cancers. In the study presented here, we analysed BTAK copy-number and expression, and their relation to the ploidy pattern in 72 primary gastric cancers. Furthermore, wild-type BTAK and its deletion mutants were transfected to gastric cancers to examine changes in cell proliferation and DNA ploidy pattern. Evaluation of 72 unselected primary gastric cancers found BTAK amplification in 5% and overexpression in more than 50%. All four clinical samples with BTAK amplification showed aneuploidy and poor prognosis. Transfection of BTAK in near-diploid gastric cancers induced another aneuploid cell population. In contrast, the c-terminal-deleted mutant of BTAK induced no effect in DNA ploidy pattern and inhibited gastric cancer cell proliferation. These results suggest that BTAK may be involved in gastric cancer cell aneuploid formation, and is a candidate gene for the increase in the number of copies of the 20q, and thus may contribute to an increase in the malignant phenotype of gastric cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

During development, control of proliferation of neuronal precursor cells plays a crucial role in determining the number of neurons. Proliferation is driven by mitogens, but how it is terminated remains a mystery. In this study, we examined the role of cyclin-dependent kinase inhibitors in the control of proliferation of cerebellar granule cell precursors (GCPs). Among the inhibitors we examined, only p27/Kip1 (p27) was expressed at significant levels in cells of the granule cell lineage in the developing and adult cerebellum. In developing cerebella, p27 was expressed in the external germinal layer (the deeper regions), the molecular layer, and the granule layer. In adult cerebella, p27 was expressed in the cells of the granule layer. We isolated and purified GCPs from cerebella of developing mice and examined their bromodeoxyuridine (BrdU) uptake and p27 expression at various times. We found that there was an inverse correlation between BrdU uptake and p27 expression. Even in the presence of saturating amounts of Sonic hedgehog, a potent mitogen, the cells eventually stopped dividing and differentiated, expressing p27 strongly. We also examined mice in which one or both copies of the p27 gene have been inactivated by targeted gene disruption and found that their cerebella were larger than those of wild-type mice. In cell cultures, GCPs prepared from p27-deficient mice showed enhanced proliferation compared with GCPs from wild-type mice. Taken together, these results suggest that there is an intracellular mechanism that stops GCP division and causes GCPs to differentiate and that p27 is part of this mechanism.

We report a case benign main pancreatic ducatal stenosis which was difficult to differentiate from a small pancreatic cancer. A 73-year-old woman complaining of chest pain was admitted to our hospital. Abdominal CT scans showed dilatation of the main pancreatic duct. ERP and EUS showed main pancratic ductal stenosis in the pancreas head, and dilatation of the tail portion of the pancreatic duct. However, no pancreatic tumor was detected. Abdominal angiography also preseted no evidence of malignancy. A small pancretic cancer was suspected and duodenum preserving pancreas head resection was performed. The pathological findings revealed pancreatic tissue with fibrosis of the pancreatic duct and without chronic pancreatitis.

Our analysis of chromosomal aberrations in primary gastric cancers using comparative genomic hybridization has revealed novel, high and frequent copy number increases in the long arm of chromosome 20, indicating that this region contains novel amplified genes involved in gastric cancer progression. AIB1, a member of the steroid receptor co-activator-1 family, has been cloned on 20q12 as a candidate target gene for this amplification in human breast cancers. In this study, we examined the numbers of AIB1 copies as well as their expression and relation to clinico-pathological features in 72 primary gastric cancers. AIB1 amplification was observed in 7% and over-expression in 40% of the specimens. AIB1 amplification always coincided with its over-expression, but several cases showed AIB1 over-expression without amplification, suggesting that expression of AIB1 is regulated not only by gene amplification but also by other mechanisms, such as transcriptional activation, in human gastric cancer. Gastric cancers with AIB1 amplification showed extensive lymph node metastases, liver metastases and poorer prognosis compared to those without amplification. Our results suggest that amplification and over-expression of AIB1 are likely to increase the number of malignant phenotypes of gastric cancers and that it can be expected to be useful as a marker of poor prognosis.

1988年から1998年までに肝切除術を施行した大腸癌肝転移症例80例のうち肺転移再発を認めた14例を対象とし,初回大腸癌手術時および肝転移手術時の背景因子の検討を行うとともに肺転移をきたした際の治療方針についての検討も行った.初回大腸癌手術時の背景因子の検討では,14例中11例が原発巣の組織学的深達度がss以上であり,11例に組織学的リンパ節転移が認められ,原発巣の組織学的進行度の増大が肺転移のリスクを高めるという従来の認識を裏付けた.また肝転移手術時の背景因子の検討では新たな危険因子を見出すには至らなかった.肺転移巣の治療方針として,治癒切除可能な症例に対しては外科的切除が第一選択と考えられるが,治癒切除不能症例に対しては昇圧化学療法の有用性が示唆された.

By the spleen, we calculated a time-delay correction of the input function for quantitation of hepatic blood flow with oxygen-15 water and dynamic positron emission tomography. The time delay (deltat) between the sample site and the spleen was calculated based on nonlinear multiple regression analysis when splenic blood flow was determined. Then hepatic blood flow was quantified by a method using the input function and incorporating deltat, which was assumed to be equal to the time delay between the sample site and the liver. Then hepatic arterial and portal blood flows were estimated separately as well as the delay time for passage within the organs of the portal circulation. The mean coefficient of variation and the mean sum of squares of errors decreased to about 70% when total hepatic blood flow was calculated from the results for regions of interest in three slices of the same liver segment. We concluded that using the spleen for time-delay correction of the input function for measuring hepatic blood flow by this method gave satisfactory results.

Thirty-five hepatocellular carcinomas (HCCs) associated with hepatitis C virus (HCV) were analysed by comparative genomic hybridization (CGH), to screen for changes in copy-number of DNA sequences. Chromosomal losses were noted in 1p34–36 (37%), 4q12–21 (48%), 5q13–21 (35%), 6q13–16 (23%), 8p21–23 (28%), 13q (20%), 16q (33%) and 17p13 (37%). Gains were noted in 1q (46%), 6p (20%), 8q21–24 (31%) and 17q (43%). High level gains indicative of gene amplifications were found in 7q31 (3%), 11q13 (3%), 14q12 (6%) and 17q12 (3%); amplification at 14q12 may be characteristic for HCCs. No significant difference in chromosomal aberrations was noted between carcinomas associated with HCV-infection in our study and those reported earlier in HCCs infected with hepatitis B virus (HBV), indicating that both HBV- and HCV-related carcinomas may progress through a similar cascade of molecular events. © 1999 Cancer Research Campaign

Minimal residual lesions have been a major problem in surgical management of cancer. We transfected M5076 with murine IL-12 gene by a retroviral vector, established a stable transfectant secreting IL-12 and investigated its antitumor effects on a spontaneous liver metastasis murine model of M5076 reticulum cell sarcoma. Subcutaneous vaccination of the irradiated transfectant into the remote skin following the amputation of the tumor-bearing limb improved survival when compared with the vaccination of irradiated parental cells (control). Cytotoxic activities against parental M5076 were significantly stronger in the hepatic lymphocytes from the mice vaccinated with the IL-12 transfectant than those from the control. IFN-gamma production of hepatic lymphocytes when they were cocultured with the parental cells was significantly augmented in mice vaccinated with the IL-12 transfectant compared with the control. On the other hand, both cytotoxic activity and IFN-gamma production of spleen cells in the M5076-vaccinated and transfectant-vaccinated mice were at similar levels. Immunophenotypic analysis revealed the selective increase of CD3+NK1+ population in the liver from the transfectant-vaccinated mice. These results suggest that tumor vaccines genetically modified to secrete IL-12 continuously at a relatively low level preferentially augment local antitumor activity in the liver rather than systemic immune responses. This strategy warrants further investigation as an adjuvant modality in the management of postoperative residual tumors.

Interleukin-12 (IL-12) is a potent antitumor cytokine, which induces and enhances the activity of natural killer (NK) cells, lymphokine activated killer (LAK) cells and cytotoxic T lymphocytes (CTL). IL-12 also stimulates IFN-gamma production from both T cells and NK cells. In this study, we transfected methylcholanthrene-induced fibrosarcoma (MCA-D) with TNF gene and investigated the therapeutic effect of TNF gene-transduced cancer vaccine and whether the vaccination effect is enhanced by systemic administration of recombinant IL-12 (rIL-12), in a murine model. TNF gene-transduced cancer vaccine or systemic administration of rIL-12 showed slight or moderate inhibition of pre-established tumor. However, simultaneous application of the vaccine and rIL-12 resulted in complete eradication. The cytotoxicity of CTL against parental tumor cells was enhanced with the combination of the vaccine and rIL-12, and IFN-gamma production from spleen cells also increased synergistically. Our findings show that synergistic enhancement of CTL activity and IFN-gamma production could play an important role in the antitumor effect of combination therapy using TNF gene-transduced cancer vaccine and rIL-12.

Butyrate is a well known colonic luminal short chain fatty acid, which arrests cell growth and induces differentiation in various cell types. We examined the effect of butyrate on the expression of WAF1/Cip1, a potent inhibitor of cyclin-dependent kinases, and its relation to growth arrest in a p53-mutated human colon cancer cell line WiDr. Five millimolar butyrate completely inhibited the growth of WiDr and caused G1-phase arrest. WAF1/Cip1 mRNA was rapidly induced within 3 h by treatment with 5.0 mM butyrate, and drastic WAF1/Cip1 protein induction was detected. Using several mutant WAF1/Cip1 promoter fragments, we found that the butyrate-responsive elements are two Sp1 sites at -82 and -69 relative to the transcription start site. We also found that a TATA element at -46 and two overlapping consensus Sp1 sites at -60 and -55 are essential for the basal promoter activity of WAF1/Cip1. These findings suggest that butyrate arrests the growth of WiDr by activating the WAF1/Cip1 promoter through specific Sp1 sites in a p53-independent fashion.

Recently, interphase cytogenetics using fluorescent in situ hybridization (FISH) was performed on various kinds of solid tumor, and their inherent karyotypic heterogeneities were revealed. Concerning this heterogeneity, we evaluated both the exhibiting number of chromosome 17 and nuclear DNA content on an identical nucleus by means of computer-controlled auto-scanning stage in order to demonstrate the alteration in number of chromosome 17 among cytofluorometrically distinct subpopulations.We investigated 8 lesions of surgically resected colorectal carcinomas, which were classified as aneuploid in quantitative DNA analysis and also exhibited an increase of 17-aneusomy nuclei. We used paraffin-embedded archival blocks. First, we prepared isolated cell specimens, and memorized the position of the cells on a glass slide using computer-controlled auto-scanning stage. Next, the specimens were stained with propidium iodide, and the fluorescent intensity was evaluated as nuclear DNA content in the order of cell position data. And lastly, FISH was performed with (peri) centromerespecific DNA probes for chromosome 17, and we enumerated the number of signals in a nucleus also according to cell position data. Then, we compared the distribution of number of chromosome 17 among cytofluorometrically distinct subpopulations. Three of 8 lesions showed a single GO+G1 peak, and the rest exhibited plural GO+G1 peaks in DNA profile. And 4 of 5 lesions, which showed plural GO+G1 peaks, presented a peak at the DNA value of (near) 2c. We could detect an alteration in the distribution of number of chromosome 17 between diploid peak and aneuploid peaks in 4 of 4 lesions which presented a peak at the DNA value of (near) 2c. However, we could ot find a difference in the distribution of number of chromosome 17 between GO+G1 peak and G2+M peak. These observations indicate that the distribution of number of chromosome 17 reflects an endoreduplication of genome content, yet, it does not alter in accordance with the phase of cell cycle. It is necessary to evaluate nuclear DNA content simultaneously in order to assess an essential cytogenetic change.

手術侵襲時において脾臓がサイトカインを産生するか否かを究明するために,胃亜全摘術患者8例を対象として麻酔導入前の末梢動脈血をコントロールとし,手術開始1時間,および2時間後に脾静脈および末梢動脈血を同時に採血し,炎症性サイトカインであるインターロイキン1(以下IL-1),インターロイキン6(以下IL-6)および液性調節因子であるエンドセリン(以下ET-1),亜硝酸塩(以下NO)の濃度を測定した.IL-1はいずれも測定濃度以下であった.末梢動脈血においてコントロールと比較して,IL-6は執刀2時間後より有意な増加を認め,ET-1も執刀2時間後より有意な増加を認めた.NOは有意な変動は認めなかった.脾静脈血では,IL-6が,執刀2時間に末梢動脈血に比較して有意に上昇を認めた.NOおよびET-1は有意差は認めなかった.手術侵襲時において脾臓が,IL-6の産生臓器である可能性が示唆された.

胆管細胞癌中枢型肝切除例10例と肝門部胆管癌肝切除例13例を比較検討した.腫瘍の肉眼型は, 胆管細胞癌10例中9例では肝内に明らかな腫瘤を形成し周囲の肝実質に浸潤性に発育していたのに対し, 肝門部胆管癌では腫瘤形成よりも胆管壁に沿う浸潤が主体であった.腫瘍の体積は, 胆管細胞癌では肝門部胆管癌に比較して有意に大きかった.胆管細胞癌では, 肝門部胆管癌に比較して大血管浸潤のほかに肝胆道の周囲臓器への浸潤を高率に認めた.胆管細胞癌でも12, 13, 8番へのリンパ節転移, ly, v, pn (+) を肝門部胆管癌と同じく高率に認めた.ew (+) は両者とも80%以上の高率であり, 主にly, v, pnの存在によった.hw (+) は肝門部胆管癌で有意に高率であった.肝門部胆管癌の5年生存率は62.5%と良好であったが, 胆管細胞癌では3年生存率17.9%と不良であった.両者は同一の規約で検討されるべき多くの類似点を有しているが, 進展様式, 予後などに違いが認められた.

私たちの教室で治療した胃癌症例中で多発胃癌は5.6%あるが, 早期胃癌の中では多発のものは8.6%を占めて近年増加傾向にある. この多発早期胃癌は単発早期胃癌と比較して高齢者に多く, 隆起型, 分化型 (高分化腺癌) の頻度が高く, 占居部位は大半が胃体部, 幽門部で幽門側切除が可能であった. 私たちは多発早期胃癌の悪性度評価法として, 各病巣の癌細胞増殖動態を顕微測光法で解析してきた. 予後良, 好例では各病巣のDNAプロイディ・パターンはdiploidで増殖動態は類似し, 病巣間で著差を認めなかった. 一方, 予後不良例ではS-G2期細胞の増加, 多倍体化などの進行胃癌で見られる増殖動態を示し, これらの所見は病巣間でばらつきを示した. したがって, DNAプロイディ・パターンは多発早期胃癌の悪性度の指標になりうると考えられた. また, リンパ節転移の頻度は単発例と差がなく, 単発早期胃癌と同様な進行度評価を適用しうると考えられた.

IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.