Ryoichi Shimizu

Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism

(Cancer Sci 2010; 101: 722–727)

Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study

We previously conducted a phase I clinical trial combining the HLA‐A*2402‐restricted KIF20A‐derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single‐armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1‐year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide‐specific immune responses. All enrolled patients received therapy without the HLA‐A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1‐year survival rates between the HLA‐A*2402‐matched and ‐unmatched groups were not significantly different. In the HLA‐A*2402 matched group, patients showing peptide‐specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA‐A*2402‐matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide‐specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

The surgical management of synchronous hepatocellular carcinoma and thoracic esophageal carcinoma

A 73-year-old man was hospitalized with pathologically documented hepatocellular carcinoma and cirrhosis, and a 5.0-cm tumor located in the left lobe was resected by a left lateral segmentectomy. At the same time, metastatic squamous cell carcinoma was identified by frozen section in a perigastric lymph node in the lesser omentum. Intraoperative endoscopy revealed a 1.0-cm erosive lesion in the thoracic esophagus that was subsequently found to be primary squamous cell carcinoma. Seven weeks later, a transthoracic subtotal esophagectomy with substernal, cervical esophagogastrostomy was performed. Twenty-two months after these resections there has been no recurrence of either the hepatocellular or esophageal carcinomas.

miR-125b-1 and miR-378a are Predictive Biomarkers for the Efficacy of Vaccine Treatment against Colorectal Cancer

Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse‐transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR‐125b‐1 in cancer cells (P = 0.040), and miR‐378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis showed that expression of miR‐378a in stromal cells was the best among the three predictors (HR, 2.730; 95% CI, 1.027–7.585; P = 0.044). In conclusion, miR‐125b‐1 and miR‐378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer.

A case of hepatocellular carcinoma with tuberculoma within tumor tissue

We made a diagnosis of hepatocellular carcinoma and performed partial resection of the liver in a 72 year-old woman. Granulomas were observed within hepatocellular carcinoma in the surgical specimen. Microscopic findings demonstrated the granulomas particularly within the tumor, and showed that they were composed of epithelioid cells with caseous necrosis. These tuberculomas compressed the tumor cells, and many lymphocytes had infiltrated the tumor around the tuberculomas. The cancer stage of the patient was early and her prognosis is good.

Multicenter trial for assessing cytokine promoter gene polymorphism as a predictive parameter of PSK responder for curatively resected stage II or III colorectal cancer.

619 Background: Polysaccharide-K (PSK), a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in colorectal cancer in Japan. PSK has immunological actions including enhancement or inhibition of cytokine production. It has been reported that levels of cytokine production are influenced by polymorphisms in the promoters of cytokine genes. We hypothesized that cytokine promoter gene polymorphisms may be responsible for genetic susceptibilities to immunological effect of PSK. Methods: This is a multicenter prospective trial. One hundred and ten patients with stage II or III colorectal cancer were enrolled. All patients received adjuvant immnochemotherapy after curative resection using UFT (stage II) or UFT/LV (stage III) combined with PSK (3.0 g/day, p.o.) for 1 year. Post-operative survey of recurrence was followed with CT scan at 6-month intervals during the first 2 years after surgery and at 1-year intervals thereafter until 5 year after surgery...

Clinopathological analysis of magnetic resonance imaging of pancreatic carcinoma.

膵癌のmagnetic resonance (MR) 像の成り立ちに関わる因子を明らかにするため, 術前MR像と, 手術時所見, 切除標本割面像, 病理組織像, 切除標本MR像とを対比検討した. 術前MRimagingが施行された膵癌症例17例を対象とした. 術前MR像を, I型: 周囲膵組織と明瞭なコントラストをもつもの, II型: 周囲組織より突出する腫瘍としてのみ確認しうるもの, III型: 脈管の変形のみを認めるもの, IV型: 腫瘍を確認しえないもの, と分類した. I型は肉眼的には結節型, 組織学的には髄様型で, 末梢側の炎症や萎縮が軽度なものが多かった. III型やIV型では肉眼的には浸潤型, 組織学的には硬性型のものが多く, 末梢側の炎症や萎縮は高度であった. 術前と切険標本のMR像の間に, 大きな隔たりはなく, motionartifactの影響は小さいと判断された. 膵癌のMR像は腫瘍と周囲膵組織の性状々よく反映しており. 外科的に有用な情報を提供しうるものと思われた.