Kazunori Nojiri

The Proangiogenic Factor Ephrin-A1 Is Up-Regulated in Radioresistant Murine Tumor by Irradiation

While the pre-treatment status of cancer is generally correlated with outcome, little is known about microenvironmental change caused by anti-cancer treatment and how it may affect outcome. For example, treatment may lead to induction of gene expression that promotes resistance to therapy. In the present study, we attempted to find a gene that was both induced by irradiation and associated with radioresistance in tumors. Using single-color oligo-microarrays, we analyzed the gene expression profiles of two murine squamous cell carcinomas, NR-S1, which is highly radioresistant, and SCCVII, which is radiosensitive, after irradiation with 137-Cs gamma rays or carbon ions. Candidate genes were those differentially regulated between NR-S1 and SCCVII after any kind of irradiation. Four genes, Efna1 (Ephrin-A1), Sprr1a (small proline-rich protein 1A), Srgap3 (SLIT-ROBO Rho GTPase activating protein 3) and Xrra1 [RIKEN 2 days neonate thymus thymic cells (NOD) cDNA clone E430023D08 3′], were selected as candidate genes associated with radiotherapy-induced radioresistance. We focused on Efna1, which encodes a ligand for the Eph receptor tyrosine kinase known to be involved in the vascular endothelial growth factor (VEGF) pathway. We used immunohistochemical methods to detect expression of Ephrin-A1, VEGF, and the microvascular marker CD31 in radioresistant NR-S1 tumor cells. Ephrin-A1 was detected in the cytoplasm of NR-S1 tumor cells after irradiation, but not in SCCVII tumor cells. Irradiation of NR-S1 tumor cells also led to significant increases in microvascular density, and up-regulation of VEGF expression. Our results suggest that radiotherapy-induced changes in gene expression related with angiogenesis might also modulate microenvironment and influence responsiveness of tumors.

Two-stage hepatectomy with effective perioperative chemotherapy does not induce tumor growth or growth factor expression in liver metastases from colorectal cancer

BACKGROUND Although short- and long-term results have been described in previous reports of 2-stage hepatectomy, growth activity in metastases resected at the first versus second hepatectomy has not been compared. METHODS We analyzed growth activity of liver metastases from colorectal cancers resected at first and second hepatectomy by real-time reverse-transcription polymerase chain reaction and immunohistochemistry in 21 patients undergoing 2-stage hepatectomy to justify the 2-stage approach. RESULTS Of 24 patients planned to undergo 2-stage hepatectomy for colorectal liver metastases, 21 had completion of both stages. Although maximum tumor size and serum carcinoembryonic antigen before and after the first procedure did not differ, volume of the future liver remnant increased after the first procedure. Ki67 and proliferating cell nuclear antigen positivity rates were comparable between initially and subsequently resected tumors (P = .09 and P = .83, respectively). Expression of mRNA (relative to glyceraldehyde-3-phosphate dehydrogenase mRNA) in initially versus subsequently resected tumors for cyclin D1 (4.27 ± 1.29 vs 6.52 ± 2.23; P = .90), cyclin E1 (24.18 ± 16.81 vs 10.53 ± 2.28; P = .60), hepatocyte growth factor (3.16 ± 1.42 vs 0.58 ± 0.15; P = .11), basic fibroblast growth factor (5.42 ± 1.54 vs 5.92 ± 3.33; P = .13), epidermal growth factor (19.56 ± 14.76 vs 9.07 ± 4.54; P = .74), and transforming growth factor-α (2.63 ± 1.02 vs 2.07 ± 1.15; P = .29) showed no differences between the 2 time points. CONCLUSION Two-stage hepatectomy did not seem to induce tumor growth activity or growth factor expression. The 2-stage strategy in combination with effective preoperative chemotherapy is a valuable strategy for colorectal metastases.

Severity and prognostic assessment of the endotoxin activity assay in biliary tract infection

Acute cholangitis and cholecystitis (AC) often progress to severe septic conditions. We evaluated the endotoxin activity assay (EAA) for assessment and prediction of the severity of AC.

Hepatocyte nuclear factor-1 α inactivated hepatocellular adenomas in patient with congenital absence of the portal vein: a case report.

Hepatocellular adenomas (HCAs) have been recognized recently as a heterogeneous group, and are subclassified according to genotype as well as morphological characteristics. We report a case of a 35‐year‐old Japanese woman who exhibited hepatocyte nuclear factor (HNF)‐1α‐inactivated HCA in the background of the congenital absence of the portal vein (CAPV). On a dynamic contrast computed tomography (CT) scan, the hypovascular tumor enlarged from 1 cm to 3 cm and another tumor emerged in the course of 7 years. Because the possibility of hepatocellular carcinoma (HCC) with multiple metastases was not excluded, partial hepatectomy was performed. On a cut section, two well‐demarcated tumors were observed and one tumor had a central fibrous scar. The histological features of these tumors were similar to those of focal nodular hyperplasia (FNH) with a central scar and HCA; however, these tumors were diagnosed as HNF‐1α‐inactivated HCA by immunohistochemistry according to the criteria of the current World Health Organization (WHO) classification. In non‐tumorous liver tissue, an abnormal architecture of the vessels and a vague nodular appearance of lobuli were observed, which were likely to be those of nodular regenerated hyperplasia (NRH). We discuss its pathogenesis and relationship with CAPV.

Predictive factors for bile leakage after hepatectomy for hepatic tumors: A retrospective multicenter study with 631 cases at Yokohama Clinical Oncology Group (YCOG)

International Study Group of Liver Surgery (ISGLS) proposed the standardized definition for bile leakage (BL) after hepatectomy (Hx) at 2011 to precisely perceive incidence and predictive factors of this critical condition.

Primary neuroendocrine carcinoma of the hypopharynx: a case report

Primary neuroendocrine carcinoma of the hypopharynx is extremely rare. A 59-year-old man complaining of swollen right cervical lymph node was admitted to our hospital. Although computed tomography, upper endoscopy, and positron emission tomography scan were performed, the primary lesion was unknown. Bilateral neck lymph node dissection was performed and diagnosed as metastasis of neuroendocrine carcinoma. Sixteen months after the first operation, computed tomography scan revealed multiple liver metastases. There was no another metastatic lesion, and hepatectomy with negative margin was performed. Three months after the second operation, a small tumor of the hypopharynx was detected by upper endoscopy, and biopsy revealed neuroendocrine carcinoma. Concurrent chemotherapy (cisplatin + docetaxel) and radiotherapy (60 Gy) were carried out. This therapy was highly effective, and primary lesion disappeared. After the chemoradiotherapy, lung metastasis and bone metastasis emerged and treated by radiotherapy and chemotherapy (cisplatin + irinotecan). These therapies were also effective, but multiple liver metastases appeared. The patient died 39 months after the first surgery. Although neuroendocrine carcinoma is a high-grade malignancy which metastasizes easily, combined treatment strategy may be useful for these patients. We have here reported, with bibliographic consideration, a case in which multimodal treatment was employed for primary hypopharyngeal neuroendocrine carcinoma with distant metastases.

Postchemotherapy histological analysis of major intrahepatic vessels for reversal of attachment or invasion by colorectal liver metastases.

Although tumor reduction via present‐day prehepatectomy chemotherapy can render initially unresectable disease potentially resectable, little is known about the effects of such chemotherapy on liver metastases with known attachment to or invasion of major intrahepatic vessels. We histologically assessed the relationships of liver tumors to major intrahepatic vessels after chemotherapy.

Abstract CT318: FOLFOXIRI+B-mab showed powerful effect as preoperative chemotherapy for multiple liver metastases of colorectal cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background; R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Powerful regimen FOLFOXIRI including 3 cytotoxic drugs; 5FU, irinotecan and oxaliplatin was reported as promising treatment for advanced colorectal cancer (J Clin Oncol 2007; 25: 1670-76). In our department Phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative chemotherapy has been conducted now, and Phase II was on going. In this study, we report effect and safety of FOLFOXIRI+B-mab. Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted to decide tolerated dose (MTD) of irinotecan and 150 mg/m2 was decided as recommended dose. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, irinotecan; 150 mg/m2, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. R0 resection rate of liver metastases as primary endpoint will be evaluated. Results: Currently, 16 patients were enrolled. Two patients dropped out because of grade 3 diarrhea and grade 3 thromboembolism. One patient is waiting for liver resection and R0 resection of liver metastases was performed for 9 patients. In the 14 patients excluding 2 drop out, 13 showed PR and average of reduction rate was 51%. There was no pathological CR in the 9 patients who was performed R0 resection. There was no severe postoperative complication in them. Conclusion: This regimen is safe and shows high PR rate. So, the regimen is effective and improve R0 resection rate for multiple liver metastases of colorectal cancer. Further investigation of this study is still ongoing now. Citation Format: Yasushi Ichikawa, Ayumu Goto, Noritoshi Kobayashi, Motohiko Tokuhisa, Takashi Ishikawa, Atsushi Ishibe, Kazuteru Watanabe, Kazunori Nojiri, Yoshibumi Kumamoto, kazuhisa Takeda, Mitsuyoshi Ota, Hirotoshi Akiyama, Kuniya Tanaka, Itaru Endo. FOLFOXIRI+B-mab showed powerful effect as preoperative chemotherapy for multiple liver metastases of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT318. doi:10.1158/1538-7445.AM2014-CT318

Abstract 3693: Power of FOLFOXIRI+B-mab as preoperative chemotherapy for multiple liver metastases of colorectal cancer -Relationship between clinical response and pathological response-

Background; R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Recently, effective anti-cancer drugs and various regimens using them were created and some advanced inoperable liver metastases were converted to operable by those chemotherapy (CT). Therefore, development of powerful regimens to shrink liver metastases strongly is an important issue. In our department Phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative CT has been conducted now. In this study, this regimen9s effect on shrinkage of liver lesions from gross view of clinical response and micro view of pathological response are evaluated. Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted as sequential dose escalation to define the maximum-tolerated dose (MTD) of irinotecan. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. Dose escalation of Irinotecan was planned from level 1; 150 mg/m2, level 2; 180 mg/m2 and level 0; 125 mg/m2. In Phase II, R0 resection rate of liver metastases as primary endpoint will be evaluated using MTD of irinotecan estimated in Phase I. After 6 cycles of the CT, R0 operability was evaluated. Now 6 patients were studied in level 1 dose, in them, one patient dropped out because of DLT, 4 were converted to R0 resection and another is waiting for resection. To evaluate power of this regimen, macroscopic and microscopic response of resected hepatic lesions of these 4 patients were investigated. Results: Median number of metastases of each patient was 9 (4-21). Total number of metastases of the 4 patients was 43. Median long span of the all tumors was 12 mm (5-76 mm). All 4 patients showed PR in CT and median of reduction rate was 38% (34-67%). Four tumors (9.3%) showed clinical CR. Twelve tumor (27.9%) showed pathological CR, 26 (60.5%) were moderate response (2/3 or more of tumor showed necrosis or disappear), and only one (2.3%) was mild response. Conclusion; FOLFOXIRI+B-mab showed powerful effect to shrink liver metastases of colorectal cancer. It is a good regimen for pre-operative CT for liver metastases. Further investigation of this study is still ongoing now. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3693. doi:1538-7445.AM2012-3693