Shouji Natsugoe

Truncated midkine as a marker of diagnosis and detection of nodal metastases in gastrointestinal carcinomas

Midkine (MK) is a growth factor identified as a product of a retinoic acid-responsive gene. A truncated form of MK mRNA, which lacks a sequence encoding the N-terminally located domain, was recently found in cancer cells. We investigated the expression of the truncated MK mRNA in specimens of 47 surgically removed human gastrointestinal organs using polymerase chain reaction. Truncated MK was not detected in all of the 46 corresponding non-cancerous regions. On the other hand, this short MK mRNA was expressed in the primary tumours in 12 of 16 gastric cancers, 8 of 13 colorectal carcinomas, five of nine hepatocellular carcinomas, two of two oesophageal carcinomas and one ampullary duodenal cancer. In addition, truncated MK was detectable in all of the 14 lymph node metastases but in none of three metastatic sites in the liver, suggesting that truncated MK mRNA could become a good marker of nodal metastases in gastrointestinal tract.

The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma

The p53 family regulates cell-cycle arrest, triggers apoptosis or is involved in repair of DNA damage. In the present study, we analysed the expression of some p53 family proteins and their responses to chemoradiation therapy (CRT) in cases of oesophageal squamous cell carcinoma (ESCC). We immunohistochemically investigated the relationship between p53, p53R2, and p21 expression in biopsy specimens of untreated primary tumours and their clinical and histological responses to CRT in 62 patients with ESCC. Chemoradiation therapy consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The rates of clinical and histological responses (complete or partial) to CRT were 71.0% (clinical) and 52.8% (histological). The rate of positive expression was 43.5% for p53, 37.1% for p53R2, and 54.8% for p21 expression. Statistically significant correlations were found between p53 or p53R2 expression and favourable response to CRT (P=0.0001 or 0.041 clinical, P=0.016 or 0.0018 histological, respectively). Furthermore, in p53-negative tumours, CRT was more effective in tumours with p53R2 negative expression than those with p53R2 positive expression (P=0.0014). We demonstrated that the negative expression of p53 and p53R2 expression was closely related to the effect of CRT and should predict the CRT outcome in patients with ESCC.

Extranodal connective tissue invasion and the expression of desmosomal glycoprotein 1 in squamous cell carcinoma of the oesophagus.

We investigated extranodal connective tissue involvement (ECTI) in 39 patients with oesophageal carcinoma. Both the primary tumour and ECTI were immunohistochemically examined using the monoclonal antibody 32-2B for desmosomal glycoprotein 1 (DG1). Connective tissue carcinoma deposits were identified as cells within small lymph nodes, as lymphatic or venous vessel invasion or as widespread invasion beyond the capsule of metastatic lymph nodes. These histological findings were present in at least one area in 20 of 39 patients (51.3%). DG1 immunostaining intensity by tumour was graded as DG1 (++), DG1 (+) or DG1 (-). DG1 (+) or DG1 (-) primary tumours demonstrated lymph node metastases and ECTI more frequently than DG1(++) tumours (P<0.05). Among 17 patients in whom DG1 immunohistochemistry was performed on ECTI, there were three DG1(++), five DG1(+) and nine DG1(-) patients. The DG1 expression of ECTI was equal to or less intense than the primary tumour. These results indicate that reduction or loss of DG1 expression may promote ECTI and lymph node metastases. One should be aware of the potential for ECTI in oesophageal carcinomas. In the future, adjuvant therapy may be advisable for some oesophageal carcinomas based on the phenotype of individual cancer cells, including expression of DG1.

Antrum preserving double tract method for reconstruction following proximal gastrectomy

The antrum preserving double tract method was originally designed in order to gain the smooth transfer of larger foods through the duodenal route. Surgical improvement was then made at a few points when carrying out the anastomosis between the residual stomach and the jejunum. In the clinical field, this method is characterized by a better transfer of large foods into the duodenum than the conventional double tract method. The clinical investigation revealed that gastrin release remained after the operation due to both the good passage and the presence of food in the residual stomach. The antrum preserving double tract method is a reasonable and simple method which can maintain physiological pancreaticocibal synchronism.

Abstract 3264: Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC)

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: PDAC is a leading cause of cancer-related death worldwide, and most patients have incurable disease at diagnosis. Life expectancy is only 3-6 months post-diagnosis, ostensibly due to early dissemination to liver and other vital organs. Results: By transfecting a shRNA library into non-metastatic PDAC line S2-028 followed by experimental metastasis assay, ITIH5 was identified. Metastatic PDAC cell lines (e.g., S2-007, MIAPaCa-2, Panc-1) had significantly lower ITIH5 protein expression compared to immortalized pancreatic ductal epithelial cells and non-/poorly-metastatic PDAC cell lines (e.g., S2-028 and BxPC3). By manipulating expression in different PDAC cell lines (over-expression in S2-007 and MIAPaCa-2, knockdown in non-metastatic S2-028 with two different shRNA) functional and selective regulation of metastasis was observed. Orthotopic tumor growth of PDAC cells was not blocked. Thus ITIH5 qualifies as a metastasis suppressor. Overexpression of ITIH5 significantly inhibited invasion and migration, while down-regulation increased these cellular properties. Immunohistochemistry of a human PDAC tissue microarray (n = 81) revealed that negative expression of ITIH5 showed significantly higher incidence of liver metastasis (P = 0.0482) corresponding with worse prognosis after surgery (P = 0.0299). Conclusions: ITIH5 is a potent metastasis suppressor with suggestive prognostic value in PDAC. Future studies will continue to characterize biochemical properties of ITIH5, identify interaction partners, and investigate the molecular mechanism(s) of action. Support: National Foundation for Cancer Research, Steiner Family Fund and CA168524. Citation Format: Ken Sasaki, Hiroshi Kurahara, S Natsugoe, Tomoo Iwakuma, Danny R. Welch. Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3264. doi:10.1158/1538-7445.AM2015-3264

The Evaluation of Endoscopic Mucosal Resection for Early Esophageal Carcinoma.

教室では, 原則として深達度m2までの早期食道癌は内視鏡的粘膜切除 (endoscopic mucosal resec tion, EMR) の対象としている. 1992年5月から96年8月までにEMRによって切除された30症例, 38病巣について, その適応の妥当性, 治療成績について検討した. その結果, 1) 内視鏡所見は28病集 (73.7%) が, 0-IIbまたは0-IIcであった. 2) 大きさは30病巣 (78.9%) が20mm以下であった. 3) 予測深達度と組織学的深達度の一致率はdysplasiaであった4例を除いて70.6% (24/34病巣) であった. 4) 合併症として, 動脈性出血が5例 (16.7%) に, 穿孔, 皮下気腫がそれぞれ1例 (3.3%) にみられた. 5) 再発が3例, 異時性食道癌が1例にみられ, いずれも再EMRを施行した. 6) 他病死1例, 深達度sm3で手術を施行した1例が癌死した. その他は最長4年5か月を含め, 全例生存中である. 深達度m2までの, 全周性でない癌はEMRの適応であり, その治療成績も満足できるものであった.

Indication of Cervical Lymph Node Dissection for Thoracic Esophageal Carcinoma According to Preoperative Diagnosis with Ultrasonic Examination.

胸部食道に対する頸部郭清の適応について, 鎖骨上と反回神経沿いリンパ節の術前超音波診断ならびに手術成績の面から検討した. 対象は1986年から93年にcl以上の切除を行った胸部食道癌136例 (3領域郭清105例, 2領域郭清31例) とした. 3領域郭清例において, 術前に鎖骨上リンパ節転移陰性とした84例中7例 (8.3%) に組織学的に転移が認められた. False negative 7例中5例は反回神経沿いに術前超音波診断および術中に転移を認めた. したがって, 術前超音波診断による鎖骨上リンパ節の転移の有無のみで頸部郭清を省略するのは危険であるが, 反回神経沿いリンパ節の術前・術中診断を加味すると97.6% (82/84例) の症例で頸部郭清の適応を術前診断にて判断可能であった. また術前に鎖骨上・反回神経沿いに転移陰性としたmp以上の症例における5生率は頸部郭清の有無に関係なく37%であった. 術前診断による鎖骨上または反回神経沿い転移陽性症例が頸部郭清の適応である.

Surgical Approach for Gastric Cancer Extended to the Esophagus

In a total of 179 patients with gastric cancer invading the esophagus, the authors retrospectively assessed the surgical approach. These patients were divided into two groups according to the tumor location; 88 cardiac cancer and 91 non-cardiac cancer. Clinicopathologic characteristics, such as gross appearance, cell type, serosal invasion, and peritoneal dissemination were significantly different between cardiac and non-cardiac cancer. A thoracoabdominal approach was performed in 95 and a abdominal approach in 84. Since 1986, the incidence of thoracotomy has decreased because of using endoscopic ultrasonography (EUS) and device of automatic suture. EUS imaging of the boundary between liver and heart was useful in assessing the esophageal invasion. In cases of esophageal invasion longer than 20 mm in localized type, 10 mm in diffuse type, and/or nodal involvement in the medistinum was detected, thoracoabdominal approach should be performed toobtain tumor-free margin at the proximal stump and a better prognosis.

A comparative study on fine structure of inflammatory and neoplastic dysplasia of the esophagus

To clarify the fine structure of esophageal dysplasia, desmosomes and nuclei were evaluated numerically and morphologically using the electron microscope. Thirteen punch biopsies were taken from patients with esophageal dysplasia ascertained by iodine staining and showing up as unstained or faintly stained areas. We conducted a morphological study of two types of esophageal dysplasia, one with reactive immature epithelium (RIE) and the other classified as an intra-epithelial neoplastic lesion (INL). The ultrastructural differences observed between the RIE and INL were the degree of the cellular or nuclear atypia, the number of desmosomes or hemidesmosomes, and the amount of intercellular space. The nucleocytoplasmic ratio in INL was higher than in RIE. In the cells of RIE, the number of desmosomes was smaller than in normal epithelium, but larger than in INL. The hemidesmosomes were found predominantly between the RIE cells and basal laminae, but were very few or absent in INL and tumor cells.

The problems of surgical treatment for esophageal cancer invading the adjacent structures - From a viewpoint of the degree of residual cancer mass after esophagectomy.

他臓器浸潤胸部食道癌切除例70例を対象として切除の意義と問題点を検討した.絶対非治癒切除62例, 相対非治癒切除8例 (11%) で, 合併切除は18例 (26%) に行った.積極的に切除を行ったが, 結果的に, わずかに遺残癌巣を認めた17例中10例 (59%) を合併症で失った.死亡例の31% (20/65例) および術後2か月以内死亡の75% (18例) が合併症死であった.術後3か月以降の78%は再発, 再燃による死亡であった.残存癌巣の程度とn因子の有無では, 生存月数に有意の相違は認めなかった.術後2年以上生存した2例は他臓器への浸潤範囲がわずか (2cm2未満) であり, 合併切除を行い, 相対非治癒切除となった症例であった.対象例の50%生存月数は4.5か月, 3年生存率は3%であった.