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Investigation of the role of laparoscopic surgery in stomach gastrointestinal stromal tumor and the expression of Cdk5 and p35 proteins in stomach gastrointestinal stromal tumor, thyroid and breast cancer
|關鍵字:||胃腸基質瘤;腹腔鏡手術;甲狀腺癌;乳癌;Cdk5 protein;p35 protein;gastrointestinal stromal tumor;laparoscopic surgery;thyroid cancer;breast cancer||引用:||1.Hwang JH, Saunders MD, Rulyak SJ, Shaw S, Nietsch H, Kimmey MB. A prospective study comparing endoscopy and EUS in the evaluation of GI subepithelial masses. Gastrointestinal endoscopy. 2005;62:202-208. 2.Furuhashi S, Takamori H, Abe S, Nakahara O, Tanaka H, Horino K et al. Solid-pseudopapillary pancreatic tumor, mimicking submucosal tumor of the stomach: A case report. World journal of gastrointestinal surgery. 2011;3:201-203. 3.Lee YT, Lin H, Guo JC, Yan SL, Hou HJ, Lai YS et al. Laparoscopy-assisted billroth I gastrectomy for ectopic pancreas in the prepyloric region. Case reports in gastroenterology 2012;6:712-719. 4.Hsu SD, Wu HS, Kuo CL, Lee YT. Robotic-assisted laparoscopic resection of ectopic pancreas in the posterior wall of gastric high body: case report and review of the literature. 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The Role of Laparoscopic Surgery in Gastrointestinal Stromal Tumor of Stomach
Gastrointestinal stromal tumors (GISTs) often occur in the alimentary tract and less common, originating from omentum, mesentery and peritoneum. They usually present as subepithelial masses in the gastrointestinal tract or intraabdominal component and possess malignant potential. The tumors might cause abdominal pain, gastrointestinal tract bleeding, obstruction and intraabdominal hemorrhage but might also be disclosed as incidental findings. Gastroscopy, ultrasonography and computed tomography scan are employed for detection and evaluation. GISTs are differential diagnosis with other mesenchymal tumors by pathological target specially. The surgical principles are to excise the tumor with margin free of tumor microscopically. GISTs are one kind of submucosal tumor. Based on our published documents, we investigated the feasibility and security of laparoscopic surgery for stomach GISTs.
We retrospectively analyzed twenty four patients who was diagnosed as primary stomach GISTs and operated at our institutes during 2008 to 2012. The patients were divided to laparoscopy group (18 patients) and laparotomy group (6 patients) depending on the surgical methods. The patients' age, gender, hospital stay, operative time, blood loss, tumor size and complication rate were compared in the two groups. The role of laparoscopic surgery in the indication and safety for the primary gastrointestinal stromal tumor of stomach was explored and investigated. Tumor size and operative blood loss were significantly different in the two groups. The patients' age, gender, hospital stay, operative time and complication rate were not statistically different in both groups. However, there was a trend of shorter hospital stay in the laparoscopic group. In the past 4 years, 75% of primary gastric GISTs in our hospital were managed by laparoscopic surgery safely and efficiently. Our experience showed that laparoscopic surgery is feasible for primary stomach GISTs in selective patients with small tumors.
Expression of cyclin-dependent kinase 5 (Cdk5) in the gastrointestinal stromal tumor, thyroid cancer and breast cancer
In the past, Cdk5 protein was usually recognized as the decisive roles in neuromuscular development. Recent reports demonstrated the roles not only in cell cycle but also in cancer biology. Its new findings on tumor proliferation such as prostate cancer, thyroid cancer, breast cancer and lung cancer highlight Cdk5 as a potential therapeutic target. We have published the effect of expressed Cdk5 protein in the prostate and thyroid cancer cell growth. Furthermore, we investigated the expression of Cdk5 protein and its activator, p35 protein in gastrointestinal stromal tumor, thyroid cancer and breast cancer. The studies focused on three kinds of tumors, GISTs, thyroid cancer and breast cancer. The paraffin-embedded specimens were stained by hematoxylin & eosin staining method to differ the tumor portion and non-tumor portion by optic microscopy. The immunohistochemical staining method was performed by interaction of Cdk5 and p35 antibody (purchased from Upstate Biotechnology, Inc. Lake Placid, New York, 12946, USA) with antigen on the paraffin-embedded specimens. The results were observed and recorded by Allred semi-quantitative method. The results were recorded as scores 0, 2-8 and 0 %, 20 %, 50 %, 75 % respectively.
Twenty two patients with primary stomach GISTs who underwent surgery in the past four years were enrolled. The results were compared with prognostic factors such as tumor size and tumor cell mitosis. By analyzing thirty four clinical cancerous specimens from differentiated thyroid cancer (papillary and follicular), we investigated the expression of Cdk5 and p35 proteins in both tumor tissue and adjacent normal tissue by immunohistochemistry method. The results were compared with patients' age, gender, tumor characteristics, whether nuchal lymph nodes metastases or not. In breast cancer study, we collected fifty six clinical specimens and forty commercial tissue array. We surveyed the expression of Cdk5 and p35 proteins in both tumor tissue and adjacent normal tissue by Western blotting methods in 28 specimens. Thirty nine clinical specimens and thirty eight commercial specimens were studied by anti-Cdk5 and anti-p35 IHC staining. The expression of Cdk5 and p35 proteins were analyzed with the parameters of breast cancer pathology such as patients' age, tumor size, nodal status in axillae, distal metastasis, tumor grade, hormone receptor, Her-2/neu receptor, and Ki-67 proliferating factor, etc. Commercial tissue microarray chips were purchased from US Biomax, Inc. (Rockville, MD 20850, USA). They consisted of forty breast cancer tissues and neighboring normal tissue from 40 patients abroad. Data was quantified and analyzed by Chi square-test, independent T test, paired T-test and Pearson correlation methods according to the variables. Partial research work was supported by research fund of Show Chwan Health System with approval of the Institutional Review Board.
Compared with normal tissue, overexpression of Cdk5 and p35 proteins were noted in 86.4 % and 81.8 % of twenty two GIST specimens respectively. The statistical trend was obvious in larger tumor and tumor with higher mitosis, up to 100 % of specimens. In the thyroid cancer study, overexpression of Cdk5 and p35 were noted in the tumor portion compared with non-tumor portion significantly (Chi-square test, p<0.05). In 24 papillary carcinoma patients, both Cdk5 and p35 proteins overexpressed in 23 patients (95.8 %). In ten follicular carcinoma patients, Cdk5 overexpressed in six (60.0 %) and p35 overexpressed in seven (70 %) patients. The studies in thyroid demonstrated overexpression of Cdk5 protein in 29 specimens (85.3 %) and p35 protein in 30 specimens (88.2 %). For five patients with neck lymph nodes metastases, all the primary tumors presented overexpression of Cdk5 and p35 protein (100.0 %). In breast cancer clinical results, we found that Cdk5 and p35 proteins overexpressed in 61.0 % (47/77) and 55.8 % (43/77) of clinical and commercial specimens. Co-overexpression of Cdk5 and p35 was noted in 42.9 % (33/77) of specimens. There was difference in pathological parameters between in clinical (Taiwanese) and commercial (Foreigners). Cdk5 and p35 proteins expressed differently in both groups also (71.8 % for Cdk5, 61. 5% for p35 and co-expression in 48.7 % in clinical specimens compared with 47.5 % for Cdk5, 47.5 % for p35 and co-expression in 35 % in commercial specimens). We found Cdk5 and p35 overexpression in 29.0 % and 32.1 % of breast cancer patients respectively with co-expression in 21.4 % of patients by Western blotting experiments. By in vitro kinase assay, we proved higher activity of Cdk5 in tumor than that in normal tissue. However, we noted that Cdk5 and pr35 proteins overexpression negatively correlated with axillary lymph nodes metastasis in breast cancer patients with statistical significance. According to the studies on our patients, Cdk5 and its activator p35 might play an important role in GISTs, thyroid cancer and breast cancer cells.
To sum up the conclusion of part I and part II, we confirm the role of laparoscopic surgery in the management of primary gastric GISTs. By investigating on the expression of Cdk5 and p35 proteins, we explored the roles of Cdk5 and p35 proteins in the GISTs, thyroid cancer and breast cancer. We are looking forward the further cell lines studies to identify the mechanism of Cdk5 and p35 proteins in tumors of epithelial and non-epithelial origination.
台灣胃腸基質瘤(gastrointestinal stromal tumor)的年發生率約每百萬人口13.7人。這種源自間葉組織的腫瘤好發於胃、十二指腸及近端小腸，其他部位包括下端腸道、大網膜、腸系膜及腹膜。胃腸基質瘤有其特別的病理特性及免疫組織診斷方式，有惡性變化的可能，包括復發及轉移。手術切除是標準治療，手術切除時必須切除到微觀下無殘留細胞。對於腫瘤有c-kit(CD-117)標靶表現者可給與標靶藥物治療。近年來文獻認為對於胃部原發性的胃腸基質瘤腹腔鏡手術是可行及安全的。胃部的胃腸基質瘤屬於胃部黏膜下層腫瘤之一，我們基於之前以腹腔鏡針對胃部黏膜下層腫瘤之經驗，以4年的時間研究胃部原發性的胃腸基質瘤接受手術的患者。比較腹腔鏡手術及傳統開腹手術在手術時間、出血量、住院日、腫瘤大小及併發症之關係。共有24名罹患胃部原發性的胃腸基質瘤接受手術的患者。平均年紀為64.3±15.7歲(43~91歲)。男性8名，女性16名。依病患手術種類分類為腹腔鏡手術有18位，傳統開腹手術有6位。我們以卡方檢定比較兩組病人在手術時間、出血量、住院日、腫瘤大小及併發症之關係並探討腹腔鏡對於胃原發性的胃腸基質瘤患者接受手術的適應症與安全性。
Cdk5蛋白質是一種 cyclin-dependent kinase，p35蛋白質為其致活蛋白質。Cdk5原本被認為和神經與肌肉的生長和發育有關。近年來被發現與細胞生長、分化、凋亡甚至於細胞癌化有關。胃腸基質瘤是屬於非上皮性的間葉組織來源的腫瘤，而甲狀腺癌及乳癌均屬於上皮性的腫瘤。林赫教授實驗室之前陸續發表了Cdk5蛋白對攝護腺癌、甲狀腺癌細胞生長的影響。本部份研究探討Cdk5及p35蛋白質在甲狀腺癌及乳癌等上皮性腫瘤與胃腸基質瘤此類非上皮性的腫瘤之表現。針對所研究之三項腫瘤，將手術取得之標本以石蠟包埋切片，厚度為4μm。先以蘇木精和嗜伊紅(hematoxylin & eosin)染劑來將病理玻片染色並用顯微鏡觀察標本的腫瘤和非腫瘤部分的細胞。用Cdk5及p35的抗體來進行免疫組織化學染色，使用光學顯微鏡觀察腫瘤細胞和非腫瘤細胞之Cdk5及p35蛋白的表現。並且以Allred半定量的方法，以染色細胞的比例和染色的深度判讀並且定量紀錄。所得結果以分數及百分比兩種結果呈現，分別是0、2至8分八個等級以及0、20%、50%、75%四種等級。
有22名胃部原發性的胃腸基質瘤的樣本，比較了Cdk5及p35蛋白在腫瘤和非腫瘤部分的表現。也比較了Cdk5及p35蛋白表現和腫瘤大小(tumor size)及腫瘤細胞有絲分裂(mitosis)等兩項惡性程度的指標。對於胃腸基質瘤這類非上皮性腫瘤，我們除了比較同樣屬中胚層之腫瘤細胞和非腫瘤細胞的Cdk5及p35蛋白表現，也比較手術標本上屬於正常上皮之胃黏膜細胞之Cdk5及p35蛋白表現。甲狀腺癌部分有34份進行Cdk5及p35蛋白的免疫組織化學染色。也比較了Cdk5及p35蛋白表現和病人年紀、性別、腫瘤特性(乳突癌或濾泡癌)及淋巴結之轉移情形等預後指標之相關性。乳癌部分則由53位患者取得了56件標本，加上40位國外商用標本(tumor array)。同樣有腫瘤部分及腫瘤旁的非腫瘤部分。28件標本使用西方墨點法，39份標本以免疫組織化學染色法來比較同一位患者腫瘤部分及非腫瘤部分Cdk5與p35表現之差異。同時也比較了Cdk5與p35和乳癌病理組織特性諸如病人年紀、腫瘤大小、罹癌乳房同側腋下淋巴結之轉移情形、是否有遠處器官轉移、癌細胞分裂等級、癌細胞賀爾蒙接受器、細胞膜上Her-2/neu接受器、細胞核Ki-67指數等之相關性。數值依變項之特質以卡方檢定(Chi square-test)、獨立T檢定(independent T test) 、配對T檢定(paired T test)或皮爾森相關(Pearson correlation)分析。在22名胃部原發性的胃腸基質瘤的患者的石蠟包埋切片以免疫組織學染色發現，腫瘤細胞相對於非腫瘤細胞有過度的Cdk5及p35蛋白質表現，在22位病人中有19位(86.4%)有Cdk5過度表現，p35則有18位(81.8%)有過度表現。其中Cdk5的過度表現在有絲分裂高的腫瘤及腫瘤較大者更明顯。值得一提的是Cdk5及p35蛋白質表現在正常之胃黏膜細胞並不下於腫瘤細胞，同樣比正常的間葉組織明顯，意味著Cdk5在像胃粘膜這類經常細胞更新的上皮細胞比中胚層組織細胞有較高的表現。在得自32名甲狀腺癌患者的38份石蠟包埋切片中有34份以免疫組織化學染色實驗。我們發現，腫瘤細胞相對於非腫瘤細胞有過度的Cdk5及p35蛋白質表現，在甲狀腺乳突癌患者24人中有23人(95.8%)有Cdk5蛋白質過度的表現，p35蛋白質同樣在24人中有23人(95.8%)有過度的表現。在甲狀腺濾泡癌患者10人中有6人(60.0%)有Cdk5蛋白質過度的表現，p35蛋白質同樣在10人中有7人(70.0%)有過度的表現。在8位有頸部淋巴結轉移的患者，其中5人進行Cdk5及p35的免疫組織化學染色研究。結果相較於正常組織，5人(100%)在原發的腫瘤Cdk5及p35蛋白質均有過度的表現。以上結果均達到統計學上的意義。乳癌部分由53位患者取得了56件標本染色實驗同樣發現，對同一位病人而言，腫瘤組織之Cdk5及p35蛋白質表現相對於非腫瘤組織有明顯之過度表現。在國內患者部分，Cdk5蛋白質在39人中的28人(71.8%)有過度之表現，p35蛋白質則在39人中的24人(61.5%)有過度之表現。國外商用標本40份中Cdk5及p35蛋白質均為40份中的19份(47.5%)有過度之表現。將國內外標本合併統計共有77件有效以免疫組織化學染色的實驗標本，其中Cdk5蛋白有47件(61.0%)過度表現，p35蛋白則有43件(55.8%)過度表現。國內的標本使用西方墨點法的實驗發現Cdk5蛋白質有29.0%、p35蛋白質有32.1%相對於正常組織的過度表現。兩者同時有蛋白質的過度表現則可見於21.4%的乳癌病人。使用體外激酶分析(in vitro kinase assay)，也可見Cdk5活性在腫瘤表現較正常細胞高。然而，臨床統計分析乳癌腫瘤Cdk5及p35蛋白過度表現與乳癌患者腋下淋巴結轉移有統計學上的負相關。我們的實驗結果顯示Cdk5和p35蛋白在胃腸基質瘤、甲狀腺癌與乳癌細胞有過度之表現。希望此研究結果能解答Cdk5蛋白在胃腸基質瘤、甲狀腺癌與乳癌中的重要性，並開啟後續相關研究。
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