SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma.

Since the SOX2 amplification was identified in lung squamous cell carcinoma (lung SCC), SOX2 transcriptional downstream targets have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including 4 lung SCC cell lines) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A

A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor

The PI3K–AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC

Amino acid signaling in the intestine : The roles of glutamine, leucine and arginine

Amino acids have an influence on the function of organs, glands, tendons and arteries. Some of them play crucial roles in the control of gene expression by controlling the initiation phase of mRNA translation. Furthermore, recent studies have revealed that some kinds of amino acids directly participate in important signal transduction in the immune system. Glutamine, leucine and arginine play crucial roles in intestinal growth, integrity, and function through cellular signaling mechanisms. In this paper, we review amino acid signal transduction in the intestinal function

A case report of isolated presacral squamous cell carcinoma developed four years after gastrectomy

Chemoradiation therapy and a transsacral resection were performed to treat isolated squamous cell carsinoma that occurred in presacral tissues in the pelvis four years after gastrectomy due to early gastric cancer, with the prognosis continuing to be favorable. The patient was a 57-year-old woman, who came to our hospital having symptoms of anemia four years after gastrectomy. After a rectal examination, a tumor mass the size of a sparrowegg was discovered on the left rectal wall. An abdominal CT showed a tumor, 3.7cm × 3.7cm in size, on the outer left wall of the upper rectum. After a CT-guided biopsy, squamous cell carcinoma was detected. Irradiation (total 40 Gy) and chemotherapy (MMC+5-FU) were performed, mass shrinkage was confirmed, and a transsacral tumor resection was performed. According to the histopathological examination, a very small but viable cancer was found to be remaining. 4 years after the tumor removal, no recurrence has been discovered. Squamous cell carcinoma in the pelvis often originates from the vagina. However, the patient didn\u27t have any malignant findings from a genital examination at the time the symptoms appeared, and this case was diagnosed as isolated squamous cell carcinoma. A transsacral approach to remove such a tumor is considered to be useful because it is relatively low invasion and preserves anal functions

Skin Tube Reconstruction for Esophageal Defects due to Postoperative Complications: Applying a skin flap in esophageal resection and reconstruction

Numerous improvements and advances in operational methods and techniques have occurred in the area of reconstruction for esophageal cancer. Patients with thoracic esophageal cancer who have previously had a gastrectomy usually undergo reconstruction using the colon and small intestine. The incidence of organ necrosis is not necessarily low after reconstruction with those organs. Generally, the main types of skin flaps and musculocutaneous flaps used for cervical and other esophageal reconstructions are deltopectoral (DP) flaps, pedicled musculocutaneous latissimus dorsi flaps and free anteriolateral thigh flaps. This kind of reconstruction is low invasive, relatively simple, and also causes very few fatal post-operative complications. Therefore, it is considered to be an effective reconstruction choice for the following types of patients: poor risk patients, patients whose gastrointestinal (GI) tract cannot be used for their reconstruction for some reason, and patients having a second reconstruction due to complications caused by organ necrosis after their first GI tract reconstruction

A Case of Cholesterol Crystal Embolization with Hemorrhagic Intestinal Ulcer

Cholesterol crystal embolization (CCE) is a rare systemic embolism caused　by formation of cholesterol crystals from atherosclerotic plaques. CCE usually occurs during　vascular manipulation such as vascular surgery or endovascular catheter manipulation, or　due to anticoagulation or thrombolytic therapy. We report a rare case of localized intestinal　ulcer with active hemorrhage caused by spontaneous CCE. An 83-year-old man with a history　of hypertension and diabetes was treated with a percutaneous coronary intervention (PCI)　for myocardial infarction. Melena occurred eight days after PCI. An abdominal computed　tomography revealed small intestinal ulcer, extravasation of the gastrointestinal tract and　bleeding in the abdominal cavity. The patient was diagnosed as bleeding from the small　intestinal ulcer, so an emergency laparotomy was performed. Partial resection of the small　intestine was performed. A histopathological examination indicated that small intestine　obstruction was caused by CCE. A histopathological examination indicated that small intestinal　obstruction was caused by CCE. Therefore, in cases of intestinal obstruction after vascular　manipulation, CCE should also be considered

Evaluation of intra-ductal cancer spread using contrast superb micro-vascular imaging (SMI) : a case report

Currently, breast conserving surgery has been adopted to treat more than half of all breast cancer patients in Japan. When performing breast-conserving surgery, an appropriate margin needs to be determined for radical cure. The resection volume influences the esthetic outcome, but a cancer-positive resection stump is also important risk factor of local recurrence. Additionally, the degree of cancer progression influences the surgical method, so understanding the appropriate resection margin is necessary for the surgeons. We report here on a 50- year old patient whose intra-ductal cancer progression was shown, as predicted, by contrast SMI (superb micro-vascular imaging). A one-cm size tumor mass was palpable with a clear boundary. B-mode ultrasound confirmed the presence of a breast duct towards the nipple from the tumor mass. Using contrast SMI, an accelerated blood flow was detected around the duct, which suggested intra-ductal progression. The pathological results also showed intra-ductal progression to the nipple from the tumor. Around the progression area, a meandering vessel was found and the vessel was able to be visualized by contrast SMI

肝転移を伴う胆嚢腺内分泌細胞癌の一例

症例は50歳代,女性.20XX 年1月ごろより前屈での心窩部付近の疼痛と右季肋部違和感を認めていた.同年3月初旬に疼痛が増強したため近医を受診し,CTで胆嚢に造影効果のある腫瘤と肝内の腫瘤陰影が認められた.肝転移を伴う胆嚢癌が疑われ,精査加療目的に当院へ紹介された.当院での画像検査でも胆嚢底部から体部にかけて約4.5cm大の隆起性病変を認めた.胆嚢底部では漿膜面が腫瘤に引き込まれ陥入している像を認め,肝床と一部で接しており境界不明瞭ではあったが,肝実質内への浸潤像は認めなかった.肝S4に約2cm大のリング状に造影される腫瘤を認め,肝転移が疑われた.ERCPでは胆嚢頸部,胆嚢管,総胆管への浸潤は認めなかった.胆汁細胞診はClass Vであった.単発の肝転移以外には遠隔転移を認めず,主要血管への浸潤も認めないため肝S4a+5切除,胆嚢摘出術,リンパ節郭清を施行した.切除標本では,病変は約4.5cm大の乳頭・結節型であり漿膜外まで浸潤していた(T3).組織学的には腺管構造を呈する腺癌とシナプトフィジン,クロモグラニンAが陽性の内分泌細胞癌が混在していた.肝転移巣は約2cmの結節・浸潤型であり,組織学的には同様にCD56強陽性,シナプトフィジン,クロモグラニンA陽性となる内分泌細胞癌が認められた(M1).リンパ節転移は認めなかった(N0).病理診断は腺内分泌細胞癌,UICC Stage-IVBであった.本症例は孤立性の肝転移を伴った胆嚢癌であったが,肝転移がS4であり,通常の胆嚢癌手術の切除範囲内であり,大きなリスクもなかったため,切除手術を行った.術後,gemcitabineとcisplatinによる補助化学療法を行った.A 57 year-old-female was referred to our hospital, because of an epigastric pain and discomfort for 2 months. Contrast-enhanced CT showed the tumor in the gallbladder body with a liver tumor in S4. An ERCP and other examinations showed no evidence of invasion to bile duct, vessels and other distant metastasis. It was diagnosed as the gallbladder cancer with a solitary liver metastasis. Preoperatively, we assessed that the curative operation might be possible. Then, we performed subsegmentectomy of liver S4a+5, cholecystectomy, and lymphadenectomy. The gallbladder cancer invasion remained extra serosa and no direct invasion to the liver tissue. Immuno-histochemical examinations showed that the tumor contained tubular adenocarcinoma and endocrine cell carcinoma with synaptophysin and chromogranin A positive. Also, the metastasis in liver S4 showed almost same results in synaptophysin, chromogranin A and CD56 positive. According to those results, she was diagnosed as mixed adeno - neuroendocrine carcinoma and Stage-IVB. Although she recovered uneventfully, she developped other liver metastases, 4 months after surgery. The chemotherapy including gemcitabine and cisplatin was introduced. Clinical cases of mixed adenoneuroendocrine carcinoma of gallbladder have been rarely reported. We present this case with a review of literatures

A dialysis patient with multiple intestinal diverticula in whom partial penetration was recognized.

　小腸憩室は比較的稀な疾患で，多くが無症状で経過するが，穿孔した場合は腸間膜内に穿通し膿瘍形成をきたす．高齢者に多く，その診断および治療の遅れから重篤な経過をたどることも少なくない．その診断にはコンピュータ断層撮影（CT）が有用とされているが，穿孔部位や憩室の特定は困難とされ，術前に指摘できるものは決して多くない．透析患者では高リン血症に対し陰イオン交換樹脂剤などが一般的に使用されるが，消化管穿孔の注意が記載されている．今回我々は，透析患者の腸管穿孔の原因検索に体外式超音波（US）が有用であった１例を経験したので，文献的考察を含めて報告する．症例は70歳台男性，18年前から血液透析を行っている．10日前に発熱で近医を受診し，保存的に経過を見ていたが炎症反応の上昇を認め当院紹介受診した．身体所見は心窩部付近に軽度の圧痛を認めたが腹膜刺激兆候は明らかでなかった．単純 CT で消化管外の free air が疑われ，精査目的に US が行われた．US では空腸に多発している憩室と，憩室周囲の膿瘍形成およびその内部の free air と思われる点状高エコーが認められ，小腸憩室穿通と診断した．同日小腸切除術が行われ，病理組織学的検索の結果，US と同様の所見であった．また穿通した憩室にセベラマー結節が認められ，憩室穿通に関与した可能性が示唆された．US は透析患者における憩室穿通の診断に有用である．　Jejunal diverticula (JD) are considered to be rare and are asymptomatic in most cases. However, they are potentially associated with serious complications, such as diverticulitis and perforation/penetration, especially in the elderly. In the event of perforation/ penetration, JD usually penetrates the mesentery, resulting in the formation of an abscess in the mesentery, which is difficult to diagnose, because there are no specific signs. Anion exchange resin agents, such as sevelamer hydrochloride (SH), are often used for hyperphosphatemia in dialysis patients, but the package insert cautions against the development of the adverse effect of gastrointestinal perforation. Herein, we report a case in which abdominal ultrasonography (US) was useful for the diagnosis of jejunal diverticular penetration in a hemodialysis patient. The patient was a male in his 70s who had been on hemodialysis for 18 years and was receiving SH 2.25g/day. He presented to a neighborhood hospital with a 10-days’history of fever. The fever did not improve with conservative therapy, and the patient was referred to our hospital. Physical examination revealed mild epigastric tenderness, but there were no signs of peritoneal irritation. Computed tomography (CT) was performed, and the presence of free air was suspected. Abdominal US performed subsequently showed multiple jejunal diverticula and abscess formation around the diverticulum. Furthermore, free air was recognized in the abscess, which was finally diagnosed as a mesenteric abscess complicating JD penetration. On the same day, jejunal resection was performed and histopathological examination of the surgical specimen revealed findings consistent with the US findings. Histopathology revealed sevelamer crystals in the penetrated diverticulum. US is useful for the diagnosis of penetration of JD in dialysis patients

穿孔性腹膜炎を契機に発見された小腸GIST破裂の1例

症例は57歳の男性で,近医より急性虫垂炎の疑いにて当院救急外来へ紹介初診の際の理学所見にて下腹部正中に圧痛を認め,血液生化学検査では炎症反応の上昇を伴っていた.腹部造影CT検査にて圧痛部位に一致して小腸と連続した直径13cm大の巨大腫瘍を認め,腫瘍内部及び周囲腹腔内に遊離ガスを認めた.小腸腫瘍破裂による穿孔性腹膜炎の診断にて緊急開腹手術を施行したところ,トライツ靭帯より約30cmの空腸に連続した直径13.5cm大の腫瘍を認め,空腸内腔との交通を有する粘膜下腫瘍の形態を示し,腫瘍表面が一部破綻して穿孔していた.腫瘍を含めて空腸を部分切除し,腹腔内洗浄ドレナージを行った.摘出組織を検索するに,空腸粘膜に5mm大の瘻孔口が開口し,瘻孔は腫瘍内部に通じていた.腫瘍表面には線維性被膜を有し,内容は白色充実性で出血や壊死巣が存在し,組織学的観察では紡錘形細胞が索状に錯綜しながら密に浸潤増殖していた.免疫組織学的検討において,腫瘍細胞はc-kit陽性,CD34は一部陽性で,空腸原発のGastrointestinal stromal tumor(GIST)と診断した.核分裂像は3/50HPF程度で,MIB-1は約19%の細胞で陽性であった.術中の肉眼的観察及び術後のFDG-PETにて腫瘍の残存は認めなかったものの,小腸原発,腫瘍径,腫瘍破裂を伴うことから高リスク症例に分類され,術後補助化学療法の適応症例であった.穿孔性腹膜炎を契機に発見されたGIST症例は比較的稀ではあるが,小腸GISTは無症候で巨大化した後に発見されることが多く,他部位原発のGISTと比し予後不良である.本症例のような破裂を伴って診断される症例においては,再発の高リスク群に該当することから,術後補助化学療法の適応であり,また厳重なフォローアップを要する.A 57-year old man, who had complained of lower abdominal pain since the previous evening, was referred to our hospital with suspected acute appendicitis. Enhanced computer tomography scanning revealed a giant tumor (approximately 13 cm in width) connected to the small intestine and intraperitoneal free air in and around the tumor. The patient was given an emergency open laparotomy, due to a diagnosis of perforated peritonitis caused by a ruptured intestinal tumor. The ruptured tumor was located on the jejunum at 30 cm from the ligament of Treiz and appeared to be a type of submucosal tumor with a connective route to the jejunal lumen. We removed the tumor with the responsible jejunum and the resected tissue was subjected to further pathological examination. The tumor contained histologically infiltrative spindle cells with a mitotic ability of 3/50HPF; immunohistochemical examinations revealed positive c-kit, partially positive CD34, and 19% positive staining of MIB-1 in tumor cells, leading to the final pathological diagnosis of gastrointestinal stromal tumor (GIST) originating in the jejunum. Since this case was classified as a high risk case by the Miettinen risk table, Imatinib administration was given to the patient though postoperative FDG-PET examination showed negative for the existence of residual or metastatic tumor. Intestine-origin GISTs can be found as a large mass without any symptoms and thus lead to a poor outcome compared to those of stomach-origin. Enlarged GISTs would increase the possibility of rupture before radiographic recognition. Since ruptured GISTs are known to have a high risk of recurrence, we should take a definitive surgical treatment promptly and should give subsequent adjuvant chemotherapy with Imatinib