Klf5 maintains the balance of primitive endoderm versus epiblast specification during mouse embryonic development by suppression of Fgf4.

The inner cell mass of the mouse blastocyst gives rise to the pluripotent epiblast (EPI), which forms the embryo proper, and the primitive endoderm (PrE), which forms extra-embryonic yolk sac tissues. All inner cells coexpress lineage markers such as Nanog and Gata6 at embryonic day (E) 3.25, and the EPI and PrE precursor cells eventually segregate to exclusively express Nanog and Gata6, respectively. Fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signalling is involved in segregation of the EPI and PrE lineages; however, the mechanism involved in Fgf4 regulation is poorly understood. Here, we identified Klf5 as an upstream repressor of Fgf4Fgf4 was markedly upregulated in Klf5 knockout (KO) embryos at E3.0, and was downregulated in embryos overexpressing Klf5 Furthermore, Klf5 KO and overexpressing blastocysts showed skewed lineage specification phenotypes, similar to FGF4-treated preimplantation embryos and Fgf4 KO embryos, respectively. Inhibitors of the FGF receptor (Fgfr) and ERK pathways reversed the skewed lineage specification of Klf5 KO blastocysts. These data demonstrate that Klf5 suppresses Fgf4-Fgfr-ERK signalling, thus preventing precocious activation of the PrE specification programme.

[A Resected Case of Leiomyosarcoma Originating from the Ovarian Vein].

We present a 46-year-old female patient who underwent resection of a retroperitoneal tumor, which was found by medical check-up. The tumor which was elastic hard and had good mobility displaced the duodenum to her abdominal wall. Since her right ovarian vein adhered to the tumor, we removed the tumor with the ligated vein. Pathological findings showed the tumor consisted of spindle-shaped cells with pleomorphic nucleus and it presented the fascicular growth pattern. Additional immunostaining showed positive for HHF35, h-caldesmon. Because the leiomyosarcoma connected with the smooth muscle of the right ovarian vein, we considered the vascular smooth muscle was the origin of the tumor. It is 2 years after the operation, there has been no local recurrence or metastasis.

[A Case of Advanced Rectal Cancer Successfully Treated with Preoperative Radiochemotherapy].

An 80-year-old woman who visited our hospital with chief complaints of decreased appetite and diarrhea. Lower gastrointestinal endoscopy showed a type 2 tumor in the rectal Ra, and biopsy revealed a well-differentiated adenocarcinoma. The patient had locally advanced rectal cancer with widespread contact with the sacrum, and preoperative radiochemotherapy (S-1 100 mg/day plus radiotherapy 50 Gy/25 Fr)was performed. After the treatment was completed, the tumor was remarkably reduced, but the surgery was strongly rejected, and therefore chemotherapy became the policy. XELOX plus bevacizumab therapy was started, but in the second course was performed, obstructive symptoms appeared, so a semi-urgent lower anterior resection and ileostomy were performed. Postoperative pathological findings showed only a small amount of tumor cells in the mucosa, suggesting that preoperative treatment was effective.

[A Case of Small Bowel Perforation Due to Lung Cancer Metastasis].

A 79-year-old man was diagnosed with Stage ⅢB(T4N2M0)adenocarcinoma of the lung, administered. He suddenly developed abdominal pain with muscle guarding and rebound tenderness. An abdominal computed tomography scan revealed a thickened small bowel wall and mesenteric mass, as well as massive ascites and free air. He underwent an emergency laparotomy following a diagnosis of pan-peritonitis due to intestinalperforation. A partialresection of the smallintestine and abdominal drainage were performed. The resected specimen included an ulcerative lesion on the mucosal surface. The pathological diagnosis was a metastasis of lung cancer. The patient died in hospice 29 days postoperatively. In the present case, however, surgery improved the patient's quality of life. Although lung cancer metastasis to the small bowel is associated with a poor prognosis, palliative surgery is indicated in otherwise fatal circumstances.

[Radical Surgery Following Chemotherapy in a Patient with Mesenteric Recurrence Associated with Hematoma upon ESD for Rectal Cancer Three Years Six months Later].

A63 -year-old man complaining of anal pain visited our hospital. Three years 6 months previously, the patient underwent endoscopic submucosal dissection(ESD)for early-stage rectal cancer. Based on the pathological findings, adenocarcinoma with invasion to the submucosal layer(2,000 mm)and lymphovascular invasion were diagnosed. Abdominal computed tomography( CT)revealed a solid tumor 50mm in diameter and hematoma measuring approximately 90mm in length adjoining the tumor in the mesorectum. We performed exploratory laparoscopy. Ahematoma was confirmed in the mesentery from the sigmoid colon and rectum. After the surgery, endoscopic ultrasound-guided fine needle aspiration(EUS-FNA)revealed well-differentiated adenocarcinoma. We diagnosed a hematoma associated with mesenteric recurrence following ESD for rectal cancer. The patient received chemotherapy first because of the large size of the recurrent cancer. Four courses of mFOLFOX6(5-FU: bolus 400mg/m / / / 2,2,400mg/m2,oxaliplatin 85 mg/m2) and panitumumab(6 mg/kg)were administered. Based on the CT findings following chemotherapy, the hematoma had disappeared, and the size of the recurrent cancer in the mesorectum reduced to 28 mm. The patient underwent laparoscopic lower anterior resection with D3 lymph node dissection and ileostomy. The postoperative course was uneventful. Currently, the patient has no recurrence.

[A Case of Locally Far-Advanced Colon Cancer Resected by Laparoscopic Surgery after Colonic Stent Insertion and Neoadjuvant Chemotherapy].

We report a case of locally far-advanced colon cancer resected by laparoscopic surgery after colonic stent insertion and neoadjuvant chemotherapy. A 71-year-old man with obstructive symptoms was admitted to our hospital in July 2015. CT revealed a sigmoid colon tumor infiltrating the retroperitoneum and small intestine. Lower gastrointestinal endoscopy showed a sigmoid colon cancer. Self-expandable metallic stent insertion for obstructive colon cancer alleviated the patient's symptoms quickly. Four courses of neoadjuvant chemotherapy(XELOX)reduced the primary tumor in size, allowing for laparoscopic surgical resection. Combination therapy with colonic stenting and neoadjuvant chemotherapy can be an effective treatment for obstructive colon cancer. However, further studies and additional cases are needed to assess the safety and efficacy of this combination therapy.

[New FP Therapy Was Effective for a Case of Massive Hepatocellular Carcinoma].

A 62 year-old woman was hospitalized with the diagnosis of pneumonia, and a huge mass was recognized in the right lobe of the liver during a CT scan. AFP and PIVKA-Ⅱ were elevated to 101.05 ng/mL and 2,177 mAU/mL. The liver function test indicated Child-Pugh classification A, liver damage degree B, and ICG R15 34%. We judged a radical cure resection impossible. We treated the patient with arterial injections of modified new FP therapy. No side effect occurred during the first course. Liver dysfunction with fever and hematuria occurred during the second course, leading to discontinuation of therapy. Because a prominent reduction in the size of the tumor was achieved, liver resection is scheduled. New FP therapy can be expected to attain a favorable result that may allow for curative resection of the tumor.

Pulmonary resection after chemoradiotherapy for advanced non-small cell lung cancer: the impact of presurgical radiation therapy.

PURPOSE: Chemoradiation therapy (CRT) is recommended as standard care for stage III non-small cell lung cancer (NSCLC), but some patients experience local recurrence after the treatment. Surgical resection after CRT involves high surgical risk, but is expected to increase the curability. This study was performed to investigate the impact of presurgical CRT on the postoperative outcome, focusing especially on the effect of radiation therapy. METHODS: Twenty-six patients with stage III (N2 or T3-4) NSCLC underwent pulmonary resection after CRT. A radiation dose up to 40-70 Gy was given with concurrent chemotherapy. The morbidity, mortality and survival after surgical resection were examined. RESULTS: Lung resection was performed as lobectomy (73 %) or pneumonectomy (19 %). Postoperative complications occurred in 12 patients (morbidity 46.1 %). The overall 5-year survival of the entire cohort was 69.7 %. The factors associated with favorable long-term survival included a pathological complete response (CR) and mediastinal node negative condition after CRT, and microscopic complete resection. CONCLUSION: Surgical resection for stage III patients after CRT may provide a survival benefit with acceptable morbidity. The surgical morbidity may be increased by prior radiation therapy, thus, surgeons should be familiar with the available countermeasures to reduce the surgical risk.

[A case report of pulmonary aspergillosis in lung transplant recipient successfully treated with inhalation administration of liposomal amphotericin B].

We report a case of pulmonary aspergillosis in lung transplant recipient who was successfully treated with inhalation administration of anti-fungal agent. The case was 33-year-old female. Two years ago, she had received lung transplant because of lymphangioleiomyomatosis. One year ago, she had diagnosed of pulmonary aspergillosis and successfully treated with micafungin and itraconazole. Then she had been continuous administered with itraconazole. In June 20xx, she had nausea and vomiting and was diagnosed of viral enteritis. Although abdominal symptoms were relieved, ground glass opacity was discovered in her right lung. Bronchoscopic examination revealed ulceration of bronchus with white necrotic substance. Laboratory culture test demonstrated Aspergillus spp. Finally she was diagnosed of recurrent pulmonary aspergillosis. First, she was treated with intravascular administration of micafungin. Then, inhalation administration of liposomal amphotericin B was changed. Ground glass opacity and bronchial region of pulmonary aspergillosis was improved. Thereafter, inhalation of amphotericin B was continued and no recurrence of pulmonary aspergillosis has been found. Inhalation of anti-fungal agent could be an option for pulmonary aspergillosis.

Serum level of HE4 is closely associated with pulmonary adenocarcinoma progression.

The human epididymis 4 (HE4) protein is expressed in the epididymis and respiratory tract. We previously reported that HE4 is also expressed in pulmonary adenocarcinoma. The purpose of this study was to investigate serum levels of HE4 as a biological marker in pulmonary adenocarcinoma. As the trained set, 102 patients with pulmonary adenocarcinoma who underwent surgery in our institute from 2008 to 2011 were evaluated. They were compared with 58 healthy controls and 16 cases of benign lung disease. In the validation, we used 104 patients with pulmonary adenocarcinoma operated on between 2000 and 2007. Postoperative changes of serum HE4 levels were investigated in 35 patients. The level of HE4 was determined by enzyme immunometric assay and compared with clinicopathological factors. In the trained set, HE4 levels in sera in pulmonary adenocarcinoma were significantly higher than in healthy controls and benign lung disease. Receiver operating characteristic curve showed that HE4 was a good discriminator of pulmonary adenocarcinoma (cut-off point, 50.3 pM; area under curve, 0.825; 95 % confidence interval, 0.76-0.89, p < 0.001). In the validation set, serum HE4 levels were significantly correlated with age, nodal status, and carcinoembryonic antigen. Furthermore, postoperative increase of HE4 serum levels showed a significant correlation with recurrence (p = 0.032). The 5-year overall survival rate was 52.6 % in the HE4-positive group compared with 97.1 % in the HE4-negative group (p = 0.001). These data showed that HE4 expression in sera is associated with progression of pulmonary adenocarcinoma and a possible biomarker.

Off-the-job training for VATS employing anatomically correct lung models.

We evaluated our simulated major lung resection employing anatomically correct lung models as "off-the-job training" for video-assisted thoracic surgery trainees. A total of 76 surgeons voluntarily participated in our study. They performed video-assisted thoracic surgical lobectomy employing anatomically correct lung models, which are made of sponges so that vessels and bronchi can be cut using usual surgical techniques with typical forceps. After the simulation surgery, participants answered questionnaires on a visual analogue scale, in terms of their level of interest and the reality of our training method as off-the-job training for trainees. We considered that the closer a score was to 10, the more useful our method would be for training new surgeons. Regarding the appeal or level of interest in this simulation surgery, the mean score was 8.3 of 10, and regarding reality, it was 7.0. The participants could feel some of the real sensations of the surgery and seemed to be satisfied to perform the simulation lobectomy. Our training method is considered to be suitable as an appropriate type of surgical off-the-job training.

[Surgical management for lung cancer in less than 1 cm].

Recently, the greater utilization of computed tomography (CT) has led to an increasing proportion of small-sized stage I A lung cancer in less than 1 cm in diameter. However, a treatment strategy for these small-sized lung cancers has not yet been defined. The aim of this study was to investigate surgical outcomes regarding these lung cancers. A total of 123 patients who underwent complete surgical resection for lung cancer in less than 1 cm between January 1995 and March 2010 were retrospectively evaluated. The 123 study subjects consisted of 54 male and 69 female patients. The mean age was 64.0 (43~82) years. The mean tumor size was 0.9( 0.3~1.0) cm. In this study, 70 patients underwent lobectomy (56.9%). Segmentectomy and wedge resection were underwent 23( 18.7%) and 30 patients( 24.4%), respectively. The 3-, 5- and 10-year survival rates were 95.7, 92.3 and 85.7%, respectively, after the operation for lung cancer in less than 1 cm. There were no significant difference between sublobar resection and lobectomy. However, 2 patients( 1.6%) had recurrent cancer and 7 patients (5.7%) had lymph node metastasis. We suggested surgical procedure for patients with lung cancers in less than 1 cm should be selected with the greatest care, because recurrent cancer and lymph node metastasis can occur in patients.

Successful treatment of bronchial anastomotic stenosis with modified Dumon Y-stent insertion in lung transplantation: report of a case.

Bronchial complications owing to airway anastomosis still remain a cause of morbidity and mortality following lung transplantation, and bronchial stenosis is the most common manifestation. Current treatment strategies include endoscopic balloon dilation, laser ablation, and stent insertion. Although a variety of stent types are currently available, it is unclear as to which type of prosthesis is most suitable for post-transplant bronchial complications with regard to the primary effects and long-term outcomes. We herein discuss a case of stenosis of the right bronchial anastomosis in a patient who underwent right single lung transplantation for idiopathic pulmonary fibrosis. This complication was successfully treated with the placement of a modified Dumon Y-stent. The stent was removed 2 months after insertion, and the patient has subsequently maintained an adequate airway caliber. Computed tomography, especially the sagittal section through the chest, is useful for detecting bronchial stenosis and monitoring the healing of this condition.

Tracheal resection for malignant and benign diseases: surgical results and perioperative considerations.

PURPOSE: Tracheal surgery is an established treatment for various diseases; however, it is still a potentially challenging procedure. We herein discuss the safety of this procedure with regard to the coordination with airway interventional and anesthetic support. METHODS: A tracheal resection was performed on 18 patients. The dyspnea due to pre-existing severe airway stenosis, which was considered to be a risk factor for the safe induction of general anesthesia, was present in 12 (66.7%) cases. RESULTS: Seven of the 12 patients with pre-existing airway obstruction required interventional airway treatment before surgery. One case with a polyp-like tracheal tumor required venoarterial percutaneous cardiopulmonary support to establish adequate oxygenation before surgery. All 18 cases underwent a segmental resection of the trachea, with the average length of 3.6 rings. Postoperative recovery was uneventful for all but one patient with postintubation tracheal stenosis, who died 17 days after surgery due to a methicillin-resistant Staphylococcus aureus infection. Complications in the other patients included four cases of laryngeal nerve palsy, three of aspiration, and one patient with Horner syndrome, with a total morbidity of 27.7%. CONCLUSIONS: A tracheal resection is currently a safe procedure; however, cooperation with sophisticated airway interventional treatment teams, cardiopulmonary bypass support, or a well-trained anesthesiologist is essential for obtaining a successful outcome, especially for the cases with pre-existing severe airway obstruction.

Does pneumothorax occurrence correlate with a change in the weather?

PURPOSE: There has been speculation that weather changes correlate with the incidence of spontaneous pneumothorax, although this has not been verified. Moreover, there are no significant data available on the meteoropathic pneumothorax in Asia. The aim of this study was to investigate the possible correlation and to compare our results to those of the United States and Europe. METHODS: From January 2000 to December 2009, 317 spontaneous pneumothorax cases with clear dates of onset were treated in our institution. Using the meteorological data of Fukuoka, Japan, the days with and without an occurrence of pneumothorax were statistically compared in terms of atmospheric pressure, the amount of precipitation, temperature, humidity, hours of sunshine, and occurrence of a typhoon and lightning. RESULTS: Multivariate analysis revealed that a decrease in the hours of sunshine, an increase in mean temperatures 2 days before the incidence, and the days following a day with lightning were all significantly correlated with the occurrence of pneumothorax (P = 0.2 days before the incidence, and the days following a day with lightning were all significantly correlated with the occurrence of pneumothorax (P = 0.0083, 0.0032, 0.0351, respectively). However, typhoons, as an "unusual" weather condition, did not influence the incidence of pneumothorax (P = 0.983). CONCLUSIONS: Our results show strong similarities with reports from European countries despite the different climates. We conclude that the occurrence of pneumothorax appears to correlate with some weather conditions in Japan.

Subtotal gastrectomy for gastric tube cancer using intraoperative indocyanine green fluorescence method.

INTRODUCTION: Currently, the frequency of evaluating the flow of a reconstructed gastric tube using indocyanine green (ICG) fluorescence has been increasing. However, it has been difficult to decide on the operation method for patients with gastric tube cancer (GTC). We herein report a case in which ICG was effective in a patient with resection of GTC. PRESENTATION OF CASE: An 83-year-old man underwent subtotal esophagectomy with gastric tube reconstruction via the retrosternal route for esophageal cancer and right hemicolectomy for ascending colon cancer 16 years earlier. Postoperatively, the proximal part of the gastric tube had poor blood flow. Therefore, the patient underwent proximal-side resection of the gastric tube. Thereafter, free jejunal graft reconstruction was performed. The patient had not developed recurrence at that point. Recently, the patient visited the hospital complaining of nausea and chest discomfort. Upper gastrointestinal endoscopy revealed a type 0-IIa + IIc lesion located around the pylorus. A biopsy showed adenocarcinoma. Based on these findings, the patient was diagnosed with gastric tube cancer (cT1bN0M0StageI). The invasion depth of the cancer was predicted to be widespread submucosal invasion. Therefore, the patient underwent surgery. Intraoperatively, we evaluated the flow of the gastric tube after clamping the right gastroepiploic artery using ICG fluorescence. As a result, the flow of the gastric tube was deemed insufficient. Consequently, subtotal gastrectomy was performed with preservation of the right gastroepiploic artery via Roux-en-Y reconstruction. DISCUSSION: ICG fluorescence is useful for evaluating the flow of the gastric tube helping to decide the operating method. CONCLUSION: We herein report a case of subtotal gastrectomy for GTC using intraoperative ICG fluorescence.

Association between the expression of chemokine receptors CCR7 and CXCR3, and lymph node metastatic potential in lung adenocarcinoma.

Chemokines and their receptors are essential for leukocyte trafficking, and are also involved in cancer metastasis to specific organs. Although the migration of tumor cells into the lymph nodes is an important aspect of cancer, the processes involved are poorly understood. Chemokine receptors CCR7 and CXCR3 have been shown to play an important role in tumor cell migration and lymph node metastasis. Therefore, the assessment of chemokine receptor expression on lung adenocarcinomas may improve the prediction of the spread of this carcinoma to the lymph nodes. In this study, we examined the expression and function of these two chemokine receptors (CCR7 and CXCR3) in lung adenocarcinoma. By using flow cytometry, they were detected in all of the lung adenocarcinoma cell lines examined. In the chemotaxis assays, A549 cells exhibited CCL21-induced migration, which was significantly suppressed by neutralizing anti-CCR7 antibody. The CXCL10-induced migration of A549 cells was also significantly suppressed by neutralizing anti-CXCR3 antibody. In clinical lung adenocarcinoma samples, we found the expression of CCR7 and CXCR3 in 65 and 90% cases, respectively, most of which had lymph node metastasis. Importantly, the expression of CCR7 was significantly associated with lymph node metastasis, although the expression of CXCR3 was not. These results suggest that the activation of CCR7 and CXCR3 with their ligands preferentially stimulates lung adenocarcinoma metastasis to the draining lymph nodes.

Sonodynamic therapy of cancer using novel sonosensitizers.

Sonodynamic therapy (SDT) of cancer is based on preferential uptake and/or retention of a sonosensitizing drug (sonosensitizer) in tumor tissues and subsequent activation of the drug by ultrasound irradiation. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer. This is a unique advantage in the non-invasive treatment of nonsuperficial tumors when compared to laser light used for photodynamic therapy. Recently, it has been found that photochemically active porphyrins also show significant antitumor effects when activated with ultrasound. The mechanism of sonodynamic action has been suggested to involve photoexcitation of the sensitizer by sonoluminescent light, with subsequent formation of singlet oxygen. This mini-review provides a brief overview of the following four sonosensitizers useful in SDT: i) a homogeneous complex of oligomers of hematoporphyrin, Photofrin II; ii) a gallium porphyrin complex, ATX-70; iii) a hydrophilic chlorin derivative, A7X-S10, and iv) a novel porphyrin derivative devoid of photosensitivity, DCPH-P-Na (I).

Comprehensive Identification of Krüppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming.

Pluripotency is maintained in mouse embryonic stem (ES) cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Krüppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF)-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naïve pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.

Metachronous bilateral pulmonary metastases from cancer of the ampulla duodeni.

We present a 76-year-old man who underwent two lung resections for metastases originating from cancer of the Ampulla duodeni, 9 years-after pancreaticoduodenectomy with lymphadenectomy. Pancreaticoduodenectomy was performed in 2002; histological examination of the original tumor revealed a stage III tubular adenocarcinoma (pT3, N0, M0). Repetitive lung resection was performed in 2007 (left S8) and 2011 (right S1 and extirpation of a pericardial cyst). Although rarely performed, resection of bilateral pulmonary metastases from carcinoma of the papilla of Vater was done to improve the patient's chances for longterm survival.