Development and basic performance verification of a rapid homogeneous bioassay for agonistic antibodies against the thyroid-stimulating hormone receptor.

Graves' disease is a type of autoimmune hyperthyroidism caused by thyroid-stimulating antibodies (TSAb).1 The combination of a porcine thyroid cell bioassay and cyclic adenosine monophosphate (cAMP) immunoassay (TSAb-enzyme immunoassay; EIA) is a clinically approved TSAb measurement method. Due to the requirement of multiple procedures and a long assay time of 6 h in the TSAb-EIA, a simplified and rapid assay is desired. Herein, we developed a rapid homogeneous TSAb bioassay (rapid-TSAb assay) using the human embryonic kidney cell line (HEK293), engineered to express the human thyroid-stimulating hormone receptor (TSHR), along with a cAMP-dependent luminescence biosensor. The measurement consists of three steps: thawing frozen cells, blood sample addition, and luminescence detection. The procedures can be conducted within 1 h. The World Health Organization International Standard TSAb (NIBSC 08/204) stimulated the cells co-expressing TSHR and cAMP biosensor. The intra- and inter-assay coefficients of variance were < 10%. Stimulation activity using wild-type TSHR and chimeric TSHR (Mc4) almost completely correlated with the tested Graves' disease and normal samples. In the rapid-TSAb assay, the evaluation of 39 samples, including TSHR antibody-positive sera, yielded a sensitivity of 100.0% and a specificity of 90.9%, compared to the TSAb-EIA control. The rapid-TSAb assay enables simple and rapid measurement of TSAb and is promising for improving the diagnosis of autoimmune thyroid diseases.

Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities.

Glioblastoma is the most common brain tumor, with high recurrence and low survival rates. An integrative bioinformatics analysis demonstrated that anaplastic lymphoma kinase (ALK) is a promising therapeutic target for glioblastoma. We designed and synthesized a series of 3-(arylmethylene)indole derivatives, which were further evaluated for antiproliferative activity using glioma cell lines. Among them, compound 4a significantly inhibited the viability of glioblastoma cells. With favorable pharmacokinetic characteristics and blood-brain barrier permeability, 4a improved the survival rate and inhibited the growth of orthotopic glioblastoma. The Phospho-Totum system revealed that ALK was a potential target for the antiglioblastoma activity of 4a. Further experiments indicated that 4a might be a novel ALK modulator, which interacted with the extracellular ligand-binding domain of ALK, thus selectively induced ERK-mediated autophagy and apoptosis. Our findings provide an alternative ALK-based targeting strategy and a new drug candidate for glioblastoma therapy.

Prognostic Impact of Prehospital Simple Risk Index in Patients With ST-Elevation Myocardial Infarction.

BACKGROUND: The simple risk index recorded in the emergency room (ER-SRI), which is calculated using the formula (heart rate × [age / 10]2) / systolic blood pressure, was shown to be able to stratify the prognosis in ST-elevation myocardial infarction (STEMI) patients. However, the prognostic impact of the prehospital simple risk index (Pre-SRI) remains unknown.Methods and Results: This study enrolled 2,047 STEMI patients from the Mie Acute Coronary Syndrome (ACS) registry. Pre-SRI was calculated using prehospital data and ER-SRI was calculated using emergency room data. The primary endpoint was 30-day all-cause mortality. The cut-off values of Pre-SRI and ER-SRI for predicting 30-day mortality were 34.8 and 34.1, with accuracies of 0.816 and 0.826 based on receiver operating characteristic analyses (P<0.001 for both). There was no difference in the accuracy of the 2 indices. Multivariate Cox regression analysis demonstrated that a High Pre-SRI (≥34) was a significant independent predictor of 30-day mortality. With combined Pre-SRI and ER-SRI assessment, patients with High Pre-SRI/High ER-SRI showed significantly higher mortality than those with High Pre-SRI/Low ER-SRI, Low Pre-SRI/High ER-SRI, and Low Pre-SRI/Low ER-SRI (P<0.001). The addition of High Pre-SRI to High ER-SRI showed incremental prognostic value of the Pre-SRI. CONCLUSIONS: Pre-SRI can identify high-risk STEMI patients at an early stage and combined assessment with Pre-SRI and ER-SRI could be of incremental prognostic value for risk stratification in STEMI patients.

Surgical Laparotomy for Repeated Delayed Arterial Hemorrhage after Pancreaticoduodenectomy.

Postpancreatectomy hemorrhage is one of the major life-threatening complications of pancreatic surgery. Radiological intervention is used as a first-line approach for the initial treatment of late arterial hemorrhage. However, rehemorrhage has a high risk for mortality, and it is undecided which urgent intervention provides optimal management for rehemorrhage. We experienced a successful surgical laparotomy for the repeated delayed arterial hemorrhage caused by a pancreaticoduodenectomy (PD) for chronic pancreatitis. A 57-year-old man had undergone PD with pancreaticogastrostomy for tumor-forming pancreatitis with possible pancreatic cancer. A delayed massive hemorrhage from the drain developed 11 days after surgery. Although angiography was done, the bleeding site was not clearly detected. Therefore, urgent surgical laparotomy was performed. Arterial bleeding was detected from the stump of the gastroduodenal artery. Surgical ligation, using the suture technique, was performed for hemostasis, and a closed drain was placed in the area due to drainage of pancreatic juice and an abscess. However, rehemorrhage from the drain developed 7 days after the initial hemorrhage. Relaparotomy was performed immediately. The surgical ligation and compression hemostasis with absorbable hemostatic cotton was done. After relaparotomy for rehemorrhage, there was no hemorrhage or fatal hepatic failure. He left our hospital 64 days after initial surgery. Surgical laparotomy is one of the feasible procedures for hemostasis of a massive arterial hemorrhage. Proper blood vessel ligation is necessary for reliable hemostasis and proper drainage of pancreatic juice and abscesses to prevent hemorrhage.

Phosphorescent ruthenium complexes with a nitroimidazole unit that image oxygen fluctuation in tumor tissue.

Understanding oxygen fluctuation in a cancerous tumor is important for effective treatment, especially during radiotherapy. In this paper, ruthenium complexes bearing a nitroimidazole group are shown to report the oxygen status in tumor tissue directly. The nitroimidazole group was known to be accumulated in hypoxic tumor tissues. On the other hand, the ruthenium complex showed strong phosphorescence around 600 nm. The emission of ruthenium is quenched instantaneously by molecular oxygen due to energy transfer between triplet states of oxygen and ruthenium complex, but the emission is then recovered by the removal of oxygen. Thus, we could observe oxygen fluctuation in tumor tissue in a real-time manner by monitoring the phosphorescence of the ruthenium complex. The versatility of the probe is demonstrated by monitoring oxygen fluctuation in living cells and tumor tissue planted in mice. The ruthenium complex promptly penetrated plasma membrane and accumulated in cells to emit its oxygen-dependent phosphorescence. In vivo experiments revealed that the oxygen level in tumor tissue seems to fluctuate at the sub-minute timescale.

Glasgow prognostic score is a useful predictive factor of outcome after palliative gastrectomy for stage IV gastric cancer.

BACKGROUND/AIM: The Glasgow prognostic score (GPS) is a predictor of outcome for several cancer types. The present study examined the significance of modified GPS (mGPS) in the prognosis of patients undergoing palliative surgery for stage IV gastric cancer. PATIENTS AND METHODS: A total of 42 patients with stage IV gastric cancer treated with palliative gastrectomy and gastrojejunostomy were included in the study. Univariate and multivariate analyses were performed to evaluate the relationship between clinicopathological factors and cancer-specific survival (CS). RESULTS: Among patients who underwent palliative surgery including gastrectomy and gastrojejunostomy, univariate analysis of CS identified the following significant risk factors: surgical treatment, chemotherapy and mGPS, and multivariate analysis revealed that mGPS was independently-associated with CS. In particular, among patients who underwent palliative gastrectomy, mGPS was shown to be the strongest independent predictive factor for CS. CONCLUSION: The mGPS was an independent predictive factor for survival in patients who underwent palliative surgery for stage IV incurable gastric cancer, especially for those who underwent palliative gastrectomy.

Simultaneous laparoscopic Nissen fundoplication and percutaneous endoscopic gastrostomy to treat an elderly patient with a large paraesophageal hernia: a case report.

Laparoscopic Nissen fundoplication (LNF) and gastrostomy are often performed in children with gastroesophageal reflux disease. With a population that is increasingly aging, the number of elderly patients with paraesophageal hernia who have a nutritional disorder due to dysphagia has increased. In these patients with feeding difficulties, LNF and percutaneous endoscopic gastrostomy (PEG) are effective procedures for providing nutritional support. Here, we describe the case of an 82-year-old woman with paraesophageal hernia and certain comorbidities. She was receiving enteral feeding through a nasogastric tube, which was discontinued because aspiration pneumonia occurred. Therefore, LNF and crural repair without mesh placement were performed. The PEG tube was placed using the Ponsky pull technique under direct visualization with a laparoscope and gastroscope. The patient's nutritional status improved after she received enteral nutrition through the PEG tube. Thus, LNF and PEG may be useful techniques for nutritional support in elderly patients with a large paraesophageal hernia.

Gastric Cancer Arising from an Upside-Down Stomach through a Paraesophageal Hiatal Hernia.

We report the rare case of an elderly patient with an advanced gastric cancer arising from an upside-down stomach through a paraesophageal hiatal hernia (PEH). An 82-year-old man presented with appetite loss and anemia. Upper gastrointestinal endoscopy revealed a type 1 tumor located in the middle body of the stomach. An upper gastrointestinal series and computed tomography showed organoaxial rotation of the stomach, which was located in the mediastinum, through a PEH, indicating an upside-down stomach. The preoperative diagnosis was gastric cancer arising from an upside-down stomach through a PEH. The patient underwent total gastrectomy with lymph node dissection and closure of the hernial orifice. Although a large PEH is a chronic disorder, gastric malignancies should be considered in patients with PEH manifested as an upside-down stomach due to its anatomical characteristics, and careful preoperative diagnosis is mandatory.

Chemotherapy for liver metastasis originating from colorectal cancer with portal vein tumor thrombosis: a case report.

The patient was a male in his 70s with a history of chronic renal failure and dilated cardiomyopathy. In January 2011, he underwent abdominoperineal resection of the rectum, right hepatic lobectomy, and resection of a portal vein tumor thrombus with a diagnosis of rectal cancer and metastatic liver cancer accompanied by portal vein tumor thrombosis. Although 5-fluorouracil + l-leucovorin therapy (RPMI regimen) was carried out as postoperative adjuvant chemotherapy, the tumor marker (CEA and VA19-9) levels increased 8 months after surgery. Since the functions of major organs were impaired, UFT(®) + UZEL(®) therapy was started. The tumor marker levels decreased temporarily, but increased again 12 months after surgery, and so intravenous instillation of panitumumab was initiated. Nine administrations have been performed to date, with no increase in tumor marker levels or exacerbation of the condition. Also, no grade 2 or severer adverse event has been noted according to CTCAE v.4.0. The experience with this patient suggests the possibility that exacerbation of the condition of patients with liver metastasis of colorectal cancer accompanied by portal vein tumor thrombosis with abnormalities in the functions of major organs can be controlled temporarily by the administration of panitumumab alone.

Killian-jamieson diverticula presenting synchronously with thyroid adenoma.

Killian-Jamieson diverticulum is a rare hypopharyngeal diverticulum, less commonly encountered compared with Zenker's diverticulum. These hypopharyngeal diverticula that cause dysphagia often mimic a thyroid tumor incidentally detected on neck ultrasonography. However, to our knowledge, Killian-Jamieson diverticula complicated by a thyroid tumor have not been previously described. We experienced a rare case of bilateral Killian-Jamieson diverticula synchronously complicated by a thyroid adenoma in a 74-year-old woman who became aware of dysphagia and a tumor in the left side of her neck. Pharyngoesophagography revealed bilateral diverticula protruding from the lateral wall of the esophagopharyngeal junction, but the appearance of the cricopharyngeal bar representing the cricopharyngeus muscle above the diverticula had become unclear because the thyroid tumor was pressing on the diverticula and the cervical esophagus. However, the diverticula were diagnosed as Killian-Jamieson diverticula because cervical computed tomography showed bilateral diverticula arising from the cervical esophagus just below the level of the cricoid cartilage, and operative finding showed that the diverticula were located above the upper esophageal longitudinal muscle. Radiographic imaging is useful for diagnosis as cause of dysphagia and cervical tumor.

Delayed gastric emptying after pancreaticoduodenectomy in diabetes mellitus.

INTRODUCTION: Delayed gastric emptying (DGE) is one of the most troublesome complications of pancreaticoduodenectomy (PD). Diabetes mellitus (DM) is one of the risk factors for pancreatic cancer. Moreover, several studies have shown that diabetic patients tend to have a high incidence of upper gastrointestinal symptoms such as nausea, vomiting and DGE. Here, we compared the influence of DM on the incidence of DGE after PD. METHODS: We retrospectively analysed 67 cases of PD with pancreaticogastrostomy. These patients were categorized into the following two groups: the DM group included patients with DM, and the NDM group included patients without DM. The incidence of DGE was determined and compared between the two groups. RESULTS: In the DM group, 76.5%, 5.9% and 17.6% of the subjects developed classes A, B and C DGE, respectively; the corresponding values in the NDM group were 58%, 22%, and 20%. The incidence of DGE did not differ between the two groups (P < 0.2771). CONCLUSIONS: DM does not accelerate DGE in patients who have undergone PD. Preoperative DM does not appear to play a key role in post-operative DGE after PD.

Diffuse Peritonitis due to Perforated Gastric Ectopic Pancreas.

Ectopic pancreas is frequently found in the gastrointestinal tract. Lesions comprise well-developed and normally organized pancreatic tissue outside the pancreas, without anatomic or vascular connections with the true pancreas. Most patients with ectopic pancreas are asymptomatic or exhibit nonspecific symptoms. A 68-year-old Japanese woman had been experiencing intermittent pain in the right upper abdomen. Suddenly, the abdominal pain changed to intense pain in the right flank of the abdomen 2 days later. On initial medical examination, the abdomen exhibited rebound tenderness and distension. The results of laboratory tests revealed increased inflammatory reaction. Abdominal computed tomography showed free air and ascites on the surface of the liver and elevated levels of adipose tissue around the antrum and pylorus of the stomach. Perforation of the upper gastrointestinal tract was diagnosed and we performed urgent surgery. The site of perforation, whose size was 25 mm, was the lesser curvature of the antrum of the stomach. Since it was not possible to perform omentopexy, we performed extensive gastric resection. The reconstruction was a Billroth II operation. Microscopic analysis revealed pancreatic tissue within the ulceration, showing islets of Langerhans, acini, and ducts; the lesion was diagnosed as type I using Heinrich's criteria. The postoperative course was uneventful. The patient was discharged on day 13 and remains clinically healthy. Gastric perforation due to ectopic pancreas has been reported in 2 cases, including our patient, and is extremely rare. Once gastric perforation has been diagnosed, the presence of ectopic pancreas might be considered.

Minimal incision based on measurement of the to-be-resected specimen in laparoscopic hepatectomy.

Recent technological improvements in laparoscopic devices have significantly extended the surgeon's ability to perform laparoscopic liver surgery safely. Hand-assisted laparoscopy has been proposed in order to achieve greater safety and accessibility in laparoscopic liver surgery. Moreover, in order to expand the indications of minimally invasive liver resection and improve its safety, the "hybrid procedure" or "laparoscopy-assisted resection" has been proposed. Hand-assisted laparoscopic liver resection consists of the placement of a gas-tight port through an 8cm incision that enables a hand to be introduced into the abdomen. The "hybrid procedure" is performed through an 8-12cm midline or subcostal incision. Such a minimal abdominal incision is preferred not only for cosmetic reasons but also for obtaining adequate surgical margin. We performed laparoscopic liver resection via a minimal incision that was based on the measurement of the to-be-resected specimen intraoperatively by ultrasonography. Here, we have described our procedure and evaluated its efficacy.

Horizontal vs. vertical incision on the anterior gastric wall in pancreaticogastrostomy.

BACKGROUND/AIMS: Pancreaticogastrostomy during pancreaticoduodenectomy is associated with a very low rate of anastomotic leakage. However, gastric peristalsis is disturbed by pancreaticogastrostomy, which stabilizes the posterior stomach at that point leading to delayed gastric emptying. We evaluated which anterior gastrostomy, i.e. horizontal or vertical incision on the anterior gastric wall, is better for maintaining peristaltic movement of the anterior stomach to prevent delayed gastric emptying after pancreaticogastrostomy. METHODOLOGY: We retrospectively studied 50 patients who underwent subtotal stomach-preserving pancreaticoduodenectomy with pancreaticogastrostomy. These patients were divided into 2 groups depending on the type of anterior gastrostomy: horizontal incision (H group) and vertical incision (V group). RESULTS: The observed grade of delayed gastric emptying was lower in the V group than in the H group; however, the difference was not significant. CONCLUSIONS: We conclude that a vertical incision on the anterior gastric wall is preferable for preventing delayed gastric emptying after a pancreaticogastrostomy.

[A case of intussusception due to sigmoid colon cancer during mFOLFOX6 therapy].

We experienced a rare case of intussusception due to sigmoid colon cancer during chemotherapy. A-62-year-old female was started on mFOLFOX6 due to sigmoid colon cancer and hepatic metastases(stage IV). After 2 courses, she had abdominal pain and bloody stool. Abdominal ultrasonography showed a target sign, and abdominal CT showed edema of the mucosa of the sigmoid colon and invagination. She was diagnosed with intussusception due to sigmoid colon cancer, and underwent a bloodless reduction. However, because it was unavailable, we performed an emergency operation. The sigmoid colon invaginated 10 cm to the anal side. We then performed sigmoidectomy and lymphadenectomy(D2). The histopathological diagnosis was mucinous carcinoma, stage I. There was no report of intussusception with the chemotherapy. It is important to consider the intussusception of colon cancer even during chemotherapy.

Jejunal scarf-covering method in pancreaticojejunostomy after total gastrectomy.

Pancreatic fistula is the most serious postoperative complication after pancreaticoduodenectomy, and it leads to intra-abdominal abscess, sepsis, hemorrhage and high mortality. To prevent pancreatic fistula, wrapping of skeletonized vessels and the anastomotic site of the pancreaticoenterostomy using the round ligament, greater omentum, or both has been evaluated. However, the round ligament and greater omentum have already been resected in patients who have previously undergone total gastrectomy, making them unavailable in pancreaticoduodenectomy. Therefore, we developed a procedure for wrapping the anastomotic site of the pancreaticojejunostomy using the jejunum, namely the 'jejunal scarf-covering method' as a novel technique to prevent pancreatic fistula following pancreaticoduodenectomy in patients who have previously undergone total gastrectomy.

Anterior vs. posterior mediastinal routes in colon interposition after esophagectomy.

BACKGROUND/AIMS: Colon interposition is the most commonly used method of esophageal reconstruction when the stomach cannot be used; however, this method may cause surgical complications such as anastomotic leakage and sepsis due to colon necrosis. Therefore, many surgeons use a retrosternal or subcutaneous route because it is easier to manage the subcutaneous drainage when anastomotic leakage occurs. However, some researchers have reported that the posterior mediastinal route provides better long-term functional outcomes after surgery than the anterior mediastinal route. Thus, in this study, we compared these reconstruction routes used for colon interposition, with or without the supercharge technique, in patients with a history of distal gastrectomy, who have undergone colon interposition after esophagectomy. METHODOLOGY: We retrospectively studied 30 patients who underwent esophagectomy with colon interposition. These patients were divided into 2 groups based on the reconstruction route: the anterior mediastinal or subcutaneous route (A group), or the posterior mediastinal route (R group). RESULTS: Anastomotic leakages were observed in 4 patients (26.7%) in the A group and in 1 patient (6.7%) in the R group. CONCLUSIONS: Ischemia is not always the result of arterial failure, but may also originate from venous blood flow impairment due to injury or distortion of veins.

Spleen enlargement after distal gastrectomy in patients without hepatitis.

BACKGROUND/AIMS: Platelet count-to-spleen diameter ratio is reported to be the best non-invasive predictor of esophageal varices in cirrhotic patients. However, spleen enlargement is frequently detected during follow-up of patients after gastrectomy. Thus, we studied the relationship of the platelet count-to-spleen diameter ratio with the development of esophageal varices after distal gastrectomy in patients without liver cirrhosis or hepatitis. METHODOLOGY: We retrospectively studied 64 patients who underwent distal gastrectomy. Their platelet counts, spleen diameters and platelet count-to-spleen diameter ratios were correlated with the occurrence rate of esophageal varices after the surgery. RESULTS: Esophageal varices were not detected during the first 6 months after surgery; however, esophageal varices were detected in 2 patients (3%) at 12 months after surgery and their mean platelet count-to-spleen diameter ratio was 2,628 ± 409. CONCLUSIONS: The platelet count-to-spleen diameter ratio is a useful parameter for non-invasive prediction of esophageal varices after distal gastrectomy. In addition, we suggest that the occurrence rate of esophageal varices increases beyond 6 months after distal gastrectomy and when the platelet count-to-spleen diameter ratio is less than approximately 2600 and thus, endoscopy should be performed to determine the presence of esophageal varices.

Hand-assisted laparoscopic hepatectomy for primary clear cell hepatocellular carcinoma of the liver.

We report a case of primary clear cell hepatocellular carcinoma of the liver (PCCCL) for which we performed hand-assisted laparoscopic hepatectomy. A 71-year-old female with hepatitis C infection and diabetes mellitus was admitted to our department for a hepatic tumor with gallstone. Abdominal computed tomography revealed a tumor 25 mm in diameter on the surface in segment 5 of the liver. The imaging results suggested small hepatocellular carcinoma located on the surface in segment 5 of the liver, and we performed laparoscopic surgery aiming at a minimally invasive procedure. We performed laparoscopic cholecystectomy and hand-assisted laparoscopic hepatectomy. Histopathological findings showed moderately differentiated hepatocellular carcinoma, and as the proportion of clear cells was 75%, the tumor was diagnosed as PCCCL. This is the first report of hand-assisted laparoscopic hepatectomy for PCCCL. Laparoscopic hepatectomy is a useful minimally invasive surgical procedure when the tumor is located on the surface of the liver.

Cholecystitis or cholestasis after total gastrectomy and esophagectomy.

BACKGROUND/AIMS: Increased incidences of gallbladder disorders after esophagectomy and gastrectomy have been reported. Moreover, several researchers have reported increased incidences of gallbladder diseases in patients receiving long-term total parenteral nutrition. We studied the incidence of cholecystitis or cholestasis and determined its relationship with total parenteral nutrition; further, we compared the incidence after esophagectomy and after total gastrectomy. METHODOLOGY: We retrospectively studied 109 patients who underwent total gastrectomy or esophagectomy. These patients were divided into 2 groups, those who underwent total gastrectomy (TG group) and those who underwent esophagectomy (E group). RESULTS: The 2 groups did not significantly differ with respect to the mean duration of perioperative administration of total parenteral nutrition and the incidence rate of cholecystitis or cholestasis after esophagectomy. CONCLUSIONS: Postoperative hyperbilirubinemia after esophagectomy may not contribute to the development of gallbladder complications. We suggest that parenteral modalities such as tube feeding be initiated immediately after surgery for preventing gallbladder complications after esophagectomy. Further, a short duration of administration of total parenteral nutrition and immediate postoperative initiation of oral feeding may prevent gallbladder complications after esophagectomy and total gastrectomy.