The State Scientific Automated Medical Registry, Kazakhstan: an important resource for low-dose radiation health research.

Direct quantitative assessment of health risks following exposure to ionizing radiation is based on findings from epidemiological studies. Populations affected by nuclear bomb testing are among those that allow such assessment. The population living around the former Soviet Union's Semipalatinsk nuclear test site is one of the largest human cohorts exposed to radiation from nuclear weapons tests. Following research that started in the 1960s, a registry that contains information on more than 300,000 individuals residing in the areas neighboring to the test site was established. Four nuclear weapons tests, conducted from 1949 to 1956, resulted in non-negligible radiation exposures to the public, corresponding up to approximately 300 mGy external dose. The registry contains relevant information about those who lived at the time of the testing as well as about their offspring, including biological material. An international group of scientists worked together within the research project SEMI-NUC funded by the European Union, and concluded that the registry provides a novel, mostly unexplored, and valuable resource for the assessment of the population risks associated with environmental radiation exposure. Suggestions for future studies and pathways on how to use the best dose assessment strategies have also been described in the project. Moreover, the registry could be used for research on other relevant public health topics.

Feasibility of endoscopic mucosal resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage IB, II, and III esophageal squamous cell cancer.

Local failure after definitive chemoradiotherapy (CRT) for stage IB, II, and III esophageal cancer is one of the causes of poor outcome. Endoscopic mucosal resection (EMR) is an effective treatment for superficial esophageal cancer. However, its feasibility as a salvage treatment for local recurrent or residual tumors after definitive CRT for stage IB, II, and III esophageal cancer remains unclear. Between January 2000 and February 2008, 274 patients with stage IB, II, and III esophageal squamous cell cancer excluding T4 received definitive CRT at the National Cancer Center Hospital, Japan. Of these patients, nine patients with local recurrence after achieving complete response and two patients with residual tumor underwent salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively reviewed the 11 patients (13 lesions). Characteristics of all 11 patients were as follows: median age of 69 (range: 45-78); male/female: 10/1; baseline clinical stage (Union for International Cancer Control 7th) IB/IIA/IIB/III: 1/3/7/0. The depth of resected tumor was limited to the mucosal layer in seven lesions and submucosal in six lesions. En bloc resection was performed on six lesions (46%). The vertical margin was free of cancer cells in 11 lesions (84.6%). No major complications, such as hemorrhage requiring blood transfusion and perforation, were experienced. At a median follow-up period of 38.9 months (range: 5.3-94 months) after salvage EMR, no recurrence was detected in six patients (54%). Local recurrence was detected in five patients (27%). Of these patients, two had lung metastasis simultaneously, and one was also detected lung metastasis 2 months after the detection of local recurrence. The 5-year survival rate after salvage EMR was 41.6%. Salvage EMR is a feasible treatment option for local recurrent or residual lesions after definitive chemotherapy and/or radiotherapy for stage IB, II, and III esophageal squamous cell cancer.

Is endoscopic submucosal dissection an effective treatment for operable patients with clinical submucosal invasive early gastric cancer?

BACKGROUND AND STUDY AIMS: Gastrectomy with lymph node dissection is the gold standard curative treatment for clinical submucosal invasive early gastric cancer (cSM EGC), but a relatively small number of operable patients with cSM EGC have undergone endoscopic submucosal dissection (ESD) instead because they refused surgery. The aim of this study was to determine the effectiveness of ESD in these operable patients. METHODS: The therapeutic outcomes of ESD were retrospectively assessed for 38 patients with 38 operable cSM EGC lesions who initially refused surgery at the National Cancer Center Hospital, Tokyo, from January 1999 to December 2008. RESULTS: The en bloc resection rate was 84.2% (32 lesions) and the complete (R0) resection rate was 63.2% (24 lesions). A total of 33 lesions (86.8%) involved submucosal invasion on pathology. Resection was non-curative in 34 patients (89.5%), 22 of whom (64.7%) underwent subsequent gastrectomy after the need for such surgery was carefully explained to them again. The median follow-up period was 73.2 months (range 3-115 months). Local recurrence was detected in one patient, distant metastasis in two patients, and both local recurrence and distant metastasis were detected in one patient. None of these four patients with recurrence (10.5%) had undergone surgery when their recurrent disease was detected and all of them died from gastric cancer. The 5-year cause-specific survival rate for all patients was 91.8%. CONCLUSION: The 5-year cause-specific survival rate for all patients was lower than the previously reported rate of 96.7% for pathologically submucosal invasive EGC patients after gastrectomy; therefore, ESD appears to have been an ineffective treatment for operable patients with cSM EGC.

Differential diagnosis of cystic tumors of the pancreas by endoscopic ultrasonography.

BACKGROUND AND STUDY AIMS: Generally, cystic tumors are divided into two categories: neoplastic cystic tumors and non-neoplastic cystic (NNC) tumors. Neoplastic cystic tumors include mucinous cystic neoplasm (MCN), intraductal papillary-mucinous neoplasm (IPMN), and serous cystic neoplasm (SCN). MCNs and IPMNs have the potential to progress to a malignant state, whereas SCNs are known for their almost benign behavior. Thus, in order to make management decisions, it is important to distinguish between potentially malignant (MCN and IPMN), and benign (SCN and NNC) tumors. The aim of this study was to retrospectively investigate the value of endoscopic ultrasonography (EUS) for the differential diagnosis of cystic tumors of the pancreas. PATIENTS AND METHODS: A total of 76 patients with cystic tumors of the pancreas were preoperatively examined by EUS. Eight cases were MCNs, 45 were IPMNs, 13 were SCNs, and 10 were NNC tumors. The EUS findings relevant to distinguishing between potentially malignant and benign were analyzed statistically. RESULTS: All patients with MCNs were female and all these tumors were located in the pancreatic body/tail. IPMN, however, occurred predominantly in men, and in the pancreatic head. Eight of 11 monolocular cystic tumors were NNC in nature. Eleven of 13 SCNs included microcystic areas within the tumors. All MCNs were round in appearance, whereas 93 % of IPMNs were not round in appearance. Mural nodules were present in 25 % of MCN and 38 % of IPMN cases. In univariate analysis, age, tumor size, locularity, the number of cystic formation, cystic component, and appearance were significant variables. In multivariate analysis, locularity and cystic component were important for differential diagnosis of potentially malignant cystic tumors. CONCLUSIONS: The characteristics of cystic tumors of the pancreas revealed by EUS are useful for their differential diagnosis.

Impact of double-balloon endoscopy on the diagnosis of jejunoileal involvement in primary intestinal follicular lymphomas: a case series.

In recent years, primary gastrointestinal follicular lymphoma has been increasingly detected in the duodenum on esophagogastroduodenoscopy (EGD). Primary gastrointestinal follicular lymphomas are frequently distributed to multiple sites in the gastrointestinal tract. Therefore, investigation into the spread of follicular lymphomas in the small bowel is important in order to determine the most appropriate treatment strategy. The performance of double-balloon endoscopy (DBE) in the diagnosis of jejunoileal follicular lymphoma lesions has not been fully evaluated. We aimed to investigate the value of DBE in addition to computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the diagnosis of jejunoileal follicular lymphoma. DBE with biopsy was performed in seven patients with primary duodenal follicular lymphoma diagnosed by EGD, in order to investigate jejunoileal involvement. Jejunoileal follicular lymphoma lesions were detected by DBE in six out of the seven patients (three in the jejunum and three in the jejunum and ileum), whereas CT and (18)F-FDG-PET failed to detect the existence of these lesions. Endoscopic findings of the jejunoileal lesions revealed multiple white nodules and white villi, which were similar to those of duodenal lesions. DBE was more useful for the diagnosis of jejunoileal involvement in primary intestinal follicular lymphoma than CT and (18)F-FDG-PET. The use of DBE will become important for determining the most appropriate treatment for gastrointestinal follicular lymphoma.

An increase in the serum amylase level in patients after peroral double-balloon enteroscopy: an association with the development of pancreatitis.

BACKGROUND AND STUDY AIMS: Double-balloon enteroscopy (DBE) is a novel technique that allows the enteroscope to be inserted deep into the small intestine. The procedure has been thought to be safe, but cases of acute pancreatitis after peroral DBE have recently been observed. The aim of this study was to confirm the occurrence of hyperamylasemia after peroral DBE. PATIENTS AND METHODS: Peroral DBE was carried out in 13 patients from July 2005 to February 2006. Blood samples were taken before and 3 h after the procedure, and serum pancreatic amylase levels were measured. The patients were also evaluated for pancreatic-type abdominal pain after the procedure. Hyperamylasemia after peroral DBE was defined as an elevation of the serum pancreatic amylase level to more than the upper normal limit and twice the level before the procedure. Pancreatitis was diagnosed on the basis of both pancreatic-type abdominal pain and hyperamylasemia. RESULTS: Hyperamylasemia after peroral DBE occurred in six patients (46.2 %). One of the six patients with hyperamylasemia had pancreatic-type abdominal pain after the procedure and developed acute pancreatitis. The average procedure time was 105 min (range 65 - 155 min) in the patients with hyperamylasemia, and did not significantly differ from that in the group without hyperamylasemia (99 min). CONCLUSIONS: Hyperamylasemia after peroral DBE occurs frequently and may be associated with development of pancreatitis.

The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization.

B7-H3, a member of the B7 family of the Ig superfamily proteins, is expressed on the surface of the antigen-presenting cells and down-regulates T cell functions by engaging an unknown counterreceptor on T cells. Although B7-H3 is ubiquitously expressed, its potential nonimmune functions have not been addressed. We found that B7-H3 is highly expressed in developing bones during embryogenesis and that its expression increases as osteoblast precursor cells differentiate into mature osteoblasts. In vitro bone formation by osteoblastic cells was inhibited when B7-H3 function was interrupted by the soluble recombinant protein B7-H3-Fc. Analysis of calvarial cells derived from neonatal B7-H3 knockout (KO) mice revealed normal numbers of osteoblast precursor cells possessing a normal proliferative capacity. However, the B7-H3-deficient calvarial cells exhibited impaired osteogenic differentiation, resulting in decreased mineralized bone formation in vitro. These results suggest that B7-H3 is required for the later phase of osteoblast differentiation. Although B7-H3 KO mice had no gross skeletal abnormalities, they displayed a lower bone mineral density in cortical (but not trabecular) bones compared with WT controls. Consistent with the reduced bone mineral density, the femurs of B7-H3 KO mice were more susceptible to bone fracture compared with those of WT mice. Taken together, these results indicate that B7-H3 and its unknown counterreceptor play a positive regulatory role in bone formation. In addition, our findings identified B7-H3 as another molecule that has a dual role in the bone-immune interface.

Genetic susceptibility to thymic lymphomas and K-ras gene mutation in mice after exposure to X-rays and N-ethyl-N-nitrosourea.

PURPOSE: Ras activation is one of the major mechanisms for the development of murine thymic lymphomas by radiation and chemical carcinogens. To gain insight into the relationship between genetic susceptibility and ras gene mutation, the frequency and spectrum of ras gene mutation was examined in thymic lymphomas from susceptible and resistant mice. MATERIALS AND METHODS: K- and N-ras mutations in thymic lymphomas that arose in X-ray-irradiated and N-ethyl-N-nitrosourea (ENU)-treated mice of susceptible C57BL/6, rather resistant C3H and their hybrid B6C3F1 were analysed by polymerase chain reaction-single-strand conformation polymorphism and subsequent DNA sequencing. RESULTS: C57BL/6 exhibited a higher incidence of thymic lymphomas after exposure to X-rays and ENU than C3H, with B6C3F1 being intermediate. K-ras gene mutations occurred frequently in the pathogenesis of ENU-induced thymic lymphomas in susceptible C57BL/6 as opposed to resistant C3H. The ras mutations were more frequent in ENU-induced thymic lymphomas than X-ray-induced thymic lymphomas, and with the latter, there was no clear evidence for strain differences, suggesting that the genetic susceptibility to X-rays was independent of ras activation. The mutations of K-ras in thymic lymphomas from C57BL/6 were predominantly GGT to GAT in codon 12, whereas this mutation type was never found in those from C3H. No strain difference was observed in the nucleotide sequence or expression levels of O(6)-alkylguanine alkyltransferase, indicating that this enzyme did not account for the genetic susceptibility to ras activation. CONCLUSIONS: The results indicate that there is a clear strain and carcinogen dependency of K-ras mutation and that the frequency of ras mutation might determine the genetic susceptibility to ENU-induced lymphomagenesis, whereas pathways independent of ras activation might determine the susceptibility to X-ray-induced lymphomagenesis.

Transit endoscopic ultrasound of colorectal cancer using a 12 MHz catheter probe.

The objective of this study was to examine the accuracy of a 12 MHz ultrasound catheter probe in the pre-operative staging of colorectal cancer by assessing the depth of tumour infiltration and involvement of pericolonic lymph nodes. 159 patients with colorectal cancer who underwent ultrasound examination with a 12 MHz catheter probe were studied prospectively. The results of this imaging procedure were compared with the histological findings of the resected specimens. The accuracy of the 12 MHz ultrasound catheter probe for depth of invasion (T category) was 85% (131/154) for all tumours, 87% (46/53) for pT1 tumours, 60% (9/15) for pT2 tumours, 89% (74/83) for pT3 tumours and 67% (2/3) for pT4 tumours. The accuracy for tumours of the rectum and colon was 81% and 89%, respectively. The accuracy of the probe for nodal staging (N category) was 67% (76/114) overall. The sensitivity was 70% (33/47), the specificity 64% (43/67), the positive predictive value 58% (33/57) and the negative predictive value 75% (43/57). Endoscopic ultrasound using a 12 MHz catheter probe accurately assessed tumour stage, although nodal staging remained suboptimal. This method may aid in the selection of treatment for patients with colorectal cancer.

ICOS is essential for effective T-helper-cell responses.

The outcome of T-cell responses after T-cell encounter with specific antigens is modulated by co-stimulatory signals, which are required for both lymphocyte activation and development of adaptive immunity. ICOS, an inducible co-stimulator with homology to CD28, is expressed on activated, but not resting T cells, and shows T-cell co-stimulatory function in vitro. ICOS binds specifically to its counter-receptor B7RP-1 (refs 5,6,7), but not to B7-1 or B7-2. Here we provide in vivo genetic evidence that ICOS delivers a co-stimulatory signal that is essential both for efficient interaction between T and B cells and for normal antibody responses to T-cell-dependent antigens. To determine the physiological function of ICOS, we generated and characterized gene-targeted ICOS-deficient mice. In vivo, a lack of ICOS results in severely deficient T-cell-dependent B-cell responses. Germinal centre formation is impaired and immunoglobulin class switching, including production of allergy-mediating IgE, is defective. ICOS-deficient T cells primed in in vivo and restimulated in vitro with specific antigen produce only low levels of interleukin-4, but remain fully competent to produce interferon-gamma.

Stimulatory effects of B7-related protein-1 on cellular and humoral immune responses in mice.

Inducible costimulator (ICOS) and B7-related protein-1 (B7RP-1) constitute a receptor-ligand pair involved in T cell costimulation. In this study, the stimulatory effects of B7RP-1 on cellular and humoral immune responses were investigated giving mice a construct with the extracellular domain of murine B7RP-1 fused with human IgG1 Fc (B7RP-1-Fc). B7RP-1-Fc stimulated contact hypersensitivity (CH) given near either the time of sensitization or challenge with oxazolone. When given near challenge time, B7RP-1-Fc stimulated CH more than a construct containing the extracellular domain of murine B7.2 and Fc (B7.2-Fc). B7RP-1-Fc increased the number of cells in lymph nodes draining the skin sensitized with oxazolone, especially activated T cells. B7RP-1-Fc also increased the ability of the cells in these lymph nodes to induce CH when transfused into naive mice. B7RP-1-Fc stimulated the production of anti-keyhole limpet hemocyanin (KLH) Ab, increasing anti-KLH IgG, IgG2a, and IgE, whereas B7.2-Fc did not affect this production. B7RP-1-Fc also increased the number of cells in lymph nodes draining the skin immunized with KLH and their production of IFN-gamma, IL-4, and IL-10 in response to KLH. Finally, B7RP-1-Fc increased the presence of eosinophils in the bronchoalveolar lavage and lungs of mice sensitized and challenged with OVA so to mount an asthmatic reaction. B7RP-1-Fc stimulates both cellular and humoral immune responses in vivo by increasing number and function of T and B cells reacting to Ag exposure.

Scalp cavernous angioma presenting as sinus pericranii: diagnostic value of cerebral angiography and magnetic resonance imaging.

OBJECTS: Sinus pericranii is only a symptom complex, and it can have a variety of etiologies. Therefore, it is important to differentiate these etiologies preoperatively by means of radiological examinations. A 5-year-old boy was admitted with a soft and fluctuant tumor in the right parietal region near the midline. The tumor appeared when the child was in a recumbent position, distending noticeably with the Valsalva maneuver and disappearing completely when the patient was in the sitting position. METHODS: Magnetic resonance imaging showed the lesion with honeycomb-like heterogeneous iso- and low-intensity signals on the T1-weighted image and with heterogeneous high- and isointensity signal on the T2-weighted image. Dynamic study with an injection of gadolinium diethylene-triaminopentaacetic acid demonstrated and nodular peripheral enhancement at early phase and subsequent progressive enhancement towards the center of tumor. The internal carotid angiogram was normal. The external carotid angiogram, however, showed a tumor stain fed by the superficial temporal arteries. The stain was retained until the late phase and drained into the scalp veins and into the superior sagittal sinus. Following direct injection of contrast medium into the tumor there was prolonged retention of the medium in the tumor and leakage into scalp veins and the superior sagittal sinus. The mass under the periosteum was totally removed and proved to be a cavernous angioma. CONCLUSIONS: Scalp cavernous angioma is one of the etiologies of sinus pericranii and may be diagnosed preoperatively by cerebral angiography or magnetic resonance imaging. Serial dynamic magnetic resonance imaging will be particularly helpful for this diagnosis.

Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS.

Optimal T cell activation requires the interactions of co-stimulatory molecules, such as those in the CD28 and B7 protein families. Recently, we described the co-stimulatory properties of the murine ligand to ICOS, which we designated as B7RP-1. Here, we report the co-stimulation of human T cells through the human B7RP-1 and ICOS interaction. This ligand-receptor pair interacts with a K:(D) approximately 33 nM and an off-rate with a t((1/2)) > 10 min. Interestingly, tumor necrosis factor (TNF)-alpha differentially regulates the expression of human B7RP-1 on B cells, monocytes and dendritic cells (DC). TNF-alpha enhances B7RP-1 expression on B cells and monocytes, while it inhibits it on DC. The human B7RP-1-Fc protein or cells that express membrane-bound B7RP-1 co-stimulate T cell proliferation in vitro. Specific cytokines, such as IFN-gamma and IL-10, are induced by B7RP-1 co-stimulation. Although IL-2 levels are not significantly increased, B7RP-1 co-stimulation is dependent on IL-2. These experiments define the human ortholog to murine B7RP-1 and characterize its interaction with human ICOS.

Hyponatremia-induced metabolic encephalopathy caused by Rathke's cleft cyst: a case report.

Rathke's cleft cysts are sometimes associated with aseptic meningitis or metabolic encephalopathy due to hyponatremia. We treated such a case manifest by lethargy, fever and electroencephalographic abnormalities. A 68-year-old man was admitted to our ward after experiencing general malaise, nausea and vomiting and then high fever and lethargy. On admission, he was drowsy and had nuchal rigidity and Kernig's sign. Physically, he was pale with dry, thickened skin. He had lost 5.0 kg of body weight in the last month. His serum sodium was 115 mEq/l. He had a low serum osmotic pressure (235 mOsmol/l) and a high urine osmotic pressure (520 mOsmol/l). His urine volume was 1200-1900 ml/24 h with a specific gravity of 1008-1015. The urine sodium was 210 mEq/l. He did not have an elevated level of antidiuretic hormone. Electroencephalograms showed periodic delta waves over a background of theta waves. With sodium replacement, the patient become alert and symptom free, and his electroencephalographic findings normalized. However, the serum sodium level did not stabilize, sometimes falling with a recurrence of symptoms. Magnetic resonance imaging clearly delineated a dumbbell-shaped intrasellar and suprasellar cyst. The suprasellar component subsequently shrunk spontaneously and finally disappeared. An endocrinologic evaluation showed panhypopituitarism. The patient was given glucocorticoid and thyroxine replacement therapy, which stabilized his serum sodium level and permanently relieved his symptoms. A transsphenoidal approach was performed. A greenish cyst was punctured, and a yellow fluid was aspirated. The cyst proved to be simple or cubic stratified epithelium, and a diagnosis of Rathke's cleft cyst was made. The patient was discharged in good condition with a continuation of hormonal therapy. Rathke's cleft cyst can cause aseptic meningitis if the cyst ruptures and its contents spill into the subarachnoid space. Metabolic encephalopathy induced by hyponatremia due to salt wasting also can occur if the lesion injures the hypothalamus and pituitary gland.