Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002).

AIMS: Gastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. MATERIALS AND METHODS: Paraffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. RESULTS: There was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). CONCLUSION: Low thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

Mesenteric phlebosclerosis associated with long-term oral intake of geniposide, an ingredient of herbal medicine.

BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, characterised by thickening of the wall of the right hemicolon with calcification of mesenteric veins. However, the aetiology remains unknown. AIM: To investigate the possible association of herbal medicines with IMP. METHOD: The clinical data of four of our own patients were collected. Furthermore, we searched for previous reports about similar patients with detailed descriptions of herbal prescriptions that they had taken. We compared herbal ingredients to identify the toxic agent as a possible aetiological factor. RESULTS: Clinical data on a total of 25 patients were summarised. Mean age was 61.8 years and there was female predominance (6 men and 19 women). The used Kampo prescription, the number of cases, and the mean duration of use were as follows: kamisyoyosan in 12 cases for 12.8 years, inshin-iseihaito in 5 cases for 13.4 years, orengedokuto in 4 cases for 14.3 years, inchinkoto in 1 case for 20 years, kamikihitou in 1 case for 19 years, seijobofuto in 1 case for 10 years and gorinsan in 1 case for an unknown duration. Only one ingredient, sansisi, was common to the herbal medicines of all 25 patients. This crude drug called geniposide in English is a major constituent of the Gardenia fruits. CONCLUSION: The long-term use of geniposide in herbal medicines appears to be associated with mesenteric phlebosclerosis.

Glomerulocystic kidney disease (GCKD) associated with Henoch-Schoenlein purpura: a case report and a review of adult cases of GCKD.

We report on a 71-year-old male with Henoch-Schoenlein purpura (HSP) who developed glomerulocystic kidney disease (GCKD) without congenital abnormality. He had mild renal dysfunction. Renal biopsy findings showed mild proliferation of mesangial cells and matrixes, and tubular atrophy, interstitial fibrosis, cystic dilation of Bowman's capsule and atrophy of the glomerular tuft. The deposition of IgA and C3 in the mesangial area was observed with the fluorescent antibody technique. Therefore he was diagnosed with GCKD-associated HSP. This was the oldest patient among the previous case reports and the patient was the first case to be reported for concurrent GCKD and HSP. In this study, we also reviewed the patient to previously reported adult patients with GCKD.

Pregnancy outcome in nephrotic syndrome with mixed connective tissue disease.

We describe two pregnancies of a young woman with mixed connective tissue disease. In June 1983, she was diagnosed as having Raynaud's phenomenon, arthralgia, and proteinuria. She then developed nephrotic syndrome. Methylprednisolone was initially prescribed at a large dose of 1 g/day which was slowly tapered to 5 mg/day. The proteinuria disappeared. During both pregnancies (the first beginning in December 1988 and the second in May 1992), the patient was placed on a prednisolone maintenance dose (5 mg/day). Both neonates were born healthy at term with no complications. Continuing prednisolone may be useful in pregnant women, and aggressive treatment to prevent mixed connective tissue disease exacerbation may be appropriate during pregnancy.

An algorithm using projection onto subspace of prior distributions for long-wavelength sound wave CT.

The stationary long-wavelength sound wave computed tomography is a nonlinear inverse problem that requires the use of prior information of the object. However, the prior assumptions that are usually used in similar inverse problems are more or less inappropriate. In this paper, a new reconstruction algorithm using the prior information is proposed and compared with subspace regularization method and Marquardt reconstruction algorithms. The simulation shows that the proposed algorithm can give a better reconstructed result whether the actual distribution is compatible or incompatible with the prior distributions.

Treatment of severe hypothyroidism reduced serum creatinine levels in two chronic renal failure patients.

Short-term hypothyroidism has been associated with a reversible rise in serum creatinine levels in patients with normal renal function. A remarkable decline in serum creatinine levels associated with a treatment of severe and prolonged hypothyroidism has rarely been reported so far. We present here 2 patients with chronic renal failure in whom treatment for hypothyroidism resulted in a significant and sustained reduction of their serum creatinine levels. These cases indicate that because hypothyroidism may aggravate the serum creatinine levels, TSH should be considered in screening procedures of patients with chronic renal failure presenting with recent accelerated aggravation of renal function. Hypothyroidism per se, one of its complications or one of its associated autoimmune diseases might play a role in modifying the underlying renal problem.

Prognosis of patients with rounded atelectasis undergoing long-term hemodialysis.

We present 4 patients undergoing hemodialysis in whom thoracic computed tomography (CT) suggested a diagnosis of rounded atelectasis (RA) with pleural effusion. The clinical setting and follow-up CT of all 4 patients confirmed this diagnosis. The pleural fluid of each appeared serosanguineous or hemorrhagic and predominantly consisted of lymphocytes. Biochemical analysis of this fluid revealed high levels of total protein, lactate dehydrogenase and glucose. Bacterial culture and polymerase chain reaction for Mycobacterium tuberculosis DNA was negative. Pleural biopsy specimens from 2 of the 4 patients showed evidence of fibrinous change and mesothelial cell hyperplasia. Pleural effusion from all 4 patients did not respond to either fluid restriction or aggressive hemodialysis-induced dehydration. The subsequent clinical course and thoracentesis were repeated, and in 1 patient, this was followed by tetracycline pleurodesis. However, 2 patients died during pre-pleurodesis and 1 died during post-pleurodesis, all due to respiratory failure. We propose that the clinical setting and follow-up thoracic CT and thoracentesis of patients receiving long-term hemodialysis confirmed a diagnosis of rounded atelectasis with uremic pleural effusion. We also propose that the prognosis of patients with refractory pleural effusion receiving long-term hemodialysis would be improved by early pleurodesis.

Cause of residual hypertension after adrenalectomy in patients with primary aldosteronism.

The cause of residual hypertension after adrenalectomy for primary aldosteronism (PA) is unknown. The purpose of this study is to investigate the characteristic pathological kidney features associated with PA. Between 1977 and 1999 at our hospital, 26 patients with PA caused by a unilateral adrenal cortical adenoma (Conn's syndrome) underwent unilateral adrenalectomy with concurrent open-wedge renal biopsy. Patients were categorized into two groups: (1) those with normotension with diastolic blood pressure less than 90 mm Hg who were not administered antihypertensive drugs, and (2) those with residual hypertension with diastolic blood pressure of 90 mm Hg or greater who were administered medication for 6 months after surgery. Thirteen patients were cured of hypertension postoperatively, and 12 patients were administered antihypertensive medications. Glomerulosclerosis, renal arteriolosclerosis, and preoperative left ventricular mass (LVM) index were worse in the group with residual hypertension than in that with normotension (17.8% +/- 7.8% versus 9.6% +/- 3.8%; P = 0.01; 2.5 +/- 0.5 versus 1.6 +/- 0.4, Bader's grade; P = 0.005; and 165 +/- 31 versus 139 +/- 24 g/m(2); P = 0.02, respectively). Severity of tubulointerstitial injury, preoperative duration of hypertension, preoperative severity of proteinuria, plasma aldosterone level, and serum potassium concentration were not significantly different between the two groups. In conclusion, severity of glomerulosclerosis and arteriolosclerosis and LVM are related to blood pressure after adrenalectomy in patients with PA.

Selective extraction of gallium from aluminum and indium using tripod phenolic ligands.

Solvent extraction of trivalent group 13 metal cations such as aluminum, gallium and indium with tripod quadridentate phenolic ligand, tris(2-hydroxy-3,5-dimethylbenzyl)amine (H(3)tdmba), was investigated as fundamental study for their mutual separation. Gallium was extracted almost quantitatively as Ga(tdmba) (logK(ex)=-6.66+/-0.06 on using chloroform as extraction solvent), whereas aluminum and indium were hardly extracted due to steric hindrance on complexation of them with the ligand. The extracted Ga species was estimated as trigonal bipyramidal complex with one H(2)O molecule. Furthermore, extractability of Ga was increased by changing the ligand to more acidic tris(5-chloro-2-hydroxy-3-methylbenzyl)amine (H(3)tcmba) (logK(ex)=-6.18+/-0.18 on using dichloroethane as extraction solvent).

Type II diabetes mellitus and primary Sjögren's syndrome complicated by pleural effusion.

A 73-year-old man was admitted to our hospital because of pleural effusion and nephrotic syndrome. Sjogren's syndrome (Sjs) was diagnosed based on a positive test for antibodies to Ro and La, and the result of labial salivary gland biopsy. The pleural effusion showed a high number of lymphocytes and high titers of antibodies to Ro and La. By immunohistochemistry, it was determined that infiltrating CD3+ cells predominated over infiltrating CD20+ cells in the pleura. Nephrotic syndrome was also present, which, as confirmed by renal biopsy was due to advanced diabetic nephropathy. Here, we report a case of Type II diabetes mellitus and primary Sjs complicated by pleural effusion, discuss the available treatment for pleural effusion.

Microvascular ischemia in patients with myotonic dystrophy.

Two women with myotonic dystrophy underwent dipyridamole thallium-201 (201Tl) myocardial perfusion imaging, after which one patient developed flat T waves in lead I and aV(L), and inverted T waves in leads V(2-6). The other patient developed a nonspecific intraventricular block that progressed to complete left bundle branch block and was associated with chest discomfort. Reversible scintigraphic defects were observed in both women. Although there was evidence that suggested myocardial ischemia on the ECG changes and 201Tl scintigraphic findings, coronary angiography demonstrated no significant stenoses in either patient. These findings suggest that microvascular dysfunction may lead to myocardial ischemia and conduction disturbances in patients with myotonic dystrophy.

Stunned myocardium after hip arthroplasty.

We report a case of ST-segment elevation occurring in all leads of the ECG during hip arthroplasty. It is thought that this resulted from a stunned myocardium because wall motion abnormalities were reversible, there was no evidence of fixed or vasospastic coronary occlusion and there was only a slight increase in serial cardiac enzymes. Treatment with nicorandil improved the patient's cardiac function. A [123I]MIBG test revealed a high myocardial washout rate, suggesting that the stunned myocardium was caused by exposure to excessive norepinephrine induced by anaesthesia or surgery.

Phospholipase A2 mediates nitric oxide production by alveolar macrophages and acute lung injury in pancreatitis.

OBJECTIVE: Reportedly, nitric oxide (NO) derived from alveolar macrophages (AMs) and increased serum phospholipase A2 (PLA2) activity are associated with the pathogenesis of lung injury in acute pancreatitis. The authors examined the possibility that PLA2 causes, in part, the induction of NO production by AMs in pancreatitis. METHODS: Pancreatitis was induced in rats by selective pancreatic duct ligation (SPL). AMs were stimulated with PLA2 or SPL rat serum, with or without administration of the PLA2 inhibitor quinacrine. Then NO production from the AMs was measured by the Griess method, inducible NO synthase mRNA expression of AMs was analyzed by the reverse transcription-polymerase chain reaction, and cytotoxic effects of AMs on human umbilical vein endothelial cells was examined by a 51Cr release assay. In vivo, the effect of quinacrine on lung injury was determined by measuring the arterial blood oxygen pressure (PaO2), lung weight, and lung permeability using Evans blue dye concentration of SPL rat. RESULTS: In vitro, the serum with high PLA2 activity induced NO production by rat AMs. PLA2 (50 ng/ml) induced significant amounts of NO production, inducible NO synthase mRNA expression, and cytotoxicity toward the human umbilical vein endothelial cells in normal rat AMs, and these activities were significantly inhibited by quinacrine. In vivo, rats with pancreatitis that were given quinacrine showed decreased concentrations of NO2- and NO3- in the bronchoalveolar lavage fluid, and the PaO2, lung edema, and lung permeability were improved significantly. CONCLUSION: PLA2 induces AMs to release NO, which contributes to lung injury in acute pancreatitis. This lung injury was prevented by the administration of the PLA2 inhibitor quinacrine.

Expression of vascular endothelial growth factor and its receptors in rats with protein-overload nephrosis.

BACKGROUND: Based on the fact that vascular endothelial growth factor (VEGF) increases vascular permeability, it is speculated that VEGF might be involved in the development of proteinuria, although this remains unconfirmed. The production and site of action of VEGF remains unclear in nephrotic renal diseases. METHODS: Non-radioactive in situ hybridization was performed to examine the expression of VEGF mRNA and its receptors, flt-1 and KDR/flk-1, in a rat model of nephrosis induced by intraperitoneal injection of bovine serum albumin (BSA). Saline injected rats were served as control animals. RESULTS: Neither morphological changes nor deposition of immunoglobulin or complement were observed in our model. Proteinuria developed, reaching a maximum level in rats injected with BSA for 3 days, followed by persistent proteinuria until day 14. The expression of mRNA for VEGF and the two receptors was markedly upregulated in glomeruli of BSA-induced nephritis compared with the control group. VEGF mRNA was localized in glomerular cells, including cells in mesangium, visceral and parietal epithelial cells. In contrast, flt-1 mRNA and KDR/flk-1 mRNA were expressed on glomerular endothelial cells and cells in mesangium. The ratio of glomerular cells positive for VEGF mRNA and its receptors mRNA increased proportionately with the severity of proteinuria. Immunohistochemistry for ED-1 and proliferating cell nuclear antigen showed no significant increase in infiltrating macrophage or cellular proliferation. CONCLUSIONS: Our results suggest that altered glomerular expression of VEGF and its receptors is not associated with proliferation of endothelial cells, but rather with proteinuria in BSA-induced nephritis in rats. VEGF may play a different role in different renal diseases.

Expression of inducible nitric oxide synthase in circulating neutrophils of the systemic inflammatory response syndrome and septic patients.

There is increasing evidence that nitric oxide (NO) is an important factor in the pathogenesis of septic shock. It is known that polymorphonuclear neutrophils (PMNs) are activated during sepsis or after surgical stress, and they then release various toxic mediators including free radicals. It has not been clear whether NO synthesis can be induced in circulating PMNs. Blood samples were obtained from 11 patients with sepsis, 23 patients with systemic inflammatory response syndrome (SIRS), and 16 patients without SIRS (nonSIRS) who underwent operation. We examined mRNA expression of inducible NO synthase (iNOS) in circulating PMNs from those patients pre- and postoperatively using the reverse transcriptase polymerase chain reaction (RT-PCR) method and measured their serum nitrate (NO2-) + nitrate (NO3-) concentration, peripheral blood white cell (WBC) count, and serum C-reactive protein (CRP) level. The frequency of iNOS expression in PMNs increased in sepsis (100%) and SIRS (70%) patients compared to that in nonSIRS patients (18%) (p < 0.001). The peripheral WBC count and CRP level were significantly higher in iNOS-positive patients than in iNOS-negative patients (p < 0.05 and p < 0.01, respectively). Postoperatively, the serum NO2- + NO3- concentration increased in 87% of septic patients and in 56% of patients with SIRS (p < 0.05 for both). Our study indicated that iNOS mRNA expression is induced in human circulating PMNs of patients with postoperative sepsis and SIRS and may be involved in the pathogenesis of the sepsis syndrome.