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.

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.

Amplification and abnormal chromosomal distribution of ribosomal genes (rDNA) in rat erythroleukemia cells.

The ribosomal cistrons (rDNA)/genome ratio was measured in five cell lines derived from three chemically induced erythroblastic leukemias (D-1, D-2, and NE26) in the Long-Evans (LE) rat and compared with values in the normal liver, bone marrow, and fetus. The ratio was 20-42% higher in the leukemias than in normal tissues. The number of autoradiographic silver grains of 125I-labeled rRNA hybridized in situ over three nucleolus organizer regions (NORs) of leukemia cells was determined and compared with that of the normal cells. Although the distribution of silver grains of normal cells averaged 44.6%, 25.9%, and 29.5% in NORs of chromosomes #3, #11, and #12, respectively, their distribution was abnormal in two of the leukemias examined; rDNA was amplified in chromosomes #12 of two sublines (K1DA and K1DB) of one leukemias (D-1), and in one chromosome #3 of two sublines (K2D and K3D) of another leukemia (D-2). We consider the possibility that these abnormal patterns of rDNA distribution are related to the increase in rDNA in leukemia cells.

Molecular and cytogenetic studies on nucleolar cistrons (rDNA) in mouse leukemia cells.

The gene dosage change of nucleolar cistrons (rDNA) in tumor cells has not been extensively studied. The present studies showed that increased dosage, as well as abnormal distribution of rDNA, was frequently associated with leukemia cells of SL/Ni and AKR mice. In normal SL cells, 37%, 39%, and 25% of rDNA was located in nucleolar organizer regions (NOR) of chromosomes #12, #18, and #19, respectively. Increase of rDNA/DNA was shown by hybridization on filter membranes in SL1, SL2, SL3, and M1 leukemia cells. Direct measurement of rDNA/DNA in G1 cells revealed an 11% increase in synchronized M1 cells. The increased rDNA dosage was explained by trisomy 12 in SL1 and SL2, the ectopic NOR of #9 in SL3, and the double t(X;19) marker chromosomes in M1. On the other hand, in normal AKR cells, 27%, 29%, and 45% of rDNA was assigned to NORs of chromosomes #15, #16, and #18, respectively. The relative rDNA distribution among NORs estimated by autoradiographic grain counting was suggested to be abnormal in AKR leukemia cells despite their normal karyotype; 36% rDNA was shown to be in chromosomes #15 and #16, respectively, by relative reduction in chromosome #18 in AKR1; the trisomy 15 explained the increased rDNA in AKR2; a relative increase was found in chromosome #15 in AKR3. These results were discussed with reference to the reported NOR involvement in chromosome translocation and amplification in tumor cells.

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.

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.

Synthesis of type III collagen and type IV collagen by tubular epithelial cells in diabetic nephropathy.

Overproduction of extracellular matrix (ECM) is considered to be primarily responsible for both glomerular and tubulointerstitial (TI) changes in diabetic nephropathy (DN). To clarify the possible role of the collagens in TI damage in DN, type III interstitial collagen and type IV basement membrane collagen were studied in 10 cases of DN and 10 control cases by immunohistochemistry and in situ hybridization techniques. In control cases, no immunostaining for type III collagen was found in the renal tubules, while strongly positive in the adjacent interstitium. On the other hand, type IV collagen was found weakly in the tubular basement membrane (TBM) in control cases. In DN, increased immunostaining for both type III and type IV collagens were found in the damaged tubulointenstitium (TI). To determine the sources of these collagens in TI damage, non-radioactive in situ hybridization was performed utilizing thymine-thymine (T-T) dimerized synthetic oligonucleotides complementary to either human pro alpha 1 (III) chain or pro alpha 1 (IV) chain mRNA as probe. In normal tubules, tubular epithelial cells were not uniformly but persistently positive for pro alpha 1 (IV) mRNA. Meanwhile, no specifically detectable positive hybridization signals for pro alpha 1 (III) mRNA was found in the normal tubular epithelial cells. Accelerated synthesis of both type III and type IV collagens by tubular epithelial cells was noted in TI damage in DN. From the results we concluded that excessive synthesis of both type III and type IV collagens by tubular epithelial cells might significantly contribute to the TI damage found in DN.

Quantitation of myocardial fibrosis and its relation to function in essential hypertension and hypertrophic cardiomyopathy.

Myocardial interstitial fibrosis is an important microscopic feature of hypertrophic cardiomyopathy. To determine whether interstitial fibrosis of the myocardium in hypertrophic cardiomyopathy and essential hypertension differ in quality or quantity, and to determine whether fibrosis affects cardiac function directly, we measured the percentage of fibrosis in patients of both categories and compared the severity of fibrosis with several cardiac functions. Left and right ventricular endomyocardial biopsies were performed in 25 patients with essential hypertension and in 19 patients with hypertrophic cardiomyopathy. Interstitial fibrosis was classified into four different microscopic types, and the percentage of total and of each type was calculated using the point-counting method. Although the percentage of total fibrosis was similar between the two groups, the type of fibrosis was different. There was no correlation between the percentage of total fibrosis and the mean size of myocytes in either group. Although there was a significant correlation between the percentage of total fibrosis and the thickness of the interventricular septum in hypertrophic cardiomyopathy, such correlation was lacking in hypertension. There was no correlation between the percentage of total fibrosis and the ejection fraction, cardiac index, or left ventricular end-diastolic pressure in either group. We concluded that the amount of myocardial interstitial fibrosis in hypertrophic cardiomyopathy is no greater than that in essential hypertension, but the type of fibrosis is different. Furthermore, in subjects in whom the ejection fraction is normal or only slightly decreased, fibrosis does not influence global cardiac functions.

Severe chest pain due to gastric anisakiasis.

We treated two cases of gastric anisakiasis presenting with severe chest pain. In both cases, there was a history of prior ingestion of raw saltwater fish. After endoscopic removal of larvae, the chest pain disappeared and never recurred. Other diseases causing chest pain were ruled out by symptoms, signs, blood tests, electrocardiography, chest radiograph, and ultrasonic examination of the heart and abdomen. Thus the chest pain was considered to be caused by gastric anisakiasis. Gastric anisakiasis should be included in the differential diagnosis of acute chest pain.

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.

Severe hypercalcemia and polyuria in a near-drowning victim.

A 73-year-old man was admitted because of near-drowning in a hot springs bath. Transient severe hypercalcemia and polyuria were seen during the first hospital day. It seemed that the hypercalcemia was due to acute intoxication from calcium contained in the water of the spring absorbed mainly through the alveoli. To our knowledge, this is the first case of acute hypercalcemia complicating a near-drowning in a hot spring. Analysis of serum and urine electrolytes during the polyuric phase revealed saline diuresis, which was probably due to interference by the hypercalcemia of the reabsorption of sodium and free water.

Pulmonary sclerosing hemangioma: report of a case with emphasis on dynamic MR imaging findings.

We report a case of pulmonary sclerosing hemangioma, a rare benign neoplasm. Marked homogeneous enhancement was noted on postcontrast CT. On the dynamic magnetic resonance (MR) imaging study, peak enhancement occurred 2 minutes after the administration of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA).

Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis.

Prolonged hypertension causes structural changes including glomerulosclerosis and tubulointerstitial damage of the kidney, termed benign nephrosclerosis. It is generally accepted that, in benign nephrosclerosis, increased accumulation of extracellular matrix in the glomeruli results in glomerulosclerosis. Little is known, however, about the possible role of the extracellular matrix in the tubulointerstitial damage in benign nephrosclerosis. In this study, the possible roles of type IV basement-membrane collagen and type III interstitial collagen in tubulointerstitial damage caused by hypertension were explored. Immunohistochemical techniques were used to investigate the distribution of type III and type IV collagens in the kidney sections of 15 patients with benign nephrosclerosis with tubulointerstitial damage and in 10 controls. In the control renal sections strong immunostaining for type III collagen was found in the interstitium and immunostaining for type IV collagen was present in the tubular basement membrane and weakly in the interstitium. In the patients with tubulointerstitial damage there was increased immunostaining for both type III and type IV collagens in the expanded interstitium and damaged tubules than was found in the control kidney sections. These findings indicate that increased accumulation of both type III and type IV collagens might play a significant role in the tubulointerstitial damage in benign nephrosclerosis.

[A case of systemic lupus erythematosus associated with minimal change nephrotic syndrome].

A case of systemic lupus erythematosus (SLE) associated with minimal change nephrotic syndrome (MCNS) in a 25-year-old female is described. The patient suddenly manifested butterfly rash and proteinuria was first pointed out on March, 1994. On admission, her skin biopsy indicated SLE. Subsequently, she developed nephrotic syndrome. Urinalysis showed heavy proteinuria (4.1 g/day), with no other abnormalities in the urinary sediment. Immunological examination revealed positive antinuclear antibody at a titer of 1:80 with a speckled pattern. Anti-ssDNA and anti-SS-A antibodies were positive, but other antibodies were negative. Serum complement (CH50) was within the normal range (30.5 U/ml). The renal biopsy showed no apparent cellular proliferation or increase of extracellular matrices in glomeruli by light microscopy. Slight deposition of IgG, IgM, C3 and C1q was focally seen in the mesangium and capillary wall by immunofluorescence. Electron microscopic examination revealed small and scattered dense deposits in the mesangium, subepithelium and subendothelium, associated with diffuse fusion of the foot processes of epithelial cells along the glomerular basement membrane. According to the WHO classification, the histological features were compatible with those of lupus nephritis (LN), class Ib. The patient was treated with PREDNISOLONE, Mizorbine and Dilazep, resulting in the disappearance of proteinuria and a normal serum level of total protein. The association of LN and MCNS is very rare. We also investigated the relationship between the intensity of proteinuria and histological types of 53 cases with LN examined in our laboratory. The cases with heavy proteinuria were mostly classified as WHO-Class IV and Class V. We report here a case of LN associated with MCNS and also review the literatures.

[Hepatic artery and portal vein infusion of adriamycin in experimental liver metastasis].

Hepatic artery and portal vein infusion of adriamycin (ADM) to normal rabbit and the experimental liver metastasis model of VX2 tumor were discussed in this study. The concentration of ADM in the peripheral blood, liver, myocardium, lung of normal rabbit and metastatic tumor were measured in the HPLC method. There was no difference between arterial infusion and portal infusion in the normal rabbits. In the metastatic tumor, one hour after the infusion, concentration of ADM showed no difference between arterial and portal infusion, but two and three hours later, the concentration was significantly higher after portal infusion than arterial infusion. It was suspected that portal infusion would be more effective for liver metastasis. The number of tumor nodules for estimation of the anti-tumor effect on metastatic models was decreased significantly after arterial and portal infusion compared with the controls, but there was no statistical difference between arterial and portal infusion.

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.