Relationship between mast cells in the tubulointerstitium and prognosis of patients with IgA nephropathy.

There have been a few reports suggesting that mast cells may play an important role in the development of fibrosis and/or the degradation of extracellular matrix. We examined the relationship between the number of distribution of mast cells in tubulointerstitium and prognosis of patients with IgA nephropathy. Renal biopsy specimens were stained with mouse monoclonal antihuman mast cell tryptase antibody and then with aniline blue. Specimens from 45 patients with IgA nephropathy and from 5 patients with minimal-change nephrotic syndrome were used. There was a significant correlation between the number of mast cells per unit area of the whole tubulointerstitium and the degree of tubulointerstitial fibrosis or renal function. Patients with IgA nephropathy were divided into two groups (group 1: 'minimal' and 'slight'; group 2: 'moderate' and 'advanced') according to the classification by a previously reported method. Mast cells were mainly observed in the fibrotic areas in group 1. In group 2, many mast cells were detected not only in the fibrotic but also in the nonfibrotic areas. It appears that the number of mast cells in the nonfibrotic areas may be one of the predictive factors for the prognosis of patients with IgA nephropathy.     

Effects of Growth Hormone Following Chronic Angiotensin-converting Enzyme Inhibition in Chronic Heart Failure: Their Relation to Infarct Size

Growth hormone (GH) has been attracted as a possible adjunctive treatment for severe heart failure. However, its treatment effects have been still controversial. To assess severity of basal cardiac disease states in which GH might be effective, we analyzed the relation of treatment effects of GH following chronic angiotensin-converting enzyme (ACE) inhibition on cardiac function and structures to infarct size in rat model of chronic heart failure after myocardial infarction. One day after coronary occlusion, rats were randomized to either an ACE inhibitor, temocapril (T) (80 mg/L in drinking water) or placebo for 12 weeks. The animals received concomitant recombinant human (rh) GH (2 mg/kg/day, SC) (T + GH) or vehicle during the final 2 weeks. Compared with the T group, the T + GH group with large MI had smaller increments of left ventricular (LV) dP/dt _max (0 vs 17%) and cardiac output (9 vs 49%), less improvement of LV relaxation (tau) (–3 vs 29%) and systemic vascular resistance (8 vs 29%), and a greater increase in LV end-diastolic pressure (123 vs –5%) than did the T + GH group with moderate MI. In the T + GH group when compared with the T group, these functional alterations were associated with a 12% reduction in the LV capillary density and a 21% increase in hydroxyproline contents in rats with large MI, whereas a 12% increase in the density and similar collagen contents were found in rats with moderate MI. Thus, prominent beneficial cardiovascular effects of the additive short-term, high-dose GH to chronic high-dose ACE inhibition were obtained in rats with moderate MI, whereas little additional benefit or even detrimental effects of GH were found in rats with large MI. The present study may provide an insight into the therapeutic strategy of GH given late after MI in the presence of chronic ACE inhibition in congestive heart failure.     

Distinctive Multidrug Sensitivity and Outcome of Acute Erythroblastic and Megakaryoblastic Leukemia in Children With Down Syndrome

We assessed the in vitro chemosensitivity of acute erythroblastic and megakaryoblastic leukemia cells from children with Down syndrome (DS) compared to non-DS children. We conducted in vitro tests using the MTT assay of bone marrow samples from 12 children with DS and 16 children without DS. Patients were newly diagnosed based on the morphology and expression of platelet-specific antigens. Induction failure occurred more frequently in the non-DS group (n = 4) than in the DS group (n = 0, P = .053). Children with DS had a superior event-free survival (EFS) probability of 0.750 at 4 years, compared to an EFS probability of 0.375 for non-DS children (P = .049). Blast cells from DS patients were significantly more sensitive to daunorubicin, melphalan, mitoxantrone, 4-hydroperoxy-cyclophosphamide, vincristine, etoposide, bleomycin, and pirarubicin than those from non-DS patients. Four of the 16 non-DS patients were found to have acquired an extra chromosome 21 in their leukemia cells: blasts from these patients also tended to have greater chemosensitivity than those from patients without an extra chromosome 21. Blast cells from DS patients are markedly sensitive to various drugs. These results suggest that the fragility of blast cells derived from DS patients may be related to an increased susceptibility to apoptosis.     

A basic study on lesion detectability for hot spot imaging of positron emitters with dedicated PET and positron coincidence gamma camera

The aim of this study was to explore the correlations of detectability and the semi-quantification for hot spot imaging with positron emitters in positron emission tomography (PET) and with a positron coincidence detection system (PCD). Phantom study results for the measurement of the lesion-to-background (L/B) ratio ranged from 2.0 to 30.3, and detectability for hot spot lesion of PET and PCD were performed to correspond to clinical conditions. The detectability and semi-quantitative evaluation of hot spots from 4.4 mm to 36.9 mm in diameter were performed from the PET and PCD images. There were strong correlations between the L/B ratios derived from PET and PCD hot spot images and actual L/B ratios; but the L/B ratio derived from PET was higher than that from PCD with a significant difference of 10% to 54.8%. The detectability of hot spot imaging of PCD was lower than that of PET at 64.8% (PCD) versus 77.8% (PET). Even the actual L/B ratio was 8.0, hot spots more than 10.6 mm in diameter could be clearly identified with PCD imaging. The same identification could be achieved with PET imaging even when the actual L/B ratio was 4.0. This detailed investigation indicated that FDG PCD yielded results comparable to FDG PET on visual analysis and semi-quantitative analysis in detecting hot spots in phantoms, but semi-quantitative analysis of the L/B ratio with FDG PCD was inferior to that with FDG PET and the detectability of PCD in smaller hot spots was significantly poor.     

Protein localization and mRNA expression of epimorphin in mouse and human kidneys.

Epimorphin is a mesenchymal cell surface protein which induces epithelial branching morphogenesis. However, the role of epimorphin in the kidney has not been addressed. In the present study, the localization of epimorphin protein and the expression of its mRNA were investigated in the developing mouse and adult human kidneys using immunohistochemistry and semiquantitative RT-PCR. The in vitro expression of epimorphin protein and its mRNA was also explored in cultured mouse and human mesangial cells. Epimorphin protein was expressed in the renal interstitium and the circumference of the comma-shaped body at day 16 of gestation. The intensity and distribution of epimorphin were gradually increased during kidney differentiation and maturation. Epimorphin was first observed in glomeruli at 1 week of age. The localization of epimorphin in glomerular mesangial cells and interstitial fibroblasts was confirmed by immunoelectron microscopy of 2-week-old mouse kidneys. The highest mRNA expression of epimorphin was observed at day 16 of gestation, thereafter it diminished with the maturation of the kidney. A similar localization of epimorphin was observed in a normal adult human kidney. Cultured human mesangial cells expressed epimorphin mRNA 150-kD protein. These results suggest that epimorphin may play a role in the development of the kidney and in the differentiation of fibroblast and mesangial cells.     

Impending rupture in an aortic arch aneurysm by Candida infection

A 68-year-old man was hospitalized with the complaints of left back pain and fever. He had a history of using steroids to treat uveitis for about thirty years. Computed tomography on the chest demonstrated an impending rupture in an aortic arch aneurysm, which was consequently surgically excised. Candida albicans was identified in the wall of the aneurysm, so fluconazole and itraconazole were administered. The patient was discharged at 120 days after surgery without recrudescence of the candida. To our knowledge, this is the fifteenth case of a successfully treated aneurysm caused by candida infection.     

Fulminant amoebic colitis during chemotherapy for advanced gastric cancer

A 52-year-old man had bloody stools during chemotherapy for gastric cancer. A colonoscopy revealed necrotizing ulcer-like changes. A biopsy confirmed the presence of amoebic trophozoites. Subsequently, peritonitis with intestinal perforation developed, and emergency peritoneal lavage and colostomy were performed. After surgery, endotoxin adsorption therapy was performed and metronidazole was given. Symptoms of peritonitis and colonitis resolved. However, the patient＇s general condition worsened with the progression of gastric cancer. The patient died 50 d after surgery. Fulminant amoebic colitis is very rarely associated with chemotherapy. Amoebic colitis should be considered in the differential diagnosis of patients who have bloody stools during chemotherapy.     

Correlation of angiogenesis with 18F-FMT and 18F-FDG uptake in non-small cell lung cancer

L-[3-¹⁸F]-α-methyltyrosine (¹⁸F-FMT) is an amino-acid tracer for positron-emission tomography (PET). We have conducted a clinicopathologic study to elucidate the correlation of angiogenesis with ¹⁸F-FMT and 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) uptake in patients with non-small cell lung cancer (NSCLC). Thirty-seven NSCLC patients were enrolled in this study, and two PET studies with ¹⁸F-FMT and ¹⁸F-FDG were performed. Uptake of PET tracers was evaluated with standardized uptake value. Vascular endothelial growth factor (VEGF), CD31, CD34, L-type amino acid transporter 1 (LAT1) and Ki-67 labeling index of the resected tumors were analyzed by immunohistochemical staining, and correlated with the clinicopathologic variables and the uptake of PET tracers. The median VEGF rate was 45% (range, 10–78%). High expression was seen in 30 patients (81%, 30/37). VEGF expression was statistically associated with progressively growing microvessel count. VEGF showed a correlation with LAT1 expression ( P  = 0.04) and Ki-67 labeling index ( P  = 0.01). However, it showed no correlation with age, gender, disease stage, tumor size, and histology. Microvessel density (MVD) showed no correlation with any parameters. ¹⁸F-FMT and ¹⁸F-FDG uptake correlated significantly with VEGF ( P  < 0.0001, P  = 0.026, respectively), whereas the correlation of ¹⁸F-FMT and VEGF was more meaningful. The present study demonstrated that the metabolic activity of primary tumors as evaluated by PET study with ¹⁸F-FMT and ¹⁸F-FDG is related to tumor angiogenesis and the proliferative activity in NSCLC. ( Cancer Sci 2009; 100: 753–758)     

Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity

Objective  Frizzled homolog 10 (FZD10) is expressed at high levels on the cell surface of almost all synovial sarcoma tissues, but is absent in most normal organs. In a previous study, yttrium-90 (⁹⁰Y)-labeled anti-FZD10 antibody (MAb 92-13) showed considerable therapeutic efficacy in synovial sarcoma cell-bearing mice. The purpose of the present study was to elucidate the factors associated with this therapeutic efficacy of ⁹⁰Y-MAb 92-13. Methods  FZD10 expression levels of SYO-1 (FZD10-overexpressing synovial sarcoma cell line) and DLD-1/FZD10 (FZD10-transfected DLD-1 cell) were determined by the cell binding assay, and their radiosensitivity was evaluated by incubation with ⁹⁰Y-MAb 92-13 in vitro. Biodistribution study of indium-111 (¹¹¹In)-MAb 92-13 was performed in SYO-1 and DLD-1/FZD10 tumor-bearing mice. For therapeutic studies, SYO-1 and DLD-1/FZD10 tumor-bearing mice were treated with ⁹⁰Y-MAb 92-13 (100, 150, and 200 μCi), after which the change in tumor volume was measured. Immunohistochemical staining was performed on the excised tumor. Results  Expression level of FZD10 on DLD-1/FZD10 was much greater than that on SYO-1. The accumulation of ¹¹¹In-MAb 92-13 was much higher in DLD-1/FZD10 tumor-bearing mice than in SYO-1 tumor-bearing mice (49.0 ± 4.2 and 22.0 ± 4.5% ID/g, respectively, at 48 h after administration). In SYO-1 tumor, substantial tumor size reduction was observed in all mice treated with ⁹⁰Y-MAb 92-13 (tumor volume decreased to less than 0.1 cm³ at 11 days after treatment) and tumor regrowth was not observed in most of them. In contrast, only slow progression was observed in DLD-1/FZD10 tumor. When incubated with ⁹⁰Y-MAb 92-13, high radioactivity was needed to damage DLD-1/FZD10. Immunohistochemical study indicated apoptosis of SYO-1 tumor. Conclusions  The therapeutic efficacy of RIT seems to largely depend on the tumor radiosensitivity.