The impact of angiogenesis on the prognosis of advanced renal cell carcinomas

We studied the relationship between angiogenic factors and clinical responses in advanced renal cell carcinomas (RCCs) and evaluated the angiogenic factors to clarify the potential impact of these factors on the cancer-specific survival. From January 1990 to December 2000, 148 patients underwent a nephrectomy for RCCs at our institution. Of the 32 patients who had distant metastasis, 17 met the histopathologic analysis requirements for an immuno-histochemical investigation. Fifteen of them were administered interferon-gamma and the remaining two patients were added to interferon-alpha and eight of seventeen patients also underwent radiation therapy. Both thymidine phosphorylase (TP) and Factor VIII immunostaining were performed. The overall survival rates at 1, 5 and 10 years were 82.4%, 30% and 30%, respectively. Three of these patients were diagnosed with lung metastasis and a complete response was seen in two, while a partial response was observed in one. In addition another patient who was diagnosed with bone metastasis also showed a partial response (group A). The remaining 13 patients showed progressive disease (group B). Group A had a higher TP-positive ratio (TP-PR) than that of group B. A multivariate analysis of the clinicopathologic data showed that a positive mean vascular area (PMVA) could be an independent factor regarding the potential impact of these factors on a long survival in advanced RCCS. PMVA was thus found to be an independent factor regarding the prognosis with advanced RCCs.     

Color Doppler ultrasonography: diagnosis of ectopic thyroid gland in patients with congenital hypothyroidism caused by thyroid dysgenesis

The etiology of congenital hypothyroidism (CH) may play an important role in determining disease severity, outcome, and, therefore, its treatment schedule. Radionuclide imaging (RI) is currently the most precise diagnostic technique to establish the etiology of CH. Conventional ultrasound can identify an athyrotic condition at the normal neck position and has gained acceptance for the initial evaluation of CH; however, its ability in delineating ectopic thyroid is limited. We used color Doppler ultrasonography (CDU) to assess blood flow and morphology in the detection of ectopic thyroid in 11 CH patients disclosed by neonatal screening; thyroid glands were undetectable at the normal location by gray-scale ultrasonography (GSU). The patients studied consisted of two infants for initial investigation and nine children for reevaluating the cause of CH. All of the patients underwent GSU, CDU, RI, and magnetic resonance imaging (MRI) investigation. We set RI as the defining diagnostic test for detecting ectopic thyroid and compared the imaging of CDU with those of GSU and MRI. The results of RI showed 10 ectopic thyroids and one athyreosis. In the patients with ectopic thyroid, the sensitivity of CDU, GSU, and MRI for detecting ectopic thyroid was 90, 70, and 70%, respectively. We conclude that CDU is superior to GSU and MRI for detecting ectopic thyroid and that CDU may be adopted as the diagnostic tool for the initial investigation of suspected CH.     

Ventricular afterload and ventricular work in fontan circulation: comparison with normal two-ventricle circulation and single-ventricle circulation with blalock-taussig shunts

BACKGROUND: Recent studies have indicated that there are inherent limitations associated with Fontan physiology. However, there have been no quantitative analyses of the effects of right heart bypass on ventricular afterload, hydraulic power, and resultant overall hemodynamics. Methods and Results- During routine cardiac catheterization, aortic impedance and ventricular hydraulic power were determined, both at rest and under increased ventricular work induced by dobutamine, in 17 patients with Fontan circulation, 15 patients with a single ventricle whose pulmonary circulation was maintained only by Blalock-Taussig shunts, and 13 patients who had normal 2-ventricle circulation. Both vascular resistance (nonpulsatile load on the ventricle) and pulsatile components of ventricular afterload (represented by low-frequency impedance) were significantly higher in the Fontan group than in the other groups (P<0.01), and this was associated with decreased cardiac output in the Fontan patients. In addition, hydraulic power cost per unit forward flow was 40% lower in the 2-ventricle circulation than in the single-ventricle circulation, suggesting lower ventricular efficiency in single-ventricle circulation attributable to the lack of a pulmonary ventricle. Furthermore, in the Fontan group, beta-adrenergic reserve was markedly decreased because of a limited preload reserve. CONCLUSIONS: Fontan physiology is associated with disadvantageous ventricular power and afterload profiles and has limited ventricular reserve capacity. Thus, to improve the long-term prognosis of patients after Fontan surgery, future research should be conducted into medical interventions that can overcome these limitations inherent in Fontan circulation.     

Effects of selected growth factors on porcine meniscus in chemically defined medium

Some evidence shows that selected growth factors can increase proteoglycan synthesis and that fibrin clot aids in the repair of meniscal tears. A significant (P<.05) dose-dependent stimulation of proteoglycan synthesis was found with platelet-derived growth factor AB (PDGF-[AB]), transforming growth factor-beta1 and bone morphogenetic protein-7 (osteogenic protein-I). In separate experiments, a significant increase in cellularity was found in the deep and superficial aspects of the explants treated with PDGF-(AB) compared with those treated with basal medium alone. The current study provides data as to which growth factors might prove most useful in the maintenance and repair of menisci.     

CD27/CD70, CD134/CD134 ligand, and CD30/CD153 pathways are independently essential for generation of regulatory cells after intratracheal delivery of alloantigen

BACKGROUND: We investigated whether blockade of tumor necrosis factor receptor-ligand pathways could generate regulatory cells induced by intratracheal delivery of alloantigen. METHODS: CBA (H-2k) mice were pretreated with intratracheal delivery of splenocytes (1x10(7)) from C57BL/10 (H-2b) mice and intraperitoneal administration of monoclonal antibody (mAb) specific for CD70, CD134 ligand (CD134L), CD153, or CD137L. Seven days later, C57BL/10 hearts were transplanted into pretreated CBA mice. Some naive CBA mice underwent adoptive transfer of splenocytes (5x10(7)) from pretreated CBA mice and transplantation of a C57BL/10 heart on the same day. RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time [MST] 12 days). Pretreatment with intratracheal delivery of C57BL/10 donor splenocytes prolonged graft survival significantly (MST 84 days). Mice given intratracheal delivery of alloantigen plus anti-CD70, anti-CD134L, or anti-CD153 mAb, but not those given intratracheal delivery of alloantigen plus anti-CD137L mAb, rejected their graft acutely (MST 16, 14, 10, and 65 days, respectively). Adoptive transfer of splenocytes from mice pretreated with intratracheal delivery of alloantigen plus anti-CD70, CD134L, or CD153 mAb did not prolong survival of C57BL/10 cardiac grafts in naive secondary CBA recipients (MST 14, 11, and 11 days, respectively), whereas adoptive transfer of splenocytes from mice given intratracheal delivery of alloantigen plus anti-CD137L mAb did (MST 75 days). CONCLUSION: The CD27/CD70, CD134/CD134L, and CD30/CD153 pathways are independently required for generation of regulatory cells in our model.     

A novel carbazole topoisomerase II poison,ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo

We have discovered a novel topoisomerase II (topo II) poison, ER-37328 (12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]py-rimido[5,6,1- jk ]carbazole-4,6,10(5H, 11H)-trione hydrochloride), which shows potent tumor regression activity against Colon 38 cancer inoculated s.c. Here, we describe studies on the cell-killing activity against a panel of human cancer cell lines and the antitumor activity of ER-37328 against human tumor xenografts. In a cell-killing assay involving 1-h drug treatment, ER-37328 showed more potent cell-killing activity (50% lethal concentrations (LC₅₀s) ranging from 2.9 to 20 μM ) than etoposide (LC₅₀s>60 μM ) against a panel of human cancer cell lines. ER-37328 induced double-stranded DNA cleavage, an indicator of topo II-DNA cleavable complex formation, within 1 h in MX-1 cells, and the extent of cleavage showed a bell-shaped relationship to drug concentration, with the maximum at 2.5 μM . After removal of the drug (2.5 μM ) at 1 h, incubation was continued in drug-free medium, and the amount of cleaved DNA decreased. However, at 10 μM , which is close to the LC₅₀ against MX-1 cells, DNA cleavage was not detected immediately after 1-h treatment, but appeared and increased after drug removal. This result may explain the potent cell-killing activity of ER37328 in the 1-h treatment. In vivo , ER-37328 showed potent tumor regression activity against MX-1 and NS-3 tumors. Moreover, ER-37328 had a different antitumor spectrum from irinotecan or cisplatin against human tumor xenografts. In conclusion, ER-37328 is a promising topo II poison with strong cell killing activity in vitro and tumor regression activity in vivo , and is a candidate for the clinical treatment of malignant solid tumors. (Cancer Sci 2003; 94: 119–124)     

A case of recurrent bacterial meningitis by delayed cerebrospinal fluid (CSF) leakage due to a head trauma]

A 42-year-old man was admitted due to recurrent bacterial meningitis, as he had been treated here for bacterial meningitis three years prior to the current event. He had a remote history of head injury that he had almost forgotten, and his laboratory data showed no immunodeficiency state. 111In-DTPA cisternography showed an abnormal radioactive accumulation in the frontal lobe adjacent to the left frontal sinus at 23 hours after intrathecal injection, and MPR CT images revealed the left frontal sinus bone fracture. These findings indicated that he had a head injury by which a delayed CSF fistula has been formed. He was surgically treated for a CSF leakage. Although a combination therapy of ABPC and CTRX was efficacious for this patient, this regimen may not be ideal, as meningitis by PRSP has been increasing in incidence. Pneumococcal meningitis, once not a difficult infection to treat, could be a difficult one, as resistant strains to ABPC and CTRX have been more common.