Effects of immunosuppressants on the progression of hepatitis C in hepatitis C virus-positive renal transplantation and the usefulness of interferon therapy

OBJECTIVE: The purpose of this study was to analyze the effects of immunosuppressants on hepatitis C virus (HCV) replication to establish optimal immunosuppressive therapy in HCV-positive renal transplantation. MATERIALS AND METHODS: Cyclosporine (CsA), tacrolimus (Tac), mycophenolate acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and methylprednisolone (MP) were administered to HCV replicon cells alone or in combination with interferon (IFN). HCV RNA was quantitatively determined. Of our 2064 recipients of renal transplantations between 1980 and 2005, 153 were HCV-positive. We analyzed changes in hepatic function and the efficacy of IFN therapy in these patients. RESULTS: Only CsA strongly inhibited the growth of HCV RNA (13.1% at 1.0 mug/mL). MPA enhanced the inhibition of the growth of HCV RNA in the presence of IFN. Tac and MP reduced, rather than enhanced, the efficacy of IFN. Progression to chronic hepatitis occurred in a significantly smaller number of patients in the CsA than the Tac group (6 vs 19; P = .04). Serum alanine aminotransferase (ALT) levels were comparable pretransplantation and posttransplantation in the CsA group (24.8 +/- 20.5 vs 28.9 +/- 28.3 IU/L, respectively, while a significant elevation was noted in the Tac group (22.2 +/- 21.5 vs 32.6 +/- 30.8 IU/L, respectively; P = .024). Two of 4 patients who underwent combination therapy with IFN and ribavirin during treatment with CsA and MMF obtained an HCV-negative status for over 24 weeks. CONCLUSIONS: CsA effectively prevents the progression of chronic hepatitis in HCV-positive renal transplant patients. A greater response rate can be expected by concurrent administration of CsA and MMF under IFN therapy.     

Clinical application of modified polyurethane graft to blood access.

Based on a study of 34 clinical implantations, a porous poly(ether-urethane) graft developed for blood access was evaluated. Although it became clear that the graft has several advantages over expanded polytetrafluoroethylene (E-PTFE), it was also revealed that the occlusion at the anastomotic site was more frequently observed than that with E-PTFE. To improve the patency rate, a small modification of the luminal surface was attempted to give a better anchoring of the neointima. The results so far are better than those with the unmodified graft. However, the number of cases is small and the period of observation is short. More work will be necessary to confirm these preliminary results.     

The Japanese Interferon Study Group (JISG) has established the efficacy of human interferon-β for serious CMV pneumonitis in kidney recipients

The Japanese Interferon Study Group (JISG) is a research organization formed by 30 special hospitals for organ transplantation. A joint multi-centre, double-blind trial was conducted in order to investigate the efficacy of human interferon-β(HuIFN-β) against serious cytomegalovirus pneumonitis in kidney recipients.     

Continuous intra-arterial infusion chemotherapy by implantable catheter access connected with a continuous infusion pump

Eleven non-resectable cancer patients have been successfully treated by means of a one-shot and continuous intra-arterial infusion chemotherapy, utilizing an implantable vascular access device (Catheter Access) connected to a continuous infusion pump (Nipro portable syringe infusion pump) via a non-corning needle (Nipro coreless needle set). This result suggests that this simple and inexpensive method can be applied not only for cancer chemotherapy but also for intravenous hyper-alimentation and for treatment of epidural anesthesia.     

Prediction of iopromide reduction rates during haemodialysis using an in vitro dialysis system.

BACKGROUND: In clinical studies, it has been difficult to evaluate the influence of haemodialysis (HD) parameters on HD clearance (CL(HD)) and reduction rate (RR) of non-ionic contrast medium during HD sessions. We therefore predicted clinical values of CL(HD) and RR of iopromide, a non-ionic contrast medium, from findings obtained from in vitro experiments, and confirmed that these predictive values were comparable with the actual values in clinical cases. METHODS: We developed a correlation equation for predicting CL(HD) on the basis of in vitro HD experiments by varying blood flow rates between 100 and 200 ml/min with a cuprammonium rayon dialyser (AM-SD-10H). Total body clearance of iopromide (CL(PT)) was estimated by the Cockroft-Gault equation. The volume of distribution (V(d)) was obtained from the reported value. By using the HD and three pharmacokinetic parameters (CL(HD), CL(PT) and V(d)), we predicted CL(HD) and RR for seven patients undergoing HD after the administration of iopromide. RESULTS: In the in vitro study, the mean values (+/-SD) of iopromide clearance at blood flow rates of 100, 150 and 200 ml/min were 45.35 (2.54), 53.88 (6.46) and 57.61 (4.72) ml/min, respectively. There were highly significant correlations between clearance and blood flow rate (r = 0.975). Although the predicted CL(HD) showed a tendency towards underestimation, a good correlation was found. Predicted RR values were similar to observed values except for one case. CONCLUSION: The in vitro model used in the present study provides pertinent information about CL(HD) and is helpful for predicting RR during HD in individual patients undergoing HD.     

CD24, not CD47, negatively impacts upon response to PD‐1/L1 inhibitors in non–small‐cell lung cancer with PD‐L1 tumor proportion score < 50

CD24, a heavily glycosylated glycosylphosphatidylinositol–anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti‐phagocytic factors and the immune response with immune–checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non–small‐cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival (PFS) of ICI when PD‐L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD‐L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4‐6 wk later, and such increase was notably observed only when PD‐L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)‐A, D and PDGF‐AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non–small‐cell lung cancer with PD‐L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414).     

Usefulness of late gadolinium enhancement combined with MRI and 67-Ga scintigraphy in the diagnosis of cardiac sarcoidosis and disease activity evaluation

We report a case in which late gadolinium enhancement (LGE) and 67-Ga scintigraphy were useful for the diagnosis of cardiac sarcoidosis and for the evaluation of the disease activity.The patient was a 60-year-old woman who had been diagnosed as having eye sarcoidosis when she was 48. Two years previously her electrocardiogram had shown abnormalities but the coronary angiography had shown normal coronary arteries; however, an aneurysm was detected in the apical portion by left ventriculography. A II degree AV block was noted on the electrocardiogram and she was referred to us for further detailed evaluation. Since the biopsy findings of skin eruptions on both eyelids indicated an epithelial cell granuloma, she was diagnosed as having cutaneous sarcoidosis. On the 67-Ga scintigram, myocardial accumulation of gallium was recognized, and on cardiovascular magnetic resonance (CMR), LGE was recognized. She was diagnosed as cardiac sarcoidosis and steroid therapy started with 30 mg prednisolone. The myocardial accumulation of gallium on the 67-Ga scintigram disappeared after the 30th day of steroid therapy. On the other hand, no changes in LGE patterns were seen after steroid therapy. In this case, LGE was useful for the diagnosis of cardiac sarcoidosis, and 67-Ga scintigram was useful for the evaluation of the disease activity. This case shows that both imaging techniques are important for the diagnosis of cardiac sarcoidosis and evaluation of the disease.     

Vascular endothelial growth factor promotes proliferation and function of hepatocyte-like cells in embryoid bodies formed from mouse embryonic stem cells

BACKGROUND/AIMS: Embryoid bodies (EBs) formed from embryonic stem cells (ESCs) differentiate into hepatocyte-like cells (HLCs), and are thus thought to be a useful cell source for drug testing and bioartificial liver. The aim of this study was to induce proliferation and function of ESC-derived HLCs in EBs using HLC-endothelial cell interaction. METHODS: EBs were cultured in the presence of vascular endothelial growth factor (VEGF) and/or VEGF receptor (VEGFR) inhibitors. To reproduce HLC-endothelial cell interaction, we overexpressed VEGF in ESC-derived HLCs under the control of Cyp7a1 gene in EBs. RESULTS: VEGF added to the cultured EBs increased the proliferation of ESC-derived endothelial cells, resulting in the promotion of proliferation and function of ESC-derived HLCs. In EBs, the VEGFR2 inhibitor suppressed expression of albumin and endothelial cell marker genes, whereas the inhibitor for both VEGFR1 and VEGFR2 suppressed expression of Cyp7a1 and hepatocyte growth factor (Hgf) genes. Upon exposure to VEGF, the endothelial cells in EBs increased Hgf mRNA expression. Forced VEGF expression in ESC-derived HLCs in EBs induced angiogenesis around the HLCs and resulted in an increase in the amount of HLCs. CONCLUSIONS: VEGF indirectly induces the proliferation and function of ESC-derived HLCs through VEGFR1 and VEGFR2 signaling in endothelial cells.