Kiyohiko Hotta

Clinical importance of B7-H3 expression in human pancreatic cancer

Background:B7-H3 is a new member of the B7 ligand family and regulates T-cell responses in various conditions. However, the role of B7-H3 in tumour immunity is largely unknown. The purpose of this study was to evaluate the clinical significance of B7-H3 expression in human pancreatic cancer and the therapeutic potential for cancer immunotherapy.Methods:We investigated B7-H3 expression in 59 patients with pancreatic cancer by immunohistochemistry and real-time PCR. Furthermore, we examined the anti-tumour effect of B7-H3-blocking monoclonal antibody in vivo in a murine pancreatic cancer model.Results:Tumour-related B7-H3 expression was abundant in most human pancreatic cancer tissues and was significantly higher compared with that in non-cancer tissue or normal pancreas. Moreover, its expression was significantly more intense in cases with lymph node metastasis and advanced pathological stage. B7-H3 blockade promoted CD8+ T-cell infiltration into the tumour and induced a substantial anti-tumour effect on murine pancreatic cancer. In addition, the combination of gemcitabine with B7-H3 blockade showed a synergistic anti-tumour effect without overt toxicity.Conclusion:Our data show for the first time that B7-H3 may have a critical role in pancreatic cancer and provide the rationale for developing a novel cancer immunotherapy against this fatal disease.

Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury.

Prognostic significance of CD45RO+ memory T cells in renal cell carcinoma

Background:Memory T cells are well known to have a critical role for host defense in humans. However, their role in actual human cancer remains largely unknown. In this study, we tried to reveal the clinical importance of tumour-infiltrating CD45RO+ memory T cells in renal cell carcinoma (RCC).Methods:We analysed 105 patients with RCC, who received radical or partial nephrectomy. Those were 65 in TNM stage I, 7 in stage II, 15 in stage III, and 18 in stage IV, respectively. CD45RO expression was evaluated by immunohistochemistry. CD4 and CD8 expressions were also systematically assessed in the same manner.Results:Patients with higher TNM stage or high nuclear grade were found to have higher densities of CD45RO. Furthermore, CD45RO status was positively correlated with preoperative C-reactive protein level. In prognostic analysis, CD45RO+lo patients had a significantly better prognosis than CD45RO+hi patients. There was also a significant difference between CD4+lo and CD4+hi groups, whereas no significant difference was observed in CD8 T-cell status. Finally, multivariate analysis revealed that CD45RO+ status was the independent prognostic factor for patient overall survival.Conclusion:CD45RO+ memory T-cell status has a significant independent prognostic value, indicating that the adaptive immune response is functionally critical in human RCC.

PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis.

The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease.

Clinical Significance of Prostate Stem Cell Antigen Expression in Non-small Cell Lung Cancer

OBJECTIVE Prostate stem cell antigen was originally identified as an overexpressed gene in prostate cancer and its overexpression correlated with disease progression and prognosis. In this study, we investigated the clinical significance and therapeutic potential of prostate stem cell antigen expression in non-small cell lung cancer. METHODS Prostate stem cell antigen expression was examined by immunohistochemistry in 97 primary tumors and 21 metastatic lymph nodes from non-small cell lung cancer patients who underwent curative resection from January 2001 through March 2003. Therapeutic potential of targeting prostate stem cell antigen was further examined by small interfering RNA method using human lung cancer cell line (A549). RESULTS Prostate stem cell antigen protein expression was detected in 94 of 97 primary lesions (97%) and all metastatic lymph nodes. Prostate stem cell antigen expression intensity was positively correlated with advanced pathological T-factor and stage (T1 vs. T2-4, P = 0.014; Stage I vs. Stages II-IV, P = 0.029, respectively). The prognosis of patients with low prostate stem cell antigen expression was significantly better than those with high prostate stem cell antigen expression (5-year disease-free survival rate; 90% vs. 53%, P = 0.001). Finally, small interfering RNA-mediated knockdown of prostate stem cell antigen resulted in the inhibition of lung cancer cell growth. CONCLUSIONS Prostate stem cell antigen is highly expressed in non-small cell lung cancer and may be functionally important for this fatal disease.

Clinical impact of tumor-infiltrating CD45RO+ memory T cells on human gastric cancer

Memory T cells survive for months and even years and are critical for host defense in humans. They have been recently suggested to play a significant role in tumor immunity. In this study, we aimed to investigate the clinical impact of tumor-infiltrating memory T cells on human gastric cancer. We evaluated CD45RO(+)T cells infiltrating into primary gastric cancer tissues by immunohistochemistry in 101 patients with gastric cancer. Patients were classified into 2 groups (CD45RO(+Hi) and CD45RO(+Lo)) based on the number of positively stained T cells. There was no significant correlation observed between CD45RO status and post-operative prognosis in early gastric cancer. By contrast, in advanced cancer, the post-operative overall and disease-free survival of patients with CD45RO(+Hi) were significantly improved compared to those of patients with CD45RO(+Lo). In addition, CD45RO status in the primary tumors significantly correlated with the development of post-operative recurrence, particularly peritoneal recurrence. Furthermore, the local expression of interferon-γ (IFN-γ) in the CD45RO(+Hi) tumors was significantly higher than that in the CD45RO(+Lo) tumors, suggesting that CD45RO(+) T cells induced local immune activation. Multivariate analysis indicated that the CD45RO(+) status was an independent prognostic factor in advanced gastric cancer. In conclusion, tumor-infiltrating CD45RO(+) memory T cells are functional and have significant prognostic value in human gastric cancer. Our data suggest that adaptive immune response is clinically critical in gastric cancer.

Tonsillectomy ameliorates histological damage of recurrent immunoglobulin A nephropathy after kidney transplantation.

Recurrence of immunoglobulin A (IgA) nephropathy (IgAN) after renal transplantation is important as a cause of graft failure under improving rejection control. However, no specific therapy for recurrent IgAN is currently available. In this study, we evaluated the histological efficacy of tonsillectomy for allograft IgAN.

Pediatric kidney transplantation is safe and available for patients with urological anomalies as well as those with primary renal diseases

Abstract:  The aim of the current study was to evaluate long‐term outcomes of pediatric live kidney transplantation in patients with genitourinary anomalies relative to those with primary kidney diseases. The study included 35 pediatric patients who received a live kidney transplantation during the last 25 yr (28 males, six females). Median age at the time of transplantation was nine yr (range 1–15 yr), and the median follow‐up period was 151 months (range 6–239 month). The patients were divided into two groups. The urological group (n = 14) included patients with primary obstructive/reflux nephropathy. The renal group (n = 20) included patients with primary renal disorders. Differences between groups in graft survival, clinical course, and final graft function were evaluated. Original diseases represented in the urological group included five cases with primary VUR and eight cases with secondary VUR. Diseases in the renal group included eight cases with bilateral hypo‐dysplastic kidney, three cases with focal/segmental glomerular sclerosis, two cases with membranous proliferative glomerulonephritis, two cases with congenital nephrotic syndrome and five cases with other forms of chronic nephritis. Ten of 14 cases in the urological group, relative to six of 20 in the renal group, were preemptive. Median age at transplantation was 7.5 or 10 yr old, respectively, in the urological or renal group. Twelve kidney recipients in the urological group had also undergone other urinary surgeries, including upper urinary tract drainage, ureteroneocystostomy, augmentation cystoplasty, endoscopic incision of posterior‐urethral valve, urethroplasty, etc. Cumulative post‐operative complications occurred in nine or 16, respectively, in the urological or renal group. The acute rejection free and overall graft survival were similar in both groups. One patient in the urological group lost his graft while six patients in the renal group lost their grafts. Thus, the post‐transplant clinical outcome of pediatric transplantation in patients with urological anomalies is comparable to that of recipients with primary renal disease. Appropriate urinary tract reconstruction and management is essential to reduce the risk of graft dysfunction because of urinary problems.

Successful kidney transplantation ameliorates arterial stiffness in end-stage renal disease patients.

PURPOSE Successful kidney transplantation (KTx) can ameliorate bodily damage caused by end-stage renal disease (ESRD). Arterial stiffness (AS) is one of the critical factors that shorten the survival of patients due to cardiovascular events. KTx may reduce AS as well; however, this has not been investigated well. We therefore conducted a retrospective study using noninvasive pulse wave velocity (PWV), which is a useful index of aortic damage. PATIENTS AND METHODS Fifty-eight consecutive kidney recipients (34 men, 24 women) were enrolled in this study. Mean age at transplantation was 40.5 ± 12.3 years and the dialysis period was 73.1 ± 95.8 months. The brachial-ankle PWV was measured preoperatively and 6 months postoperatively. First, we investigated the relationship between the PWV and the other parameters related to AS. Second, we studied the pre- to posttransplant change in PWV to evaluate the amelioration of AS after successful KTx. RESULTS PWV showed significant positive correlations with age, systolic blood pressure (BP), diastolic BP, and abdominal aortic calcification index. After successful KTx, PWV significantly decreased (P < .01). In addition, systolic and diastolic BP significantly decreased (P < .01 and P < .05, respectively). CONCLUSION Successful KTx ameliorates AS in ESRD patients. This might explain the improved cardiovascular prognosis of ESRD patients who undergo KTx.

Granulomatous tubulointerstitial nephritis in a renal allograft: three cases report and review of literature

Granulomatous interstitial nephritis (GIN) is a rare histologic diagnosis in renal allografts. We report three cases with GIN. Case 1: a 37‐yr‐old woman received a kidney from her mother. On follow‐up 15 months later, serum creatinine was increased and a graft biopsy showed epithelioid granuloma in the center of massive mononuclear cell infiltration. She had presented with refractory urinary tract infection treated with antibiotics before biopsy. The case was presumed to be GIN associated with UTI or hypersensitivity to medication. Case 2: a 47‐yr‐old woman received a second graft from a non‐heart‐beating donor. A protocol graft biopsy was performed six months after transplantation and showed several granulomatous nodules. She was followed closely without therapy. Case 3: a 27‐yr‐old woman received an ABO‐incompatible kidney from her father. A protocol graft biopsy was performed three months after transplantation and showed granulomatous reaction with severe mononuclear cell infiltration. She received steroid pulse therapy. The two latter patients had no obvious factor contributing to GIN. Therefore, they were presumed to have idiopathic GIN. Infection is considered to be the main causative factor of GIN in renal allografts. This paper describes rare cases of GIN that had no infectious episode in the renal allografts.