Satoshi Ashimine

Stromal Macrophage Expressing CD204 is Associated with Tumor Aggressiveness in Lung Adenocarcinoma

Background: Tumor tissue is composed of variable numbers of cancer cells and stromal cells, and tumor-associated macrophages are recruited into cancer-induced stroma and produce a specific microenvironment. Alternatively, activated macrophages (M2 phenotype) are known to be related to tumor progression and outcome, and CD204 has been reported to be expressed in M2 macrophages in some tumors. Methods: To investigate whether CD204-positive macrophages reflect tumor aggressiveness in adenocarcinoma of the lung, we investigated the relationships between the numbers of CD204-positive stromal macrophages and both clinicopathological features and outcome in 170 consecutive resected cases. We also examined the relationships between the numbers of CD204-positive macrophages and the expression levels of cytokines involved in the migration and differentiation of M2 macrophages. Results: The numbers of CD204-positive macrophages were significantly correlated with several prognostic factors. The log-rank test showed a significant association between the numbers of CD204-positive macrophages and a poor outcome (p = 0.0073), whereas the numbers of macrophages expressing CD68, a pan-macrophage/monocyte marker, were of marginal prognostic significance (p = 0.0789). We evaluated associations between the levels of expression of the cytokines IL-6, IL-10, IL-12a, IL-12b, M-colony-stimulating factor, IFN-gamma-., and monocyte chemoattractant protein-1 in cancer tissue and the numbers of CD204-positive macrophages. The expression levels of IL-10 and monocyte chemoattractant protein-1, which are involved in differentiation, accumulation, and migration of M2 macrophages, were significantly correlated with the numbers of CD204-positive macrophages (p = 0.031 and p = 0.031, respectively). Conclusion: These findings demonstrated that CD204-positive macrophages clearly reflect the tumor-promoting phenotype of tumor-associated macrophages in lung adenocarcinoma.

Targeting of Bone-Derived Insulin-Like Growth Factor-II by a Human Neutralizing Antibody Suppresses the Growth of Prostate Cancer Cells in a Human Bone Environment

Purpose: Advanced prostate cancer frequently involves the bone, where the insulin-like growth factor (IGF)-II is abundant. However, the importance of IGF-II in bone metastasis from prostate cancer is uncertain. The present study was aimed at examining the therapeutic importance of targeting IGF-II in bone metastases from prostate cancer. Experimental Design: We investigated whether inhibiting IGF-II using a human neutralizing antibody (m610) suppresses the growth of prostate cancer cells in a human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of nonobese diabetic/severe combined immunodeficient mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody (m102.4) once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells. Results: Histomorphologic examination indicated that m610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. m610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. m610 prevented the in vitro IGF-II–induced proliferation of MDA PCa 2b cells. Conclusions: Our results indicate that IGF-II plays an important role in the prostate cancer cell growth in human bone, suggesting that targeting it by neutralizing antibodies offers a new therapeutic strategy for bone metastasis from prostate cancer. Clin Cancer Res; 16(1); 121–29

Neither pre-transplant rituximab nor splenectomy affects de novo HLA antibody production after renal transplantation

The long-term effect of rituximab and splenectomy on de novo HLA antibody production and chronic antibody-mediated rejection after renal transplantation is uncertain. In order to gain insight on this, we studied 92 ABO-incompatible and 228 ABO-identical/compatible consecutive renal transplant patients and determined their de novo HLA antibody production and graft outcome. Patients with pretransplant donor-specific antibodies had been excluded. ABO-incompatible transplants included 30 recipients treated with rituximab, 51 by splenectomy, or 11 with neither, due to low anti-A or -B antibody titer. Graft survival in ABO-identical/compatible patients (97.7% at 5 years) was significantly higher than in ABO-incompatible (87.0% at 5 years), rituximab (96.7% at 3 years), or splenectomy (85.7% at 5 years) patients. Only four patients had clinical chronic antibody-mediated rejection (two each identical/compatible and incompatible). There was no significant difference in prevalence of de novo HLA antibody, including donor-specific and nondonor-specific antibodies among ABO-identical/compatible patients (13.9%), patients receiving rituximab (14.3%) or splenectomy (13.2%), or among those receiving cyclosporine, tacrolimus, mycophenolate mofetil, mizoribine, and everolimus. Renal function remained stable in most recipients with de novo HLA antibody. Thus, neither pretransplant splenectomy nor rituximab treatment has an inhibitory effect on de novo HLA antibody production during medium-term follow-up. Further study on long-term effects is needed.

Serum amino acids as indicators of cerebrospinal neuronal activity in patients with micturition disorders

Objective: Our previous study showed that the spinal glycine level in rats was changed by spinal injury or bladder outlet obstruction, and this change was reflected by serum glycine levels. Therefore, we measured the serum glutamate and glycine levels in healthy volunteers and patients with cerebrospinal damage or benign prostatic hyperplasia (BPH) to confirm whether the change of serum amino acid levels was obtained from these patients as well as the animal experiment.

Langerhans cell histiocytosis on the penis: a case report

BackgroundLangerhans cell histiocytosis affects mainly young children and features an accumulation of CD1a+ dendritic Langerhans cells in the bone, skin, and other organs. A few cases of Langerhans cell histiocytosis on the penis have been reported in the literature. We present a case of Langerhans cell histiocytosis on the penis and review the similar cases in the literature.Case presentationThe patient was a 13-year-old boy who had a history of lymph node, femur bone, and pituitary-thalmic axis lesions from Langerhans cell histiocytosis who noticed a painful nodule on the prepuce of his penis. The histological and immunohistochemical examination fulfilled the criteria of Langerhans cell histiocytosis.ConclusionWe herein describe the case reported of Langerhans cell histiocytosis on the penis.

Distal ureteral atresia: Recovery of renal function after relief of obstruction at ten months old

Abstract  A large cystic mass that occupied more than half of the abdomen was identified by ultrasound in a 10‐month‐old boy. Intravenous pyelography failed to visualize the right kidney, so we created a loop ureterocutaneostomy followed by temporary nephrostomy to improve renal function. Exploratory surgery revealed complete atresia of the distal right ureter. A ureteral stricture developed after ureteroneocystostomy and undiversion of the loop, so a second reconstruction procedure was required (pelvi‐ureteroplasty and reimplantation of the right ureter with a psoas hitch) to free the patient from dependence on catheters. Despite the occurrence of giant hydronephrosis secondary to complete ureteral obstruction at the age of 10 months, the function of the right kidney could be preserved. Accordingly, aggressive attempts to promote functional recovery may be justified even when patients have advanced hydronephrosis.

Kidney autotransplantation in a patient with renal pelvic and bladder carcinomas

A 66‐year‐old Japanese woman, whose left kidney was non‐functioning, was referred to us with a diagnosis of invasive bladder carcinoma and right renal pelvic carcinoma. The latter tumor was clearly packed in the renal calyx and was considered to be of low‐grade malignancy. Nephron preserving surgery of the right kidney was performed, followed by radical cystectomy and construction of an ileal conduit. The postoperative course was good, without significant complications. Renal function was restored and a postoperative imaging study showed a well‐functioning transplanted kidney. At present (20 months after surgery), the patient is doing well and has presented no signs of recurrence of the disease.

Abstract B129: Preclinical assessment of targeting insulin‐like growth factor‐2 in bone metastasis from prostate cancer by a human neutralizing antibody (m610) and human adult bone implanted model

Background: Insulin‐like growth factor (IGF)‐2 activates IGF‐1 receptor (IGF‐1R) as well as insulin receptor (IR). Recently, it is becoming increasingly evident that IR activation by IGF‐2 enhances the growth of neoplasms such as Ewing sarcoma and breast cancer in addition to the IGF‐1R activation. Advanced prostate cancer frequently and organ‐specifically metastasizes to the bone, where the IGF‐2 is abundant. However, the role of IGF‐2 in bone metastasis from prostate cancer is still uncertain. The present study was aimed at exploring the role of IGF‐2 in the growth of prostate cancer cells in a human bone environment and the therapeutic potential of inhibiting IGF‐2 by a neutralizing antibody in the bone metastasis. Materials and Methods: Using our human neutralizing antibody to IGF‐2 (m610) and human adult bone implanted mouse model, we investigated whether inhibiting IGF‐2 suppresses the growth of prostate cancer cells in the human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of NOD/SCID mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells. At 4 weeks after the treatments, histological analyses of the obtained specimens were performed. Results: M610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki‐67 immunostaining revealed that the percentage of proliferating cancer cells in the m610‐treated bone tumor sections was significantly lower than that in the control. M610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. IGF‐1R and IR expressions on the MDA PCa 2b tumors were confirmed by immunostaining. M610 prevented in vitro IGF‐2‐induced cell proliferation, phosphorylation of the receptors and phosphorylation of Akt in MDA PCa 2b cells. Conclusions: These results demonstrate that IGF‐2 plays a crucial role in the prostate cancer cell growth in human bone. Targeting IGF‐2 by neutralizing antibodies would be a promising therapeutic approach to preventing bone metastasis from prostate cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B129.