High-dose chemotherapy for high-risk retinoblastoma: clinical course and outcome of 14 cases in the National Cancer Center, Japan.

The prognosis of high-risk retinoblastoma (RB) with extraocular disease, relapse, or invasion of the cut end of the optic nerve is extremely poor. Following the discontinuation of thiotepa production in Japan, BU- and melphalan (Mel)-based regimens have been used, followed by the standard treatment for neuroblastoma. This study retrospectively analyzed 14 high-risk RB patients who underwent high-dose chemotherapy (HDC) and hematopoietic SCT; 8 received a BU/Mel conditioning regimen and 6 received other regimens. The disease status at HDC was relapse in 8 patients and extraocular involvement in 5. All patients received peripheral blood stem cell infusion >1.5 × 10(6)/kg. Engraftment occurred within a median of 11 days (BU/Mel: 10-13, others: 9-13). Primary toxicities included mucositis (⩾grade 3) in 9 patients (4 with BU/Mel, 5 with others). Veno-occlusive disease (VOD) occurred in two 1-year-old patients in the BU/Mel group. There were no treatment-related deaths. Of 4 (2 with BU/Mel, 2 with others) patients with central nervous system (CNS) relapse after HDC, 3 died. In conclusion, the BU/Mel regimen may be feasible for high-risk RB under careful monitoring for VOD, particularly in younger patients. CNS relapse associated with a lethal prognosis occurred after all regimens; therefore, further evaluation of HDC efficacy for high-risk RB is required.

Changes in microtubule-related proteins and autophagy in long-term vitamin E-deficient mice.

Vitamin E deficiency induces neuronal dysfunction and while oxidative stress is likely to be involved in mediating this process, the detailed mechanisms remain to be elucidated. Previously, we found axonal degeneration in the hippocampal CA1 region in vitamin E-deficient mice of 6 months of age (long-term). However, 3 month-old (short-term) vitamin E-deficient mice did not exhibit axonal degeneration in same region. In order to characterize the mechanisms involved in axonal degeneration in long-term vitamin E-deficient mice, we examined changes in microtubule-related proteins. Long-term vitamin E-deficiency led to significantly increased expression of the phosphorylated form of collapsin response mediator protein (CRMP)-2 compared to short-term deficiency. It is well known that CRMP-2 plays a crucial role in the maintenance of neurite function. Similarly, long-term vitamin E-deficiency significantly decreased the expression of silent mating type information regulation (SIRT)-2 mRNA compared to short-term deficiency. SIRT-2 belongs to a family of class III histone deacetylases (HDACs) and functions in the deacetylation of tubulins. Furthermore, the expression of microtubule-associated protein light chain (MAP-LC)3-2, which is a key autophagy protein was significantly higher in the short-term vitamin E-deficiency than the long-term deficiency. These results indicate that the mechanisms of axonal injury in long-term vitamin E-deficient mice are related to dysfunction in microtubules assembly via alterations in microtubule-related proteins and autophagy.

A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement.

The prognosis of patients with metastatic retinoblastoma is poor with conventional chemotherapy and radiation. Since retinoblastoma is highly chemosensitive, dose-escalation of chemotherapeutic agents with stem cell support should be promising. We report our experience with high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) in patients with metastatic retinoblastoma. Five patients with metastatic retinoblastoma underwent HDC with autologous SCT following conventional chemotherapy and local radiation therapy. Stem cells (bone marrow in four and peripheral blood stem cells in one) were collected after marrow involvement was cleared. Melphalan was a key drug in all patients, and was administered in combination with other agents such as cisplatin, cyclophosphamide, carboplatin or thiotepa. Three patients are currently alive disease-free at 113, 107 and 38 months, respectively, from the time of SCT. They had no central nervous system (CNS) involvement. The two patients who died of disease had CNS involvement. No long-term sequelae of HDC have been noted. Our treatment strategy using HDC appears to be effective for treating metastatic retinoblastoma without CNS involvement.

Augmentation of superoxide generation in phagocytosing murine peritoneal macrophages by dietary restriction.

The effects of dietary restriction on the generation of superoxide anion (O2-) in phagocytosing mouse peritoneal macrophages (MPs) were investigated. MPs obtained from diet-restricted mice generated larger amount of O2- during phagocytosis of opsonized zymosan than those from unrestricted mice. This augmentation of the O2- generation was not inhibited by the protein kinase C (PKC) inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). However, the augmentation was clearly disappeared when the calmodulin (CaM) antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) was added. These results strongly suggest that the augmentation of O2- generation in phagocytosing MPs by dietary restriction is due to the increased activity of CaM in the MPs, and that PKC is not involved in the augmentation. It is thought that one of the major factors for the reduced incidence of tumor and infection in diet-restricted animals is the augmentation of O2- generation in MPs.

Effects of intraperitoneally administered dietary fibers on superoxide generation from peritoneal exudate macrophages in mice.

To clarify whether edible polysaccharides (dietary fibers) have a host defense stimulating activity, the effects of intraperitoneally administered dietary fiber on the generation of microbicidal superoxide anion (O2-) in mouse peritoneal exudate macrophages (MP) were investigated. MP obtained from mice injected cellulose or pectin generated larger amount of O2- when stimulated by 12-o-tetradecanoylphorbol-13-acetate (TPA) or during phagocytosis of opsonized zymosan than those from mice injected proteose peptone, a widely used elicitor for MP. Especially, generated O2- from cellulose-elicited MP was as strikingly large as that from MP elicited by lentinan, a strong antitumor polysaccharide, when stimulated by TPA. Yeast mannan had no effect on O2(-)-generation. These results suggest the possibility that cellulose and pectin may act as host defense stimulators. The augmentation by cellulose or pectin of O2(-)-generation during phagocytosis was not inhibited by the calmodulin (CaM) antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). However, the augmentation was completely disappeared when the protein kinase C (PKC) inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) was added. These results strongly suggest that the augmentation of O2(-)-generation in phagocytosing MP by cellulose or pectin might be due to the increased activity of PKC in the MP, and that CaM may not be involved in the augmentation.

Dietary restriction augments superoxide generation in mouse peritoneal macrophages: an investigation using a chemiluminescence probe specific for superoxide anion.

It has not been clarified whether dietary restriction alters macrophage functions, although the augmentation of T cell functions by dietary restriction is well known. Forty percent dietary restriction on 9-week-old male C3H/He mice caused a decrease of body weight. However, one of the major macrophage functions, the generation of superoxide anion (O2), was augmented in proteose peptone-elicited peritoneal macrophages (MPs) from diet-restricted mice. This increase was more striking when the cells were stimulated by 12-o-tetradecanoylphorbol-13-acetate (TPA), which directly activated protein kinase C, than by opsonized zymosan which binded to receptors on the cells. These results strongly suggest that the augmentation of O2- generation in MPs by dietary restriction is due to the increased activity of protein kinase C which phosphorylate and activate O2-generating enzyme system NADPH oxidase. It is thought that one of the major factors for the reduced incidence of tumor and infection in diet-restricted animals is the augmentation of O2-generation in MPs.

[Case of hepatocellular carcinoma with a marked reduction in the tumor size induced by PSK administration alone].

A 56-year-old man was admitted to our hospital because of right abdominal pain. The edge of the liver was felt 4.5 fingers breadth below the xiphoid process. AFP was 20100 ng/ml and CEA was 5.6 ng/ml. The chest X-ray indicated existence of lymphangitis and some nodular density suggesting lung metastasis in the both lower-lung fields. 99mTc-phytate liver scan showed a large defect along the antero-inferior margin of the right hepatic lobe, which revealed an abnormal uptake of 67Ga-citrate. Ultrasonograms demonstrated a solid mass, 8 X 9 cm, in the right lobe of the liver. A CT-scan of the abdomen also showed a large, rounded, low attenuation mass with central necrosis in the right hepatic lobe: the pancreas and the remaining retroperitoneal structures appeared normal. Following the administration of PSK alone, 3 g daily, for three months, a remarkable regression of both hepatomegaly and lung metastasis was observed. Liver scan, ultrasonograms and CT-scan showed a striking resolution of the intrahepatic mass except central necrosis. AFP decreased to 33.7 ng/ml and CEA was 8.2 ng/ml. After about one year, however, ultrasonogramms showed a newly growing solid mass, 3.5 X 3.5 cm, in the left lobe of the liver. A needle biopsy specimen was taken from the intrahepatic mass, and it was interpreted as hepatoma. He is now healthy.