Polymer design and incorporation methods for polymeric micelle carrier system containing water-insoluble anti-cancer agent camptothecin

A water-insoluble anti-cancer agent, camptothecin (CPT) was incorporated to a polymeric micelle carrier system forming from poly(ethylene glycol)-poly(aspartate) block copolymers. Incorporation efficiency and stability were analyzed in correlation with chemical structures of the inner core-forming hydrophobic blocks as well as with incorporation methods. Among three incorporation methods (dialysis, emulsion and evaporation methods), an evaporation method brought about much higher CPT yields with less aggregation than the other two methods. By the evaporation method, CPT was incorporated to polymeric micelles in considerably high yields and with high stability using block copolymers possessing high contents of benzyl and methylnaphtyl ester groups as hydrophobic moieties. This indicates importance of molecular design of the hydrophobic block chain to obtain targeting using polymeric micelle carriers as well as importance of the drug incorporation method.     

Combination of alpha-fetoprotein mRNA-based detection of hematogenously disseminating hepatocellular carcinoma cells and analysis of cancer cell membrane fluidity is more accurate in screening patients at risk of postoperative recurrence

We developed an mRNA-based, highly specific and sensitive method to detect hepatocellular carcinoma cells present in blood. However, the reason for some patients being positive for blood analysis and negative for recurrence has yet to be found. We recently established a method to measure membrane fluidity of hepatocellular carcinoma cells, and used it to analyze the actual membrane fluidity of human hepatocellular carcinoma cells. We found that patients with carcinoma cells with lower membrane fluidity less frequently developed recurrence. The analysis of both membrane fluidity and alpha-fetoprotein mRNA thus greatly increased the accuracy of the prediction of postoperative recurrence.     

Richter's syndrome presenting as a nasal lymphoma

Richter's syndrome (RS) is a high-grade large cell lymphoma arising in patients with B-cell chronic lymphocytic leukemia (CLL). The prognosis of RS is very poor and the development of RS is a serious complication of CLL. We present a case of a patient with a 4-year history of B-cell CLL who developed diffuse large B-cell nasal lymphoma. The patient exhibited good response to chemotherapy and irradiation and achieved complete remission. Five months later, the patient suffered leptomeningeal involvement and has been treated with repeated intrathecal chemotherapy. Leukemic cells of the patient expressed CD13. CD13+ CLLs have been reported to have an unfavorable prognosis and this case may support the view.     

DNA methylation profiles of lymphoid and hematopoietic malignancies.

PURPOSE: Aberrant methylation of the 5' gene promoter regions is an epigenetic phenomenon that is the major mechanism for silencing of tumor suppressor genes in many cancer types. The aims of our study were (a) to compare the methylation profiles of the major forms of hematological malignancies and (b) to determine the methylation profile of monoclonal gammopathy of undetermined significance (MGUS) and compare it with that of multiple myeloma (MM). EXPERIMENTAL DESIGN: We compared the aberrant promoter methylation profile of 14 known or suspected tumor suppressor genes in leukemias (n = 48), lymphomas (n = 42), and MMs (n = 40). We also examined the methylation profile of MGUS (n = 20), a premalignant plasma cell dyscrasia. The genes studied represent five of the six "hallmarks of cancer." RESULTS: Peripheral blood lymphocytes (n = 14) from healthy volunteers were negative for methylation of all genes, and methylation percentages in 41 nonmalignant tissues (peripheral blood mononuclear cells, bone marrows, and lymph nodes) from hematological patients were low (0-9%) for all 14 genes, confirming that methylation was tumor specific. Ten of the genes were methylated at frequencies of 29-68% in one or more tumor types, and the methylation indices (an indicator of overall methylation) varied from 0.25 to 0.34. With two exceptions, the methylation patterns of leukemias and lymphomas were similar. However, the pattern of MMs varied from the other tumor types for six genes. In general, the methylation pattern of MGUS was similar to that of MM, although the methylation frequencies were lower (the methylation index of MGUS was 0.15, and that of MM was 0.3). However, the methylation frequencies of six genes were significantly higher in MGUS than in control tissues. The relatively high frequencies of methylation in MGUS are consistent with it being a premalignant condition. CONCLUSIONS: The three major forms of lymphoid/hematopoietic malignancies show overlapping but individual patterns of methylation.     

A case of chondromatous tumor of the breast

This report describes an exceedingly rare case of a benign cartilage-containing breast tumor that developed in the right breast of a 52-year-old woman. She found the mass on self examination. Physical examination revealed a 1.5 x 1.4 cm, firm, smooth and mobile lump in the lower medial quadrant close to the nipple of the right breast. Mammography revealed a slightly indistinct margined, oval-shaped, and high density nodule without microcalcifications. On ultrasonography, the lesion was a hypoechoic, oval-shaped mass with an echogenic spot. The border was slightly rough. Fine needle aspiration cytology revealed some giant cells and necrotic tissue. Excisional biopsy was then performed. Histopathologically, the lesion consisted of islands of mature hyaline cartilage with intervening strands of fibrous stroma. Mammary lobules and ducts were lacking within the mass. Fat and muscular components were not present. Therefore chondromatous tumor of the breast was diagnosed.     

Surgical resection deteriorates gemcitabine-induced leukopenia in pancreatic cancer

Background Gemcitabine hydrochloride (GEM) is one of the most effective chemotherapeutic agents for pancreatic cancer; however, factors affecting GEM-induced leukopenia have not been clarified yet. In the present study, we analyzed the relationship between patients backgrounds and GEM-induced leukopenia.Methods Thirty-eight patients with pancreatic cancer were analyzed for correlation between the dose of GEM and the blood leukocyte number. Moreover, we compared leukopenia in resected and non-resected patients.Results The incidence of grade 3 or 4 leukopenia was 25% in the non-resected patients, whereas equivalent leukopenia was observed in 57% of the resected patients (P = 0.048 by the ² test). The relative decrease in blood leukocytes induced by GEM administration was more severe in resected patients (41.3 ± 9.9%), as compared to non-resected patients (52.6 ± 16.0%; P = 0.023 by t-test).Conclusion In the present study, we found that the administration of GEM to patients after surgical resection caused more severe leukopenia, as compared to findings in non-resected patients. These data suggested that more frequent monitoring of the leukocyte count and prolonged intervals between GEM administrations are necessary for resected patients with pancreatic cancer.     

Formation of advanced glycosylation end products and oxidative stress in young patients with type 1 diabetes

Increased production of advanced glycosylation end products (AGEs) and augmented oxidative stress may contribute to vascular complications in diabetes. Little is known about the formation and accumulation of AGEs in young patients with type 1 diabetes. The aim of the present study was to investigate whether AGE production and oxidative stress are augmented in young patients with type 1 diabetes at early clinical stages of the disease. Urine samples of 38 patients with type 1 diabetes [mean age (+/-SD), 12.8 +/- 4.5 y; diabetes duration, 5.7 +/- 4.3 y; HbA1c, 8.0 +/- 1.6%; urinary albumin excretion, 12.6 +/- 14.4 mg/g creatinine (Cr)] and those of 60 age-matched healthy control subjects were assayed for AGEs, pentosidine and pyrraline, and markers of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and acrolein-lysine. Of these four markers, urinary concentrations of pentosidine, 8-OHdG, and acrolein-lysine were significantly higher in the patients with diabetes than in the healthy control subjects. For the patient group, pentosidine correlated significantly with 8-OHdG and acrolein-lysine, and pyrraline correlated significantly with acrolein-lysine. Urinary pentosidine, 8-OHdG, and acrolein-lysine but not pyrraline correlated significantly with urinary albumin excretion. Patients with microalbuminuria (> or =15 mg/g Cr) showed significantly higher levels of all four markers than did normoalbuminuric patients and control subjects. The present study indicates that accumulation of AGEs, whose formation is closely linked to oxidative stress, and resultant endothelial dysfunction may start early in the course of type 1 diabetes. This means that the risk of vascular complications may be present at an early age and that the best possible glycemic control should be emphasized from the diagnosis of diabetes.     

Whole-blood manganese levels and brain manganese accumulation in children receiving long-term home parenteral nutrition

Recent reports attribute neurological and cerebral disorders to the accumulation of manganese (Mn) in the brain in patients receiving home parenteral nutrition (HPN). It is desirable to control the amount of Mn delivered to these patients, but a suitable method for monitoring an individual's Mn status and assessing Mn accumulation remains debatable. The aim of this study was to evaluate whether whole-blood manganese levels (WB-Mn) correlate with the accumulation of Mn in the brains of children who receive long-term HPN, using magnetic resonance imaging (MRI) of the brain. Six patients who had received HPN (duration of HPN, 18-137 months) were included in this study. The daily parenteral doses of Mn were calculated while on HPN. WB-Mn was measured and T1-weighted MRI of the brain was obtained for each patient with a 1.5-T MR imager. Twelve months after the withdrawal of Mn from HPN, measurements of WB-Mn and brain MRI were repeated in all patients except for one who was lost after initial examination. The same examinations were performed on an additional patient who had been successfully weaned off a 179 month course of HPN 20 months prior to the initial examination. The parenteral dose of Mn while receiving HPN ranged from 15.7 to 91.5 micro g/kg/day. Initially, MRI showed hyperintensity in the globus pallidus in all patients and in the anterior pituitary in one patient. WB-Mn was elevated in four patients, but was in the normal range in the remaining three. Following subsequent measurements 12 months later, WB-Mn was normal in all patients and MRI hyperintensity remained in the globus pallidus in one patient. One patient was lost after the initial examinations. WB-Mn does not necessarily correlate with the accumulation of Mn in the brain. Periodic MRI should be performed in patients receiving long-term NPN to monitor for excessive Mn accumulation in the brain.     

Ruptured middle cerebral artery aneurysm with intramural myxoid degeneration in a child

A 9-year-old girl presented with a subarachnoid hemorrhage. Cerebral angiography showed a saccular aneurysm arising from the horizontal portion of the right middle cerebral artery. The aneurysm was successfully clipped, and the dome of the aneurysm was excised for pathological study. Histological examination of the aneurysm wall showed that the entire thickness of the wall showed an increased myxoid degeneration. No dissection was present. Most intracranial aneurysms in childhood are believed to be of the saccular type similar to that in adults, but the pathogenesis of the aneurysm formation remains controversial. Myxoid degeneration may cause intracranial saccular aneurysm with eventual rupture, even in the absence of dissection. This is the first case reported of a ruptured saccular aneurysm caused by myxoid degeneration in a child. The possible pathophysiology is discussed.     

Amyloidosis modifier genes in the less amyloidogenic a/j mouse strain

Apolipoprotein A-II is deposited as an amyloid fibril in aged mice (senile AApoAII amyloidosis). Although mouse strains with the apolipoprotein A-II c allele (Apoa2(c)) generally develop early-onset and severe senile amyloidosis, the A/J strain shows significantly less amyloid deposition. To identify genes that modify spontaneous amyloidosis development in the A/J mouse, we performed a genome-wide screening using hybrid mice derived from A/J and SAMP1 mice, which have Apoa2(c) and age-associated severe amyloid deposition. Our genetic analysis revealed that the lower levels of amyloidosis in the A/J strain were polygenically controlled. We found two chromosome locations associated with amyloidosis. One of these regions was in the chromosome 19 telomeric region, where the A/J alleles modify amyloidosis in an additive manner. The second region was in the chromosome 4 telomeric region, where the A/J alleles modify amyloidosis in a dominant manner. Perlecan and group II secretory phospholipase A2, located on the significantly linked region of chromosome 4, were compared in this study. These findings are for understanding the genetic mechanism of amyloidosis-related diseases and their prevention.