Clinical outcomes of a novel therapeutic vaccine with Tax peptide‐pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study

Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type‐I (HTLV‐I)‐infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV‐I Tax‐specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti‐ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate‐ to high‐risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax‐specific CTL responses were observed with peaks at 16–20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide‐pulsed DC vaccine is a safe and promising immunotherapy for ATL.     

Morphometric investigation of the hippocampal formation in Ihara's genetically epileptic rats using magnetic resonance images and histopathology

The newly developed Ihara's genetically epileptic rat (IGER) is thought to be a useful tool for studying epilepsy of the limbic type. Morphological changes in the hip-pocampus, which is one of the characteristic findings in the brains of patients with temporal lobe epilepsy, were presumed to occur also in IGER during the course of epileptic activities. We investigated chronological changes in volume of the IGER hippocampal formation using mag-netic resonance (MR) imaging. The experiment consisted of two protocols. First, MR imaging was performed for volumetric measurement of the cerebrum and the hippocampus in four male IGER, each at 2, 4, 6, 8, 10 and 12 months of age. After MR examination, the brains were subjected to histological and morphometric examinations. Second, changes in the hippocampal volume were traced chronologically in three IGER at the ages of 2, 4, 6, 8 and 10 months. Age-matched Wistar rats were used as controls. In IGER, the volume of the cerebrum, especially of the hippocampus, and the ratio of the hippocampal to the cerebral volume increased, in concert with the increase in seizure activities. Histological and morphometric invest-igations revealed that there was mild astrogliosis and marked microgliosis with hypertrophic change in the hippocampal formation with aging, but no loss of neurons was observed. Neither an increase in volume nor gliosis was found in the brains of control rats. The enlargement of the hippocampal formation in IGER brains was assumed to be partially due to gliosis of astrocyte and microglia with hypertrophy.     

Assessment of safety in hepatic resection for hepatocellular carcinoma focusing on indirect hyperbilirubinemia

Background/purpose

The indications for hepatic resection for hepatocellular carcinoma (HCC) patients with total bilirubin (T-Bil) equal to or higher than 1.2 mg/dl remain controversial. The aim of this study was to investigate the safety of hepatic resection for HCC patients who showed high T-Bil (≥1.2 mg/dl) with low direct bilirubin (D-Bil ≤ 0.5 mg/dl).

Methods

Thirty-four HCC patients showing high T-Bil with low D-Bil were treated with mono- to tri-segmentectomy between January 2000 and December 2010. The perioperative clinical parameters and prognosis of the high T-Bil/low D-Bil patients were compared with those of 253 HCC patients showing normal T-Bil. In addition, complication rates of the patients with high T-Bil/high D-Bil (n = 4) were analyzed.

Results

The prothrombin time activity, indocyanine green clearance test, asialo-scintigraphy, and platelet count were similar in the two groups. The mean serum albumin in high T-Bil/low D-Bil patients was significantly higher than that of normal T-Bil patients (4.2 ± 0.5 vs. 4.0 ± 0.4 g/dl, P = 0.004). There were no significant differences in operation time, intraoperative bleeding, red cell concentrate transfusion rate, postoperative complication rate, and disease-free and overall survivals between the two groups. Postoperative hyperbilirubinemia (T-Bil >5 mg/dl) with ascites was observed in one of four high T-Bil/high D-Bil patients (25 %).

Conclusions

Mono- to tri-segmentectomy can be performed in patients with low D-Bil (≤0.5 mg/dl) similarly to patients with low T-Bil (<1.2 mg/dl), even in HCC patients showing high T-Bil (≥1.2 mg/dl).     

Anastomosis between the inferior alveolar artery branches and submental artery in human mandible

The mental artery displays several branches internal to the anterior region of the mandible as confirmed by macroscopic observation and computed tomography. The inferior alveolar artery formed complex branches and divided into mental and incisive branches, which were found in the right internal side of the mandible of one male cadaver (88 years old). The branches of these two arteries ran through the bony lingual canal to the lingual foramen between the canine and premolar region of the inner surface of the mandible body, where they emerged to enter the mylohyoid and anterior belly of the digastric muscles and communicate with the submental artery. The observation of the anastomotic artery is considered important for surgical placement of dental implants in the mandibular region.     

Phenotype Analysis and Quantification of Proliferating Cells in the Cortical Gray Matter of the Adult Rat

In intact adult mammalian brains, there are two neurogenic regions: the subependymal zone and the subgranular layer of the hippocampus. Even outside these regions, small numbers of proliferating precursors do exist. Many studies suggest that the majority of these are oligodendrocyte precursors that express NG2, a chondroitin sulfate proteoglycan, and most of the residual proliferating cells seem to be endothelial cells. However, it is still unclear whether NG2-immunonegative proliferating precursors are present, because previous studies have neglected their possible existence. In this study, we systematically analyzed the phenotypes of the proliferating cells in the intact adult rat cortical gray matter. We improved our techniques and carefully characterized the proliferating cells, because there were several problems with identifying and quantifying the proliferating cells: the detection of NG2-expressing cells was dependent on the fixation condition; there were residual proliferating leukocytes in the blood vessels; and two anti-NG2 antibodies gave rise to different staining patterns. Moreover, we used two methods, BrdU and Ki67 immunostaining, to quantify the proliferating cells. Our results strongly suggest that in the intact adult cerebral cortical gray matter, there were only two types of proliferating cells: the majority were NG2-expressing cells, including pericytes, and the rest were endothelial cells.     

VGLUTs: 'exciting' times for glutamatergic research?

Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate is first synthesized in the cytoplasm of presynaptic terminals before being loaded into synaptic vesicles, which fuse with the plasma membrane, releasing their contents, in response to neuronal activity. The important process of synaptic vesicle loading is mediated by a transport protein, collectively known as vesicular glutamate transporter (VGLUT). Controlling the activity of these transporters could potentially modulate the efficacy of glutamatergic neurotransmission. In recent years, three isoforms of mammalian VGLUTs have been cloned and molecularly characterized in detail. Probing these three VGLUTs has been proven to be the most reliable way of visualizing sites of glutamate release in the mammalian CNS. Immunohistochemical studies on VGLUTs suggest that glutamatergic neurons are categorized into subgroups depending on which VGLUT isoform they contain. Recent studies on VGLUT1-deficient mice have led various models to be postulated concerning the possible roles of VGLUTs in synaptic physiology, such as presynaptic regulation of quantal size and activity-dependent short-term plasticity.     

Giant inflammatory polyposis of the descending colon associated with a Crohn's disease-like colitis

A case of giant inflammatory polyposis associated with a localized inflammatory bowel disease of the descending colon in a 49-year-old man is presented. Lower abdominal distension rapidly appeared without any previous history of gastrointestinal disease. Two months later, he underwent a left hemicolectomy. Postoperative recovery was complete and he remains in good health more than 2 years later. The resected colon showed a giant and bizarre polyposis measuring up to 12 cm in length and 2 cm in height and covering the entire circumference of the colon. The polyposis consisted of narrow worm- or noodle-like polyps that bridged over the irregularly shaped ulcers, which sometimes extended into muscularis propria. Although longitudinal ulcers or scars, stricture, and a cobble-stone appearance were not observed, transmural inflammation and deep fissures were found in the interpolypoid area. From these findings, this case seems to be more similar to Crohn's disease than other inflammatory bowel diseases.     

Oxysterol binding protein‐related protein‐5 is related to invasion and poor prognosis in pancreatic cancer

In previous studies, the gene expression profiles of two hamster pancreatic cancer cells with different potentials for invasion and metastasis were analyzed. In the present study, we identified that one of the genes expressed strongly in the highly metastatic cell line is hamster oxysterol binding protein‐related protein (ORP)‐5. The aim of the present study was to clarify the relationship between ORP5 and invasion and poor prognosis of human pancreatic cancer. Invasion assays were carried out in both hamster and human pancreatic cancer cells by suppressing the ORP5 gene with short interfering RNA or inducing its expression by introducing an expression vector. To evaluate the relationship between ORP5 and the characteristics of human pancreatic cancer, 56 pancreatic cancer tissue specimens were analyzed and the ORP5 expression in each pancreatic cancer tissue specimen was analyzed by immunohistochemistry. In both the hamster and human pancreatic cancer cells, suppression of ORP5 significantly reduced the invasion rate of the cells and induction of ORP5 significantly enhanced the invasion rate of the cells. In the clinical sample, the median survival times of the patients with ORP5‐positive (n = 33) and ORP5‐negative (n = 23) cancer were 8.3 and 17.2 months, respectively (P = 0.02). Also, the 1‐year survival rates of patients with ORP5‐positive and ORP5‐negative cancer were 36.4 and 73.9%, respectively (P = 0.005). The ORP5 expression level was related to both invasion and poor prognosis in human pancreatic cancer. These findings suggest that the expression of ORP5 may induce cancer cell invasion, resulting in the poor prognosis of pancreatic cancer. (Cancer Sci 2008; 99: 2387–2394)