Cancer detection using a PET tracer, 11C-glycylsarcosine, targeted to H+/peptide transporter.

H+/peptide transporter, PEPT1, is functionally expressed in some human cancer cell lines and might be a candidate molecular target for detection of cancers in vivo using PET. The aim of the present study was to establish a novel tumor-imaging technology using a PET tracer targeted to H+/peptide transporter(s). We also compared the tracer with 18F-FDG, focusing on the specificity of their accumulation between tumor and inflammatory tissues. METHODS: A dipeptide PET tracer, 11C-glycylsarcosine (11C-Gly-Sar), was injected intravenously into athymic mice transplanted with human pancreatic, prostate, and gastric cancer cells. The distribution patterns of 11C-Gly-Sar and 18F-FDG in the tumor-bearing mice, and in mice with inflammatory tissue, were assessed by imaging with a positron planar imaging system (PPIS). Tissue distributions of tracer radioactivity were also measured. The expression levels of PEPT1 and PEPT2 (PEPTs) proteins in tumor xenografts and inflammatory tissue were examined by immunohistochemical analysis. The messenger RNA expression levels of PEPTs in 58 available cancer cell lines were quantified by means of real-time polymerase chain reaction. RESULTS: All 3 tumor xenografts were well visualized with the PPIS after injection of 11C-Gly-Sar. Expression of PEPTs in those xenografts was confirmed by immunohistochemical analysis. Tumor-to-blood concentration ratios of 11C-Gly-Sar increased in a time-dependent manner and were much higher than unity. Most of the radioactivity found in the tumor tissue was recovered as the intact tracer. These results indicated that 11C-Gly-Sar was taken up by the PEPTs in tumor xenografts. It is noteworthy that 11C-Gly-Sar was minimally present in inflammatory tissues that expressed no PEPT1 or PEPT2 protein, whereas 18F-FDG was highly accumulated, with the values of the selectivity index being >25.1 and 0.72 for 11C-Gly-Sar and 18F-FDG, respectively. The mRNAs of PEPT1 and PEPT2 were expressed in 27.6% and 93.1%, respectively, of the cancer cell lines examined in the present study. CONCLUSION: The present study indicates that 11C-Gly-Sar is a promising tumor-imaging agent and is superior to 18F-FDG for distinguishing between tumors and inflammatory tissue. Because PEPTs were ubiquitously expressed in various types of tumor cells examined, 11C-Gly-Sar could be useful for the detection of many types of cancers.     

Dissecting aneurysm of the vertebral artery as a cause of Wallenberg's syndrome

Although it is well known that Wallenberg's syndrome is caused by occlusion of the vertebral artery (VA) or the posterior inferior cerebellar artery (PICA), the etiology of the occlusion is rarely documented. During the course of Wallenberg's syndrome, patients often complain of headache. We thought that these headaches might be caused by dissecting aneurysm (DA) of the vertebral artery, and so we studied the incidence of DA in our cases with Wallenberg's syndrome. Although many variants exist, Wallenberg's syndrome encompasses several neurological symptoms due to a disorder of the nucleus and nerve tracts located in the lateral part of the medulla. We diagnosed our patients as having Wallenberg's syndrome on the basis of symptoms such as loss of pain and temperature sensation in the unilateral face and contralateral body, cerebellar ataxia, and dysphasia. We investigated 22 cases of Wallenberg's syndrome over a five-year period, and excluded patients who developed subarachnoid hemorrhage upon onset of the syndrome. Our cases can be divided into two groups; one with severe stenosis or occlusion of VA (n = 15) and the other with occlusion of PICA (n = 5). The angiograms of the two remaining patients showed no abnormal findings. The mean age of the VA group (42.5 yrs.) was younger than that of the PICA group (64.2 yrs.). The age distribution of the PICA group is similar to that of other occlusive cerebrovascular diseases. Seven cases of the VA group demonstrated aneurysmal dilatation and luminal stenosis, and so they were diagnosed as having dissecting aneurysm of VA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rheumatoid arthritis in patients aged above 75 years old at onset]

Elderly onset rheumatoid arthritis (RA) is difficult to diagnose definitively when the patients note their first symptoms of arthritis above the age of 75 years old. In this report, we reviewed the clinical features of elderly onset RA and its diagnosis. The subjects included 4 females, aged 78, 83, 84 and 93 years, respectively. The onsets were abrupt in 2 cases and more slowly arriving in the other 2. Shoulder joints and wrist joints were involved in all cases. Knee joints, finger joints and foot joints were involved in 3 cases and the elbow was involved in one case. Anti-RA treatment quickly attenuated the acute and severe arthritis and brought down the high CRP level associated with vivid inflammatory activity of RA. The RAPA value was very high in all but one of the cases. Severe destructive findings in radiography was undetectable in the major joints (e.g. shoulder, hip and knee joints). Radiographic findings in wrist and finger joints were also very difficult to differentiate from arthrosis and osteoporosis. On the other hand, RA involvement in the cervical spine was certain in the radiographs; 1 case had anterior atlantoaxial subluxation and 2 cases had subaxial intervertebral erosion. Pathological radiographic findings in the cervical spine are useful for the diagnosis of elderly onset RA.     

Investigation of where schizophrenic patients receive treatment

Schizophrenic patients receiving treatment in Kagawa Prefecture were studied as to where treatment was obtained. Analysis showed that there was a tendency by schizophrenic patients to seek treatment in institutions distant from their place of residence. The direction in which a patient proceeded to seek treatment varied and showed no pattern. Analysis by age groups showed that patients in the 15 to 39 years age group were most likely to seek treatment in locations other than where they lived and traveled the longest distance. The tendency to seek treatment away from their place of residence decreased with increasing age. However even among the elderly there were patients who traveled long distances for treatment. Factors associated with geographical or social relationships between the cities/towns could not explain the tendency observed. Neither was there a relationship to specialized medical care. Factors such as the related to the mental health care system, including prejudice and lack of societal understanding were inferred to be associated to this problem. Results of this study indicate a need to organize the community mental health system to serve districts with wider areas than that established for other diseases. However in the future there should be a gradual narrowing of the district area, a broadening of services offered, and a removal of societal prejudice against psychiatric patients.     

Phenotypic and Genotypic Lineage Switch of a Lymphoma with Shared Chromosome Translocation and T-Cell Receptor γ Gene Rearrangement

A case of non-Hodgkin's lymphoma showed a phenotypic and genotypic cell lineage switch twice during nine years of his clinical history; first, T-cell type, pleomorphic small cell lymphoma developed, followed by B-cell type, diffuse centroblastic/centrocytic lymphoma, and finally T-zone lymphoma without follicles again developed, from which AST-1 cultured cell line was established. Karyotype analysis demonstrated a shared abnormal chromosome, der(1)t(1;?)(p36;?), among the first relapsed B-cell tumor, the second relapsed T-cell tumor and AST-1 cell line. Furthermore, T-cell receptor (TCR) γ gene rearrangement bands of the same size were observed in the first relapsed B-cell tumor and the second relapsed T-cell tumor as well as AST-1 cell line. These results suggested that both relapsed tumors of different cell lineages are derived from a common malignant clone, presumably a committed lymphoid stem cell. A unique translocation, t(2;14)(q37;q11.2), which may involve TCR δ/α gene complex, was observed in the second relapsed tumor and AST-1 cells. To attempt to isolate the breakpoint of this translocation, the configuration of TCR δ/α gene complex was studied. The result showed that two rearrangements of TCR α gene detected with J_α probes were the products of the normal TCR rearrangement process, and were not involved in the translocation at this region. This patient, together with the AST-1 cell line, provided us a unique opportunity to study the development and clonal evolution of malignant lymphoma.     

Immune response to intraocular injection of retinal S-antigen in adjuvant

It has been proposed that the introduction of foreign material into the eye at the moment of a penetrating trauma provides an adjuvant effect which, coupled with the release of antigen, might be responsible for sensitizing the immune system to produce a contralateral sympathetic ophthalmia. We addressed that hypothesis by injecting S-antigen with complete Freund's adjuvant (CFA) into the anterior chamber (AC) of the eye of Lewis rats. The injection of an identical dose of antigen (30 g S-Ag in CFA in a total volume of 10 l) via the foodpad (FP) or under the conjunctiva (SC) could induce typical experimental autoimmune uveitis (EAU). By immunizing via the AC route, we could demonstrate a positive sensitization of the immune system, manifested by serum antibody production against S-Ag and by the presence of S-Ag-specific, responsive T-lymphocytes in the spleen. However, immunization via the AC route did not induce contralateral uveitis, and the animals did not produce a DTH skin response when challenged intradermally with S-Ag as they did after FP immunization. In the light of these results, we evaluated the possibility that a DTH suppressive response was elicited by intracameral (IC) injection as seen in anterior chamber-associated immune deviation (ACAID): we tested the effect of splenectomy and cyclophosphamide pretreatment before IC immunization and the effect of secondary footpad immunization as well as T-helper cell transfer after IC immunization. The results given by these approaches argue against the induction of suppressor cells by IC immunization. We believe that the absence of lymphatic drainage from the interior of the eye is probably responsible for the absence of EAU induction through the IC route and that extrusion of the antigen under the conjunctiva might be required for the activation of EAU effector cells.