Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice

Germ-line mutations of the human TSC2 tumor suppressor gene cause tuberous sclerosis (TSC), a disease characterized by the development of hamartomas in various organs. In the Eker rat, however, a germ-line Tsc2 mutation gives rise to renal cell carcinomas with a complete penetrance. The molecular mechanism for this phenotypic difference between man and rat is currently unknown, and the physiological function of the TSC2/Tsc2 product (tuberin) is not fully understood. To investigate these unsolved problems, we have generated a Tsc2 mutant mouse. Tsc2 heterozygous mutant (Tsc2+/-) mice developed renal carcinomas with a complete penetrance, as seen in the Eker rat, but not the angiomyolipomas characteristic of human TSC, confirming the existence of a species-specific mechanism of tumorigenesis caused by tuberin deficiency. Unexpectedly, approximately 80% of Tsc2+/- mice also developed hepatic hemangiomas that are not observed in either TSC or the Eker rat. Tsc2 homozygous (Tsc2-/-) mutants died around embryonic day 10.5, indicating an essential function for tuberin in mouse embryonic development. Some Tsc2-/- embryos exhibited an unclosed neural tube and/or thickened myocardium. The latter is associated with increased cell density that may be a reflection of loss of a growth-suppressive function of tuberin. The mouse strain described here should provide a valuable experimental model to analyze the function of tuberin and its association with tumorigenesis.     

Increased serum soluble Fas ligand associated with recurrent B-cell non-Hodgkin's lymphoma after autologous peripheral blood stem cell transplantation.

Fas-ligand (FasL) is a member of the tumor necrosis factor family and transmits apoptotic cell death signal by binding to its receptor, Fas. FasL is expressed on the cell surface of activated T-cell and natural killer (NK) cell. It has been shown that the FasL can be released from the cell surface by metalloproteinase. The serum soluble FasL (sFasL) is increased in some patients with NK cell lymphoma/large granular lymphocytic leukemia. We have recently seen a patient with recurrent B-cell lymphoma accompanied with an increased serum sFasL level after autologous peripheral blood stem cell transplantation. The sFasL was markedly decreased with the tumor regression induced by the chemotherapy. We present here the first case of an elevated serum sFasL level associated with B-cell lineage malignancy and discuss the possible clinical value of sFasL.     

Three dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer under field adjustment with implanted gold markers: early clinical outcome

Three dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer under field adjustment with gold marker implantation was performed according to the treatment strategy based on the clinical risk factors to the patients who chose external beam radiotherapy. The treatment strategy contains indications for laparoscopic staging lymphadenectomy and neoadjuvant combined androgen blockade (CAB). This protocol was applied to 19 patients at Kagawa University Hospital from July 2001 to December 2003. The patients were divided into high-risk group (n=14): T3-4N0M0 or PSA > or = 20 ng/ml or Gleason sum > or = 8 or suspicious node, and low-risk group (n=5): T1c-2bN0M0 and PSA < 20 ng/ml and Gleason sum < or = 7 and no suspicious nodes. Basically, high-risk patients underwent laparoscopic staging lymphadenectomy prior to radiotherapy. One of the 14 patients had a positive node and underwent endocrine therapy. The high-risk group received neoadjuvant CAB for 3 to 4 months, followed by gold marker implantation. One patient chose endocrine therapy at this point. Low-risk patients underwent marker implantation without endocrine therapy. Every patient successfully completed planned irradiation. The changes of prostate volume and serum PSA after neoadjuvant CAB were significant [28.7 ml to 15.7 ml (p=0.004) and 53.9 ng/ml to 1.4 ng/ml (p=0.023), respectively]. Only one patient in the high-risk group had biochemical failure. No grade 3 or 4 adverse events occurred in NCI-CTC grading. The analysis of gravity center migration of the implanted gold markers in the first 8 patients showed that the planned safety margin might not be wide enough to avoid neighboring organ irradiation. These results suggested that 3D-CRT under field adjustment with implanted gold markers contributes to both higher efficacy and lower morbidity.     

Follow-up pulmonary perfusion scintigraphy pulmonary arterial embolization in two cases of familial pulmonary arteriovenous fistula

Follow-up pulmonary perfusion scintigraphy in evaluating pulmonary arterial embolization were assessed by two cases of pulmonary familial arteriovenous fistula. Pulmonary arteriovenous fistula was found for brain abscess in the older brother, and for dyspnea on effort in the younger brother. Pulmonary arterial embolizations were performed. (older brother: 4 times, younger brother: 5 times) Before embolization, pulmonary perfusion scintigram showed pale defect, clear asymmetric perfusion between right and left lung, and clear renal visualization. On the other hand, after the embolization, clear multiple defects agreed with the sites of embolization, and asymmetric pulmonary perfusion and renal visualization disappeared. We conclude that follow-up pulmonary perfusion scintigraphy is useful to evaluate in pulmonary arteriovenous fistula after embolization.     

A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36).

It has recently been shown that the Naka antigen, which is absent in 3% to 11% of Japanese blood donors, is expressed on platelet glycoprotein IV (GPIV; CD36) (Tomiyama et al, BLOOD, 75:684, 1990). In the present studies, flow cytometry was used to distinguish differences in the reactivity of Naka+ and Naka- platelets with both OKM5, a monoclonal antibody that recognizes an epitope on GPIV, and with polyclonal anti-GPIV antibody. OKM5 was also used to screen 871 platelet concentrates prepared from healthy US blood donors. Three of these showed markedly deficient binding of 125I-OKM5 or an incidence of 0.34%. Two of these donors were re-accessed and showed less than 1% binding of 125I-OKM5 as compared with 10,300 +/- 1,500 binding sites per platelet in controls (n = 4). Platelets from these two US donors were radiolabeled (125I, 3H) and compared with control platelets and with platelets from Japanese Naka+ and Naka- donors by crossed immunoelectrophoresis, protein blots, immunoprecipitation, and two-dimensional gel electrophoresis. GPIV could not be detected by any of these techniques in the Naka- platelets nor in the donors whose platelets showed deficient binding of OKM5. These results suggest that GPIV functions as an isoantigen rather than an alloantigen in immunizing Naka- platelet recipients. This is the first report of the absence of a major platelet membrane GP in healthy blood donors.     

Detection of restenosis after successful percutaneous transluminal coronary angioplasty (PTCA)--usefulness of exercise thallium scintigraphy

We studied the efficacy of stress thallium scan in detecting restenosis after primary successful PTCA. There were 21 patients with angina pectoris and 16 patients with previous myocardial infarction. The sensitivity and the specificity of stress thallium scan in detecting restenosis were superior to those of stress electrocardiography or chest pain complained in follow-up period. In multi-vessel disease, we could assess the vessel developing restenosis more easily than stress electrocardiography. Initial thallium %UPTAKE RATIO was significantly improved after PTCA but redecreased in patients developing restenosis. In patients showing residual redistribution despite of not developing restenosis, we could judge vessel patency by gradually improving initial %UPTAKE RATIO after PTCA. Thus, stress thallium scan proved to be useful in detecting restenosis after PTCA.