BCL-6-positive human herpesvirus 8-associated solid lymphoma arising from liver and spleen as multiple nodular lesions

We report a case of BCL-6-positive B cell lymphoma with human herpesvirus 8 (HHV-8) infection. A human immunodeficiency virus-infected patient developed a diffuse large B cell lymphoma, which was found exclusively in the liver and spleen with the absence of lymphadenopathy and effusion in any body cavities. The lymphoma cells were composed of medium to large-sized cells positive for CD20, CD45, and BCL-6, and negative for epithelial cell membrane antigen, CD30, CD45RO, and CD138/syndecan-1, suggesting a germinal center B cell origin. The patient was serologically positive for HHV-8, and HHV-8 was detected in the liver biopsy tissue both by polymerase chain reaction and by immunohistochemistry for HHV-8-encoded latency-associated nuclear antigen. Other HHV-8-associated diseases, such as Kaposi's sarcoma, primary effusion lymphoma, or multicentric Castleman's disease were not detected in the patient. Chemotherapy was effective and reduced the size of the lymphoma dramatically. This is the first case report of a germinal center B cell-originating lymphoma with HHV-8 infection.     

The critical role of type-1 innate and acquired immunity in tumor immunotherapy

The discovery of a large array of tumor antigens has demonstrated that host lymphocytes can indeed recognize and destroy tumor cells as originally proposed in the cancer immunosurveillance hypothesis. Recent reports that led to the cancer immunoediting concept also strongly support the immunosurveillance hypothesis, and they further indicate that the host immune system plays a critical role not only in promoting host protection against cancer but also in selecting tumors that can better escape from immune attack. Thus, it is now clear that T cells have the ability to recognize and destroy spontaneously arising tumors. However, the generation of antitumor immunity is often difficult in the tumor-bearing host because of various negative regulatory mechanisms. Here, we review our recent work on tumor immunotherapy, which utilizes the activation of type-1 innate and/or acquired immunity as a potent strategy to overcome immunosup-pression in the tumor-bearing host. We have established a variety of tumor therapeutic protocols that aim to activate type-1 immunity, such as tumor-vaccine therapy with CpG encapsulat-ed in liposomes, cell therapy using tumor-specific Th1 cells, and gene therapy using gene-engineered Th1 cells. We found that CpG encapsulated in liposomes stimulated IL-12-producing DC and induced IFN-gamma-producing NK cells, NKT cells, and tumor-specific CTL. Th1 cell therapy was also shown to be beneficial for acceleration of APC/Th1 cell-cell interaction in the DLN, which was critical for inducing tumor-specific CTL at the tumor site. Therefore, we conclude that the activation of type-1 innate and acquired immunity is crucial for tumor immunotherapy in order to overcome strong immunosuppression in the tumor-bearing host.     

PIVKA-II-producing advanced gastric cancer

We describe the case of a 68-year-old man with primary advanced adenocarcinoma of the stomach, who displayed extremely high plasma levels of protein induced by vitamin K antagonist (PIVKA)-II (15600mAU/ml) and normal levels of alphafetoprotein (AFP) (4ng/ml). Ultrasonography and dynamic computed tomography ruled out hepatocellular carcinoma (HCC) or liver metastasis. After preoperative chemotherapy, pancreatico-spleno total gastrectomy with D2 lymphadenectomy was performed. Postoperatively, plasma levels of PIVKA-II returned to within the normal range (29mAU/ml). Microscopic examination revealed stomach adenocarcinoma showing various histological types, such as moderately to poorly differentiated mucinous adenocarcinoma, but hepatoid differentiation of gastric adenocarcinoma was not detected. Localization of PIVKA-II and AFP within tumor cells was demonstrated by immunohistochemical staining using monoclonal antibodies. These results indicate that tumor cells from gastric cancer may produce PIVKA-II. Some cases of PIVKA-II- and AFP-producing advanced gastric cancer with liver metastasis have been reported, but this is the first report of gastric cancer without liver metastasis producing PIVKA-II alone.     

Detrended fluctuation analysis of genome-wide copy number profiles of glioblastomas using array-based comparative genomic hybridization

We examined whole genomic aberrations of biopsied samples from 19 independent glioblastomas by array-based comparative genomic hybridization analysis. The highest frequencies of copy number gains were observed on RFC2 (73.3%), EGFR (63.2%), and FGR, ELN, CDKN1C , FES, TOP2A, and ARSA (57.9% each). The highest frequencies of copy number losses were detected on TBR1 (52.6%), BMI1 (52.6%), EGR2 (47.4%), DMBT1 (47.4%), MTAP (42.1%), and FGFR2 (42.1%). The copy number gains of CDKN1C and INS and the copy number losses of TBR1 were significantly correlated with longer survival of patients. High-level amplifications were identified on EGFR, SAS/CDK4, PDGFRA, MDM2, and ARSA. These genes are assumed to be involved in tumorigenesis or progression of glioblastomas. The first attempts to apply detrended fluctuation analysis to copy number profiles by considering the reading direction as the time axis demonstrated that higher long-term fractal scaling exponents (alpha2) correlated well with longer survival of glioblastoma patients. The present study indicates that array-based comparative genomic hybridization analysis has great potential for assessment of copy number changes and altered chromosomal regions of brain tumors. Furthermore, we show that nonlinear analysis methods of whole genome copy number profiles may provide prognostic information about glioblastoma patients.     

Milk sphingomyelin accelerates enzymatic and morphological maturation of the intestine in artificially reared rats

OBJECTIVES: Sphingomyelin (SPM) is the dominant phospholipid, comprising 38% of total human milk phospholipids. Although little is known about the nutritional importance of SPM during the neonatal period, SPM may affect the growth and development of tissues in the newborn infant through mechanisms regulating cell proliferation and differentiation. We evaluated the effect of sphingomyelin (SPM) in artificially reared rats as a suitable model of gut maturation in the suckling infant. METHODS: Seven-day-old Sprague-Dawley rat pups were cannulated intragastrically and reared artificially on milk containing 0.5% SPM or 0.5% phosphatidylcholine (PC) for 1 week. RESULTS: Intestinal lactase activity in the SPM group was significantly lower than that in the control or PC group. Upon histologic examination, intestinal villi were found to be occupied with vacuolated cells in the control and the PC group, whereas the vacuolated cells were restricted to the tip of villi in the SPM group. The Auerbach nerve plexus area of the ileum in the SPM group was significantly greater, possibly due to accelerated development, than that in the control group or PC group. CONCLUSIONS: The present results suggest that SPM, the dominant phospholipid in milk, plays an important role in neonatal gut maturation during the suckling period.     

Decreased cerebrospinal fluid hypocretin-1 levels near the onset of narcolepsy in 2 prepubertal children

We present 2 cases of narcolepsy with prepubertal onset. Although excessive daytime sleepiness and cataplexy had appeared early in both patients, the presence of sleep-onset rapid eye movement periods was detected several months after the onset of hypersomnia. The levels of hypocretin in the cerebrospinal fluid were reduced when measured 3 weeks (Patient 1) and 2 months (Patient 2) after the appearance of hypersomnia, before the presence of sleep-onset rapid eye movement periods was confirmed. Because the symptoms of narcolepsy in children are often obscure and easily mistaken as other diseases, and the electrophysiologic studies may not be specific in the early stage, the definite diagnosis tends to be delayed. Measurement of hypocretin-1 levels in the cerebrospinal fluid is useful for the early diagnosis of narcolepsy with prepubertal onset.     

Usefulness and prognostic value of transvaginal hydrolaparoscopy in infertile women

OBJECTIVE: To evaluate the usefulness and prognostic value of transvaginal hydrolaparoscopy (THL) in infertile women. DESIGN: Retrospective study. SETTING: Jichi Medical School Hospital, Tochigi, Japan. PATIENT(S): Thirty-six patients who were followed up for 6 months or longer after THL was performed. INTERVENTION(S): Transvaginal hydrolaparoscopy findings in comparison with hysterosalpingography (HSG).MAIN OUTCOME MEASURES: Transvaginal hydrolaparoscopy findings, HSG findings, treatment strategy, and prognosis. RESULT(S): Twenty of 36 patients (55.5%) became pregnant, including 7 by coitus, 7 by artificial insemination with the husband's semen, and 6 by assisted reproductive technology (ART). In 11 of these pregnant patients, information obtained during THL differed from findings on HSG. CONCLUSION(S): Transvaginal hydrolaparoscopy is useful in selecting a future treatment strategy.     

Levels of lipoprotein(a) in normal and compromised pregnancy

OBJECTIVE: To study maternal lipoprotein(a) levels in normal pregnancy and in pregnancy with evidence of vascular disease in the maternal uteroplacental circulation defined by Doppler ultrasound study. SAMPLES: Maternal venous blood was collected from 75 normal pregnant women and 68 pregnant women with evidence of potential uteroplacental vascular disease identified by Doppler ultrasound study. METHODS: Plasma lipoprotein(a) levels in maternal blood were measured using an enzyme-liked immunosorbent assay method. MAIN OUTCOME MEASURES: Plasma lipoprotein(a) levels and pregnancy outcome were examined. RESULTS: None of the normal group had lipoprotein(a) levels greater than 30 mg/dl, a cutoff level which has been associated with increased risk of atherosclerosis. 28 of the 68 women with uteroplacental insufficiency had lipoprotein(a) levels greater than this cutoff level. In this group there was a statistically significant higher prevalence of preeclampsia in comparison with women with a normal lipoprotein(a) level (p < 0.001). The lipoprotein(a) level was significantly higher in severe (n = 13, median 60.5 mg/dl, P < 0.001] than in mild preeclampsia (n = 5, median 34 mg/dl). Those with high levels (> 30 mg/dl) exhibited significantly more adverse indices of fetal outcome. CONCLUSION: This study has demonstrated that high levels of lipoprotein(a) interfere with uteroplacental circulation and play a role in the pathophysiology of preeclampsia. Lipoprotein(a) concentrations are associated with the severity of the disease. We suggest that high levels of lipoprotein(a) might affect the placenta and fetus.