Diagnosis, pathology, staging, treatment, and outcome of epithelial ovarian neoplasia in patients age < 21 years

BACKGROUND: Epithelial ovarian neoplasms are rare in patients under the age of 21 years. This is a report of a series of such patients documenting their presentation, histologic type, stage of disease, treatment, and outcome. METHODS: Clinical findings, histology, stage, treatment, and outcomes of 19 patients with epithelial ovarian neoplasia are reported. All histology was rereviewed. RESULTS: The median age at the time of diagnosis was 19.7 years (range, 14.1-21.8 years), and the median follow-up was 5.6 years (range, 0.2-19.5 years). The most common presenting symptom was dysmenorrhea (100%) followed by abdominal pain (68%), and the initial diagnosis usually was made ultrasonographically. There were nine (47%) serous tumors, 7 (37%) mucinous tumors, 2 (11%) small cell carcinomas, and 1 (5%) endometrioid carcinoma. Seventy-nine percent of tumors were unilateral, and 84% were low malignant potential or well differentiated tumors. Surgical treatment included unilateral salpingo-oophorectomy in 12 patients (63%), total abdominal hysterectomy and bilateral salpingo-oophorectomy in 6 patients (32%), and ovarian cystectomy in 1 patient (5%). Fifteen patients (79%) had Stage I disease, and 4 patients (21%) had Stage III disease at the time of diagnosis. There were two deaths in this series, and both occurred in patients with small cell anaplastic carcinoma. CONCLUSIONS: Epithelial ovarian neoplasias are rare in patients in this age group but must be included in the differential diagnosis of an ovarian mass. Most patients present with Stage I tumors of low malignant potential. In these patients, good survival is achieved with unilateral salpingo-oophorectomy and preservation of fertility. In contrast, small cell carcinomas are very aggressive, and patients with this variant require intensive therapy.     

The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid

Histone deacetylase inhibitors (HDACIs) inhibit the growth of a variety of transformed cells in culture. We demonstrated previously that the hybrid-polar HDACI m-carboxycinnamic acid bis-hydroxamide (CBHA) induces apoptosis of human neuroblastoma in vitro and is effective in lower doses when combined with retinoids. The current study investigates the effect of CBHA on the growth of human neuroblastoma in vivo, both alone and in combination with all-trans retinoic acid (atRA), using a severe combined immunodeficiency-mouse xenograft model. CBHA (50, 100, and 200 mg/kg/day) inhibited growth of SMS-KCN-69n tumor xenografts in a dose-dependent fashion, with 200 mg/kg CBHA resulting in a complete suppression of tumor growth. The efficacy of 50 and 100 mg/kg CBHA was enhanced by the addition of 2.5 mg/kg atRA. This dose of atRA was ineffective when administered alone. Treatment was accompanied by mild weight loss in all groups except the lowest dose of CBHA. Our results suggest HDACIs alone or combined with retinoids may have therapeutic utility for neuroblastoma.     

Physical activity and risk of ovarian cancer: an Italian case-control study

The relationship between physical activity and the risk of ovarian cancer was analyzed using data from a case-control study conducted between 1992 and 1999 in Italy. Cases were 1,031 women with incident, histologically confirmed, invasive epithelial ovarian cancer and controls were 2,411 women admitted to hospital for acute non-neoplastic, non-hormonal conditions. Compared to women with the lowest level of occupational physical activity, the ORs of ovarian cancer obtained adjusting for center, year of interview and age for women with the highest level of physical activity were 0.70, 0.52 and 0.64 (all statistically significant) respectively, at ages 15-19, 30-39 and 50-59 years, with significant trends in risk for the 2 youngest age groups. The corresponding ORs became 0.89, 0.67 and 0.76 after further allowance for several co-variates of ovarian cancer, including education, which was positively associated with cancer risk. No significant association was found with leisure-time physical activity though the risk was below unity in women with the highest level of activity. The multivariate OR was 0.44 for women with the highest level of combined occupational plus leisure-time physical activity. The inverse relationship between occupational physical activity and ovarian cancer risk was not heterogeneous across strata of selected co-variates.     

Endothelial dysfunction, nitric oxide and platelet activation in hypertensive and diabetic type II patients

Alterations in the synthesis or enhanced inactivation of nitric oxide (NO) and an increase in endothelin-1 production lead to an imbalance that can induce arterial hypertension. Type II diabetes is characterized by impaired endothelium-dependent vasodilation and vascular disease. NO is produced through L-arginine pathway by three different isoforms of nitric oxide synthase (NOS), an inducible form that can be activated by cytokines such as tumor necrosis factor alpha (TNFalpha). We evaluated NO plasmatic levels, endothelial damage markers such as von Willebrand factor (vWF), platelet activation, soluble P-selectin (sP-Sel), TNFalpha levels, insulinaemia (I), glycosylated haemoglobin (HbA1c), glycaemia and blood pressure in 32 hypertensive diabetic type II patients (Group A), 37 hypertensive patients (Group B) and 35 healthy subjects (Group C) matched in sex, age, body mass index and dietary habits. The level of I was increased in patients compared to the controls and correlated with their NO levels. vWF plasmatic levels were increased in Group A compared to Groups B and C. We also found significant differences in platelet activation among all the groups. In diabetic patients, increased NO levels correlated with TNFalpha, HbA1c and platelet activation showed greater endothelial damage than in Group B. These parameters described a prothrombotic state associated with an insulin resistance state, an increased vWF release, raised sP-Sel and TNFalpha levels and, maybe, low NO bioavailability, which could lead to a higher risk of development of thrombotic events in hypertensive diabetic patients (Group A) than in the hypertensive patients in Group B.     

Cloning of dopamine, norepinephrine and serotonin transporters from monkey brain: relevance to cocaine sensitivity

We used RT-PCR to clone monoamine transporters from Macaca mulatta, Macaca fasicularis and Saimiri sciureus (dopamine transporter; DAT) and Macaca mulatta (norepinephrine transporter; NET and serotonin transporter; SERT). Monkey DAT, NET and SERT proteins were >98% homologous to human and, when expressed in HEK-293 cells, displayed drug affinities and uptake kinetics that were highly correlated with monkey brain or human monoamine transporters. In contrast to reports of other species, we discovered double (leucine for phenylalanine 143 and arginine for glutamine 509; Variant I) and single (proline for leucine 355; Variant II) amino acid variants of DAT. Variant I displayed dopamine transport kinetics and binding affinities for various DAT blockers (including cocaine) versus [3H] CFT (WIN 35, 428) that were identical to wild-type DAT (n=7 drugs; r(2)=0.991). However, we detected a six-fold difference in the affinity of cocaine versus [3H] cocaine between Variant I (IC(50): 488+/-102 nM, SEM, n=3) and wild-type DAT (IC(50): 79+/-8.2 nM, n=3, P<0.05). Variant II was localized intracellularly in HEK-293 cells, as detected by confocal microscopy, and had very low levels of binding and dopamine transport. Also discovered was a novel exon 5 splice variant of NET that displayed very low levels of transport and did not bind cocaine. With NetPhos analysis, we detected a number of highly conserved putative phosphorylation sites on extracellular as well as intracellular loops of the DAT, NET, and SERT, which may be functional for internalized transporters. The homology and functional similarity of human and monkey monoamine transporters further support the value of primates in investigating the role of monoamine transporters in substance abuse mechanisms, neuropsychiatric disorders and development of diagnostic and therapeutic agents.     

Expression of inducible nitric oxide synthase in the liver of bile duct-ligated Wistar rats with modulation by lymphomononuclear cells

BACKGROUND: The current study evaluated whether biliary tract obstruction stimulates inducible nitric oxide synthase (iNOS) protein expression in the liver and analyzed the implication of lymphomononuclear cells and interleukin-4 (IL-4). METHODS: Male Wistar rats were used. Bile flow interruption was achieved by a complete division of the extrapancreatic common bile duct. iNOS expression was determined by both the Western blot technique and immunohistochemistry. RESULTS: iNOS protein was markedly expressed in the liver 7 days after bile duct obstruction. Treatment with thymostimulin (TP-1), a partially purified thymic extract, reduced the intensity of the expression of iNOS protein in the liver after bile duct ligation. Recent data have suggested that IL-4 attenuates iNOS protein expression. We then analyzed the involvement of this anti-inflammatory cytokine on the modulation of iNOS expression in the liver. The liver from rats that underwent bile duct ligation (BDL) showed a lower content of IL-4 than that of sham-operated (SO) rats. TP-1 treatment increased the content of IL-4 in the liver. Liver slices incubated in vitro with Escherichia coli lipopolysaccharide (LPS, 10 microg/mL) stimulated the expression of iNOS protein. The level of LPS-induced iNOS expression was reduced by lymphomononuclear cells obtained from sham-operated animals. However, lymphomononuclear cells isolated from BDL rats potentiated the induction of iNOS expression by LPS-stimulated liver. However, lymphomononuclear cells from TP-1-treated BDL rats failed to modify LPS-stimulated iNOS expression. The different effect of lymphomononuclear cells on the modulation of iNOS expression in the liver was associated with their ability to generate IL-4. CONCLUSIONS: The liver of jaundiced rats markedly expressed iNOS protein, which was associated to modifications in the content of IL-4 in the liver. Furthermore, lymphomononuclear cells modulate iNOS protein expression in the liver by a mechanism in which IL-4 is involved.     

Trends in asthma mortality in Italy and Spain, 1980–1996

Asthma is a major public health problem, with variable trends in several countries. We analysed mortality trends from asthma in Italy and Spain between 1980 and 1996. Overall asthma-related mortality at all ages increased between 1980 and 1987 in both sexes in Italy, from 16.6 in 1980–1981 to 29.0 in 1986–1987 per million males, and from 8.0 in 1980–1981 to 13.8 in 1986–1987 per million females, but decreased thereafter to reach 14.6 per million in males and 8.7 in females in 1996. The downward trends after 1987 were consistent in middle age and elderly population, but asthma mortality tended to rise in children and young adults over the last few years. In Spain, overall age-standardized mortality rates from asthma declined in men from 37.8 in 1980–1981 to 10.1 in 1996, and from 19.5 in 1980–1981 to 13.2 per million females in 1996. In women, the fall in mortality rates was smaller, and overall mortality was higher than in males since early 1990s. Trends of asthma mortality in Italy and Spain were favourable over the last decade.