Phenotypic and functional characteristics of tumor-associated lymphocytes in patients with malignant ascites receiving intraperitoneal infusions of recombinant interleukin-2 (rIL-2)

In the course of a phase I trial, in which recombinant IL-2 (rIL-2) was infused intraperitoneally (i.p.) in patients with peritoneal carcinomatosis, we evaluated the effect on "tumor-associated lymphocytes" (TAL) isolated from the ascitic fluid. No major changes in the percentages of cells expressing the CD3, CD4, CD8, Leu-7, OKM1 and WT-31 antigens were detected either in TAL or in peripheral blood lymphocytes (PBL) after 7 days of rIL-2 infusion. In contrast the percentages of TAL (but not PBL) expressing surface IL-2 receptor (Tac), or LAK-1 antigen were sharply increased. Analysis of cytolytic functions showed a potentiation of the lytic activity against natural-killer (NK) sensitive K562 target cells and the de novo appearance of lytic activity against fresh melanoma cells. In one patient IFN-gamma was detected in the ascitic fluid following rIL-2 infusion. T-cell clones derived from the patient were analyzed for the IFN-gamma production. While only approximately 40% of PB-derived control clones produced medium to low amounts of IFN-gamma, all of the TAL-derived clones produced medium to high amounts of the lymphokine.     

Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

Vitiligo is a skin disorder characterized by depigmented macules secondary to melanocyte loss. An unusual facet is its relation to melanoma: cytotoxic T lymphocytes directed to melanocyte antigens are found in both conditions and imply a breakdown of tolerance, yet the resulting immune reaction is the opposite. The mechanisms at the basis of these opposite effects are not known. Here, we performed a direct comparison of whole melanocyte-specific T cell populations in the two diseases. We demonstrate that neither precursor frequencies of Melan-A/MART-1-specific T lymphocytes nor their status of activation differ significantly. However, by using a tetramer-based T cell receptor down-regulation assay, we documented a higher affinity of vitiligo T cells. We calculated that the peptide concentration required for 50% of maximal receptor down-regulation differed by 6.5-fold between the two diseases. Moreover, only vitiligo T cells were capable of efficient receptor down-regulation and IFN-gamma production in response to HLA-matched melanoma cells, suggesting that this difference in receptor affinity is physiologically relevant. The differences in receptor affinity and tumor reactivity were confirmed by analyzing Melan-A/MART-1-specific clones established from the two diseases. Our results suggest that the quality, and not the quantity, of the melanocyte-specific cytotoxic responses differs between the two pathologies.     

Molecular cytogenetic characterization of proximal-type epithelioid sarcoma

Proximal-type epithelioid sarcoma is a recently described soft-tissue tumor that is distinguished from conventional-type epithelioid sarcoma by a far more aggressive clinical course, frequent location in the proximal anatomic regions, and variable rhabdoid morphology. Because of their rarity and peculiar morphology, proximal-type epithelioid sarcomas frequently pose serious diagnostic dilemmas, being easily misdiagnosed as a variety of other malignant neoplasms. To date, the information available on the genetic alterations associated with this tumor entity has been confined to single conventional cytogenetic reports. In this article, we present the results of a conventional and molecular cytogenetic analysis of six proximal-type epithelioid sarcomas. Spectral karyotyping analysis of these cases deciphered the characteristics of several marker chromosomes and complex translocations, leading to the recognition of recurrent rearrangements. The most frequently involved chromosome arm was 22q, and the identification of two cases with a similar translocation, t(10;22), suggests a role for one or more genes on chromosome 22 in the pathogenesis of this tumor and provides an opportunity for finely mapping the translocation-associated breakpoints. Chromosome arm 8q gain was also a frequent event and correlated with gain of MYC gene copy number, as demonstrated by fluorescence in situ hybridization. A review of both cases reported in the literature and those presented in this study reinforced the involvement of chromosomes 8 and 22 and also indicated frequent rearrangements of chromosomes 7, 14, 18, and 20.     

Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells

Summary: Emerging evidence indicates that the Achilles' heel of cancer immunotherapies is often the complex interplay of tumor-derived factors and deviant host properties, which involve a wide range of immune elements in the lymphoid and myeloid compartments. Regulatory lymphocytes, tumor-conditioned myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and dysfunctional and immature dendritic cells take part in a complex immunoregulatory network. Despite the fact that some mechanisms governing tumor-induced immune tolerance and suppression are starting to be better understood and their complexity dissected, little is known about the diachronic picture of immune tolerance. Based on observations of MDSCs, we present a time-structured and topologically consistent idea of tumor-dependent tolerance progression in tumor-bearing hosts.     

Endometriosis: Leuprolide in a 3-monthly versus a monthly depot formulation for the treatment of symptomatic endometriosis: a pilot study

An open-label randomized pilot study was conducted to evaluatethe efficacy and acceptability of 6 months treatment with leuprolidein a 3-monthly versus a monthly i.m. depot injection for therelief of chronic pelvic pain in women with endometriosis. Atotal of 30 women aged 18-38 years were allocated to the 3-monthlydepot arm (n = 15) or to the monthly depot arm (n = 15) afterlaparoscopic diagnosis of pelvic endometriosis. Mean (SD) deepdys-pareunia scores according to a 0–3 point verbal ratingscale decreased from 1.8 (0.9) at baseline to 1.3 (0.7) at theend of treatment in the 3-monthly depot group and from 2.1 (1.2)to 1–3 (0.7) in the monthly depot group. Correspondingvalues in non-menstrual pain scores fell from 2.1 (0.6) to 1.1(03), and from 2.1 (0.8) to 1.2 (0.4) respectively, withoutstatistically significant differences between the groups. Serumluteinizing hormone (LH) and 17-oestradiol concentrations weresignificantly suppressed at 12 and 24 weeks compared with baselinevalues, without differences between the groups. The monthlydepot caused a slightly more marked inhibition of serum folliclestimulating hormone (FSH) levels with respect to the 3-monthlypreparation. Mean (SD) endometriosis scores at baseline andat 6-month follow-up laparoscopy were respectively 32.8 (25.1)and 12.2 (9.3) in the 3-monthly depot group and 29.0 (22.7)and 13.1 (15.3) in the monthly depot group (paired Mest, P 0.05). Mean percentage decrease in lumbar spine bone mineraldensity was 5.2% in the former and 4.9% in the latter subjects.In the 3-monthly depot group, 13 women graded the tolerabilityof their treatment schedule as ‘good’ compared withseven in the monthly depot group (² = 5.40, P = 0.02).     

The effect of intravenously administered salbutamol on serum potassium in asthmatic and nonasthmatic atopic subjects

The role of adrenergic mechanism in the pathogenesis of allergic disease is controversial. Recent experimental and clinical reports have suggested that -adrenergic blockade impairs and stimulation enhances extrarenal potassium uptake in humans. This led us to study the effect of the intravenous administration of salbutamol, a specific -2-adrenergic agonist, on serum potassium in 9 healthy subjects and in 23 patients with allergic asthma and/or rhinitis. Serum potassium fell significantly and reached a peak decline at the end of venous infusion in all the normal subjects. Seventeen atopic subjects showed a lower or absent serum K⁺ decrement: there was no difference between asthmatic and rhinitic patients. There was no relation among the salbutamol-induced serum potassium decrement, serum glucose increment, blood pressure and heart-rate changes, and nonspecific bronchial reactivity. These findings suggest that -2-adrenergic hyporesponsiveness is present only in some allergic patients.     

Congenital infection with human herpesvirus 6 variant B associated with neonatal seizures and poor neurological outcome

Human herpesvirus 6 (HHV 6) has neurotropic and neuroinvasive properties. The virus has been found in the cerebrospinal fluid of many children with aseptic meningoencephalitis. Intrauterine transmission has been documented by HHV 6 DNA detection in cord blood specimens of apparently healthy newborns and in fetuses following spontaneous abortions. A patient is described with early neonatal afebrile seizures resulting from a congenital HHV 6 variant B infection disclosed by repeated detection of viral genome by polymerase chain reaction (PCR) in cerebrospinal fluid in the first days of life. At follow-up, magnetic resonance imaging (MRI) studies disclosed hyperintensities in the periventricular white matter and basal ganglia, associated with cerebral atrophy. Further follow-up at 18 months revealed poor neurological outcome with mild neurodevelopmental retardation, strabismus and hypertonia of legs. This report provides evidence of neurological involvement after HHV 6 vertical transmission, and the association with neurological sequelae.     

HER-2/neu and bcl-2 in ovarian carcinoma: clinicopathologic, immunohistochemical, and molecular study in patients with shorter and longer survival.

The bcl-2 protein is a membrane protein involved in prolonging cell survival by inhibiting apoptosis. The HER-2 oncogene, which is located on chromosome 17 and encodes for a tyrosine-kinase growth factor receptor, is amplified and HER-2/neu is overexpressed in 25% to 30% of breast carcinomas. The authors analyzed the bcl-2 expression and the bcl-2 gene and HER-2/neu overexpression and amplification in FIGO stage IIIC, serous, G3, ovarian carcinomas obtained from living patients who had no evident disease 5 years after primary treatment compared with ovarian carcinomas obtained from patients, matched for stage, grade of differentiation, and treatment, who had died of progression of disease no later than 2 years after primary treatment. bcl-2 overexpression was statistically correlated with progression of disease during first-line chemotherapy (P=0.021). The HER-2/neu status was found not to correlate with progression of disease during first-line chemotherapy. Both bcl-2 and HER-2/neu expression were not statistically associated with the clinical outcome of ovarian cancer patients. Gene amplification of the HER-2/neu chromosome 17 was found in all the HER-2/neu, 3+ score, positive-staining ovarian carcinomas. None of the analyzed samples revealed a translocation t(14;18)(q32;q21) in the bcl-2 gene. The knowledge of additional prognostic or even predictive factors, such as bcl-2 expression, in patients with advanced ovarian carcinoma before the primary chemotherapeutic treatment may help in the management of patients who require a more tailored treatment. In addition, the gene amplification of the HER-2/neu suggests that HER-2 is a potential target for treatment in ovarian cancer.     

Correlation of epidermal growth factor receptor expression with tumor microdensity vessels and with vascular endothelial growth factor expression in ovarian carcinoma

We analyzed in advanced ovarian serous G3 carcinoma the correlation between epidermal growth factor receptor (EGFR) overexpression and tumor angiogenesis and their relation with clinical outcome. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) were statistically correlated with disease-free interval and death from disease both in univariate and multivariate analyses while EGFR expression was not correlated with clinical outcome. MVD was significantly associated with progression of disease during chemotherapy while VEGF and EGFR expression were not correlated with responsiveness to chemotherapy (Fisher's exact test). VEGF expression was correlated with MVD (Fisher's exact test). EGFR showed a trend to correlation with MVD. Further studies focusing on the use of angiogenesis inhibitors in addition to EGFR inhibitors on ovarian carcinoma cells may produce therapeutic strategies in the selection of tailored therapies in ovarian cancer patients.