A review of the pattern of AIDS defining, HIV associated neoplasms and premalignant lesions diagnosed from 2000-2011 at Kenyatta National Hospital, Kenya.

BACKGROUND: Sub-Sahara Africa hosts up to 71 % of all HIV infected people in the world. With this high incidence of Human immunodeficiency virus ( HIV) comes the burden of co-morbidities such as malignant and premalignant lesions. Aids defining malignancies have been listed as Kaposi's sarcoma, Non-Hodgkin's lymphoma and invasive squamous cell carcinoma of the cervix. People with HIV/AIDS(PLWAS) have a higher risk of developing these neoplasms than the rest of the population. The pathogenesis of these neoplasms in people with HIV has been linked to immune suppression, persistent antigenic stimulation and cytokine dysregulation. Current study analyzes and presents the patterns and trends in the presentation of HIV related malignancies in patients diagnosed through histopathology at Kenyatta National Hospital. AIM: To describe the patterns of AIDS- defining and non-AIDS- defining malignancies and premalignant lesions 10 years pre- and post HAART period at Kenyatta National hospital, Kenya. METHODS AND TECHNIQUES: This was a hospital based descriptive cross sectional study. The Formalin fixed paraffin embedded (FFPE) blocks and histological reports of patients diagnosed between 2000 and 2011 were traced from archives. The patients' demographic data and clinical presentation was entered in an excel spreadsheet and the diagnosis and coding confirmed by a histopathologist. The data was then cleaned and analyzed using SSPS version 17.0 Ink. RESULTS: A total of 173 lesions were reviewed and analyzed. Of these 118 (68 %) were from females and 55 from males (32 %). The male to female ratio was 1:2. The age range was from two to 56 years with a median of 36 years. Kaposi sarcoma is the leading AIDS defining malignancy in Kenya while invasive squamous cell carcinoma of the conjunctiva is the leading non-AIDS defining malignancy. This is closely followed by invasive squamous cell carcinoma of the cervix and NHL. CONCLUSION: Kaposi sarcoma is the leading AIDS associated neoplasm in Kenya. Physicians and caretakers managing and following up on HIV/AIDS patients should look out for Kaposi sarcoma as a form of IRIS following the institution of HAART in all HIV/AIDS patients. The incidence of invasive squamous cell carcinoma of the conjunctiva is increasing in PLWAS in Kenya. There is therefore a need to introduce early screening programs for squamous intraepithelial neoplasm of the conjunctiva in HIV/AIDS patients.

Epstein-Barr nuclear antigen 1 induces expression of the cellular microRNA hsa-miR-127 and impairing B-cell differentiation in EBV-infected memory B cells. New insights into the pathogenesis of Burkitt lymphoma.

Epstein-Barr Virus (EBV) is a γ-herpesvirus that infects >90% of the human population. Although EBV persists in its latent form in healthy carriers, the virus is also associated with several human cancers. EBV is strongly associated with Burkitt lymphoma (BL), even though there is still no satisfactory explanation of how EBV participates in BL pathogenesis. However, new insights into the interplay between viruses and microRNAs (miRNAs) have recently been proposed. In particular, it has been shown that B-cell differentiation in EBV-positive BL is impaired at the post-transcriptional level by altered expression of hsa-miR-127. Here, we show that the overexpression of hsa-miR-127 is due to the presence of the EBV-encoded nuclear antigen 1 (EBNA1) and give evidence of a novel mechanism of direct regulation of the human miRNA by this viral product. Finally, we show that the combinatorial expression of EBNA1 and hsa-miR-127 affects the expression of master B-cell regulators in human memory B cells, confirming the scenario previously observed in EBV-positive BL primary tumors and cell lines. A good understanding of these mechanisms will help to clarify the complex regulatory networks between host and pathogen, and favor the design of more specific treatments for EBV-associated malignancies.

The different epidemiologic subtypes of Burkitt lymphoma share a homogenous micro RNA profile distinct from diffuse large B-cell lymphoma.

Sporadic Burkitt lymphoma (sBL) can be delineated from diffuse large B-cell lymphoma (DLBCL) by a very homogeneous mRNA expression signature. However, it remained unclear whether all three BL variants-sBL, endemic BL (eBL) and human immunodeficiency virus-associated BL (HIV-BL)-represent a uniform biological entity despite their differences in geographical occurrence, association with immunodeficiency and/or incidence of Epstein-Barr virus (EBV) infection. To address this issue, we generated micro RNA (miRNA) profiles from 18 eBL, 31 sBL and 15 HIV-BL cases. In addition, we analyzed the miRNA expression of 86 DLBCL to determine whether miRNA profiles recapitulate the molecular differences between BL and DLBCL evidenced by mRNA profiling. A signature of 38 miRNAs containing MYC regulated and nuclear factor-kB pathway-associated miRNAs was obtained that differentiated BL from DLBCL. The miRNA profiles of sBL and eBL displayed only six differentially expressed miRNAs, whereas HIV and EBV infection had no impact on the miRNA profile of BL. In conclusion, miRNA profiling confirms that BL and DLBCL represent distinct lymphoma categories and demonstrates that the three BL variants are representatives of the same biological entity with only marginal miRNA expression differences between eBL and sBL.

MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation.

The molecular feature of Burkitt lymphoma (BL) is the translocation that places c-Myc under the control of immunoglobulin gene regulatory elements. However, there is accumulating evidence that some cases may lack an identifiable MYC translocation. In addition, during the EUROFISH project, aiming at the standardization of FISH procedures in lymphoma diagnosis, we found that five cases out of 35 classic endemic BLs were negative for MYC translocations by using a split-signal as well as a dual-fusion probe. Here we investigated the expression pattern of miRNAs predicted to target c-Myc, in BL cases, to clarify whether alternative pathogenetic mechanisms may be responsible for lymphomagenesis in cases lacking the MYC translocation. miRNAs are a class of small RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have reported their involvement in cancer and their association with fragile sites in the genome. They have also been shown to control cell growth, differentiation, and apoptosis, suggesting that these molecules could act as tumour suppressors or oncogenes. Our results demonstrated a modulation of specific miRNAs. In particular, down-regulation of hsa-let-7c was observed in BL cases, compared to normal controls. More interestingly, hsa-mir-34b was found to be down-regulated only in BL cases that were negative for MYC translocation, suggesting that this event might be responsible for c-Myc deregulation in such cases. This hypothesis was further confirmed by our in vitro experiments, which demonstrated that increasing doses of synthetic hsa-mir-34b were able to modulate c-Myc expression. These results indicate for the first time that hsa-mir-34b may influence c-Myc expression in Burkitt lymphoma as the more common aberrant control exercised by the immunoglobulin enhancer locus.

Distribution and ecological relevance of fine sediments in organic-enriched lagoons: the case study of the Cabras lagoon (Sardinia, Italy).

In organic-enriched sedimentary systems, like many Mediterranean coastal lagoons, a detailed analysis of sediment grain size composition and partitioning within the muds is crucial to investigate sedimentological trends related to both hydrodynamic energy and basin morphology. In these systems, sediment dynamics are particularly important because the partitioning and transport of fine sediments can strongly influence the redistribution and accumulation of large amounts of organic matter, and consequently the distribution of benthic assemblages and the trophic status and functioning of a lagoon. Nevertheless, studies on benthic-sediment relationships have been based mainly on a rather coarse analysis of sediment grain size features. In muddy systems, however, this approach may impede a proper evaluation of the relationships and effects of the distribution of fine sediment and organic matter on the biotic benthic components. Here we show that the distribution of sedimentary organic matter (OM) and total organic carbon (TOC) in the Cabras lagoon (Sardinia, Italy) can be explained (i.e., predicted) as a function of a nonlinear increase in the amount of the cohesive fraction of sediments (< or = 8 microm grain size particles) and that this fraction strongly influences the structure, composition and distribution of macrobenthic assemblages. Even in such a homogeneously muddy system, characterized by "naturally" occurring impoverished communities, impaired benthic assemblages were found at < or = 8 microm, OM, TOC contents of about 77%, 11% and 3.5%, respectively. A review of studies conducted in Mediterranean coastal lagoons highlighted a lack of direct integrated analysis of sediment features and the biotic components. We suggest that, especially in organic-enriched coastal lagoons, monitoring programs should primarily investigate and consider the cohesive fraction of sediments in order to allow a better assessment of benthic-sediment relationships and ecological quality of the system.

HIV-1 Tat mimetic of VEGF correlates with increased microvessels density in AIDS-related diffuse large B-cell and Burkitt lymphomas.

Angiogenic switch marks the beginning of tumor's strategy to acquire independent blood supply. In some subtypes of non-Hodgkin's lymphomas, higher local vascular endothelial growth factor (VEGF) expression correlates with increased microvessel density. However, this local VEGF expression is higher only in tumors with elevated expression of the receptors of the growth factor, suggesting an autocrine growth-promoting feedback loop. Several studies have indicated that VEGF receptors are also targeted by Tat protein from the HIV-1-infected cells. Given the similarity of the basic region of Tat to the angiogenic factors (basic fibroblast growth factor, VEGF), Tat mimics these proteins and binds to their receptors. We evaluated the role of HIV-1 Tat in regulating the level of VEGF expression and microvessel density in the AIDS-related diffuse large B-cell (DLBCL) and Burkitt lymphomas (BL). By luciferase assay, we showed that VEGF promoter activity was downregulated in vitro in cells transfected with Tat. Reduced VEGF protein expression in primary HIV-1 positive BL and DLBCL, compared to the negative cases, supported the findings of promoter downregulation from the cell lines. Microvascular density assessed by CD34 expression was, however, higher in HIV-1 positive than in HIV-1 negative tumors. These results suggest that Tat has a wider angiogenic role, besides the regulation of VEGF expression. Thus, targeting Tat protein itself and stabilizing transient silencing of VEGF expression or use of monoclonal antibodies against their receptors in the AIDS-associated tumors will open a window for future explorable pathways in the management of angiogenic phenotypes in the AIDS-associated non-Hodgkin's lymphomas.

Placental neurokinin B mRNA expression increases at preterm labor.

INTRODUCTION: Neurokinin B (NKB) is a neuropeptide belonging to the family of tachykinins-related peptides that elicits contractility of human myometrial strips in vitro. The present study evaluates whether placental mRNA and peptide expression of NKB change in women at preterm labor. METHODS: A group of 26 women with singleton pregnancies were enrolled in the study. Placental tissue specimens were collected from pregnant women delivering after elective cesarean section, after labor at term, or after preterm labor. Changes in placental NKB mRNA and protein expression were evaluated by real-time quantitative RT-PCR analysis and by immunofluorescence respectively. RESULTS: Placental mRNA expression of NKB was significantly higher after term and preterm labor (P<0.001) than cesarean section, and highest after preterm labor. Immunofluorescent staining in placentas from preterm or term labor was more intense than after cesarean section (P<0.001). In particular, NKB protein expression was higher in placentas collected after preterm labor than those collected after term labor. DISCUSSION: Neurokinin B mRNA and protein are highly expressed in placenta at term and preterm labor; thus, the involvement of this neuropeptide in the events cascade leading to parturition may be suggested.

Sediment characteristics and macrofauna distribution along a human-modified inlet in the Gulf of Oristano (Sardinia, Italy).

We studied the spatial variability and within-year temporal changes in hydrological features, grain size composition and chemical characteristics of sediments, as well as macrofaunal assemblages, along a heavily modified inlet in the Gulf of Oristano (western Sardinia, Italy). The inlet connects the Cabras lagoon to the gulf through a series of convoluted creeks and man-made structures, including a dam and fish barriers built in the last three decades. Sediments were muddy and mainly composed of the "non-sortable" fraction (i.e., <8 microm particle size) in all four areas investigated: Lagoon, Creeks, Channel and Seaward. Along the inlet, however, the ratio between the <8 microm and the 8-64 microm fractions was highest in Creeks and Channel, between the fish barriers and the dam, suggesting impaired hydrodynamics. Consistently, steep gradients in water salinity, temperature and dissolved oxygen concentrations were found in proximity to the fish barriers. The whole inlet was characterized by a major organic enrichment of sediments, with up to an annual mean of 33.6% of organic matter and 11.7% of total organic carbon in Seaward due to the presence of seagrass leaf litter. Acid-volatile sulphide and chromium-reduced sulphur concentrations were highest throughout the year in Seaward and Lagoon, respectively, with a peak in summer. Consistently, the whole inlet supported low structured macrofaunal assemblages dominated by few opportunist species, with a relatively lower diversity in Lagoon throughout the year and the highest abundances in Seaward in summer. We infer that the presence of artificial structures along the inlet, such as fish barriers and the dam, impair the lagoon-gulf hydrodynamics, sediment exchange and animal recruitment and colonization. We suggest that the removal of these structures would favour water renewal in the Cabras lagoon, but would also increase the outflow of organic C-bonding fine particles into the gulf with serious consequences for Posidonia oceanica and Cymodocea nodosa seagrass meadows. We conclude that all possible consequences of such initiatives should be carefully considered before any action is taken.

Secretory endometrium highly expresses urocortin messenger RNA and peptide: possible role in the decidualization process.

BACKGROUND: Urocortin (UCN) gene expression and synthesis have been reported in epithelial and stromal cells of the human endometrium. In this study we evaluated (i) UCN messenger RNA (mRNA) expression and peptide production in uterine specimens collected throughout the endometrial cycle, (ii) UCN secretion after decidualization of cultured human endometrial stromal cells (HESCs) and (iii) the effect of UCN on endometrial decidualization. METHODS: HESCs were isolated from samples of human endometrium collected from healthy patients with normal menstrual cycle and cultured in presence of cAMP, 17-beta-estradiol (E(2)) + medroxyprogesterone acetate (MPA) and UCN. UCN levels were measured in endometrial extracts by an enzyme immunoassay, and changes of endometrial UCN mRNA expression were measured by RT-PCR analysis. RESULTS: UCN peptide concentrations and mRNA expression were highest in the secretory phase of the menstrual cycle (P < 0.001, late secretory versus early and late proliferative phase) and higher in the late than the early secretory phase (P < 0.01). After decidualization of HESC with cAMP or E(2) + MPA, UCN levels rose in parallel with prolactin concentrations by days 6 (P < 0.01, for all). Finally, the addition of UCN to HESCs, with or without E(2) + MPA, induced the release of prolactin. CONCLUSIONS: The evidence that (i) UCN is highly expressed in the secretory phase of the endometrial cycle; (ii) cAMP and E(2) + MPA modulate secretion of UCN and (iii) UCN induces HESCs decidualization together suggest a possible role for UCN in endometrial physiology.

Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family.

AIMS: Germline mutation of the E-cadherin gene (CDH1) accounts for the Hereditary Diffuse Gastric Cancer (HDGC) syndrome. Fourteen pedigrees with Diffuse Gastric Cancer that fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria were selected and screened for CDH1 germline mutations. METHODS: The entire coding region of the CDH1 gene and all intron-exon boundaries were analyzed by direct sequencing in the 14 families fulfilling the IGCLC criteria. E-cadherin immunohistochemical expression was evaluated on tumour as well as normal formalin-fixed paraffin embedded tissues. RESULTS: A novel germline missense mutation was found. It was a single C-->T substitution in exon 8, resulting in a transition of CCG-->CTG (C1118T; Pro373Leu) demonstrated in the proband and her brother. At immunohistochemical analysis, the staining intensity was reduced and considered weakly positive (15%). CONCLUSIONS: The first CDH1 germline mutation of an Italian family is herein reported. The present missense mutation has never been described so far.

pRb: master of differentiation. Coupling irreversible cell cycle withdrawal with induction of muscle-specific transcription.

The protein product of the retinoblastoma (RB) gene is necessary for the completion of the muscle differentiation program and for myogenic basic helix-loop-helix-dependent transcription. In fact, in addition to induction and maintenance of permanent cell cycle withdrawal through negative regulation of E2F-responsive genes involved in proliferation, pRb also plays a positive role in the activation of muscle-specific genes. In pRb-/- myocytes, the expression of late myogenic markers is defective and myoblast fusion into myotubes occurs without irreversible cell cycle exit. This evidence demonstrates only a partial functional redundancy between pRb and its relatives p107 and pRb2/p130, as these pRb-/- multinucleated cells, which display p107 levels higher than normal myotubes, respond to mitogens with cell cycle re-entry and DNA synthesis. At the molecular level, pRb myogenic functions are mediated by cooperation with MyoD, Myocyte enhancer factor 2 (MEF2), High mobility group box protein-1 (HBP1) and histone deacetylase1, affecting chromatin configuration and tissue-specific transcription, and by post-translational modification in response to intracellular signaling cascades.

Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus.

Human polyomaviruses (JC virus, BK virus and simian virus 40) are causative agents of some human diseases and, interestingly, are involved in processes of cell transformation and oncogenesis. These viruses need the cell cycle machinery of the host cell to complete their replication; so they evolved mechanisms that can interfere with the growth control of infected cells and force them into DNA replication. The retinoblastoma family of proteins (pRb), which includes pRb/p105, p107 and pRb2/p130, acts as one of the most important regulators of the G1/S transition of the cell cycle. Rb proteins represent an important target for viral oncoproteins. Early viral T antigens can bind all members of the pRb family, promoting the activation of the E2F family of transcription factors, thus inducing the expression of genes required for the entry to the S phase. The interaction between early viral antigens and cell cycle regulators represents an important mechanism through which viruses deregulate cell cycle and lead to cell transformation. In this review, we will discuss the effects of the interaction between large T antigen and Rb proteins in JC virus-mediated oncogenesis.

Retinoblastoma gene family expression in lymphoid tissues.

It appears more and more clear that retinoblastoma (RB) family of proteins represents key molecules in tumour suppression. This family consists of pRb/p105, p107 and pRb2/p130, which participate in a gene regulatory network that governs the cellular response to antimitogenic signals, and whose deregulation constitutes one of the hallmarks of cancer. Irrespective of their structural and biochemical similarities, RB proteins carry out different functional tasks. The expression of RB gene family in the reactive lymphoid tissues again confirms the different role of each member in cell cycle control and differentiation of normal cells. These different functional properties appear to be maintained in tumours lymphoid tissues, where alterations of the RB/p105 gene appear to be relatively rare. In this review, we will summarize the current knowledge about the role of the RB proteins in reactive and neoplastic lymphoid tissue.

pRb2/p130: a new candidate for retinoblastoma tumor formation.

Retinoblastoma is the most common primary intraocular tumor in childhood. Mutations in both the alleles of the RB1 gene represent the causative agent for the tumor to occur. It is becoming evident that, although these alterations represent key events in the genesis of retinoblastoma, they are not sufficient per se for the tumor to develop, and other additional genetic or epigenetic alterations must occur. A supportive role in the genesis of retinoblastoma has recently been proposed for the RB1-related gene RB2/p130. Additionally, several other genetic alterations involving different chromosomes have been described as relevant in the tumorigenic process. In this review we will analyse current knowledge about the molecular mechanisms involved in retinoblastoma, paying particular attention to the mechanisms of inactivation of the biological function of the retinoblastoma family of proteins.

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis.

The role of HPV in the carcinogenesis of intraepithelial and invasive anogenital lesions is currently well established. E6 and E7 oncoproteins of high-risk HPV genotypes are known to inactivate p53 and pRb pathways. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative cases. For these reasons, cervical cancer is considered an AIDS-defining neoplasm. Unlike other AIDS-associated neoplasms, the occurrence of cervical cancer is independent of immune suppression. HIV-1 infection in patients with high grade precancerous lesions and invasive cervical cancers results in a therapy refractory and more aggressive disease phenotype, which is not yet well understood at the molecular level. An upregulation of HPV E6 and E7 gene expressions by HIV-1 proteins such as Tat has been documented by some authors. However, the role of HIV-1 in cervical carcinomas is still unclear. It is already known that HIV-1 Tat protein is able to influence cell cycle progression. Altogether, these facts led us to investigate the effects of Tat on the expression of cell cycle regulator genes. After transfection of HeLa cells with Tat, we analyzed the expression of cell cycle regulators from these cells by IHC and Real-time PCR. A significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers were observed. These results suggest that HIV-1 may enhance cervical carcinogenesis by promoting cell cycle progression. We also found that this HIV-1 Tat-induced cell proliferation was not dependent on the E2F family of transcription factors, and therefore postulate that Sp factors may be involved.

Genotoxicity biomarkers and acetylcholinesterase activity in natural populations of Mytilus galloprovincialis along a pollution gradient in the Gulf of Oristano (Sardinia, western Mediterranean).

A year-round biomonitoring study on blue mussels (Mytilus galloprovincialis) was carried out in 4 selected sites along the Gulf of Oristano (Sardinia, Italy): a commercial port (Port), the outlet of the S'Ena Arrubia and Marceddì lagoons (in the catchment area of intensive agricultural and diary activities, and abandoned mining), and a reference site (North). Heavy metal concentrations in sediments from Marceddì were 2-3 to 10-20 times higher in Pb, Cd and Zn, respectively, than those found at North and S'Ena Arrubia. Higher values (P<0.05) of micronuclei frequency were detected in mussels from Marceddì and Port compared to those detected in mussels from North and S'Ena Arrubia. DNA damage in animals from North was significantly lower than that at the other sites. Results of acetylcholinesterase inhibition consistently showed the strongest effects in mussels from Port and Marceddì. Our results suggest that these biomarkers can be used in coastal marine biomonitoring as early signals of exposure and adverse effects along a pollution gradient.

High fetal urocortin levels at term and preterm labor.

CONTEXT: Placental urocortin has a role in the cascade of events leading to parturition by stimulating myometrial contractility and placental uterotonins secretion. OBJECTIVE: The objective of this study was to evaluate urocortin levels in maternal and fetal [umbilical cord artery (UCA) and vein (UCV)] plasma at term and preterm labor. DESIGN: The study design was a controlled cross-sectional study performed from November 2003 to June 2004. SETTING: This study was performed at the Division of Obstetrics and Gynecology, University of Siena (Siena, Italy). PATIENTS: Plasma samples were collected at term in the absence of labor (TNL; n = 27; 39.3 +/- 0.1 gestational weeks), at term spontaneous vaginal delivery (TL; n = 24; 40.1 +/- 0.2 gestational weeks), and at preterm labor (PTL; n = 19; 32.4 +/- 0.4 gestational weeks). Changes in urocortin mRNA expression were also evaluated in placentas collected from TNL (n = 11), TL (n = 11), and PTL (n = 10). INTERVENTION: Urocortin levels were measured by specific RIA. Changes in placental mRNA expression were determined by real-time quantitative RT-PCR analysis. RESULTS: Maternal and UCA plasma urocortin levels were significantly (P < 0.0001 for all) higher in TL and PTL than in TNL. Furthermore, UCA concentrations were significantly (P < 0.0001 for all) higher than and correlated with maternal concentrations (TNL: r = 0.45; P < 0.05; TL: r = 0.959; P < 0.0001; PTL: r = 0.7719; P < 0.0001). UCV levels were significantly (P < 0.001) higher in TL and PTL than in TNL and were significantly (P < 0.0001 for all) higher than and significantly (P < 0.0001 for all) correlated with maternal values, but were significantly (P < 0.0001 for all) lower than and correlated with UCA values (TNL: r = 0.9548; P < 0.0001; TL: r = 0.927; P < 0.0001; PTL: r = 0.838; P < 0.0001). Placental urocortin mRNA expression did not differ among TNL, TL, and PTL samples. CONCLUSIONS: Fetal urocortin secretion is increased in term and preterm labor. Whether these changes are a consequence rather than a cause of human parturition remains to be addressed.

Pathologic aspects of AIDS malignancies.

Since the emergence of the HIV pandemic, a close association between HIV infection and the development of a selected group of cancers has been acknowledged. The introduction of highly active antiretroviral therapy, however, has had a dramatic impact on the incidences of several AIDS-defining malignancies. This suggests the possibility of a direct and indirect role of HIV in HIV-related tumor genesis. The aim of this paper is to review the pathology of AIDS-related malignancies, taking into account the pathogenetic mechanisms and their potential for improving the treatment of these tumors.

Burkitt's lymphoma: new insights into molecular pathogenesis.

The World Health Organisation classification reports three subcategories of Burkitt's lymphoma (BL)--endemic, non-endemic, and immunodeficiency associated--proposed to reflect the major clinical and genetic subtypes of this disease. These different types of BL have been reviewed and studied by immunohistochemistry and molecular methods. The results point out the heterogeneity of BL and suggest that AIDS related BL may have a different pathogenesis from that of classic BL.

Angiogenesis and anti-angiogenesis in neuroblastoma.

Angiogenesis is a biological process by which new capillaries are formed from pre-existing vessels. It occurs in physiological and pathological conditions, such as tumours, where a specific critical turning point is the transition from the avascular to the vascular phase. Tumour angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells that able to stimulate the growth of the host's blood vessels. This review summarises the literature concerning the relationship between angiogenesis and progression in human neuroblastoma, the most common extracranial solid tumour of infancy and childhood. It is becoming increasingly evident that agents which interfere with blood vessel formation also block tumour progression. Accordingly, anti-angiogenic tumour therapy has gained much interest in preclinical and clinical assessments. The recent applications of anti-angiogenic agents which interfere or block neuroblastoma progression are reviewed.