DNA methylation variations in familial female and male breast cancer.

In total, ~25% of familial breast cancer (BC) is attributed to germline mutations of the BRCA1 and BRCA2 genes, while the rest of the cases are included in the BRCAX group. BC is also known to affect men, with a worldwide incidence of 1%. Epigenetic alterations, including DNA methylation, have been rarely studied in male breast cancer (MBC) on a genome-wide level. The aim of the present study was to examine the global DNA methylation profiles of patients with BC to identify differences between familial female breast cancer (FBC) and MBC, and according to BRCA1, BRCA2 or BRCAX mutation status. The genomic DNA of formalin-fixed paraffin-embedded tissues from 17 women and 7 men with BC was subjected to methylated DNA immunoprecipitation and hybridized on human promoter microarrays. The comparison between FBC and MBC revealed 2,846 significant differentially methylated regions corresponding to 2,486 annotated genes. Gene Ontology enrichment analysis revealed molecular function terms, such as the GTPase superfamily genes (particularly the GTPase Rho GAP/GEF and GTPase RAB), and cellular component terms associated with cytoskeletal architecture, such as 'cytoskeletal part', 'keratin filament' and 'intermediate filament'. When only FBC was considered, several cancer-associated pathways were among the most enriched KEGG pathways of differentially methylated genes when the BRCA2 group was compared with the BRCAX or BRCA1+BRCAX groups. The comparison between the BRCA1 and BRCA2+BRCAX groups comprised the molecular function term 'cytoskeletal protein binding'. Finally, the functional annotation of differentially methylated genes between the BRCAX and BRCA1+BRCA2 groups indicated that the most enriched molecular function terms were associated with GTPase activity. In conclusion, to the best of our knowledge, the present study was the first to compare the global DNA methylation profile of familial FBC and MBC. The results may provide useful insights into the epigenomic subtyping of BC and shed light on a possible novel molecular mechanism underlying BC carcinogenesis.

A Developmental Perspective on Paragangliar Tumorigenesis.

In this review, we propose that paraganglioma is a fundamentally organized, albeit aberrant, tissue composed of neoplastic vascular and neural cell types that share a common origin from a multipotent mesenchymal-like stem/progenitor cell. This view is consistent with the pseudohypoxic footprint implicated in the molecular pathogenesis of the disease, is in harmony with the neural crest origin of the paraganglia, and is strongly supported by the physiological model of carotid body hyperplasia. Our immunomorphological and molecular studies of head and neck paragangliomas demonstrate in all cases relationships between the vascular and the neural tumor compartments, that share mesenchymal and immature vasculo-neural markers, conserved in derived cell cultures. This immature, multipotent phenotype is supported by constitutive amplification of NOTCH signaling genes and by loss of the microRNA-200s and -34s, which control NOTCH1, ZEB1, and PDGFRA in head and neck paraganglioma cells. Importantly, the neuroepithelial component is distinguished by extreme mitochondrial alterations, associated with collapse of the ΔΨm. Finally, our xenograft models of head and neck paraganglioma demonstrate that mesenchymal-like cells first give rise to a vasculo-angiogenic network, and then self-organize into neuroepithelial-like clusters, a process inhibited by treatment with imatinib.

Novel BRAF mutation in melanoma: A case report.

In melanoma, a number of specific genetic and genomic aberrations have been identified to be important in tumorigenesis. In particular, the mutant B-Raf proto-oncogene, Serine/Threonine kinase (BRAF) gene is the target of tailored therapy with kinase inhibitor molecules. Identification of the array of mutations in patients with melanoma will be useful in determining a genetic profile of the tumor with potential implications for treatment decisions. A rare aminoacidic insertion in codon 599 of the BRAF gene (c.1797_1798insACA, T599insT) was detected by using both direct (Sanger) sequencing and pyrosequencing techniques in a metastatic melanoma of a female elderly patient. As suggested in other clinical contexts including pilocytic astrocytoma, papillary thyroid carcinomas and anaplastic thyroid carcinomas, this unusual mutation may be associated with a modified spatial structure of activated P-loop, resulting in a constitutional activation of the BRAF protein. The patient died shortly following the test, thus no biological therapy was performed. Comparable data regarding treatment of melanoma patients with rare BRAF mutations is lacking, and the response to BRAF inhibitors requires further investigation.

Correction to: Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.

The given and family names of two co-authors were incorrect in the published article. The correct spelling should read as: Sampath Chandra Prasad and Vinagolu K Rajasekhar.

Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.

Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts. We comparatively investigated these unique complementary materials using morphofunctional, ultrastructural and flow cytometric assays accompanied by microRNA studies. We found that paragangliomas contain stem-like cells with hybrid mesenchymal/vasculoneural phenotype, stabilized and expanded in the derived cultures. The viability and growth of such cultures depended on the downregulation of the miR-200 and miR-34 families, which allowed high PDGFRA and ZEB1 protein expression levels. Both tumour tissue- and cell culture-derived xenografts recapitulated the vasculoneural paraganglioma structure and arose from mesenchymal-like cells through a fixed developmental sequence. First, vasculoangiogenesis organized the microenvironment, building a perivascular niche which in turn supported neurogenesis. Neuroepithelial differentiation was associated with severe mitochondrial dysfunction, not present in cultured paraganglioma cells, but acquired in vivo during xenograft formation. Vasculogenesis was the Achilles' heel of xenograft development. In fact, imatinib, that targets endothelial-mural signalling, blocked paraganglioma xenograft formation (11 xenografts from 12 cell transplants in the control group versus 2 out of 10 in the treated group, P = 0.0015). Overall our key results were unaffected by the SDHx gene carrier status of the patient, characterized for 70 out of 77 cases. In conclusion, we explain the biphasic vasculoneural structure of paragangliomas and identify an early and pharmacologically actionable phase of paraganglioma organization.

Strong Notch activation hinders bevacizumab efficacy in advanced colorectal cancer.

AIM: To assess the role of Notch activation in predicting bevacizumab efficacy in colorectal cancer (CRC). MATERIALS & METHODS: Notch activation was evaluated by immunohistochemistry (IHC) on 65 CRC enrolled within randomized clinical trials assessing first-line bevacizumab-based chemotherapy and on 21 CRC treated with chemotherapy alone. RESULTS: Strong Notch (IHC 3+) activation was negatively associated with response (18 vs 62% in low Notch cases [IHC 0, 1, 2+]; p = 0.016), progression-free survival (4.9 vs 12.1 months; p = 0.002) and overall survival (19.3 vs 30.4 months; p = 0.039). No correlation was found between Notch activation and clinical outcome in CRC treated with chemotherapy alone. CONCLUSION: A potential role of Notch activation in the antitumor activity of bevacizumab could be hypothesized.

Salivary gland choristoma of the middle ear.

Choristoma of the middle ear is a rare condition characterized by the presence of normal salivary gland tissue in the middle ear space. Salivary gland choristomas are benign lesions that are frequently associated with ossicular chain and facial nerve anomalies. Total surgical excision is indicated when there is no risk of damaging the facial nerve. We describe a new case of salivary gland choristoma of the middle ear, and we discuss the etiology, histologic features, and management of such lesions. Our patient was a 22-year-old woman in whom we surgically removed a whitish retrotympanic mass. Intraoperatively, we also detected an ossicular chain malformation. Histologic examination of the choristoma revealed the presence of salivary gland tissue. Furthermore, the lesion contained an extensive and previously undescribed component: a well-defined pseudostratified respiratory-type epithelium, similar to that of a normal eustachian tube. Ten months after removal of the choristoma, we surgically repaired the ossicular chain anomalies. No recurrence was noted on follow-up.

Primary squamous cell carcinoma of the breast after cured bilateral breast cancer.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the breast is a rare and aggressive neoplasm that constitutes approximately 0.1% of all breast carcinomas. Before the tumor can be classified as a true SCC of the breast, certain criteria need to be fulfilled. These are: i) more than 90% of the malignant cells must be of squamous cells origin; ii) tumor is independent from the overlying skin and nipple; iii) other sites of primary SCC have been excluded. CASE REPORT: We describe a case of pure SCC of the breast that arose 15 years after local radiation for a primary adenocarcinoma of the breast in a 54-year-old woman with history of bilateral breast cancer. The tumor was triple-negative with a high Ki-67 index. The patient underwent adjuvant chemotherapy with docetaxel and oral fluorouracil. CONCLUSION: There are no specific guidelines for the treatment of primary SCC of the breast. Larger series are necessary to determine if different strategies of treatment and follow-up are necessary and if prognosis is really comparable to other histotypes of cancers of the breast.

HER2-positive gastric cancer showing marked thickening of the gastric wall on ultrasonographic and computed tomographic scans. a chance phenomenon or a specific behaviour of this cancer type? Report of three cases.

Worldwide, gastric cancer is the fourth most commonly diagnosed type of cancer and the second most common cause of cancer-related death. Recently, it was demonstrated that 15-20% of advanced gastro-oesophageal carcinomas overexpress human epidermal receptor 2 (HER2), one of a family of four identified human epidermal receptors. As in HER2-positive breast cancer, trastuzumab, a monoclonal antibody targeting HER2 receptor, with chemotherapy improves prognosis, time-to-progression and overall survival in patients with advanced gastric cancer. Computed tomography (CT) and ultrasound (US) imaging of gastric cancer has been previously reported, however, to our knowledge HER2-positive gastric adenocarcinoma appearance on US and CT scans has not been previously described and no CT and US images of this variant of adenocarcinoma have been found. We herein report three cases of patients with HER2-positive gastric cancer that showed a marked thickening of the gastric wall on US and CT examination.

Giant cell tumors of the skull base: case series and current concepts.

OBJECTIVE: To study the clinical features, tumor characteristics and outcomes of giant cell tumors (GCTs) in the skull base based on long-term follow-up. We also report the largest series of GCTs in the temporal bone and the lateral skull base. MATERIALS AND METHODS: A retrospective study was conducted of all GCTs managed at the Gruppo Otologico, a quaternary referral skull base institute, in Italy from 1993 to 2013. The clinical features, investigations, surgical management and follow-up were recorded. The surgical approaches used were infratemporal fossa approach (ITFA) type B and D and middle cranial fossa (MCF) approaches. RESULTS AND OBSERVATIONS: A total of 7 patients with GCTs of the skull base were treated at our institution. The principal complaints were hearing loss reported in 6 (85.71%) patients, tinnitus in 5 (71.43%) and swelling in 3 (42.9%). Pure-tone audiometry showed conductive hearing loss in 5 (71.43%) patients. High-resolution CT scan and MRI with gadolinium enhancement were done in all patients. Radiology showed involvement of the ITF and middle ear in 6 (85.71%) patients each, temporomandibular joint in 4 (57.14%) patients, invasions of the squamous part of the temporal bone, mastoid, MCF and greater wing of sphenoid in 3 (42.9%) patients each and the petrous bone in 2 (28.6%) patients. ITFA type B was applied as an approach for tumor removal in 5 (71.43%) patients, including a case where an additional MCF approach was employed, and ITFA type D and the transmastoid approach were applied in 1 (14.3%) patient each. Total tumor removal and successful cure was achieved in 6 (85.71%) patients. Subtotal removal leading to recurrence and eventual mortality was the result in 1 (14.3%) patient. CONCLUSIONS: A thorough knowledge of the anatomy of the skull base and the various skull base approaches is necessary to tackle GCTs. ITFA type B and D combined with MCF approaches provide good exposure of the tumor with minimal postoperative sequelae and good locoregional control. Recurrence due to either subtotal removal or suboptimal treatment may have disastrous consequences for the patient.

Solitary fibrous tumors of the pleura: a case report and review of the literature.

BACKGROUND: Solitary fibrous tumors of the pleura are rare and slow-growing neoplasms originating from the mesenchymal tissue underlying the mesothelial layer of the pleura. These tumors may have an unpredictable clinical course. Most cases occur in the sixth or seventh decades of life with no gender predilection, and more than 80% of cases are benign. The predominant clinical symptoms and signs are dyspnea, cough, chest pain, finger clubbing and hypoglycemia. However, because many patients are asymptomatic, the incidence rates are affected by the likelihood of its incidental detection, often through medical imaging of the chest. Surgical resection is the treatment of choice and is usually curative, even though local recurrence can occur many years after an adequate resection. METHODS: We reviewed the literature by performing a computerized search of MEDLINE, CANCERLIT and Embase with the terms fibrous tumor, pleura, surgery, immunohistochemical analysis. Articles and s were also identified by back-referencing from other relevant papers. RESULTS: The clinical, radiological and pathological features of a 48-year-old woman with a primary solitary fibrous tumor of the pleura are reviewed and a literature search for other reported cases has been performed. CONCLUSIONS: Although localized fibrous tumors of the pleura are considered histologically benign, there is a risk of recurrence and malignant transformation. Complete surgical resection is mandatory and long-term clinical and radiological follow-up is indicated in all patients. For malignant cases complete surgical resection may not be adequate and studies are needed to define the role of preoperative and postoperative systemic treatment. Diagnosis is very difficult in limited samples such as fine-needle aspiration or needle-core tissue biopsy, and immunohistochemical analysis may be useful to differentiate solitary fibrous tumor of the pleura from mesothelioma and other similar tumors.

Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling.

Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The "NOTCH signaling pathway" was the most significantly enriched term in the list (P = 0.002 after Bonferroni or Benjamini correction). Expression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunohistochemistry in 47 head and neck paraganglioma cases. There were no relationships between level and pattern of NOTCH1/JAG2 protein expression and germline mutation status in the SDH genes, implicated in paraganglioma predisposition, or the presence/absence of immunostaining for SDHB, a surrogate marker of SDH mutations. Interestingly, NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of this pathway. To address this issue we performed microarray-based microRNA expression analyses. Notably 5 microRNAs (miR-200a,b,c and miR-34b,c), including those most downregulated in the tumors, correlated to NOTCH signaling and directly targeted NOTCH1 in in vitro experiments using SH-SY5Y neuroblastoma cells. Furthermore, lentiviral transduction of miR-200s and miR-34s in patient-derived primary tympano-jugular paraganglioma cell cultures was associated with NOTCH1 downregulation and increased levels of markers of cell toxicity and cell death. Taken together, our results provide an integrated view of common molecular alterations associated with head and neck paraganglioma and reveal an essential role of NOTCH pathway deregulation in this tumor type.

Laser-assisted surgery with different wavelengths: a preliminary ex vivo study on thermal increase and histological evaluation.

Since the introduction of laser in clinical practice, different wavelengths have been used for oral surgery on the basis of the different characteristics and affinities of each one. The aim of this study was a comparison of different laser wavelengths in relation to both thermal increase and "histological quality" in a model of soft tissue surgery procedures. Thermal evaluation was realized, during laser-assisted surgery excision performed on a bovine tongue, by a thermal camera device to evaluate thermal increase on the surface of the sample and with four thermocouples to evaluate thermal increase on the depth of the specimen; temperature was recorded before starting surgical procedure and at the peak of every excision. The quality of excision, in terms of tissue damage and regularity, was realized by two blind examiners on the basis of established criteria. The highest superficial thermal increase was recorded for Superpulse 5-W CO2 laser, the lowest one for Er:YAG laser. The highest in depth thermal increase was recorded for 5 W Diode laser, the lowest one for Er:YAG laser. The best quality of incision was obtained with a 3-W CO2 laser and 3-W diode laser; epithelial, stromal, and vascular damages were evaluated with different degrees for all the used wavelengths with the best result, in terms of "tissue respect," for Er:YAG laser. In all the surgical procedures performed, thermal increase was evaluated until the end of the procedure; at remaining tissue level, thermal decrease was evaluable in the few seconds after surgery. The Er:YAG laser was the device with a lower influence on thermal increase; CO2 and diode lasers revealed a good histological quality. Further studies may be necessary to test the reliability of laser devices for the excision of all the types of specimens needing histological evaluation and diagnosis.

The Gruppo Otologico experience of endolymphatic sac tumor.

OBJECTIVE: Endolymphatic sac tumor (ELST) is a rare low grade adenocarcinoma of the skull base. During the past decade the number of the reported cases has increased. This study exposes our experience in the management of ELST with a review of the literature. STUDY DESIGN: Retrospective study of patients with ELST at a quaternary referral otology and skull base center. METHODS: A review of the records from the Gruppo Otologico revealed 7 patients treated for ELST. All papers containing series of three or more cases of ELST published in the English literature were selected for analysis. RESULTS: Hearing loss and tinnitus were present in almost all our cases. All of them were evaluated with audiometric tests, computed tomography and magnetic resonance imaging. All the patients were treated surgically with preservation of the facial nerve and preoperative embolization was performed in 5 patients. Genetic study was performed on all our cases and revealed the presence of von Hippel-Lindau syndrome in one patient who had the tumor as the initial manifestation of his syndrome. None of the patients received postoperative radiotherapy and one of them had recurrence of the tumor 13 years following surgery. CONCLUSIONS: Complete surgical resection with preoperative embolization of large tumors is the mainstay treatment for ELST. The facial nerve should not be sacrificed unless it is totally invaded by the tumor. A long term follow up is recommended and the role of postoperative adjunctive radiotherapy is still controversial.

Malignancy in vestibular schwannoma after stereotactic radiotherapy: a case report and review of the literature.

OBJECTIVES/HYPOTHESIS: A relation between conventional radiotherapy and the development of intracranial neoplasma is well known, but radiation-associated tumor following stereotactic radiotherapy of vestibular schwannoma is underestimated. In this article we will study this relation by doing a complete literature review on all the malignant intracranial tumors that appeared following radiosurgery and adding a case of malignant vestibular schwannoma following stereotactic radiotherapy in a Neurofibromatosis type 2 patient. METHODS: Literature review and discussion. RESULTS: We found 26 cases of malignant brain tumor following stereotactic radiotherapy including our case. In 13 cases the tumor occurred in context of Neurofibromatosis type 2. None of the patients had a tumor size less than 2.5 cm. and the mean latency period between the radiotherapy and malignant tumor development was 5.8 years. CONCLUSION: Patients with vestibular schwannoma should be made aware of the low incidence of the radiation-induced malignant changes and long-term follow-up is mandatory.

Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy.

BACKGROUND: CD4(+) regulatory T cells are a specialized subset of T cells that actively control immune responses. Several experimental protocols have been used to expand natural regulatory T cells and to generate adaptive type 1 regulatory T cells for regulatory T-cell-based therapies. DESIGN AND METHODS: The ability of exogenous recombinant human interleukin-10 to induce alloantigen-specific anergy in T cells was investigated and compared to that of interleukin-10 derived from tolerogenic dendritic cells, in mixed lymphocyte cultures. A detailed characterization of the effector functions of the resulting anergized T cells is reported. RESULTS: Interleukin-10, whether exogenous or derived from tolerogenic dendritic cells, induces a population of alloantigen-specific T cells (interleukin-10-anergized T cells) containing type 1 regulatory T cells, which are anergic and actively suppress alloantigen-specific effector T cells present within the mixed population. Interleukin-10-induced anergy is transforming growth factor-ß independent, and is associated with a decreased frequency of alloantigen-specific cytotoxic T lymphocyte precursors, but interleukin-10-anergized T cells are still responsive to third-party, bacterial, and viral antigens. Tolerogenic dendritic cells are more powerful than exogenous interleukin-10 in generating type 1 regulatory T-cell precursors, and are also effective in the context of HLA-matched donors. CONCLUSIONS: Based on these studies, we have developed an efficient and reproducible in vitro method to generate antigen-specific type 1 regulatory T-cell precursors starting from total peripheral blood cells with minimal cell manipulation and suitable for generating type 1 regulatory T cells for regulatory T-cell-based therapies.

Unusual myogenic and melanocytic differentiation of soft tissue pPNETs: an immunohistochemical and molecular study of 3 cases.

All of the members of the peripheral primitive neuroectodermal tumor family (Ewing sarcomas, neuroectodermal tumors of bone, peripheral neuroepitheliomas, and Askin tumors) have similar morphologic and immunophenotypical features (ie, the proliferation of small and medium-sized round cells in a fibrous background showing strong and diffuse immunohistochemical positivity for CD99), and the common cytogenetic abnormality of a nonrandom translocation involving the EWS gene and one of several members of the erythroblastosis virus transforming sequence family of transcription factors. The combination of clinical information and morphologic/immunophenotypical characteristics is usually sufficient for a correct diagnosis, but there are rare cases in which an unusual predominant or multidirectional immunophenotypical differentiation makes diagnosis a challenge and requires the use of molecular cytogenetic or molecular techniques. We describe 3 such cases in which we employed fluorescence in-situ hybridization analysis to detect translocation involving the EWS gene and reverse transcription polymerase chain reaction followed by sequencing to detect the fusion transcript EWS-FLI1.

High grade B-cell gastric lymphoma with complete pathologic remission after eradication of Helicobacter pylori infection: report of a case and review of the literature.

BACKGROUND: Treatment of primary gastric diffuse large B-cell lymphoma is still controversial. The treatment of localized disease was based on surgery alone, or followed by chemotherapy and/or radiotherapy. High-grade gastric lymphomas are generally believed to be Helicobacter pylori (HP)-independent growing tumors. However a few cases of regression of high-grade gastric lymphomas after the cure of Helicobacter pylori infection had been described. CASE PRESENTATION: We report here a case with primary diffuse large B-cell lymphoma that showed a complete pathologic remission after HP eradication and we reviewed the literature. A computerized literature reach through Medline, Cancerlit and Embase were performed, applying the words: high grade gastric lymphoma, or diffuse large B cell, MALT gastric lymphoma, DLBCLL (MALT) lymphoma and Helicobacter. Articles and abstracts were also identified by back-referencing from original and relevant papers. Selected for the present review were papers published in English before January 2007. CONCLUSION: Forty two cases of primary high grade gastric lymphoma that regressed with anti HP treatment were found. There were anecdotal cases reported and patients belonging to prospective studies; four trials studied the effect of eradication of Helicobacter pylori as first line therapy in high grade gastric lymphoma: 22 of a total of 38 enrolled patients obtained complete remission. Depth of gastric wall infiltration and clinical stage were important factors to predict the response to antibiotic therapy. Our case and the review of the literature show that high-grade transformation is not necessarily associated with the loss HP dependence. In early stage, for high-grade B-cell HP-positive gastric lymphomas, given the limited toxicity of anti-HP therapy, this treatment may be considered as one of the first line treatment options.

Naive HIV/HCV-coinfected patients have higher intrahepatic pro-inflammatory cytokines than coinfected patients treated with antiretroviral therapy.

In the era of antiretroviral therapy, liver disease has emerged as an important cause of morbidity and mortality in HIV/hepatitis C virus (HCV) coinfected patients. It is believed that HCV is a non-cytopathic virus and that T-cell-mediated events (including the production of pro-inflammatory cytokines) have an important role in promoting both liver damage and viral clearance. Whether HIV coinfection or antiretroviral therapies influence such events is still unclear. In the current study, we compared the expression of NKp46 (a natural killer cell marker), CD3 (a T-cell marker), interferon-gamma (IFN-gamma), tumour-necrosis factor-alpha (TNF-alpha; pro-inflammatory cytokines) and interleukin-10 (IL-10; an anti-inflammatory cytokine) mRNA in the liver of naive HIV/HCV-coinfected patients (group one, n=14), coinfected patients treated with antiretroviral therapy (group two, n=23) and naive HCV mono-infected patients (group three, n=24). All three groups had comparable HCV viremia, with coinfected patients showing similar and relatively high CD4+ T-cell counts and significantly different HIV vireamia. Interestingly, when compared to groups two and three, group one showed significantly higher intrahepatic mRNA levels for CD3, IFN-gamma and TNF-alpha, whereas the expression of NKp46 and IL-10 were comparable in all three groups. Further, higher histopathological grading scores within each group were independently associated with higher mRNA contents for CD3 and IFN-gamma and higher serum alanine aminotransferase levels at the time of liver biopsy. Together, these results suggest that HIV infection may exacerbate the immune-mediated inflammatory response in the liver of patients chronically infected with HCV and antiretroviral therapy may prevent this effect.