Angiomatosis bacilar y sarcoma de Kaposi en lesión cutánea de paciente VIH positivo / Bacillary angiomatosis and Kaposi's sarcoma in skin lesion of HIV positive patient

La angiomatosis bacilar (AB) es una enfermedad infec-ciosa poco frecuente, causada por bacterias del género Bartonella spp. transmitidas por vectores como pulgas, piojos y mosquitos. En el ser humano provoca diferentes síndromes clínicos. En pacientes con infección por el virus de inmunodeficiencia humana (VIH) con recuento de LT CD4 + <100 cél/µL se asocia a lesiones angiomatosas con neovascularización que comprometen la piel y, en menor medida, mucosas, hígado, bazo y huesos.El sarcoma de Kaposi (SK) es una neoplasia caracteriza-da por hiperplasia vascular multifocal de origen endotelial relacionada con el herpes virus humano 8. También puede afectar piel, mucosas y vísceras, siendo la variante epidé-mica una enfermedad marcadora de la infección avanzada por VIH. El principal diagnóstico diferencial clínico para las lesiones cutáneas y mucosas del SK es la AB.Presentamos un paciente con enfermedad VIH/sida que desarrolló AB y SK en forma concomitante en la misma lesión cutánea

Bacillary angiomatosis (BA) is a rare infectious disease, caused by bacteria of the genus Bartonella spp, transmitted by vectors such as fleas, lice and mosquitoes. It causes different clinical syndromes in humans. In patients with human immunodeficiency virus (HIV) infection with an LT CD4 + <100 cell/µL count, it is associated with the development of angiomatous lesions with neovascularization involving the skin and, with less frequency, mucous membranes, liver, spleen and bones. Kaposi's sarcoma (KS) is a neoplasm characterized by multifocal vascular hyperplasia of endothelial origin related to human herpes virus 8. It can also compromiso the skin, mucous membranes and viscera, with the epidemic variant being a marker disease of advanced HIV infection. The main clinical differential diagnosis for KS skin and mucosal lesions is the BA.Herein we present a patient with HIV/AIDS disease that developed BA and KS concomitantly in the same skin lesion

Diagnostic Features of Blastocystis Life Cycle Forms in the Small Intestine in an HIV-Infected Patient.

PURPOSE: Blastocystis spp. are parasites of the intestinal tract found in many hosts including humans. This pathogen is commonly found in immunocompetent in asymptomatic individuals and in patients with gastrointestinal and extra-intestinal symptoms. Recently, it has been implicated as an important cause of diarrheal illness in immunocompromised individuals, including HIV-infected patients. At least six life cycle stages have been described in faeces and cultures, namely vacuolar, granular, multi-vacuolar, avacuolar, ameboid and cyst forms. The aim of the present study was to describe the histological findings of Blastocystis infection in an adult HIV-infected patient with gastrointestinal symptoms. METHODS: Parasitological techniques and PCR were applied to stool samples. Histological analysis was performed on duodenal biopsy specimens. RESULTS: Standard parasitological methods revealed vacuolar, granular, cyst and multi-vacuolar forms of Blastocystis in faecal samples with the presence of Blastocystis DNA being confirmed by PCR. DNA sequencing revealed Blastocystis subtype ST1. Histological findings in duodenal samples showed an inflammatory infiltrate with plasma cells and lymphocytes. We identified cyst, granular, ameboid and multi-vacuolar forms in the lumen. CONCLUSION: To our knowledge, there are no previous peer review reports describing these four different forms of Blastocystis in histological sections from the lumen and the brush border of the enterocytes.

Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome.

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy.

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity.

The safety and feasibility of dendritic cell (DC)-based immunotherapies in cancer management have been well documented after more than twenty-five years of experimentation, and, by now, undeniably accepted. On the other hand, it is equally evident that DC-based vaccination as monotherapy did not achieve the clinical benefits that were predicted in a number of promising preclinical studies. The current availability of several immune modulatory and targeting approaches opens the way to many potential therapeutic combinations. In particular, the evidence that the immune-related effects that are elicited by immunogenic cell death (ICD)-inducing therapies are strictly associated with DC engagement and activation strongly support the combination of ICD-inducing and DC-based immunotherapies. In this review, we examine the data in recent studies employing tumor cells, killed through ICD induction, in the formulation of anticancer DC-based vaccines. In addition, we discuss the opportunity to combine pharmacologic or physical therapeutic approaches that can promote ICD in vivo with in situ DC vaccination.

Recapitulation of Hypoxic Tumor-stroma Microenvironment to Study Photodynamic Therapy Implications.

Tumor microenvironment (TME) is a dynamic ecosystem where fibroblasts are recruited in order to provide a niche to support growth and, in some extent, to promote therapeutic resistance. However, the role of fibroblasts in stimulating or impairing photodynamic therapy (PDT) outcome has not yet been fully addressed. PDT is based on interactions between light, oxygen and photosensitizer, leading to phototoxic reactions that culminate in cell death. In this study, we demonstrated the consequences of a hypoxic stromal phenotype on tumor mass for exploring PDT response. We mimicked TME complexity implementing colon cancer cells and fibroblasts 3D cultures called spheroids. Using hypoxia reporting lines, we verified that homotypic spheroids exhibited a size-dependent transcriptional HIF-1 activity. When cocultured, fibroblasts were localized in the hypoxic core. In homotypic stromal spheroids, the distribution of the endogenous photosensitizer PpIX was homogeneous while decreased in hypoxic areas of tumor 3D cultures. When monocultured, fibroblasts were more efficient to produce PpIX from its prodrug Me-ALA. Interestingly, the cross talk between cancer cells and fibroblasts attenuated PpIX accumulation and conferred tumor PDT resistance when compared to homotypic 3D cultures. Overall, our data suggest that stroma and tumor act in an integrated, reciprocal fashion which could ultimately influence on therapeutic response.

Photodynamic Modulation of Type 1 Interferon Pathway on Melanoma Cells Promotes Dendritic Cell Activation.

The immune response against cancer generated by type-I-interferons (IFN-1) has recently been described. Exogenous and endogenous IFN-α/ß have an important role in immune surveillance and control of tumor development. In addition, IFN-1s have recently emerged as novel DAMPs for the consecutive events connecting innate and adaptive immunity, and they also have been postulated as an essential requirement for induction of immunogenic cell death (ICD). In this context, photodynamic therapy (PDT) has been previously linked to the ICD. PDT consists in the administration of a photosensitizer (PS) and its activation by irradiation of the affected area with visible light producing excitation of the PS. This leads to the local generation of harmful reactive oxygen species (ROS) with limited or no systemic defects. In the current work, Me-ALA inducing PpIX (endogenous PS) was administrated to B16-OVA melanoma cells. PpIX preferentially localized in the endoplasmic reticulum (ER). Subsequent PpIX activation with visible light significantly induced oxidative ER-stress mediated-apoptotic cell death. Under these conditions, the present study was the first to report the in vitro upregulation of IFN-1 expression in response to photodynamic treatment in melanoma. This IFN-α/ß transcripts upregulation was concurrent with IRF-3 phosphorylation at levels that efficiently activated STAT1 and increased ligand receptor (cGAS) and ISG (CXCL10, MX1, ISG15) expression. The IFN-1 pathway has been identified as a critical molecular pathway for the antitumor host immune response, more specifically for the dendritic cells (DCs) functions. In this sense, PDT-treated melanoma cells induced IFN-1-dependent phenotypic maturation of monocyte-derived dendritic cells (DCs) by enhancing co-stimulatory signals (CD80, MHC-II) and tumor-directed chemotaxis. Collectively, our findings showed a new effect of PDT-treated cancer cells by modulating the IFN-1 pathway and its impact on the activation of DCs, emphasizing the potential relevance of PDT in adoptive immunotherapy protocols.

Secretome profiling of heterotypic spheroids suggests a role of fibroblasts in HIF-1 pathway modulation and colorectal cancer photodynamic resistance.

PURPOSE: Previous analyses of the tumor microenvironment (TME) have resulted in a concept that tumor progression may depend on interactions between cancer cells and its surrounding stroma. An important aspect of these interactions is the ability of cancer cells to modulate stroma behavior, and vice versa, through the action of a variety of soluble mediators. Here, we aimed to identify soluble factors present in the TME of colorectal cancer cells that may affect relevant pathways through secretome profiling. METHODS: To partially recapitulate the TME and its architecture, we co-cultured colorectal cancer cells (SW480, TC) with stromal fibroblasts (MRC-5, F) as 3D-spheroids. Subsequent characterization of both homotypic (TC) and heterotypic (TC + F) spheroid secretomes was performed using label-free liquid chromatography-mass spectrometry (LC-MS). RESULTS: Through bioinformatic analysis using the NCI-Pathway Interaction Database (NCI-PID) we found that the HIF-1 signaling pathway was most highly enriched among the proteins whose secretion was enhanced in the heterotypic spheroids. Previously, we found that HIF-1 may be associated with resistance of colorectal cancer cells to photodynamic therapy (PDT), an antitumor therapy that combines photosensitizing agents, O2 and light to create a harmful photochemical reaction. Here, we found that the presence of fibroblasts considerably diminished the sensitivity of colorectal cancer cells to photodynamic activity. Although the biological significance of the HIF-1 pathway of secretomes was decreased after photosensitization, this decrease was partially reversed in heterotypic 3D-spheroids. HIF-1 pathway modulation by both PDT and stromal fibroblasts was confirmed through expression assessment of the HIF-target VEGF, as well as through HIF transcriptional activity assessment. CONCLUSION: Collectively, our results delineate a potential mechanism by which stromal fibroblasts may enhance colorectal cancer cell survival and photodynamic treatment resistance via HIF-1 pathway modulation.

NQO1 induction mediated by photodynamic therapy synergizes with ß-Lapachone-halogenated derivative against melanoma.

The elevated expression of NQO1 in many human solid tumors along with its ability to activate quinone-based anticancer agents makes it an excellent target for enzyme-directed drug development. NQO1 plays an important role in melanogenesis and given its correlation with a poor patient outcome we propose this enzyme as an intriguing target for molecular-based therapeutic regimen against melanoma. Unfortunately, the natural product ß-Lapachone (ß-Lap), whose antitumor activity is based on NQO1, reported dose-limiting toxicity which hampered its pre-clinical and clinical use. Therefore, new effective and safe therapeutic NQO1-bioactivatable agents for melanoma treatment are desirable. Regarding NQO1, we demonstrated that halogenated ß-Lap derivative named PFB is an excellent substrate and effective tumor-selective anticancer compound. In addition, PFB resulted more attractive than the parent ß-Lap for treating metastatic-derived melanoma cells. In this context, it would be interesting to design strategies to induce NQO1 activity in cancer cells as a promising combinatorial approach with bioreductive drugs. In this sense, we had reported that photodynamic therapy (PDT) significantly upregulated NQO1 expression. Based on this event, here we demonstrated that the cytotoxic regimen consisting of PFB plus PDT improved synergistic therapeutic combination on melanoma cells. In conclusion, our contribution provides a strong rationale for using therapies that associate photo- and chemotherapy to effectively treat melanoma with modular NQO1 status.

First detection of Cryptosporidium DNA in blood and cerebrospinal fluid of HIV-infected patients.

Human cryptosporidiosis is an intestinal infection caused by different species belonging to the genus Cryptosporidium in both immunocompetent and immunocompromised individuals. The life cycle of Cryptosporidium sp. when affecting the digestive system is well known but the infection of other organs is less studied. Molecular methods are necessary for species and subtypes identification. The goal of this work is to propose a new approach that contributes to the diagnosis of the extra-intestinal dissemination process of Cryptosporidium infection. Cryptosporidium sp. was detected in stool and biopsy samples of two HIV-infected patients. DNA was extracted from feces, biopsy specimens, blood, and cerebrospinal fluid (CSF). All samples were analyzed by nested PCR-RFLP of the 18S rDNA, real-time PCR, and gp60 subtyping. Cryptosporidium DNA was detected in stool and tissue samples and it was also present in blood and CSF samples. Both cases were characterized as Cryptosporidium hominis subtype IeA11G3T3. This is the first report that demonstrates the presence of Cryptosporidium DNA in blood and CSF of HIV-infected patients.

Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy.

Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT.

Pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in the era of antiretroviral therapy.

Toxoplasmosis is a severe opportunistic infection in patients infected with the human immunodeficiency virus (HIV). The lung is a major site of infection after the central nervous system. In this report we described two cases of pneumonia due to Toxoplasma gondii infection in HIV patients with antiretroviral therapy. Clinical and radiological abnormalities are not specific. Pulmonary toxoplasmosis should be considered in HIV-infected patients with late stage of HIV, CD4 count less than 100 cells/µl and a poor adherence to HAART.

Contribution of resident and recruited macrophages to the photodynamic intervention of colorectal tumor microenvironment.

The study of cellular interactions in the tumor microenvironment has become one of the main areas of research in the fight against cancer. Tumor-associated macrophages (TAMs) influence tumor progression and therapy response due to its functional plasticity. Regarding cancer treatment, photodynamic therapy (PDT) is a minimally invasive and clinically approved procedure that involves the administration of a photosensitizer (PS), a nontoxic photosensitizing drug which is selectively retained in neoplastic tissue. Here, we investigated the role of resident and nonresident macrophages in the context of a PDT-treated colorectal tumor by developing a combination of 2-D and three-dimensional (3-D) experimental platform, recreating tumor-stroma interactions in vitro. Enhancement of cytotoxicity of PDT was achieved in the presence of nonresident macrophages which had a strong anti-tumor phenotype mediated by the production of nitric oxide, IL-6, and tumor necrosis factor alpha (TNF-α). On the contrary, tumor resident macrophages induced a pro-tumor phenotype promoting tumor cell migration and endothelial stimulation. Due to their plasticity, tumor-resident or tumor-recruited macrophages can differentially influence the response of tumors to PDT, so their multifactorial roles should be considered in the overall design of anti-tumor therapeutic.

MENINGOENCEPHALITIS DUE TO VARICELLA ZOSTER VIRUS IN AIDS PATIENTS. REPORT OF ELEVEN CASES AND REVIEW OF THE LITERATURE / Meningoencefalite pelo vírus varicela-zoster em pacientes com AIDS. Relato de onze casos e revisão da literatura

Neurological complications of varicella-zoster virus (VZV) are infrequent and include various clinical pictures. The reactivation of VZV in patients with AIDS is generally associated with an acute and severe meningoencephalitis. We report the epidemiological, clinical and virological data from 11 consecutive patients with diagnosis of HIV/AIDS and central nervous system (CNS) involvement due to VZV. All patients were male and seropositive for HIV. The primary risk factor for HIV infection was unprotected sexual contact. The median of CD4 T cell count was 142 cells/µL. All of them presented signs and symptoms of meningoencephalitis. Six patients (54.5%) presented pleocytosis; they all showed high CSF protein concentrations with a median of 2.1 g/dL. Polymerase chain reaction of cerebrospinal fluid specimen was positive for VZV in all of them and they were treated with intravenous acyclovir at doses of 30/mg/kg/day for 21 days. Overall survival was 63% (7 of 11 patients). The four dead patients had low cellular counts in CSF, below the median of this parameter. VZV should be included among the opportunistic pathogens that can involve CNS with a diffuse and severe meningoencephalitis in patients with advanced HIV/AIDS disease.

As complicações neurológicas do vírus varicela-zoster (VVZ) são pouco frequentes e incluem vários quadros clínicos. A reativação do VVZ em pacientes com AIDS é geralmente associada com meningoencefalite aguda e grave. Nós relatamos os dados epidemiológicos, clínicos e virológicos de onze pacientes consecutivos com diagnóstico de HIV/AIDS e comprometimento do sistema nervoso central (SNC) devido ao VVZ. Todos os pacientes eram do sexo masculino e soropositivos para HIV. O principal fator de risco para a infecção pelo HIV foi o contato sexual sem proteção. A mediana da contagem de células CD4 T foi de 142 cel/µL. Todos apresentavam sinais e sintomas devido à meningoencefalite. Seis pacientes (54,5%) apresentaram pleiocitose; todos apresentaram hiperproteinorraquia com mediana de 2,1 g/dL. A reação em cadeia da polimerase de amostra do líquido cefalorraquidiano foi positiva para VVZ em todos eles. Todos os pacientes foram tratados com aciclovir por via intravenosa em doses de 30 mg/kg/dia durante 21 dias. A sobrevida global foi de 63% (sete de 11 pacientes). Os quatro pacientes mortos tiveram uma escassa resposta celular no LCR abaixo da mediana para este parâmetro. O VVZ deve ser incluído entre os patógenos oportunistas que podem comprometer o SNC com meningoencefalite difusa e grave em pacientes com doença avançada por HIV/SIDA.

Developing strategies to predict photodynamic therapy outcome: the role of melanoma microenvironment.

Melanoma is among the most aggressive and treatment-resistant human skin cancer. Photodynamic therapy (PDT), a minimally invasive therapeutic modality, is a promising approach to treating melanoma. It combines a non-toxic photoactivatable drug called photosensitizer with harmless visible light to generate reactive oxygen species which mediate the antitumor effects. The aim of this review was to compile the available data about PDT on melanoma. Our comparative analysis revealed a disconnection between several hypotheses generated by in vitro therapeutic studies and in vivo and clinical assays. This fact led us to highlight new preclinical experimental platforms that mimic the complexity of tumor biology. The tumor and its stromal microenvironment have a dynamic and reciprocal interaction that plays a critical role in tumor resistance, and these interactions can be exploited for novel therapeutic targets. In this sense, we review two strategies used by photodynamic researchers: (a) developing 3D culture systems which mimic tumor architecture and (b) heterotypic cultures that resemble tumor microenvironment to favor therapeutic regimen design. After this comprehensive review of the literature, we suggest that new complementary preclinical models are required to better optimize the clinical outcome of PDT on skin melanoma.

MENINGOENCEPHALITIS DUE TO VARICELLA ZOSTER VIRUS IN AIDS PATIENTS. REPORT OF ELEVEN CASES AND REVIEW OF THE LITERATURE.

Neurological complications of varicella-zoster virus (VZV) are infrequent and include various clinical pictures. The reactivation of VZV in patients with AIDS is generally associated with an acute and severe meningoencephalitis. We report the epidemiological, clinical and virological data from 11 consecutive patients with diagnosis of HIV/AIDS and central nervous system (CNS) involvement due to VZV. All patients were male and seropositive for HIV. The primary risk factor for HIV infection was unprotected sexual contact. The median of CD4 T cell count was 142 cells/µL. All of them presented signs and symptoms of meningoencephalitis. Six patients (54.5%) presented pleocytosis; they all showed high CSF protein concentrations with a median of 2.1 g/dL. Polymerase chain reaction of cerebrospinal fluid specimen was positive for VZV in all of them and they were treated with intravenous acyclovir at doses of 30/mg/kg/day for 21 days. Overall survival was 63% (7 of 11 patients). The four dead patients had low cellular counts in CSF, below the median of this parameter. VZV should be included among the opportunistic pathogens that can involve CNS with a diffuse and severe meningoencephalitis in patients with advanced HIV/AIDS disease.

Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity.

Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article will discuss recent progress in research focused mainly on assessing the efficacies of various photosensitizers used in photodynamic therapy, as well as the combinatory strategies of various therapeutic modalities for improving treatments of parenchymal and/or stromal tissues of breast cancer solid tumors. Cytotoxic agents are used in cancer treatments for their effect on rapidly proliferating cancer cells. However, such therapeutics often lack specificity, which can lead to toxicity and undesirable side effects. Many approaches are designed to target tumors. Selective therapies can be established by focusing on distinctive intracellular (receptors, apoptotic pathways, multidrug resistance system, nitric oxide-mediated stress) and environmental (glucose, pH) differences between tumor and healthy tissue. A rational design of effective combination regimens for breast cancer treatment involves a better understanding of the mechanisms and molecular interactions of cytotoxic agents that underlie drug resistance and sensitivity.

[Brunner's gland adenoma: a rare tumor as cause of pyloric syndrome in an AIDS patient]. / Adenoma de glándulas de Brunner: un tumor raro como causa de sindrome pilórico en un paciente con SIDA.

Brunner's gland adenoma is a rare neoplasm that accounts for only the 0.008% of all benign duodenal tumors. Here we describe the case ofan HIV-seropositive man who developed a severe pyloric stenosis due to a Brunner's adenoma of the bulb and the first duodenal portion. Gastroduodenoscopy showed a large polypoid tumor that obstructed the pyloric region. The lesion was resected by surgery and a gastroduodenal anastomosis was made. The histopathologic examination of the surgical specimen showed a large proliferation of Brunner's glands into a large pedunculated polyp that confirmed the diagnosis of this hamartoma.

Anal squamous cell carcinoma in HIV/AIDS patients in the HAART era: Report of 8 cases and literature review.

BACKGROUND: Anal squamous cell carcinoma is a rare neoplasm with a higher incidence in the HIV-seropositive population. PATIENTS AND METHODS: Epidemiologic, clinic, immunologic, virologic and therapeutic characteristics of 8 HIV-positive patients with anal squamous cell carcinoma were descriptively and retrospectively analyzed from 2005 to 2011. RESULTS: Median of age ofpatients was 39 years, 75% were male and 83% were men who have sex with men. Median elapsed time from HIV infection to anal cancer diagnosis was 10.5 ± 9.5 years. Anal pain and local large tumors detected by physical examination were the most common clinical manifestations; pain with or without itching was marginally correlated with poor survival. The median of CD4 T-cell countfor the whole study group was 330 cells/µL. At the time ofthe neoplasm diagnosis, CD4 T-cell count was more than 200 cell/µL in 62.5% of the patients. In the descriptive analysis, higher CD4 T-cell count was significantly associated with a prolonged survival. In the overall population, 71% were receiving highly active antiretroviral therapy (HAART) and all of them had undetectable viral load at the time ofneoplasm diagnosis. HAART was correlated with better survival in the overallpopulation. Histopathologic examination showed that 4 cases (50%) had in situ carcinoma and 4 patients (50%) had diagnosis of invasive anal carcinoma. One patient underwent surgical tumorectomy plus HAART, 2 patients received chemotherapy plus HAART and 3 patients were treated with fractionated radiotherapy plus systemic chemotherapy plus HAART. One patient died without the possibility of treatment due to his poor clinical condition and for one patient was no available data. After a follow up of 2 years, overall survival rate was 71%. CONCLUSION: A carefully evaluation of anal infiltrative or tumoral lesions is necessary to achieve an early diagnosis and to improve the survival in this kind of patients.

Synergistic enhancement of antitumor effect of ß-Lapachone by photodynamic induction of quinone oxidoreductase (NQO1).

ß-Lapachone is a phytochemotherapeutic originally isolated from Lapacho tree whose extract has been used medicinally for centuries. It is well known that NAD(P)H:quinone oxidoreductase (NQO1) activity is the principal determinant of ß-Lapachone cytotoxicity. As NQO1 is overexpressed in most common carcinomas, recent investigations suggest its potential application against cancer. Photodynamic therapy (PDT) is a clinically approved and rapidly developing cancer treatment. PDT involves the administration of photosensitizer (PS) followed by local illumination with visible light of specific wavelength. In the presence of oxygen molecules, the light illumination of PS can lead to a series of photochemical reactions and consequently the generation of cytotoxic reactive oxygen species (ROS). It has been reported that ß-Lapachone synergistically interacts with ionizing radiation, hyperthermia and cisplatin and that the sensitivity of cells to ß-Lapachone is closely related to the activity of NQO1. So, the present study aimed to investigate the feasibility of PDT to increase the anticancer effect of ß-Lapachone by up-regulating NQO1 expression on breast cancer MCF-7c3 cells. NQO1 expression was evaluated by Western blot analysis at different times after PDT using ME-ALA as PS. The cytotoxicity of the photodynamic treatment and ß-Lapachone alone or in combination was determined by MTT assay and the combination index (CI)-isobologram method and the dose reduction index (DRI) analysis were used to assess the effect of drug combinations. Our studies for the first time demonstrated that the expression of NQO1 is induced 24h after photodynamic treatment. The sensitivity of cancer cells to ß-Lapachone treatment increased 24h after PDT and a synergistic inhibitory effect on MCF-7c3 cells was showed. Taken together, these results lead us to conclude that the synergistic interaction between ß-Lapachone and PDT in killing cells was consistent with the up-regulation of NQO1. The combination of ß-Lapachone and PDT is a potentially promising modality for the treatment of cancer.

Direct and indirect photodynamic therapy effects on the cellular and molecular components of the tumor microenvironment.

Photodynamic therapy (PDT) is a novel cancer treatment. It involves the activation of a photosensitizer (PS) with light of specific wavelength, which interacts with molecular oxygen to generate singlet oxygen and other reactive oxygen species (ROS) that lead to tumor cell death. When a tumor is treated with PDT, in addition to affect cancer cells, the extracellular matrix and the other cellular components of the microenvironment are altered and finally this had effects on the tumor cells survival. Furthermore, the heterogeneity in the availability of nutrients and oxygen in the different regions of a tridimensional tumor has a strong impact on the sensitivity of cells to PDT. In this review, we summarize how PDT affects indirectly to the tumor cells, by the alterations on the extracellular matrix, the cell adhesion and the effects over the immune response. Also, we describe direct PDT effects on cancer cells, considering the intratumoral role that autophagy mediated by hypoxia-inducible factor 1 (HIF-1) has on the efficiency of the treatment.