Melanoma metastático causando intussuscepção do intestino delgado: diagnóstico por 18F-FDG PET/TC

Melanoma maligno é uma doença comum e agressiva que frequentemente causa metástase para o intestino delgado. Este estudo ilustra um caso de intussuscepção do intestino delgado causada por uma lesão metastática de melanoma visualizada à 18F-FDG PET/TC em uma paciente de 48 anos idade que realizou exame de reestadiamento.

Simulação e análise dosimétrica de protonterapia e íons de carbono no tratamento do melanoma uveal

OBJETIVO: Este artigo apresenta a avaliação dosimétrica da radioterapia por íons de carbono em comparação à protonterapia. MATERIAIS E MÉTODOS: As simulações computacionais foram elaboradas no código Geant4 (GEometry ANd Tracking). Um modelo de olho discretizado em voxels implementado no sistema Siscodes (sistema computacional para dosimetria em radioterapia) foi empregado, em que perfis de dose em profundidade e curvas de isodose foram gerados e superpostos. Nas simulações com feixe de íons de carbono, distintos valores de energia do feixe foram adotados, enquanto nas simulações com feixe de prótons os dispositivos da linha de irradiação foram incluídos e diferentes espessuras do material absorvedor foram aplicadas. RESULTADOS: As saídas das simulações foram processadas e integradas ao Siscodes para gerar as distribuições espaciais de dose no modelo ocular, considerando alterações do posicionamento de entrada do feixe. Os percentuais de dose foram normalizados em função da dose máxima para um feixe em posição de entrada específica, energia da partícula incidente e número de íons de carbono e de prótons incidentes. CONCLUSÃO: Os benefícios descritos e os resultados apresentados contribuem para o desenvolvimento das aplicações clínicas e das pesquisas em radioterapia ocular por íons de carbono e prótons.

Brain metastasis as initial presentation of papillary adenocarcinoma of the lung: case report

The authors describe the case of a 33-year-old patient with history of seizures alone without any previous symptom, being diagnosed with brain metastases from primary papillary adenocarcinoma of the lung. Emphasis is given to the diagnostic investigation for brain metastasis and prognostic evaluation of papillary adenocarcinoma of the lung, and a brief literature review on such diseases is performed.

Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus.

Leishmaniaparasites cause a broad range of disease, with cutaneous afflictions being, by far, the most prevalent. Variations in disease severity and symptomatic spectrum are mostly associated to parasite species. One risk factor for the severity and emergence of leishmaniasis is immunosuppression, usually arising by coinfection of the patient with human immunodeficiency virus (HIV). Interestingly, several species ofLeishmaniahave been shown to bear an endogenous cytoplasmic dsRNA virus (LRV) of theTotiviridaefamily, and recently we correlated the presence of LRV1 withinLeishmaniaparasites to an exacerbation murine leishmaniasis and with an elevated frequency of drug treatment failures in humans. This raises the possibility of further exacerbation of leishmaniasis in the presence of both viruses, and here we report a case of cutaneous leishmaniasis caused byLeishmania braziliensisbearing LRV1 with aggressive pathogenesis in an HIV patient. LRV1 was isolated and partially sequenced from skin and nasal lesions. Genetic identity of both sequences reinforced the assumption that nasal parasites originate from primary skin lesions. Surprisingly, combined antiretroviral therapy did not impact the devolution ofLeishmaniainfection. TheLeishmaniainfection was successfully treated through administration of liposomal amphotericin B.

CD8 engineered cytotoxic T cells reprogram melanoma tumor environment.

NlmCategory="UNASSIGNED">Cytotoxic T lymphocytes (CTL) from CD8β-deficient mice have powerful FasL-mediated cytotoxicity and IFNγ responses, but ablated Ca(2+) and NFAT signaling, which can be restored by transduction with CD8β. Upon infection with lymphocytic choriomeningitis virus (LCMV), these cells yielded GP33-specific CTL (CD8βR) that exhibited high FasL/Fas-mediated cytotoxicity, IFNγ CXCL9 and 10 chemokine responses. Transfer of these cells in B16-GP33 tumor bearing mice resulted in (i) massive T cell tumor infiltration, (ii) strong reduction of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) and IL-17-expressing T helper cells, (iii) maturation of tumor-associated antigen-presenting cells and (iv) production of endogenous, B16 melanoma-specific CTL that eradicated the tumor long after the transferred CD8βR CTL perished. Our study demonstrates that the synergistic combination of strong Fas/FasL mediated cytotoxicity, IFNγ and CXCL9 and 10 responses endows adoptively transferred CTL to reprogram the tumor environment and to thus enable the generation of endogenous, tumoricidal immunity.

El Contexto Epidemiológico del Melanoma en la Teledermatología

Peer-reviewed

Review and new therapeutic alternatives for the treatment of cutaneous Leishmaniasis

Leishmaniasis comprises a group of diseases caused by protozoa of the genus Leishmania and has two basic clinical forms, visceral Leishmaniasis and cutaneous Leishmaniasis. The clinical features of Leishmaniasis depend on the species of Leishmania, the interaction between host and parasite and the immune response. This work focuses on cutaneous leishmaniosis because although it is not a deadly disease it results in significant scars and facial disfigurements, thus being clinically important. Furthermore, the first-line treatment consists of intravenous or intramuscular administration of intralesional pentavalent antimonials, which are highly toxic, making hospitalization of patients compulsory during treatment, with the associated financial costs. Herein, we review studies on drugs and treatments with fewer side effects and easier routes of administration such as topical administration. Recent research shows that the topical route of administration holds promise for the future treatment of cutaneous leishmaniosis.

Review and new therapeutic alternatives for the treatment of cutaneous Leishmaniasis

Leishmaniasis comprises a group of diseases caused by protozoa of the genus Leishmania and has two basic clinical forms, visceral Leishmaniasis and cutaneous Leishmaniasis. The clinical features of Leishmaniasis depend on the species of Leishmania, the interaction between host and parasite and the immune response. This work focuses on cutaneous leishmaniosis because although it is not a deadly disease it results in significant scars and facial disfigurements, thus being clinically important. Furthermore, the first-line treatment consists of intravenous or intramuscular administration of intralesional pentavalent antimonials, which are highly toxic, making hospitalization of patients compulsory during treatment, with the associated financial costs. Herein, we review studies on drugs and treatments with fewer side effects and easier routes of administration such as topical administration. Recent research shows that the topical route of administration holds promise for the future treatment of cutaneous leishmaniosis.

Cytoplasmic accumulation of NCoR in malignant melanoma: Consequences of altered gene repression and prognostic significance

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.

Osteolytic metastasis detected in a patient with lung carcinoma by F18-FDG PET

We present a 53-year-old man with a vocal cord paralysis observed as a primary manifestation of lung carcinoma. Tc-99m MDP whole body bone scan was performed and resulted in a normal scintiscan. The bone scan did not reveal any suspicious foci of uptake. The possibility of bone metastasis was taken into consideration. A whole body F18-FDG-PET scan showed intense uptake in the left upper lung corresponding to the primary tumor. A bronchial biopsy confirmed infiltration by small cell lung carcinoma (SCLC). SCLC is composed of poorly differentiated, rapidly growing cells with diseases usually occurring centrally rather than peripherally. It metastasizes early. The whole-body F18-FDG-PET scan clearly demonstrated a focus of increased uptake in the second lumbar vertebral body suspicious for osteolytic metastasis. A lytic bone metastasis was confirmed by MRI. The patient then received therapy and underwent follow up abdominal CT. The scan showed blastic changes in the L2 vertebra suggesting response to treatment.

Orthotopic PC-3 Tumor Xenografts in Studies on Prostate Cancer Growth and Metastasis

Prostate cancer is generally a slowly developing disease. However, some cancers develop into an aggressive, metastasic and consequently life-threatening state. The mechanisms of prostate cancer spread are still mainly unidentified but hormones and growth factors are known to been involved. The forming of new blood vessels i.e. angiogenesis is crucial for tumor growth. Blood vessels and lymphatic vessels are also prominent routes for metastasis. Both angiogenic and lymphangiogenic factors are overexpressed in prostate cancer. We established an in vivo model to study the factors effecting human prostate cancer growth and metastasis. Tumors were produced by the orthotopic inoculation of PC-3 prostate cancer cells into the prostates of immunodeficient mice. Like human prostate tumors, these tumors metastasized to prostate-draining lymph nodes. Treatment of the mice with the bisphosphonate alendronate known to decrease prostate cancer cell invasion in vitro inhibited metastasis and decreased tumor growth. Decreased tumor growth was associated with decreased angiogenesis and increased apoptosis of tumor cells. To elucidate the role of angiogenesis in prostate cancer progression, we studied the growth of orthotopic PC-3 tumors overexpressing fibroblast growth factor b (FGF8b) known to be expressed in human prostate cancer. FGF8b increased tumor growth and angiogenesis, which were both associated with a characteristic gene expression pattern. To study the role of lymphangiogenesis, we produced orthotopic PC-3 tumors overexpressing vascular endothelial growth factor C (VEGF-C). Blocking of VEGF-C receptor (VEGFR3) completely inhibited lymph node metastasis whereas overexpression of VEGF-C increased tumor growth and angiogenesis. VEGF-C also increased lung metastases but, surprisingly, decreased spread to lymph nodes. This suggests that the expanded vascular network was primarily used as a route for tumor spreading. Finally, the functionality of the capillary network in subcutaneous FGF8b-overexpressing PC-3 tumors was compared to that of tumors overexpressing VEGF. Both tumors showed angiogenic morphology and grew faster than control tumors. However, FGF8b tumors were hypoxic and their perfusion and oxygenation was poor compared with VEGF tumors. This suggests that the growth advantage of FGF8b tumors is more likely due to stimulated proliferation than effective angiogenesis. In conclusion, these results show that orthotopic prostate tumors provide a useful model to explore the mechanisms of prostate cancer growth and metastasis.

The Role of Integrins in Enterovirus Infections and in Metastasis of Cancer

Integrins are a family of transmembrane glycoproteins, composed of two different subunits (alpha and beta). Altered expression of integrins in tumor cells contributes to metastasis tendency by influencing on the cells‟ attachment to adjacent cells and their migration. Viral pathogens, including certain enteroviruses, use integrins as receptors. Enteroviruses have also been suggested to be involved in the etiopathogenesis of type 1 diabetes. The study focuses on the role of integrins in the pathogenesis of metastasis to cortical bone and on type 1 diabetes (T1D) and echovirus 1 infection. In the first part of the thesis, the role of different integrins in the initial attachment of MDA-MD-231 breast cancer cells to bovine cortical bone disks was studied. A close correlation between alpha2beta1 and alpha3beta1 integrin receptor expression and the capability of the tumor to attach to bone were observed. In the second part, a possible correlation between susceptibility to enterovirus infections in diabetic children and differences in enterovirus receptor genes, including certain integrins, was investigated. In parallel, virus-specific neutralizing antibodies and diabetic risk alleles were studied. In the diabetic group, an amino acid change was detected in the polio virus receptor and the neutralizing antibody titers against echovirus 30 were lower. However, to obtain statistically sustainable results, a larger number of individuals should be analyzed. Echovirus 1 (EV1) enters cells by attaching to the alpha2I domain of the alpha2beta1 integrin. In the third part EV1 was shown to attach to a chimeric receptor construct of the transferrin receptor and the alpha2I domain and to enter cells through clathrin-mediated endocytosis that is normally not used by the virus. The chimeric receptor was recycled to the plasma membrane, whereas the virus remained in intracellular vesicles. The virus replication cycle was initiated in these cells, suggesting that evolution pressure could possibly cause the virus to evolve to use a different entry mechanism. Moreover, a cDNA microarray analysis of host gene expression during EV1 replication showed that 0.53% of the total genes, including several immediate early genes, were differently expressed.

Targeted Therapy Possibilities for Metastatic Melanoma

The incidence of malignant melanoma of the skin has been steadily rising worldwide during the past decades. Most early detected primary tumors can be removed surgically and the prognosis is good. However, at the same time there still is no permanent cure for metastatic melanoma and its prognosis is poor, although lately new effective drugs have emerged. In this thesis, four different approaches of experimental therapy for metastatic melanoma were studied. Endogenous cis-Urocanic acid (UCA) is found in every individual’s skin, where exposure to UV light from the sun generates it from its inactive trans conformation. Cis- UCA was found to destroy malignant melanoma cells in culture under an acidified pH and sufficient concentration through caspase-3 mediated apoptosis. Furthermore, cis-UCA is able to considerably diminish the growth rate in human melanoma tumors on living SCID mice. Using replication-competent Semliki Forest viruses, human melanoma tumors grown in SCID mice were dramatically shrunken as the fulminant production of viruses in melanoma cells leads them to apoptosis within 72 hours. Small oligopeptides attaching to melanoma cells were identified using in vivo phage display. The melanoma-specific peptides found were further tested in vitro on adenoviruses. Ultimately, the adenoviral retargeting using the peptides was tested in vivo. One peptide homed to human transferring receptor upregulated on melanoma cells. In order to kill the malignant melanoma cells with the retargeted adenoviruses, the viruses should carry genetic material producing apoptotic proteins in the cancer tissue. TIMP-3 has been identified as a good candidate for such a protein, as it inhibits malignant cell adhesion as well as promotes apoptosis through a caspase-8 pathway. It is further shown here that adenovirally delivered TIMP-3 is even more potent, as it could kill non-adherent cancer cells, lacking the fully functional death receptor signalling pathway. Adenovirally delivered TIMP-2 also showed marked antitumor effects in human malignant melanoma xenografts on SCID mice both in ex vivo and systemic delivery.