Tumor miofibroblástico inflamatório da bexiga em criança: relato de caso

Tumores miofibroblásticos inflamatórios raramente acometem vias urinárias ou crianças, comumente mimetizando neoplasias malignas nos exames de imagem. Foram descritos apenas 35 casos desses tumores na bexiga de crianças, segundo a literatura recente. Os autores apresentam o caso de uma criança com um tumor miofibroblástico vesical que evoluiu favoravelmente após ressecção cirúrgica completa.

Giant cell tumor of the frontal sinus: case report

The authors report the case of a giant cell tumor of the frontal sinus in a 54-year-old male patient. This tumor location is rare, and this is the third case reported in the literature with radiographic documentation and histopathological confirmation. The patient underwent surgery, with curettage of frontal sinus and placement of a prosthesis. He died because a voluntary abrupt discontinuation of corticosteroids.

Prognostic value of baseline total metabolic tumor volume (TMTV0) measured on FDG-PET/CT in patients with peripheral T-cell lymphoma (PTCL).

BACKGROUND: Most peripheral T-cell lymphoma (PTCL) patients have a poor outcome and the identification of prognostic factors at diagnosis is needed. PATIENTS AND METHODS: The prognostic impact of total metabolic tumor volume (TMTV0), measured on baseline [(18)F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, was evaluated in a retrospective study including 108 PTCL patients (27 PTCL not otherwise specified, 43 angioimmunoblastic T-cell lymphomas and 38 anaplastic large-cell lymphomas). All received anthracycline-based chemotherapy. TMTV0 was computed with the 41% maximum standardized uptake value threshold method and an optimal cut-off point for binary outcomes was determined and compared with others prognostic factors. RESULTS: With a median follow-up of 23 months, 2-year progression-free survival (PFS) was 49% and 2-year overall survival (OS) was 67%. High TMTV0 was significantly associated with a worse prognosis. At 2 years, PFS was 26% in patients with a high TMTV0 (>230 cm(3), n = 53) versus 71% for those with a low TMTV0, [P < 0.0001, hazard ratio (HR) = 4], whereas OS was 50% versus 80%, respectively, (P = 0.0005, HR = 3.1). In multivariate analysis, TMTV0 was the only significant independent parameter for both PFS and OS. TMTV0, combined with PIT, discriminated even better than TMTV0 alone, patients with an adverse outcome (TMTV0 >230 cm(3) and PIT >1, n = 33,) from those with good prognosis (TMTV0 ≤230 cm(3) and PIT ≤1, n = 40): 19% versus 73% 2-year PFS (P < 0.0001) and 43% versus 81% 2-year OS, respectively (P = 0.0002). Thirty-one patients (other TMTV0-PIT combinations) had an intermediate outcome, 50% 2-year PFS and 68% 2-year OS. CONCLUSION: TMTV0 appears as an independent predictor of PTCL outcome. Combined with PIT, it could identify different risk categories at diagnosis and warrants further validation as a prognostic marker.

Local behavior and lymph node metastases of Wilms' tumor: accuracy of computed tomography

Objective To evaluate the accuracy of computed tomography for local and lymph node staging of Wilms' tumor. Materials and Methods Each case of Wilms' tumor was evaluated for the presence of abdominal lymph nodes by a radiologist. Signs of capsule and adjacent organ invasion were analyzed. Surgical and histopathological results were taken as the gold standard. Results Sensitivity was 100% for both mesenteric and retroperitoneal lymph nodes detection, and specificity was, respectively, 12% and 33%, with positive predictive value of 8% and 11% and negative predictive value of 100%. Signs of capsular invasion presented sensitivity of 87%, specificity of 77%, positive predictive value of 63% and negative predictive value of 93%. Signs of adjacent organ invasion presented sensitivity of 100%, specificity of 78%, positive predictive value of 37% and negative predictive value of 100%. Conclusion Computed tomography tumor showed low specificity and low positive predictive value in the detection of lymph node dissemination. The absence of detectable lymph nodes makes their presence unlikely, and likewise regarding the evaluation of local behavior of tumors.

Analysis of TRIP expression in different types of skin tumor

TRAF-interacting protein (TRIP) is a ubiquitously expressed nucleolar E3 ubiquitin ligase. Ubiquitination of proteins is a post-translational modification, which decides on the cellular fate of the protein. TRIP in vivo substrate has not been yet identified. However, TRIP has been shown to play an important role in cellular proliferation, especially in keratinocytes. TRIP was found to be up-regulated in basal cell carcinoma (BCC) at the mRNA level. This prompted us to elucidate its role in skin proliferative diseases such as cancer by analyzing its expression in BCCs at protein level and in squamous cell carcinoma (SCC) at mRNA and protein level. To that purpose, we performed a real-time PCR (qPCR) analysis followed by an immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded (FFPE) biopsies. The real-time PCR was performed on 12 RNA samples of which 6 were extracted from SCC biopsies and 6 from normal human skin. The results were statistically insignificant. Further analyses are needed on new RNA samples. The IHC assay was performed on 20 biopsies from BCCs, 21 biopsies from SCCs and on 5 tissues from normal human skin. The results obtained showed an extensive expression of TRIP in keratinocytes nuclei. Due to various limitations related to the technique and to doubts about preservation of the antigens in the tissues from normal human skin, we could not highlight a clear difference in TRIP expression between the different tissues. In conclusion, further analyses are needed on new RNA samples (qPCR) and on better preserved FFPE tissues from normal skin (IHC) to assess TRIP relative expression in BCCs and SCCs versus normal human skin.

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.

Vestibular schwannoma : the evolution of hearing and tumor size in natural course and after treatment by Linac stereotactic radiosurgery

Objectif : D'analyser l'évolution naturelle de la taille de la tumeur et de l'audition chez 151 patients avec schwannome vestibulaire (VS) en suivi et d'évaluer les mêmes paramètres pour une partie du group traité par Radiochirurgie Stéréotaxique Linac (SRS). Méthodes: Etude prospective des patients bilantés par IRM et tests audio-vestibulaires à l'inclusion, pendant la période du suivi et après SRS. L'audition a été gradé selon l'échelle de Gardner-Robertson (GR) et la taille tumorale selon l'échelle de Koos. L'analyse statistique inclut l'analyse de survie de Kaplan-Meier, analyse multivariée avec régression linéaire et logistique. Les patients avec une audition utile ont étés spécifiquement analysés. Résultats: Pendant la période du suivi (moyenne 24 mois, déviation 6-96), le risqué annuel de dégradation de la classe GR était 6% pour les patients GRI et 15% pour les GRII. La perte auditive comme symptôme initial était un facteur signifïcativement prédictif pour une aggravation auditive ultérieure (p=0.003). La croissance tumorale était de 25% à la dernière observation pendant le suivi. Pour les patients traités par Linac, la préservation d'une audition utile était 51% à 1 an et 36% à 3 ans. Le contrôle tumoral était 94 % and 91% respectivement. Conclusion: Chez les patients avec VS, la perte auditive déjà présente au diagnostique est un facteur prédictif négatif pour l'évolution de l'audition. La Radiochirurgie Stéréotaxique Linac est efficace pour le contrôle tumoral. Les patients ayant préservés leur status auditif prétraitement présentent un rythme annuel de perte auditive diminué après SRS compare à celle-ci avant le traitement. Cette constatation suggère un effet protectif potentiel de la SRS, à condition que la fonction cochléaire soit préservée.

Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle

Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hall- mark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM (the calcein acetoxymethyl-ester) on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phos-phate pathway was significantly altered. To elucidate whe-ther these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.

Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors.

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.