Usefulness of Choline-PET for the detection of residual hemangiopericytoma in the skull base: comparison with FDG-PET

<p>Abstract</p> <p>Background</p> <p>Choline is a new PET tracer that is useful for the detection of malignant tumor. Choline is a precursor of the biosynthesis of phosphatidylcholine, a major phospholipid in the cell membrane of eukaryotic cells. Malignant tumors have an elevated level of phosphatidylcholine in cell membrane. Thus, choline is a marker of tumor malignancy.</p> <p>Method</p> <p>The patient was a 51-year-old man with repeated recurrent hemangiopericytoma in the skull base. We performed Choline-PET in this patient after various treatments and compared findings with those of FDG-PET.</p> <p>Results</p> <p>Choline accumulated in this tumor, but FDG did not accumulate. We diagnosed this tumor as residual hemangiopericytoma and performed the resection of the residual tumor. FDG-PET is not appropriate for skull base tumor detection because uptake in the brain is very strong.</p> <p>Conclusion</p> <p>We emphasize the usefulness of Choline-PET for the detection of residual hemangiopericytoma in the skull base after various treatments, compared with FDG-PET.</p

Nucleolar protein CSIG is required for p33ING1 function in UV-induced apoptosis

Cellular senescence-inhibited gene (CSIG) protein, a nucleolar protein with a ribosomal L1 domain in its N-terminus, can exert non-ribosomal functions to regulate biological processes, such as cellular senescence. Here, we describe a previously unknown function for CSIG: promotion of apoptosis in response to ultraviolet (UV) irradiation-induced CSIG upregulation. We identified p33ING1 as a binding partner that interacts with CSIG. After UV irradiation, p33ING1 increases its protein expression, translocates into the nucleolus and binds CSIG. p33ING1 requires its nucleolar targeting sequence region to interact with CSIG and enhance CSIG protein stability, which is essential for activation of downstream effectors, Bcl-2-associated X protein, to promote apoptosis. Thus, our data imply that p33ING1–CSIG axis functions as a novel pro-apoptotic regulator in response to DNA damage

The Influence of Mirror-Visual Feedback on Training-Induced Motor Performance Gains in the Untrained Hand

The well-documented observation of bilateral performance gains following unilateral motor training, a phenomenon known as cross-limb transfer, has important implications for rehabilitation. It has recently been shown that provision of a mirror image of the active hand during unilateral motor training has the capacity to enhance the efficacy of this phenomenon when compared to training without augmented visual feedback (i.e., watching the passive hand), possibly via action observation effects [1]. The current experiment was designed to confirm whether mirror-visual feedback (MVF) during motor training can indeed elicit greater performance gains in the untrained hand compared to more standard visual feedback (i.e., watching the active hand). Furthermore, discussing the mechanisms underlying any such MVF-induced behavioural effects, we suggest that action observation and the cross-activation hypothesis may both play important roles in eliciting cross-limb transfer. Eighty participants practiced a fast-as-possible two-ball rotation task with their dominant hand. During training, three different groups were provided with concurrent visual feedback of the active hand, inactive hand or a mirror image of the active hand with a fourth control group receiving no training. Pre- and post-training performance was measured in both hands. MVF did not increase the extent of training-induced performance changes in the untrained hand following unilateral training above and beyond those observed for other types of feedback. The data are consistent with the notion that cross-limb transfer, when combined with MVF, is mediated by cross-activation with action observation playing a less unique role than previously suggested. Further research is needed to replicate the current and previous studies to determine the clinical relevance and potential benefits of MVF for cases that, due to the severity of impairment, rely on unilateral training programmes of the unaffected limb to drive changes in the contralateral affected limb

Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells

BACKGROUND: HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed. METHODS: Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and Bcl(XL). RESULTS: Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade. CONCLUSION: The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment

HIF-1 and c-Src Mediate Increased Glucose Uptake Induced by Endothelin-1 and Connexin43 in Astrocytes

In previous work we showed that endothelin-1 (ET-1) increases the rate of glucose uptake in astrocytes, an important aspect of brain function since glucose taken up by astrocytes is used to supply the neurons with metabolic substrates. In the present work we sought to identify the signalling pathway responsible for this process in primary culture of rat astrocytes. Our results show that ET-1 promoted an increase in the transcription factor hypoxia-inducible factor-1α (HIF-1α) in astrocytes, as shown in other cell types. Furthermore, HIF-1α-siRNA experiments revealed that HIF-1α participates in the effects of ET-1 on glucose uptake and on the expression of GLUT-1, GLUT-3, type I and type II hexokinase. We previously reported that these effects of ET-1 are mediated by connexin43 (Cx43), the major gap junction protein in astrocytes. Indeed, our results show that silencing Cx43 increased HIF-1α and reduced the effect of ET-1 on HIF-1α, indicating that the effect of ET-1 on HIF-1α is mediated by Cx43. The activity of oncogenes such as c-Src can up-regulate HIF-1α. Since Cx43 interacts with c-Src, we investigated the participation of c-Src in this pathway. Interestingly, both the treatment with ET-1 and with Cx43-siRNA increased c-Src activity. In addition, when c-Src activity was inhibited neither ET-1 nor silencing Cx43 were able to up-regulate HIF-1α. In conclusion, our results suggest that ET-1 by down-regulating Cx43 activates c-Src, which in turn increases HIF-1α leading to the up-regulation of the machinery required to take up glucose in astrocytes. Cx43 expression can be reduced in response not only to ET-1 but also to various physiological and pathological stimuli. This study contributes to the identification of the signalling pathway evoked after Cx43 down-regulation that results in increased glucose uptake in astrocytes. Interestingly, this is the first evidence linking Cx43 to HIF-1, which is a master regulator of glucose metabolism

Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis

<p>Abstract</p> <p>Purpose</p> <p>to investigate the factors affecting survival and toxicity in patients treated with stereotactic radiosurgery (SRS), with special attention to volumes of brain receiving a specific dose (V10 - V16 Gy) as predictors for brain radionecrosis.</p> <p>Patients and Methods</p> <p>Two hundred six consecutive patients with 310 cerebral metastases less than 3.5 cm were treated with SRS as primary treatment and followed prospectively at University of Rome La Sapienza Sant'Andrea Hospital. Overall survival, brain control, and local control were estimated using the Kaplan-Meier method calculated from the time of SRS. Univariate and multivariate analysis using a Cox proportional hazards regression model were performed to determine the predictive value of prognostic factors for treatment outcome and SRS-related complications.</p> <p>Results</p> <p>Median overall survival and brain control were 14.1 months and 10 months, respectively. The 1-year and 2-year survival rates were 58% and 24%, and respective brain control were 43% and 22%. Sixteen patients recurred locally after SRS, with 1-year and 2-year local control rates of 92% and 84%, respectively. On multivariate analysis, stable extracranial disease and KPS >70 were associated with the most significant survival benefit. Neurological complications were recorded in 27 (13%) patients. Severe neurological complications (RTOG Grade 3 and 4) occurred in 5.8% of patients. Brain radionecrosis occurred in 24% of treated lesions, being symptomatic in 10% and asymptomatic in 14%. On multivariate analysis, V10 through V16 Gy were independent risk factors for radionecrosis, with V10 Gy and V12 Gy being the most predictive (p = 0.0001). For V10 Gy >12.6 cm³and V12 Gy >10.9 cm³the risk of radionecrosis was 47%.</p> <p>Conclusions</p> <p>SRS alone represents a feasible option as initial treatment for patients with brain metastases, however a significant subset of patients may develop neurological complications. Lesions with V12 Gy >8.5 cm³carries a risk of radionecrosis >10% and should be considered for hypofractionated stereotactic radiotherapy especially when located in/near eloquent areas.</p

The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? TARGET POPULATION: These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. RECOMMENDATIONS: Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS + or - WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (\u3e3 cm) or for those causing significant mass effect (\u3e1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below

Expression and function of G-protein-coupled receptorsin the male reproductive tract

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisão enfatiza a expressão e a função dos receptores muscarínicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressão dos receptores muscarínicos e adrenoceptores α1 em compartimentos específicos de dúctulos eferentes, epidídimo, ductos deferentes, vesícula seminal e próstata de várias espécies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do músculo liso, incluindo efeitos na fertilidade masculina. Além disso, a ativação dos receptores muscarínicos leva à transativação do receptor para o fator crescimento epidermal e proliferação das células de Sertoli. Os receptores para relaxina estão presentes no testículo, RXFP1 nas espermátides alongadas e células de Sertoli de rato e RXFP2 nas células de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogênico. A localização de ambos os receptores na porção apical das células epiteliais e no músculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL