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Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

ABSTRACT: Objective: Leiomyosarcomas are mesenchymal tumors that very rarely present as a primary adrenal malignancy.Methods: We present the complete clinical presentation, imaging, and anatomicopathologic features of a unique case of recurrent primary adrenal leiomyosarcoma (PAL) after initial surgery. This case is accompanied by an updated literature review.Results: A 63-year-old Hispanic female referred to our clinic 4 months after having right adrenalectomy. Eight months prior to this encounter, she started to notice bilateral lower extremity edema with skin changes. Computed tomography of the abdomen revealed a large 6.8 × 4.4 cm adrenal mass that appeared to be encroaching in the inferior vena cava with hypodense areas, irregular borders, and a necrotic center. A preoperative hormonal evaluation failed to reveal evidence of a functional adrenal tumor. Microscopic examination revealed spindle cell neoplasia. Immunohistochemistry of the surgical specimen revealed positive staining for desmin, smooth muscle actin, and focal myogenin (MYF-4). S-100 protein and inhibin were negative. The diagnosis of intermediate-grade leiomyosarcoma was confirmed. Two months after surgery, surveillance positron emission tomography scan revealed another right adrenal mass measuring 5.6 × 5 cm, with a standardized uptake value of 2.1.Conclusion: PAL is excessively rare. To our knowledge, this is only the second case of PAL with documented recurrence and the 19th case reported in the current medical literature. Surgical removal of the tumor is the first step in treatment. Adjuvant therapies are still not well standardized based on the low incidence of cases.Abbreviations: CT computed tomography PAL primary adrenal leiomyosarcoma SMA smooth muscle actin

Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.

Adenomas clinicamente não-funcionantes de hipófise, não produzem clínica de hipersecreção hormonal. Por esse motivo, seus sinais e sintomas dependem de seu efeito de massa no sistema nervoso central. A sua etiopatogenia é complexa com vários fatores provavelmente influenciando seu desenvolvimento como os hormônios hipotalâmicos (GHRH), fatores de crescimento (FGF), fatores de proliferação (PCNA, e KI-67), proteína P53 e proto-oncogene c-erb-B2. OBJETIVOS: 1) Determinar as características clínicas da população de 117 pacientes tratados com adenoma clinicamente não-funcionante de hipófise (idade, sexo, tamanho do tumor, número de procedimento cirúrgico, desenvolvimento de deficiência hormonal e hiperprolactinemia). 2) Identificar, após a caracterização clínica desses pacientes, aqueles com adenoma clinicamente não-funcionante que apresentam imunoistoquímica positiva para os hormônios hipofisários PRL LH, FSH, GH, TSH e ACTH. 3) Precisar nessa população a positividade imunoistoquímica para o fator de proliferação celular Ki-67, para a proteína P53 e para a proteína C-erb-B2 correlacionando a sua positividade com o tamanho e invasão tumoral. Dessa forma avaliando o valor prognóstico desses fatores de proliferação. 4) Confrontar os resultados da imunoistoquímica realizada através do bloco padrão com os resultados da imunoistoquímica obtidos através do tissue micro-array. MÉTODO: Estudo das características clínicas de 117 pacientes com adenoma clinicamente não-funcionate de hipófise (idade, sexo, tamanho do tumor, número de procedimento cirúrgico, desenvolvimento de deficiência hormonal e hiperprolactinemia). Estudo imunoistoquímico (H&E) de 39 pacientes para hormônios hipofisários, para a proteína P53, proteína C-erb-B2, Ki-67 e sua correlação com crescimento tumoral. A seguir, também foi realizado o tissue micro-array dos 39 casos, estudados anteriormente, com imunoistoquímica para os hormônios hipofisários, para a proteína P 53, proteína C-erb-B2, Ki-67 e sua correlação com o crescimento tumoral. RESULTADOS: Não houve diferença estatisticamente significante entre os sexos masculino e feminino com relação à idade, tamanho tumoral e número de procedimentos cirúrgicos (p=0,279, p=0,813, p=0,139 respectivamente). Existe uma correlação estatisticamente significativa entre tamanho do tumor, número de procedimentos cirúrgicos realizados e deficiência hormonal (p=0,032, p=0,0223 respectivamente). Não houve correlação estatisticamente significativa entre imunoístoquímica positiva para proteína P53, para a proteína C-erb-B2, Ki-67 e o tamanho do tumor (r=0,182, p=0,396; r=-0,181, p=0,397; r=0,272, p=0,199, respectivamente) .O tissue micro-array também não demonstrou uma correlação entre a imunoistoquímica positiva para Ki-67 e C-erb-B2 e o tamanho do tumor, porém mostrou uma correlação negativa estatisticamente significativa entre a positividade imunoistoquímica para p53 e o tamanho do tumor (r=-0,696;pClinically non-functioning pituitary adenomas do not produce clinical signs of hormonal hypersecretion. Therefore, signs and symptoms will depend on the mass effect of these adenomas over the central nervous system. Their etiopathogeny is complex and their development is probably influenced by several factors, such as hypothalamic hormones (GHRH), growth factors (FGF), proliferation factors (PCNA, and KI-67), protein P53 and the proto-oncogene c-erb-B2. OBJECTIVE: 1) Determining the clinical features of a population of 117 patients treated for clinically non-functioning pituitary adenoma (age, sex, tumor size, number of surgical procedures, development of hormonal deficiency and hyperprolactinemia). 2) Identifying, after the patients had been clinically characterized, those with clinically non-functioning adenomas with positive immunohistochemistry for hypophyseal hormones (PRL, LH, FSH, GH, TSH and ACTH). 3) Determining if the immunohistochemistry of this population was positive for the cellular proliferation factor Ki-67, protein P53 and protein C-erb-B2 and establishing a correlation with tumor size and tumor invasiveness. This will help in the evaluation of the prognostic value of these proliferation factors. 4) Confronting the results of immunohistochemistry using a standard block with the results of immunohistochemistry using a tissue micro-array. METHOD: Study of the clinical features of 117 patients with clinically non-functioning pituitary adenoma (age, sex, tumor size, number of surgical procedures, development of hormonal deficiency and hyperprolactinemia). Immunohistochemical study (H&E) of 39 patients for hypophyseal hormones, protein P53, protein C-erb-B2, Ki-67 to establish their correlation to tumor growth. The next step was a tissue micro-array of the 39 previously studied cases, using immunohistochemistry for hypophyseal hormones, protein P 53, protein C-erb-B2, Ki-67 to establish their correlation to tumor growth. RESULTS: There was no statistically significant difference between males and females with regards to age, tumor size and number of surgical procedures (p=0.279, p=813, p=139 respectively). There is a statistically significant correlation between the size of the tumor, the number of surgical procedures and hormonal deficiency (p=0.032, p=0.223 respectively). There was no statistically significant correlation between a positive immunohistochemistry for protein P53, protein C-erb-B2, Ki-67 and tumor size (r=0.182, p=0.396; r=-0.181, p=0.397; r=0.272, p=0.199, respectively). The tissue micro-array also did not demonstrate a correlation between positive immunohistochemistry for Ki-67 and C-erb-B2 and tumor size, but it showed a statistically significant correlation between a positive immunohistochemistry for p53 and tumor size (r=-0.696; p=001). CONCLUSION: The biological behavior of the clinically non-functioning adenoma is similar for both sexes. The larger the tumor the greater the number of surgical procedures needed. Hormonal deficiency also becomes more significant as the size of the tumor increases. This paper suggests that a positive immunohistochemistry for p53 is negatively correlated to tumor size, thus demonstrating that it has a predictor value. However, a positive immunohistochemistry for Ki-67 and protein C-erb-B2 does not seem to be a prognostic factor for clinically non-functioning pituitary adenomas, as is the case with other neoplasias.

Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.

We present a unique case of an extensively ossified carcinoma ex pleomorphic adenoma (CXPA) in a 76-year-old man with a five-year history of a slowly growing parotid mass. Fine-needle aspiration of the mass was nondiagnostic. A computed tomography (CT) scan of the lesion revealed a well-circumscribed mass with peripheral calcification. Initial pathological analysis suggested a benign parotid mass, but rigorous decalcification revealed noninvasive CXPA. The patient underwent complete resection of the mass and remained disease-free nine months later. Extensive ossification of a seemingly benign parotid mass may mask areas of carcinoma that may progress if left untreated.

Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury.Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-alpha receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-alpha receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway.Inhibition of MMP and TACE activity with Marimastat during chronic CCl4 administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases.

A associação de malformações vasculares intracerebrais com neoplasias cerebrais primárias é rara. Mais comumente encontrados são os aneurismas arteriais intracranianos com neoplasias primárias. Relatamos dois casos de malformações vasculares associadas a neoplasias cerebrais primárias, com estudo histopatológico e imuno-histoquímico.

OBJECTIVE: This study aimed to analyse whether a marker of proliferative activity (PCNA) could provide a prognosis of tumor evolution and to determine whether different interpretation criteria could alter the results. METHOD: The presence of PCNA in 59 patients of state II (T2 NO,1 MO) mammary carcinoma was determined. RESULT: Numerical proportions of total and intensely stained cells were established. These data were compared with anatomopathological parameters. A significant association between higher cyclin values and worse histological and nuclear grading was encountered, particularly in patients with a "negative axilla" using the PCNA index. Cyclin values were not significant in relation to any parameters when indices from the intensely stained cells were considered exclusively. CONCLUSION: Higher nuclear (NG3) and histological (HGIII) grading, associated with a high PCNA index (>50), distinguish high-risk patients, and it is more appropriate considering all the stained cells as representative of PCNA indices, thus reflecting tumor aggressiveness.

The authors report the case of a chronic myeloid leukemia (CML) patient submitted to allogenic bone marrow transplantation, who had probably never entered complete remission. The disease was reactivated as a granulocytic sarcoma, next to a platinum plate installed to correct a tibia fracture 11 years earlier. Its final event was a myeloid Ph1+ blastic crisis that was unsuccessfully treated with high doses of sc interferon and citarabine.