Roger Gejman

Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase

Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose‐ and time‐dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase‐8 and ‐9; BID cleavage, cytochrome C release and PARP cleavage. Statin‐sensitive cancers expressed high levels of HMG‐CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG‐CoA reductase since mevalonate pre‐incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG‐CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

Metástasis cerebral y sobrevida

BACKGROUND Brain metastases are the most common cerebral tumors, have a poor prognosis and their incidence is five times higher than primary brain tumors. AIM To analyze the survival of patients with the diagnosis of brain metastases, operated in our institution. PATIENTS AND METHODS We retrospectively reviewed all patients operated from January 1989 to December 2001, whose pathological diagnosis confirmed the presence of cerebral metastases. The death date of each patient was obtained from the analysis of death certificates, obtained from the computerized National Registry. RESULTS In 46 operated patients, the date of death was determined. In 23 of them, information about primary site of malignancy, type of surgery performed and adjunctive treatment with Holocerebral Radiotherapy (Rt) was obtained. The overall median survival time of the 46 patients was 29 weeks (range 4-207). Thirty percent of patients were alive one year after surgery. Among those patients with complete clinical information, the median survival of 16 patients who received postoperative Rt was 41 weeks (range 12-207), compared to a survival of 18 weeks (range 8-72), among those that did not receive Rt (p = 0.04). CONCLUSIONS The median survival for patients operated for cerebral metastases in our institution is 29 weeks. Those who are operated and receive Rt, have a longer survival, than those who did not receive Rt.

Hiperandrogenismo avanzado en una mujer postmenopáusica. Caso clínico

We report a 76-year-old woman with a virilization syndrome characterized by progressive androgenic alopecia, clitoris enlargement and hirsutism predominating in the face. Plasma testosterone was 711 ng/dl. Magnetic resonance imaging showed slightly enlarged ovaries with a cyst in the left. A bilateral oophorectomy was performed, demonstrating the presence of a Leydig cell hilar tumor in the right ovary. The patient had a good postoperative evolution with reduction of androgen levels and reversion of alopecia.

Tumor de las células de granulosa: pubertad precoz en lactante menor de 1 año. Caso clínico

INTRODUCTION Juvenile granulosa cell tumors (JGCT) are very rare, especially in infants under the age of one. The most frequent presentation is with signs of precocious puberty. OBJECTIVE Present an in fant with peripheral precocious puberty, diagnosis of JGCT and follow up. CLINICAL CASE 10-month-old female infant with thelarche, pubic hair and palpable abdominal mass accompanied with eleva ted levels of estradiol, very low gonadotrophins and images that show a very large ovarian mass. A sapingooforectomy was carried out with full regression of symptoms and signs and improvement of laboratory exams. The biopsy showed TCGJ so inhibin B (InB) was taken as tumoral marker after surgery. This hormone was high initially, but rapidly declined. Follow-up was based on InB, antimu-llerian Hormone (AMH) and estradiol as described in this type of tumors. CONCLUSIONS Juvenil gra nulosa cell tumors are very infrequent in pediatric age, but should be suspected in girl with peripheral precocious puberty. The majority of cases improve with surgery, but strict surveillance of tumoral markers is needed. The most specific markers are inhibin B and anti mullerian hormone (AMH), followed by estradiol levels.Introduction: Juvenile granulosa cell tumors (JGCT) are very rare, especially in infants under the age of one. The most frequent presentation is with signs of precocious puberty. Objective: Present an infant with peripheral precocious puberty, diagnosis of JGCT and follow up. Clinical case: 10-monthold female infant with thelarche, pubic hair and palpable abdominal mass accompanied with elevated levels of estradiol, very low gonadotrophins and images that show a very large ovarian mass. A sapingooforectomy was carried out with full regression of symptoms and signs and improvement of laboratory exams. The biopsy showed TCGJ so inhibin B (InB) was taken as tumoral marker after surgery. This hormone was high initially, but rapidly declined. Follow-up was based on InB, antimullerian Hormone (AMH) and estradiol as described in this type of tumors. Conclusions: Juvenil granulosa cell tumors are very infrequent in pediatric age, but should be suspected in girl with peripheral precocious puberty. The majority of cases improve with surgery, but strict surveillance of tumoral markers is needed. The most specific markers are inhibin B and anti mullerian hormone (AMH), followed by estradiol levels.

Heteroplasmia de la mutación del ADN mitocondrial m.3243A>G en la diabetes y sordera de herencia materna

Maternally Inherited Diabetes and Deafness (MIDD) is caused by mutations in mitochondrial DNA (mtDNA), mainly m.3243A>G. Severity, onset and clinical phenotype of MIDD patients are partially determined by the proportion of mutant mitochondrial DNA copies in each cell and tissue (heteroplasmy). The identification of MIDD allows a corred treatment with insulin avoiding drugs that may interfere with mitochondrial electron chain transpon. We estimated the degree of heteroplasmy of the mutation m.3243A>G from blood, saliva, hair root and a muscle biopsy using quantitative PCR (qPCR) in a femole adult patient. For this purpose, PCR producis were inserted in a vector creating plasmids with 3243A or G. Mutant and wild-type vectors were mixed in different proportions to create a calibration curve used to interpolate heteroplasmy percentages with qPCR threshold cycles. The proportions of m.3243A>G heteroplasmy were 62% (muscle), 14% (saliva), 6% (blood leukocytes) and 3% in hair root. Quantitative analysis of heteroplasmy showed marked variations in different tissues (highest in muscle and lowest in blood). Given the relatively high heteroplasmy found in saliva, this type of biological sample may represent an adequate non-invasive way for assessing the presence of m.3243A>G mutations in epidemiologic studies.