Genome-wide CRISPR/Cas9 library screening identified ATM signaling network genes as critical drivers for resistance to ATR inhibition in soft-tissue sarcomas: synthetic lethality and therapeutic implications.

Soft-tissue sarcoma (STS) are a heterogeneous group of rare tumors with different biological behavior that are fatal in more than 40% of cases, due to their metastatic evolution and inadequate treatment options. ATR inhibition already showed an activity, even if modest, in broad pre-clinical models of STS. By using genome-wide CRISPR/Cas9 library screening, we identified ATM signaling network genes as critical drivers for resistance to the specific ATR inhibitor AZD6738. The role of such genes in resistance to AZD6738 was confirmed by using CRISPR/Cas9 knockout models. More strikingly, the ATM inhibitor AZD0156 works synergistically with AZD6738 in vitro and abolishes STS growth in vivo in our models of most frequent histotypes (such as dedifferentiated liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma among others). Moreover, the combination of AZD6738 and AZD0156 induced significantly higher levels of DNA damage than either drug used as single agent alone. In summary, our results demonstrate that targeting ATM is an effective approach to overcome resistance to ATR inhibition in different STS subtypes, including the most frequent histologies.

An immunological signature to predict outcome in patients with triple-negative breast cancer with residual disease after neoadjuvant chemotherapy.

BACKGROUND: When triple-negative breast cancer (TNBC) patients have residual disease after neoadjuvant chemotherapy (NACT), they have a high risk of metastatic relapse. With immune infiltrate in TNBC being prognostic and predictive of response to treatment, our aim was to develop an immunologic transcriptomic signature using post-NACT samples to predict relapse. MATERIALS AND METHODS: We identified 115 samples of residual tumors from post-NACT TNBC patients. We profiled the expression of 770 genes related to cancer microenvironment using the NanoString PanCancer IO360 panel to develop a prognostic transcriptomic signature, and we describe the immune microenvironments of the residual tumors. RESULTS: Thirty-eight (33%) patients experienced metastatic relapse. Hierarchical clustering separated patients into five clusters with distinct prognosis based on pathways linked to immune activation, epithelial-to-mesenchymal transition and cell cycle. The immune microenvironment of the residual disease was significantly different between patients who experienced relapse compared to those who did not, the latter having significantly more effector antitumoral immune cells, with significant differences in lymphoid subpopulations. We selected eight genes linked to immunity (BLK, GZMM, CXCR6, LILRA1, SPIB, CCL4, CXCR4, SLAMF7) to develop a transcriptomic signature which could predict relapse in our cohort. This signature was validated in two external cohorts (KMplot and METABRIC). CONCLUSIONS: Lack of immune activation after NACT is associated with a high risk of distant relapse. We propose a prognostic signature based on immune infiltrate that could lead to targeted therapeutic strategies to improve patient prognosis.

GSK3-beta as a candidate therapeutic target in soft tissue sarcomas.

Soft tissue sarcoma (STS) is a predominantly fatal rare malignancy with inadequate treatment options. Glycogen synthase kinase 3ß (GSK-3ß) is an emerging target in human malignancies. Its therapeutic relevance in STS is unknown. We analyzed the prognostic impact of GSK-3ß gene and protein expression in two independent cohorts of patients with STS. We then treated STS cell lines and mice xenografts with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. We demonstrated that 9-ING-41 treatment induced significant STS cells apoptosis and was synergistic in vivo when combined with chemotherapy. Mechanistically, 9-ING-41 induces significant apoptosis of STS cells via suppression of NF-κB-mediated X-linked inhibitor of apoptosis protein (XIAP) expression. These data support the inclusion of patients with STS in clinical studies of 9-ING-41 alone and in combination with chemotherapy.

Antibiotic-resistant Staphylococcus aureus strains of swine origin: molecular typing and susceptibility to oregano (Origanum vulgare L.) essential oil and maqui (Aristotelia chilensis (Molina) Stuntz) extract.

AIM: The molecular typing and the susceptibility of Staphylococcus aureus strains of swine origin to antibiotics, oregano (Origanum vulgare L.) essential oil (EO) and Chilean blackberry maqui (Aristotelia chilensis (Molina) Stuntz) extract were determined. METHODS AND RESULTS: Twenty S. aureus strains of swine origin were subjected to molecular typing, of which six strains were selected for antimicrobial susceptibility testing. The epsilon test (Etest) was used to determine the antibiotic susceptibility. The susceptibility to natural antimicrobials (NAs): oregano EO, maqui extract, thymol (Thy) and carvacrol (Carv), was carried out using the disk diffusion method. The S. aureus strains were genetically diverse. All strains were resistant to at least one class of antibiotic, and two strains were multidrug-resistant. The minimum inhibitory concentration of oregano EO, Thy and Carv was 0·01-0·04%. Maqui extract did not show antistaphylococcal activity. CONCLUSIONS: Natural antimicrobials extracted from oregano have an inhibitory activity against S. aureus strains from swine origin, with no effect using maqui extract. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides information about the characteristics of S. aureus strains of swine origin, and about the potential use of NAs from oregano to enhance the control of antibiotic-resistant S. aureus strains in the pork supply chain.

CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications.

Background: Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1. Methods: We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were carried out by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC-0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed. Results: We found that GDC-0575 abrogated DNA damage-induced S and G2-M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase I study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2. Conclusion: We provide the first preclinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase II setting.

Factores fisiopatológicos y metas terapéuticas perioperatorias que influyen en procedimientos quirúrgicos reconstructivos mediante colgajos en pacientes con Diabetes Mellitus / Pathophysiologic factors and perioperative therapeutic goals that affect reconstructive surgical procedures with flaps in patients with Diabetes Mellitus

RESUMEN Introducción: la diabetes mellitus es considerada un factor de riesgo para complicaciones locales y fracaso quirúrgico en cirugías reconstructivas mediante el uso de colgajos debido a las alteraciones en el proceso de cicatrización propias de esta patología. Objetivo: hacer una revisión de la literatura disponible sobre los factores fisiopatológicos que influyen en los resultados posquirúrgicos a corto, mediano y largo plazo en la población diabética, así como de las metas terapéuticas perioperatorias asociadas a mayores tasas de éxito. Metodología de Búsqueda: se realizó búsqueda en las bases de datos PUBMED, MEDLINE Y SCIELO, mediante el gestor de búsqueda utilizando los términos: "Period perioperative", "Reconstructive surgical procedures", "Surgical flaps", "Diabetes mellitus", obteniendo un total de 160 artículos de revistas en línea, de los cuales se seleccionaron 50. Resultados: la realización de colgajos en pacientes con diabetes mellitus se asocia a mayor riesgo de fracaso y complicaciones, las cuales disminuyen considerablemente si se realiza un estricto manejo perioperatorio enfocado en metas. Conclusiones: la diabetes mellitus causa alteraciones en la respuesta inflamatoria, disfunción microvascular y mayor estrés oxidativo, lo cual se ve reflejado en un proceso de cicatrizacion anormal, generando mayores tasas de infeccion y perdidas de colgajos; un estricto manejo peri operatorio guiado por metas logra disminuir las complicaciones y aumentar el exito quirurgico. MÉD.UIS. 2017;30(1):35-43.

ABSTRACT Introduction: diabetes mellitus is considered a risk factor for local complications and surgical failure in reconstructive surgeries, mainly in flaps due to the fact that it causes alterations in the cicatrization process. Objective: to review the available literature on the pathophysiological factors that influence the short-, medium- and long-term results in the diabetic population, the perioperative therapeutic goals associated with higher success rates, and to establish a baseline protocol for the perioperative management of these patients. Searching methodology: we searched the PUBMED, MEDLINE and SCIELO databases using the search terms "Period perioperative", "Reconstructive surgical procedures", "Surgical flaps", "Diabetes mellitus", obtaining a total of 160 online journal articles, of which 50 were selected. Results: the performance of flaps in patients with diabetes mellitus is associated with an increased risk of failure and complications, which decrease considerably when a strict goal-directed perioperative management is performed. Conclusions: diabetes mellitus causes alterations in the inflammatory response, microvascular dysfunction and increases oxidative stress, which is reflected in an abnormal healing process, generating higher infection rates and graft loss, but if glycemic management goals are achieved in the perioperative period it is possible to reduce the complications and to increase the surgical success. MÉD.UIS. 2017;30(1):35-43.

Dexamethasone treatment in chronic subdural haematoma.

INTRODUCTION: Neurosurgeons are familiar with chronic subdural haematoma (CSH), a well-known clinical entity, which is usually treated by some modality of trepanation. Despite the excellent outcomes obtained by surgery, complications may occur, some of which may be potentially severe or fatal. Furthermore, up to 25% recurrence rate is reported. The authors present a novel approach to the management of CSH based on the use of dexamethasone as the treatment of choice in the majority of cases. PATIENTS AND METHODS: Medical records of 122 CSH patients were retrospectively reviewed. At admission, symptomatic patients were classified according to the Markwalder Grading Score (MGS). Those scoring MGS 1-2 were assigned to the Dexamethasone protocol (4 mg every 8h, re-evaluation after 48-72 h, slow tapering), and those scoring MGS 3-4 were, in general, assigned to the Surgical protocol (single frontal twistdrill drainage to a closed system, without irrigation). Patients were followed in the Outpatient Office with neurological assessment and serial CT scans. RESULTS. Between March 2001 and May 2006, 122 consecutive CSH patients (69% male, median aged of 78, range 25-97) were treated. Seventy-three percent of the patients exhibited some kind of neurological defect (MGS 2-3-4). Asymptomatic patients (MGS 0) were left untreated. Initial treatment assignment was: 101 dexamethasone, 15 subdural drain, 4 craneotomy and 2 untreated. Twenty-two patients on dexamethasone ultimately required surgical drain (21.8%). Favourable outcome (MGS 0-1-2) was obtained in 96% and 93.9% of those treated with dexamethasone and surgical drain, respectively. Median hospital stay was 6 days (range 1- 41) for the dexamethasone group and the whole series, and 8 days (range 5-48) for the surgical group. Overall mortality rate was 0.8% and re-admissions related to the haematoma reached 14.7% (all maintained or improved their MGS). Medical complications occurred in 34 patients (27.8%), mainly mild hyperglycemic impairments. Median outpatient follow up was 25 weeks (range 8-90), and two patients were lost. DISCUSSION: The rationale for the use of dexamethasone in CSH lies in its anti-angiogenic properties over the subdural clot membrane, as it is derived from experimental studies and the very few clinical observations published. Surgical evacuation of CSH is known to achieve excellent results but no well-designed trials compare medical versus surgical therapies. The experience obtained from this series lets us formulate some clinical considerations: dexamethasone is a feasible treatment that positively compares to surgical drain (and avoided two thirds of operations); the natural history of CSH allows a 48-72 h dexamethasone trial without putting the patient at risk of irreversible deterioration; eliminates all morbidity related to surgery and recurrences; does not provoke significant morbidity itself; reduces hospital stay; does not preclude ulterior surgical procedures; it is well tolerated and understood by the patient and relatives and it probably reduces costs. The authors propose a protocol that does not intend to substitute surgery but to offer a safe and effective alternative. CONCLUSION: Data obtained from this large retrospective series suggests that dexamethasone is a feasible and safe option in the management of CSH. In the author's experience dexamethasone was able to cure or improve two thirds of the patients. This fact should be confirmed by others in the future. The true effectiveness of the therapy as compared to surgical treatment could be ideally tested in a prospective randomized trial.

Preservation of bone flap after craniotomy infection.

INTRODUCTION: The estimated incidence of craniotomy infection is 5%, ranging from 1-11% depending on the presence of certain risk factors, such as, prior radiation therapy, repeated surgery, CSF leak, duration of surgery over 4h, interventions involving nasal sinuses and emergency surgeries. The standard treatment for infected craniotomies is bone flap discarding and delayed cranioplasty. Adequate cosmetic results, unprotected brain and disfiguring deformity until cranioplasty are controversial features following bone removal. We present a limited series of five patients with craniotomy infection, that were successfully treated with wound debridement, in situ bone sterilization, reposition of the bone flap and antibiotic irrigation through a wash-in and wash-out draining system, all in the same surgical procedure. All infections cleared and every patient saved his/her bone flap. PATIENTS AND METHODS: We retrospectively reviewed the records of 5 patients with craniotomy infection that presented with wound swelling, purulent discharge and fever. The operative technique consisted on three manoeuvres: wound debridement, bone flap sterilization (either autoclaved or soaked in a sterilizing solution), and insertion of subgaleal/epidural drains for non-continuous antibiotic irrigation (vancomycin 50mg in 20cc of saline every 12h alternating with cephotaxime 100mg in 20cc of saline every 12h). Also, patients received equal systemic endovenous antibiotherapy and oral antibiotics after discharge, until complete resolution of infection and wound healing. RESULTS: Patients in the series (2 women and 3 men) ranged in age from 36 to 77. No patient had received prior radiation therapy and only one had undergone surgery involving nasal sinuses. The initial operations correspond to craniotomies performed for two intracranial tumours (meningiomas), one arteriovenous malformation and two decompressive craniotomies (haemorrhagic contusions and acute subdural haematoma). The duration of surgeries ranged from 1h30' to 5h30', only two operations extending over 4 hours. The interval between the initial surgery and the reintervention ranged from 11 to 227 days. Staphyloccocus spp were cultured in all patients. For bone sterilization povidone scrubbing was used in all patients, autoclave in two and soaking the flap in a sterilizing solution in three. All patients cleared infection and achieved complete wound healing in 2-3 weeks after the re-operation. Follow up ranged from 4 to 18 months. One patient died as a consequence of sepsis in the context of pneumonia some weeks after wound healing. DISCUSSION: Recent multivariate analyses have demonstrated that the presence of a CSF leak and the performance of repeated operations are the most important independent risk factors for craniotomy infection, with associated odds ratios for infection as high as 145 and 7, respectively. Regular antibiotic administration at anaesthesia induction seems to decrease the rate of craniotomy infection by half, both in the entire population and in low-risk subsets. Organisms involved in craniotomy infections are common pathogens usually contaminating neurosurgical procedures or normal skin flora germs. Auguste and McDermott have recently presented a case series of 12 patients in which successful salvage procedures for infected craniotomy bone flaps were performed using a continuous wash-in, wash-out indwelling antibiotic irrigation system, that needed close observation of the neurological status since obstruction of the outflow system could precipitate brain herniation. The method we present is as effective as theirs and avoids such complication since only small quantities of antibiotic solutions (20 cc) are instilled during each dose administration.

[Plasmacytoid urothelial carcinoma of the urinary bladder. A study of 7 cases]. / Carcinoma urotelial plasmocitoide de vejiga urinaria. Estudio de 7 casos.

OBJECTIVE: Plasmacytoid urothelial carcinoma is a rare and aggressive variant of bladder cancer that mimics plasmacytoma histologically and that can be confused with hemolymphoid neoplasms secondarily affecting the urinary bladder. Only single cases and short series have been described so far. PATIENTS AND METHODS: Seven cases of plasmacytoid urothelial carcinoma have been found among 720 high grade urothelial carcinomas of the urinary bladder. RESULTS: In our series, 0.97% of high grade urothelial carcinomas of the urinary bladder show plasmacytoid phenotype. All the cases were smoking males between 58 and 75 years old. Histologically, two cases showed pure plasmacytoid features, while in the other five cases the plasmacytoid phenotype was mixed with conventional transitional cell or glandular histologies. By immunohistochemistry, all the plasmacytoid areas showed fair epithelial differentiation. The clinical behaviour was aggressive in all the cases, with distant metastases at diagnosis in three cases and early tumor recurrence after chemotherapy in four of them. CONCLUSIONS: In our experience, the plasmacytoid urothelial carcinoma of the urinary bladder is a rare tumor that can also be detected in association with areas of conventional urothelial carcinoma. It is mandatory to recognize this histological subtype due to the clinical and prognostic implications of this diagnosis.

Large chondroma of the dural convexity in a patient with Noonan's syndrome. Case report and review of the literature.

INTRODUCTION: Intracranial chondromas are extremely rare intracranial tumours that usually arise from the skull base synchondrosis. Exceptionally, they may grow from cartilage rests within the dura mater of the convexity or the falx. They may be part of Ollier's multiple enchondromatosis or Maffuci's syndrome. We describe the case of a young male diagnosed of Noonan's syndrome that underwent resection of a large intracranial chondroma arising from the dural convexity. To our best knowledge this is the first report of such association. CASE REPORT: An 18-year-old male presented with a single generalized seizure. The patient was previously diagnosed of Noonan's syndrome on the basis of his special phenotype (Turner-like), low stature, cardiac malformation, retarded sexual and bone development and normal karyotype. He harboured mild psychomotor retardation. Physical and neurological examinations were unremarkable. Brain Magnetic Resonance image showed a large well-circumscribed intracranial mass in the dural convexity of the left frontal-parietal lobes, with heterogeneous contrast enhancement and no peritumoural oedema. The patient was initiated on valproic acid and underwent craniotomy and complete excision of the tumour. The tumour was firm, white-greyish, avascular and could be finely dissected away from the cortex. Postoperative seizures required additional anticonvulsant therapy. He was discharged uneventfully. The pathological study revealed a mature chondroma. Subsequent brain MRI studies have shown no evidence of recurrence after 33 months of follow up. DISCUSSION: Chondromas comprise less than 0.3% of intracranial tumours. Only twenty-five cases of intracranial dural convexity chondromas are reported in the literature. Several hystopathogenetic theories have been proposed: metaplasia of meningeal fibroblasts and perivascular meningeal tissue, traumatic or inflammatory cartilaginous activation of fibroblasts and growth of aberrant embryonal cartilaginous rests in the dura mater. Chondromas present clinical features similar to meningiomas. CT scan imaging shows a mass of variable density due to different degrees of calcification with minimum to moderate contrast enhancement. MRI studies show a well-circumscribed lesion without surrounding tissue oedema, that exhibit heterogeneous signal with intermediate to low intensity on T1-weighted images and mixed intensity on T2-weighted images with minimum enhancement. Angiogram is clue to differentiate from meningiomas since chondromas are completely avascular. Complete tumour resection including its dural attachment is the treatment of choice. Long-term prognosis is favourable. Radiation therapy is currently not recommended for residual tumours or inoperable patients due to risk of malignization. Noonan's syndrome (also known as pseudo-Turner syndrome) is a complex familial genetic disorder with a phenotype that resembles that of Turner's syndrome but exhibits no chromosomal defect. No predisposition of Noonan's syndrome for tumoural development is reported in the literature. Association of a dural convexity chondroma with Noonan's syndrome is unique as far as the literature is concerned.

Metastatic meningioma to the eleventh dorsal vertebral body: total en bloc spondylectomy. Case report and review of the literature.

INTRODUCTION: One in every thousand intracranial meningiomas metastatize extracranially. Lung and intraabdominal organs are most frequently affected. Only 7% involve vertebrae and just a dozen cases have been reported in the literature. To our knowledge, this is the first description of a total en bloc spondylectomy through a posterior approach for the treatment of an intraosseous metastatic meningioma to the eleventh dorsal vertebra. CASE REPORT: In March 1996, a 37 year-old male underwent surgical resection for a left occipital intraventricular benign meningioma (WHO I). He was reoperated in February 2002 due to local recurrence. By the end on 2003 he developed progressively invalidating dorsolumbar pain. MRI studies revealed a T11 intraosseous mass. In March 2004, a percutaneous biopsy and vertebroplasty were performed. The pathological specimen was identified as adenocarcinoma and he initiated chemotherapy. Advice from a second pathologist was seeked, who suggested the diagnosis of intraosseous meningioma. Workup studies failed to reveal any primary tumor. In May 2004 the patient was admitted to our department and a new transpedicular biopsy confirmed the diagnosis. In June 2004 he underwent T11 total en bloc spondylectomy (Tomita's procedure), fusion with bone and calcium substitute-filled stackable carbon-fiber cages, and T9 to L1 transpedicular screw fixation. No postoperative complications ocurred and he is, so far, free from primary and secondary disease. Definite pathology: benign meningioma (WHO I). DISCUSSION: Distant metastases from intracranial meningiomas are rare entities, arising from benign lesions in, at least, 60% of cases. Enam et al proposed a specific pathological score to differentiate benign, atypic and malignant meningiomas. Such score correlates with the chance of metastatizing: more than 40% in malignant meningiomas compared to 3.8% of brain tumors overall. The ability to metastatize seems to be linked to vascular or lifatic invasiveness. Metastases ocurr more frequently in angioblastic, papillary and meningothelial variants. Hematogenous (especially venous; Batson's perivertebral plexus), linfatic and cerebrospinal fluid are the main routes involved in the spreading of the tumor. Craniotomy itself may also play a role, for the majority of patients have been previously operated on repeatedly. The interval between the onset of the intracranial disease and the appearance of the metastasis varies from months to many years. The value of transpedicular biopsy is widely recognized (efficacy over 80%) and the suitability of the specimen for pathological examination improves when wide inner caliber trephines are used. In the case presented we applied the oncologic concept of vertebral en bloc resection. We believe this case represents a paradigmatic indication of this technique because it respects the concepts of radical resection and spinal stability, and offers an opportunity for the curation of the disease.

[Role of surgery in spinal degenerative disease. Analysis of systematic reviews on surgical and conservative treatments from an evidence-based approach]. / Papel de la cirugía en la enfermedad degenerativa espinal. Análisis de revisiones sistemáticas sobre tratamientos quirúrgicos y conservadores desde el punto de vista de la medicina basada en la evidencia.

INTRODUCTION: The lifetime prevalence of invalidating back pain in general population caused by Spinal Degenerative Disease (SDD) is about 70-80%. Global costs related to this disease are enormous (1-2% gross domestic product). From an Evidence-based point of view, there is a striking discrepancy between the use of many available surgical techniques (especially for spinal fusion) and the lack of scientific support. METHODS: The authors carefully reviewed all published metaanalysis on SDD therapies up to December 2003. Treatment recommendations were classified according to levels of evidence (strong, moderate, mild or lack of evidence) for both surgical and conservative measures. RESULTS: Forty-four metaanalysis were selected (nine on lumbar surgery, three on cervical surgery and thirty-two on other therapies). Relating surgery, there is strong evidence favouring early laminectomy in cauda equina syndrome secondary to lumbar disc herniation; discectomy or microdiscectomy are superior to chemo-nucleolysis in lumbar prolapse and spondylosis; and fusion surgery (probably noninstrumented) in adult isthmic spondylolysthesis or degenerative spondylolysthesis with spinal stenosis. In cervical spondylosis and radiculomyelopathy, discectomy seems as effective as discectomy plus fusion, which does not seem to be better than untreated SDD beyond 24 months. Preoperative antibiotics seem to prevent infection in spinal surgery. No benefit of surgery is demonstrated in discogenic pain. None of conservative therapies are supported by strong evidence. Antidepressants improve pain perception but do not influence the functional status. DISCUSSION: Although lumbar instrumented surgery has nearly doubled over two decades and the annual growth is about 20%, clinical results do not seem to have improved, not even global fusion rates. The increasing use of fusion surgery for cases other than spinal deformities, spondylolysthesis or spinal stenosis plus lysthesis may be related to multiple technical and clinical-epidemiological factors where huge financial and commercial interests must be considered. It is crucial to differentiate subsets of patients prone to benefit from surgery. It is discussed whether randomized trials incorporating sham operations are ethically justifiable, because of the lack of sound evidence for many spinal procedures. The efficacy of most conservative treatments is mild or moderate (mainly transient) and they should be probably used in combination. CONCLUSIONS. There is no strong evidence favouring most of surgical procedures for SDD from an evidence-based approach. It seems necessary that scientific organizations studying SDD create clinical guidelines relating its multidisciplinary and integral management, recognizing that, up to now, few interventions positively modify in the long-term the natural history of the disease.

[Giant aneurysm of fast development]. / Aneurisma gigante de rápido crecimiento.

The percentage of aneurysms measuring more than 2'5 cm in diameter ranges from 3 to 13%, and occur more commonly in females. They come to clinical attention later than nongiant aneurysms, but 20% of them appear in patients 20 years of age or younger. Its natural history is incompletely understood. We present the case of a 24-year-old female admitted following a generalized seizure with postictal dysphasia and right hemiparesis caused by a subarachnoid hemorrhage due to a ruptured giant aneurysm located in the left temporal fossa, who died few hours later because of rebleeding. This patient had been followed during the last seven years at our unit because of untreated frontal osteomas, without evidence of any intracranial lesion in the computerized axial tomography (CT). Some months before her death, she had suffered a left micotic otitis, and she was studied because of the reappearance of her left cephalalgia without neurological deficit. This case is another evidence of quick appearance of a giant aneurysm, "silent" until the fatal outcome.

[Intradural cervical lipoma without neurologic involvement; report of a case]. / Lipoma cervical intradural sin compromiso neurológico; a propósito de un caso.

Lipomas are masses composed of mature adipose tissue, usually affecting lumbosacral levels, often associated with neural tube defects. Spinal lipomas at more rostral levels are usually unassociated with congenital abnormalities, but may produce a more severe neural compromise. Rare reports of cervical lipoma without neurological deficit have been described. We present the case of a 10-years-old girl who complained of cervical pain and stiff neck related to a C7-T1 intradural lipoma, without neurological affectation. The lipoma was partially resected without postoperative deterioration.

[Permanent AV junction (Coumel type) reciprocal tachycardia]. / Taquicardia reciprocante permanente de la unión AV (tipo Coumel).

UNLABELLED: Permanent auriculo-ventricular junctional reciprocating tachycardia is a special form of tachycardia usually incessant, secondary to an slow retrograde conduction pathway. OBJECTIVE: To establish the clinical, electrophysiological characteristics and therapy results in patients with this diagnosis. METHOD: Descriptive study. RESULTS: Nine patients with average age 28.1 +/- 19.2 years, six women. Seven patients presented with dyspnea or palpitations. The left ventricular ejection fraction before treatment was 43.3 +/- 19.5%. The electrocardiographic findings were: heart rate of 139.2 +/- 16.7 bpm, QRS 78.9 +/- 16.2 ms and RP'/P'R relation of 1.8 +/- 0.5. The location of the accessory pathways was: right postero-septal in seven (77.7%), left lateral in one (11.15%) and left postero-lateral in one (11.15%). Radiofrequency ablation was performed in eight patients with an 87.5% success rate, two cases were taken to surgery with successful treatment, one of them after percutaneous ablation failure. Those with systolic left ventricular dysfunction recover their function in the follow-up. Any case has recurred. CONCLUSIONS: In our center, permanent auriculo-ventricular junctional reciprocating tachycardia is an infrequent arrhythmia, predominantly in women and associated with reversible left ventricular dysfunction. Right postero-septal was the most frequent localization of the pathway. Radiofrequency ablation was performed successfully in 87.5% of cases.

Identification of chromosome inheritance modifiers in Drosophila melanogaster.

Faithful chromosome inheritance is a fundamental biological activity and errors contribute to birth defects and cancer progression. We have performed a P-element screen in Drosophila melanogaster with the aim of identifying novel candidate genes involved in inheritance. We used a "sensitized" minichromosome substrate (J21A) to screen approximately 3,000 new P-element lines for dominant effects on chromosome inheritance and recovered 78 Sensitized chromosome inheritance modifiers (Scim). Of these, 69 decreased minichromosome inheritance while 9 increased minichromosome inheritance. Fourteen mutations are lethal or semilethal when homozygous and all exhibit dramatic mitotic defects. Inverse PCR combined with genomic analyses identified P insertions within or close to genes with previously described inheritance functions, including wings apart-like (wapl), centrosomin (cnn), and pavarotti (pav). Further, lethal insertions in replication factor complex 4 (rfc4) and GTPase-activating protein 1 (Gap1) exhibit specific mitotic chromosome defects, discovering previously unknown roles for these proteins in chromosome inheritance. The majority of the lines represent mutations in previously uncharacterized loci, many of which have human homologs, and we anticipate that this collection will provide a rich source of mutations in new genes required for chromosome inheritance in metazoans.

[Neurocardiogenic syncope in children]. / Síncope neurocardiogénico en población pediátrica.

Between december of 1994 and june 1997, 90 children and adolescents were referred to the Shaio Clinic Foundation for evaluation of recurrent unexplained syncope. Head-up tilt testing was positive in 45 (50%), 23 male, with a mean age of 12.7 years (range 5-17 years). The response during Head-up tilt testing was predominantly vasodepressor (57%), followed by mixed in 24% and cardioinhibitory in the remaining 17%. The majority of patients had a positive response during pharmacological phase with isoproterenol infusion at a mean time of 17 +/- 8 minutes. Head-up tilt is a safe diagnostic test and defines the cause of unexplained syncope in up to 50% of children and young adults with recurrent syncope. The management was based on education, control of risk factors and psychological and/or physical rehabilitation. In the 15.2 months follow up we observed complete remission or a significant reduction of symptoms in 95% of the cases. Only 5% of the patients persisted or had worsening of their symptoms.