Clinical outcome of stereotactic radiosurgery for central nervous system metastases from renal cell carcinoma.

BACKGROUND: Current treatment modalities for central nervous system (CNS) metastases from renal cell cancer (RCC) include surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiotherapy. Existing studies describing treatment outcomes for CNS metastases include multiple tumor types and thus provide little insight into how RCC CNS metastases respond to these modalities. MATERIALS AND METHODS: RCC patients with brain metastases treated with SRS at the Cleveland Clinic between 1996 and 2010 were retrospectively identified. Radiosurgery and systemic therapy characteristics were recorded. Patients were followed up radiographically at 1 to 2 months after radiosurgery and every 3 to 6 months thereafter with magnetic resonance imaging scans. RESULTS: Of the 166 patients identified, local control was obtained in 90% of patients. In 38% of patients there were additional distant CNS metastases at a median of 12.8 months (95% CI, 8.5-21.1) after SRS. The median time to progression (either local or distant) was estimated to be 9.9 months (95% CI, 5.9-12.9). Higher (> 2.5) RCC-specific graded prognostic assessment (GPA) score was the only factor examined that was found to be a significant prognostic factor for improved outcome (P = .02); however, there was some suggestion that a single target lesion (P = .07) and age ≥ 60 years (P = .07) may also be associated with better CNS control. CONCLUSION: Stereotactic radiosurgery for a limited number of CNS metastases from RCC is associated with excellent local control and is an effective if not preferred treatment modality.

SU-E-T-423: Dosimetric Effect of Rotation on Stereotactic Body Radiotherapy (SBRT) of the Spine.

PURPOSE: To study the dosimetric effects of the residual setup rotation errors in spine SBRT. METHODS: We selected 25 patients with 26 lesions from an IRB approved registry. All patients were setup with Exactrac IGRT and treated with Novalis. Excatrac provided 6D shifts (3 translational, 3 rotational). The translational shifts were corrected by moving the couch. The rotational shifts >2 degrees were corrected by repositioning the patient, while smaller shifts were ignored. For each patient, we rotated the simulation CT rigidly around the CTV center by the recorded residual angles, using the MIM 4.22 software. The resulting rotated CT with all contours were imported into the TPS. The clinical plans used for treatment were mapped onto the rotated CT. Dosimetric endpoints were extracted for the rotated CTV (mean, max, D90) and the rotated cord (D0.1cc, D1cc, V10, max). These endpoints were compared to those from the clinical plan. RESULTS: For the CTV, the average ratio of the mean doses was 1.001 (0.996-1.004), the average ratio of D90 was 1.003 (0.998-1.011), and the average ratio of the maximum doses was 1.005 (0.995-1.029). For the cord, the average ratio of DO.lcc was 1.01 (0.94-1.06), the average ratio of D1cc was 1.036 (0.92-1.23), the average max doses ratio was 1.03 (0.95-1.11), and the average V10 ratio was 1.43 (0.56-2.78). CONCLUSIONS: Rotational errors in patient setup as small as 2 degrees do have dosimetric effects in spine SBRT treatments. The use of a robotic table to eliminate translational and rotational shifts is strongly recommended. It is important to note that, eventhough, the residual rotations resulted in up to 11% variation (cord max dose) from the planned doses, none of these cases violated our clinical treatment plan acceptance criteria (tolerance of the critical organs).

Stereotactic radiosurgery for spinal metastases: update on treatment strategies.

Metastatic tumors are the most common tumors that affect the spinal column and are the source of significant pain and disability in cancer patients. The management of symptomatic spinal metastases presents unique challenges to surgeons as a number of considerations specific to the underlying tumor histology, extent of disease, the functional status of the patient and response to systemic therapy often affect the role, timing and effectiveness of any surgical intervention. As surgical techniques have evolved, the focus of therapy has shifted towards minimizing the morbidity associated with treatments for patients in whom limited nutrition and functional reserve impact their overall survival. As such, stereotactic spinal radiosurgery (SRS) has emerged as a powerful adjunct to surgery as well as a stand-alone treatment option for patients with metastatic disease. Recent technological innovations such as intensity-modulated radiation therapy, image-guidance, and non-invasive spine immobilization have made significant improvements to the delivery of highly conformal radiation to spinal tumors. In this article, current treatment strategies utilizing SRS in the multidisciplinary management of spinal metastases are discussed.

Expression of vascular endothelial growth factor by reactive astrocytes and associated neoangiogenesis.

Injury to the central nervous system (CNS) invokes a reparative response known as astrogliosis, characterized largely by hypertrophy, proliferation and increased expression of glial fibrillary acidic protein (GFAP), resulting in reactive astrocytosis. Based on our prior observation that peritumoral reactive astrocytes express Vascular Endothelial Growth Factor (VEGF), a highly potent and specific angiogenic growth factor, we have hypothesized that reactive astrocytosis also contributes to the neovascularization associated with astrogliosis. To evaluate this hypothesis we evaluated human surgical/autopsy specimens from a variety of CNS disorders that induce astrogliosis and an experimental CNS needle injury model in wild type and GFAP:Green Fluorescent Protein (GFP) transgenic mice. Using computer image semi-quantitative analysis we evaluated the number of GFAP-positive reactive astrocytes, degree of VEGF expression by these astrocytes, associated Factor VIII-positive microvascular density (MVD) and Ki-67 proliferating endothelial cells. The degree of reactive astrocytosis correlated to levels of VEGF immunoreactivity and MVD in the neuropathological specimens. The mouse-needle-stick brain injury model demonstrated this correlation was temporally and spatially related and maximal after 1 week. These results, involving both human pathology specimens augmented by experimental animal data, supports our hypothesis that the neoangiogenesis associated with reactive astrogliosis is correlated to increased reactive astrocytosis and associated VEGF expression.

Inhibition of angiogenesis by blocking activation of the vascular endothelial growth factor receptor 2 leads to decreased growth of neurogenic sarcomas.

Neurogenic sarcomas are incurable, common malignant human peripheral nerve tumors subject to local recurrence and systemic metastasis. In this study, the vascularity, vascular endothelial growth factor (VEGF) expression, and effects of inhibiting VEGF receptor on growth of neurogenic sarcomas were examined. Vascularization and VEGF expression were 6.4- and 15-fold higher in tumors than in normal nerves. The small molecule inhibitor (SU5416) of VEGF receptor 2 had no effect on neurogenic sarcoma cell lines in vitro, but the growth of a human tumor explant xenograft model was reduced by 54.8% compared to vehicle. Reduction in tumor growth was due to decreased tumor angiogenesis, leading to reduction of tumor cell proliferation and increased apoptosis. Inhibiting VEGF function may therefore be a useful adjuvant therapy for neurogenic sarcomas.

Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway.

BACKGROUND: Neurofibromatosis Type 1 (NF1) is an autosomal dominant transmitted cancer predisposing syndrome, with peripheral nerve tumors being a prominent feature. The NF1 gene encodes a large cytoplasmic protein called neurofibromin, which is a major negative regulator of Ras, a key protein in a major signal transduction pathway. It is hypothesized, based on data from neurogenic sarcoma cell lines, that loss of neurofibromin leads to increased levels of activated Ras-GTP, and subsequent uncontrolled mitogenic signals to the nucleus. However, it is not known whether aberrant activity of the Ras pathway is also a prevalent molecular pathogenetic mechanism in actual peripheral nerve tumors. METHODS: To investigate whether aberrant Ras activity was present, and varied with increased tumorigenic potential in peripheral nerve tumors, we have recently developed and published an enzymatic luciferase-based assay that allows measurement of Ras activity in tissues for the first time. RESULTS AND CONCLUSIONS: Neurofibromin, the gene product of the NF1 gene, was not expressed in the NF1 tumors. Levels of activated Ras-GTP in NF1 neurogenic sarcomas and NF1 plexiform neurofibromas were approximately 15 and 5 times higher, respectively, compared with non-NF1 schwannomas, supporting the hypothesis that aberrant activity of this key signaling pathway is important in the pathogenesis of these tumors. In this article we review this data, the molecular genetics of NF1, and the current knowledge of the role of neurofibromin in cellular control. Our understanding of the molecular pathogenic mechanisms of NF1 tumors should be transferable to sporadic peripheral nerve tumors, and allow development of biological therapies directed against relevant targets such as Ras.

Neurogenic sarcomas: experience at the University of Toronto.

OBJECTIVE: Elucidation of the natural history and optimal management of neurogenic sarcomas is not straightforward, because of diagnostic difficulties and the low incidence of this disease. The majority of neurogenic sarcomas are categorized and treated as soft tissue sarcomas, and only a few centers have sufficient experience to add to our understanding of these malignant tumors. This article proposes an algorithm for the management of these tumors. METHODS: A cohort of 18 cases of neurogenic sarcoma (overall mean follow-up period after oncological diagnosis, 33.7 mo), representing approximately 3% of all soft tissue sarcomas treated at the University of Toronto Musculoskeletal Oncology Unit (Toronto, Canada) between 1989 and 1995, were reviewed. The clinical and pathological criteria used to establish the diagnosis of neurogenic sarcoma, the presenting symptoms, the tumor size and grade, the ability to obtain tumor-free margins during en bloc resection, the time to recurrence, and the overall survival rates were noted. A centralized pathological review of the biopsy was undertaken in all cases. RESULTS: A metastatic survey demonstrated localized disease for 16 of the 18 patients. The overall management strategy for these 16 neurogenic sarcomas with localized disease was to obtain local control by en bloc resection. Tumor size, tumor grade, and, most importantly, the ability to obtain tumor-free margins were all relevant prognostic factors for survival. Tumor-free surgical margins were obtained for 11 of 16 patients, with 9 of these 11 patients remaining disease-free. In contrast, all patients for whom tumor-free margins could not ultimately be achieved died as a result of their disease. CONCLUSION: Based on our experience, we propose an algorithm for the management of these rare tumors, for both optimal patient care and oncological research.

Clinical and laboratory evidence of the importance of the tick D. marginatus as a vector of B. burgdorferi in some areas of sporadic Lyme disease in Bulgaria.

56 adult ticks D. marginatus and 38 adult ticks H. punctata were sampled by the flagging method, transferred to the laboratory, dissected and tested for infection with Lyme disease spirochetes. 3 (7.9%) of the adult H. punctata and 2 (3.57%) of the adult D. marginatus were infected with B. burgdorferi (Bb). This report also presents the case of a patient, who developed Lyme disease symptoms after he had been bitten by a D. marginatus tick. The clinical diagnosis was confirmed by serological testing and by a biopsy, taken from the patient's skin lesion. The skin biopsy was examined under an electron microscope and Bb was found in the sections of the deeper strata of the dermis in two structural forms: (a) cylindrical bodies (protoplasm cylinder) with circular ends covered with a three-layered membrane; (b) granules, situated among the collagenous fibres either closely adhered to them or covered with a membrane. The result of the study demonstrates that in single cases in some ecosystems, ticks D. marginatus might be implicated in Bb transmission to humans as secondary vectors.

Unusual features in the epidemiology of Lyme borreliosis.

In this study two cases of Lyme borreliosis are presented. First, the author describes how he contracted Lyme borreliosis 24 hours after he visited an endemic area. The second case described is that of a woman who developed Lyme borreliosis symptoms, when intestinal content of an infected tick came into contact with her conjunctiva. In both cases the diagnosis is based on clinical picture and positive serological tests. The first case shows the probability of contracting Lyme borreliosis when the duration of the tick's attachment to the skin is less than 24 hours. The second case, described demonstrates transmission of B. burgdorferi by contact.

Sera from habitual aborters induce monocyte procoagulant activity: a lymphocyte-dependent event.

Placental thrombosis is a prominent feature in patients with unexplained recurrent fetal loss. To determine whether induction of monocyte procoagulant activity might be a relevant mechanism for unexplained recurrent fetal loss, peripheral blood mononuclear cells isolated from normal healthy controls were cocultured with (a) sera from normal healthy controls (n = 16), (b) sera from habitual aborters (n = 41), and (c) lipopolysaccharide as a positive control. Sera from three patients were fractionated on Sephracryl S-300 and the inducing molecule(s) characterized. Sera from normal healthy controls failed to induce procoagulant activity above basal levels of 21 +/- 4.6 mU/10(5) peripheral blood mononuclear cells. Of the sera from 41 habitual aborters examined 26 (63%) induced procoagulant to a mean value of 410 +/- 48 mU/10(5) peripheral blood mononuclear cells (P < 0.01). Sera from 15 patients failed to augment procoagulant activity. The induction of procoagulant activity was maximal after 6 hr of incubation and was lymphocyte dependent. Fractionation of serum from the three patients on Sepharcryl S300 revealed the procoagulant activity (PCA)-inducing factor(s) to have a molecular weight of between 300,000 and 800,000 Da. The serum factor was found to be heat, alkaline, and acid sensitive. Both anti-IgM and anti-IgA immunoabsorbents reduced the PCA-inducing factor. We conclude that IgM and IgA from some patients with unexplained recurrent fetal loss are capable of inducing procoagulant activity and could contribute to the development of placental microthrombi and infarction, prominent features of this syndrome.

Results of Therapy for Acute Myeloid Leukemia in First Relapse.

Fifty-four consecutive patients with acute myeloid leukemia (AML) in first relapse presenting at a single institution were studied to determine factors affecting response to re-induction therapy. For purposes of analysis, re-treatment protocols were grouped into two categories, one with high dose and the other with standard dose cytosine arabinoside. Most regimens also included an anthracycline, mitoxantrone or amsacrine. Thirty-one of the 51 patients (61%) who received therapy achieved a second complete remission (CR-2). Median duration of CR-2 was 6 months (range 1-24+ months). Five patients remain in CR-2, three of whom received bone marrow transplants (median follow-up 24 months). The variables, age, gender, FAB subtype, leukocyte and platelet count, duration of CR-1, the initial and re-induction regimens were analyzed for prognostic value in attaining and maintaining CR-2. Only younger age (p < 0.001) and longer CR-1 duration (p < 0.05) were significantly correlated with greater likelihood of attaining CR-2 with univariate analysis, and only age was correlated with CR-2 rate using multivariate analysis (p = 0.018). Younger age was associated with longer CR-2 duration (p = 0.003) using multivariate analysis, a correlation that persisted when transplanted patients were excluded. There was no advantage to the use of high dose versus standard dose cytosine arabinoside in the reinduction regimen with respect to the ability to either achieve or sustain CR-2. Our data indicate that although the remission induction rate for AML in first relapse is high, remissions are brief and other strategies are required to improve outcome of patients in second remission.

[Data on the epidemiology of Lyme disease in Bulgaria]. / Materialy po épidemiologii bolezni Laima v Bolgarii.

134 patients with clinically, epidemiologically and serologically confirmed Lyme's disease have been examined. 89.5% of them had erythema chronicum migrans, 112 patients (83.6%) were known to have had tick bites. The majority of patients were white-collar workers and townspeople. Hungry ticks collected from plants were shown to contain B. burgdorferi. 497 foresters and animal farmers have been serologically examined, using an indirect immunofluorescence test. Antibodies to B. burgdorferi in diagnostic titres have been revealed in 15.3% of foresters and 17.8% of animal farmers.

[Lyme disease and the forms of its manifestation in Bulgaria]. / Laimskata bolest i neinite formi na proiavlenie u nas.

Two cases of serologically proved cardiac form of Lyme's disease are presented (for the first time in Bulgaria). An A-V block III degree was found in the first patient and an A-V block I degree in the second patient. The diagnosis is supported by epidemiologic data--endemic region, other patients with Lyme's disease, insects bite, season, etc.

[Cefacetril in treatment of clinical bovine mastitis]. / Lekuvane na klinichni mastiti pri kravite s cefacetril.

The dynamic of the reconvalescence process was followed up in the udder of cows treated with the intramammary preparation Cefacetril. Complete therapeutic effect was recorded with 93.10 per cent of the cases, elimination of the infection -- with 86 per cent, and normalization of the cell content -- with 37.93 per cent. It was also established that during recovery the chlorine content of milk dropped, while lactose rose. The percent content of the protein fractions changed, whereupon the serum albumin and the immunoglobulins decreased, and the beta-lactoglobulin and the gamma-lactoglobulin increased.

[Clinical, cytological and microbiological studies of the MMA syndrome]. / Klinichni, tsitologichni i mikrobiologichni prouchvaniia na sindroma MMA.

Clinical, cytological, and microbiological investigations were carried out of a total of 793 sows in the course of 10 days after farrowing. It was found that the MMA syndrome was manifested in the first days following farrowing with higher temperature, changes in the genital organs with a purulent discharge from the first to the third day, and lesions in the mammary gland with inflammatory processes or decrease in the milk secretion. The cell content of milk of the diseased sows was higher. The microbiologic study of uterine, vaginal, and milk secretion led to the isolation of Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis as well as mixed infections and other bacteria as causative agents of MMA.