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2542 Background: Detection of ctDNA is a promising tool for managing pts in oncology. Most methods require whole-genome sequencing of tumor samples followed by the design of personalized panels for tracking purposes. In this work, we evaluated the prognostic and predictive value of total ctDNA quantification, using shallow whole-genome sequencing (shWGS) exclusively from plasma samples, in a prospective cohort of pts treated with ICIs in early clinical trials. Methods: IchorCNA pipeline was used to quantify ctDNA of shWGS from plasma ctDNA samples of pts treated with ICIs in phase 1 trials, collected at baseline and prior to cycle 2 (prec2). We investigated the association and correlation of ctDNA levels with surrogate markers for tumor burden (LDH levels, summatory of target lesions (TL), liver metastasis) using Spearman and Kruskal-Wallis tests. Kaplan-Meier estimates of overall survival (OS) of pts with baseline detectable ctDNA levels versus undetectable ctDNA were calculated. A multivariate Cox proportional hazards model, including continuous classical prognostic factors (LDH, albumin, hemoglobin, derived Neutrophil-to-Lymphocyte ratio (dNLR), platelets, number of metastases sites, ECOG PS) and ctDNA was performed. An estimate of progression free survival (PFS) of pts with ctDNA increase levels in preC2 versus a non-increase group was evaluated. Results: Since January 2018, 113 pts with no standard-treatment options were included. Median (m) follow up was 14.8 months (mo). Baseline ctDNA levels correlated significantly with baseline TL (R = 0.4, p < 0.001) and LDH levels (R = 0.61, p < 0.001). Pts with liver metastasis had higher levels of ctDNA (11,68 ng/ml) versus pts with no liver disease (2,31 ng/ml) (p < 0,001). In the survival analysis pts with detectable baseline ctDNA (74 pts) had significantly shorter OS compared with pts with undetectable ctDNA (39 pts); median 9.6 m (8.4 – 16.4) and NA m (13.6-NA), respectively (HR = 2.25 [1.18-4.29] p < 0.01). In the multivariate analysis, only ctDNA and albumin levels maintained the impact in OS (HR = 1.03, p < 0.05 and HR = 0.22, p < 0.05, respectively). Pts with early increases in ctDNA had a shorter PFS compared with those with a stabilization or decrease, median 1.9 m (1.6 – 4.0) and 3.0 m (2.6 – 3.8), respectively (HR = 2.19 [1.31-3.67], p < 0.01). Conclusions: Quantification of baseline ctDNA using shWGS is a strong independent prognostic factor. Early dynamic changes of ctDNA could be a useful tool to predict PFS outcomes.

10563 Background: Young-onset colorectal cancer (YOCR) is defined as diagnosis below the age of 50. Over the past decades, the incidence of YOCRC has increased at an alarming rate, but causes and pathogenesis still remain unknown. Early detection of colorectal cancer (CRC) has demonstrated to improve survival. Despite these facts, adults < 50 years old are not yet included in screening programs and YOCRC is not well characterized. We aimed to characterize the clinical and molecular characteristics of YOCRC in patients (pts) diagnosed at our institution. Methods: Consecutive pts with a diagnosis of CRC below the age of 50 visited for the first time at Vall d’Hebron University Hospital in Spain between January 2017 and October 2020 were included in the analysis. Data of clinicopathologic features and treatment were collected retrospectively from medical records. Results: 205 pts met the inclusion criteria, 111 (54%) were females, 8 (4%) presented a personal history of cancer at diagnosis and 109 (53%) a family history of cancer. Age at diagnosis was: < 30: 10 (5%), {30 – 40): 52 (25%), {40-45): 51 (25%), {45-50): 92 (45%). Site of primary tumor was: right colon: 50 (24%), left colon: 107 (52%): rectum: 48 (24%). Stage at diagnosis was I: 3 (1%), II: 14 (7%), III: 60 (29%), IV: 128 (63%). 6 of 14 (43%) and 44 of 60 patients (73%) with stage II and III CRC presented disease progression after initial treatment, respectively. Molecular status was: KRAS mutation: 74 (36%), NRAS mutation: 7 (3%), BRAF mutation: 12 (6%), MSI-H: 12 (6%). 43 pts (21%) had documentation of genetic counseling. Median (range) number of lines of treatment for metastatic disease was 3 (1-7), 53 pts (30%) received at least 4 lines of treatment. Median (range) number of metastatic sites was: 2 (1-6). 114 patients (55.6%) had died at the cut-off timepoint. Conclusions: YOCR is usually diagnosed with a more advanced stage than standard-onset CRC, with a poorer course of the disease. Further studies in young adults with CRC should address this phenomenon to understand the underlying causes, and prioritize genetic counseling. Our results support the unmet need of initiating screening programs in adults younger than 50 years, the urgency for a global consensus and a call for action.

2597 Background: In order to improve the expected response rate (ORR) of less than 10% in cold tumors, several ICI combinations are being evaluated in clinical trials. However, most of these trials don’t require any biomarker and pts are included based solely in histology. We aimed to assess the benefit of ICI combinations in pts with unselected cold tumors included in early CT. Methods: ICI naïve pts with cold tumors treated from 2015 to 2021 with ICI combinations in early CT at VHIO were reviewed. Clinico-pathological data and anti-tumor activity were extracted from a prospective database. ORR was defined as per RECIST v1.1 and clinical benefit rate (CBR) as complete/partial response (CR/PR) + stable disease (SD) for ≥ 4 months (m). Kaplan Meier estimates of progression-free survival (PFS) and overall survival (OS) were calculated and a Cox model according to LIPI (Lung Immune Prognostic Index = baseline LDH and derived neutrophil to lymphocyte ratio) was constructed. Immune-related adverse events (irAE) were classified as per CTCAE v.4.03. Hyperprogressive disease (HPD) was evaluated using RECIST v1.1 (Matos et al, 2020). Results: Out of 97 pts, median age was 62y, 61% had ECOG 0 and 29.8% had LIPI 0 (good prognostic score). Most pts had microsatellite stable (MSS) colorectal cancer (60.8%) or ovarian cancer (14.4%). Regimens included anti-PD1/L1 + another ICI in 69% (most commonly anti-LAG3 [26,8%] and CD40 agonist [20.9%]), anti-PD1/L1 + other molecule in 21.7% (most commonly SHP2 inhibitor [33.3%] and anti p53-HDM2 [28.5%]) and bispecific antibodies in 9.3% (anti-PD1/L1 + anti-LAG3 or CD137 agonist). No patient achieved a response. CBR was 15.3% (11 pts with MSS colorectal cancer, 2 ovarian cancer, 1 olfactory neuroblastoma, 1 paraganglioma). 33 pts (34%) presented irAE, 15 pts (15.5%) had irAE ≥ G2, 4 pts (4.1%) had G3 irAE (dry mouth, hypertransaminasemia, myocarditis and neutrophils count decreased) and 1 patient (1%) had G4 hyperglicemia. 58 pts (59.7%) had progressive disease (PD) as best response, 19 of these pts (32.7%) presented irAE. Overall, 20 pts (20.6%) met definition of HPD, representing 34.4% of pts with PD as best response. Median PFS for overall and CBR population were 1.9 m (CI95% 1.7-2.0) and 5.9 m (5.4-NR), respectively. Median OS for overall population was 7.6 m (5.9-9.5), with a trend for improved OS if LIPI good score vs. others (12.6 m vs. 6.2 m, hazard ratio 1.9, (CI 95% 1.1-3.3), p = 0.02). Among hyperprogressors, median OS was 5.33 m (3.39 - NR) and significantly worse LIPI scores (intermediate [1] or poor [2]) were observed as compared to pts with CBR (75% vs 53.3% p = 0.001). Conclusions: ICI combinations demonstrated very limited activity in pts with unselected cold tumors. However, the risk for irAE and HPD remain substantial. Further drug-biomarker co-development strategies are urgently needed to increase the risk benefit ratio for these pts.

The customary electrical circuit configuration for estimating mechanical loads with strain gauges uses Wheatstone full- or half-bridges. For each mechanical load to be estimated, a dedicated bridge with two or four gauges has to be mounted, placing the strain gauges in specific configurations along the measured part. In this paper the strain of individual gauges is measured by means of quarter-bridges and all the mechanical loads exerted on a shaft are estimated jointly as different linear combinations of the strains of the gauges. The location of the gauges on the shaft are determined optimally and the influence of apparent strain related to temperature variations is avoided. Results show several configurations of reduced sets of gauges capable of optimally estimating the six components of the mechanical loads exerted on a circular cross-section shaft. The validation of the approach in a dedicated rig has shown the complexity of its experimental implementation.

In this work, a Hopf bifurcation at infinity in three-dimensional symmetric continuous piecewise linear systems with three zones is analyzed. By adapting the so-called closing equations method, which constitutes a suitable technique to detect limit cycles bifurcation in piecewise linear systems, we give for the first time a complete characterization of the existence and stability of the limit cycle of large amplitude that bifurcates from the point at infinity. Analytical expressions for the period and amplitude of the bifurcating limit cycles are obtained. As an application of these results, we study the appearance of a large amplitude limit cycle in a Bonhoeffer–van der Pol oscillator.

3541 Background: So far, no biomarkers of response to anti-angiogenic drugs are available in colorectal cancer (CRC) treatment. Liquid biopsy tracks dynamic mutational changes in CRC patients (pts). RAS mutant allele fraction in plasma (plMAF) is an independent prognostic marker in metastatic CRC (mCRC). We explored the predictive value of plMAF in RAS mutant pts treated in 1st line with chemotherapy +/- bevacizumab (bev). Methods: A multicentric prospective/retrospective analysis was conducted. We collected data from 226 mCRC pts and selected the subset not eligible for metastasis resection with basal plMAF sample evaluable for RAS mutant MAF quantification with digital PCR (BEAMing). Pts were stratified as high (≥ 5.8%) or low ( < 5.8%) plMAF. We investigated associations between clinicopathological variables and progression-free survival (PFS) stratified by plMAF RAS levels using Cox regression models and survival data were calculated by Kaplan-Meier method. Computational analysis of baseline CT scan data extracted 93 radiomics features of all the lesions per patient including 1) 1st class from density histogram distribution and texture analysis by 2) 2nd order and 3) higher order feature classes. The radiomic features distribution between pts with high and low pIMAF was assessed with Student’s t-test analysis. Results: From October 17 to May 19, 63 basal plasma samples were analysed with BEAMing. 42 pts (67.7%) were classified as high and 21 pts (32,3%) as low plMAF. In high plMAF subgroup, a statistically significant longer PFS favouring FOLFOX+bev was observed, compared to FOLFOX alone (10.7 vs 6.9 mts; HR: 0.30; p = 0.002). In low RAS plMAF subgroup, no differences in terms of PFS were observed in either arm (8.9 vs 8.7 mts; HR: 0.7; p = 0.6). Multivariate PFS model showed no association between RAS plMAF and clinicopathological variables, except for high RAS plMAF and treatment benefit with FOLFOX+bev. The CT-radiomics signature, that may translate tumor vascularization, differentiated patients with high vs low pIMAF (p = 0.002). 58 patients (92%) had similar radiomic score; 5 patients with high plMAF (8%) presented very heterogeneous radiomic score distribution. Conclusions: Tumor-borne RAS plMAFs may constitute a potential predictive biomarker of efficacy for anti-angiogenic drugs in mCRC. Next steps will include the identification of -histological, transcriptomic and radiomic- surrogate biomarkers of response that reflect tumor irrigational status.

4112 Background: BRAF V600 mt mCRC is an aggressive disease with poor OS under standard chemotherapy. Treatment with doublet and triplet targeted combinations, such as BRAF inhibitor+ antiEGFR+/- MEK inhibitor, has been shown to improve outcomes. Prognostic factors in this targeted treated population remain to be studied. Methods: Prospective international cohort of patients who received doublet or triplet anti-BRAF combinations in clinical trials or as compassionate use. Univariate Cox models for OS were constructed and the strongest predictors in stepwise variable selection were used to develop a prognostic score. The final multivariate model with selected predictors was stratified by prior lines. Results: In total, 42 patients were enrolled. Median age 60.7 y (33-83), 61% female, 61% right-sided tumors, 26% received 2 or more prior chemotherapy lines. One patient (2.6%) achieved complete response and 36% had partial response with median follow-up of 14.3 months. Median progression-free survival was 5.5 months (CI95% 4.4-10.4) and median OS (mOS) was 10.7 months (CI95% 8.4-22.1). In univariate models, ECOG performance status (1 vs 0), CEA levels (high - > 3.5 ng/mL- vs low - < 3.5 ng/mL), CA 19.9 (high vs. low), LDH (high vs. low), number of metastatic sites and presence of liver metastasis were significant prognostic factors. On the other hand, MSI status and peritoneal or nodal metastasis did not associate with outcome. In multivariable model, strongest determinants of OS were ECOG and baseline CEA levels. If high-risk for both factors (ECOG 1 and CEA high, 46% of the patients), mOS was 5.6 months (CI95% 4.2-NA); if intermediate-risk (either ECOG 1 or CEA high, 33%), mOS was 13.5 months (CI95% 10.6-NA); if low-risk (ECOG 0 and CEA low, 21%), mOS not reached (CI95% 16.5-NA). Differences between intermediate- and high-risk prognostic groups compared to low-risk were significant (HR = 5.9, p = 0.03; and HR = 25.9, p < 0.001, respectively). Conclusions: Patients characteristics such as ECOG and surrogates of tumor burden like CEA levels remain important OS determinants in BRAF V600 mt mCRC treated with doublet or triplet targeted therapy. In fact, there are not prognostic scores regarding BRAF mt mCRC treated with targeted therapies. Our study suggests that these prognostic factors may be considered as stratification factors in future clinical trials.

Introduction Patients who receive or have received anti-programmed cell-death-1 (PD-1) monoclonal antibodies can develop immune-related adverse events due to activation of the immune system. Case presentation We report a case of a patient who received pembrolizumab and presented with cardiac tamponade. Despite pericardial drainage, she persisted with refractory arterial hypotension due to secondary adrenal insufficiency. After initiating corticosteroid therapy, the patient recovered successfully. Discussion The association of pericarditis, hypophysitis and thyroid dysfunction support the diagnosis of a life-threatening immune-related adverse event due to pembrolizumab. In case of immune-related adverse events secondary to anti-PD-1 monoclonal antibodies, corticosteroid therapy should be promptly initiated in order to avoid major complications.

BACKGROUND Trigeminal neuralgia caused by superior cerebellar artery aneurysms (TGN-SCAAs) is a rare event without previous analysis. OBJECTIVE To describe the features of TGN-SCAA based on 8 cases (7 from literature +1 illustrative case). METHODS All cases were thoroughly studied with gathering of their epidemiological, radiological, clinical, therapeutic, and outcome data. RESULTS The mean age at diagnosis was 61 yr. Gender distribution showed a female predominance (M: F = 2:6). Side distribution had a left dominance (75%). The aneurysms mean size was 15.4 mm (range: 5-27). All 5 proximal SCAAs (SCA-Basilar junction) presented a lateral-posterior projection, while all 3 distal SCAAs (s2 segment) had variable projections but constant direct trigeminal nerve (TN) contact. No hemorrhage occurred. TGN was the clinical onset in all 8 cases. The most frequent pain distribution was V1-2-3 (n = 3), followed by V1-2 (n = 1) and V1 alone (n = 1). Proximal SCAAs caused TGN through direct TN compression (n = 1), third nerve compression (n = 1), cavernous sinus compression (n = 1), or a combination thereof (n = 2). However, all distal SCAAs caused TGN by direct TN compression (n = 3). Two different treatment options were used: clipping (n = 4) and coiling (n = 4). The post-treatment Barrow Neurological Institute score for pain control was I in all cases (100%). The mRS score was 0 in 75% of cases. CONCLUSION TGN-SCAAs are infrequent lesions, characterized by large size, variable TGN mechanisms depending on their anatomic location, and mostly affecting the first and second trigeminal divisions. Both SCAA clipping and coiling were used equally, providing good neurological and pain relief results.

Based on the impulsive-dynamics formulation, this article presents the analysis of different strategies to regulate the energy dissipation at the heel-strike event in the context of human locomotion. For this purpose, a seven-link 2D human-like multibody model based on anthropometric data is used. The model captures the most relevant dynamic and energetic aspects of the heel-strike event in the sagittal plane. The pre-impact mechanical state of the system, around which the analysis of the heel impact contribution to energy dissipation is performed, is defined based on published data. In the context of the proposed impulsive-dynamics framework, different realistic strategies that the subject can apply to modify the impact dynamics are proposed and analyzed, namely, the trailing ankle push-off, the torso configuration and the degree of joint blocking in the colliding leg. Detailed numerical analysis and discussions are presented to quantify the effects of the mentioned strategies. Javier Ros gratefully acknowledges the support received from the Spanish Ministry of Education under the 'Salvador de Madariaga' fellowship #PR2009-0259.

This paper presents a new algorithm to obtain the symbolic expressions of any of the possible base inertial parameter sets of a multibody system. Based on the “inertia transfer concept”, a procedure is proposed to write a system of equations from which the base parameters are obtained. This leads to an automatizable and general method to obtain these parameters symbolically. The method can also be used to determine base inertial parameters numerically, and it can be even more straightforward to implement and use than the standard numerical methods. An example is presented to illustrate in detail the application of the algorithm, and to compare its results with those of a standard numerical procedure. The symbolic base inertial parameters can be of interest in symbolic simplification of the dynamic equations for real-time applications, design optimization, dynamic parameter identification, model reduction, and in other fields.

Objetivos: comprender las características de la sociedad de lo humano o sociedad dopo-moderna propuesta por Pierpaolo Donati como marco para la reintroducción del sujeto humano en los procesos sociales superando la dicotomía individuo/sistema.Metodología: estudio de Revisión que aplicó el análisis documental de fuentes y, secundariamente, recurrió a la entrevista en profundidad. Se accedió, además, a fuentes primarias para seleccionar y analizar la información relevante y, dada la magnitud de la obra del autor considerado, se hizo una revisión selectiva de libros y de artículos científicos.Resultados: el concepto de sociedad de lo humano es resultado de la fértil confrontación del paradigma relacional de Donati con el funcionalismo, especialmente el de Luhmann, así como de la respuesta a la modernidad reflexiva y a la posmodernidad. La activación de las nuevas relacionalidades sociales fruto de la creciente complejidad social conlleva la posibilidad de distinguir lo humano de lo no humano en la sociedad y así facilitar la consecución de mayores cotas de humanidad frente a unas dinámicas sociales que parece excluirlas fruto de un modelo lib/lab de estructuración social.Conclusiones: la sociedad de lo humano no es una sociedad distinta de la existente, es resultado de poner en activo en ella la distinción humano/no humano de modo relacional y reflexivo con la consecuencia de hacer evidente y efectiva la posibilidad de prevalencia del sujeto humano frente al contexto o la estructura social. Objective: to understand the characteristics of the humane society or dopo-modern society proposed by Pierpaolo Donati, as a framework for the reintroduction of the human subject into the social processes that overcomes the dichotomy of the individual and system. Methodology: a study review was applied to a documentary analysis of sources and an in-depth interview was conducted. Relevant information was selected and analyzed from the primary sources. A selective review of books and scientific articles was carried out due to the amount of published works from the author. Results: the concept of humane society is the result of the fruitful confrontation of the relational paradigm of Donati and the functionalism approach, especially that of Luhmann, as well as, the response to the reflexive concepts of modernity and postmodernity. The activation of the new social relationships results in increasing social complexity meaning the possibility of differentiating between the humane society from the non-humane society; thus, facilitating the achievement of greater levels of humanity against some social dynamics which seem to exclude them from a Lib-Lab model of social structure. Conclusions: the humane society is no different to that of the existing. It is the result of putting into practice the distinction between human and non-human, a relational and reflexive way of making evident and effective, the possibility of the prevalence of the human subject against the context or social structure. Objetivo: entender as características da sociedade do humano ou sociedade dopo-moderna proposta por Pierpaolo Donati como um quadro para a reintrodução do sujeito humano nos processos sociais superando a dicotomia indivíduo / sistema. Metodologia: estudo de revisão que aplicou a análise documental de fontes e secundariamente, recorreu à entrevista em profundidade. Acedeu-se também a fontes primárias para selecionar e analisar informações relevantes e dada a magnitude da obra do autor considerado, se fez uma revisão seletiva de livros e artigos científicos. Resultados: o conceito de sociedade do humano é o resultado do paradigma relacional de Donati com o funcionalismo, especialmente aquele de Luhmann, assim como a resposta à modernidade reflexiva e pós-modernidade. A ativação das novas relacionalidades sociais, resultado da crescente complexidade social acarreta a possibilidade de distinguir o humano do não- humano na sociedade e assim, facilitar a obtenção de níveis mais elevados da humanidade contra algumas dinâmicas sociais que parece exclui-las, resultado de um modelo lib / lab de estruturação social. Conclusões: a sociedade do humano não é uma sociedade diferente da existente; É o resultado de ativar nela, a distinção humano / não humano de modo relacional e reflexivo, com a consequência de fazer clara e efetiva a possibilidade de prevalência do sujeito humano frente do contexto ou estrutura social. Humanidades

Posterior communicating aneurysms are commonly associated with oculomotor nerve palsy. However, trigeminal nerve involvement among these aneurysms is a rare event with no previous analysis. In order to describe the main features of posterior communicating aneurysms causing trigeminal neuralgia (TGN-PComAAs) eight cases (six from the literature plus two more illustrative cases) were included in the present series. All cases were thoroughly studied in order to collect their epidemiological, radiological, clinical, therapeutic, pathogenic, and outcome data. The mean age at diagnosis was 57 years. Gender distribution showed a female predominance (M-to-F ratio 3:5), while side distribution showed a slight left dominance (62%). The aneurysms mean size was 24.7mm (range: 7-40mm). In 7 cases (87.5%) the PComAA was reported to project posteriorly, associated with cavernous sinus extension/compression in two of them and posterior fossa extension in three. No case presented with hemorrhage. Facial pain was the clinical onset in all eight cases, which was reported as an atypical TGN (continuous with exacerbating fits) in 87.5%. Trigger points were absent in all cases but one (87.5%). The most frequent anatomical distribution of the pain was V2 alone (n=3), followed by V1-2 (n=2) and V1-2-3 (n=2). Three different mechanisms for trigeminal neuralgia were observed, namely, cavernous sinus compression (n=4), direct trigeminal root compression (n=3), and oculomotor nerve compression (n=1). Three different treatment options were performed: surgery (n=6), trigeminal thermo-rhizotomy (n=1) and medical management (n=1). According to the Barrow Neurological Institute (BNI) score the pain control after main treatment was I (no pain with no medication) in 7 cases (87.5%). The average modified Rankin scale (mRS) score was 1. In sum, TGN-PComAAs are infrequent lesions characterized by large size and posterior-medial-inferior projection. They mainly cause atypical TGN, most commonly involving the first and second trigeminal distributions (V1-V2). Surgical aneurysmal clipping has been the most frequent treatment option for these aneurysms, providing good neurological results in a vast majority and complete trigeminal pain relief in all cases.

Arteriovenous malformations of the temporalis muscle (TM-AVMs) are rare lesions commonly considered as a variant of scalp AVMs. A study was designed in order to analyze TM-AVMs features and to confirm them as a certain entity different from scalp AVMs. Seven TM-AVMs cases (5 from literature plus 2 from our database) were studied. Clinical, epidemiological, radiological, and therapeutic data were analyzed and compared to common scalp AVMs features. All TM-AVMs presented as large soft tumor-like masses on the temporal region (mean diameter: 6 cm). Pain was referred in half of cases, while overlying cutaneous stigmas were described only once. No masticatory malfunction was reported. TM-AVMs tend to appear in young patients (mean: 29 yr), commonly as longstanding and slow-evolving lesions (mean evolution time before diagnosis: 5 yr). All cases displayed a diffuse slow-flow blush on angiogram. All TM-AVMs were completely located within the TM, with no involvement of scalp or bone. The pathological analysis of all cases demonstrated the presence of striate muscular bundles intermingled with fairly mature arterial and venous vessels. No clearly distorted vessel was found within the TM-AVMs. Surgery was performed for all cases with complete removal. Preoperative embolization was done in 4 cases to reduce blood loss during surgery. No clinical/radiological recurrence was reported. Opposite to TM-AVMs, scalp AVMs commonly present as high-flow lesions with no evident tumor mass, mainly located in the subcutaneous tissue. TM-AVMs present clearly distinct features compared to scalp AVMs, for which they should be considered as a certain pathological entity and not as a variant of scalp AVMs.

Objectives To demonstrate the surgical clipping of a lateral petrosal tentorial dural arteriovenous fistula (DAVF), located in the cerebellopontine angle (CPA), through a retrosigmoid approach. Method A previously healthy 49-year-old man presented a sudden episode of headache, photophobia, and dizziness. Due to the persistence of his symptoms despite proper analgesic treatment, he sought medical attention. The initial computed tomography (CT) scan showed a hyperdense lesion in the left CPA. Magnetic resonance imaging (MRI) demonstrated the vascular nature of the lesion, corresponding to an engorged superior petrosal vein (SPV) and Rosenthal's vein. The preoperative angiography showed a lateral tentorial DAVF (Lawton's type 5), fed by multiple transpetrous branches coming off the external carotid artery, and draining into the SPV. A standard retrosigmoid approach was planned for clipping and exclusion of the DAVF. Results Through a left retrosigmoid craniotomy the DAVF was approached, along with the different neurovascular structures of the CPA. The DAVF originated at the tentorial petrosal junction. The fistulous vein was closely attached to the trigeminal nerve and the anterior inferior cerebellar artery (AICA). The fistulous vein was dissected and clipped close to its base at the lateral tentorium, achieving complete occlusion of the DAVF. The patient fully recovered after surgery with neither relapse of his symptoms nor postoperative complications. Conclusion The retrosigmoid craniotomy is the best surgical approach for lateral tentorial DAVFs, as it provides a direct way to the fistula origin and permits a successful clipping of the draining vein.The link to the video can be found at: https://youtu.be/Fj3uqrTPX5c.

Background Nutritional status affects survival of pts with HNC. Close to half HNC pts require enteral nutrition, with percutaneous endoscopic gastrostomy (PEG) being the preferred route. We studied whether PEG placement technique and timing impact on HNC pts outcomes. Methods We retrospectively analyzed all HNC pts who underwent PEG insertion between February 2014 and August 2018 at Vall d´Hebron University Hospital. The primary objectives were to assess overall survival (OS) and PEG complication rate in light of nutritional parameters (albumin, cholesterol and PCR) and disease stage (local and locally-advanced [LA] vs recurrent-metastatic [R/M]) when PEG is placed in a prophylactic (P-PEG) or symptomatic (S-PEG) setting with endoscopic or radiologic intervention. Results Out of 125 pts, 52% had LA disease and 48% R/M, 37% had P-PEG, 63% S-PEG [tumor related symptoms (61%), treatment toxicity (30%), nasogastric tube intolerance or dysfunction (6%), and other feeding disorders (3%)]. High albumin and cholesterol levels associated with better of OS [HR = 0.64 (CI 95% 0.42-0.98), p = 0.04 and HR = 0.65 (CI 95% 0.43-0.99), p = 0.04, respectively]. In the R/M setting, no difference in median OS was observed between P-PEG 18.9 months (m) (CI 95% 12.7-45) and S-PEG 15.6 m (CI 95% 11.5-22.2, HR = 0.89, CI 95% 0.57-1.4, p = 0.62). In the LA setting, we found numerically longer median OS in pts with P-PEG 42.2 m (CI 95% 21.9-NA) vs PEG-S 16.2 m (CI 95% 11.5-NA, HR = 0.72, CI 95% 0.37-1.94, p = 0.33). Complication rate was 28% in the P-PEG group vs 30% S-PEG group (p = 0.8). Most common complications included infection 35%, ileus and delayed gastric emptying (22%), and bronchial aspiration (13%). Complications led to treatment interruption in 4 pts (3.2%). Complication rate was lower in LA setting than in R/M setting (24% vs 35%, p = 0.2). Endoscopic PEG placement was associated with less complications (9%) than radiologic placement (47%, p = 0.08). Conclusions We confirmed that nutritional parameters impact on HNC pts OS. In the LA setting, P-PEG might be associated with a better outcome. Endoscopic PEG placement appears to be related to fewer complications. Our results will help design a PEG placement algorithm to further evaluate the role of P-PEG. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Tabernero: Advisory / Consultancy: Arrays Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genentech; Advisory / Consultancy: Inc; Advisory / Consultancy: Genmab A/S; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Imugene Limited; Advisory / Consultancy: Inflection Biosciences Limited; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Kura Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Menarini; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS. E. Felip: Advisory / Consultancy: AbbVie, AstraZeneca, Blue Print Medicines, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Guardant Health, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Janssen; Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Merck KGaA, Merck sharp & dohme, Novartis, Pfizer, Roche, Takeda.; Research grant / Funding (self): Fundacion Merck Salud Grant for Oncology Innovation. R. Dienstmann: Advisory / Consultancy: Roche ; Speaker Bureau / Expert testimony: Roche, Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Research grant / Funding (self): Merck. All other authors have declared no conflicts of interest.

Background Life expectancy longer than 12 weeks(w) is a common inclusion criteria for most Ph1. Despite the presence of several prognostic indeces in drug development, their value for patient selection in clinical trials is not well established. VIO is a immune-oncology score validated in patients treated in Ph1 with immunotherapy (Hierro C. ESMO 2018), which includes 5 variables: albumin upper limit normal, dNLR (derived neutrophil/(leukocytes minus neutrophils) ratio) >3, >2 sites of metastases, and presence of liver metastases. Methods VIO variables were retrospectively collected from 384 patients with advanced disease treated in Ph1 with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) since 2011 to 2017 at Vall d´Hebron Hospital. The following VIO clusters were defined based on Kaplan Meier OS estimates: good prognosis (0‐1), intermediate (2‐3) and poor prognosis (4‐5). We aimed to improve patient selection for Ph1 (independent of treatment type) by developing a composite VIO score that is associated with overall survival (OS), progression free survival (PFS) and objectively estimated life expectancy at 12 w. Results From the 384 patients treated with ICIs (53.6%) or TAs (45.4%) in Ph1, 206 (53.6%) were female, 210 were treated with monotherapy (54.7%). Most frequent tumor types were: colorectal (17.4%), breast (14.1%) and lung (9.4%). The median follow-up was of 8.4 months (m) [IC95% 7.3-9.5]. Estimated median OS in good prognosis (33.3% of all pts), intermediate (54.2%) and poor prognosis (12.5%) was 16.2 m (13.3‐19.1), 7.8 m (6.9‐8.6) and 2.9 m (2.1-3.8), respectively (log rank test, p Conclusions VIO score is a strong prognostic index independent of the treatment type and it could be useful as a tool to estimate objectively life expectancy Legal entity responsible for the study The authors. Funding This research has been funded by the Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) supported by the Banco Bilbao Vizcaya Argentaria Foundation (FBBVA) (grant 89/2017). Disclosure J. Martin-Liberal: Advisory / Consultancy: Bristol-Myers Squibb, Novartis, Pierre Fabre, Roche; Speaker Bureau / Expert testimony: Astellas, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche; Honoraria (self): Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Ipsen. A. Azaro: Honoraria (self), Advisory / Consultancy: Novartis, Roche, Orion. I. Brana: Advisory / Consultancy: Orion pharma; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Merck Serono; Research grant / Funding (self): AstraZeneca, BMS, Celgene, Gliknik, GSK, Janssen, KURA, MSD, Novartis, Northern Biologics, Orion Pharma, Pfizer, Roche.. M. Vieito Villar: Honoraria (self), Travel grant: Roche. E. Munoz-Couselo: Advisory / Consultancy: Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche; Honoraria (self): Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche. E. Elez Fernandez: Honoraria (institution): Array, MSD, Abbvie, Amgen, GSK, AstraZeneca,Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche; Advisory / Consultancy: Hoffman La-Roche, Bristol-Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime; Research grant / Funding (self): Fundacion Merck Salud, Grant for Oncology Innovation EMD Serono.. J. Carles: Research grant / Funding (self): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim Espana, S.A., Bristol-Myers Squibb Inter; Advisory / Consultancy: Bayer / Johnson & Johnson / Bristol-Myers Squibb / Astellas Pharma / Pfizer / Sanofi / MSD Oncology / Roche/ AstraZeneca; Speaker Bureau / Expert testimony: Bayer / Johnson & Johnson / Asofarma / Astellas Pharma. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. R. Dienstmann: Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Roche, Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Research grant / Funding (self): Merck. E. Garralda: Advisory / Consultancy: F.Hoffmann-La Roche,Ellipses Pharma ,Neomed Therapeutics1 Inc,Boehringer Ingelheim ,Janssen Global Services; Speaker Bureau / Expert testimony: Bristol-Mayers Squibb; Honoraria (self): Menarini, Glycotope, Menirarini. All other authors have declared no conflicts of interest.

9071 Background: ICIs have significantly changed the therapeutic landscape of advanced NSCLC. As such, characterizing predictive markers of long-term clinical benefit is a critical objective. TMB quantification using targeted gene panels associates with long-term response to ICIs in NSCLC patients (Rizvi H ASCO 18). Although TMB quantified by targeted NGS correlates with that of WES, caution may be needed when using smaller panels. Methods: Here we analyzed WES of tumors and matched normal tissue from 67 NSCLC patients including 42 treated with ICIs. We correlated TMB with clinico-pathological features and outcomes. TMB was categorized as high vs. low according to the upper quartile of cohort distribution. Results: The median TMB was 2.68 non-synonymous variants (nSNVs)/Mb, ranging from 0 to 15.6 nSNVs/Mb, with upper quartile at 5.42 nSNVs/Mb. TMB was higher for smoker/current smoker (median 3.51) compared to never smokers (median 0.94, p = 0.0048) but no differences were seen in elderly ( > 70 years) vs. young patients or across histologies (squamous, adeno and other) and stages at diagnosis. In patients treated with ICIs, median TMB was 5.44 for those achieving complete response, 3.87 for patients with partial response and 2.42 for patients with progressive disease (PD) (p = 0.04). Moreover, improved clinical outcomes were associated with higher TMB (Table). In patients treated with ICIs, TMB as continuous variable had an impact on progression free survival (PFS) (p = 0.03). Median PFS was 22.3 months (mo) (14-not reached) for those with high TMB and 6.4 mo (3-16) for those with low TMB (HR 0.34, 0.13-0.9, p = 0.03). Median overall survival was not reached for those patients with high TMB and 32 mo (22-43) for those with low TMB (HR 0.29, 0.1-0.86, p = 0.02). Conclusions: High TMB correlates with long-term ICI benefit in NSCLC patients. Mutations in individual genes potentially linked to long-term benefit or resistance to ICIs will be presented. [Table: see text]

4531 Background: Immune-checkpoints inhibitors (ICIs) represents the standard of care for platinum-pretreated advanced urothelial cancer patients (pts). By enhancing T-cell activation, a unique spectrum of inflammatory side effects has emerged, also known as immune-related adverse events (irAEs). Data regarding the association between irAEs and pts outcomes are conflicting. Here we conducted a retrospective analysis to investigate the association between irAEs profile and disease outcome in metastastic urothelial carcinoma (mUC) pts. Methods: Medical records from pts with mUC included in clinical trials between July 2013 and June 2018 and treated with ICIs were reviewed. Pts previously treated with platinum-based chemotherapy or cisplatin ineligible pts who had not been previously treated with chemotherapy were included. Clinical responses were assessed as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to RECIST v1.1. Adverse events were graded based CTCAE v4.03. Overall survival (OS) was calculated from the date of initiation of ICI to the date of death. X2 test was used to determine differences in rates. OS was estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: From a total of 52 pts, 44 (84.6%) were treated with ICI monotherapy and 8 (15.3%) in combination (anti-CTLA4 or targeted therapy). Median age was 65 years, 42 pts (80.8%) were male, 44 patients (84.6%) had ECOG PS 0-1, 14 pts (26.9%) had liver metastasis. Overall irAEs were observed in 30 pts (57.7%) and 10 pts (19.2%) developed grade 3/4 irAES. Most common grade 3/4 irAEs were diarrhea (6.6%), rash (6.6%) and hepatitis (6.6%). Disease control rate (CR [26%]+PR[33%]+SD[20%]) was higher for patients with irAEs compared to those patients who did not developed irAEs (CR [13.6%]+PR[0%]+SD[22.7%], this difference was statically significant (P = 0.002). Median OS was 11.23 mo (CI 95%, 3.76-18.70) for the overall cohort, while median OS was 21.91 mo for those patients with irAEs compared to 6.47 mo in patients who did not developed irAEs (P = 0.004). Conclusions: In this analysis we found that the development of irAEs was a strong predictor of improved OS in mUC patients treated with ICI.

Three-dimensional symmetric piecewise linear differential systems near the conditions corresponding to the fold-Hopf bifurcation for smooth systems are considered. By introducing one small parameter, we study the bifurcation of limit cycles in passing through its critical value, when the three eigenvalues of the linear part at the origin are at the imaginary axis of the complex plane. The simultaneous bifurcation of three limit cycles is proved. Conditions for stability of these limit cycles are provided, and analytical expressions for their period and amplitude are obtained. Finally, we apply the achieved theoretical results to a generalized version of Chua’s circuit, showing that the fold-Hopf bifurcation takes place for a certain range of parameters.

A family of piecewise linear oscillators whose oscillation can be completely characterized by algebraic methods is studied. It represents up to the best of authors's knowledge, the first planar example where all the oscillation properties can be determined for all the values of the bifurcation parameter. In fact, algebraic expressions for coordinates of representative points, period and characteristic multiplier of the corresponding periodic orbit are provided. Thus, the studied family of oscillators deserves to be considered a good benchmark for testing approximate methods of analysis in nonlinear oscillation theory. The piecewise linear oscillators studied are called nodal oscillators, since their relevant linear parts are of node type, and they are not perturbations of the harmonic oscillator. They represent real models in practice, as it is shown for an electronic circuit modeling a piecewise linear version of the classical Van der Pol oscillator.

Operator training is the best way to reduce occupational risks in any type of industrial activity. In the case of forklift driving, good training can prevent accidents that can result in large economic and social costs. This paper presents a forklift simulator developed for the training of forklift drivers and reduction of occupational risks. The simulator is preceded by a thorough study of occupational risks associated with forklift driving, so the virtual environment and the exercises to be performed are designed with the aim of training the operator at risk situations. Two versions of the simulator have been implemented, having a different level of immersion: the first one can be installed on PC platforms and therefore it offers the possibility of having training classrooms. The second one provides an increased level of immersion by a structure of monitors and the use of controls of a real forklift. The simulator is used in forklift driving courses given by the Specific Vocational Training Institute (IEFPS) Miguel Altuna de Bergara and they are approved by Osalan (Basque Institute for Occupational Safety and Health), with a growing demand from they were instaled.

We study a one-parameter family of symmetric piecewise linear differential systems in R 3 which is relevant in control theory. The family, which has some intersection points with the adimensional family of Chua’s circuits, exhibits more than one attractor even when the two matrices defining its dynamics in each zone are stable, in an apparent contradiction to the three-dimensional Kalman’s conjecture. For these systems we characterize algebraically their symmetric periodic orbits and obtain a partial view of the one-parameter unfolding of its triple-zero degeneracy. Having at our disposal exact information about periodic orbits of a family of nonlinear systems, which is rather unusual, the analysis allows us to assess the accuracy of the corresponding harmonic balance predictions. Also, it is shown that certain conditions in Kalman’s conjecture can be violated without losing the global asymptotic stability of the origin.

The authors report the case of a 23-year-old woman with café-au-lait spots and axillary and inguinal freckling who presented with a diploic chronic spontaneous hematoma of the left parietal bone. To the authors' knowledge, this case represents the first description of a diploic hematoma in a patient with stigmata of neurofibromatosis Type 1 unrelated to head trauma. Plain skull radiography showed an osteolytic lesion with well-circumscribed margins, corresponding to the hematoma, together with exuberant perilesional vascular markings. Angiography demonstrated an incidental aneurysm of the left supraclinoidal internal carotid artery and an unusual cortical venous drainage toward the diploic vessels. The blood flow of these vessels on the right hemicranium was sluggish and exhibited enlarged diploic venous lacunas. The authors hypothesize that the hematoma was formed by both an abnormal venous drainage toward the diploic vascular net, together with a vasculopathy that caused stenosis and obstruction of the normal drainage pathways from these vessels.

We present a case report of an early-onset drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) induced by vemurafenib (BRAF inhibitor) in a middle-age man affected by a metastatic, BRAF mutant melanoma who was started on first-line metastatic treatment with vemurafenib and cobimetinib.After initiating the treatment, the patient presented an extensive cutaneous rash with eosinophilia and renal impairment. Due the constellation of signs and symptoms, a diagnosis of DRESS syndrome was made which strongly contraindicated the reintroduction of vemurafenib due to its hypersensibility reaction. Thus, vemurafenib was stopped immediately, and we started corticoid treatment with clinical improvement.Due to the contraindication to start vemurafenib again, after multidisciplinary view of the case and having balanced the risks and benefits, we successfully performed a switch to another BRAF inhibitor in a progressively ascending pattern, without any skin toxicity and with a good response of the metastatic melanoma.

e21541Background: Immunotherapy (iTx) and BRAF targeted therapy (tTx) have radically changed the outcomes of MM pts. However, data on real life use are scant and optimal sequence is unknown. Our ai...

The counter-intuitive appearance of stable periodic orbits in three-dimensional piecewise linear systems has been recently reported for stable saturated control systems with high gain and real triple eigenvalues [Moreno & Suárez 2004]. In this letter using several mathematical tools, the reported sudden phenomenon is explained, and the analysis is completed by providing a global bifurcation diagram of the symmetric periodic orbits. Approximate methods are used only to illustrate the nonlinear behavior with respect to the bifurcation parameter. Analytical methods are employed to rigorously prove the main result. The employed techniques are useful not only for the family studied but also for generic three-dimensional symmetric piecewise linear systems.

Starting from previous analytical results assuring the existence of a saddle-node bifurcation curve of periodic orbits for continuous piecewise linear systems, numerical continuation is done to get some primary bifurcation curves for the piecewise linear Chua's oscillator in certain dimensionless parameter plane. The primary period doubling, homoclinic and saddle-node of periodic orbits' bifurcation curves are computed. A Belyakov point is detected in organizing the connection of these curves. In the parametric region between period-doubling, focus-center-limit cycle and homoclinic bifurcation curves, chaotic attractors coexist with stable nontrivial equilibria. The primary saddle-node bifurcation curve plays a leading role in this coexistence phenomenon.

Accurate robot dynamic models require the estimation and validation of the dynamic parameters through experiments. To this end, when performing the experiments, the system has to be properly excited so that the unknown parameters can be accurately estimated. The experiment design basically consists of optimizing the trajectory executed by the robot during the experiment. Due to the restricted workspace with parallel robots this task is more challenging than for serial robots; thus, this paper is focused on the experiment design aimed at dynamic parameter identification of parallel robots. Moreover, a multicriteria algorithm is proposed in order to reduce the deficiencies derived from the single-criterion optimization. The results of the identification using trajectories based on a single criterion and the multicriteria approaches are compared, showing that the proposed optimization can be considered as a suitable procedure for designing exciting trajectories for parameter identification.

A degeneration in a two-parameter setting for the focus-center-limit cycle bifurcation of symmetric 3D piecewise linear systems with three zones is studied. The analysis gives a rigorous mathematical explanation for the appearance in piecewise linear oscillators of up to two limit cycles along with a related hysteresis phenomenon. A piecewise linear oscillator, which is a member of the generic Chua's circuit family, is shown to exhibit bistability, that is, coexistence of stable oscillations with a stable steady state. Also, the corresponding hysteresis in the appearance of periodic oscillations is explained. The analytical results included in the paper predict accurately the observed behavior.

Increased intra-abdominal pressure has been reported to result in raised intracranial pressure in a variety of conditions such as obesity and pregnancy, and it also constitutes an infrequent cause of ventriculoperitoneal (VP) shunt malfunction. Patients with neurological deficits, as those with myelomeningocele or cerebral palsy, are prone to developing a neurogenic bowel and to suffer chronic constipation. Although previously recognized, VP shunt failure attributed to constipation has only recently been described. We briefly review the etiopathogenesis, diagnosis and management of severe constipation leading to VP shunt malfunction. Our aim is to draw the attention of pediatric neurosurgeons towards severe constipation as a possible cause of VP shunt failure thus avoiding unnecessary surgical valve revisions, to which children with hydrocephalus are often submitted to.We report two children that developed transient VP shunt failure because of intense constipation that caused exacerbation of previously shunted hydrocephalus. One of the patients constitutes the first description of this complication associated with an anteriorly placed anus and the other with intestinal paresis after ileostomy. Conservative treatment aimed at alleviating the increased intra-abdominal pressure resulted in complete resolution of the children's manifestations of VP shunt failure, without having to resort to surgical revision of the VP shunt.

In this paper, a possible degeneration of the focus-center-limit cycle bifurcation for piecewise smooth continuous systems is analyzed. The case of continuous piecewise linear systems with two zones is considered, and the coexistence of two limit cycles for certain values of parameters is justified. Finally, the Chua's circuit is shown to exhibit the analyzed bifurcation. The obtained bifurcation set in the parameter plane is similar to the degenerate Hopf bifurcation for differentiable systems.

We propose for symmetric three-dimensional piecewise linear systems with three zones a unified approach to analyze both Hopf and Hopf-pitchfork bifurcations. For the equilibrium at the origin, the crossing of a complex eigenvalue pair through the imaginary axis of complex plane, with the possible simultaneous crossing of a real eigenvalue, is considered. Some results related to the bifurcation of limit cycles are provided, and an illustrative example is included.

Two patients with intracranial arachnoid cysts, one with myelomeningocele-hydrocephalus and the other with a subdural fluid collection, were given a cerebrospinal (CSF) extracranial shunt. All four patients developed features of CSF overdrainage following shunting and were treated by cranial vault expanding procedures. Before undergoing decompressive craniotomy, the patients were treated by a variety of procedures, including changing of obstructed ventricular catheters (n=4), insertion or upgrading of programmable valves (n=3), and foramen magnum decompression (n=1). Clinical manifestations of these four patients were attributed to craniocerebral disproportion caused by chronic and progressive skull changes due to dampening of the CSF pulse pressure, which is necessary for maintaining normal cranial growth. On the basis of our previous experience with expanding craniotomies in cases of minimal forms of craniosynostosis, we treated these patients with bilateral parietal craniotomies, with satisfactory results. In conclusion, biparietal decompressive craniotomy constitutes a useful and safe procedure for relieving the clinical manifestations of some CSF overdrainage syndromes, especially in cases with slit-ventricle syndrome and craniocerebral disproportion that prove to be refractory to simpler management procedures.

Hydrocephalus associated with intraspinal tumors constitutes a well-documented occurrence. The accepted mechanisms for this association seem to be well established. On the contrary, hydrocephalus in the context of intraspinal dermoids has been rarely recognized and its pathogenetic mechanism appears to be different.The authors report four pediatric cases of spinal dermoid tumors and dermal sinuses that developed hydrocephalus during the evolution of these congenital lesions of ectodermal origin.In two children, the mechanism leading to the development of hydrocephalus consisted of leptomeningeal inflammation due to bacterial meningitis or to spillage of dermoid cyst contents in the cerebrospinal fluid spaces. We hypothesize that ventricular dilatation in the other two might be the result of chemical meningitis occurring during intrauterine life. Two cases developed ventriculomegaly prior to the diagnosis of their spinal cord disease.The unusual evolution of these cases suggests that neuroimaging studies that include the spine should be performed in cases of childhood "unexplained hydrocephalus".

The generic case of three-dimensional continuous piecewise linear systems with two zones is analyzed. From a bounded linear center configuration we prove that the periodic orbit which is tangent to the separation plane becomes a limit cycle under generic conditions. Expressions for the amplitude, period and characteristic multipliers of the bifurcating limit cycle are given. The obtained results are applied to the study of the onset of asymmetric periodic oscillations in Chua's oscillator.

The case of a 14-year-old girl who presented with a 2-week history of raised intracranial pressure is reported. A left frontal extra-axial tumor was totally removed, whose histopathologic diagnosis was rhabdoid meningioma (RM). Rhabdoid meningiomas constitute a special malignant phenotype of meningioma that has been recently included in the WHO classification of tumors of the nervous system. Usually, RMs affect middle-aged and elderly individuals. We report the fourth case of a RM occurring in a child to illustrate that the diagnosis of this tumor subtype, given its prognostic implications, must also be considered in pediatric patients

The birth of limit cycles in 3D (three-dimensional) piecewise linear systems for the relevant case of symmetrical oscillators is considered. A technique already used by the authors in planar systems is extended to cope with 3D systems, where a greater complexity is involved. Under some given nondegeneracy conditions, the corresponding theorem characterizing the bifurcation is stated. In terms of the deviation from the critical value of the bifurcation parameter, expressions in the form of power series for the period, amplitude, and the characteristic multipliers of the bifurcating limit cycle are also obtained. The results are applied to accurately predict the birth of symmetrical periodic oscillations in a 3D electronic circuit genealogically related to the classical Van der Pol oscillator. Ministerio de Ciencia y Tecnología DPI2000-1218-C04-04 Ministerio de Ciencia y Tecnología BFM2001-2668 Ministerio de Ciencia y Tecnología BFM2003-00336 Junta de Andalucía TIC-130

The bifurcation of limit cycles in single-input single-output control systems with saturation is considered. Under some non-degeneracy conditions, a theorem characterizing such bifurcation is stated for the cases of dimension two and three. In terms of the deviation from the critical value of the bifurcation parameter, expressions in form of power series for the period, amplitude and the characteristic multipliers of the bifurcating limit cycle are obtained. These results are similar to the Hopf bifurcation theorem for differentiable systems, but they show some differences coming from the non-smooth character of the saturation characteristic.