SYLVIUS: A multimodal and multidisciplinary platform for epilepsy surgery.

BACKGROUND AND OBJECTIVE: We present SYLVIUS, a software platform intended to facilitate and improve the complex workflow required to diagnose and surgically treat drug-resistant epilepsies. In complex epilepsies, additional invasive information from exploration with stereoencephalography (SEEG) with deep electrodes may be needed, for which the input from different diagnostic methods and clinicians from several specialties is required to ensure diagnostic efficacy and surgical safety. We aim to provide a software platform with optimal data flow among the different stages of epilepsy surgery to provide smooth and integrated decision making. METHODS: The SYLVIUS platform provides a clinical workflow designed to ensure seamless and safe patient data sharing across specialities. It integrates tools for stereo visualization, data registration, transfer of electrode plans referred to distinct datasets, automated postoperative contact segmentation, and novel DWI tractography analysis. Nineteen cases were retrospectively evaluated to track modifications from an initial plan to obtain a final surgical plan, using SYLVIUS. RESULTS: The software was used to modify trajectories in all 19 consulted cases, which were then imported into the robotic system for the surgical intervention. When available, SYLVIUS provided extra multimodal information, which resulted in a greater number of trajectory modifications. CONCLUSIONS: The architecture presented in this paper streamlines epilepsy surgery allowing clinicians to have a digital clinical tool that allows recording of the different stages of the procedure, in a common multimodal 2D/3D setting for participation of different clinicians in defining and validating surgical plans for SEEG cases.

A new aggressive xenograft model of human colon cancer using cancer-associated fibroblasts.

BACKGROUND: Colorectal cancer is the second leading cause of cancer death. Almost half of the patients present recurrence within 5 years after the treatment of the primary tumor, the majority, with metastasis. On the other hand, in the search for new animal models that simulate metastatic cancer, it has been suggested that fibroblasts immersed in the peritumoral stroma (cancer-associated fibroblasts (CAFs)), play a relevant role in the development of cancer. The objective of this study was to identify an adequate animal model to study metastatic colon cancer and the application of new treatments. METHODS: Human CAFs and normal fibroblasts (NF) for transplant and culture were obtained from surgical fresh samples of patients with adenocarcinoma of sigmoid colon. Stromal cell purity was evaluated by morphology and immunostaining with vimentin (VIM) as a fibroblast marker and anti-proColXIα1 as a specific human CAF marker. Phenotypic characterization of cultured stromal cells was performed by co-staining with mesenchymal and epithelial cell markers. For identification in mice, human CAFs were labeled with the PKH26 red fluorescence dye. Cell line HT-29 was used as tumor cells. Transplant in the head of the pancreas of 34 SCID mice was performed in four different groups, as follows: I. 150,000 CAFS (n = 12), IIa. 1.5 million HT29 cells (n = 7), IIb. 150,000 NF+1.5 million HT29 cells (n = 5), III. 150,000 CAFS+1.5 million HT29 cells (n = 10). After euthanasia performed one month later, histological analysis was made using hematoxylin-eosin and anti-proColXIα1. A histopathological score system based on three features (tumor volume, desmoplasia and number of metastasized organs) was established to compare the tumor severity. RESULTS: The CAFs and NF cultured were proColXIα1+/VIM+, proColXIα1/alphaSMA+ and proColXIα1+/CK19+ in different proportions without differences among them, but the CAFs growth curve was significantly larger than that of the NF (p < 0.05). No tumor developed in those animals that only received CAFs. When comparing group II (a + b) vs. group III, both groups showed 100% hepatic metastases. Median hepatic nodules, tumor burden, lung metastases and severity score were bigger in group III vs group II (a + b), although without being significant, except in the case of the median tumor volume, that was significantly higher in group III (154.8 (76.9-563.2) mm3) vs group II (46.7 (3.7-239.6) mm3), p = 0.04. A correlation was observed between the size of the tumor developed in the pancreas and the metastatic tumor burden in the liver and with the severity score. CONCLUSION: Our experiments demonstrate that cultured CAFs have a higher growth than NF and that when human CAFs are associated to human tumor cells, larger tumors with liver and lung metastases are generated than if only colon cancer cells with/without NF are transplanted. This emphasizes the importance of the tumor stroma, and especially the CAFs, in the development of cancer.

Response to chemoradiotherapy and lymph node involvement in locally advanced rectal cancer.

AIM: To establish the association between lymph node involvement and the response to neoadjuvant therapy in locally advanced rectal cancer. METHODS: Data of 130 patients with mid and low locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation followed by radical surgery over a 5-year period were reviewed. Tumor staging was done by endorectal ultrasound and/or magnetic resonance imaging. Tumor response to neoadjuvant therapy was determined by T-downstaging and tumor regression grading (TRG). Pathologic complete response (pCR) is defined as the absence of tumor cells in the surgical specimen (ypT0N0). The varying degrees TRG were classified according to Mandard's scoring system. The evaluation of the response is based on the comparison between previous clinico-radiological staging and the results of pathological evaluation. χ (2) and Spearman's correlation tests were used for the comparison of variables. RESULTS: Pathologic complete response (pCR, ypT0N0, TRG1) was observed in 19 cases (14.6%), and other 18 (13.8%) had only very few residual malignant cells in the rectal wall (TRG2). T-downstaging was found in 63 (48.5%). Mean lymph node retrieval was 9.4 (range 0-38). In 37 cases (28.5%) more than 12 nodes were identified in the surgical specimen. Preoperative lymph node involvement was seen in 77 patients (59.2%), 71 N1 and 6 N2. Postoperative lymph node involvement was observed in 41 patients (31.5%), 29 N1 and 12 N2, while the remaining 89 were N0 (68.5%). In relation to ypT stage, we found nodal involvement of 9.4% in ypT0-1, 22.2% in ypT2 and 43.7% in ypT3-4. Of the 37 patients considered "responders" to neoadjuvant therapy (TRG1 and 2), there were only 4 N+ (10.8%) and the remainder N0 (89.2%). In the "non responders" group (TRG 3, 4 and 5), 37 cases were N+ (39.8%) and 56 (60.2%) were N0 (P < 0.001). CONCLUSION: Response to neoadjuvant chemoradiation in rectal cancer is associated with lymph node involvement.

Computation of the change in length of a braided device when deployed in realistic vessel models.

PURPOSE: An important issue in the deployment of braided stents, such as flow diverters, is the change in length, also known as foreshortening, underwent by the device when is released from the catheter into a blood vessel. The position of the distal end is controlled by the interventionist, but knowing a priori the position of the proximal end of the device is not trivial. In this work, we assess and validate a novel computer method to predict the length that a braided stent will adopt inside a silicon model of an anatomically accurate vessel. METHODS: Three-dimensional rotational angiography images of aneurysmatic patients were used to generate surface models of the vessels (3D meshes) and then create accurate silicon models from them. A braided stent was deployed into each silicon model to measure its length. The same stents deployed on the silicon models were virtually deployed on the 3D meshes using the method being evaluated. RESULTS: The method was applied to five stent placements on three different silicon models. The length adopted by the real braided device in the silicon models varies between 15 and 30% from the stent length specified by the manufacturer. The final length predicted by the method was within the estimated error of the measured real stent length. CONCLUSIONS: The method provides, in a few seconds, the length of a braided stent deployed inside a vessel, showing an accurate estimation of the final length for the cases studied. This technique could provide useful information for planning the intervention and improve endovascular treatment of intracranial aneurysms in the future.

COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human invasive carcinoma-associated stromal cells and carcinoma progression.

The COL11A1 human gene codes for the α1 chain of procollagen 11A1 and mature collagen 11A1, an extracellular minor fibrillar collagen. Under regular conditions, this gene and its derived products are mainly expressed by chondrocytes and mesenchymal stem cells as well as osteoblasts. Normal epithelial cells and quiescent fibroblasts from diverse locations do not express them. Mesenchyme-derived tumors and related conditions, such as scleroderma and keloids, are positive for COL11A1/(pro)collagen 11A1 expression, as well as high-grade human gliomas/glioblastomas. This expression is almost absent in benign pathological processes such as breast hyperplasia, sclerosing adenosis, idiopathic pulmonary fibrosis, cirrhosis, pancreatitis, diverticulitis, and inflammatory bowel disease. By contrast, COL11A1/(pro)collagen 11A1 is highly expressed by activated stromal cells of the desmoplastic reaction of different human invasive carcinomas, and this expression is correlated with carcinoma aggressiveness and progression, and lymph node metastasis. COL11A1 upregulation has been shown to be associated to TGF-ß1, Wnt, and Hh signaling pathways, which are especially active in cancer-associated stromal cells. At the front of invasive carcinomas, neoplastic epithelial cells, putatively undergoing epithelial-to-mesenchymal transition, and carcinoma-derived cells with highly metastatic capabilities, can express COL11A1. Thus, in established metastases, the expression of COL11A1/(pro)collagen 11A1 could rely on both the metastatic epithelial cells and/or the accompanying activated stromal cells. COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human carcinoma-associated stromal cells and carcinoma progression.

Predictive markers of response to neoadjuvant therapy in rectal cancer.

BACKGROUND: Neoadjuvant therapy followed by radical surgery is the standard treatment in locally advanced rectal cancer. It is important to predict the response because the treatment has side effects and is costly. The aim of this study was to establish the relationship among clinical, pathologic, and molecular biomarkers and the response to neoadjuvant therapy. METHOD: A total of 130 patients with locally advanced mid and low rectal cancer who underwent long-course radiotherapy with 5-FU based chemotherapy followed by radical surgical resection were included in the study. Clinical and pathologic data were collected. Paraffin-embedded sections obtained in diagnostic biopsies were assessed by immunohistochemical staining for molecular markers and classified using a semiquantitative method. Results were related with T-downstaging and tumor regression grade using Mandard scoring system on surgical specimens. RESULTS: Pathologic complete response was found in 19 patients (14.6%), while in another 18 (13.8%) only minor residual disease was seen in the rectal wall. T-downstaging was observed in 63 (48.5%). The average of lymph node retrieval in the surgical specimens was 9.4. Regarding predictive markers of response, there was significant correlation between the expression of B-cell lymphoma 2 (P = 0.005), ß-catenin (P = 0.03), vascular endothelial growth factor (P = 0.048) and apoptotic protease activating factor 1 (P = 0.03), tumor differentiation grade (P < 0.001), and response in the univariate analysis. T-downstaging was associated with vascular endothelial growth factor expression (P = 0.03) and tumor differentiation grade (P < 0.001). Significant parameters found in the multivariate analysis were tumor differentiation grade and Bcl-2 expression. CONCLUSIONS: Pathologic and molecular biomarkers in the diagnostic biopsies may help us predict tumor response to chemoradiation in rectal cancer patients.

A three-dimensional computer-based perspective of the skull base.

OBJECTIVE: To describe our designed protocol for the reconstruction of three-dimensional (3D) models applied to various endoscopic endonasal approaches that allows performing a 3D virtual dissection of the desired approach and analyzing and quantifying critical surgical landmarks. METHODS: All human cadaveric heads were dissected at the Laboratory of Surgical Neuroanatomy of the University of Barcelona. The dissection anatomic protocol was designed as follows: 1) virtual surgery simulation systems, 2) navigated cadaver dissection, and 3) postdissection analysis and quantification of data. RESULTS: The virtual dissection of the selected approach, the preliminary exploration of each specimen, the real dissection laboratory experience, and the analysis of data retrieved during the dissection step provide a complete method to improve general knowledge of the main endoscopic endonasal approaches to the skull base, at the same time allowing the development of new surgical techniques. CONCLUSIONS: The methodology for surgical training in the anatomic laboratory described in this article has proven to be very effective, producing a depiction of anatomic landmarks as well as 3D visual feedback that improves the study, design, and execution in various neurosurgical approaches. The Dextroscope as a virtual surgery simulation system can be used as a preoperative planning tool that can allow the neurosurgeon to perceive, practice reasoning, and manipulate 3D representations using the transsphenoidal perspective acquiring specifically visual information for endoscopic endonasal approaches to the skull base. The Dextroscope also can be used as an advanced tool for analytic purposes to perform different types of measurements between surgical landmarks before, during, and after dissection.

Validation of COL11A1/procollagen 11A1 expression in TGF-ß1-activated immortalised human mesenchymal cells and in stromal cells of human colon adenocarcinoma.

BACKGROUND: The human COL11A1 gene has been shown to be up-regulated in stromal cells of colorectal tumours, but, so far, the immunodetection of procollagen 11A1, the primary protein product of COL11A1, has not been studied in detail in human colon adenocarcinomas. Some cancer-associated stromal cells seem to be derived from bone marrow mesenchymal cells; the expression of the COL11A1 gene and the parallel immunodetection of procollagen 11A1 have not been evaluated in these latter cells, either. METHODS: We used quantitative RT-PCR and/or immunocytochemistry to study the expression of DES/desmin, VIM/vimentin, ACTA2/αSMA (alpha smooth muscle actin) and COL11A1/procollagen 11A1 in HCT 116 human colorectal adenocarcinoma cells, in immortalised human bone marrow mesenchymal cells and in human colon adenocarcinoma-derived cultured stromal cells. The immunodetection of procollagen 11A1 was performed with the new recently described DMTX1/1E8.33 mouse monoclonal antibody. Human colon adenocarcinomas and non-malignant colon tissues were evaluated by immunohistochemistry as well. Statistical associations were sought between anti-procollagen 11A1 immunoscoring and patient clinicopathological features. RESULTS: Procollagen 11A1 was immunodetected in human bone marrow mesenchymal cells and in human colon adenocarcinoma-associated spindle-shaped stromal cells but not in colon epithelial or stromal cells of the normal colon. This immunodetection paralleled, in both kinds of cells, that of the other mesenchymal-related biomarkers studied: vimentin and alpha smooth muscle actin, but not desmin. Thus, procollagen 11A1(+) adenocarcinoma-associated stromal cells are similar to "activated myofibroblasts". In the series of human colon adenocarcinomas here studied, a high procollagen 11A1 expression was associated with nodal involvement (p = 0.05), the development of distant metastases (p = 0.017), and advanced Dukes stages (p = 0.047). CONCLUSION: The immunodetection of procollagen 11A1 in cancer-associated stromal cells could be a useful biomarker for human colon adenocarcinoma characterisation.

A novel bidirectional continuous perfusion bioreactor for the culture of large-sized bone tissue-engineered constructs.

This works reports the development and preliminary assessment of a new bioreactor for culturing large-sized three-dimensional constructs in bone tissue engineering. The bidirectional continuous perfusion bioreactor (BCPB) promotes mechanical stimulation of cells through the creation of shear forces induced by flow perfusion. The main innovation consists in the possibility of culturing scaffolds of large dimensions that can be suitable for the regeneration of critical sized defects. The functionality of BCPB was preliminarily evaluated by culturing starch-polycaprolactone scaffolds/goat bone marrow stromal cells for 14 and 21 days. Cylindrical blocks were stacked (42 mm thick). Static culture was used as controls. The samples were collected for DNA, alkaline phosphatase (ALP), scanning electron microscopy (SEM), and histological analysis. The results showed higher ALP levels in the bioreactor cultures than those obtained under static conditions. The number of cells in constructs cultured in the bioreactor showed lower values compared to static cultures, suggesting that static conditions tend to privilege the metabolic path way for cellular proliferation while dynamic conditions tend to privilege the metabolic path for osteogenic differentiation. SEM observations show that, the migration and cell distribution was observed in the bioreactor. These results demonstrate the feasibility and the benefit of culturing constructs in BCPB.

Image-guided neurosurgery with 3-dimensional multimodal imaging data on a stereoscopic monitor.

BACKGROUND: In the past 2 decades, intraoperative navigation technology has changed preoperative and intraoperative strategies and methodology tremendously. OBJECTIVE: To report our first experiences with a stereoscopic navigation system based on multimodality-derived, patient-specific 3-dimensional (3-D) information displayed on a stereoscopic monitor and controlled by a virtual user interface. METHODS: For the planning of each case, a 3-D multimodality model was created on the Dextroscope. The 3-D model was transferred to a console in the operating room that was running Dextroscope-compatible software and included a stereoscopic LCD (liquid crystal display) monitor (DexVue). Surgery was carried out with a standard frameless navigation system (VectorVision, BrainLAB) that was linked to DexVue. Making use of the navigational space coordinates provided by the VectorVision system during surgery, we coregistered the patient's 3-D model with the actual patient in the operating room. The 3-D model could then be displayed as seen along the axis of a handheld probe or the microscope view. The DexVue data were viewed with polarizing glasses and operated via a 3-D interface controlled by a cordless mouse containing inertial sensors. The navigational value of DexVue was evaluated postoperatively with a questionnaire. A total of 39 evaluations of 21 procedures were available. RESULTS: In all 21 cases, the connection of VectorVision with DexVue worked reliably, and consistent spatial concordance of the navigational information was displayed on both systems. The questionnaires showed that in all cases the stereoscopic 3-D data were preferred for navigation. In 38 of 39 evaluations, the spatial orientation provided by the DexVue system was regarded as an improvement. In no case was there worsened spatial orientation. CONCLUSION: We consider navigating primarily with stereoscopic, 3-D multimodality data an improvement over navigating with image planes, and we believe that this technology enables a more intuitive intraoperative interpretation of the displayed navigational information and hence an easier surgical implementation of the preoperative plan.

Characterization of a novel mouse monoclonal antibody, clone 1E8.33, highly specific for human procollagen 11A1, a tumor-associated stromal component.

A novel IgG1, κ mouse monoclonal antibody (clone 1E8.33) to human procollagen 11A1 has been generated. This antibody is poorly mutated, essentially in germ line configuration; its complementarity determining regions (CDRs) are especially rich in tyrosine and serine residues. The epitope recognized is encompassed in the YNYGTMESYQTEAPR amino acid stretch within the variable region of human procollagen 11A1. Human procollagens 5A1 and 11A1 are very similar. However, this antibody does not cross-react with human procollagen 5A1. In human breast tumors, only the activated peritumoral myofibroblasts show a strong intracytoplasmic staining with this antibody. As procollagen 11A1 is overexpressed in the stroma of human tumors with desmoplastic reaction, this antibody represents a valuable tool for diagnostic purposes.

Glucagonoma syndrome: a case report.

INTRODUCTION: Glucagonoma syndrome is a rare paraneoplastic phenomenon, with an estimated incidence of one in 20 million, characterized by necrolytic migratory erythema, hyperglucagonemia, diabetes mellitus, anemia, weight loss, glossitis, cheilitis, steatorrhea, diarrhea, venous thrombosis and neuropsychiatric disturbances in the setting of a glucagon-producing alpha-cell tumor of the pancreas. Necrolytic migratory erythema is the presenting manifestation in the majority of cases, so its early suspicion and correct diagnosis is a key factor in the management of the patient. CASE PRESENTATION: We present the case of a 70-year-old Caucasian woman with glucagonoma syndrome due to an alpha-cell tumor located in the tail of the pancreas, successfully treated with surgical resection. CONCLUSION: Clinicians should be aware of the unusual initial manifestations of glucagonoma. Early diagnosis allows complete surgical resection of the neoplasm and provides the only chance of a cure.

Neurosurgical craniotomy localization using a virtual reality planning system versus intraoperative image-guided navigation.

PURPOSE: Accurate craniotomy placement is essential for frameless neuronavigation in minimally invasive neurosurgery. A craniotomy using virtual reality (VR) can be as accurate as neuronavigation. METHODS: We prospectively enrolled 48 patients that underwent minimally invasive cranial procedures planned using VR, followed by neuronavigation. First, craniotomies were planned using VR derived measurements. Second, frameless neuronavigation was applied to define the craniotomy. The locations of these paired craniotomies were compared. A correctly placed craniotomy was defined as one that enabled the surgeon to totally remove the pathology without need to enlarge the craniotomy intraoperatively. RESULTS: Using VR, the size and the position of the craniotomy were measured correctly in 47 of 48 cases (98%). In 44 of 48 cases (92%), neuronavigation identified the craniotomy site correctly. In cases where neuronavigation failed, minimally invasive surgery was successfully completed using preoperative VR surgery planning. No statistically significant difference was found between craniotomy localization using VR surgery planning or standard frameless neuronavigation (p = 0.36). CONCLUSION: The craniotomy for minimally invasive neurosurgical procedures can be identified accurately using VR surgery planning or neuronavigation. In cases of neuronavigation failure, VR surgery planning serves as an effective backup system to perform a minimally invasive operation.

Dex-ray: augmented reality neurosurgical navigation with a handheld video probe.

OBJECTIVE: We developed an augmented reality system that enables intraoperative image guidance by using 3-dimensional (3D) graphics overlaid on a video stream. We call this system DEX-Ray and report on its development and the initial intraoperative experience in 12 cases. METHODS: DEX-Ray consists of a tracked handheld probe that integrates a lipstick-size video camera. The camera looks over the probe's tip into the surgical field. The camera's video stream is augmented with coregistered, multimodality 3D graphics and landmarks obtained during neurosurgical planning with 3D workstations. The handheld probe functions as a navigation device to view and point and as an interaction device to adjust the 3D graphics. We tested the system's accuracy in the laboratory and evaluated it intraoperatively with a series of tumor and vascular cases. RESULTS: DEX-Ray provided accurate and real-time video-based augmented reality display. The system could be seamlessly integrated into the surgical workflow. The see-through effect revealing 3D information below the surgically exposed surface proved to be of significant value, especially during the macroscopic phase of an operation, providing easily understandable structural navigational information. Navigation in deep and narrow surgical corridors was limited by the camera resolution and light sensitivity. CONCLUSION: The system was perceived as an improved navigational experience because the augmented see-through effect allowed direct understanding of the surgical anatomy beyond the visible surface and direct guidance toward surgical targets.

Contouring in 2D while viewing stereoscopic 3D volumes.

The ability to manually specify contours in a volumetric data is often required in situations when automatic algorithms are unable to accurately extract the desire volume. Conventionally, the contours are drawn over a slice, working on plane-by-plane basis usually constrained to orthogonal planes. In defining the contour on a 2D image, the user faces the problem of loosing 3D context (does the tissue belong to inside the contour or outside?). This requires the constant back and forth movement from a plane view where the interaction takes place (usually with the mouse) to the 3D volumetric view that provides the contextual information. We present an interactive environment that allows for efficient contouring while providing contextual 3D information to the user.

A cytological study of the O5 chromosomal inversion of Drosophila subobscura (Diptera, Drosophilidae)

The O5 chromosomal inversion has been a cornerstone for understanding different aspects of the American colonization by Drosophila subobscura. To obtain more information of this evolutionary event it is important to know the pattern of bands of this inversion in detail. Comparing this pattern with that of D. melanogaster it is possible to predict which genes are located inside or close to the O5 inversion and use them as genetic markers. In this study, the complete band pattern of the O5 inversion is presented. Furthermore, the most important genes located inside it have been predicted. Finally, a constriction located close to the proximal breakage point of the O5 inversion has been observed many times and its possible genetic significance is discussed

The DextroBeam: a stereoscopic presentation system for volumetric medical data.

This paper describes an interaction system called the DextroBeam designed for manipulating objects in 3D space while looking at a 3D stereoscopic display located in front of the user. Three-dimensional interaction is two-handed and is achieved by means of a stylus with a single button or switch. We have been planning several neurosurgical cases with the DextroBeam, including the separation of Nepalese Siamese twins in April 2001, and have conducted a course on surgery of the Temporal Bone (as part of the 9th ASEAN ORL Head and Neck Congress in Singapore, March 2001).

Métodos psicofísicos no glaucoma: contribuiçäo do estudo da sensibilidade ao contraste / Psychophysic methods in glaucoma: a contribution to the study of contrast sensitivity

Os autores usaram as tábuas de contraste de Arden no estudo de doentes portadores de hipertençäo ocular näo acompanhada de outros sinais conclusivos de glaucoma e também no controle de doentes glaucomatosos. Tiraram algumas conclusöes a cerca do interesse clínico deste método usado em associaçäo a outros exames psico-físicos tais como a campimetria e o estudo da visäo cromática