Beyond image defined risk factors (IDRFs): a delphi survey highlighting definition of the surgical complexity index (SCI) in neuroblastoma.

PURPOSE: Preoperative evaluation of Image Defined Risk Factors (IDRFs) in neuroblastoma (NB) is crucial for determining suitability for upfront resection or tumor biopsy. IDRFs do not all carry the same weighting in predicting tumor complexity and surgical risk. In this study we aimed to assess and categorize a surgical complexity (Surgical Complexity Index, SCI) in NB resection. METHODS: A panel of 15 surgeons was involved in an electronic Delphi consensus survey to identify and score a set of shared items predictive and/or indicative of surgical complexity, including the number of preoperative IDRFs. A shared agreement included the achievement of at least 75% consensus focused on a single or two close risk categories. RESULTS: After 3 Delphi rounds, agreement was established on 25/27 items (92.6%). A severity score was established for each item ranging from 0 to 3 with an overall SCI range varying from a minimum score of zero to a maximum score of 29 points for any given patient. CONCLUSIONS: A consensus on a SCI to stratify the risks related to neuroblastoma tumor resection was established by the panel experts. This index will now be deployed to critically assign a better severity score to IDRFs involved in NB surgery.

Impacto de la presentación tardía al servicio de Urgencias por cólico renal agudo en los resultados bioquímicos y clínicos / Impact of a delayed presentation to the emergency department for acute renal colic on biochemical and clinical outcomes

Introducción y objetivo Verificar el impacto en los resultados bioquímicos y clínicos de la demora en acudir al servicio de Urgencias (SU) ante un cólico renal agudo. Materiales y métodos Los datos se recogieron retrospectivamente en 3 instituciones de 2 países europeos, desde el 1 de enero hasta el 30 de abril del 2020. Se incluyó a los pacientes que acudieron a Urgencias con un cólico renal unilateral o bilateral causado por urolitiasis confirmada por imagen durante el periodo de estudio. La consulta en el SU después de 24 h desde el inicio de los síntomas se consideró tardía. Los pacientes que acudieron antes de las 24 h desde el inicio de los síntomas se incluyeron en el grupo A y los pacientes que se presentaron después de las 24 h se adjudicaron al grupo B. Se compararon los parámetros clínicos y bioquímicos, así como el manejo recibido por cada paciente. Resultados Se analizó a 397 pacientes que acudieron a Urgencias con urolitiasis confirmada (grupo A, n = 199; grupo B, n = 198). La mediana (RIC) de demora hasta la consulta fue de 2 días (1,5-4). En el momento de la consulta, no se encontraron diferencias estadísticamente significativas entre los 2 grupos de pacientes en cuanto a los síntomas como fiebre y dolor en el flanco, o la mediana de los niveles séricos de creatinina, proteína C reactiva y leucocitos. No se encontraron diferencias en cuanto al tratamiento conservador o quirúrgico. Conclusiones La demora > 24 h hasta acudir al SU no se asocia a un empeoramiento de los parámetros bioquímicos ni de los resultados clínicos. La mayoría de los pacientes con dolor lumbar agudo no siempre necesitan acudir de forma inmediata a urgencias, pudiendo ser tratados en consultas externas (AU)

Introduction and objective To verify the impact of delay on biochemical and clinical outcomes for patients presenting to the emergency department (ED) with acute renal colic. Materials and methods Data were retrospectively collected from 3 institutions of 2 European countries between 01 January and 30 April 2020. Patients who presented to the ED with unilateral or bilateral renal colic caused by urolithiasis confirmed by imaging tests during the study period were included. A presentation after 24 hours since the onset of symptoms was considered a delay. Patients presenting before 24 hours from the symptom onset were included in Group A, while the patients presenting after 24 hours in Group B. Clinical and biochemical parameters and management were compared. Results 397 patients who presented to ED with confirmed urolithiasis were analyzed (Group A, n = 199; Group B, n = 198. The median (IQR) delay in presentation was 2 days (1,5-4). At presentation, no statistically significant differences were found amongst the 2 groups of patients regarding presenting symptoms such as fever and flank pain, and the median serum levels of creatinine, C reactive protein and white blood cells. No differences were found in terms of conservative or operative management. Conclusions Delay in consultation >24 hours is not associated with worsening biochemical parameters and clinical outcomes. Most patients with acute loin pain do not necessarily need urgent attendance to the ED and may be managed in the outpatients (AU)

Impact of a delayed presentation to the emergency department for acute renal colic on biochemical and clinical outcomes.

INTRODUCTION AND OBJECTIVE: To verify the impact of delay on biochemical and clinical outcomes for patients presenting to the emergency department (ED) with acute renal colic. MATERIALS AND METHODS: Data were retrospectively collected from three institutions of two European countries between 01 January and 30 April 2020. Patients who presented to the ED with unilateral or bilateral renal colic caused by urolithiasis confirmed by imaging tests during the study period were included. A presentation after 24 h since the onset of symptoms was considered a delay. Patients presenting before 24 h from the symptom onset were included in Group A, while the patients presenting after 24 h in Group B. Clinical and biochemical parameters and management were compared. RESULTS: A total of 397 patients who presented to ED with confirmed urolithiasis were analyzed (Group A, n = 199; Group B, n = 198. The median (IQR) delay in presentation was 2 days (1,5-4). At presentation, no statistically significant differences were found amongst the two groups of patients regarding presenting symptoms such as fever and flank pain, and the median serum levels of creatinine, C reactive protein and white blood cells. No differences were found in terms of conservative or operative management. CONCLUSION: Delay in consultation >24 h is not associated with worsening biochemical parameters and clinical outcomes. Most patients with acute loin pain do not necessarily need urgent attendance to the ED and may be managed in the outpatients.

Comparison of fetal and neonatal sonographic measurements of ventricular size in second- and third-trimester fetuses with or without ventriculomegaly: cross-sectional three-dimensional ultrasound study.

OBJECTIVES: To assess, in a population comprising normal fetuses and fetuses with primary or post-hemorrhagic ventriculomegaly, the reproducibility of measurement of neonatal ultrasound indices in the fetus and to compare the performance of various cut-offs of these parameters to diagnose ventriculomegaly and classify its severity. METHODS: This was a retrospective cross-sectional study including 182 singleton fetuses assessed by transvaginal neurosonography. The sample populations included 116 normal fetuses and 66 fetuses with primary (n = 56) or post-hemorrhagic (n = 10) ventriculomegaly. In all cases, the atrial width (AW) was measured according to standard protocols and the findings were compared with four sonographic indices developed in the neonate: the anterior horn width (AHW), the ventricular index (VI), the thalamo-occipital distance (TOD) and the fronto-occipital horn ratio (FOHR). Reproducibility of measurements was assessed using the intraclass correlation coefficient (ICC) and diagnostic accuracy of the neonatal indices was assessed against AW using areas under the receiver-operating-characteristics curves (AUC). RESULTS: The intra- and interoperator reproducibility of measurement of AW and the neonatal measurements was excellent, with ICCs > 0.99 for all measures. The association in the fetus of all four variables developed in the neonate with the degree of ventriculomegaly as defined by the AW was strong for severe ventriculomegaly (AW > 15.0 mm; all AUC > 0.95), whereas the separation of cases with mild ventriculomegaly (AW, 10.0-15.0 mm) from those with normal AW (< 10.0 mm) was less effective. CONCLUSIONS: When applied in the fetus, all four indices of ventriculomegaly developed in neonates (AHW, VI, TOD, FOHR) were associated strongly with fetal AW when the AW measurement indicated severe fetal ventriculomegaly. However, for mild ventriculomegaly, the association was weaker, probably due to the fact that, in the fetus, mild ventriculomegaly is not caused by obstruction of the ventricular system. Considering the similar performance of the four neonatal variables and the technical issues involved in determination of TOD and FOHR in the fetus, use of VI and AHW is preferred. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Frontal lobe growth is impaired in fetuses with congenital heart disease.

OBJECTIVES: The primary objective of this study was to assess whether fetuses with congenital heart disease (CHD) have smaller frontal brain areas compared with normal controls. The secondary objective was to evaluate whether there are any differences in frontal brain area between cases with different types of CHD, grouped according to their impact on hemodynamics. METHODS: This was a retrospective cross-sectional study, including 421 normal fetuses and 101 fetuses with isolated CHD evaluated between 20 and 39 gestational weeks at our fetal medicine and surgery unit in the period January 2016-December 2019. The study group was subdivided, according to the CHD hemodynamics, as follows: (1) hypoplastic left heart syndrome and other forms of functionally univentricular heart defect; (2) transposition of the great arteries; (3) conotruncal defects and other CHDs with large shunts; (4) right ventricular outflow tract obstruction, without a hypoplastic right ventricle; (5) left outflow tract obstruction; (6) others. The transventricular axial view of the fetal head was used as the reference view, on which the frontal lobe anteroposterior diameter (FAPD) and the occipitofrontal diameter (OFD) were measured, assuming the former to be representative of the area of the frontal lobes. The FAPD/OFD ratio was then calculated as FAPD/OFD × 100. These two variables (FAPD and FAPD/OFD ratio) were then evaluated and compared between the study and control groups. Adjustment for gestational age, both via multiple linear regression and by using a-posteriori matching based on the propensity score, was employed. RESULTS: In normal fetuses, FAPD showed a linear positive correlation with gestational age. In fetuses with CHD, the FAPD was shorter than in normal fetuses from the 20th gestational week onwards, with the difference increasing after 30 gestational weeks. FAPD/OFD ratio was significantly smaller in fetuses with CHD than in normal fetuses (P < 0.0001) at all gestational ages, with no apparent differences among the various CHD categories, all of which had smaller FAPD/OFD ratio compared with controls. CONCLUSIONS: Fetuses with CHD have a shorter FAPD and a smaller FAPD/OFD ratio compared with normal fetuses. This impaired growth of the frontal area of the brain seems to occur in all types of CHD, regardless of their impact on hemodynamics. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Evaluación de las tendencias y presentación clínica de pacientes con cólico nefrítico que acuden al servicio de urgencias durante la era pandémica del COVID-19 / Assessment of trends and clinical presentation in the emergency department of patients with renal colic during the COVID-19 pandemic era

INTRODUCCIÓN: Nuestra hipótesis es que la pandemia por COVID-19, y el estado de alarma impuesto por los gobiernos, pueden haber retrasado las visitas a urgencias por cólicos nefríticos, debido al miedo a contagiarse en los centros sanitarios. Este atraso en acudir a los servicios de urgencias puede llevar a un empeoramiento clínico y aumentar las complicaciones relacionadas con la enfermedad o el tratamiento recibido. MATERIAL Y MÉTODOS: Realizamos una revisión retrospectiva de 3 centros hospitalarios en España e Italia. Fueron incluidos pacientes atendidos en el servicio de urgencias por cólico renal (unilateral o bilateral) secundario a litiasis confirmadas en pruebas de imagen durante los 45 días previos y posteriores a la declaración del estado de alarma de cada país. Se recolectaron datos demográficos, síntomas y signos de presentación, análisis de sangre y orina, pruebas de imagen, y manejo terapéutico. El análisis estadístico se realizó entre dos grupos, Grupo A: pacientes que acudieron antes de la declaración del estado de alarma y Grupo B: pacientes que acudieron tras la declaración del estado de alarma. RESULTADOS: Un total de 397 pacientes que acudieron a urgencias por cólicos nefríticos secundarios a litiasis fueron incluidos en el estudio, 285 (71,8%) en el Grupo A y 112 (28,2%) en el Grupo B (p < 0,001). Un total de 135 (47,4%) en el Grupo A y 63 (56,3%) en el Grupo B (p = 0,11) admitieron haber pospuesto su búsqueda de atención médica urgente. En el momento de la valoración inicial, no se encontraron diferencias entre ambos grupos en los niveles de creatinina sérica, leucocitosis, fiebre, oliguria, dolor, o hidronefrosis. Además, no se observaron diferencias en relación con la estancia media, ingreso en el servicio de urología, o necesidad de tratamientos invasivos. CONCLUSIÓN: Nuestros resultados muestran una disminución significativa de atenciones en urgencias por cólicos nefríticos tras la declaración del estado de alarma en España e Italia. A diferencia de otros estudios publicados recientemente, no encontramos diferencias en la estancia media, ingreso al servicio de urología, o necesidad de tratamientos invasivos en pacientes que se presentaron antes y después del estado de alarma

INTRODUCTION: We hypothesized that the recent COVID-19 pandemic may lead to a delay in renal colic patients presenting to the Emergency Department due to the fear of getting infected. This delay may lead to a more severe clinical condition at presentation with possible complications for the patients. MATERIAL AND METHODS: Retrospective review of data collected from three institutions from Spain and Italy. Patients who presented to Emergency Department with unilateral or bilateral renal colic caused by imaging confirmed urolithiasis during the 45 days before and after each national lockdown were included. Data collected included patients’ demographics, biochemical urine and blood tests, radiological tests, signs, symptoms and the therapeutic management. Analysis was performed between two groups, Group A: patients presenting prior to the national lockdown date; and Group B: patients presenting after the national lockdown date. RESULTS: A total of 397 patients presented to Emergency Department with radiology confirmed urolithiasis and were included in the study. The number of patients presenting to Emergency Department with renal/ureteric colic was 285 (71.8%) patients in Group A and 112 (28.2%) patients in Group B (p < 0.001). The number of patients reporting a delay in presentation was 135 (47.4%) in Group A and 63 (56.3%) in Group B (p = 0.11). At presentation, there were no statistical differences between Group A and Group B regarding the serum creatinine level, C reactive protein, white blood cell count, fever, oliguria, flank pain and hydronephrosis. In addition, no significant differences were observed with the length of stay, Urology department admission requirement and type of therapy. CONCLUSION: Data from our study showed a significant reduction in presentations to Emergency Department for renal colic after the lockdown in Spain and Italy. However, we did not find any significant difference with the length of stay, Urology department admission requirement and type of therapy

Assessment of trends and clinical presentation in the emergency department of patients with renal colic during the COVID-19 pandemic era. / Evaluación de las tendencias y presentación clínica de pacientes con cólico nefrítico que acuden al servicio de urgencias durante la era pandémica del COVID-19.

INTRODUCTION: We hypothesized that the recent COVID-19 pandemic may lead to a delay in renal colic patients presenting to the Emergency Department due to the fear of getting infected. This delay may lead to a more severe clinical condition at presentation with possible complications for the patients. MATERIAL AND METHODS: Retrospective review of data collected from three institutions from Spain and Italy. Patients who presented to Emergency Department with unilateral or bilateral renal colic caused by imaging confirmed urolithiasis during the 45 days before and after each national lockdown were included. Data collected included patients' demographics, biochemical urine and blood tests, radiological tests, signs, symptoms and the therapeutic management. Analysis was performed between two groups, Group A: patients presenting prior to the national lockdown date; and Group B: patients presenting after the national lockdown date. RESULTS: A total of 397 patients presented to Emergency Department with radiology confirmed urolithiasis and were included in the study. The number of patients presenting to Emergency Department with renal/ureteric colic was 285 (71.8%) patients in Group A and 112 (28.2%) patients in Group B (p<0.001). The number of patients reporting a delay in presentation was 135 (47.4%) in Group A and 63 (56.3%) in Group B (p=0.11). At presentation, there were no statistical differences between Group A and Group B regarding the serum creatinine level, C reactive protein, white blood cell count, fever, oliguria, flank pain and hydronephrosis. In addition, no significant differences were observed with the length of stay, Urology department admission requirement and type of therapy. CONCLUSION: Data from our study showed a significant reduction in presentations to Emergency Department for renal colic after the lockdown in Spain and Italy. However, we did not find any significant difference with the length of stay, Urology department admission requirement and type of therapy.

Hindbrain morphometry and choroid plexus position in differential diagnosis of posterior fossa cystic malformations.

OBJECTIVE: To assess the differential diagnostic significance of a series of quantitative and qualitative variables of the cerebellar vermis in fetuses with posterior fossa cystic malformation, including Dandy-Walker malformation (DWM), vermian hypoplasia (VH) and Blake's pouch cyst (BPC). METHODS: This was a retrospective study of confirmed cases of DWM, VH and BPC, diagnosed at the Fetal Medicine and Surgery Unit of the Federico II University between January 2005 and June 2013 or the Fetal Medicine and Surgery Unit of G. Gaslini Hospital between July 2013 and September 2017. All included cases had good-quality three-dimensional (3D) volume datasets of the posterior fossa, acquired by transvaginal ultrasound through the posterior fontanelle. The midsagittal view of the posterior fossa was the reference view for the study. We assessed brainstem-tentorium angle and brainstem-vermis angle (BVA), as well as craniocaudal (CCVD) and anteroposterior (APVD) vermian diameters and vermian area (VA), which were normalized by biparietal diameter (BPD) to take into account gestational age (CCVD/BPD × 100, APVD/BPD × 100 and VA/BPD × 100, respectively). Finally, the position of the fourth ventricular choroid plexus (4VCP) was defined as normal ('up') or abnormal ('down'), relative to the roof/cyst inlet of the fourth ventricle. RESULTS: We analyzed 67 fetuses with posterior fossa malformations (24 cases of DWM, 13 of VH and 30 of BPC). The mean gestational age at diagnosis was 23.6 weeks. Regardless of gestational age, the BVA differed significantly between the three groups, and the VA/BPD was able to differentiate between VH and BPC. In differentiating between VH and BPC, the greatest areas under the receiver-operating characteristics curve were those for VA/BPD ratio. The 4VCP position was down in all cases of DWM and VH, while it was up in all cases of BPC. CONCLUSIONS: Our data support the concept that VA/BPD ratio and 4VCP position may be used to differentiate between DWM, VH and BPC in the fetus. In our series, the position of the 4VCP had the highest accuracy, but a larger number of VH cases should be evaluated to confirm that an up position of the 4VCP indicates BPC while a down position indicates DWM or VH. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Childhood infectious diseases and risk of multiple myeloma: an analysis of the Italian multicentre case-control study.

Common childhood infectious diseases have been associated with a reduced risk of following haematopoietic malignancies, but investigations on multiple myeloma (MM) are scarce. Information about 213 MM cases and 1128 healthy controls were obtained from a multicentre population-based Italian case-control study. The association between chickenpox, measles, mumps, pertussis and rubella and the MM risk was estimated by unconditional logistic regression, adjusting for age, gender and residence area. No association was found between MM risk and any considered infectious disease. The number of infections was slightly inversely associated with the risk of MM, but statistical significance was not reached (OR 0.87, 95% CI 0.55-1.4 for 1-2 diseases vs. none and OR 0.68, 95% CI 0.41-1.1 for 3-5 diseases, respectively, P = 0.131). We did not find a clear evidence that common infections during childhood are associated with the subsequent risk of developing MM.

Restricted ROC curves are useful tools to evaluate the performance of tumour markers.

In Clinical Epidemiology, receiver operating characteristic (ROC) analysis is a standard approach for the evaluation of the performance of diagnostic tests for binary classification based on a tumour marker distribution. The area under a ROC curve is a popular indicator of test accuracy, but its use has been questioned when the curve is asymmetric. This situation often happens when the marker concentrations overlap in the two groups under study in the range of low specificity, corresponding to a subset of values useless for classification purposes (non-informative values). The partial area under the curve at a high specificity threshold has been proposed as an alternative, but a method to identify an optimal cut-off that separates informative from non-informative values is not yet available. In this study, a new statistical approach is proposed to perform this task. Furthermore, a statistical test associated with the area under a ROC curve corresponding to informative values only (restricted ROC curve) is provided and its properties are explored by extensive simulations. Finally, the proposed method is applied to a real data set containing peripheral blood levels of six tumour markers proposed for the diagnosis of neuroblastoma. A new approach to combine couples of markers for classification purposes is also illustrated.

Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.

Risk of non-Hodgkin's lymphoma and residential exposure to air pollution in an industrial area in northern Italy: a case-control study.

The aim of this study was to evaluate the risk of non-Hodgkin's lymphoma (NHL) in an adult population residing in an area in northern Italy exposed to industrial air pollution from a big power plant, a coke oven, 2 chemical factories, and some minor plants. The design was a population-based case-control study and information about residential history and the main risk factors for NHL was obtained interviewing 133 cases and 279 controls using a structured questionnaire. Three exposure categories (heavy, moderate, and slight) were defined on the basis of the location of the major facilities with respect to the subject residence. NHL risk was not associated either with location or duration of residence in the heavily polluted area. However, the unavoidable limitations of this study prevent us from drawing definitive conclusions.

Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study.

BACKGROUND: In children older than 1 year with localised unresectable neuroblastoma (NB), treatment strategies are heterogeneous according to the national groups. The objective of this phase III non-randomised study was to evaluate the efficacy of conventional chemotherapy followed by surgery. PATIENTS AND METHODS: In the presence of surgical risk factors (SRF), six courses of chemotherapy alternating Carboplatin-Etoposide and Vincristin-Cyclophosphamide-Doxorubicin were given, and surgical resection was attempted after four. Survival analyses were performed using an intention-to-treat approach. The main objective was to achieve a 5-year survival over 80%. RESULTS: Out of 191 registered children, 160 were evaluable. There were 62.5% older than 18 months and 52.5% had unfavourable histology according to International Neuroblastoma Pathology Classification (INPC). Chemotherapy reduced the number of SRFs by one third. Delayed surgery was attempted in 86.3% of patients and was complete or nearly complete in 74%. The 5-year EFS and OS were 76.4% and 87.6% respectively, with significant better results for patients younger than 18 months or with favourable histology. CONCLUSION: This strategy provides encouraging results in children older than 1 year or 12 months with localised unresectable NB without MYCN amplification. However, in children older than 18 months and with unfavourable histology, additional treatment is recommended.

Role of angiogenesis inhibitors in colorectal cancer: sensitive and insensitive tumors.

Angiogenesis is a key factor in the carcinogenesis process. In oncological practice, angiogenesis inhibition, mainly through the blockade of the VEGF family and its receptors, has been robustly demonstrated to produce clinical benefits and, in specific disease subsets such as colorectal cancer, to extend the overall survival of treated patients. VEGF is a multifunctional growth factor that mediates its functions through cognate receptors on endothelial cells and it has been discovered for its capability to induce macromolecule hyperpermeability in veins and venules. Several approaches have been taken to target angiogenesis in cancer: drugs that target one or more soluble ligands of the VEGF family, drugs that selectively inhibit one or more receptors of the VEGF receptor family, and drugs that inhibit VEGF receptor(s) among other, non VEGF-related targets. At present, two compounds have shown significant clinical activity, bevacizumab, Avastin® and aflibercept, Zaltrap®, and only one of these (bevacizumab) has so far been registered for use in clinical practice. In the present review, we explore and summarize the main features of the angiogenetic process, concerning in particular a common and potentially lethal disease as colorectal cancer. We overview the molecular pathways that characterize angiogenesis, focusing on VEGF family, the current applications and limitations of its blockade in oncology, and the hypothetical future perspectives of anti-angiogenic therapy.

Patient-tailored treatments with anti-EGFR monoclonal antibodies in advanced colorectal cancer: KRAS and beyond.

Personalized medicine emphasizes the practice of considering individual patient characteristics as opposed to that centered on standards derived from epidemiological studies which, by definition, do not take into account the variability of individuals within a given population. When applied to oncology, personalized medicine is an even more complex concept because it extends the variability beyond the individual patient to the individual tumor. Indeed, the great genotypic and phenotypic variability (both in primary and metastatic sites of cancer) the development of targeted therapies, and the growing availability of biological assays complicate the scenario of personalized medicine in the oncological field. In this paper we review the results of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy in metastatic colorectal cancer (mCRC) in the context of tumor biology, delineating the future prospects of patient-tailored medicine in this area. In particular, we deal with EGFR inhibition by Cetuximab, a chimeric mouse human IgG1 mAb, and panitumumab, a fully human IgG2 mAb. We discuss the clinical impact of anti-EGFR mAbs on wild-type (WT) KRAS mCRC, also taking into account the feasibility of novel multi-marker approaches to treatment decision-making, aimed at increasing the predictive power of pre-therapy biomarkers. Experimental topics and fields of ongoing research, such as targeting microRNAs (miRNAs) with novel anticancer drugs and epigenetics in CRC are also addressed.

A multi-scale approach to colorectal cancer: from a biochemical- interaction signaling-network level, to multi-cellular dynamics of malignant transformation. Interplay with mutations and onco-protein inhibitor drugs.

This review article is part of a special Current Cancer Drug Targets issue devoted to colorectal cancer and molecularly targeted treatments. In our paper we made an attempt to connect more basic aspects with preclinical, pharmacological / therapeutic and clinical aspects. Reconstruction of a Molecular Interaction Map (MIM) comprising an important part of the G0 - G1 - S cell cycle transition, was a major component of our review. Such a MIM serves also as a convenient / organized database of a large set of important molecular events. The frequency of mutated / altered signaling-proteins indicates the importance of this signaling-network region. We have considered problems at different scale levels. Our MIM works at a biochemical-interaction level. We have also touched the multi-cellular dynamics of normal and aberrant colon crypts. Until recently, dynamic simulations at a biochemical or multi-cellular scale level were considered as a sort of esoteric approach. We tried to convince the reader, also on the basis of a rapidly growing literature, mostly published in high quality journals, that suspicion towards simulations should dissipate, as the limitations and advantages of their application are better appreciated, opening the door to their permanent adoption in everyday research. What is really required is a more interdisciplinary mentality and an interdisciplinary approach. The prize is a level of understanding going beyond mere intuition.

Structural comparison of the interaction of tubulin with various ligands affecting microtubule dynamics.

Microtubules (MTs), which are highly dynamic assemblies of the protein tubulin, play important and diverse roles in eukaryotic cells. MT dynamics are regulated during the cell cycle by interacting with a large number of endogenous cellular regulators. In addition, many anti-tumour drugs and natural ligands that interact directly with tubulin are able to either stabilise or destabilise MTs and to disrupt the normal dynamics. Herein, we compare the structures of tubulin when complexed with different ligands in order to analyse: (i) various binding-sites of the protein and different positions of ligands within the microtubule (ii) the diverse effect on the microtubule dynamics. The structures and data given are essential for understanding tubulin-ligand interactions and their influence on the regulation of the microtubule system.

Tratamiento quirúrgico de fractura de cabeza femoral mediante luxación controlada de cadera: resultados a mediano plazo / Surgical treatment through controlled hip dislocation for femoral head fractures: mid term results

Femoral head fractures associated to hip dislocations are uncommon lesions. Most reports present only short-term results. Objectives: To show functional outcome after a mid term follow up of patients with Pipkin II femoral head fractures treated operatively. Materials and Methods: A retrospective and descriptive evaluation of a 4 consecutive case series (four men, mean age of 36.5 years) treated operatively with an 89-month average follow up (range form 72-108 month). Controlled femoral head dislocation was performed in all patients and two 2.4 mm screws were used for fixation. At final follow up, the Harris Hip Score (HHS) and complications were assessed. Results: No immediate or late complications were reported. The mean HHS was of 95 points (range from 89 to 100 points).No signs of postraumatic arthritis or femoral head osteonecrosis were seen at the last radiographic assessment. Conclusion: in this series of patients with Pipkin II femoral head fractures mid-term functional results are good and no postraumatic arthritis or femoral head osteonecrosis were observed at final follow-up.

Las fracturas de cabeza femoral, asociada a luxación de cadera, corresponden a lesiones infrecuentes. La mayoría de los estudios reportan resultados a corto plazo. Objetivo: Describir el resultado funcional de pacientes con fractura Pipkin II operados con seguimiento a mediano plazo. Material y Métodos: Evaluación retrospectiva y descriptiva de una serie consecutiva de 4 pacientes (cuatro hombres, mediana de edad 36,5 años) operados con un seguimiento de mediana de 89 meses (72-108 meses). En todos los casos se realizó luxación controlada de la cabeza femoral y se utilizaron 2 tornillos de 2,4 mm. Se evaluaron complicaciones y Harris Hip Score (HHS) al último control clínico. Resultados: No se presentaron complicaciones tempranas ni tardías. El HHS promedio fue de 95 puntos (89-100 puntos). La última evaluación radiográfica no demostró signos de artrosis postraumática ni signos de necrosis avascular de cabeza femoral. Conclusión: En este grupo de pacientes con fractura de Pipkin tipo II los resultados funcionales a mediano plazo son buenos, no registrándose en el seguimiento artrosis de cadera postraumática ni necrosis avascular de la cabeza femoral.

Cirugía de revisión acetabular utilizando un cotilo modular con superficie de metal trabecular de tantalio: resultados a corto plazo / Acetabular revision surgery using a modular acetabular cup coated with trabecular metal of tantalum: short term results

Objectives: To evaluate short-term clinical results of patients performed acetabular revision surgery using a Trabecular Tantalum coated modular acetabular cups. Materials and Methods: This is a retrospective and descriptive analysis of a serie of 32 consecutive patients (34 hips) with acetabular revision surgery (23 women, 9 men, mean age 70.7 years), mean follow-up 32 month (12-60). The Paprosky and the AAOS acetabular defects classifications were assessed. According to Paprosky acetabular defects classification, there were eleven type I, two IIA, three IIB, nine IIC, seven IIIA and two IIIB. According to AAOS acetabular defects classification there were thirteen patients with type 1, nine patients with type 2, ten type 3 and two type 4. The percentage of own acetabular bone in contact with the new cup was recorded for each patient at the time of surgery and was 45 percent (range from 20 to 80 percent), with 23 patients presenting less than 50 percent of bone contact (mean 35 percent). Postoperatively, osseous integration was radiographically assessed. Functional results were evaluated according to the Harris Hip Score (HSS). The complications related to the implant were also recorded. Results: In all radiographic assessments performed at 3, 6 and 12 month postoperatively an integrated cup without signs of migration or osteolysis was observed. Four patients (11.8 percent) presented recurrent hip dislocation that required a revision surgery without further cup revision. The final clinical assessment was performed at a mean of 26 month after surgery (12-60) with a mean HHS of 91.8 points. Conclusion: Trabecular tantalum coated modular acetabular cups in acetabular revision surgery shows good short term clinical results even with acetabular defects greater than 50 percent. No cup loosening was observed in these series.

Objetivo: Evaluar los resultados clínicos a corto plazo de pacientes sometidos a cirugía de revisión acetabular utilizando cotilos modulares con superficie de metal trabecular de tantalio. Material y Métodos: Estudio retrospectivo-descriptivo de una serie consecutiva de 32 pacientes (34 caderas) sometidos a cirugía de revisión acetabular (23 mujeres, 9 hombres, edad promedio 70,7 años), seguimiento promedio 32 meses (12-60). Se clasifican los defectos acetabulares de acuerdo ala clasificación de Paprosky y de la AAOS. Según la clasificación de Paprosky de los defectos acetabulares, 11 pacientes tenían categoría I, 2 categoría IIA, 3 categoría IIB, 9 categoría IIC, 7 categoría IIIA y 2 categoría IIIB. Según la clasificación de la AAOS, 13 pacientes correspondieron a nivel 1, 9 pacientes a nivel 2, 10 a nivel 3 y 2 a nivel 4. Se registra el porcentaje de hueso propio acetabular en contacto con el nuevo cotilo de cada paciente que fue en promedio 45 por ciento (20-80 por ciento), presentándose en 23 caderas un porcentaje < 50 por ciento, el cual fue en promedio 35 por ciento. En el postoperatorio se evalúa la integración ósea mediante radiografías de pelvis. Se evalúan los resultados funcionales mediante el HHS (Harris Hip Score) y las complicaciones postoperatorias relacionadas con el implante. Resultados: En todas las radiografías postoperatorias realizadas a los 3, 6 y 12 meses se evidenciaba el cotilo integrado, sin signos de migración ni osteolisis. Cuatro pacientes (11,8 por ciento) presentaron luxaciones recidivantes de cadera, las cuales requirieron de una cirugía de revisión sin recambio del cotilo. La última evaluación clínica fue en promedio 26 meses tras la cirugía (12-60 meses) constatándose un HHS promedio de 91,8 puntos. Conclusión: El uso de cotilos modulares con revestimiento de metal trabecular de tantalio en cirugías de revisión acetabular presenta buenos resultados clínicos a corto plazo incluso en defectos óseos acetabulares superiores...