Registro sanitario de Heberprot-P®, medicamento biotecnológico innovador para el tratamiento de las úlceras del pie diabético / Sanitary registration of Heberprot-P®, an innovative biotechnological drug for the treatment of diabetic foot ulcers

Introducción: Heberprot-P® obtuvo su primer registro sanitario en Cuba en el año 2006, actualmente está aprobado en otros 26 países. Objetivo: Describir el proceso de registro sanitario en México, del medicamento biotecnológico Heberprot-P® para el tratamiento de las úlceras del pie diabético. Métodos: El proceso de registro sanitario de Heberprot-P® siguió las pautas de la reglamentación sanitaria de México sobre la base de la Ley general de salud y el Reglamento de insumos para la salud. Se revisaron además la Farmacopea de los Estados Unidos Mexicanos y las normas oficiales mexicanas en función de cumplir las exigencias para la comercialización de medicamentos en este territorio. Resultados: El proceso de registro se inició en junio de 2017 en México con acciones en función de completar los documentos e informaciones exigidas en el expediente de registro sanitario a presentarse. Entre ellos resaltan las consideraciones del Subcomité de Evaluación de Productos Biotecnológicos y el Comité de Moléculas Nuevas, la evaluación del expediente por un Tercero Autorizado y documentos emitidos por el Centro Nacional de Farmacovigilancia e Instituto Mexicano de la Propiedad Industrial. Se presentó la solicitud del registro sanitario ante Cofepris y esta se aprobó en mayo de 2018. Conclusiones: El trabajo con grupos de expertos permitió a la autoridad mexicana hacer un trabajo más expedito basado en las evidencias de las evaluaciones realizadas que son parte de la información del registro sanitario. Como resultado de este proceso, se otorgó el Registro Sanitario a Heberprot-P® en mayo de 2018 y Cofepris lo reconoció como un medicamento biotecnológico innovador(AU)

Introduction: Heberprot-P® obtained its first Sanitary Registration in Cuba in 2006, and it is currently approved in 26 other countries. Objective: Describe the sanitary registration process in Mexico of the biotechnological drug Heberprot-P® for the treatment of diabetic foot ulcers. Methods: The sanitary registration process of Heberprot-P® followed the guidelines of the sanitary regulations of Mexico on the basis of the General Health Law and the Regulation of Supplies for Health. The Pharmacopoeia of the United Mexican States and the official Mexican standards were also revised in order to comply with the requirements for the marketing of medicines in this territory. Results: The registration process began in June 2017 in Mexico with actions to complete the documents and information required in the sanitary registration file to be submitted. Among them are the considerations of the Sub-committee on the Evaluation of Biotechnological Products and the Committee on New Molecules, the evaluation of the file by an Authorized Third Party and documents issued by the National Center for Pharmacovigilance and the Mexican Institute of Industrial Property. The application for sanitary registration was submitted to Cofepris and this was approved in May 2018. Conclusions: The work with groups of experts allowed the Mexican authority to do a more expeditious work based on the evidence of the evaluations carried out that are part of the information of the sanitary registry. As a result of this process, Heberprot-P® was granted the Sanitary Registry in May 2018 and COFEPRIS recognized it as an innovative biotechnological medicine(AU)

OCT-Angiography Findings in Patients with Amblyopia: Comparison between Healthy Controls, Treatment-Responsive, and Treatment-Unresponsive Amblyopic Patients.

There is no consensus on whether amblyopia affects the retinal vascular plexus and morphology. Previous studies focused on the differences between amblyopic patients and normal controls without evaluating amblyopic eyes after patching. To evaluate differences in the superficial vascular density of amblyopic eyes, normal eyes, and amblyopic eyes reaching normal BCVA after patch therapy, OCTA was used. All patients underwent a comprehensive ophthalmological examination, including visual acuity, refraction, ocular motility tests, and anterior and posterior segment examination. OCTA was performed by an expert physician using the Zeiss Cirrus 5000-HD-OCT Angioplex (Carl Zeiss, Meditec, Inc., Dublin, OH, USA). OCTA scans were performed using a 3 × 3 mm2 and 6 × 6 mm2 fovea-centered image setting. The mean outer macular vessel density in the previously amblyopic group was 19.15 ± 0.51%. This was statistically significantly higher than in both the amblyopic group (18.70 ± 1.14%) and the normal controls (18.18 ± 1.40%) (p = 0.014). The previously amblyopic group also significantly differed from both normal controls and amblyopic eyes with regards to the inner (p = 0.011), outer (p = 0.006), and full (p = 0.003) macular perfusion. Finally, linear regression analysis revealed that BCVA was linearly correlated to outer perfusion in amblyopic (p = 0.003) and ex amblyopic eyes (p < 0.001). Considering the cross-sectional nature of our study, from our results, we can only hypothesize a possible correlation between light stimulation and retinal vasculature development. However, further longitudinal studies are needed to support this hypothesis.

11C-Methionine PET/CT in patients with primary hyperparathyroidism and inconclusive pre-operative imaging work-up: diagnostic accuracy and role of semi-quantitative analysis.

OBJECTIVE: 11C-Methionine PET/CT (C-MET) is a promising method in detecting abnormal parathyroid glands in patients with primary hyperparathyroidism (PHPT). The first aim of the study was to evaluate which is the diagnostic role of C-MET in patients with PHPT and inconclusive pre-operative imaging. Second, we aimed to investigate whether C-MET semi-quantitative parameters may reflect biochemical and histological characteristics of involved glands. METHODS: Patients with PHPT, undergoing C-MET after an inconclusive pre-operative imaging and having a parathyroid surgery, were retrospectively included. C-MET visual and semi-quantitative assessment was performed. Parameters, as SUVmax, SUVpeak, SUVmean, functional lesion volume (FLV) and total lesion activity (TLA), were measured for each detected lesion; SUVmean, FLV and TLA were calculated on 40-90% thresholds of SUVmax to define SUVmean40-90, FLV40-90 and TLA40-90, respectively. Results were correlated with patients' clinical-laboratory (calcium and PTH values) and histological data (size and weight of excised glands). Mann-Whitney test was used and P value < 0.05 was considered significant. RESULTS: Thirty-eight patients (36 female, age: 57.69 ± 15.13 years) were included. Pre-operative median calcium and PTH values were 11.1 mg/dl [interquartile range (IQR) 10.6-11.5] and 154.6 pg/ml (IQR 101.8-227.0), respectively. C-MET showed a parathyroid uptake in 30 out of thirty-eight patients (78.9%). Among 42 nodules excised, C-MET correctly detected the side of the neck (right/left) in 30/42 with sensitivity, specificity and accuracy of 79, 75 and 79%, respectively. C-MET correctly identified the exact position (superior/inferior) in 27/42 with sensitivity, specificity and accuracy of 75, 50 and 71%, respectively. SUVpeak, FLV50-70 and TLA40-70 were significantly (P < 0.05) higher in patients with higher PTH results. The histological size resulted significantly (P < 0.05) higher in abnormal glands with higher SUVmax, SUVpeak, FLV40-80 and TLA40-90, the weight was higher in glands with higher SUVpeak, SUVmean40-50, FLV40-80 and TLA40-90. CONCLUSIONS: C-MET showed a good performance in detecting hyperfunctioning parathyroid glands in PHPT patients with inconclusive pre-operative imaging. Semi-quantitative PET-derived parameters closely correlated with PTH as well as with size and weight of the excised gland, thus reflecting some biochemical and histological characteristics of involved glands.

Evaluation of intraoperative slow-release dexamethasone implant combined with idiopathic epiretinal membrane removal.

PURPOSE: To evaluate the efficacy of intraoperative slow-release dexamethasone implant (DEX) combined with removal of idiopathic epiretinal membrane (ERM). METHODS: In this observational retrospective study, data of 40 patients with phakic eyes affected by idiopathic ERM were analysed. All patients underwent cataract phacoemulsification, 25-gauge (G) pars plana vitrectomy (PPV), ERM removal with DEX implant ("DEX YES" group, #20) or without DEX implant ("DEX NO" group, #20). We collected data on best-corrected visual acuity (BCVA) < 20/40 Snellen charts, central macular thickness (CMT) ≤ 400 µm (measured by SD-OCT) and integrity of sub-foveal ellipsoid/myoid zone. BCVA, CMT and intraocular pressure (IOP) were evaluated at baseline as well as 15, 30 and 90 days after surgery. RESULTS: In the "DEX YES" group, statistically significant BCVA improvement was observed at 15, 30 and 90 days (p < 0.001), while in the "DEX NO" group, improvements were observed only at 30 and 90 days (p < 0.001). In both groups, CMT significantly decreased at each follow-up visit (p < 0.001), and no statistically significant increase of IOP was detected at each follow-up visit. CONCLUSIONS: In this study, DEX accelerated the improvement of BCVA at 15 days after surgery. However, no evidence of further anatomical (CMT) and functional (BCVA) DEX effectiveness combined with removal of idiopathic ERM by 25-G PPV at 30 and 90 days follow-up was observed.

Long-Term Arrhythmic Risk Assessment in Biopsy-Proven Myocarditis.

OBJECTIVES: This study sought to assess long-term arrhythmic risk in patients with myocarditis who received an implantable cardioverter-defibrillator (ICD). BACKGROUND: The arrhythmic risk of patients with myocarditis overtime remains poorly known. METHODS: The study enrolled 56 patients with biopsy-proven myocarditis who received an ICD for either primary (57%) or secondary prevention (43%) according to current guidelines. Clinical characteristics, biopsy findings, electrophysiological data from endocardial 3-dimensional electroanatomic voltage mapping, and device interrogation data were analyzed to detect arrhythmic events overtime. Coronary angiography excluded significant coronary artery disease in all patients. RESULTS: At a mean follow-up of 74 ± 60 months (median 65 months), 25 (45%) patients had major ventricular arrhythmias treated by ICD intervention (76% being terminated by ICD shock and 24% by antitachyarrhythmia burst pacing). At multivariable analysis, the presence of sustained ventricular tachycardia on admission (hazard ratio: 13.0; 95% confidence interval: 2.0 to 35.0; p = 0.032) and the extension of the areas of low potentials at the bipolar endocardial mapping (hazard ratio: 1.19; 95% confidence interval: 1.04 to 1.37; p = 0.013) were the only independent predictors of appropriate ICD interventions. A cutoff value of 10% of abnormal bipolar area at electroanatomical ventricular mapping discriminated patients with appropriate ICD interventions with a sensitivity of 89% and a specificity of 85%. CONCLUSIONS: The study demonstrates that the prevalence of life-threatening ventricular arrhythmias in patients with myocarditis receiving an ICD according to current guidelines is high and the arrhythmic risk persists late overtime. Electroanatomical ventricular mapping may be a useful tool to identify patients at greater arrhythmic risk.

Role of extensive diagnostic workup in young athletes and nonathletes with complex ventricular arrhythmias.

BACKGROUND: Ventricular arrhythmias (VAs) are the most common cause of death in athletes. The differences in the electroanatomic substrate in athletes and nonathletes with complex VA are unknown. OBJECTIVE: The purpose of this study was to compare the electroanatomic substrate of complex VA in athletes vs nonathletes. METHODS: The study prospectively enrolled young athletes and nonathletes with VA. Patients underwent 2-dimensional echocardiography, cardiac magnetic resonance (CMR) imaging, coronary angiography, 3-dimensional electroanatomic mapping (3D-EAM), and 3D-EAM-guided endomyocardial biopsy (EMB). Follow-up included 24-hour electrocardiographic Holter or implantable cardioverter-defibrillator/loop recorder interrogation for VA recurrence. RESULTS: Thirty-three patients were enrolled: 18 competitive athletes (56%) and 15 nonathletes (44%). Left ventricular and right ventricular (RV) findings by echocardiography and CMR did not show structural disease. Nine athletes (50%) were asymptomatic compared to 1 nonathlete (7%; P <.05). Unifocal origin of VA was reported in 14 athletes (93%) and 17 nonathletes (94%). Athletes showed a larger RV unipolar than bipolar scar (18 ± 17 cm2 vs 3 ± 3.8 cm2; P = .04). Diagnostic yield of EMB was 50% in athletes and 40% in nonathletes. Among athletes, the final diagnosis was myocarditis in 2, arrhythmogenic ventricular right cardiomyopathy in 1, and focal replacement fibrosis in 1. Among nonathletes, EMB revealed focal replacement fibrosis in 4 cases. At median follow-up of 18.7 months, Kaplan-Meier curves showed lower VA recurrence in detrained athletes than nonathletes (53% vs 6%; P = .02). CONCLUSION: This study showed the need for extensive diagnostic workup in apparently healthy young patients with complex VA in order to characterize concealed cardiomyopathies.

A novel gallbladder umbrella stent (the Shai™ Stent) for prevention of stone migration and impaction: results on feasibility and short-term safety in a porcine model.

BACKGROUND AND AIMS: Cholelithiasis is the most common biliary tract disorder. Surgery is the treatment of choice for symptomatic gallstones. Aims of this study were to investigate the feasibility and short-term safety of a new endoscopic procedure with a specially designed Nitinol gallbladder stent for blockage of gallstone migration, the Shai™ Stent. The Shai stent is designed to enable free bile flow, which will be supposed to prevent recurrent attacks. METHODS: The Shai™ Stent was inserted into the gallbladder during a standard ERCP procedure using a conventional metal stent delivery system. The aim of the present study was to investigate the feasibility and safety of insertion and deployment and removal of the stent into the gallbladder of pigs. In addition, the short-term safety of the stent was evaluated. RESULTS: Fifteen stents were placed in the gallbladder of 15 pigs. Mean procedure time was 25 min (15-37). The maximum follow-up before sacrifice was 42 days. The stent in 1 pig had migrated at the 42 days follow-up but there were no macroscopic changes in its gallbladder or other organs. The stent remained in place in the remaining 12 pigs at autopsy, and the gallbladder and bile ducts were macroscopically normal. Stent removal was easily done in two pigs immediately after placement. CONCLUSIONS: Correct placement and removal of the Shai™ Stent in the gallbladder is safe and feasible in pigs. Further clinical trials are warranted to confirm these results and to effectively evaluate the capability of this stent as an innovative biotechnology to block gallstones from migration and impaction.

Initial experience with the novel EmboTrap II clot-retrieving device for the treatment of ischaemic stroke.

INTRODUCTION: We report our experience with the novel stent-type clot-retrieval device EmboTrap II for the revascularization of large artery occlusions in acute ischaemic stroke. MATERIALS AND METHODS: Twenty-nine patients with acute ischaemic stroke due to large artery occlusion underwent mechanical thrombectomy with the new EmboTrap II in two Italian centres. Clinical, procedural and radiological data were collected. Angiographic results and neurological outcomes were analysed. RESULTS: Only large vessel occlusions were included. Intravenous thrombolysis was administered in 72% of patients. Successful reperfusion (TICI 2b-3) was obtained in 76% of patients treated exclusively with EmboTrap II. No device-related permanent complications occurred. CONCLUSION: In our experience, mechanical thrombectomy with EmboTrap II is safe and effective. Reperfusion rate was comparable to that obtained with other stent retrievers.

Delta radiomics for rectal cancer response prediction with hybrid 0.35 T magnetic resonance-guided radiotherapy (MRgRT): a hypothesis-generating study for an innovative personalized medicine approach.

The aim of this study was to evaluate the variation of radiomics features, defined as "delta radiomics", in patients undergoing neoadjuvant radiochemotherapy (RCT) for rectal cancer treated with hybrid magnetic resonance (MR)-guided radiotherapy (MRgRT). The delta radiomics features were then correlated with clinical complete response (cCR) outcome, to investigate their predictive power. A total of 16 patients were enrolled, and 5 patients (31%) showed cCR at restaging examinations. T2*/T1 MR images acquired with a hybrid 0.35 T MRgRT unit were considered for this analysis. An imaging acquisition protocol of 6 MR scans per patient was performed: the first MR was acquired at first simulation (t0) and the remaining ones at fractions 5, 10, 15, 20 and 25. Radiomics features were extracted from the gross tumour volume (GTV), and each feature was correlated with the corresponding delivered dose. The variations of each feature during treatment were quantified, and the ratio between the values calculated at different dose levels and the one extracted at t0 was calculated too. The Wilcoxon-Mann-Whitney test was performed to identify the features whose variation can be predictive of cCR, assessed with a MR acquired 6 weeks after RCT and digital examination. The most predictive feature ratios in cCR prediction were the L_least and glnu ones, calculated at the second week of treatment (22 Gy) with a p value = 0.001. Delta radiomics approach showed promising results and the quantitative analysis of images throughout MRgRT treatment can successfully predict cCR offering an innovative personalized medicine approach to rectal cancer treatment.

Endoscopy robotics: Current and future applications.

Many different types of endoscopy robot have been developed or are under development. Some of these innovative biotechnologies are dedicated to complex endoscopic procedures such as endoscopic submucosal dissection whereas others are purely diagnostic. In endoscopy robotics, there are still several problems that need a solution. These problems basically concern robotic locomotion and instrument control, as well as clinical application. In most cases, the technology is still under development. The current fields of investigation are augmented reality, advances in actuation and reduction of hysteresis, optical analysis, wireless movement transmission and many others. Besides endoscopic submucosal dissection, other promising fields of implementation of endoscopy robots are natural orifices transluminal endoscopic surgery and bariatric endoscopy. Obviously, endoscopy robots are expensive, but both doctors and health system providers are becoming more aware of the possibilities that these platforms can offer. Improvement of the performance of endoscopy robots undoubtedly will lead to their widespread use and, therefore, a balance in cost-effectiveness.

Short-Term Assessment of Intravitreal Dexamethasone Implant Using Enhanced-Depth Image Optical Coherence Tomography and Optical Coherence Tomography Angiography in Patients with Retinal Vascular Diseases.

INTRODUCTION: To evaluate the short-term efficacy and safety of intravitreal dexamethasone implant (IDI) in patients with macular oedema associated with diabetic retinopathy (DR) and retinal vein occlusion (RVO) using enhanced-depth image optical coherence tomography (EDI-OCT) and to estimate the effect of dexamethasone on the choroid and the retinal vascular network using OCT angiography (OCTA). METHODS: Fifteen eyes in 15 patients with macular oedema secondary to diabetes (DR, n = 8) or retinal vein occlusion (RVO, n = 7) were treated with intravitreal injection of sustained-release IDI. Primary efficacy end points were changes in best corrected visual acuity and central macular thickness (CMT). Secondary end points were changes in choroidal thickness and choroidal and retinal vascular networks as determined by OCTA. RESULTS: CMT was significantly reduced from baseline by 3 h after injection (p < 0.01) and improved further during the 3-month follow-up. Visual acuity improvement was consistent with CMT reduction. No alterations in IOP or systemic side effects were observed. OCTA showed improvement from baseline in terms of decreased number and size of cysts and restoration of the retinal vascular network; flow choroidal thickness did not change significantly. CMT and visual acuity variations were similar in the two groups. CONCLUSIONS: CMT reduced as early as 3 h after the injection of IDI, with further reduction during follow-up. Choroidal thickness was unchanged, whereas the vascular retinal network improved from baseline to the end of study. Both EDI-OCT and OCTA were useful in demonstrating the early beneficial effects of IDI on the macula and the perifoveal vascular network. FUNDING: The article processing charges, the open access fee and the medical writing and editorial assistance was funded by Allergan.

Swept source optical coherence tomography and optical coherence tomography angiography in pediatric enhanced S-cone syndrome: a case report.

BACKGROUND: Enhanced S-cone syndrome is an autosomal recessive retinal dystrophy related to a defect in a nuclear receptor gene (NR2E3) that leads to alteration in cells development from rod to S-cone. This retinal dystrophy may be associated with retinal schisis. The aim of this report is to describe structural optical coherence tomography and optical coherence tomography angiography features in a case of enhanced S-cone syndrome associated with macular schisis. CASE PRESENTATION: A Caucasian 13-year-old girl underwent measurement of best corrected visual acuity, ophthalmoscopic evaluation, and fundus autofluorescence examination. Photopic and scotopic electroretinography were carried out as well. Enhanced S-cone syndrome was suspected on the basis of clinical and electrophysiological findings. Structural optical coherence tomography and optical coherence tomography angiography allowed the further characterization of the associated macular schisis. Genetic analysis not only confirmed the diagnosis but increased the clinical novelty of this case report by showing two variations in the NR2E3 gene probably related to the phenotype: a missense variation c.1118T>C which leads to the substitution of leucine with proline in amino acid position 373, and c.349+5G>C, which involves a gene sequence near a splicing site. CONCLUSIONS: Swept source structural optical coherence tomography (B scans and "en face" images) and optical coherence tomography angiography allowed the observation of retinal structural details and the involvement of each retinal layer and capillary plexus in enhanced S-cone syndrome. Of interest, neither of the two NR2E3 gene variants found in this case report have been linked to any form of retinopathy.

Laparoscopic versus robotic hysterectomy in obese and extremely obese patients with endometrial cancer: A multi-institutional analysis.

OBJECTIVE: The aim of this study was to evaluate the surgical and oncological outcome of robotic surgical staging with hysterectomy (RH) plus or less pelvic and aortic lymphadenectomy, compared to the same procedures performed by laparoscopic surgery (LH) in obese patients (BMI≥30 kg/m2) with endometrial cancer. MATERIAL AND METHODS: From October 2001 to April 2017, obese patients (BMI > 30 kg/m2) with primary, histologically confirmed endometrial carcinoma who underwent LH or RH using the Da Vinci Si or Xi Surgical System® (Intuitive Surgical Inc®, 1266 Kifer Road, Building 101 Sunnyvale, CA) were eligible for the study. RESULTS: We identified 655 women with endometrial cancer and BMI >30 kg/m2. Out of 655 patients, 249 (38%) underwent RH and 406 (62%) underwent LH plus or less pelvic and aortic lymphadenectomy. Our study showed that, compared to the 406 patients treated in LPS, 249 patients treated in robotics have a statistically significant difference in terms of increased operating time and a decreased conversion rate. In addition, the rate of pelvic lymphadenectomies in robotic surgeries is twice the one reported in LPS surgeries. Furthermore, a reduction in hospital stay was observed in the robotic group. We observed that the oncological outcomes do not vary according to the surgical approach and BMI variation. CONCLUSIONS: robotic surgery in severely obese women with endometrial cancer is feasible, safe, and reproducible and could be a valid alternative to laparoscopy in the treatment of these patients. Prospective studies could confirm our results.

Effect of intravitreal dexamethasone on macular edema in von Hippel-Lindau disease assessed using swept-source optical coherence tomography: a case report.

BACKGROUND: Von Hippel-Lindau disease is a rare hereditary syndrome caused by germinal mutations in a von Hippel-Lindau tumor-suppressing gene. Retinal hemangioblastoma is the ocular hallmark lesion of von Hippel-Lindau disease. CASE PRESENTATION: A 20-year-old Caucasian woman presented to our institution with painless visual impairment in the right eye. A fundus ophthalmoscopic evaluation and swept-source optical coherence tomographic examination revealed a retinal hemangioblastoma associated with cystoid macular edema. On the basis of the clinical ocular findings and genetic analysis, von Hippel-Lindau disease was diagnosed. Following an intravitreal injection of ranibizumab, off-label administration of intravitreal dexamethasone was considered to reduce the edema. An almost complete resolution of the edema in the macular area was observed 1 week after the injection. Finally, laser photocoagulation and transconjunctival cryotherapy were performed; the patient developed "ablatio fugax" after cryotherapy. CONCLUSIONS: In our experience, intravitreal dexamethasone administration has proven to be a useful tool for reducing retinal hemangioblastoma-related macular edema in von Hippel-Lindau disease and may be considered a potentially valuable treatment that can be used in combination with other therapies.

Endometrial cancer prognosis correlates with the expression of L1CAM and miR34a biomarkers.

BACKGROUND: Patients with endometrial cancer (EC) and presumably with good prognosis may develop a recurrence indicating that the classification of this tumor is still not definitive and that new markers are needed to identify a subgroup at risk of relapse. The cell adhesion molecule L1CAM is highly expressed in several human carcinomas and has recently been described as a new marker for endometrial and ovarian carcinomas. The aim of this study was to determine the relevance of L1CAM in recurrent EC. METHODS: In this work we have analyzed, by immunohistochemical and RT-qPCR analysis, the expression of L1CAM in a cohort of 113 endometrial cancers at different stages, which 50% have relapsed. As a predictor of good outcome, the tumors were also analyzed for the expression of miR-34a, a post-transcriptional regulator of L1CAM. RESULTS: Among metastatic EC, the highest levels (60%) and the median level (24%) of L1CAM in tumors correlate with the progression, suggesting that the expression of this molecule is linked to the tumor component most involved in metastatic processes. We also found an inverse correlation between miR-34a and L1CAM protein expression, suggesting that miR-34a is a positive prognostic marker of EC. CONCLUSIONS: Our results demonstrate the expression of L1CAM and miR-34a in EC as prognostic factors that identify subgroup of patients at high risk of recurrence suggesting for them more aggressive schedules of treatment.