Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial).

RATIONALE: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated. AIMS: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. SAMPLE SIZE ESTIMATES: Two hundred forty patients will be enrolled, 120 in every treatment arm. METHODS AND DESIGN: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months. STUDY OUTCOMES: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage. DISCUSSION: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. TRIAL REGISTRATION: The trial is registered as NCT05225961. February, 7th, 2022.

Safety and efficacy of tirofiban in acute ischemic stroke due to tandem lesions undergoing mechanical thrombectomy: A multicenter randomized clinical trial (ATILA) protocol.

Background: In-stent thrombosis after mechanical thrombectomy (MT) worsen outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Although an optimal antiplatelet therapy is needed, the best approach to avoid in-stent thrombosis is yet to be elucidated. Hypothesis: Low-dose intravenous tirofiban is superior to intravenous aspirin in avoiding in-stent thrombosis in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. Methods: The ATILA-trial is a multicenter, prospective, phase IV, randomized, controlled (aspirin group as control), assessor-blinded clinical trial. Patients fulfilling inclusion criteria (AIS due to TL, ASPECTS ⩾ 6, pre-stroke modified Rankin Scale ⩽2 and onset <24 h) will be randomized (1:1) at MT onset to experimental (intravenous tirofiban) or control group (intravenous aspirin). Intravenous aspirin will be administered at a 500 mg single dose and tirofiban at a 500 µg bolus followed by a 200 µg/h infusion during first 22 h. All patients will be followed up to 3 months. Sample size estimated is 240 patients. Outcomes: The primary efficacy outcome is the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. The primary safety outcome is the rate of symptomatic intracranial hemorrhage. Secondary outcomes include functional independence defined as modified Rankin Scale 0-2, proportion of patients undergoing rescue therapy due to in-stent aggregation during MT and carotid reocclusion at 30 days. Discussion: ATILA-trial will be the first clinical trial regarding the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. Trial registration: NCT0522596.

Chronic Treatment with Somatostatin Analogues in Recurrent Type 1 Gastric Neuroendocrine Tumors.

BACKGROUND: Type 1 gastric neuroendocrine tumors (GC-1) represent an uncommon subtype of neoplasms. Endoscopic resection has been proposed as the treatment of choice; active surveillance may be performed in those smaller than 1 cm, while gastric surgery may be performed for those with frequent recurrences. The antiproliferative effect of somatostatin analogues (SSA) is well known, and their action on GC-1s has been postulated as a chronic treatment to reduce recurrence. METHODS: A two-centered, retrospective, observational study that included nine patients (55.6% women) diagnosed with GC-1, receiving long-term treatment with SSA, with a median follow-up from baseline of 22 months, was undertaken. Endoscopic follow-up, extension study, and analytical values of chromogranin A (Cg A) and gastrin were collected. RESULTS: In total, 88.9% of patients presented partial or complete response. Treatment with SSA was the only independent factor with a trend to prevent tumor recurrence (Odds Ratio 0.054; p = 0.005). A nonsignificant tendency toward a decrease in CgA and gastrin was observed; lack of significance was probably related to concomitant treatment with proton pump inhibitors in some patients. CONCLUSIONS: Chronic treatment with SSA is a feasible option for recurrent GC-1s that are difficult to manage using endoscopy or gastrectomy. Randomized clinical trials to provide more scientific evidence are still needed.

Thrombectomy aspiration post-market study in acute stroke with the Q aspiration catheter: the TAPAS study.

BACKGROUND: The Q Aspiration Catheter (MIVI Neuro) has demonstrated greater aspiration flow rates and ingestion forces compared with conventional catheters in vitro. The safety and performance of the Q Catheter was assessed using a direct aspiration first pass technique in patients with acute ischemic stroke at four neurointerventional centers in Spain. METHODS: We included adult patients who underwent mechanical thrombectomy between March 2019 and March 2020 using the Q Catheter as first-line therapy. Performance endpoints included final successful revascularization of the target vessel (defined as modified thrombolysis in cerebral infarction (mTICI) grade 2B/3), first pass revascularization, and overall Q Catheter revascularization. Safety endpoints were symptomatic intracranial hemorrhage (sICH), embolization to new territory (ENT), and procedural complications. Modified Rankin Scale (mRS) score and all-cause mortality were also assessed. RESULTS: Forty-five subjects were enrolled. The Q Catheter successfully navigated to the lesion in 95.5% (43/45) of patients. Final successful mTICI 2B/3 revascularization was achieved in 93.3% (42/45), first pass mTICI 2B/3 revascularization with the Q Catheter was 55.3% (21/38), and overall with Q Catheter mTICI 2B/3 revascularization was 65.8% (25/38). Favorable clinical outcome of mRS 0-2 was achieved in 55.6% (25/45). There were no cases of ENT. sICH and mortality rates were 2.2% (1/45) and 13.3% (6/45), respectively. CONCLUSION: In this multicenter, observational study, the Q Aspiration Catheter used as first-line therapy demonstrated a good and safe profile in terms of navigation, revascularization, and safety in patients with acute ischemic stroke.

Bridging Therapy and Occlusion Site Influence Symptomatic Hemorrhage Rate after Thrombectomy: A Daily Practice Study in 623 Stroke Patients.

BACKGROUND: Comparison of symptomatic intracranial hemorrhage (SICH) rates between stroke patients treated with bridging therapy (BT) and primary mechanical thrombectomy (PMT) are scarce and difficult to interpret due to baseline differences between both populations. METHODS: Retrospective analysis of patients with acute ischemic stroke treated with endovascular therapy (BT or PMT) was performed at our center between January 2010 and June 2017. RESULTS: Six hundred twenty-three patients were included. Global SICH rate was 9% overall: 6.8% in the PMT group and 12.6% in the BT group. The following factors significantly associated with SICH after multivariate analysis: MCA occlusion (p: 0.047), stroke of unknown origin (p: 0.025), BT (p: 0.024), and procedural time over 65 min (p: 0.027). The following variables presented a statistically significant higher frequency in patients treated with PMT: atrial fibrillation (p: 0.005), anticoagulant medication (p < 0.001), wake-up strokes (p < 0.001), atherothrombotic etiology (p < 0.05), combined thrombectomy technique (p: 0.008), longer procedural times (p: 0.025), and favorable outcome at 3 months (p: 0.011). The following variables presented a statistically significant higher frequency in patients treated with BT: antiplatelet medication (p: 0.048), MCA occlusions (p: 0.017), cardioembolic etiology (p < 0.05), stent retriever/aspiration technique (p: 0.008), and SICH (p: 0.013). Patients with MCA occlusions had twice the risk of SICH after BT than after PMT (16.4 and 8.6%, p: 0.038). CONCLUSIONS: In this clinical series, the SICH rate was higher in patients treated with BT than in those treated with PMT. Relevant differences in baseline (related to IVT contraindications) were found between both groups. Randomized studies of BT versus PMT in populations with similar baseline characteristics might be of interest.

Are modified Fisher Scale and bleeding pattern helpful predictors of neurological complications in non-aneurysmal subarachnoid hemorrhage?

PURPOSE: Non-aneurysmal subarachnoid hemorrhage (NA-SAH) is a clinical-radiological entity with a different prognosis than aneurysmal SAH (A-SAH). The purpose of this study is to assess the predictive value of the modified Fisher Scale (mFS) for neurological complications in patients with this diagnosis. METHODS: We recruited patients admitted at our hospital services between 2009 and 2017 who were diagnosed with spontaneous SAH, with either perimesencephalic (PM-SAH) or diffuse pattern (D-SAH), an initial negative angio-CT, and at least one digital subtraction angiography of brain vessels discarding underlying brain aneurysms or other vascular malformations. RESULTS: The retrospective observational study included 116 patients. The mean age was 54.4, and the sample included predominantly male subjects (62.9%). Hunt and Hess (HH) scores on admission ranged from 3 to 5 in 18.1% of patients. The prevalence of hydrocephalus requiring ventricular drainage was 18.1%. The prevalence of symptomatic vasospasm was 4.3%. A modified Rankin Scale (mRS) 0-2 at discharge was found in 95.6%. In a multivariate logistic regression for the presence of neurological complications including age, sex, admission HH 3-5 compared with < 3, mFS 4 compared with mFS < 4, D-SAH compared with PM-SAH, and mRS score at discharge of 0-2 compared with > 2, the only significant predictors were mFS 4 compared with mFS < 4 (OR 4.47 (95% CI 1.21, 16.66) p value = 0.03) and D-SAH compared with PM-SAH (OR 7.10 (95% CI 1.24, 40.8) p value = 0.03). CONCLUSION: In patients with NA-SAH, a mFS score of 4 and/or a D-SAH bleeding pattern in non-contrast cranial CT on admission predicted the development of relevant neurological complications.

Mechanical Thrombectomy in Acute Stroke Due to Carotid Occlusion: A Series of 153 Consecutive Patients.

BACKGROUND: Strokes due to carotid artery occlusion (CAO) are associated with bad clinical prognosis and poor response to intravenous thrombolysis. Several studies in the past have shown the benefits of mechanical thrombectomy (MT) and compared bridging therapy (BT) and primary MT (PMT) in large vessel occlusions, but only a few studies have focused on the specific population of CAO and their response to endovascular treatment. METHODS: Retrospective review of patients treated at our center between January 2010 and June 2017 that (1) presented with acute ischemic stroke caused by CAO in the first 4.5 h since symptom onset, and (2) were treated with MT (BT or PMT). Baseline characteristics of the population, comparison between BT and PMT, intrahospital mortality, symptomatic intracranial hemorrhage, and functional outcome were investigated. RESULTS: A total of 153 patients were included. Baseline characteristics: 51.6% were male, and the median age was 71 years. The most frequent risk factor was hypertension (71.9%). The main stroke etiology was atherothrombotic (40.5%). The mean admission National Institute of Health Severity Score (NIHSS) was 19, mean discharge NIHSS was 7. Isolated occlusion of the Extracranial or Intracranial Internal Carotid Artery was the most frequent occlusion location (52.3%). TICI 2b-3 was achieved in 87.6%, intrahospital mortality was 26.8%, symptomatic hemorrhage was 8.5%, and 3 months-modified Rankin Score (mRS) 0-2 was 26.8%. Definitive carotid stenting was needed in 33.3% of the cases. BT versus PMT: Patients treated with PMT presented a higher incidence of atrial fibrillation, anticoagulation, and cardioembolic stroke compared to those treated with BT. No differences in TICI 2b-3, 3 months-mRS or symptomatic hemorrhage were found between both groups. Intrahospital mortality: Poor perfusion-CT mismatch (p = 0.005), isolated Internal carotid artery location (p = 0.024), and symptomatic hemorrhage (p < 0.001) were independent predictors. Symptomatic intracranial hemorrhage: Patients with post-treatment symptomatic hemorrhage had higher intrahospital mortality (p < 0.001) and worse 3 months-mRS (p = 0.033). Functional outcome: Admission NIHSS (p = 0.012) independently predicted 3 months-mRS. CONCLUSIONS: In our population, patients with CAO clinically present with severe strokes. Isolated occlusions of the extra- or intracranial segments of the carotid are more frequent than tandem occlusions. Successful recanalization after thrombectomy is achieved in most of the patients, but association with favorable functional outcome is poor. Clinical evolution is similar in patients treated with PMT and BT. Intracranial symptomatic hemorrhage after treatment is associated with higher intrahospital mortality and worse 3 months-mRS. Poor perfusion-CT mismatch, symptomatic hemorrhage, and isolated CAO are independent predictors of intrahospital mortality. Admission NIHSS is an independent predictor of 3 months-mRS.

Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real-World Data from the Spanish Tumor Registry (R-GETNE).

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs. SUBJECTS, MATERIALS, AND METHODS: A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 <2%), G2 (Ki-67 3%-20%), or G3 (Ki-67 >20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3. RESULTS: Five-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%-5%], 72% [Ki-67 6%-10%], 52% [Ki-67 11%-20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%-50%], 22% [Ki-67 51%-100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%). CONCLUSION: Substantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index. IMPLICATIONS FOR PRACTICE: Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.

[Managing the discharge of diabetic patients from the emergency department: a consensus paper]. / Documento de consenso sobre el manejo al alta desde urgencias del paciente diabético.

EN: Eighty to 90% of patients attended in emergency departments are discharged to home. Emergency department physicians are therefore responsible for specifying how these patients are treated afterwards. An estimated 30% to 40% of emergency patients have diabetes mellitus that was often decompensated or poorly controlled prior to the emergency. It is therefore necessary to establish antidiabetic treatment protocols that contribute to adequate metabolic control for these patients in the interest of improving the short-term prognosis after discharge. The protocols should also maintain continuity of outpatient care from other specialists and contribute to improving the long-term prognosis. This consensus paper presents the consensus of experts from 3 medical associations whose members are directly involved with treating patients with diabetes. The aim of the paper is to facilitate the assessment of antidiabetic treatment when the patient is discharged from the emergency department and referred to outpatient care teams.

ES: El 80-90% de los pacientes atendidos en los servicios de urgencias son dados de alta desde los mismos, y por tanto los facultativos de urgencias son los responsables del tratamiento al alta en dichos pacientes. Se estima que la frecuencia de diabetes mellitus en urgencias es de un 30-40% y en muchos casos dicha diabetes está descompensada o con un mal control metabólico previo, por lo que es necesario establecer pautas de tratamiento antidiabético adecuadas de cara al alta que contribuyan a un adecuado control metabólico de dichos pacientes y favorezca un mejor pronóstico a corto plazo tras el alta, así como mantener una continuidad con la atención ambulatoria por parte de otras especialidades y contribuir a una mejoría del pronóstico a largo plazo. El presente documento es por tanto un consenso de expertos de tres sociedades científicas implicadas directamente en la atención del paciente diabético, que pretende facilitar la valoración del tratamiento al alta desde urgencias en cuanto a la diabetes se refiere y su continuidad asistencial ambulatoria.

Clinical and radiological control of highly active relapsing-remitting multiple sclerosis with first-line natalizumab.

A 33-year-old man with gait instability, weakness of the left lower extremity, decreased visual acuity in the left eye, and urgency and urine incontinence was diagnosed of relapsing-remitting multiple sclerosis. He was treated with natalizumab (300 mg intravenously every 4 weeks) as first-line therapy, which reached at 6 months a favorable clinical evolution and dramatic radiological improvement (T2-weighted lesion load decreased by 50% and no gadolinium-enhancing T1 lesions) sustained over the course of 8 years. This clinical case shows the efficacy of natalizumab in a real-world setting and, particularly, the sustained effect of this drug in the long term as demonstrated by persistent radiological improvement. Natalizumab can be considered as the treatment of choice in relapsing-remitting multiple sclerosis forms presenting with two relapses and gadolinium-enhancing (Gd+) lesions.

Unresectable Recurrent Multiple Meningioma: A Case Report with Radiological Response to Somatostatin Analogues.

Medical treatment of meningiomas is reserved for cases in which surgery and radiotherapy have failed. Given that a high percentage of meningiomas express somatostatin receptors, treatment with somatostatin analogues has been proposed. In addition, these medications have been shown to have an antiproliferative and antiangiogenic effect in vitro. To date, very few cases with clinical response and none with radiological response have been described. The case described here is the first to report a radiological response. A 76-year-old Caucasian male was first diagnosed with unresectable meningioma at age 47. The patient experienced multiple recurrences and underwent three surgeries and radiotherapy over the years from the initial diagnosis. Despite treatment, the disease continued its progression. Based on an Octreoscan positive for tumour uptake, therapy with extended-release somatostatin analogues was started. Although no clinical neurological improvement was observed, magnetic resonance imaging scans revealed a discreet but continuous radiological response over time. After >2 years of continuous administration of lanreotide, the patient remains progression free. In highly selected cases, somatostatin analogue treatment for meningioma may be beneficial. Based on our findings, treatment with somatostatin analogues should be maintained longer than previously described before evaluating treatment response.

[Gastroenteropancreatic neuroendocrine tumors: clinical characteristics, diagnosis and prognosis at Hospital Universitario Clínico San Carlos (Madrid)]. / Tumores neuroendocrinos gastroenteropancreáticos: características clínicas, proceso diagnóstico y pronóstico en el Hospital Universitario Clínico San Carlos (Madrid).

INTRODUCTION: Neuroendocrine tumors are a group of neoplasms arising from the neural crest and endoderm and very heterogeneous as regards localization, clinical behavior, aggressiveness, and prognosis. Pancreas and gastrointestinal tract are the most common sites where neuroendocrine tumors can be found. MATERIAL AND METHODS: A review was made of all cases of neuroendocrine tumors diagnosed at Hospital Universitario Clínico San Carlos (HUCSC) from January 2007 to May 2012. Data were compared to the results provided by the Registry of the Spanish Group on Neuroendocrine Tumors (RGETNE). RESULTS: The study cohort comprised 78 patients. Gastroenteric nonfunctional tumors were the most common neoplasms. Metastases were found at diagnosis in50.6% of patients, with nodal involvement being most prevalent. Tumors located in the rectum were associated to the highestrate of metastasis. Overall 2-year survival rate was 74.8% and was related to sex, Ki-67 expression, and presence of metastasis.

Diabetic foot units in Spain: knowing the facts using a questionnaire.

OBJECTIVE: To ascertain the number of diabetic foot units (DFUs) in Spain, the specialists working in them, and the population covered by them. MATERIAL AND METHODS: The Spanish Group on the Diabetic Foot (SGDF) prepared and agreed a questionnaire based on the recommendations of the 2011 International Consensus on the Diabetic Foot (ICDF). From October to December 2012, the questionnaire was sent to members of three scientific societies formed by professionals involved in the care of patients with diabetes mellitus. Population coverage of the responding centers and DFUs was estimated using the 2012 population census. RESULTS: Seventy five questionnaires were received, 64 of them from general hospitals, which accounted for 13% of the general hospitals of the National Health System. It was calculated that they provided coverage to 43% of the population. Thirty four centers answered that they had a DFU. Specialized diabetic foot care was only provided to 25% of the population. The number of different professionals working at diabetic foot units was 6.3±2.7. Classification of DFUs based on their complexity was as follows: 5 basic units (14.7%), 20 intermediate units (58.8%), and 9 excellence units (26.5%). CONCLUSIONS: The number of DFUs reported in this study in Spain is low, and allow for foot care of only one out of every four patients with diabetes. Spanish health system needs to improve diabetic foot care by creating new DFUs and improving the existing ones.

Prognostic factors and long-term outcome of pancreatic neuroendocrine neoplasms: Ki-67 index shows a greater impact on survival than disease stage. The large experience of the Spanish National Tumor Registry (RGETNE).

INTRODUCTION: Pancreatic neuroendocrine neoplasms (PNENs) are uncommon neoplasms with a wide spectrum of clinical behavior. The objective of this study was to assess in a large cohort of patients the relative impact of prognostic factors on survival. METHODS: From June 2001 through October 2010, 1,271 patients were prospectively registered online (www.getne.org) at the Spanish National Cancer Registry for Gastroenteropancreatic Neuroendocrine Tumors (RGETNE) by participating centers. Clinical and histopathological features were assessed as potential prognostic factors by uni- and multivariate analyses. RESULTS: Of 483 PNENs, 171 (35%) were functional (F) and 312 (65%) non-functional (NF). NF-PNENs were associated with a higher incidence of histological features denoting more aggressive disease, such as poor tumor differentiation, Ki-67 >20%, or vascular invasion (NF- vs. F-PNENs, respectively, p < 0.05). Nevertheless, functionality was not a significant predictor of survival (p = 0.19). Stage at diagnosis, Ki-67 index, tumor differentiation and surgical resection of the primary tumor were all significant prognostic factors in univariate analysis. However, Ki-67 (>20 vs. ≤2%) (hazard ratio (HR) 2.21, p = 0.01) and surgical resection (yes vs. no) (HR 0.92, p = 0.001) were the only independent predictors of survival in multivariate analysis. Among patients who underwent surgery, high Ki-67 index (HR 10.37, p = 0.02) and poor differentiation (HR 8.16, p = 0.03) were the only independent predictors of clinical outcome. CONCLUSION: Ki-67 index and tumor differentiation are key prognostic factors influencing survival of patients with PNENs and, in contrast to what it is observed for other solid malignancies, they seem to have a greater impact on survival than the extent of disease. This should be borne in mind by physicians in order to appropriately tailor therapeutic strategies and surveillance of these patients.