Prospective Randomized Multicenter Trial Research Articles

CAN ARTHOPLASTY STEM INFLUENCE OUTCOME (CASINO): A RANDOMIZED CONTROLLED TRIAL OF STEM LENGTH IN CEMENTED TOTAL HIP ARTHROPLASTY

In this RCT the primary aim was to assess whether a short (125mm) Exeter V40 stem offered an equivalent hip specific function compared to the standard (150mm) stem when used for cemented total hip arthroplasty (THA). Secondary aims were to evaluate health-related quality of life (HRQoL), patient satisfaction, stem height and alignment, radiographic loosening, and complications between the two stems.A prospective multicentre double-blind randomised control trial was conducted. During a 15-month period, 220 patients undergoing THA were randomised to either a standard (n=110) or short (n=110) stem Exeter. There were no significant (p≥0.065) differences in preoperative variables between the groups. Functional outcomes and radiographic assessment were undertaken at 1- and 2-years.There were no differences (p=0.428) in hip specific function according to the Oxford hip score at 1-year (primary endpoint) or at 2-years (p=0.767) between the groups. The short stem group had greater varus angulation (0.9 degrees, p=0.003) when compared to the standard group and were more likely (odds ratio 2.42, p=0.002) to have varus stem alignment beyond one standard deviation from the mean. There were no significant (p≥0.083) differences in the Forgotten joint scores, EuroQol-5-Dimension, EuroQol-VAS, Short form 12, patient satisfaction, complications, stem height or radiolucent zones at 1 or 2-years between the groups.The Exeter short stem offers equivalent hip specific function, HRQoL, patient satisfaction, and limb length when compared to the standard stem at 2-years post-operation. However, the short stem was associated with a greater rate of varus malalignment which may influence future implant survival.

From the lab to the clinic: Lessons learned from a translational working group.

e12576 Background: Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET), is a phase III multicenter prospective randomized clinical trial comparing the risks/benefits of active monitoring (AM) versus surgery for women with low-risk DCIS. Funded by the Patient-Centered Outcomes Research Institute, accrual opened 06/30/17 and closed 01/13/23 with 995 women enrolled. Biospecimens (blood/tissue) and breast images were collected at specified timepoints (funded by the Breast Cancer Research Foundation) and stored in central tissue/image repositories. To date, more than 90% of requested samples/images have been submitted. Methods: In 2017, the COMET Translational Working Group (TWG) was formed to facilitate the collection, submission, storage, and subsequent analysis of biospecimens/images. The TWG, consisting of clinicians, pathologists, radiologists, researchers, and patient advocates (PAs), discuss topics such as categorization of biospecimens into discovery/validation sets; development of a pathology workflow/sample tracking process; and potential areas of future research that may improve DCIS diagnostics, prognostics, and care management. Results: The TWG consists of multiple partner institutions, and team members have complementary areas of expertise/experience. While competing views may exist, consensus has been achieved in relation to major issues such as authorship, biospecimen ownership, intellectual property and criteria relevant to patient needs, through targeted discussion at monthly meetings. Logistical barriers, including data sharing and the technicalities of biospecimen release, have also been resolved through this process. The TWG has played an integral role in resolving recruitment challenges. In 2019, guidance from the TWG related to standardizing pathology eligibility criteria resulted in evidence-based protocol amendments that subsequently increased accrual. A retrospective review of biospecimens was performed to determine adequacy for ensuing correlative molecular and spatial profiling studies. PAs are integral to the TWG, assisting with logistical issues (resource requests); identifying study topics relevant to patients; providing guidance on existing (commercial) predictive/prognostic tests; promoting effective stewardship of a finite resource (tissue samples); and ensuring that the overall focus of the TWG remains firmly on advancing clinical utility. Conclusions: The COMET TWG serves the important role of overseeing biospecimen/image collection including its use and sharing. This facilitates development of research and technology that can impact the decision for surgery vs AM in women with low-risk DCIS, and ensure the translation of research findings into everyday clinical practice. Subsequent correlative science studies identified by the TWG stand to improve future DCIS pathology diagnostics, prognostics and care management.

The “Aberdeen Home Continence Stress Test”: a novel objective assessment tool for female stress urinary incontinence

Introduction and hypothesisClinical trials for stress urinary incontinence (SUI) require a robust, reliable, and responsive tool for objective assessment of SUI post-intervention. The Aberdeen Home Continence Stress Test (HCST) is a novel patient-reported objective assessment tool, aimed to be patient-friendly and reduce attrition rates by avoiding hospital appointments and prolonged pad-wearing. We aim to describe the HCST for the first time and evaluate its reliability, diagnostic accuracy, and response to change.MethodsA secondary analysis of the Single-Incision Mini-Slings (SIMS) study (a prospective multicentre randomised control trial (RCT) comparing two surgical treatments of SUI was performed. In SIMS (n = 600 women), the objective outcome was assessed by the 24-h pad test, while the patient-reported success rates were assessed using the Patient Global Impression of Improvement (PGI-I) at 15 months, 2 years and 3 years post-randomisation. Participants were instructed to perform the HCST before and after the 24-h pad test. The HCST was analysed in relation to reliability, validity, and the relationship between the 24-h pad test and HCST results and finally with regard to its responsiveness to change in PGI-I. (Trial registration-number ISRCTN93264234, registration date 14/01/2014).ResultsCompared to the 24-h pad test, the sensitivity of the HCST ranged from 0.81–0.95, specificity was 0.76–0.79, negative predictive value was 0.96–0.99 and positive predictive value was 0.32–0.43. Reliability was indicated by high-performing Cronbach’s alpha value (> 0.7). An improvement of ≥ 2 leakage groups on the HCST (for example from Large at baseline to Small leakage at follow-up) was strongly associated with patient-reported success on PGI-I (OR 4.38, 95% CI 2.31, 8.31).ConclusionsThe HCST is a valid and reliable patient-reported objective assessment tool that can be used for assessing SUI in surgical trials with good specificity, sensitivity, and consistency.

104 A Safety and Efficacy Study of NicaPlant® in Aneurysmal Subarachnoid Haemorrhage Patients Undergoing Aneurysm Clipping

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) has high morbidity and mortality. Secondary mechanisms of injury can aggravate the high negative impact. Cerebral vasospasm (CV) is one of the most relevant causes of this secondary injury. To improve the current treatment options, NicaPlant® was developed. METHODS: The trial was performed as an international randomized, controlled, single-blinded multicenter study. 40 Patients with WFNS grade 3 and 4 SAH undergoing surgical repair of their ruptured aneurysm were randomized to receive ten pellets of NicaPlant® (40 mg) plus standard of care or standard of care alone. The implants were administered immediately following clip ligation of the ruptured aneurysm in proximity to all the exposed cerebral blood vessels. The primary endpoint was the incidence of moderate to severe CV (day 8 ± 1). A blinded independent outcome accessor analyzed all imaging data. RESULTS: In the implant group, 20% (4/20) of patients reached the primary endpoint, compared to 58% (11/19) of patients in the control group (p = 0.024). Including mild CV, 75% of all patients in the control group developed CV compared to 30% in the implant group (p = 0.0129). 32% (6/19) of the patients in the control group developed new cerebral infarction, compared to 10% (2/20) in the implant group (p = 0.1273). Endovascular rescue therapy was performed in 10% of the patients in the implant group compared to 58% in the control group (p = 0.002). 4 subjects (20%) in the control group experienced Treatment-emergent adverse events (TEAE), compared with none in the active group. CONCLUSIONS: In this prospective randomized multicenter Phase 2b trial, we could demonstrate the safety and efficacy of NicaPlant® implants in preventing CV in patients with SAH.

Treatment outcomes for acute T-lymphoblastic leukemias/lymphomas: data from the ALL-2016 multicenter prospective randomized trial

Background . The effectiveness of therapy for acute T-lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LBL) has significantly improved over the past decades, including through the implementation of hematopoietic stem cell transplantation (HSCT). The Russian multicenter ALL-2009 study (ClinicalTrials.gov NCT01193933) showed that performing autologous HSCT (auto-HSCT) in patients with T-ALL/LBL improves long-term results. However, the study was non-randomized and the need for auto-HSCT in clinical practice requires careful study. Aim . To assess the significance of auto-HSCT in patients with T-ALL/LBL in the framework of ALL-2016 multicenter, prospective, randomized study (ClinicalTrials.gov NCT03462095). Materials and methods . The study included 109 adult patients with T-ALL/LBL (m:f 82:27). Median age was 31 (18– 52) years. T-ALL was diagnosed in 88 (81 %) patients, T-LBL in 21 (19 %) patients. All patients are treated according to the ALL-2016 protocol. Using the web platform, upon completion of induction therapy (+70 days), all T-ALL/LBL patients who achieved clinical and hematological remission were randomized to the auto-HSCT arm or chemotherapy alone (CT). Centralized monitoring of minimal residual disease (MRD) in bone marrow samples was performed by multicolor flow cytometry at the control points according to the ALL-2016 protocol. Statistical analysis was performed using SAS 9.4. Results . 87 patients with T-ALL/LBL were randomized: 44 to the auto-HSCT arm and 43 to the CT arm. Further analysis included 25 patients who underwent auto-HSCT and 36 patients receiving only CT. Three-year relapse-free survival in T-ALL is estimated at 62 % (auto-HSCT) vs. 81 % (CT) (p = 0.3422), and in T-LBL – 67 % (auto-HSCT) vs. 79 % (CT) (p = 0.59). MRD persistence on the +70 th day of therapy according to the ALL-2016 protocol was determined in 40 % of patients (autoHSCT) and in 67 % (CT) (p = 0.057). In a multivariate analysis, it was determined that T-ALL from early T-cell precursor (ETP-variant) and MRD persistence after the end of II phase induction are the main risk factors for relapse in the treatment according to the ALL-2016 protocol. Conclusion . Performing auto-HSCT both in patients with T-ALL and T-LBL, and with MRD persistence on day +70 according to the ALL-2016 protocol did not improve long-term results. The development of new programs for the treatment of patients with MRD persistence, as well as the ETP variant of T-ALL, is of current interest.

Effects of Aerobic Exercise in the Intensive Care Unit on Patient-Reported Physical Function and Mental Health Outcomes in Severely Burned Children-A Multicenter Prospective Randomized Trial.

Forty-eight children between the ages of seven and seventeen with ≥30% total body surface area (TBSA) burn were randomized in a 1:2 fashion to receive treatment with standard-of-care (SOC) or standard-of-care plus exercise (SOC+Ex). Surveys administered at admission and discharge collected patient-reported information regarding physical and mental health outcomes. The results are given as means +/- standard deviation. Significance was set at p < 0.05. The average age of the SOC and SOC+Ex groups were 12 ± 3 and 13 ± 4 years, respectively. The average %TBSA burned in the SOC and SOC+Ex groups were 54 ± 17 and 48 ± 14, respectively. The SOC+Ex group averaged 10 ± 9 exercise sessions (range of 1 to 38 sessions) with an attendance rate of 25% (10 sessions out of 40 BICU days). Both groups demonstrated significant improvement in patient-reported physical and mental outcomes during hospital admission (p < 0.05) However, additional exercise did not exhibit any additional benefits for measured levels. Our recommendation is for all pediatric patients in the BICU to continue with the SOC and consult with their physician over the benefits of additional aerobic exercise. This study suggests that perhaps there is potential for increasing the amount of exercise that can be administered to pediatric burn survivors beyond SOC as we did not find aerobic exercise to be of any harm to any patients if it is performed properly and under supervision.

A comparison of heart failure patients with reduced ejection fraction in the Moravian Midlands Registry with the LCZ696 patients in the Paradigm-HF trial.

There are limited data on real clinical practice in heart failure patients in the Czech Republic. We analysed the clinical parameters from the Moravian Midlands Registry (MMR) and compared them to LCZ696 patients in the Paradigm-HF trial. The Moravian Midlands Registry is a retrospective patient database from two outpatient cardiology centres in the Czech Republic. The Paradigm-HF is a large-scale prospective randomized multicentre trial with more than 8000 individuals with stabilized chronic heart failure. A retrospective analysis of heart failure with reduced ejection fraction patients from two outpatient cardiology centres in the Czech Republic from October 2016 to December 2019. Patients in the MMR were younger (60.5 ± 10.7 vs 63.8 ± 11.5 years, P<0.05), had a higher body mass index (30.3 ± 5.0 vs 28.1 ± 5.5, P<0.05) and higher serum creatinine level (101.9 ± 36.0 vs 99.9 ± 26.5 µmol/L, P<0.05). MMR patients had lower left ventricular ejection fraction (27.8 ± 6.9 vs 29.6 ± 6.1%, P<0.05). The serum N-terminal pro-B-type natriuretic peptide, [2563.5 (377-3536) vs 1631 (885-3154), was non significantly higher P=0.07]. Pharmacotherapy use differed for mineralocorticoid antagonist (91.4% in MMR vs 54.2% in Paradigm-HF), and digoxin (13.5% vs 29.2%). Beta-blocker use was similar (96.2% vs 93.1%) as was angiotensin-converting enzyme (ACE) inhibitors - (71.2% vs 78.0%) and angiotensin-receptor blockers - ARB (27.9% vs 22.2%). Dosages of the commonly used ACE inhibitors at the screening visit (Paradigm-HF) / before angiotensin receptor-neprilysin inhibitor administration (MMR) differed significantly only for ramipril (7.0 ± 3.1 mg vs 4.8 ± 2.9 mg, P<0.05), dosages of ARB were - losartan (67.1 ± 30.2 vs 39.6 ± 32.0 mg, P=0.09) and valsartan (181.5 ± 71.1 vs 130.9 ± 82.2 mg, P=0.07). There was a substantial difference in device-based therapy (ICD in 60.6%, CRT 25.9% in MMR vs 14.9% and 7.0% in Paradigm-HF). The differences between the groups for the majority of clinical parameters compared were minimal, except for younger age, higher body mass index and serum creatinine level and lower left ventricular ejection fraction and substantially lower dosage of administered ramipril prior to commencing sacubitril/valsartan therapy. There was a higher prevalence of implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT) in the MMR group.

Efficacy and safety of clean intermittent catheterization in management of acute urinary retention: A multicenter prospective randomized trial

Efficacy and safety of clean intermittent catheterization in management of acute urinary retention: A multicenter prospective randomized trial

A prospective randomized multicenter trial for lymphadenectomy in early-stage ovarian cancer: LOVE study.

The Lymphadenectomy in Ovarian Neoplasms (LION) study revealed that systemic lymphadenectomy did not bring survival benefit for advanced ovarian cancer patients with clinically normal lymph nodes and was associated with a higher incidence of operative complications. However, there is no consensus on whether lymphadenectomy has survival benefit or not in early epithelial ovarian cancer (EOC). We designed the LOVE study, a multicenter, randomized controlled, phase III trial to compare the efficacy and safety of comprehensive staging surgery with or without lymphadenectomy in stages IA-IIB EOC and fallopian tube carcinomas (FTC). The hypothesis is that the oncological outcomes provided by comprehensive staging surgery without lymphadenectomy are non-inferior to those of conventional completion staging surgery in early-stage EOC and FTC patients who have indications for post-operative adjuvant chemotherapy. Patients assigned to experimental group will undergo comprehensive staging surgery, but lymphadenectomy. Patients assigned to comparative group will undergo completion staging surgery including systematic pelvic and para-aortic lymphadenectomy. All subjects will receive 3-6 cycles of standard adjuvant chemotherapy. Major inclusion criteria are pathologic confirmed stage IA-IIB EOC or FTC, and patients have indications for adjuvant chemotherapy either confirmed by intraoperative fast frozen section or previous pathology after an incomplete staging surgery. Major exclusion criteria are non-epithelial tumors and low-grade serous carcinoma. Patients with severe rectum involvement which lead to partial rectum resection will be excluded. The sample size is 656 subjects. Primary endpoint is disease-free survival. ClinicalTrials.gov Identifier: NCT04710797.

Physiologic Effects of the Awake Prone Position Combined With High-Flow Nasal Oxygen on Gas Exchange and Work of Breathing in Patients With Severe COVID-19 Pneumonia: A Randomized Crossover Trial.

Prospective randomized physiologic crossover multicenter trial. Four ICUs in Marseille, France. Seventeen patients with laboratory-confirmed COVID-19 pneumonia and Pao2/Fio2 less than or equal to 300 mm Hg while treated with high-flow nasal cannula oxygen therapy. Periods of APP and semirecumbent position (SRP) were randomly applied for 2 hours and separated by a 2-hour washout period. Arterial blood gases, end-tidal CO2. and esophageal pressure were recorded prior to and at the end of each period. Inspiratory muscle effort was assessed by measuring the esophageal pressure swing (∆PES) and the simplified esophageal pressure-time product (sPTPES). The other endpoints included physiologic dead space to tidal volume ratio (VD/VT) and the transpulmonary pressure swing. The APP increased the Pao2/Fio2 from 84 Torr (61-137 Torr) to 208 Torr (114-226 Torr) (p = 0.0007) and decreased both the VD/VT and the respiratory rate from 0.54 (0.47-0.57) to 0.49 (0.45-0.53) (p = 0.012) and from 26 breaths/min (21-30 breaths/min) to 21 breaths/min (19-22 breaths/min), respectively (p = 0.002). These variables remained unchanged during the SRP. The ∆PES and sPTPES per breath were unaffected by the position. However, the APP reduced the sPTPES per minute from 225 cm H2O.s.m-1 (176-332 cm H2O.s.m-1) to 174 cm H2O.s.m-1 (161-254 cm H2O.s.m-1) (p = 0.049). In spontaneously breathing patients with COVID-19-associated AHRF supported by high-flow nasal oxygen, the APP improves oxygenation and reduces the physiologic dead space, respiratory rate, and work of breathing per minute.

Overview of oxidative stress and the role of micronutrients in critical illness.

Inflammation and oxidative stress represent physiological response mechanisms to different types of stimuli and injury during critical illness. Its proper regulation is fundamental to cellular and organismal survival and are paramount to outcomes and recovery from critical illness. A proper maintenance of the delicate balance between inflammation, oxidative stress, and immune response is crucial for resolution from critical illness with important implications for patient outcome. The extent of inflammation and oxidative stress under normal conditions is limited by the antioxidant defense system of the human body, whereas the antioxidant capacity is commonly significantly compromised, and serum levels of micronutrients and vitamins significantly depleted in patients who are critically ill. Hence, the provision of antioxidants and anti-inflammatory nutrients may help to reduce the extent of oxidative stress and therefore improve clinical outcomes in patients who are critically ill. As existing evidence of the beneficial effects of antioxidant supplementation in patients who are critically ill is still unclear, actual findings about the most promising anti-inflammatory and antioxidative candidates selenium, vitamin C, zinc, and vitamin D will be discussed in this narrative review. The existing evidence provided so far demonstrates that several factors need to be considered to determine the efficacy of an antioxidant supplementation strategy in patients who are critically ill and indicates the need for adequately designed multicenter prospective randomized control trials to evaluate the clinical significance of different types and doses of micronutrients and vitamins in selected groups of patients with different types of critical illness.

Rationale and design of BROKEN-SWEDEHEART: a registry-based, randomized, parallel, open-label multicenter trial to test pharmacological treatments for broken heart (takotsubo) syndrome

Takotsubo syndrome (TS) is a life-threatening acute heart failure syndrome without any evidence-based treatment options. No treatment for TS has been examined in a randomized trial. BROKEN-SWEDEHEART is a multicenter, randomized, open-label, registry-based 2×2 factorial clinical trial in patients with TS designed to test whether treatment with adenosine and dipyridamole accelerates cardiac recovery and improves clinical outcomes compared to standard care (study 1); and apixaban reduces the risk of thromboembolic events compared to no treatment with antithrombotic drugs (study 2). The trial will enroll 1,000 patients. Study 1 (adenosine hypothesis) will evaluate 2 coprimary end points: (1) wall motion score index at 48 to 96 hours (evaluated in the first 200 patients); and (2) the composite of death, cardiac arrest, need for mechanical assist device or heart failure hospitalization within 30 days or left ventricular ejection fraction <50% at 48 to 96 hours (evaluated in 1,000 patients). The primary end point in study 2 (apixaban hypothesis) is the composite of death or thromboembolic events within 30 days or the presence of intraventricular thrombus on echocardiography at 48 to 96 hours. BROKEN-SWEDEHEART will be the first prospective randomized multicenter trial in patients with TS. It is designed as 2 parallel studies to evaluate whether adenosine accelerates cardiac recovery and improves cardiac function in the acute phase and the efficacy of anticoagulation therapy for preventing thromboembolic complications in TS. If either of its component studies is successful, the trial will provide the first evidence-based treatment recommendation in TS. The trial has been approved by the Swedish Medicinal Product Agency and the Swedish Ethical Board and is registered at ClinicalTrials.gov (NCT04666454).

ALL-REZ BFM 2002 Is Associated with Improved Outcome as Compared to ALL-R3 Strategy in Children with Standard Risk Isolated CNS Relapse of Acute Lymphoblastic Leukemia, while Maintaining Comparable Efficacy in Patients with Bone Marrow Relapse. Results of the Multi-National, Multi-Center Trial IntReALL SR 2010

Background: Around 15% of children with acute lymphoblastic leukemia (ALL) experience disease relapse. The prognosis of these patients largely depends on the site of recurrence, time to relapse and leukemia immunophenotype. The ALL-REZ BFM 2002 and the ALL R3 trials have proved to be effective in previous trials. The IntReALL SR 2010 trial, conducted under the umbrella of the I-BFM SG, aimed at investigating feasibility, toxicity and efficacy of both treatment strategies in a large multi-national, multi-center prospective randomized trial. Methods: Patients with a first standard-risk (SR) ALL relapse aged 1 - 17 years were recruited to the trial from 23/Oct/2014 to 31/Jul/2020 in 17 countries (210 centers). SR relapse criteria were: late (≥ 6 months after end of initial therapy) isolated bone marrow (BM) relapse, late or early (< 6 months after end of initial therapy and ≥ 18 months after initial diagnosis) combined BCP-ALL BM relapse, any late/early isolated extramedullary (IEM) relapse. They were randomized at a 1:1 rate to receive either arm A (ALL-REZ BFM 2002) or B (ALL R3). During consolidation, patients were randomized to receive the CD22-directed monoclonal antibody epratuzumab in addition to backbone chemotherapy. Results of this 2nd randomization will be communicated separately. Patients with late BM relapse were allocated to consolidation and maintenance chemotherapy or to allogeneic hematopoietic stem-cell transplantation (HSCT), depending on their minimal residual disease (MRD, cut-off arm A 10e-3 and arm B 10e-4) assessed after induction therapy. Patients with early either combined BM or IEM relapse were allocated to receive allogeneic HSCT. Results: Overall, 620 patients were randomized to receive arm A (n=304) or Arm B (n=316). Patient's characteristics were equally distributed among both groups (table 1). Induction death, 2nd remission rate, death in remission (5-years cumulative incidence (CI) 4.1 vs 7.4%, p=0.10), and subsequent relapse rates by arm A and B (CI 23.8 vs 22.8, p=0.80) did not differ between both groups. The MRD response rate with < 10e-4 post induction was significantly higher in Arm B (p=0.015), but not significantly different based on the arm specific cut-off, leading to comparable rates of allogeneic HSCT. The probability of 5-years event-free survival (pEFS) with arm A versus arm B was 70.2±3.1 SE versus 68.5±3.1 (p=0.61, figure 1) and that of overall survival (pOS) was 86.7±2.3 versus 87.1±2.0 (p=0.8). Subgroup analyses revealed a significantly higher pEFS in patients with isolated CNS relapse when treated with arm A (81.6±6.3, n=40) compared to arm B (43.3±8.3, n=45, p=0.001), whereas in patients with BM involvement or those with non-CNS IEM relapse, no significant difference was found (p=0.41). However, patients with isolated BM relapse experienced a higher CI of subsequent relapse with arm A (12.5±2.1, n=146) as compared to arm B (6.5±1.6, n=153, p=0.008). Patients with late BM relapse and MRD poor response after induction had comparable pDFS (arm A 65.8±6.4, n=74; arm B 68.8±6.2, n=75; p=0.71), which also did not differ from that of patients with MRD good response (arm A 67.7±5.6, n=100; arm B 68.9±5.6, n=113; p=0.77). Patients with late IEM relapse achieved a pEFS of 86.7±4.6 whereas those with early relapse and HSCT indication achieved a pEFS 61.8±5.4 (p=0.0004). Rates of reported severe adverse events (SAEs) per treatment phase did not differ between arms except nervous system disorders occurring more frequently in arm A (p=0.03, table 1). Conclusion: Both arm A and B were effective in this large multi-national trial. EFS and OS probabilities compare favorably to results recently published by other cooperative groups. In particular, the outcome of patients with early IEM relapse or with late BM relapse and MRD poor response is encouraging confirming the benefit of allo HSCT in these subgroups. Due to superior outcome of isolated CNS relapse with arm A, patients without BM involvement will receive that arm as backbone in future trials. Since arm B showed a better MRD response rate after induction and a lower relapse rate in patients with BM relapse, it will be implemented as backbone for future trials in patients with BM involvement. Toxicity (TRM and SAE rates) is substantial in both arms demonstrating the urgent medical need of replacing toxic chemotherapy elements with equally effective, but less toxic targeted immunotherapy strategies in future trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Endoscopic retrograde appendicitis therapy (ERAT) vs appendectomy for acute uncomplicated appendicitis: A prospective multicenter randomized clinical trial.

To compare the efficacy and feasibility of endoscopic retrograde appendicitis therapy (ERAT) with appendectomy for treating acute uncomplicated appendicitis. This was a prospective multicenter randomized trial in which consecutive patients were randomized at a ratio of 1:1 to receive either ERAT or appendectomy. The outcomes included technical success rate, procedure time, postoperative pain relief, postoperative analgesic use, time to soft diet intake, length of postoperative hospital stay, postoperative complications, and recurrence rate. From August 2013 to December 2015, 110 patients with acute uncomplicated appendicitis were randomized to ERAT or appendectomy. The technical success rate was 94.55% for ERAT compared with 100% for appendectomy. Recurrence of appendicitis within 3-year follow-up occurred in 8 patients following ERAT. Postoperative abdominal pain was less frequent with ERAT than with appendectomy (21.15% [11/52] vs 87.27% [48/55], P<0.001). Soft diet intakebegun earlier after ERAT than appendectomy (6h vs 48 h, P < 0.001), and post-procedure hospital stay was shorter (3 days vs 5 days, P<0.001), as was the use of analgesics postoperatively (9.09% vs 49.09%, P < 0.001). ERAT is a feasible, safe, and effective alternative approach for the management of acute uncomplicated appendicitis. Compared with appendectomy, advantages of ERAT include no skin wound, organ preservation, reduced postoperative pain, early food intake, quick recovery, fewer postoperative complications, and shorter post-procedure hospitalization. The unsolved problem related to ERAT is the recurrence of appendicitis.

Invasive Diagnostic and Therapeutic Management of Cerebral VasoSpasm after Aneurysmal Subarachnoid Hemorrhage (IMCVS)-A Phase 2 Randomized Controlled Trial.

Cerebral vasospasm (CVS) is associated with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). The most frequently used form of rescue therapy for CVS is invasive endovascular therapy. Due to a lack of prospective data, we performed a prospective randomized multicenter trial (NCT01400360). A total of 34 patients in three centers were randomized to invasive endovascular treatment or conservative therapy at diagnosis of relevant CVS onset. Imaging data was assessed by a neuroradiologist blinded for treatment allocation. Primary outcome measure was development of DCI. Secondary endpoints included clinical outcome at 6 months after SAH. A total of 18 of the 34 patients were treated conservatively, and 16 patients were treated with invasive endovascular treatment for CVS. There was no statistical difference in the rate of cerebral infarctions either at initial or at the follow-up MRI between the groups. However, the outcome at 6 months was better in patients treated conservatively (mRs 2 ± 1.5 vs. 4 ± 1.8, p = 0.005). Invasive endovascular treatment for CVS does not lead to a lower rate of DCI but might lead to poorer outcomes compared to induced hypertension. The potential benefits of endovascular treatment for CVS need to be addressed in further studies, searching for a subgroup of patients who may benefit.

The effect of minimally invasive or open radical antegrade modular pancreatosplenectomy on pancreatic cancer: A multicenter randomized clinical trial protocol.

BackgroundRadical antegrade modular pancreatosplenectomy (RAMPS) has been proven to improve R0 resection and lymph harvest in treating patients with distal pancreatic cancer. The development of minimally invasive surgery has advantages in postoperative recovery. Therefore, minimally invasive (MI-) RAMPS may combine the advantages of both benefits to improve survival. Nevertheless, evidence to validate the safety and efficacy of MI-RAMPS is limited.Method/DesignThe MIRROR trial will be the first multicenter prospective randomized clinical trial to investigate the outcome of MI-RAMPS. The hypothesis is that MI-RAMPS is superior in postoperative recovery. The primary outcome is the length of postoperative stay. Based on the hypothesis and primary outcome, the sample size is 250 patients (125 participants in each group). The trial will investigate factors related to surgical safety, short-term outcome, pathological assessment, and survival as secondary outcomes.ConclusionThis study will offer a relatively higher level of evidence to further illustrate the accessibility and benefits of MI-RAMPS for the treatment of distal pancreatic cancer.Clinical Trial Registration Clinicaltrials.gov, NCT03770559.

Effect of initial levothyroxine dose on neurodevelopmental and growth outcomes in children with congenital hypothyroidism

ObjectivesWe designed a multicentre open prospective randomized trial to evaluate the risk-benefit profile of two different initial treatment schemes with levothyroxine (L-T4), 10-12.5 μg/kg/day vs 12.6-15 μg/kg/day, on growth and neurodevelopmental outcomes in children with congenital hypothyroidism (CH) detected by neonatal screening to identify the best range dose to achieve optimal neurocognitive development.Design, patients and methodsChildren detected by neonatal screening were randomly assigned to receive an initial L-T4 dose of 10-12.5 μg/kg/day (Low) or 12.6-15 μg/kg/day (High). All patients underwent periodical clinical examination with measurement of growth parameters and measurement of TSH and FT4. Neurocognitive development was evaluated at the age of 24 months using Griffiths Mental Development Scales (GMDS) and cognitive and behavioral assessment was performed at 48 months of age using Wechsler Preschool and Primary scale of Intelligence (WIPPSI-III). The study was registered with clinicaltrials.gov (NCT05371262).ResultsTreatment schemes below or above 12.5 μg/kg/day were both associated with rapid normalization of TSH and thyroid hormone levels in most patients with no differences in the risk of over- and under-treatment episodes in the first months of life. Growth parameters were normal and comparable between the two groups. Developmental quotients at 24 months of age were normal in both groups (Low 100.6 ± 15.5 vs High 96.9 ± 16.6). Likewise, at 4 years of age IQ and subtest scores were comparable between patients from Low and High (Total IQ 104.2 ± 11.4 vs 101.0 ± 20.3, Verbal IQ 103.9 ± 11.5 vs 98.7 ± 15.1, Performance IQ 105.3 ± 10.4 vs 100.3 ± 19.8). 6/45 CH patients (13.3%) showed a total IQ below 85 (73.7 ± 5.9) regardless of age at diagnosis, L-T4 starting dose, time of FT4 and TSH normalization and episodes of over and undertreatment. Worse socioeconomic status and delayed bone age at diagnosis were the only predictors of an increased risk of having suboptimal IQ at 24 and IQ at 48 months.ConclusionsOur results indicate that initial treatment with L-T4, 10-12.5 μg/kg/day vs 12.6-15 μg/kg/day, are both associated with normal growth and neurodevelopmental outcomes in children with CH detected by neonatal screening. Further studies with a long-term follow-up on a larger number of patients are needed to confirm these results.Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT05371262?term=NCT05371262&draw=2&rank=1 identifer NCT05371262.

EP07.01-026 Primary Pulmonary Ewing'S Sarcoma: Post Hoc Analysis From Two International Multicenter Prospective Randomized Trials

Primary pulmonary sarcoma accounts for 1% of all pulmonary malignant tumors. Ewing's sarcoma (ES) is an aggressive cancer with an incidence of 1 per 1,000,000. It is most commonly diagnosed in the second decade of life. It usually derives from bony structures of the axial skeleton, pelvis and femur but can occur in every localization. Pulmonary ES is extremely rare with less than 40 cases reported mostly as case reports. Here we aimed to gain better understanding of primary pulmonary ES in describing patients treated within two international multicenter prospective randomized ES trials.

Adherence to Mediterranean Diet and NAFLD in Patients with Metabolic Syndrome: The FLIPAN Study.

Unhealthy diet is an important factor in the progression of non-alcoholic fatty liver disease (NAFLD). Previous studies showed the benefits of a Mediterranean diet (MedDiet) on Metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and cardiovascular diseases, which usually have a pathophysiological relationship with NAFLD. To assess the effect of adherence to a MedDiet on NAFLD in MetS patients after lifestyle intervention, this multicentre (Mallorca and Navarra, Spain) prospective randomized trial, with personalized nutritional intervention based on a customized MedDiet, coupled with physical activity promotion was performed to prevent, and reverse NAFLD among patients with MetS. The current analysis included 138 patients aged 40 to 60 years old, Body Mass Index (BMI) 27–40 kg/m2, diagnosed with NAFLD using MRI, and MetS according to the International Diabetes Federation (IDF). A validated food frequency questionnaire was used to assess dietary intake. Adherence to Mediterranean diet by means of a 17-item validated questionnaire, anthropometrics, physical activity, blood pressure, blood biochemical parameters, and intrahepatic fat contents (IFC) were measured. The independent variable used was changes in MedDiet adherence, categorized in tertiles after 6 months follow-up. Subjects with high adherence to the MedDiet showed higher decreases in BMI, body weight, WC, SBP, DBP, and IFC. An association between improvement in adherence to the MedDiet and amelioration of IFC after 6-month follow-up was observed. High adherence to the MedDiet is associated with better status of MetS features, and better values of IFC.

Defining the role of pre-operative hormonal therapy in hypospadias.

In hypospadias surgery, pre‐operative hormonal therapy (PHT) is primarily used to increase penile dimensions and the vascularity of tissues available for reconstruction, but its use is non‐uniform in clinical practice, with no consensus on application or utility. This review aims to summarise: (i) the penile tissue response to hormone therapy, (ii) its impact on hypospadias surgery outcomes, and (iii) the endocrinological considerations and sequelae. PHT is more often indicated for complex cases such as proximal hypospadias, hypospadias with microphallus and hypospadias reoperations. While PHT has clear effects on penile morphometry, and more recent controlled trials suggest improved surgical outcomes, the lack of consistent outcome definitions and generally inadequate follow‐up periods continue to consign many of the potential long‐term effects of PHT to the unknown. There is currently insufficient robust evidence to allow a clinical guideline to be constructed. The need for a well‐powered multi‐centre prospective randomised trial to address this question is evident but awaits a unified consensus on issues surrounding the understanding of aetiology, classification of hypospadias morphology, definition of important prognostic variables and uniform application of outcome measures. The effects of PHT may be utilised to improve outcomes in cases of proximal and severe hypospadias, which under the current paradigm represent a significant surgical challenge.