Prospective Randomized Multicenter Trial Research Articles

Apixaban vs. warfarin in patients with left ventricular thrombus: a prospective multicentre randomized clinical trial‡.

Current guidelines recommend anticoagulation with a vitamin K antagonist to treat left ventricular (LV) thrombus after myocardial infarction (MI). Data on the use of direct oral anticoagulants (DOACs) in this setting are limited. The aim of the study was to assess the efficacy of apixaban vs. warfarin in treating LV thrombus after MI. We conducted a prospective, randomized, multicentre open-label clinical trial including patients with LV thrombus detected by 2D transthoracic echocardiography 1-14 days after acute MI. Thirty-five patients were enrolled in three medical centres; 17 patients were randomized to warfarin and 18 patients to apixaban. The primary outcome was the presence and size of LV thrombus 3 months after initiation of anticoagulation. Secondary outcomes were major bleeding, stroke or systemic embolism, re-hospitalization, and all-cause mortality. Mean LV thrombus size at enrolment was 18.5 mm×12.3mm in the warfarin group and 19.9 mm×12.4mm in the apixaban group (P=NS). Thirty-two patients completed 3 months follow-up. In the warfarin group, two patients withdrew, and in the apixaban group one patient died. Thrombus completely resolved in 14 of 15 patients in the warfarin group and in 16 of 17 patients in the apixaban group (P=NS and P=0.026 for non-inferiority). Two patients had major bleeding in the warfarin group, while no major bleeding events were recorded in the apixaban group. There was one stroke in the warfarin group and one death in the apixaban group. Our results suggest that apixaban is non-inferior to warfarin for treatment of patients with LV thrombus after acute MI with a 20% non-inferiority margin.

Electrolyzed hydrogen-rich water for oxidative stress suppression and improvement of insulin resistance: a multicenter prospective double-blind randomized control trial.

Electrolyzed hydrogen-rich water (EHW) is known to have suppressive effects on oxidative stress (OS). However, its benefit in type 2 diabetes mellitus (T2DM) remains unclear. This study aimed to investigate the effect of EHW on T2DM. This was a multicenter, prospective, double-blind, randomized controlled trial of 50 patients with T2DM who were assigned to the EHW or filtered water (FW) groups. The primary endpoint was changes in insulin resistance (IR) evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). OS markers such as urinary 8-hydroxy-2'-deoxyguanosine excretion (8-OHdG), plasma diacron-reactive oxygen metabolites (d-ROM), and plasma biological antioxidant potential (BAP) and other clinical data, including serum lactate concentration (lactate), were evaluated. There were no significant differences in the changes in HOMA-IR between the EHW and FW groups. However, lactate levels decreased significantly in the EHW group, and this decrease was significantly correlated with a reduction in HOMA-IR, fasting plasma glucose, and fasting plasma insulin level. Serum lactate level also significantly correlated to decreased insulin bolus secretion after 90min with glucose loading in the EHW subjects with HOMA-IR > 1.73. No EHW treatment-related adverse effects were observed. There were no significant effect of EHW in the change in HOMA-IR in this study; larger-scale and longer-term study are needed to verify the effects of EHW in T2DM patients. The online version contains supplementary material available at 10.1007/s13340-021-00524-3.

Patient-Tailored Levothyroxine Dosage with Pharmacokinetic/Pharmacodynamic Modeling: A Novel Approach After Total Thyroidectomy.

Background: After seven decades of levothyroxine (LT4) replacement therapy, dosage adjustment still takes several months. We have developed a decision aid tool (DAT) that models LT4 pharmacometrics and enables patient-tailored dosage. The aim of this was to speed up dosage adjustments for patients after total thyroidectomy.Methods: The DAT computer program was developed with a group of 46 patients post-thyroidectomy, and it was then applied in a prospective randomized multicenter validation trial in 145 unselected patients admitted for total thyroidectomy for goiter, differentiated thyroid cancer, or thyrotoxicosis. The LT4 dosage was adjusted after only two weeks, with or without application of the DAT, which calculated individual free thyroxine (fT4) targets based on four repeated measurements of fT4 and thyrotropin (TSH) levels. The individual TSH target was either <0.1, 0.1–0.5, or 0.5–2.0 mIU/L, depending on the diagnosis. Initial postoperative LT4 dosage was determined according to clinical routine without using algorithms. A simplified DAT with a population-based fT4 target was used for thyrotoxic patients who often went into surgery after prolonged TSH suppression. Subsequent LT4 adjustments were carried out every six weeks until target TSH was achieved.Results: When clinicians were guided by the DAT, 40% of patients with goiter and 59% of patients with cancer satisfied the narrow TSH targets eight weeks after surgery, as compared with only 0% and 19% of the controls, respectively. The TSH was within the normal range in 80% of DAT/goiter patients eight weeks after surgery as compared with 19% of controls. The DAT shortened the average dosage adjustment period by 58 days in the goiter group and 40 days in the cancer group. For thyrotoxic patients, application of the simplified DAT did not improve the dosage adjustment.Conclusions: Application of the DAT in combination with early postoperative TSH and fT4 monitoring offers a fast approach to LT4 dosage after total thyroidectomy for patients with goiter or differentiated thyroid cancer. Estimation of individual TSH-fT4 dynamics was crucial for the model to work, as removal of this feature in the applied model for thyrotoxic patients also removed the benefit of the DAT.

Non-Adherence to Antihypertensive Guidelines in Patients with Asymptomatic Carotid Stenosis

ImportanceHypertension and carotid stenosis are both risk factors for stroke, but the presence of carotid stenosis might dampen enthusiasm for tight control of hypertension because of concerns for hypoperfusion. ObjectiveTo determine the extent to which there are opportunities to potentially improve pharmacotherapy for hypertension in patients known to have asymptomatic high-grade carotid stenosis. DesignWe examined anti-hypertensive medication prescription and adherence to evidence-based hypertension treatment guidelines in a cross-sectional analysis of baseline data of patients enrolled in a clinical trial. SettingThe Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) is a multicenter prospective randomized open blinded end-point clinical trial of intensive medical management with or without revascularization by endarterectomy or stenting for asymptomatic high-grade carotid stenosis. Participants1479 participants (38.6% female; mean age 69.8 years) from 132 clinical centers enrolled in the CREST-2 trial as of April 6, 2020 who were taking ≥1 antihypertensive drug at baseline. ExposuresPharmacotherapy for hypertension. Main outcomeAdherence to evidence-based guidelines for treating hypertension. ResultsOf 1458 participants with complete data, 26% were on one, 31% on 2, and 43% on ≥3 antihypertensive medications at trial entry. Thirty-two percent of participants were prescribed thiazide; 74%, angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB); 38%, calcium channel blocker (CCB); 56%, a beta blocker; 11%, loop diuretic; and 27%, other. Of those prescribed a single antihypertensive medication, the proportion prescribed thiazide was 5%; ACEI or ARB, 55%, and CCB, 11%. The prevalence of guideline-adherent regimens was 34% (95% CI, 31-36%). Conclusions and relevanceIn a diverse cohort with severe carotid disease and hypertension, non-adherence to hypertension guidelines was common. All preferred classes of antihypertensive drug were under-prescribed. Using staged iterative guideline-based care for hypertension, CREST-2 will characterize drug tolerance and stroke rates under these conditions. Trial registrationClinicalTrials.gov Number NCT02089217.

CORonavirus-19 mild to moderate pneumonia Management with blood Ozonization in patients with Respiratory failure (CORMOR) multicentric prospective randomized clinical trial

BackgroundFollowing positive experience on the use of blood ozonation in SARS-CoV-2, the CORMOR randomized trial was designed to evaluate the adjuvant role of oxygen/ozone therapy in mild to moderate SARS-CoV-2 pneumonia. MethodsThe trial (ClinicalTrial.gov NCT04388514) was conducted in four different Italian centers (April-October 2020). Patients were treated according to best available standard of care (SoC) therapy, with or without O3-autohemotherapy (O3-AHT). ResultsA total of 92 patients were enrolled: SoC + O3-AHT (48 patients) were compared to the SoC treatment (44 patients).The two groups differed in steroids therapy administration (72.7% in SoC arm vs. 50.0% in O3-AHT arm; p = 0.044). Steroid therapy was routinely started when it was subsequently deemed as effective for the treatment of COVID-19 disease.No significant differences in mortality rates, length of hospital stay, mechanical ventilation requirement and ICU admission were observed. Clinical improvement in patients with pneumonia was assessed according to a specifically designed score (decrease in SIMEU class, improvement in radiology imaging, improvement in PaO2/FiO2, reduction in LDH and requirement of oxygen therapy ≤ 5 days). Score assessment was performed on day-3 (T3) and day-7 (TEnd) of O3-AHT treatment. A significant increase in the score was reported at TEnd, in the O3-AHT treatment arm (0 [0–1] in the SoC arm vs. 2 [1–3] the O3-AHT arm; p = 0.018). No adverse events related O3-AHT treatment was observed. ConclusionIn mild-to-moderate pneumonia due to SARS-CoV-2, adjuvant oxygen/ozone therapy did not show any effect on mortality, or mechanical intubation but show a clinical improvement a day 7 from randomization in a composite clinical endpoint. Larger Randomized prospective studies alone or in combination with steroids are needed to confirm our results.

Time to positivity in bloodstream infection is not a prognostic marker for mortality: analysis of a prospective multicentre randomized control trial

ObjectivesTime to positivity (TTP), calculated automatically in modern blood culture systems, is considered a proxy for microbial load and has been suggested as a potential prognostic marker in bloodstream infections. In this large, multicentre, prospectively collected cohort, our primary analysis aimed to quantify the relationship between the TTP of monomicrobial blood cultures and mortality. MethodsData from a multicentre randomized controlled trial (RAPIDO) in bloodstream infection were analysed. Bloodstream infections were classified into 13 groups/subgroups. The relationship between mortality and TTP was assessed by logistic regression, adjusted for site, organism, and clinical variables, and linear regression was applied to examine the association between clinical variables and TTP. Robustness was assessed by sensitivity analysis. ResultsIn total 4468 participants were included in the RAPIDO. After exclusions, 3462 were analysed, with the most common organisms being coagulase-negative staphylococci (1072 patients) and Escherichia coli (861 patients); 785 patients (22.7%) died within 28 days. We found no relationship between TTP and mortality for any groups except for streptococci (odds ratio (OR) with each hour 0.98, 95%CI 0.96–1.00) and Candida (OR 1.03, 95%CI 1.00–1.05). There was large variability between organisms and sites in TTP. Fever (geometric mean ratio (GMR) 0.95, 95%CI 0.92–0.99), age (GMR per 10 years 1.01, 95%CI 1.00–1.02), and neutrophilia were associated with TTP (GMR 1.03, 95%CI 1.02–1.04). ConclusionsTime to positivity is not associated with mortality, except in the case of Candida spp. (longer times associated with worse outcomes) and possibly streptococci (shorter times associated with worse outcomes). There was a large variation between median times across centres, limiting external validity.

Comment on: Systemic versus oral and systemic antibiotic prophylaxis (SOAP) study in colorectal surgery: prospective randomized multicentre trial.

Comment on: Systemic versus oral and systemic antibiotic prophylaxis (SOAP) study in colorectal surgery: prospective randomized multicentre trial.

Author response: Systemic versus oral and systemic antibiotic prophylaxis (SOAP) study in colorectal surgery: prospective randomized multicentre trial.

Author response: Systemic versus oral and systemic antibiotic prophylaxis (SOAP) study in colorectal surgery: prospective randomized multicentre trial.

168-OR: Five-Year Follow-up after Islet Transplantation in Nonuremic Patients with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness: Favorable Long-Term Outcomes of Multicenter Trial at University of Chicago

Introduction: Prospective randomized multicenter trial did not find advantage of CXCR1/2 blocker (Reparixin) over placebo in islet transplantation in patients with type 1 diabetes mellitus and problematic hypoglycemia at 1 year follow-up. We note favorable metabolic outcomes at 5-year follow-up in trial cohort from our center. Material and Methods: 12 patients with type 1 diabetes and problematic hypoglycemia received a total 19 islet transplants (max 2 per patient) within one year. Eight patients were randomly assigned and received Reparixin and 4 received placebo within first week after each transplant in addition to standard immunosuppression (anti-thymocyte globulin, tacrolimus, and mycophenolate). Results: 11/12 patients achieved insulin independence during the study period. At 5-year follow-up 4/8 (50%) remained insulin free with HbA1c &amp;lt;6.0 % in Reparixin group vs. 1/4 (25%) in placebo group. One patient had partial islet function without severe hypoglycemic episodes (SHE). Diabetic neuropathy and renal function remained unchanged while retinopathy improved in 3/6 (50%) patients. 6/12 (50%) patients left the study: 3/6 proceeded with pancreas transplant and remain off insulin, the remaining 3/6 stopped immunosuppression with decline of islet graft function, deterioration of glucose control (HbA1c &amp;gt; 7.0 %), and recurrence of SHE. No patients experienced any cardiovascular events nor became persistently sensitized (current PRA 0%). Conclusions: Repeat islet transplantation led to insulin independence in 91% of patients; 50% of patients in Reparixin group and 25% in placebo. Secondary diabetic complications did not progress. No patients became persistently sensitized. Subsequent pancreas transplantation was feasible and effective in patients with decline of islet graft function. Disclosure P. J. Bachul: None. A. Perez-gutierrez: None. A. C. Lucander: None. J. Fung: None. P. Witkowski: None. G. S. Generette: None. P. Borek: None. J. S. Pyda: None. R. Anteby: None. L. Basto: None. L. Perea: None. K. Golab: None. M. Tibudan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK02059); Kovler Family Fund; Dompé farmaceutici S.p.A.

A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).

TPS4597 Background: Non-clear cell renal cell carcinomas (nccRCC) account for approximately 25% of RCC patients (pts.). Data on treatment strategies for this heterogenous group of RCC are still limited, since most clinical trials focus on clear-cell RCC (ccRCC) histology. Recently combination therapies with immune checkpoint inhibitors (IO, avelumab or pembrolizumab) and tyrosinekinaseinhibitors (TKI) (axitinib) have been approved for treatment in RCC in all International Metastatic RCC Database Consortium (IMDC) risk groups. Additionally nivolumab and ipilimumab (IO/IO) has been approved for treatment in intermediate and high risk pts. showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) compared to sunitinib. Moreover retrospective analysis in nccRCC pts. have shown promising results for IO-based therapies as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky &gt;70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ̃306 pts. stratified for papillary or non-papillary non-clear cell histology and by the IMDC risk score. Pts. will be randomized 1:1 to either i) nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by nivolumab fixed dose 240mg IV every 2 weeks or fixed dose 480mg IV every 4 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 214 patients (132 pts with papillary, 76 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423.

The Role of Pathological Method and Clearance Definition for the Evaluation of Margin Status after Pancreatoduodenectomy for Periampullary Cancer. Results of a Multicenter Prospective Randomized Trial.

Simple SummaryThere is no clear evidence on the most effective method of pathological analysis and clearance definition (0 vs. 1 mm) to define R1 resection after pancreatoduodenectomy (PD). However, several studies showed that the R1 resection is a poor prognostic factor in patients that have undergone PDs for periampullary cancers. In this randomized clinical trial, specimens were randomized with two pathological methods, the Leeds Pathology Protocol (LEEPP) or the conventional method adopted before the study. The 1 mm clearance is the most effective factor in determining R1 rate after PD but only when adopting the LEEP, the R1 resection represents a significant prognostic factor.Background: There is extreme heterogeneity in the available literature on the determination of R1 resection rate after pancreatoduodenectomy (PD); consequently, its prognostic role is still debated. The aims of this multicenter randomized study were to evaluate the effect of sampling and clearance definition in determining R1 rate after PD for periampullary cancer and to assess the prognostic role of R1 resection. Methods: PD specimens were randomized to Leeds Pathology Protocol (LEEPP) (group A) or the conventional method adopted before the study (group B). R1 rate was determined by adopting 0- and 1-mm clearance; the association between R1, local recurrence (LR) and overall survival (OS) was also evaluated. Results. One-hundred-sixty-eight PD specimens were included. With 0 mm clearance, R1 rate was 26.2% and 20.2% for groups A and B, respectively; with 1 mm, R1 rate was 60.7% and 57.1%, respectively (p > 0.05). Only in group A was R1 found to be a significant prognostic factor: at 0 mm, median OS was 36 and 20 months for R0 and R1, respectively, while at 1 mm, median OS was not reached and 30 months. At multivariate analysis, R1 resection was found to be a significant prognostic factor independent of clearance definition only in the case of the adoption of LEEPP. Conclusions. The 1 mm clearance is the most effective factor in determining the R1 rate after PD. However, the pathological method is crucial to accurately evaluate its prognostic role: only R1 resections obtained with the adoption of LEEPP seem to significantly affect prognosis.

Systemic antibiotics in hidradenitis suppurativa: efficacy and effects of body mass index and smoking pack-year on the response to therapy.

The combination of oral clindamycin with rifampicin is recommended by European guidelines as a first-line treatment in moderate-to-severe hidradenitis suppurativa (HS). Recent studies highlight that oral clindamycin in monotherapy (CM) may be a useful alternative treatment. We included 36 patients with a diagnosis of moderate-to-severe HS. A total of 19 patients were treated with combination oral clindamycin plus rifampicin (C + R) and 17 with oral CM for 12 weeks. The efficacy of CM vs C + R was analyzed by multilinear regression models which showed a higher reduction in mSartorius (Δ = -13.2, P = .058) and AISI (Δ = -4.91, P = .034) in the C + R group. In the C + R group, smoking pack-year was positively correlated with AISI (Spearman's rho = 0.51, P = .036) and with DLQI (0.47, P = .061). In the CM group, a positive correlation was found between BMI and AISI (0.47, P = .041). The data on the efficacy of C + R combination therapy are in line with guidelines, evidence-based approaches, and recommendations from the HS ALLIANCE working group. The rationale for combining these two drugs is to increase bactericidal action and to reduce rifampicin resistance, as rifampicin is highly mutagenic. Our results suggest that the antibiotic combination of C + R is still the treatment of choice in moderate-to-severe HS with abscesses, draining fistulae and ≥ 5 inflammatory nodules. High BMI and smoking habits seem to be predictive factors of a poor response to antibiotics. Further multicenter studies and prospective randomized controlled trials are needed to confirm these results. Potential alternative antibiotic therapies should also be investigated.

Utility of Abdominal Drain in Gastrectomy (ADiGe) Trial: study protocol for a multicenter non-inferiority randomized trial

BackgroundProphylactic use of abdominal drain in gastrectomy has been questioned in the last 15 years, and a 2015 Cochrane meta-analysis on four RCTs concluded that there was no convincing evidence to the routine drain placement in gastrectomy. Nevertheless, the authors evidenced the moderate/low quality of the included studies and highlighted how 3 out of 4 came from Eastern countries. After 2015, only retrospective studies have been published, all with inconsistent results.MethodsADiGe (Abdominal Drain in Gastrectomy) Trial is a multicenter prospective randomized non-inferiority trial with a parallel design. It aimed to verify whether avoiding routine use of abdominal drain is burdened with complications, particularly an increase in postoperative invasive procedures. Patients with gastric cancer, scheduled for subtotal or total gastrectomy with curative intent, are eligible for inclusion, irrespective of previous oncological treatment.The primary composite endpoint is reoperation or percutaneous drainage procedures within 30 postoperative days. The primary analysis will verify whether the incidence of the primary composite endpoint is higher in the experimental arm, avoiding routine drain placement, than control arm, undergoing prophylactic drain placement, in order to falsify or support the null hypothesis of inferiority. Secondary endpoints assessed for superiority are overall morbidity and mortality, Comprehensive Complications Index, incidence and time for diagnosis of anastomotic and duodenal leaks, length of hospital stay, and readmission rate.Assuming one-sided alpha of 5%, and cumulative incidence of the primary composite endpoint of 6.4% in the control arm and 4.2% in the experimental one, 364 patients allow to achieve 80% power to detect a non-inferiority margin difference between the arm proportions of 3.6%. Considering a 10% drop-out rate, 404 patients are needed. In order to have a balanced percentage between total and subtotal gastrectomy, recruitment will end at 202 patients for each type of gastrectomy. The surgeon and the patient are blinded until the end of the operation, while postoperative course is not blinded to the patient and caregivers.DiscussionADiGe Trial could contribute to critically re-evaluate the role of prophylactic drain in gastrectomy, a still widely used procedure.Trial registrationProspectively registered (last updated on 29 October 2020) at ClinicalTrials.gov with the identifier NCT04227951.

Prospective, randomised, multicentre, open-label trial, designed to evaluate the best timing of closure of the temporary ileostomy (early versus late) in patients who underwent rectal cancer resection and with indication for adjuvant chemotherapy: the STOMAD (STOMa closure before or after ADjuvant therapy) randomised controlled trial

IntroductionTemporary ileostomy is a valuable aid in reducing the severity of complications related to rectal cancer surgery. However, it is still unclear what is the best timing of its closure...

Risk factors for subsequent vertebral fracture after acute osteoporotic vertebral fractures.

To investigate the incidence and characteristics of subsequent vertebral fracture after osteoporotic vertebral fractures (OVFs) and identify risk factors for subsequent vertebral fractures. This post-hoc analysis from a prospective randomized multicenter trial included 225 patients with a 48-week follow-up period. Differences between the subsequent and non-subsequent fracture groups were analyzed. Of the 225 patients, 15 (6.7%) had a subsequent fracture during the 48-week follow-up. The annual incidence of subsequent vertebral fracture after fresh OVFs in women aged 65-85years was 68.8 per 1000 person-years. Most patients (73.3%) experienced subsequent vertebral fractures within 6months. At 48weeks, European Quality of Life-5 Dimensions, the Japanese Orthopedic Association Back Pain Evaluation Questionnaire pain-related disorder, walking ability, social life function, and lumbar function scores were significantly lower, while the visual analog scale (VAS) for low back pain was higher in patients with subsequent fracture. Cox proportional hazards analysis showed that a VAS score ≥ 70 at 0weeks was an independent predictor of subsequent vertebral fracture. After adjustment for history of previous fracture, there was a ~ 67% reduction in the risk of subsequent vertebral fracture at the rigid-brace treatment. Women with a fresh OVF were at higher risk for subsequent vertebral fracture within the next year. Severe low back pain and use of soft braces were associated with higher risk of subsequent vertebral fractures. Therefore, when treating patients after OVFs with these risk factors, more attention may be needed for the occurrence of subsequent vertebral fractures. III.

One-step versus two-step distal self-expandable metal stent placement: A multicenter prospective randomized trial.

Two methods of transpapillary covered self-expandable metal stent (SEMS) placement are used for distal malignant biliary obstruction (MBO): after initial drainage by plastic stent (two-step method) and without previous drainage (one-step method). In total, 90 patients with unresectable pancreatic cancer and distal MBO were enrolled in this prospective multicenter randomized study and allocated to one-step (n=45) and two-step (n=45) groups. The main outcome was the time to recurrent biliary obstruction (TRBO). Secondary outcomes were the rates of early and late adverse events, survival time, the time required for bilirubin level reduction, and cost-effectiveness. The median TRBO did not differ significantly between the one-step and two-step groups (not available vs 314days, P=0.134). SEMS migration occurred significantly more frequently in the two-step group (14.3% vs 0%, P=0.026). No significant difference was observed between groups in early (7.3% vs 14.3%, P=0.483) or late (12.2% and 11.9%, P=1) adverse events other than RBO, survival time (P=0.104), or the median number of days required to reach a bilirubin level considered to be acceptable for chemotherapy administration (<3mg/dL; P=0.881). The total costs of stent placement and reintervention were significantly lower in the one-step SEMS group (3347 vs 5465 US dollars, P<0.001). The superiority of TRBO with two-step SEMS placement was not demonstrated. One-step SEMS placement might be a promising method from the viewpoints of cost-effectiveness and less invasiveness (UMIN-CTR clinical trial registration number: UMIN000016010).

Predictive Factors Affecting Surgical Outcomes in Patients with Degenerative Lumbar Spondylolisthesis.

Post-hoc analysis of 5-year follow-up data from a prospective randomized multicenter trial. The purpose of this study was to identify preoperative factors that predict poor postoperative outcomes and define clinically important abnormal instabilities in degenerative lumbar spondylolisthesis. Current evidence regarding prognostic factors affecting clinical outcomes after surgery for degenerative lumbar spondylolisthesis is still limited. Moreover, there is no consensus regarding parameters that define clinically important abnormal instability in patients with degenerative lumbar spondylolisthesis. This post-hoc analysis from a prospective randomized trial that compared the effectiveness of decompression, decompression with fusion, and decompression with stabilization for degenerative lumbar spondylolisthesis at the L4/5 level included 70 patients with a 5-year follow-up period. We investigated the correlation between the postoperative recovery rate and preoperative radiographic parameters. We then investigated differences between the good recovery and poor recovery groups. Japanese Orthopaedic Association and visual analogue scale scores improved postoperatively. Of the 70 patients analyzed, 13 were judged to be in the poor recovery group based on their recovery rate. The recovery rate significantly correlated with the intervertebral angle at L4/5. Univariate analysis showed that while the degree of vertebral slippage and the presence of angulation were not associated with poor recovery, the intervertebral angle at L4/5 and the presence of translation were associated with poor recovery. Lastly, multiple stepwise logistic regression analysis revealed the intervertebral angle at L4/5 and the presence of translation as independent predictors of poor recovery after surgery for lumbar degenerative spondylolisthesis. While the degree of vertebral slippage and the presence of angulation were not associated with poor recovery after surgery for lumbar degenerative spondylolisthesis, postoperative outcomes were associated with the intervertebral angle and the presence of translation. Careful preoperative measurement of these factors may help to predict poor postoperative outcomes.Level of Evidence: 3.

Use of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor During and After Remission Induction Chemotherapy in Patients Aged 61 Years and Older With Acute Myeloid Leukemia (AML): Final Report of AML-11, a Phase III Randomized Study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer (EORTC-LCG) and the Dutch Belgian Hemato-Oncology Cooperative Group (HOVON)

AbstractWe conducted a prospective randomized multicenter clinical trial comparing the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF ) as an adjunct to intensive chemotherapy in patients of 61 years and older with untreated newly diagnosed acute myeloid leukemia (AML). Patients were randomized to either receive daunomycin-cytosine arabinoside with GM-CSF or daunomycin-cytosine arabinoside (control arm). Based on the rationale that GM-CSF might sensitize the leukemic cells to the cytotoxicity of chemotherapy as well as enhance white blood cell regeneration, GM-CSF was given during chemotherapy as well as after chemotherapy. Patients were treated with one, and in case of a partial response, with two remission induction cycles. When a complete remission was attained they received one additional cycle of consolidation therapy. Of 318 evaluable patients with a median age of 68 years, 157 were randomized to receive GM-CSF and 161 were assigned to control therapy. The effect of GM-CSF on treatment was evaluated according to intention-to-treat. Complete remission was achieved in 56% of the patients in the GM-CSF group and 55% of the control patients (P = .98). Recovery of neutrophils was significantly faster in GM-CSF–treated patients. The median time of recovery of neutrophils towards 0.5 × 109/L was 23 days in the GM-CSF group versus 25 days in the control group (P = .0002) with the percentages of patients who recovered being 81% and 71%, respectively. With a median follow-up of 36 months, the probabilities of survival at 2 years after randomization were estimated at 22% for individuals assigned to the GM-CSF treatment as well as for control patients (P = .55). Disease-free survival at 2 years compared 15% and 19% for the two treatment groups (P = .69). The number of nights spent in the hospital, number of transfusions, and frequencies and types of hemorrhages and infections did not differ either. The cytogenetic results at diagnosis of this study in elderly AML shows that there is a relatively high numerical representation of patients with abnormal cytogenetics (55% of documented cases), who showed significantly inferior response rates and survival duration. We conclude that, except for a faster neutrophil recovery, GM-CSF during and after induction chemotherapy does not improve the clinical outcome of elderly patients with AML.

Prospective Randomized Multicenter Clinical Trial on the Use of Interferon α-2a Plus Acitretin Versus Interferon α-2a Plus PUVA in Patients With Cutaneous T-Cell Lymphoma Stages I and II

AbstractCutaneous T-cell lymphoma (CTCL) constitutes a malignant proliferative disease involving mostly CD4+ T cells arising in the skin. Because of the lack of curative treatment options, interferons (IFN) have been introduced into the therapy of CTCL. Although effective even in advanced disease, response rates were about 50% and the duration of response was short. To improve the results of interferon monotherapy, combinations of IFN with oral photochemotherapy (PUVA) or retinoids were investigated in nonrandomized trials showing higher response rates. We have therefore conducted this prospective randomized multicenter trial to compare these two combination therapies, ie, IFNα plus PUVA and IFNα plus acitretin. IFN α-2a was administered at 9 MU three times weekly subcutaneously in both groups, with lower increasing doses during the first week. Photochemotherapy was applied after oral intake of 8-methoxypsoralen (0.6 mg/kg body weight) 5× weekly during the first 4 weeks, 3× weekly from weeks 5 through 23, and 2× weekly from weeks 24 through 48, with escalating doses beginning with 0.25 J/cm2. Twenty-five milligrams of acitretin was administered daily during the first week, and 50 mg was administered from weeks 2 through 48. Of 98 patients randomized in this study, 82 stage I and II patients were evaluable: 40 in the IFN+PUVA group and 42 in the IFN+acitretin group. With 70% complete remissions in the IFN+PUVA group, this treatment was significantly superior to the IFN+acitretin group with only 38.1% complete remissions. Time to response was significantly shorter in the IFN+PUVA group, with 18.6 weeks compared with 21.8 weeks in the IFN+acitretin group. Side effects were mostly mild to moderate and did not differ significantly in both treatment groups. However, there were more adverse events leading to study discontinuation in the IFN+acitretin group. Based on these findings, we conclude that IFNα plus oral photochemotherapy is superior to IFNα plus acitretin, inducing more complete remissions in patients with CTCL stages I and II.

Aerosolized Amphotericin B Inhalations as Prophylaxis of Invasive Aspergillus Infections During Prolonged Neutropenia: Results of a Prospective Randomized Multicenter Trial

AbstractWe performed a prospective, randomized, multicenter trial to evaluate the effectiveness of prophylactic inhalations with aerosolized amphotericin B (aeroAmB) to reduce the incidence of invasive aspergillus (IA) infections in patients after chemotherapy or autologous bone marrow transplantation and an expected duration of neutropenia of at least 10 days. From March 1993 until April 1996, 382 patients with leukemias, relapsed high-grade non-Hodgkin lymphomas, or solid tumors were randomized with a 13:10 ratio to receive either prophylactic aeroAmB inhalations at a dose of 10 mg twice daily or no inhalation prophylaxis in an unblinded fashion. The incidence of proven, probable, or possible IA infections was 10 of 227 (4%) in patients who received prophylactic aeroAmB. This did not differ significantly from the 11 of 155 (7%) incidence in patients who received no inhalation prophylaxis (P = .37). Moreover, no differences in the overall mortality (13% v 10%; P= .37) or in the infection-related mortality (8% v 7%;P = .79) were found. In contrast to other nonrandomized trials, we observed no benefit from prophylactic aeroAmB inhalations, but the overall incidence of IA infections was low.