Role of antithymocyte globulin in matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies

Background:High incidence of chronic graft-versus-host disease (GVHD) has been a major drawback of matched sibling donor peripheral blood stem cell transplantation (MSD -PBSCT). This study aimed to investigate the safety and efficacy of antithymocyte globulin (ATG) as a standardized part of GVHD prophylaxis in patients receiving MSD -PBSCT.Methods:A total of 72 patients with hematological malignancies receiving MSD -PBSCT who displayed similar baseline characteristics were either given rabbit ATG ( n = 42) or no ATG (n = 30), in addition to cyclosporine, methotrexate, and mycophenolate mofetil as a standard GVHD prophylaxis regimen. Either patients or donors aged ≥40 years were included in the study. Thymoglobulin was administered at a daily dose of 1.5 mg/kg on day −5 and 3.5 mg/kg on day −4 prior to transplant (the total dose was 5 mg/kg)Results:After a median follow-up of 874 days, the 3-year cumulative incidence of chronic GVHD (cGVHD) was 37.3% in the ATG group and 52.1% in the non -ATG group. The 3-year overall and disease-free survival probability were 71.0% and 62.0% (ATG versus non -ATG, P = .262) and 66.7% and 58.4% (ATG versus non -ATG, P = .334). No difference was found in the 2-year cumulative incidence of nonrelapse mortality and relapse between the ATG and non -ATG groups. This significant reduction in the incidence of cGVHD without increased relapse risk and nonrelapse mortality led to a 3-year GVHD-free, relapse-free survival probability of 66.7% and 40.0% in the ATG and non-ATG groups, respectively.Conclusions:These data suggested that rabbit antithymocyte globulin in the current protocol for GVHD prophylaxis was well tolerable and efficacious.The clinical trial was registered on January 1, 2016 (ClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT02677181","term_id":"NCT02677181"}}NCT02677181). https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02677181","term_id":"NCT02677181"}}NCT02677181.     

Dexamethasone for the treatment of traumatic brain injured patients with brain contusions and pericontusional edema: Study protocol for a prospective,randomized and double blind trial

Background:Traumatic brain injury (TBI) constitutes a leading cause of death and disability. Patients with TBI and cerebral contusions developing pericontusional edema are occasionally given dexamethasone on the belief that this edema is similar to that of tumors, in which the beneficial effect of dexamethasone has been demonstrated.Methods:The DEXCON TBI trial is a multicenter, pragmatic, randomized, triple-blind, placebo controlled trial to quantify the effects of dexamethasone on the prognosis of TBI patients with brain contusions and pericontusional edema. Adult patients who fulfill the elegibility criteria will be randomized to dexamethasone/placebo in a short and descending course: 4 mg/6 h (2 days); 4 mg/8 hours (2 days); 2 mg/6 hours (2 days); 2 mg/8 hours (2 days); 1 mg/8 hours (2 days); 1 mg/12 hours (2 days). The primary outcome is the Glasgow Scale Outcome Extended (GOSE) performed 1 month and 6 months after TBI. Secondary outcomes are: number of episodes of neurological deterioration; symptoms associated with TBI; adverse events; volume of pericontusional edema before and after 12 days of treatment; results of the neuropsychological tests one month and 6 months after TBI. The main analysis will be on an “intention-to-treat” basis. Logistic regression will estimate the effect of dexamethasone/placebo on GOSE at one month and at 6 months, dichotomized in unfavorable outcome (GOSE 1–6) and favorable outcome (GOSE 7–8). Efficacy will also be analyzed using the ''sliding dichotomy’. An interim and safety analysis will be performed including patients recruited during the first year to calculate the conditional power. A study with 600 patients would have 80% power (2 sided alpha = 5%) to detect a 12% absolute increase (from 50% to 62%) in good recovery.Discussion:This is a confirmative trial to elucidate the therapeutic efficacy of dexamethasone in a very specific group of TBI patients: patients with brain contusions and pericontusional edema. This trial could become an important milestone for TBI patients as nowadays there is no effective treatment in this type of patients.Trial Registration:eudraCT: 2019–004038–41; Clinical Trials.gov: {"type":"clinical-trial","attrs":{"text":"NCT04303065","term_id":"NCT04303065"}}NCT04303065.     

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX,in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double‐blind, non‐inferiority, cross‐over study conducted in participants aged ≥12 years weighing ≥40 kg, with severe or moderately severe haemophilia B (FIX activity ≤2 IU dL ^?1). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4–18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8–59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg^?1 or nonacog alfa. The lower limit of the one‐sided 95% confidence interval for the ratio of AUC_0‐t and AUC_0‐∞ (IB1001/nonacog alfa) was 0.90, establishing non‐inferiority. Terminal phase half‐lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non‐inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B.     

Multicentre,randomized, open‐label study of on‐demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects

Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on‐demand therapy. Male subjects aged 6–65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open‐label, four‐period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on‐demand therapy. In the intent‐to‐treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on‐demand period, the 50 IU kg^?1 twice‐weekly period, and the 100 IU kg^?1 once‐weekly period respectively. Differences in ABR between the first on‐demand period and both prophylaxis regimens were significant (P < 0.0001); no significant differences were observed between prophylaxis regimens (P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg^?1 twice weekly or 100 IU kg^?1 once weekly reduced ABR by 89.4% relative to on‐demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B.     

Prognostic value of lymphocyte-to-monocyte ratio previously determined to surgery in patients with non-metastatic renal cell carcinoma: A systematic review and a prisma-compliant meta-analysis

Background:The prognostic value of pretreatment lymphocyte to monocyte ratio in patients with renal cell carcinoma and, especially, in non-metastatic patients remains controversial.Methods:We conducted a PRISMA-compliant meta-analysis to systematically assess the prognostic value of LMR in patients with non-metastatic RCC. Overall survival, cancer-specific survival, and disease-free survival were analyzed. Pooled hazard ratios and 95% confidence intervals were calculated.Results:Seven studies comprising 4666 patients were included in the analysis. Unlike those observed in a previous meta-analysis, a lower lymphocyte to monocyte ratio was associated with poorer cancer-specific survival (fix-effect model, hazard ratio 3.04, 95% confidence intervals 2.05–4.51, P < .05). Heterogeneity Chi-squared value Q exp = 0. (P = .82) (I² = 0%). However, the association between a low lymphocyte to monocyte ratio and overall survival or disease-free survival did not obtain significance.Conclusion:A lower lymphocyte to monocyte ratio implied poor cancer-specific survival in patients with non-metastatic renal cell carcinoma. Prospective studies are required to confirm our findings.Registration number:ClinicalTrials.gov (identifier: {"type":"clinical-trial","attrs":{"text":"NCT04213664","term_id":"NCT04213664"}}NCT04213664)     

Prophylaxis in congenital factor VII deficiency: indications,efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER)

Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received freshfrozen plasma. Prophylactic schedules clustered into “frequent” courses (three times weekly, n=23) and “infrequent” courses (≤2 times weekly, n=15). Excluding courses for menorrhagia, “frequent” and “infrequent” courses produced 18/23 (78%) and 5/12 (41%) “excellent” outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on “frequent” administrations (three times weekly) and a 90 μg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency (clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01269138","term_id":"NCT01269138"}}NCT01269138).     

Efficacy and safety of the recombinant human growth hormone in short children born small for gestational age: A randomized,multicentre, comparative phase III trial

Objective:Growth hormone (GH) treatment is known to be effective in increasing stature in children with a short stature born small for gestational age (SGA). This multicentre, randomized, open-label, comparative, phase III study aimed to evaluate the efficacy and safety of Growtropin-II (recombinant human GH) and to demonstrate that the growth-promoting effect of Growtropin-II is not inferior to that of Genotropin in children with SGA (NCT ID: {"type":"clinical-trial","attrs":{"text":"NCT02770157","term_id":"NCT02770157"}}NCT02770157).Methods:Seventy five children who met the inclusion criteria were randomized into 3 groups in a ratio of 2:2:1 (the study group [Growtropin-II, n = 30], control group [Genotropin, n = 30], and 26-week non-treatment group [n = 15]). The study and control groups received subcutaneous injections of Growtropin-II and Genotropin, respectively for 52 weeks, whereas the non-treatment group underwent a non-treatment observation period during weeks 0 to 26 and a dosing period during weeks 27 to 52 and additional dosing till week 78 only in re-consenting children.Results:No significant differences in demographic and baseline characteristics between the groups were observed. The mean ± standard deviation change difference in annualized height velocity (aHV) (study group - control group) was 0.65 ±2.12 cm/year (95% confidence interval [CI], −0.53 to 1.83), whereas the lower limit for the 2-sided 95% CI was −0.53 cm/year. Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 53.33% children in the study group and 43.33% children in the control group; the difference in the incidence of TEAEs between the 2 treatment groups was not statistically significant (P = .4383). A total of 17 serious adverse events (SAEs) occurred in 13.33% children in the treatment groups, and no significant difference in incidence between groups (P = .7065) was seen. Two cases of adverse drug reaction (ADR) occurred in 2 children (3.33%): 1 ADR (injection site swelling or pain) occurred in 1 child (3.33%) each in the study and control groups.Conclusions:This study demonstrates that the change in aHV from the baseline till 52 weeks with Growtropin-II treatment is non-inferior to that with Genotropin treatment in children with short stature born SGA. Growtropin-II is well-tolerated, and its safety profile is comparable with that of Genotropin over a 1-year course of treatment.     

Phase 1b dose-escalation,safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis

Background:The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers.Methods:In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) ({"type":"clinical-trial","attrs":{"text":"NCT03487263","term_id":"NCT03487263"}}NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor.Results:IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33 days of follow up.Conclusion:IC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study.Clinical Trial Registration:{"type":"clinical-trial","attrs":{"text":"NCT03487263","term_id":"NCT03487263"}}NCT03487263     

The effect of probiotics on functional constipation in adults: Double-blind,randomized, placebo-controlled study

Background: Evacuation disorders are common in industrialized countries, affecting an average of 15% to 20% of the healthy adult population. Probiotic therapy can reduce functional constipation and increase both the number of weekly bowel movements and quality of stools. Based on the hypothesis that a combination of more strains may provide better results for constipation and facilitate adherence to treatment, this study will evaluate the efficacy and safety of a combination of different strains of Lactobacillus sp. and Bifidobacterium sp. in functional constipation.Methods: A single-centre trial of adults aged 20 to 80 years with intestinal constipation will be conducted at a Gastroenterology Clinic in Sorocaba, State of São Paulo, Brazil. Participants will be allocated into 3 groups receiving:

• 1.mixture of 3 probiotics: [Lactobacillus acidophilus, Bifidobacterium bifidum, and Lactobacillus rhamnosus (3 × 10⁹ CFU)];
• 2.mixture of 8 probiotics [Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus rhamnosus, Lactobacillus paracasei, Bifidobacterium longum, Bifidobacterium lactis, Lactobacillus defensis, Bifidobacterium animallis (8 × 10⁹ CFU)]; or
• 3.placebo, for 4 weeks.

The outcomes of interest will be change in frequency of weekly bowel movements, change in stool quality according to the 4–6 Bristol scale, number of volunteer withdrawal, number of adverse events and number of serious adverse effect.Discussion:The probiotic products are expected to induce beneficial changes in the intestinal microbiota, thereby increasing intestinal frequency to over 3 times a week and improving stool quality. The results can guide patients and healthcare practitioners and help in decision-making in the treatment of functional constipation.Trial registration and registry name:ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT04437147","term_id":"NCT04437147"}}NCT04437147: The Effect of Probiotics on Functional Constipation in Adults: Study protocol for Double blind, Randomized, Placebo controlled StudyProtocol Version:Version 01 August 30, 2020.     

A phase II,single-centre trial of neoadjuvant toripalimab plus chemotherapy in locally advanced esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) remains a challenging malignancy with poor prognosis and limited therapeutic methods. However, recent clinical trials of immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of lethal malignancies. The second-line treatment of late-stage ESCC was approved based on the results of KEYNOTE-180, KEYNOTE-181 and ATTRACTION-1, ATTRACTION-3. Combining ICIs with chemotherapy in neoadjuvant therapy may benefit patients with locally advanced, resectable ESCC.MethodsA two-arm phase II trial was launched in July 2019 in Henan Cancer Hospital. The primary outcome measure will be completed within 21 months. The pathological complete response (pCR) rate is the primary endpoint, and the secondary endpoints include overall survival (OS), disease-free survival (DFS), the toxicities of the neoadjuvant toripalimab plus chemotherapy, the relationship between combined positivity score (CPS) of specimen and the treatment response, the relationship between lymphocyte infiltration and the treatment response, the progression-free survival (PFS) rate, and adverse events (AEs). It was assumed that the pCR rate of this trial might be 25%. Therefore, the 30 enrolled patients could reject the hypothesis at 75% (α=0.1).DiscussionThe study will determine the safety and efficacy of neoadjuvant immunochemotherapy for ESCC and provide enough evidence for phase III clinical trials.Trial registrationClinical Trials.gov, {"type":"clinical-trial","attrs":{"text":"NCT03985670","term_id":"NCT03985670"}}NCT03985670, Registered: October 24, 2019, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0008Z9D&selectaction=Edit&uid=U0002MIY&ts=2&cx=-i71o4q. Registry name: “Teripalimab Plus Chemotherapy in Local Advanced Esophageal Cancer”.     

Dual therapy with an oral non-vitamin K antagonist and a P2Y12 inhibitor vs triple therapy with aspirin,a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus patients with co-existing atrial fibrillation following percutaneous coronary intervention: A meta-analysis

Background:In this analysis, we aimed to compare the efficacy and safety of dual therapy (DT) with a non-vitamin K oral anticoagulant (NOAC) and an adenosine diphosphate receptor antagonist (P2Y12 inhibitor) vs triple therapy (TT) with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus (DM) patients with co-existing atrial fibrillation (AF) following percutaneous coronary intervention (PCI).Methods:Medical Literature Analysis and Retrieval System Online (MEDLINE), http://www.ClinicalTrials.gov, Excerpta Medical data BASE (EMBASE), Web of Science, Cochrane Central and Google Scholar were the searched databases. Studies that were randomized trials or observational studies comparing DT vs TT for the treatment of DM patients with co-existing AF following PCI were included in this analysis. The adverse cardiovascular outcomes and bleeding events were the endpoints. This meta-analysis was carried out by the RevMan version 5.4 software. Risk ratios (RR) with 95% confidence intervals (CI) were used to represent data and interpret the analysis.Results:A total number of 4970 participants were included whereby 2456 participants were assigned to the DT group and 2514 participants were assigned to the TT group. The enrollment period varied from year 2006 to year 2018. Our current results showed that major adverse cardiac events (RR: 1.00, 95% CI: 0.84–1.20; P = .98), mortality (RR: 1.08, 95% CI: 0.78–1.48; P = .66), myocardial infarction (RR: 1.02, 95% CI: 0.74–1.42; P = .90), stroke (RR: 0.94, 95% CI: 0.53–1.67; P = .84) and stent thrombosis (RR: 1.09, 95% CI: 0.56–2.10; P = .80) were similar with DT versus TT in these patients. However, the risks for total major bleeding (RR: 0.66, 95% CI: 0.54–0.82; P = .0001), total minor bleeding (RR: 0.74, 95% CI: 0.64–0.85; P = .0001), Thrombolysis in Myocardial Infarction (TIMI) defined major bleeding (RR: 0.58, 95% CI: 0.35–0.95; P = .03), TIMI defined minor bleeding (RR: 0.62, 95% CI: 0.42–0.92; P = .02), intra-cranial bleeding (RR: 0.34, 95% CI: 0.13–0.95; P = .04) and major bleeding defined by the International Society on Thrombosis and Hemostasis (RR: 0.68, 95% CI: 0.51–0.90; P = .008) were significantly higher with TT.Conclusions:DT with a NOAC and a P2Y12 inhibitor was associated with significantly less bleeding events without increasing the adverse cardiovascular outcomes when compared to TT with aspirin, a P2Y12 inhibitor and a Vitamin K antagonist for the treatment of DM patients with co-existing AF following PCI. Hence, DT is comparable in efficacy, but safer compared to TT. This interesting hypothesis will have to be confirmed in future studies.     

Comparative efficacy and safety of intravenous ferric carboxymaltose and iron sucrose for iron deficiency anemia in obstetric and gynecologic patients: A systematic review and meta-analysis

Introduction:Iron deficiency anemia (IDA) is common among obstetric and gynecologic patients. This systematic review aimed to assess the comparative efficacy and safety of commonly used intravenous (IV) iron formulations, ferric carboxymaltose (FCM), and iron sucrose (IS) in the treatment of IDA in obstetric and gynecologic patients.Methods:We systematically searched PubMed, EMBASE, Cochrane CENTRAL, and Google Scholar for eligible randomized controlled trials (RCTs) comparing IV iron replacement using FCM and IS up to October 2019. The primary outcome was to compare the efficacy of FCM and IS, assessed by measuring serum hemoglobin (Hb) and ferritin levels before and after iron replacement. The secondary outcome was to compare the safety of FCM and IS, assessed by the incidence of adverse events during iron replacement. The meta-analysis was performed using RevMan 5.3.Results:We identified 9 RCTs with 910 patients (FCM group, n = 456; IS group, n = 454). Before iron replacement, FCM and IS group patients had similar baseline Hb (mean difference [MD], 0.04 g/dL; 95% confidence interval [CI], −0.07 to 015; I² = 0%; P = 0.48) and ferritin levels (MD, −0.42 ng/mL; 95% CI, −1.61 to 0.78; I² = 45%; P = 0.49). Following iron replacement, patients who received FCM had higher Hb (MD, 0.67; 95% CI, 0.25–1.08; I² = 92%; P = 0.002) and ferritin levels (MD, 24.41; 95% CI, 12.06–36.76; I² = 75%; P = 0.0001) than patients who received IS. FCM group showed a lower incidence of adverse events following iron replacement than IS group (risk ratio, 0.53; 95% CI, 0.35–0.80; I² = 0%; P = 0.003). Serious adverse events were not reported in any group.Conclusion:FCM group showed better efficacy in increasing Hb and ferritin levels and a favorable safety profile with fewer adverse events compared with IS group for IDA treatment among obstetric and gynecologic patients. However, this meta-analysis was limited by the small number of RCTs and high heterogeneity.Trial registration:The review was prospectively registered with the International Prospective Registry of Systematic Reviews (https://www.crd.york.ac.uk/prospero/, registration number CRD42019148905).     

Prospective evaluation of the efficacy of peroral endoscopic myotomy in patients with achalasia

Peroral endoscopic myotomy (POEM) is an endoscopic alternative to surgical myotomy in patients with achalasia. This study aimed to evaluate the efficacy and clinical outcomes of POEM.A total of 20 patients with achalasia who underwent POEM between October 2016 and November 2017 were prospectively recruited. The intraoperative esophagogastric junction distensibility index (mm²/mm Hg) was measured pre- and post-myotomy using an endoluminal functional lumen imaging probe. Clinical response was defined as Eckardt score ≤3. Health-related quality of life was measured by the 36-item short-form health survey score.POEM was successfully completed in all cases. The median procedure time was 68.5 minutes (range 50.0–120.0), and the median myotomy length was 13 cm (range 11–18). Major adverse events were encountered in 2 cases. Overall, clinical responses were observed in all patients during a median follow-up of 11.9 months (range 1.2–26.2). Postoperative esophagogastric junction distensibility index was significantly higher than baseline (from 1.3 [range 0.8–6.9] to 6.3 [range 25–19.2], P < .001). The median Eckardt scores were decreased after POEM (5 [range 2–11] to 1 [range 0–3], P < .001), and the 36-item short-form health survey score was also improved significantly after POEM (67.5 [range 34.5–93.9] to 85.7 [range 53.4–93.3], P = .004).POEM is an effective treatment for achalasia, based on the improvement of both symptoms and objective measures.Clinicaltrial.gov {"type":"clinical-trial","attrs":{"text":"NCT 02989883","term_id":"NCT02989883"}}NCT 02989883     

Enhanced recovery after surgery for laparoscopic gastrectomy in gastric cancer: A prospective study

Background:Laparoscopic distal gastrectomy (LDG) has been highlighted for its safety and better short-term clinical outcomes in treating gastric cancer. However, only a slight reduction of the post-operative hospital stay was observed in gastric cancer patients undergoing LDG with conventional perioperative management, compared to patients undergoing open surgery. Thus, an enhanced recovery after surgery (ERAS) program for LDG is needed to further reduce the post-operative hospital stays. This prospective, open-label, single-arm cohort study aimed to assess the safety and efficacy of the ERAS program for gastric cancer patients undergoing LDG.Material and Methods:All patients with gastric cancer indicated for LDG were consecutively enrolled from December 2016 to January 2018. The ERAS program included short fasting time, effective perioperative pain management, early, goal-oriented ambulation, and oral feeding. The safety assessment was the incidence of post-operative complications, mortality, and readmission in 30 days. The primary efficacy assessment was recovery time defined by post-operative hospital stays and rehabilitative rate on post-operative day 4.Results:Ninety-eight of 114 patients were finally enrolled. The incidence of post-operative complication, mortality, and readmission in 30 days was 20. 4%, 0%, 7.1%, respectively. The Clavien-Dindo grade III complication rate was 6.1%, while the pulmonary complication rate was 1% only. The median post-operative stay was 6 days (5.0-7.0 days), and the rehabilitative rate on post-operative day 4 was 78%.Conclusions:The ERAS program might be optimal perioperative management for gastric cancer patients after LDG without compromising safety.Trial number:{"type":"clinical-trial","attrs":{"text":"NCT03016026","term_id":"NCT03016026"}}NCT03016026     

Prospective,double-blind,randomized, placebo-controlled phase III study evaluating efficacy and safety of octagam 10% in patients with dermatomyositis (“ProDERM Study”)

Introduction:Dermatomyositis (DM) is an inflammatory myopathy characterized by distinct skin manifestations and muscle weakness. Intravenous immunoglobulin (IVIg) has been used off-label as adjuvant therapy in DM, but is not indicated for DM, due to lack of proven efficacy in a large randomized controlled trial. The objective of the ProDERM (Progress in DERMatomyositis) study was to evaluate the efficacy, safety and long-term tolerability of IVIg (Octagam 10%) in patients with DM in a randomized, placebo-controlled, double-blind, Phase III study.Methods:Adult patients with active DM who were continuing standard therapy at a stable dose were eligible for this study. Patients were randomized 1:1 to receive either 2 g/kg of IVIg or placebo, administered every 4 weeks until week 16 (First Period). Patients were switched to the alternate treatment if they showed clinical deterioration in the First Period. After response assessment at week 16, all patients on placebo and those without deterioration on IVIg entered the open-label Extension Period, receiving 2 g/kg IVIg every 4 weeks for 24 weeks.Results:The primary efficacy endpoint was the proportion of responders in the IVIg vs placebo arm at week 16, where response was defined per 2016 ACR/EULAR Myositis Response Criteria of at least minimal improvement [Total Improvement Score (TIS) ≥20] and without deterioration at 2 consecutive visits up to week 16. TIS consists of composite response criteria, combining weighted improvement in 6 core set measures (CSMs), Global Disease Activity (Physician and Patient), manual muscle testing-8 (MMT-8), Health Assessment Questionnaire, extra-muscular disease activity, and muscle enzymes. Secondary endpoints included the mean change in individual CSMs, time to improvement in TIS, time to confirmed deterioration in the First Period, and the overall proportion of patients with deteriorations. Adverse events, including infusion reactions and thromboembolic events, were recorded.Conclusions:The ProDERM study was the first to assess the long-term efficacy and safety of IVIg (Octagam 10%) in a placebo-controlled, blinded, randomized trial in DM. The study aimed to inform on the use of IVIg in the treatment of DM, and results are expected in Q3 2020.ClinicalTrials.gov Identifier:{"type":"clinical-trial","attrs":{"text":"NCT02728752","term_id":"NCT02728752"}}NCT02728752.     

Factor VIII activity and bleeding risk during prophylaxis for severe hemophilia A: a population pharmacokinetic model

During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. However, maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investigated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and information on bleeding from patients’ diaries. Each patient’s time on prophylaxis was divided into five categories of predicted activity (0-1%, >1-5%, >5-15%, >15-50%, and >50%). Exposure time, mean factor VIII activity, and number of bleeds (from the patients’ diaries) were calculated for each activity category, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. extension) and age (adults/adolescents [≥12 years] vs. children [0-<12 years]). In total (n=187 patients; 815 patient-years’ exposure), factor VIII activity was predicted to be >1% for 85.64% of the time. The annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. When making decisions regarding target trough levels and the prophylactic regimen, the patients’ age, joint disease activity, and other bleeding risk determinants should be taken into consideration. Clinical trial registration numbers: {"type":"clinical-trial","attrs":{"text":"NCT00840086","term_id":"NCT00840086"}}NCT00840086; {"type":"clinical-trial","attrs":{"text":"NCT01138501","term_id":"NCT01138501"}}NCT01138501; {"type":"clinical-trial","attrs":{"text":"NCT00984126","term_id":"NCT00984126"}}NCT00984126     

Effects of an Avocado-based Mediterranean Diet on Serum Lipids for Secondary Prevention after Ischemic Stroke Trial (ADD-SPISE): Study protocol

Background:A poor or unhealthy diet is responsible for an important fraction of ischemic stroke risk. Adherence to dietary patterns, such as the Mediterranean diet, rich in monounsaturated fatty acids mainly from olive oil, is associated with a lower stroke risk. Furthermore, lowering low-density cholesterol (LDL-C) levels decreases stroke recurrence. Interestingly, Avocado-substituted diets, which are also rich in monounsaturated fatty acids, significantly decrease LDL cholesterol levels. This study aims to evaluate whether a Mediterranean diet based on Avocados reduces LDL-C compared to a low-fat high-complex carbohydrate diet after 3 months of the intervention in patients who had a recent acute ischemic stroke. The trial will also assess safety and feasibility.Patients and methods:Prospective, randomized open-label, blinded outcome assessment clinical trial. Participants are patients within a month of being admitted with an ischemic stroke, who consent and fulfil the eligibility criteria. Patients are randomly assigned to either diet intervention in a 1:1 ratio on top of the usual secondary prevention treatment. The intervention diet is:

• A)Avocado-based Mediterranean diet with intake of 1/2 portion of Avocado per day and
• B)The control diet is a low-fat high-complex carbohydrate diet.

The main efficacy outcome is a reduction in plasma LDL-C levels at 3 months of the dietary intervention. Secondary outcomes include changes in the levels of serum lipid profile and serum inflammation markers, safety, and feasibility. A sample size of 200 patients was estimated to provide 80% power and 5% level of significance (10% loss and 5% crossover) to detect a minimum difference of 4.6 mg/dL in LDL-C after 3 months of intervention.Conclusion:We hypothesize that an Avocado-based Mediterranean diet will further reduce the levels of LDL-cholesterol at 3 months compared to the control diet, and that the intervention is safe and feasible.Registration:The study is registered under ADDSPISE at www.clinicaltrials.gov. Identifier {"type":"clinical-trial","attrs":{"text":"NCT03524742","term_id":"NCT03524742"}}NCT03524742. Protocol ID CAS-605 version 3.0 (May 2nd, 2019).     

Indonesian registry on atrial fibrillation (OneAF)

Background:Data on the optimal therapeutic international normalized ratio (INR) for non-valvular and valvular atrial fibrillation (AF) in Indonesia is currently unavailable. Therefore, we designed the Indonesian Registry on Atrial Fibrillation (OneAF) registry in order to seek a safe and beneficial range of INR in Indonesian patients with non-valvular and valvular AF.Methods/design:The OneAF registry is a nationwide collaboration of the Indonesian Heart Rhythm Society (InaHRS) enrolling all hospitals with cardiac electrophysiologists in Indonesia. It is a prospective, multicentre, nationwide, observational study aiming to recruit non-valvular and valvular AF patients in Indonesia. The registry was started in January 2020 with a planned 2 years of recruitment. There are 2 respondents for this registry: non-cohort and cohort respondents. Non-cohort registry respondents are AF patients at hospitals who fulfill inclusion and exclusion criteria but did not consent for a 24 month follow up. Whereas patients who consented for a 24 month follow up were included as cohort registry respondents. Key data collected includes basic sociodemographic information, symptoms and signs, medical history, results of physical examination and laboratory test, details of diagnostics and treatment measures and events.Results:Currently, a total of 1568 respondents have been enrolled in the non-cohort registry, including 1065 respondents with non-valvular AF (67.8%) and 503 respondents with valvular AF (32.2%). We believe that the OneAF registry will provide insight into the regional variability of anticoagulant treatment for AF, the implementation of rhythm/rate control approaches, and the clinical outcomes concerning cardiocerebrovascular events.Trial registration:Registered at clinicaltrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT04222868","term_id":"NCT04222868"}}NCT04222868).     

Acupuncture for blunt chest trauma: A protocol for a double-blind randomized control trial

Introduction:Blunt chest trauma (BCT) accounts for up to 65% of polytrauma patients. In patients with 0 to 2 rib fractures, treatment interventions are typically limited to oral analgesics and breathing exercises. Patients suffering from BCT experience symptoms of severe pain, poor sleep, and inability to perform simple daily life activities for an extended period of time thereafter. In this trial, we aim to investigate the efficacy of acupuncture as a functional and reliable treatment option for blunt chest trauma patients.Methods:The study is designed as a double-blind randomized control trial. We will include 72 patients divided into 2 groups; the acupuncture group (Acu) and placebo group (Con). The acupuncture group will receive true acupuncture using a uniquely designed press tack needle. The control group will receive placebo acupuncture treatment through the use of a similarly designed press tack needle without the needle element. The acupoints selected for both groups are GB 34, GB 36, LI 4, LU 7, ST 36, and TH 5. Both groups will receive 1 treatment only following the initial visit to the medical facility and upon diagnosis of BCT. Patient outcome measurements include: Numerical Rating Scale, Face Rating Scale, respiratory function flowmeter, Verran Snyder-Halpern sleep scale, and the total amount of allopathic medication used. Follow-up time will be scheduled at 4 days, 2 weeks, and lastly 3 months.Expected outcome:The results of this study can potentially provide a simple and cost-effective analgesic solution to blunt chest trauma patients. This novel study design can serve as supporting evidence for future double-blind studies within the field of acupuncture.Other information:The study will be conducted in the thoracic surgical department and acupuncture department in China Medical University Hospital, Taichung, Taiwan. The study will be conducted on blunt chest trauma patients and is anticipated to have minimum risk of adverse events. Enrollment of the patients and data collection will start from March 2020. Study completion time is expected in March 2022.Protocol Registration:(CMUH109-REC1-002), ({"type":"clinical-trial","attrs":{"text":"NCT04318496","term_id":"NCT04318496"}}NCT04318496).     

Optimal extent of lymphadenectomy for radical surgery of pancreatic head adenocarcinoma: 2-year survival rate results of single-center,prospective, randomized controlled study

Background:Radical pancreaticoduodenectomy is the only possible cure for pancreatic head adenocarcinoma, and although several RCT studies have suggested the extent of lymph node dissection, this issue remains controversial. This article wanted to evaluate the survival benefit of different lymph node dissection extent for radical surgical treatment of pancreatic head adenocarcinoma.Methods:A total of 240 patients were assessed for eligibility in the study, 212 of whom were randomly divided into standard lymphadenectomy group (SG) or extended lymphadenectomy group (EG), there were 97 patients in SG and 95 patients in EG receiving the radical pancreaticoduodenectomy.Result:The demography, histopathology and clinical characteristics were similar between the 2 groups. The 2-year overall survival rate in the SG was higher than the EG (39.5% vs 25.3%; P = .034). The 2-year overall survival rate in the SG who received postoperative adjuvant chemotherapy was higher than the EG (60.7% vs 37.1%; P = .021). There was no significant difference in the overall incidence of complications between the 2 groups (P = .502). The overall recurrence rate in the SG and EG (70.7% vs 77.5%; P = .349), and the patterns of recurrence between 2 groups were no significant differences.Conclusion:In multimodality therapy system, the efficacy of chemotherapy should be based on the appropriate lymphadenectomy extent, and the standard extent of lymphadenectomy is optimal for resectable pancreatic head adenocarcinoma. The postoperative slowing of peripheral blood lymphocyte recovery might be 1 of the reasons why extended lymphadenectomy did not result in survival benefits.Clinical trial registration:This trial was registered at ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02928081","term_id":"NCT02928081"}}NCT02928081) in October 7, 2016. https://clinicaltrials.gov/