Standard-dose Group Research Articles

Anti-angiogenic effect of the combination of low-dose sorafenib and EGCG in HCC-induced Wistar rats.

Background: Sorafenib is a standard drug used for advanced hepatocellular carcinoma but is often resistant and toxic. Its combination with epigallo-3-catechin gallate leads to reduced resistance and toxicity but an equally effective anti-angiogenic effect.Therefore, this study aims to assess the anti-angiogenic effect of standard-dose Sorafenib compared to the combination of low-dose Sorafenib and epigallo-3-catechin gallate. Methods: We conducted an animal study and double-blind, randomized controlled trials. A total of 25 male Wistar rats (7-weeks-old) were randomly divided into four groups, namely Sham (K), Control (O), a combination of low-dose Sorafenib and epigallo-3-catechin gallate group (X1), and standard-dose Sorafenib group (X2). All groups were injected with N-Nitrosodiethylamine 70 mg/kg body weight (BW) intraperitoneally for ten weeks, except the Sham group. After the development of hepatocellular carcinoma, X1 and X2 were treated for two weeks. Subsequently, liver tissues were examined for vascular endothelial growth factor (VEGF) level and microvascular density expression. Results: There was a significant difference (p=0.007) in the level of VEGF between group X1 (low dose Sorafenib + EGCG) and X2 (Standard dose Sorafenib). However, the differences in VEGF levels of group X1 and X2 compared to group O(Control) were significantly lower, with values p=0.000136 and p=0.019, respectively. The expression of microvascular density between groups X1 and X2 was not entirely different. Meanwhile, a significant difference (p<0.05) was discovered when both groups were compared with the control group. Conclusion: The combination of low-dose Sorafenib with epigallo-3-catechin gallate is superior in reducing the level of VEGF compared to standard-dose Sorafenib and is better than the control. Standard-dose Sorafenib and the combination of low-dose Sorafenib and epigallo-3-catechin gallate have similar effectivity in reducing the expression of microvascular density and could prevent resistance and lower toxicity effects.

High-Dose Versus Standard-Dose Intensity-Modulated Radiotherapy With Concurrent Paclitaxel Plus Carboplatin for Patients With Thoracic Esophageal Squamous Cell Carcinoma: A Randomized, Multicenter, Open-Label, Phase 3 Superiority Trial

The standard dose (SD) of definitive concurrent chemoradiotherapy (dCRT) remains 50.4 Gy in patients with esophageal cancer; a higher dose, when applied with conventional radiation therapy techniques, increases toxicities without improving survival. We investigated whether a high dose of 59.4 Gy using intensity-modulated radiation therapy (IMRT) would improve survival without increasing toxicities. Patients with inoperable thoracic esophageal squamous cell carcinoma (SCC) referred for dCRT were randomly assigned (1:1) to high-dose (HD) IMRT (59.4 Gy) or SD IMRT (50.4 Gy). Chemotherapy consisted of 6 cycles of concurrent weekly paclitaxel and carboplatin and a maximum of 2 cycles of consolidation chemotherapy. Nutritional intervention was implemented for patients with malnutrition on the basis of nutritional screening. The primary endpoint was median overall survival (mOS). Analyses were by modified intention to treat. Between April 30, 2016, and April 30, 2019, 167 patients were enrolled at 9 participating centers in China. Seventy-one patients in the HD and 73 patients in the SD groups were included in the analysis; 86.8% of the patients completed radiation therapy and 70.1% received 5 or 6 cycles of concurrent chemotherapy. The median follow-up was 36.0 months. The mOS was 28.1 and 26.0 months in the HD and SD arms, respectively (P=.54). A total of 7 treatment-related deaths were observed. Grade 3 or worse treatment-related toxicities were observed in 62% and 68.5% of the patients in the HD and SD arms, respectively (P=.675). For patients with inoperable thoracic esophageal SCC, a dose of 59.4 Gy did not improve survival compared with the SD of dCRT using IMRT.

Comparable Long-Term Outcomes of Low-Dose Versus Standard-Dose Equine Anti-Thymocyte Globulin with Cyclosporine in Aplastic Anemia

Background: Immunosuppressant therapy (IST) with equine anti-thymocyte globulin (eATG) and cyclosporine is the current standard treatment for transplant-ineligible aplastic anemia (AA) patients. Recently eltrombopag has been added to this IST backbone. The standard dose of eATG is 40mg/kg/day, however, the ideal dose of eATG is not known. We studied the efficacy of 25 mg/kg/day x 4 days (low-dose) with standard-dose eATG in transplant-ineligible AA patients at our tertiary care centre. Methods: AA patients (age >12 years) who received eATG and cyclosporine from 2003 to 2021 were retrospectively analysed.The choice of eATG dose was based on patients'finances. Patients developing nephrotoxicity with cyclosporine were switched to oral mycophenolate mofetil. Overall response rates (ORR) [complete response (CR) and partial response (PR)] were analysed at 3 months, 6 months and 12 months after eATG.Kaplan-Meier survival analyses were performed to analyse overall survival (OS) and event free survival (EFS). Results: Ninety-three AA patients received eATG during the study period. Their median age was 30 years (range 13-65 years); 60 (64.5%) were males. PNH clone was present in 33 (35.5%) patients. Median duration from symptom onset to diagnosis was 3 months (range 1-100 months). 62 patients (66.7%) received low-dose eATG; 31 patients (33.3%) received standard-dose eATG. 17 patients (18.3%) received eltrombopag in addition to eATG plus cyclosporine. The number of patients eligible for response assessment at 3 months, 6 months and 12 months were 93 (100%), 86 (92.4%) and 80 (86%), respectively. ORRs in the total study population at 3 months, 6 months, and 12 months were 49.5%, 66.3%, and 72.5%, respectively; respective CR rates were 5.4%, 14% and 20%. The differences between ORRs among low-dose versus standard-dose eATG groups at 3 months (50% vs 48.4%; p = 0.88), 6 months (63.8% vs 71.4%; p = 0.67) and 12 months (69.6% vs 79.2%; p = 0.167) were statistically insignificant. Median duration of oral cyclosporine after eATG was 25 months (range 3-144 months); 23 patients (24.7%) who were having suboptimal response at 6 months (PR 15, NR 8) and 12 months (PR 18, NR 5) achieved CR after 12 months with the continuation of cyclosporine. The median duration of follow up was 52 months (range 3-229 months). 11 patients (11.8%) relapsed after eATG (7 in low-dose group, 4 in standard-dose group) after a median duration of 32 months (range 12-84 months). Two patients (2.1%) underwent clonal evolution to AML and MDS-EB2 at 83 months and 35 months, respectively (both in standard-dose group). 15 patients (16.1%) died during follow up and 18 (19.3%) were lost to follow up. 10-year OS and 10-year EFS of the total study population were 80% and 64%, respectively. There was no significant difference between low-dose and standard-dose groups in terms of 10-year OS (82.4% vs 74.8%; p = 0.43) and 10-year EFS (64.5% vs 63.1%; p = 0.64), respectively. Conclusion: This study revealed that low-dose eATG and standard dose eATG have comparable response rates and long-term survival. CR rates continue to improve with continuation of oral cyclosporine beyond 12 months in patients who have partial or no response at 6 and 12 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Multiple Myeloma Patients Refractory to Standard Dose Vs Low Dose Lenalidomide

Background: Lenalidomide (Len) containing regimens are extensively used as first line therapy in multiple myeloma (MM). Since most patients (pts) eventually relapse while on these regimens or on Len maintenance, refractoriness to Len is an important factor in determining the choice of therapy at first relapse. It remains debatable if resistance to Len varies between pts who progress on a standard dose of Len (e.g., 25 mg daily, in combination with other agents or otherwise), and those who progress on single agent low dose Len (e.g., 10 mg daily). To this extent, often pts progressing on standard doses are considered refractory to Len, while pts progressing on maintenance doses are considered Len sensitive. In this study, we sought to assess the impact of refractoriness to standard dose vs low dose Len on outcomes with subsequent therapies in MM pts. Methods: We retrospectively reviewed MM pts diagnosed from January 2004 to December 2018, who progressed on/ after receiving first line therapy with Len containing regimens. We divided pts into 3 groups based on refractoriness to Len at first relapse- 1. Pts progressing on or within 60 days of receiving 25 mg Len (Standard Dose Refractory), 2. Pts progressing on or within 60 days of receiving 5-15 mg Len (Low Dose Refractory), and 3. Pts who received Len as a part of first line therapy but progressed after 60 days of stopping Len (Not Refractory). In addition to Len, we classified pts as refractory to proteasome inhibitors (PI) or daratumumab (Dara) at first relapse. We classified salvage regimens into Dara, PI, immunomodulatory drug (IMiD), PI+IMiD, elotuzumab, and VDT PACE like regimens. We used the International Staging System (ISS) and mSMART criteria for risk stratification. We assessed progression free survival (PFS) and overall survival (OS) on next line therapy, as well as for next Len containing line of therapy using Kaplan Meier and Cox models. Results: A total of 312 pts were included. Median age at diagnosis was 65 years and 60% pts were male. Overall, 30%, 33%, and 23% pts were ISS stage I, II, and III respectively; 33% pts had a high-risk FISH abnormality. At first relapse, 54 (17 %) pts were Standard Dose Refractory, 124 (40 %) were Low Dose Refractory, and 134 (43 %) were Not Refractory. For next line of therapy, no PFS difference was found between Standard Dose Refractory and Low Dose Refractory pts (14.5 months vs 12.6 months, p=0.76, Figure 1). As compared to Not Refractory pts (median PFS 29 months), the median PFS was inferior for both Standard Dose Refractory (PFS 14.5 months, p=0.002) and Low Dose Refractory pts (PFS 12.6 months, p<0.001). Using the Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, type of salvage regimen, and receipt of ASCT at relapse; the Not Refractory group had a better PFS (Hazard Ratio (HR)= 0.37, 95% CI: 0.24-0.57), while no difference was seen in the Standard Dose Refractory group (HR= 0.95, 95% CI: 0.59-1.51) as compared to the Low Dose Refractory group. Among the 312 pts, 124 (39.7 %) pts had received another Len containing regimen after the first line regimen at any time during the disease course. For this line of therapy, when compared to Not Refractory pts (median PFS 37 months), the median PFS for the Standard Dose Refractory group was 6 months (p<0.001) and for the Low Dose Refractory group was 10 months (p<0.001). Again, no PFS difference was found between Standard Dose vs Low Dose Refractory groups (p=0.79, Figure 1). On adjusting for parameters as above, the Not Refractory group had a better PFS (HR= 0.24, 95% CI: 0.13-0.44), while no difference was seen in the Standard Dose Refractory group (HR= 1.26, 95% CI: 0.6-2.63) when compared to the Low Dose Refractory group. In terms of OS, no differences were seen among Low Dose Refractory, Standard Dose Refractory, and Not Refractory groups, both from the time of first relapse (HR= 1 vs 1.03 (0.57-1.85) vs 0.62 (0.36-1.07) respectively), and from start of next Len containing regimen (HR= 1 vs 2.3 (0.78-6.74) vs 1.2 (0.45-3.18) respectively); after adjusting for above listed characteristics. Conclusions: The PFS for next line therapy and next Len containing line of therapy did not differ between pts refractory to standard dose vs low dose Len, and both were significantly inferior to pts who were not refractory to Len. These data suggest that resistance to Len is not dose dependent, and definition of Len refractoriness should not depend on the dose of Len to which the pts were considered refractory. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Analyses on safety and efficacy of non-standard dose of r-tPA in intravenous thrombolysis-treated AIS patients.

Intravenous 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA) is one of the most effective treatments in acute ischemic stroke patients. Practically, the dose of r-tPA is still a topic that is constantly being discussed. For this observational study, data were obtained from 537 patients who received r-tPA thrombolysis at Shanghai Sixth People's Hospital stroke center over 5 years (2014-2019). Patients were divided into two groups: a non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) and a standard dose group (0.9 mg/kg). Different outcomes were observed: efficacy: 3 months mRS 0-1 (3m-mRS0-1); safety: symptomatic intracranial hemorrhage within 24 h (24h-sICH) and 3 months mortality (3m-death). We also observed the effect of r-tPA dose coefficient on outcomes in different age groups and baseline National Institute of Health stroke scale (NIHSS) score subgroups. There were 265 patients who gave the standard dose treatment and 272 gave the nonstandard dose. There was no significant difference between the non-standard dose group and the standard dose group in 3m-mRS0-1, 3m-death, and 24h-sICH (p = 0.567, 0.327, and 0.415, respectively). The dose coefficient presents a significant negative correlation (p = 0.034, B = -4.290) with 3m-death in NIHSS < 16 sub-group. Door-to-needle time (DNT) is the most important independent outcome-influential factor (MIOIF) in the NIHSS ≥16 sub-group. The diabetes history and baseline NIHSS score were the MIOIF in the age ≥80-year sub-group. The non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) shows no difference in safety and effectiveness than the standard dose group (0.9 mg/kg) in our study. The standard dose should be considered first according to current evidence and Guidelines, but the non-standard dose (0.6 mg/kg ≤ dose < 0.9 mg/kg) might be an option in the actual diagnosis and treatment process considering the patient's clinical profile and financial condition.

Evaluation of standard versus reduced dose apixaban for the treatment of venous thromboembolism in patients with severe renal disease (ESRD-VTE)

BackgroundThere are no clear dosing recommendations when using apixaban for venous thromboembolism (VTE) treatment in patients with severe or end-stage renal disease; clinical trials excluded patients with a creatinine clearance (CrCl) <25 mL/min or on dialysis. This study compares bleeding rates in patients with severe or end-stage renal disease taking standard versus reduced dose apixaban for VTE treatment. Materials and methodsThis was a multicenter, retrospective cohort study using electronic medical records between January 1, 2013, and August 31, 2021. This study included patients 18 years or older who had severe or end-stage renal disease when prescribed apixaban for VTE treatment. Severe or end-stage renal disease was defined as at least one of the following: CrCl <25 mL/min, SCr >2.5 mg/dL, CKD stage 4 or 5, or on dialysis. The primary endpoint was rate of clinically relevant bleeding within six months of starting apixaban. Secondary endpoints were VTE recurrence within six months of starting apixaban, time to clinically relevant bleed, and time to VTE recurrence. ResultsA total of 203 patients were included in the final analysis (n = 125 on 5 mg; n = 78 on 2.5 mg). Clinically relevant bleeding rate was significantly higher in the standard dose group (14.4 % vs 3.8 %, p = 0.02). Rates of VTE recurrence appear similar (6.4 % vs 7.7 %, p = 0.21). ConclusionsA reduced dose of apixaban may be considered when treating VTE in patients with severe or end-stage renal disease.

Treatment of Choice for Resectable Cervical Esophageal Cancer: Surgery and Definitive Chemoradiotherapy with or without Dose Escalation

<h3>Purpose/Objective(s)</h3> Cervical esophageal cancer is rare subgroup which epicenter of tumor located between upper esophageal sphincter and sternum notch, for 5% to 10% of all esophageal cancers. Most of patients of cervical esophageal cancer needed hypopharyngectomy and laryngectomy for complete resection, pre-operative chemotherapy (CTx) or chemoradiotherapy (CRT) is needed, and even definitive CRT has been widely accepted treatment of choice for laryngeal preservation. We reviewed our institutional experiences to compare and tried to suggest the treatment directions for resectable cervical esophageal cancer. <h3>Materials/Methods</h3> A total of 197 patients who were diagnosed as cervical esophageal cancer without distant metastasis between January 2001 and December 2020 were identified. Of those, 47 patients were excluded in this study because of unresectable stage (e.g., initial stage T4 or extensive nodal stage), 100 patients had definitive chemoradiotherapy and 50 patients had surgery. In surgery group, 16 patients received preoperative treatment (CRT; 6 patients, CTx alone; 10 patients) and 16 patients received postoperative treatment (CRT; 6 patients, CTx alone, 6 patients, radiotherapy alone; 4 patients). Definitive CRT group patients were divided into high-dose group (≥59.4 Gy, n=71), and standard dose group (<59.4 Gy, n=29). <h3>Results</h3> The median follow-up was 30 months (5-225 months) for surviving patients. Of 50 patients with median age 63 in surgery group, 21 (42%), 9 (18%), 18 (36%), 2 (4%) patients were stage I, II, III and IV respectively. Patients in CRT group was statistically significant different in age (median 67) and stage as 19 (19%), 30 (30%), 44 (44%), 7 (7%) patients were stage I, II, III, IV. There was no statistical difference in overall survival (OS) (3-year OS: 61.2% vs 62.9%, p=0.976) and progression free survival (PFS) (3-year PFS: 47.5 % vs 53.0%, p=0.589). Treatment related toxicity (Grade≥2) were significantly higher in surgery group than CRT group (14(28%) vs 12 (12%), p=0.015), even only 6 patients received hypopharyngectomy and laryngectomy. In subgroup analysis between high-dose group and standard dose group, OS and loco-regional failure free survival (LRFS) was significantly higher in high-dose group (3-year OS: 65.4% vs 51.7%, p=0.046, 3-year LRFS 68.7% vs 42.5%). There was no significant difference between two group (High-dose group 9 (12.7%) vs Standard dose group 3 (10.3%), p=0.106). <h3>Conclusion</h3> There was no significant difference in OS and PFS between surgery and CRT group although surgery group had patient selection bias for patients with earlier stage and younger age. Also, LRFS were better with high-dose CRT than standard group which lead to better OS and consequently achieved favor OS in general CRT group. High dose RT was not associated with higher toxicity rate, mainly because recent intensity modulated RT could give higher dose while saving normal organ toxicity. Thus, high dose CRT should be considered as initial treatment for cervical esophagus than surgery.

Concurrent Chemoradiation of Different Doses (50.4 Gy vs. 59.4 Gy) and Different Target Field (ENI vs. IFI) for Locally Advanced Esophageal Squamous Cell Carcinoma: Results from a Randomized, Multicenter Phase Ⅲ Clinical Trial

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiation is standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC), while the optimal regimen of radiotherapy, especially in terms of total dose and planned range of target field, remained unclear. This phase Ⅲ clinical trial was aimed to compare the survival benefits between different total dose and different target field. <h3>Materials/Methods</h3> The clinical trial compared two radiation treatment aspects of total dose and field under two-by-two factorial design. The high radiation dose group (HD) totally received 59.4Gy radiation and standard dose group (SD) received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different radiation plans of clinical target volume (CTV), among which the CTV in IFI group was defined as GTV plus extend margin to the primary tumor and in ENI group CTV was defined as GTV plus the extend margins and the high-risk region of elective nodes. Two cycles of Tegafur/gimeracil/oteracil (S-1) and cisplatin were given with concurrent radiotherapy. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI) by simple randomization (1:1:1:1 ratio). The planned sample size was 147 in each arm (588 totally). The primary endpoint was overall survival (OS) and the second endpoints included progression-free survival (PFS) and objective response rate (ORR). All statistical analysis was performed according to intention-to-treat principle. <h3>Results</h3> The median follow-up period was 47.3 months until December 2021. The median OS were 33.6, 33.9, 41.0 and 28.3 months in HD+ENI, SD+ENI, HD+IFI and SD+IFI groups, respectively. No significant synergistic effect was detected between dose and radiation field in interaction analysis. Compared with SD arms, the HD treatment did not present significantly prolonged OS (HR=0.93, log rank test p value=0.54) but suggested improved PFS (29.1 months to 20.0 months, HR=0.77, log rank test p value=0.023). In subgroup analysis of IFI, the HD treatment was associated with more benefits (HD+IFI arm to SD+IFI arm, HR of PFS is 0.64[0.47-0.84]). In comparison of target field, patients in IFI or ENI group presented similar OS (HR=1.05, log rank test p=0.7) and PFS (HR=1.08, log rank test p=0.5). In the stratified analysis of lymph node status, the ENI treatment suggested benefits compared to IFI in N0 patients (n=108, HR of OS is 0.46[0.24-0.89]). No significant difference in occurrences of severe adverse event was detected in comparisons of dose or field groups. <h3>Conclusion</h3> The HD and SD radiation treatment did not significantly differ in OS, but HD radiation associated with better PFS. The IFI treatment brought similar outcomes to ENI in overall patients, which indicated a reasonable choice for locally advanced ESCC.

Genomic Adjusted Radiation Dose (GARD) Predicts Local Recurrence and Overall Survival in Triple-Negative Breast Cancer

<h3>Purpose/Objective(s)</h3> Although it is known that breast cancer is a heterogeneous disease with variable response to different treatments, radiation therapy (RT) is typically prescribed with a uniform approach. We have previously shown that the genomic adjusted radiation dose (GARD) is predictive of RT benefit in a pooled analysis which included hormone receptor positive and triple-negative breast cancer (TNBC) patients. Recent trials showed no benefit in overall survival (OS) with a randomized 16 Gy boost, but we hypothesize that GARD can predict outcomes in TNBC and could select patients who would benefit from dose escalation. <h3>Materials/Methods</h3> We used two IRB-approved, prospectively collected cohorts of TNBC patients treated with RT, 58 from the Netherlands Cancer Institute and 55 from Moffitt Cancer Center. Cox proportional hazards analysis was performed with GARD as a continuous variable for local recurrence (LR) and OS. We used the log-rank test to maximize the difference between groups above and below each GARD value and defined RxRSI as the physical radiation dose necessary to achieve that GARD cutpoint. Patients were stratified into 3 groups based on whether their RxRSI fell above, within, or below the standard-of-care dosing range of 50-66 Gy. To determine the minimum enrollment number needed to show a significant LR benefit in a clinical trial, we performed a power analysis by simulating an <i>in silico</i> trial with two arms. In one arm, all patients received 50 Gy, and in the other, dose was boosted to 66 Gy only for patients whose RxRSI fell within 50-66 Gy while the rest of the cohort received 50 Gy. Thus, selective dose escalation was only applied to patients who we predicted would benefit from it based on their individual RSI and GARD. The simulation was repeated with different enrollment numbers to find the smallest number needed to show a significant benefit in LR in a trial of this design. <h3>Results</h3> While the radiation dose delivered in the cohorts analyzed was between 43.5 to 75 Gy, GARD showed a much wider range (12 to 76). Cox analysis showed significant association between GARD and OS (HR=0.88, p=0.02) and strong association between GARD and LR (HR = 0.96, p=0.08). Receiving GARD of at least 22 maximized LR and OS benefit (p<0.01). By this measure, 50% of patients were optimized with 50 Gy, 22% would benefit from a boost, and 28% require higher radiation dose than is standard. Using our stochastic <i>in silico</i> method, we found that to see a significant difference in LR between boosted and standard-dosing groups in a trial of genomically stratified TNBC patients, only 30 patients would be needed. <h3>Conclusion</h3> Our analysis shows that for each unit GARD, a statistically significant increase in OS seen, and that using genomic stratification in trial design yields a small and quickly tractable trial to test the efficacy of this approach in tumor bed dose decision-making.

High dose of epinephrine does not improve survival of children with out-of-hospital cardiac arrest: Results from the French National Cardiac Arrest Registry.

ObjectivesThe pediatric resuscitation guidelines recommend the use of 0. 01 mg kg−1 epinephrine during a cardiac arrest; an epinephrine dose higher than that is not recommended. The first aim of this study was to determine the administration rate of high epinephrine dose during pediatric out-of-hospital cardiac arrest. The second aim was to compare the survival status in patients who received high or standard doses of epinephrine.MethodsThis was a multicenter comparative post-hoc study conducted between January 2011 and July 2021 based on the French National Cardiac Arrest Registry data. All prepubescent (boys < 12 years old, girls < 10 years old) victims of an out-of-hospital cardiac arrest were included. To compare survival status and control bias, patients who received a high epinephrine dose were matched with those who received a standard epinephrine dose using propensity score matching.ResultsThe analysis included 755 patients; 400 (53%) received a high dose and 355 (47%) received a standard dose of epinephrine. The median dose (mg kg−1) per bolus was higher in the high-dose group than that in the standard dose group (0.04 vs. 0.01 mg kg−1, P < 0.001). Before matching, there was no between-group difference in the 30-day survival rate or survival status at hospital discharge. Matching yielded 288 pairs; there was no between-group difference in the 30-day survival rate or survival at hospital discharge (High dose, n = 5; standard dose, n = 12; Odds ratios: 2.40, 95% confidence interval: 0.85–6.81). Only 2 patients in the standard dose group had a good neurological outcome.ConclusionMore than 50% of the patients did not receive the recommended epinephrine dose during resuscitation. There was no association between patients receiving a high dose or standard dose of epinephrine with the 30-day survival or survival status at hospital discharge. Collaboration across multiple cardiac arrest registries is needed to study the application of pediatric guidelines.

Low-dose anticoagulation for peripheral deep vein thrombosis of the lower extremities in cancer patients

Abstract Background Venous thromboembolism (VTE) is a frequent complication in cancer patients and is often detected as asymptomatic peripheral deep vein thrombosis (DVT). However, guidelines for peripheral DVT have not been established in either general cardiology or onco-cardiology. Furthermore, in cancer patients, it is generally considered difficult to administer standard doses of anticoagulants due to the high risk of bleeding caused by thrombocytopenic tendency during chemotherapy, as well as bleeding lesions such as gastrointestinal and gynecological cancers. Treatment of peripheral DVT with direct oral anticoagulants (DOACs) may minimize the worsening of bleeding and prevent the transition to proximal DVT. Objective The purpose of this study was to investigate the optimal treatment for peripheral DVT in cancer patients. Methods 242 consecutive patients with peripheral DVT of the lower extremities (excluding complications of pulmonary thromboembolism or proximal DVT) were examined by venous ultrasound from April 2019 to March 2020. 190 patients could be followed up by ultrasound examination, for up to 2 years. The course of the DVT was retrospectively examined. In cases of anticoagulant therapy, standard and low dosage of DOACs were evaluated. Results 142 patients were treated with anticoagulant (AC) therapy (group AC(+)), 48 patients were without AC therapy (group AC(−)). (4 of the 142 patients were treated with warfarin and the rest with DOACs). DVT worsened in 8 patients (5.6%) in the AC(+) group and 23 patients (47.9%) in the AC(−) group. DVT worsening was significantly less in the AC(+) group (p&amp;lt;0.0001). There were no cases of worsening to proximal type in the AC(+) group and 4 cases (17.4%) in the AC(−) group. Of the 138 patients who used DOACs as AC therapy, 62 used half or less than the standard dose for maintenance (low-dose DOAC group), and 76 used the standard dose as maintenance (standard-dose DOAC group). In the low-dose DOAC group, DVT worsened in 5 cases, remained unchanged in 7 cases, and improved in 50 cases. In the standard-dose DOAC group, there were 4 cases of worsening DVT, 3 cases of no change, and 69 cases of improvement. There was no significant difference in the DVT treatment effect between the two groups. There were no thrombus-related deaths. Conclusion Peripheral DVT worsens in about half of cancer patients without anticoagulation, and 17% of these worsen to proximal VTE. In addition, low-dose DOACs are found to be as effective as standard-dose DOACs in treating peripheral DVT in cancer patients. Peripheral DVT treatment with low-dose DOACs can reduce the risk of bleeding complications and thrombus-related mortality in cancer patients and should be one of the supportive treatments for the completion of cancer management. Funding Acknowledgement Type of funding sources: None.

Safety of off-label dose reduction of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

To investigate the effects of off-label non-vitamin K oral anticoagulant (NOAC) dose reduction compared with on-label standard dosing in atrial fibrillation (AF) patients in routine care. Population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink, comparing adults with non-valvular AF receiving an off-label reduced NOAC dose to patients receiving an on-label standard dose. Outcomes were ischaemic stroke, major/non-major bleeding and mortality. Inverse probability of treatment weighting and inverse probability of censoring weighting on the propensity score were applied to adjust for confounding and informative censoring. Off-label dose reduction occurred in 2466 patients (8.0%), compared with 18 108 (58.5%) on-label standard-dose users. Median age was 80 years (interquartile range [IQR] 73.0-86.0) versus 72 years (IQR 66-78), respectively. Incidence rates were higher in the off-label dose reduction group compared to the on-label standard dose group, for ischaemic stroke (0.94 vs 0.70 per 100 person years), major bleeding (1.48 vs 0.83), non-major bleeding (6.78 vs 6.16) and mortality (10.12 vs 3.72). Adjusted analyses resulted in a hazard ratio of 0.95 (95% confidence interval [CI] 0.57-1.60) for ischaemic stroke, 0.88 (95% CI 0.57-1.35) for major bleeding, 0.81 (95% CI 0.67-0.98) for non-major bleeding and 1.34 (95% CI 1.12-1.61) for mortality. In this large population-based study, the hazards for ischaemic stroke and major bleeding were low, and similar in AF patients receiving an off-label reduced NOAC dose compared with on-label standard dose users, while non-major bleeding risk appeared to be lower and mortality risk higher. Caution towards prescribing an off-label reduced NOAC dose is therefore required.

Imatinib dose optimization based on therapeutic drug monitoring in Chinese patients with chronic-phase chronic myeloid leukemia.

Imatinib treatment often produces various adverse reactions in patients with chronic myeloid leukemia (CML), and increasing patients are pursuing dose optimization. In this study, the authors aimed to explore imatinib dose optimization based on therapeutic drug monitoring (TDM) in CML patients. The relationship between imatinib concentration and clinical response and adverse reactions was evaluated, then the dose-reduction data in 110 Chinese CML patients was also explored. Patients with a major molecular response (MMR) had higher imatinib plasma concentration compared with those not achieving MMR (1473.70±419.13 vs. 985.8±213.32ng/ml) when receiving 400mg daily. Imatinib concentration >1000ng/ml predicted improved event-free survival and failure-free survival. In addition, imatinib concentration was significantly correlated with leukopenia or neutropenia, diarrhea, edema, and rash. Patients receiving imatinib concentration >1685ng/ml were more susceptible to diarrhea and those with levels >1575ng/ml were more susceptible to periorbital and limb edema. Thirty-nine (35.5%) patients underwent low-dose therapy and seven (6.4%) patients received discontinuation therapy. Patients with a higher imatinib concentration were more likely to maintain MMR or deep molecular response after dose reduction. No significant difference in molecular relapse-free survival rate was observed between the low-dose and standard-dose groups over 1year and 2years. Furthermore, most adverse reactions significantly improved after dose reduction. Imatinib concentration was closely associated with clinical response and adverse reactions, suggesting that dose optimization based on TDM might achieve beneficial clinical outcomes. Dose reduction based on TDM is feasible and safe for patients exhibiting optimal response, which could improve adverse reactions.

Fish Oil and Vitamin D Supplementations in Pregnancy Protect Against Childhood Croup

Croup is a prevalent respiratory disorder in early childhood most often caused by parainfluenza virus infections. There are no preventive strategies; therefore, we investigated the potential effects of prenatal micronutrient supplementations. To investigate the supplementation effects of (1) 2.4-g n-3 long-chained polyunsaturated fatty acid (n-3 LCPUFA) (fish oil) versus olive oil and (2) high-dose (2800 IU/d) versus standard-dose (400 IU/d) of vitamin D from pregnancy week 24 until 1 week after birth on the risk for offspring croup during the double-blinded first 3 years of life in a secondary analysis of a 2× 2 factorial designed randomized controlled trial. The study was completed in the Danish population-based single-center Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, which included 736 pregnant women. Croup was diagnosed by physicians' clinical examinations and medical record checks. Potential mediating mechanisms were investigated using blood metabolomics, airway cytokines, and airway microbiome. Of 695 children, 97 had croup before age 3 years (14%). The risk of croup was reduced in the n-3 LCPUFA (ncases / ntotal= 38/346; 11%) versus olive oil group (59 of 349 children; 17%) (hazard ratio= 0.62; 95% CI, 0.41-0.93; P= .02) and in the high-dose vitamin D group (32 of 295 children; 11%) versus the standard-dose group (51 of 286 children; 18%) (hazard ratio= 0.60; 95% CI, 0.38-0.93; P= .02). There was no evidence of interaction or additive effects between the supplements (Pinteraction= .56). Furthermore, the results did not change when they were adjusted for each other, persistent wheeze, and lower respiratory tract infection. This analysis of the double-blinded period of the Copenhagen Prospective Studies on Asthma in Childhood 2010 randomized controlled trial of n-3 LCPUFA and high-dose vitamin D supplementation during pregnancy demonstrated a reduced risk of croup in early childhood.

Feasibility study of three-dimensional printing knee model using the ultra-low-dose CT scan for preoperative planning and simulated surgery

ObjectiveTo explore the feasibility of the three-dimensional printing (3DP) knee model using the ultra-low-dose computed tomography (CT) scan for preoperative planning and simulated surgery.MethodsThirty-six patients were divided into the standard-dose protocol group (A) and ultra-low-dose protocol group (B). The anteroposterior diameter, left and right diameter of femur, anteroposterior diameter of tibial plateau (APTP), left and right diameter, distance from the intercondylar ridge to tibial tuberosity, lower femur angle, and upper tibial angle were measured on CT images. On the 3D printed knee joint model, Vernier calipers were used to measure: anteroposterior diameter, left and right diameter of the internal and external condyles of femur; left and right diameters, anteroposterior diameters of tibial plateau; upper and lower meridian, left and right diameters of patella.ResultsWith group A as reference, the effective radiation dose in group B was significantly reduced to 97.0% (36.4 ± 3.7 uSv and 1.1 ± 0.2 uSv, respectively). There was no difference in objective parameters for 3DP model (p = 0.31–0.84). None of the quantitative parameters of image quality showed significant difference (p = 0.11–0.96). Despite lower score of image quality and 3DP model in group B (3.0 ± 0.0 vs. 2.1 ± 0.2, 2.9 ± 0.3 vs. 2.2 ± 0.4; p < 0.05), the diagnostic performance was consistent in the two groups (all scores ≥ 2). Image quality and 3DP printed models were highly consistent (k = 0.97).ConclusionsUltra-low-dose protocol reduces the radiation dose while maintaining the image quality of knee. It meets the requirement for 3DP model, internal fixation model selection, and simulated surgery.

Safety and Effectiveness of Reduced Dose Versus Standard Dose Enoxaparin Venous Thromboembolism Prophylaxis in Underweight Medically Ill Patients.

Background: Enoxaparin is commonly used for venous thromboembolism (VTE) prophylaxis in hospitalized patients. Published literature exists for dose adjustment in higher body weights and renal dysfunction, but sparse literature on optimal dosing of prophylactic enoxaparin in underweight patients exists. Objective: To determine if there is a difference in adverse outcomes or effectiveness if enoxaparin VTE prophylaxis dosing is reduced to 30 mg subcutaneously once daily from standard dosing in underweight medically ill patients. Methods: This study was a retrospective chart review of a total of 171 patients, with 190 individual courses of enoxaparin included. Patients were ≥18 years of age, weighed ≤50 kg, and were given at least 2 days of consecutive therapy. Patients were excluded if they were taking anticoagulation upon admission, had a creatinine clearance <30 mL/min, were admitted to the ICU or a trauma or surgical service, or presented with bleeding or thrombosis. The Padua score and a modified score from the IMPROVE trial were used to evaluate baseline thrombotic risk and bleeding risk, respectively. Bleeding events were classified using the Bleeding Academic Research Consortium criteria. Results: No difference was seen in baseline risk of bleeding or thrombosis when comparing the reduced and standard dosing groups. No differences were observed with rates of bleeding, thrombotic events, mortality, or 30-day readmission. Conclusion: Both reduced and standard dosing strategies appeared effective for VTE prophylaxis, but neither showed superiority in reducing bleeding events. Additional larger studies are needed to evaluate safety and effectiveness of reduced dose of enoxaparin in this patient population.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

314.8: The Adverse Effects of High Dose Corticosteroid on Infectious and Non-infectious Sequelae in Renal Transplant Recipients With Coronavirus Disease 19 in India

Introduction: The corticosteroid dosing modulation in renal transplant recipients (RTR) with COVID-19, was not well defined. We aimed to analyze the outcomes, infectious and non-infectious sequelae in RTR with COVID-19 with reference to corticosteroid dosing and the first and second pandemic wave of COVID-19. Material and methods: This study included the RTR admitted during the two pandemic waves between March 25, 2020, and July 31, 2021. Patients were categorized into mild, moderate, and severe COVID 19. The outcomes and predictors of survival at four weeks were analyzed. The survivors were also followed for 6 months and were studied for mortality, readmission rates, infectious and non-infectious sequelae with reference to high-dose and standard-dose corticosteroids. Results: A total of 251 RTRs, 104 during the first wave and 147 during the second wave, were treated. Overall mortality was 15.1% (11.5% in first wave vs 17.5% in second wave, P= 0.23). The use of high-dose steroids was also significantly high in non-survivors (85.8% vs 11.3%, P=0.001). On multivariate analysis, the severity of COVID-19, graft dysfunction, and high dose of corticosteroid therapy were associated with increased odds for mortality. Amongst survivors, 6-months mortality (17.3% vs 0.5%, P= 0.001), readmission rate (91.3% vs 23.7%, P=0.001), fungal infection (30.4% vs. 2.2% p < 0.001), post-COVID lung sequelae (21.7% vs. 4.4%, P = 0.008) were significantly higher in the high-dose corticosteroid group than the standard-dose group. Conclusion: The high-dose corticosteroid dosing in the RTRs with COVID-19 was associated with increased infectious, particularly fungal infections, non-infectious sequelae with higher mortality on subsequent follow-up.

Postmarketing Reevaluation of Chinese Traditional Therapy Kangbingdu Oral Liquid in the Treatment of the Common Cold.

Background Observational studies from China suggest that Kangbingdu oral liquid (KBD) may be effective in treating the common cold. Objective Reevaluation of efficacy and safety of Kangbingdu oral liquid after marketing and expanding population. Design Prospective, Pragmatic randomized controlled trial (Chictr.org.cn registration number: chiCTR-TRC-12002399). Setting. Eleven hospitals from 3 provinces in China. Patients were recruited through 11 centers, including 7 teaching hospitals, 2 University health services, one military clinic, and one community hospital. Patients. 2647 persons aged 18 to 75 years with Common cold. Intervention. Patients were randomly allocated to 2 groups: the treatment group Kangbingdu oral liquid (composed of 9 Chinese herbal medicines and honey) and the placebo group were divided into a standard-dose group of 10 ml every time, a middle dose group of 20 ml every time, high dose group of 30 ml every time, 3 times daily. Interventions and control were given for 5 days. Measurements. The primary outcome is the mean amount of total scores measured by the 11-primary symptoms: to observe the change of main symptoms from severe to disappear and to calculate and compare the mean amount of total scores after the periods of observation. Secondary outcomes are the disappearance rate of each symptom and the median time of body temperature returned to normal. Results On day 5, the Kangbingdu liquid group had significant reductions in the mean amount of total scores measured by the 11-primary symptoms (7.39 [95% CI 7.26 to 7.51] compared to the placebo group (6.43 [95%: CI 6.24 to 6.62]). The Kangbingdu liquid can improve the remission rate of accompanying symptoms on day 5 including aversion to wind, aversion to cold, fever, cough, stuffy, runny nose, sore throat, muscular aches, headache, fatigue, and sweat (P < 0.0001). Significant reductions in time of body temperature to return to normal in the Kangbingdu liquid group (P50, 48.33 [95% CI 46.00 to 52.50] compared with the control group (P50, 64.59 [95% CI 51.08 to 70.50] (P=0.0022). 13 (0.7%) participants in the Kangbingdu liquid group and 1(0.2%) participants in the placebo group (P > 0.05) had treatment-related AEs, which mainly include diarrhea and dyspepsia in the Kangbingdu liquid group and constipation in the placebo group. Conclusion The study's conclusion in this paper was based on the placebo, Kangbingdu oral liquid two groups which clinically diagnosed the common cold and flu. (1) Kangbingdu oral liquid can effectively improve the comprehensive clinical symptoms of common adult cold, also improved main symptoms, including sore throat, muscle aches, headache, and so on. (2) Kangbingdu oral liquid effectively shortens the time of body temperature to return to normal.

Cost-Effectiveness of Low-Dose Compared to Standard-Dose Alteplase for Acute Ischemic Stroke in China: A Within-Trial Economic Evaluation of the ENCHANTED Study

Introduction: The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) showed that a low-dose alteplase was safe but not clearly non-inferior to standard-dose alteplase in acute ischemic stroke (AIS). Given the significant cost of this medicine, we undertook a cost-effectiveness analysis to determine the probability that low-dose is cost-effective relative to standard-dose alteplase in China. Methods: For ENCHANTED participants in China with available health cost data, cost-effectiveness and cost-utility analyses were undertaken in which death or disability (modified Rankin scale scores 2–6) at 90 days and quality-adjusted life-years (QALYs) were used as outcome measures, respectively. There was adherence to standard guidelines for health economic evaluations alongside non-inferiority trials and according to a health-care payer’s perspective. The equivalence margin for cost and effectiveness was set at USD 691 and −0.025 QALYs, respectively, for the base-case analysis. Probabilistic sensitivity analyses were used to evaluate the probability of low-dose alteplase being non-inferior. Results: While the mean cost of alteplase was lower in the low-dose group (USD 1,569 vs. USD 2,154 in the standard-dose group), the total cost was USD 56 (95% confidence interval [CI]: −1,000–1,113) higher compared to the standard-dose group due to higher hospitalization costs in the low-dose group. There were 462 (95% CI: 415–509) and 410 (95% CI: 363–457) patients with death or disability per 1,000 patients in the low-dose and standard-dose groups, respectively. The low-dose group had marginally lower (0.008, 95% CI: −0.016–0.001) QALYs compared to their standard-dose counterparts. The low-dose group was found to have an 88% probability of being non-inferior based on cost-effectiveness versus the standard-dose group. Conclusions: This health economic evaluation alongside the ENCHANTED indicates that the use of low-dose alteplase does not save overall healthcare costs nor lead to a gain in QALYs in the management of Chinese patients with AIS compared to the use of standard dose. There is little justification on economic grounds to shift from standard-of-care thrombolysis in AIS.