THE USE OF IONTOPHORESIS WITH HYALURONIC ACID ASSOCIATED WITH GOLD NANOPARTICLES ACCELERATES WOUND HEALING IN RATS

This study aimed to investigate the effects of iontophoresis with HA associated to GNPs solution in an epithelial lesion model. Fifty Wistar rats (n=10/group) were randomly assigned to the following groups: epithelial lesion (EL); (EL+MIC); (EL+MIC+HA); (EL+MIC+GNPs); (EL+MIC+HA-GNPs). The animals induced to an epithelial lesion and treatment started 24 hours after injury with microcurrents (300µA) containing gel with HA (0.9%) and/or GNPs (30mg/Kg) in the electrodes (1mL) for seven days. The animals were sacrificed 12 hours after the last treatment application. Results demonstrated a reduction in the levels of pro-inflammatory cytokines (IFNϒ, IL-1β, TNFα, IL6) in the group in which the therapies were combined; an increase in the levels of anti-inflammatory cytokines (IL-4, IL-10) and growth factors (FGF, TGFβ) in EL+MIC+HA and EL+MIC+HA-GNPs groups. As for dichlorofluorescein (DCF) and nitrite levels, decreased in the combined therapy group when compared to the control group, as well as the oxidative damage (carbonyl and sulfhydryl). In antioxidant defense, there was an increase in glutathione (GSH) and a decrease in superoxide dismutase (SOD) in the combination therapy group. Histological analysis showed a reduction in the inflammatory infiltrate in groups treated with MIC and in the combination therapy group. An increase in contraction of the wound area was obtained in all treated groups when compared to the control group, proving that the proposed therapies are effective in the process of epithelial healing. The results of this study demonstrated that the associated therapies favor the tissue repair process more significantly compared to the isolated therapies.

Clinical and Imaging Indicators of Hemorrhagic Transformation in Acute Ischemic Stroke After Endovascular Thrombectomy

Background and Purpose: Prior studies have investigated the clinical and imaging factors for hemorrhagic transformation (HT), especially symptomatic intracranial hemorrhage (sICH); however, whether alteplase increases the risk of HT after endovascular thrombectomy (EVT) is unknown. This study aimed to assess clinical and imaging features associated with HT, sICH, and parenchymal hematoma (PH) in patients with acute ischemic stroke after EVT, with and without intravenous alteplase in DIRECT-MT (Direct Intraarterial Thrombectomy to Revascularize Acute Ischemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial). Methods: The DIRECT-MT trial is a randomized trial of EVT alone versus intravenous thrombolysis combined with EVT. HT, sICH, and PH was evaluated on follow-up computed tomography. Multivariable ordinal logistic regression analysis was used to test the association of stepwise selected determinants with HT, sICH, and PH. Results: In total, 633 patients were analyzed; 261 (41.2%) had HT; 34 (5.4%) had sICH; and 85 (13.4%) had PH. The median age was 69, and 56.7% were men. The median National Institutes of Health Stroke Scale score was 18, and 320 patients were in combination-therapy group. Symptomatic intracranial hemorrhage was associated with higher baseline National Institutes of Health Stroke Scale score (adjusted odds ratio [OR], 1.06 [95% CI, 1.10–1.12]) and higher glucose level at hospital arrival (adjusted OR, 1.14 [95% CI, 1.00–1.29]). No association was found between alteplase treatment and HT, sICH, or PH. The independent predictor of sICH was higher baseline National Institutes of Health Stroke Scale score (adjusted OR, 1.09 [95% CI, 1.01–1.18]) in EVT alone group, and history of anticoagulant drugs (adjusted OR, 3.75 [95% CI, 1.07–13.06]), higher glucose level at hospital arrival (adjusted OR, 1.19 [95% CI, 1.03–1.38]), >3 passes of device (adjusted OR, 4.42 [95% CI, 1.36–14.32]) in combination-therapy group. Conclusions: In DIRECT-MT, independent predictors of sICH were baseline National Institutes of Health Stroke Scale score and glucose level at hospital arrival. Alteplase treatment did not increase the risk of HT, sICH, or PH after EVT. The independent predictor of sICH was different in EVT alone group and combination-therapy group. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03469206.

Combination of 0.05% Azelastine and 0.1% Tacrolimus Eye Drops in Children With Vernal Keratoconjunctivitis: A Prospective Study

Aims: To compare the efficacy of the combination of 0. 05% azelastine and 0.1% tacrolimus eye drops with 0.1% tacrolimus monotherapy in pediatric patients with vernal keratoconjunctivitis (VKC).Methods: Prospective study. Seventy-six patients with VKC were randomized 1:1 into monotherapy group with 0.1% tacrolimus or combination therapy group with 0.1% tacrolimus and 0.05% azelastine. The Ocular Surface Disease Index (OSDI) scores and the signs of conjunctival hyperemia, corneal involvement, and palpebral conjunctiva papillae were assessed at baseline and at 1, 2, and 6 weeks after treatment.Results: Two groups were comparable in age, sex, duration of VKC, OSDI, and clinical signs of VKC at baseline. Significant improvements in OSDI score and clinical signs were observed in both groups at all follow-up visits (all p < 0.001), compared with baseline. The combination therapy group showed a larger decrease in OSDI score from baseline (10.30 ± 0.9) compared with monotherapy group (7.30 ± 0.7, p =0.0085) at 1 week. Greater improvements in conjunctival hyperemia and conjunctival papillae were identified in the combination therapy group, compared with in the monotherapy group, at all follow-up visits (all p < 0.05). The corneal involvement scores in the combination group is significantly lower than the monotherapy group at 2 weeks after the treatment (p = 0.0488). No severe adverse effect was found in either group during the study.Conclusions: Compared with a monotherapy of 0.1% tacrolimus, the combination of 0.05% azelastine and 0.1% tacrolimus eye drops lead to faster and greater improvements in clinical signs and symptoms of vernal keratoconjunctivitis in pediatric patients.

Efficacy of different nucleoside analog rescue therapies for entecavir-resistant chronic hepatitis B patients

Background Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue. Methods Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups. Results The rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups. Conclusions TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.

IL-15-induced Lymphocytes as Adjuvant Cellular Immunotherapy for Gastric Cancer

To test the antitumor potential of adoptive cell therapy (ACT)-transferred lymphocytes in a mouse model of human gastric cancer and evaluate the clinical efficacy and safety of combining lymphocytes as adjuvant therapy with first-line chemotherapy in patients with gastric cancer.A human gastric cancer xenograft model was constructed in sublethally irradiated 6–8-week-old NCG male mice. MKN-45 cells (1 × 106 cells/mouse) were subcutaneously injected into the flanks. After tumors had become palpable, the mice were randomized into control, ACTIL-2, and ACTIL-15 groups. Human lymphocytes were injected into the mouse tail veins. In addition, 63 patients who had histological or cytologically confirmed stage III–IV gastric cancer randomly received S-1 plus oxaliplatin plus ACTIL-15 (a combination therapy group) or S-1 plus oxaliplatin alone (chemotherapy group).In the mice, treatment with ACTIL-15 cells inhibited tumor growth upon adoptive transfer, and mice that received ACTIL-15 cells had a significantly longer survival (P<0.05, ACTIL-15 vs. ACTIL-2).In the human study, the median survival of patients in the combination therapy group was 472 days (95% confidence interval (CI), 276–668 days), whereas the median survival of patients in the chemotherapy group was 266 days (95% CI, 200–332 days; P<0.05). Eleven percent (7/63) of patients had adverse reactions, but the reactions did not interfere with treatment.Adoptive transfer of ACTIL-15 cells in a mouse model of gastric cancer and patients with advanced gastric cancer treated with S1 and oxaliplatin improved survival with an acceptable safety profile.

AB0112 TNF INHIBITOR MONOTHERAPY IN RHEUMATOID ARTHRITIS: IS THERE REALLY A DIFFERENCE IN COMPARISON WITH COMBINATION THERAPY WITH CSDMARDS IN REAL-LIFE?

Background:In Rheumatoid Arthritis (RA), tumor necrosis factor inhibitors (TNFi) in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) has shown advantages concerning efficacy and immunogenicity in comparison with monotherapy. However, in clinical practice, up to 40% of patients under biological DMARDs (bDMARDs) are on monotherapy.Objectives:To compare the efficacy outcomes of TNFi in monotherapy and in combination therapy in a RA monocentric cohort.Methods:Retrospective, cross-sectional study including all the RA patients under TNFi followed at our Rheumatology Department and registered in the national database. Demographic, clinical and laboratorial data and disease activity measures were collected at the last visit of 2019 from each patient. Mann-Whitney U and chi-square tests were used to the comparison analysis between the two groups (continuous and categorical variables, respectively).Results:A total of 144 patients were included: 84% were females; at the last visit of 2019, the mean age was 56.3±10.9 years and the mean disease duration was 18.3±10.2 years; 73.6% were positive for rheumatoid factor (RF), 81.9% for anti-citrullinated protein autoantibodies (ACPA) and 45.1% had erosive disease. There were no statistically significant differences in these variables between the monotherapy and the combination therapy groups (table 1).Table 1.Demographic and disease-related variables in the monotherapy and the combination therapy group.Monotherapy(n=31)Combination therapy (n=113)Age - mean±SD59.1±14.0 years55.5±9.8 yearsDisease duration - mean±SD20.5±11.2 years17.7±9.7 yearsRF positive - n (%)20 (60.4%)86 (76.8%)ACPA positive - n (%)25 (80.6%)93 (85.3%)Erosive disease - n (%)15 (48.4%)50 (44.6%)Thirty-one patients (21.5%) were under monotherapy with TNFi and etanercept was the most frequent TNFi in both groups (54.8% vs 50.0%; monotherapy and combination therapy groups, respectively). At the start of the first bDMARD, the monotherapy group had a higher disease activity score 28 - 4 variables (DAS 28 4V; 6.083±0.930 vs 5.605±1.043, p=0.039) and a higher simple disease activity score (SDAI; 36.12±11.77 vs 28.76±9.98, p=0.035); also, in the monotherapy group more patients had already started the bDMARD in monotherapy (22.6% vs 2.7%, p<0.001), less patients were under (38.7% vs 73.2%, p=0.001) or had already been treated with (77.4% vs 93.8%, p=0.007) methotrexate, in comparison with the combination group therapy.At the last visit of 2019, the monotherapy group had a higher mean years of duration of iTNF treatment (5.5±5.8 vs 3.4±4.5, p=0.048), a higher mean patient global assessment - visual analogue scale (PGA-VAS; 49±18 vs 39±25, p=0.023), a higher mean prednisolone equivalent dose in mg/day (7.6±6.3 vs 5.6±3.2, p=0.045) and a lower proportion of American College of Rheumatology 50 and 70 responses (ACR 50: 12.9% vs 17.0%, p=0.023; ACR 70: 3.2% vs 10.7%, p=0.045) in comparison with the combination therapy group.Conclusion:In line with the literature, our real-life results demonstrate some direct (higher PGA-VAS and lower ACR 50 and 70 responses) and indirect (higher current prednisolone equivalent dose) data that suggest that patients with TNFi monotherapy may have a worst disease activity control in comparison with combination therapy.Disclosure of Interests:None declared

IL-15-Induced Lymphocytes As Adjuvant Cellular Immunotherapy For Gastric Cancer

To test the antitumor potential of adoptive cell therapy (ACT)-transferred lymphocytes in a mouse model of human gastric cancer, and evaluate the clinical efficacy and safety of combining lymphocytes as adjuvant therapy with first-line chemotherapy in patients with gastric cancer. A human gastric cancer xenograft model was constructed in sublethally irradiated 6–8-week old NCG male mice. MKN-45 cells (1 × 106 cells/mouse) were subcutaneously injected into the flanks. After tumors had become palpable, the mice were randomized into control, ACTIL-2, and ACTIL-15 groups. Human lymphocytes were injected into the mouse tail veins. In addition, 63 patients who had histological or cytologically confirmed stage III–IV gastric cancer randomly received S-1 plus oxaliplatin plus ACTIL-15 (a combination therapy group) or S-1 plus oxaliplatin alone (chemotherapy group). In the mice, treatment with ACTIL-15 cells inhibited tumor growth upon adoptive transfer, and mice that received ACTIL-15 cells had a significantly longer survival (P < 0.05, ACTIL-15 vs. ACTIL-2). In the human study, the median survival of patients in the combination therapy group was 472 days (95% confidence interval (CI), 276–668 days), whereas the median survival of patients in the chemotherapy group was 266 days (95% CI, 200–332 days; P < 0.05). Eleven percent (7/63) of patients had adverse reactions, but the reactions did not interfere with treatment. Adoptive transfer of ACTIL-15 cells in a mouse model of gastric cancer and patients with advanced gastric cancer treated with S1 and oxaliplatin improved survival with an acceptable safety profile.

High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study

Background Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. Methods In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. Results The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. Conclusions ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

High Lymphocyte Population-related Predictive Factors for a Long-term Response in Non-small Cell Lung Cancer Patients Treated with Pemetrexed: A Retrospective Observational Study

BackgroundRegimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy.MethodsIn total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n=414) or paclitaxel (PTX) combination therapy (n=90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n=301) were divided into subgroups according to the total cycles of PEM (≥17 [n=25] for the long-term administration group and ≤16 [n=276] for the intermediate/short-term group) and compared with another population (n=80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. ResultsThe long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration.ConclusionsALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

Efficacy of Different Nucleoside Analog Rescue Therapies for Entecavir-Resistant Chronic Hepatitis B Patients

Background Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue. Methods Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups. Results The rate of ETV resistance increased form 6.04% in 2011 to 15.02% in 2017. Regarding the rates of negative HBV DNA at 48 weeks, no significant differences occurred in the TDF monotherapy and TDF combination groups (74.07% vs 70.00%), while the ETV and ADV group showed the worst virologic response (28.00%). TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function between the three groups. Conclusions TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.