Patients Receiving Combination Therapy Research Articles

Treatment of Extensively Drug-Resistant (XDR) Acinetobacter in US Veterans’ Affairs (VA) Medical Centers

Background: Infections caused by Acinetobacter spp are often healthcare acquired and associated with high mortality. Extensively drug-resistant (XDR) Acinetobacter are nonsusceptible to at least 1 agent in all but 2 or fewer antibiotic classes. Few of the new antibiotics targeting multidrug-resistant gram-negative bacteria are effective against XDR Acinetobacter. Recent national guidelines for treatment of resistant gram-negative infections do not include Acinetobacter, leaving a knowledge gap in best practices. Methods: This retrospective cohort study included microbiology, clinical, and pharmacy data from all patients hospitalized between 2012 and 2018 at any Veterans’ Affairs medical center who had cultures that grew XDR Acinetobacter spp. Bivariate unadjusted analyses compared clinical outcomes by monotherapy versus combination therapy. Using mixed-effects ordinal logistic regression, propensity score–adjusted models accounting for severity of illness and other variables associated with treatment were fit to compare outcomes. Results: Of 11,546 patients with 15,364 cultures that grew Acinetobacter spp, 408 patients (3.5%) had 666 cultures (4.3%) with XDR Acinetobacter. Moreover, 276 of these patients (67.6%) had gram-negative targeted antibiotic treatment within −2 to +5 days from the culture. Furthermore, 118 patients (42.8%) received monotherapy, most commonly piperacillin-tazobactam (n = 54, 45.7%) or an anti-Pseudomonas cephalosporin (n = 21, 17.8%). Also, 158 (57.2%) patients received combination therapy, most commonly a carbapenem (n = 93, 58.9%) and/or polymyxin (n = 68, 43.0%). Moreover, 41 patients (25.9%) received both a carbapenem and polymyxin. In both unadjusted and adjusted analyses, there were no significant differences in the odds of 30-day mortality (aOR, 1.43; 95% CI, 0.86–2.38) or 1-year mortality (aOR, 1.04; 95% CI, 0.68–1.60) between combination therapy and monotherapy groups. Among 264 patients (96%) whose cultures occurred during an inpatient or long-term care admission, unadjusted analyses showed increased odds of in-hospital mortality (OR, 1.89; 95% CI, 1.08–3.29) and longer postculture length of stay in the combination therapy group: median, 23 days (IQR, 11–57) versus 14 days (IQR, 7–32) (P = .02). However, with propensity score adjustment, these associations were no longer significant. Furthermore, there was no significant difference in odds of 90-day readmission between groups in either unadjusted or adjusted analyses (aOR, 1.20; 95% CI, 0.74–1.95). Conclusions: In this large national cohort of patients with XDR Acinetobacter cultures, more patients received combination therapy than monotherapy, and carbapenems and polymyxins were the most-used classes. However, there were no significant differences in outcomes between patients receiving combination therapy and monotherapy, suggesting lack of clinical benefit to the common practice of treating XDR Acinetobacter infections with multiple antibiotics. Further research is needed to determine optimal treatment strategies for this pathogen.Funding: NoDisclosures: None

The impact of hydroxychloroquine and azithromycin on the corrected qt interval in patients with the novel Coronavirus disease 2019.

With the coronavirus disease 2019 (COVID-19) continuing to spread all over the world, although there is no specific treatment until now, hydroxychloroquine and azithromycin have been reported to be effective in recent studies. Although long-term use of hydroxychloroquine and azithromycin has been reported to cause QT prolongation and malign arrhythmia, there is not enough data about the effect of short-term use on arrhythmia. Therefore, this study aims to assess the effect of hydroxychloroquine alone and hydroxychloroquine + azithromycin on corrected QT (QTc). A baseline electrocardiogram and on-treatment baseline electrocardiogram were retrospectively collected in COVID-19 patients who received hydroxychloroquine and/or azithromycin. The QTc interval was calculated, and the baseline and peak QTc intervals were compared. In addition, the peak QTc intervals of monotherapy and combination therapy were compared. Of the 155 patients included, 102 (65.8%) patients were using hydroxychloroquine, and 53 (34.2%) patients were using hydroxychloroquine + azithromycin combination. The use of both hydroxychloroquine alone and hydroxychloroquine + azithromycin combined therapy significantly prolonged the QTc, and the QTc interval was significantly longer in patients receiving combination therapy. QTc prolongation caused early termination in both groups, 5 (4.9%) patients in the monotherapy group and 6 (11.3%) patients in the combination therapy group. In this study, patients who received hydroxychloroquine for the treatment of COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc.

Evaluation of Therapy Effectiveness in Men with Different Erectile Dysfunction Severity

Sexual health is an integral part of everyone’s quality of life. Sexual harmony depends on a man’s sexual desire and erectile function. The most common disorder of male sexual health is erectile dysfunction. Improving the treatment of patients with this pathology helps to improve both physical and mental health and thus improve the quality of life. The objective: the aim of the study was to evaluate the efficacy and safety of combination course therapy and monotherapy in patients with erectile dysfunction. Materials and methods. The observation included 89 men with erectile dysfunction of mixed genesis aged 25 to 50 years with mild to moderate severity. All patients were divided into three groups. The I group of 32 patients with moderate ED, received during the month in the morning Bodrex 1 sachet 60 minutes before meals and in the evening Strondex one spray into the oral cavity (12,5 mg sildenafil), regardless of the presence or absence of sexual activity in this day and an additional 30 minutes before sexual intercourse from 12,5 to 25 mg, followed by a comparative assessment of clinical results immediately after treatment in relation to a group of patients (II group – 32), also with moderate ED who received sildenafil in tablet form dose of 25 mg 1 hour before sexual intercourse, but not more often than once a day. The third group (III group – 25) of patients consisted of men with mild ED, who received during the month only Bodrex in the morning 1 sachet 60 minutes before meals, with comparing clinical data before and after treatment. Bodrex and Strondex preparations are presented on the market by the pharmaceutical company Geolik Pharm Marketing Group. Results. The use of course combination therapy (Strondex + Bodrex) in the treatment of patients with moderate ED was found to be significantly more effective than sildenafil monotherapy at a dose of 50 mg on demand before sexual intercourse, as evidenced by subjective assessment of patients and objective data. Namely, the integrative indicator «erectile function» in this group of patients improved almost twice, while in the second group of patients this indicator improved by 62,9% (p<0,05). Accordingly «оverall satisfaction" in group I patients improved 2,3 times, and in group II patients 1,8 times. Dopplerosonography of the penis in patients with moderate ED showed a probable decrease in hemodynamics in the corpora cavernosa, which indicated the presence of vascular factor with impaired vascular endothelial function (p<0,05). After treatment, a more pronounced increase in cavernous blood flow occurred in group I, namely an increase in peak systolic velocity by 69,5%, while in group II by 38,5% (p1<0,05). It was noted that the concentration of ET-1 in the serum of patients with moderate ED was 3 times higher than the average in the group of almost healthy men, which may indicate severe endothelial dysfunction (p<0,05). Accordingly, after treatment, the level of ET-1 in the blood of patients decreased in group I, who received combination therapy, by 44,2%, while in group II by 28,3% (p1<0,05). Before treatment, the majority of patients with moderate ED, namely 78,1%, could not have sexual intercourse due to insufficient erection. After treatment in 53,1% of group I patients receiving combination therapy (Strondex + Bodrex), erection was completely restored, while in group II erection was completely restored in 28,1% of patients. Also, according to the obtained data, it should be noted a significant positive dynamics of all integrative indicators of IIEF on the background of taking Bodrex in patients with mild ED (p<0,05). An increase in the baseline «erectile function» by 1,4 times, contributed to an increase in sexual satisfaction and sexual satisfaction in general by 2,3 times. The mean peak systolic rate of cavernous blood flow before treatment in this group of patients was lower compared with the control group by 21,2% (p<0,05). This indicator improved after treatment by 21,7%, and became not significantly different from this indicator in the control group of almost healthy men (p1<0,05; p2>0,05), which indicated the normalization of hemodynamics in penis. In patients with mild ED, the concentration of ET-1 in the serum was 1,7 times higher than in the control group (p<0,05). After treatment, this index decreased by 1.5 times, approaching the rate in the group of almost healthy men (p2>0,05). Before treatment in this group, no patient had a complete erection, and less than half of the patients (45,5%) had a pratial erection. After a course of treatment with Bodrex, complete erection was restored in 68,2% of patients, and a total of 86,4% of patients were able to have sexual intercourse. Conclusions. The use of combination course therapy (Strondex + Bodrex) in patients with moderate ED and course monotherapy (Bodrex) in patients with mild ED contributes to a more stable clinical effect, as evidenced by the dynamics of the data.

PRELIMINARY EVALUATION OF THE EFFECTIVENESS OF HIFU-THERAPY IN PATIENTS WITH PANCREATIC CANCER

Purpose: to conduct a preliminary analysis of the safety and effectiveness of hifu-therapy with a lowenergy hifu-2001 device (shenzhen Huikang Medical apparatus Co., ltd) performed concurrently with chemotherapy in pancreatic cancer patients who are not suitable for surgery or chemoradiotherapy.Material and Method. The study included 24 pancreatic cancer patients who were treated at the Hertsen Moscow Oncology Research institute in the period from 2016 to 2019. There were 17 (71 %) women and 7 (29 %) men. The percentage of patients in the elderly group was 79 %. Stage iia pancreatic cancer was diagnosed in 3 (12.5 %) patients, stage ii in 5 (21 %) patients, stage iii in 9 (37.5 %) patients, and stage iv in 7 (29 %) patients. All patients received combination therapy, including systemic chemotherapy and hifu-therapy. Results. The most frequent adverse events of treatment were skin burns (n=6), with third-degree burns occurring in 2 (8.3 %) patients. Local sclerosis of subcutaneous adipose tissue was observed in 4 (17 %) patients; development of asymptomatic pancreatic pseudocysts in the area of hifu exposure was observed in 1 (4 %) patient. Pain control was achieved in 17 (85 %) patients, and local tumor control was achieved in 19 (79.2 %) patients. The follow-up time ranged from 5 to 30 months with a median time of 14.5 months. The median total life expectancy of patients was 16 months, and the median time to progression was 9 months. The overall 6-month survival rate was 100 %. The 1- and 1.5-year survival rates were 75.0 % and 41.7 %, respectively. The 2-year survival rate was 17.2 %. The 6-month and 1-year disease-free survival rates were 62.5 % and 12.5 %, respectively. Conclusion. The short- and long-term outcomes were consistent with those described in other studies, which indicated that a combination of systemic drug therapy and hifu-therapy is an appropriate approach for the treatment of patients with pancreatic cancer.

Appropriateness of empirical antibiotic therapy and added value of adjunctive gentamicin in patients with septic shock: a prospective cohort study in the ICU

Objectives To determine the appropriateness of empiric antibiotic therapy and the possible benefit of adding short-course gentamicin in septic shock patients with abdominal, urogenital, or an unknown focus. Secondary objectives were the effect of gentamicin addition on shock reversal and the incidence of a fungal infection. Methods Microbiological cultures, antibiotic treatment, and antibiotic resistance patterns of the cultured microorganisms were recorded during the first 5 days of admission. Inappropriate antibiotic therapy was defined as a prescription within the first 24 h that did not cover cultured bacteria during the first 5 days of admission and was determined in the overall group and in patients receiving adjunctive gentamicin (combination therapy) versus patients receiving monotherapy. Binomial logistic regression analysis was used to investigate the association of gentamicin addition with shock reversal. Results Of 203 septic shock patients, with abdominal (n = 143), urogenital (n = 27) or unknown (n = 33) focus, 115 patients received monotherapy, and 88 patients received combination therapy. Inappropriate therapy occurred in 29 patients (14%), more frequently in monotherapy (17%) versus combination therapy (10%). Combination therapy would have been effective in 55% of patients with inappropriate monotherapy. We found no association between gentamicin addition and shock reversal (p = .223). A fungal infection was present in 22 patients (11%). Conclusion Inappropriate empirical antibiotic therapy occurs in 17% of septic shock patients receiving monotherapy. In 55% of these patients, additional gentamicin would have resulted in appropriate therapy. When clinical course is unfavourable, lowering the threshold for administering adjunctive aminoglycoside and antifungal therapy should be considered.

Combined treatment regimen for severe acne vulgaris

BACKGROUND: Treatment of acne vulgaris remains an actual task of practical medicine. Despite the fact that the participation of severe acne in the structure of the morbidity of acne vulgaris is relatively small, precisely they most often leave behind scars, are accompanied by a pronounced cosmetic defect and significantly reduce the patients quality of life. Systemic treatment with isotretinoin is the gold standard of management of such patients, but this type of treatment is often accompanied by an exacerbation reaction, which negatively affects the general condition of the patient and reduces the compliance of treatment.
 AIM: To determine the effectiveness of the combined use of isotretinoin and a systemic corticosteroid in the treatment of severe forms of acne.
 MATERIALS AND METHODS: We observed 27 patients (16 men and 11 women) with severe or very severe grade on the IGA scale. All patients received combination therapy with isotretinoin (Sotret) at a dose of 0.5 mg/kg/day (cumulative dose from 120 to 150 mg/kg) for 8 months and prednisolone 30 mg/day 7 days, followed by dose reduction within a month. The assessment of treatment efficacy was based on the IGA scale, indicators DIA, DLQI and counting the number of inflammatory and non-inflammatory elements.
 RESULTS: During the 8 months of the study, 81.4% of patients achieved a 2-point reduction in the degree on the IGA scale (clear or almost clear skin). The DLQI index showed 74.9% improvement compared to the start of treatment. The average DIA values decreased by 72%. The reduction in the number of inflammatory and non-inflammatory elements showed a marked clinical improvement (91.4% for nodules and 98.3% for pustules). Exacerbations of acne were recorded in 18.5% of patients.
 CONCLUSIONS: Combined systemic treatment with isotretinoin and prednisolone for severe acne decreases the number of exacerbations and reduces the duration of treatment.

Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia

Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax. To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax. A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older. Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4. Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate. Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation. The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL. ClinicalTrials.gov Identifier: NCT02756897.

Effectiveness of Switching Biologics for Severe Asthma Patients in Japan: A Single-Center Retrospective Study.

BackgroundIn Japan, biologic therapy was initiated for patients with severe asthma in 2009. In recent years, four biologics with different mechanisms of action have become available in the clinical setting. However, the efficacy of switching between biologics remains uncertain.MethodsTo elucidate the efficacy of switching between biologics, 97 patients were enrolled who had received any biologic therapy for severe asthma at Jikei University Hospital, Tokyo, Japan, from July 2009 to December 2020. We retrospectively examined the patient characteristics, biomarkers, pulmonary function test results, selected biologics, and efficacy.ResultsThirty-one males and 66 females received any biologics. The mean age was 53.3 years at the initiation of biologic therapy. Initially, 33, 41, 15 and eight patients received omalizumab, mepolizumab, benralizumab, and dupilumab, respectively. Among three representative indicators for biologics administration, the peripheral blood eosinophil count, serum IgE levels and fractional exhaled nitric oxide, 64% of the patients had two indicators, and 28% had three indicators. Thirty-four patients (35%) switched from the initial biologic to another, and the reasons for switching included persistent asthmatic symptoms (n=22), schedule of hospital visits (n=5), and other reasons. Thus, the treatment was effective in 11 patients after switching. In addition, two patients received combination therapy with different biologics. Eighteen patients (19%) interrupted treatment for various reasons. Regardless of whether the biologic was the initial therapy, the overall efficacy of the four biologics was 60% based on the global evaluation of treatment effectiveness.ConclusionSwitching between biologics can be a promising option for severe asthma patients in whom treatment with an initial biologic is ineffective.

HGG-37. UPFRONT TARGETED THERAPY FOR THE TREATMENT OF BRAFV600E-MUTANT PEDIATRIC HIGH-GRADE GLIOMA – A MULTI-INSTITUTIONAL EXPERIENCE

IntroductionSustained responses to molecular targeted therapy with BRAF with or without MEK inhibitors have been reported in patients with recurrent BRAFV600E-mutant pediatric high-grade gliomas (pHGG). The role of upfront targeted therapy in this population, however, has not yet been established. MethodsWe performed a retrospective, multi-institutional record review of patients with BRAFV600E-mutant pHGGs, treated with off-label BRAF and/or MEK inhibitors as part of their initial adjuvant therapy. ResultsSeventeen patients were identified (median age at diagnosis, 8.8 years, range 1.8–20.2). Histologic diagnoses included HGG/glioblastoma (n=10), anaplastic ganglioglioma (n=3), high-grade neuroepithelial tumor (n=2), diffuse midline glioma (n=1) and anaplastic astroblastoma (n=1). Ten patients underwent biopsy (n=8) or subtotal resection (n=2), while near-total or complete resection was accomplished in seven. Concomitant genetic alterations including CDKN2A/B loss, H3K27M and TERT promotor mutations were found in eight tumors. Thirteen patients received focal radiation therapy (RT) and one received craniospinal irradiation prior to targeted therapy. Adjuvant targeted therapy was initiated shortly after diagnosis or completion of RT. Five patients received BRAF-inhibitor monotherapy (dabrafenib or vemurafenib). Twelve patients received combination therapy with the addition of a MEK inhibitor (trametinib). For patients with measurable disease, best responses per COG criteria were CR (n=3), PR (n=7), SD (n=3) and PD (n=1). With median follow-up of 29 months (range 8–78), two-year PFS and OS for the cohort were 74.7% and 81.1%, respectively. Ten (59%) patients remain free of disease recurrence or progression. Grade 3 or higher toxicities were reported in four patients (neutropenia, skin toxicity/photosensitivity, fatigue and weight loss), leading to therapy discontinuation in two. ConclusionsUpfront targeted therapy for patients with BRAFV600E mutant pHGG appears tolerable and effective, with a durable disease control rate that is superior to historical data. This promising paradigm is currently being evaluated prospectively in the COG ACNS1723 clinical trial.

P344 Effectiveness and safety of switching patients with inflammatory bowel disease from originator infliximab to CT-P13: systematic review and meta-analysis

Abstract Background Switching from originator infliximab (IFX) to the CT-P13 biosimilar is a widespread practice, although some concerns persist, particularly about long-term outcomes. We performed a systematic review and meta-analysis to assess the effectiveness and safety of switching from originator IFX to CT-P13 in patients with inflammatory bowel disease (IBD). Methods We systematically searched electronic databases for randomised controlled trials and prospective observational studies of adult patients with IBD who had switched from originator IFX to CT-P13 and were followed up for at least 12 months. The main outcomes were the pooled rate of clinical remission (as defined by the included studies) and adverse events at 12 months. Secondary outcomes included the rate of treatment discontinuation and de novo immunogenicity. A DerSimonian-Laird random-effects meta-analysis of proportions with double arcsine transformation was performed. Variables judged to be clinically important were studied in an exploratory random-effects meta-regression analysis. Results Eleven studies with 1204 patients (71% with Crohn’s disease [CD]) switching from originator IFX to CT-P13 were identified. Pooled rates of clinical remission at 12 months were 83.6% in ulcerative colitis (UC), 75.9% in CD, and 79.6% in mixed cohorts (Figure 1). Clinical remission at 12 months was negatively associated with combined immunosuppression at switch (7% decrease in remission at 12 months per 10% increase in patients receiving combination therapy) and positively associated with remission at switch (6% increase in remission at 12 months per 10% increase in remission at switch). The pooled rate of adverse events at 12 months was 21.0% (95% confidence interval [CI] 10.4–34.1%). Pooled rates of treatment discontinuation at 12 months were 24.4% (95% CI 12.0–39.4%) in UC, 18.6% (95% CI 8.8–30.9%) in CD, and 13.1% (95% CI 0.7–35.6%) in mixed cohorts. De novo immunogenicity was rare (3.3%, 95% CI 1.5–5.6%). All estimates had at least moderate heterogeneity. Figure 1: Meta-analysis of clinical remission rates at 12 months after switching from originator infliximab to CT-P13 in ulcerative colitis and Crohn’s disease. Conclusion Switching from originator IFX to CT-P13 appears to be effective and safe, although these findings should be interpreted in the context of the limitations of the primary publications which lacked control arms. Combined immunosuppression at switch, potentially as a marker of disease severity, was negatively associated with clinical remission at 12 months after the switch.

The impact of hydroxychloroquine and azithromycin on the corrected qt interval in patients with the novel coronavirus disease 2019

Funding AcknowledgementsType of funding sources: None.BackgroundAlthough long-term use of HCQ and AZT has been reported to cause QT prolongation and malign arrhythmia, there is not enough data about the effect of short-term use on arrhythmia. Purpose: The aim of this study was to assess the effect of HCQ alone and HCQ + AZT on corrected QT (QTc).Methods: A baseline ECG and on-treatment ECGs were retrospectively collected in COVID-19 patients who received HCQ and/or AZT. Also peak QTc intervals of monotherapy and combination therapy was compared. Results: Of the 155 patients included, 102 (65.8%) were using HCQ, 53 (34.2%) were using HCQ + AZT combination. The use of both HCQ alone and HCQ + AZT combined therapy significantly prolonged the QTc and the QTc interval was significantly longer in patients received combination therapy. QTc prolongation caused early termination in both groups, 5 (4.9%) patients in the monotherapy group and in 6 (11.3%) patients in the combined therapy group.Conclusion: Patients who received HCQ for COVID-19 were at high risk of QTc prolongation, and concurrent treatment with AZT was associated with greater changes in QTc. Comparison of baseline characteristics aCharacteristicTotal (n = 155)Hydroxychloroquine (n = 102)Hydroxychloroquine /Azithromycin (n = 53)P valueLength of stay at ward, SD9.54 ± 4.289.64 ± 4.319.31 ± 4.250.88Length of stay Intensive care unite,SD7.92 ± 3.767.18 ± 3.188.46 ± 4.150.29Radiographic findings of pneumonia118(76.1%)76(74.5%)42(49.2%)0.32Mechanically ventilation16(10.3%)7(6.9%)9(17.0%)0.049In hospital death19(12.3%)10(9.8%)9(17.0%)0.15ECG findings median(IQR) (ms)Baseline QRS duration91.0(80.0-103.0)92.5(80.75-105.50)90.0(80.0-102.5)0.5Posttreatment QRS peak97.0(86.0-109.0)97.5(88.0-109.25)95.0(85.5-109)0.68ΔQRS4.0(0.0-9.0)2.0(0.0-8.25)5.0(1.0-9.5)0.14Baseline QTc duration407.0(385.0-426.0)408.0(389.25-427.50)404.0(384.0-420.0)0.1Posttreatment QTc peak437.0(414.0-460.0)428.0(412.75-449.25)456.0(422.0-467.5)<0.001ΔQTc27.0(13.0-45.0)18.0(11.0-30.0)46.0(40.5-54.5)<0.001Baseline PR duration145.50(128.7-160.0)147.0(135.0-160.0)144.0(120.0-160.0)0.53Posttreatment PR peak159.0(140.0-170.0)159.0(141.0-168.50)156.0(139.5-171.0)0.97ΔPR7.0(1.0-13.0)5.0(0.0-12.25)10.0(5.0-15.0)0.022QTc peak day5.0(4.0-5.0)5.0(4.0-6.0)4.0(3.0-5.0)0.022Drug withdrawl due to QRS prolongation11(7.1%)5(4.9%)6(11.3%)0.12

Does denosumab offer survival benefits? Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors.

e21039 Background: Lung cancer is the leading cause of cancer-related death in the United States. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. In preclinical and some clinical studies, denosumab have shown to have some anti-tumor properties. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs. Methods: This observational study used retrospective data from a tertiary cancer center from 2015-2020. Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Median overall survival (OS), progression free survival (PFS), best radiographic responses were obtained. Univariate, multivariate analyses and logistic regression analyses were done, and Kaplan-Meier curves were obtained for survival analysis. Results: We identified 69 patients and all had skeletal metastasis, and 37.7% had brain metastases. Median duration of concomitant use of denosumab and ICI was 1.5 months. Median OS was 6.3 months and median PFS was 2.8 months. Overall response rate was 18.8% and disease control rate was 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with &lt; 3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases. However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Conclusions: Patients receiving combination therapy did not perform poorly despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.

Hospital admissions and subsequent outcomes from immune-related adverse events.

e21590 Background: Checkpoint inhibitor (CPI) use has been increasing in recent years. Immune related adverse events (irAEs) are a known complication of CPIs, particularly with the concurrent use of PD-1 and CTLA-4 inhibitors (combination therapy). IrAEs are associated with increased hospital resource utilisation including admissions and immunomodulator therapy. This is a retrospective analysis of patients receiving CPI therapy for metastatic melanoma. Methods: Data was collected from a Queensland Health centre using electronic medical records and immunotherapy prescribing software. Patient demographics, CPIs, irAEs, admissions, and outcomes were recorded from 2015-2019. All patients had metastatic disease; they either received single agent or combination CPI as first line metastatic treatment or received single agent CPI as adjuvant therapy. Patients admitted to hospitals without electronic medical records were not included. Results: 51 out of 343 patients were eligible for analysis, indicating 15% of patients receiving CPI required hospital admissions due to irAEs. The mean age was 64.7 years, with 64.7% male patients. The commonest BRAF status was wild type (60.8%, n = 31). 54.9% (n = 28) of patients received combination therapy, 39.2% (n = 20) received PD-1 inhibitors, and 5.9% (n = 3) received CTLA-4 inhibitors. 24% (n = 12) of patients experienced early toxicity, defined as hospital admission after one dose. The commonest early toxicity was pneumonitis; all had received PD-1 inhibitors. In the rest of the cohort, the most frequent irAE was colitis (35.3%, n = 18). Regardless of CPI, average length of admission was 6-7 days. 17.6% (n = 9) patients had greater than one admission. Rescue immunomodulators were required in eight patients (15.7%), seven of whom had received combination therapy. Of patients with irAE from combination therapy, 28.7% (n = 8) were palliated due to progressive disease (PD), and 25% (n = 7) continued on single agent PD-1 inhibitor. In patients with irAE from PD-1 inhibitors, the majority (70%, n = 14) ceased treatment; of these, 8 had stable disease and 6 developed PD and were subsequently palliated. Conclusions: IrAEs are a well-documented complication of CPIs. Important considerations for CPI use include severe irAEs requiring admission and subsequent hospital resource utilisation. This occurs not infrequently, as demonstrated in this analysis. It is important to consider individual patient risks and benefits prior to commencement of treatment.

Dynamics of psycho-emotional status in patients with a constant form of atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ivano-Frankivsk National Medical University Topicality. Atrial fibrillation (AF) is the most common chronic heart rhythm disorder, occurring in 1-2% of people in the general population. Stable coronary heart disease, hypertension, heart failure, obesity are risk factors for AF progression. Psycho-emotional stress, anxiety and depression can also cause AF. Goal. To investigate the dynamics of the effectiveness of treatment of psychoemotional status in patients with persistent AF. Materials and methods. We examined 62 patients with a permanent form of AF, treated in the cardiology department. Patients were divided into groups: group 1a - (n = 16), received basic therapy; 1b group - (n = 16), patients who in combination treatment received mebicar; Group 1b - (n = 15) patients who received carvedilol in addition to standard therapy; Group 1g (n = 15) consisted of patients receiving combination therapy with carvedilol and mebicar. In order to study the psychological state of patients with AF, L. Reeder"s scale of psychosocial stress, perceived stress-10, hospital scale of anxiety and depression (HADS) were used. Results. The dynamics of the scale of perceived stress-10 in patients with a permanent form of AF in the dynamics of treatment showed a decrease in stress resistance after 2 weeks and a month and a half of treatment (p1 &amp;lt;0,001; p2 &amp;lt;0,001) (p1 - the significance of the difference compared to before and after p2 - the significance of the difference between the values compared with the value after 1.5 months of treatment (p &amp;lt;0,05) During treatment, the proportion of people with high and medium stress decreased by 31,43% in the group of standard treatment, and 39,95% in the group of patients where mebicar was used. It should be noted that in the same group before treatment was dominated by high levels of stress, and the average level was much less common. The share of high stress levels decreased from 53,34 to 6,66%. In this group of patients, the reduction in the score of stress was 17,78%. The level of stress in patients taking carvedilol decreased by 25,89%, and in the group where mebicar was used by 13,68%. Under the influence of standard therapy, the level of stress decreased by 13%, but this figure was not significant, despite the fact that in this group the number of patients decreased from high to medium stress. In the treatment of patients with anxiolytic drug should be noted a significant reduction in psychosocial stress (p1-2 &amp;lt;0,001). It was found that against the background of psychopharmacotherapy in patients with AF there was a reduction from clinical to subclinical levels of anxiety and depression. It should be noted that the course of therapy with carvedilol adversely affected the course of anxiety and depression. Conclusion. According to our study, psychometric parameters improved significantly against the background of comprehensive treatment in all groups of patients.

Graft-versus-Host Disease Prophylaxis with Post-Transplantation Bendamustine in Patients with Refractory Acute Leukemia: A Dose-Ranging Study

The prognosis of acute leukemia refractory to induction chemotherapy or immunotherapy is dismal. Salvage allogeneic hematopoietic stem cell transplantation (HSCT) is widely used option for these patients, but only 10% to 15% of patients are cured by the procedure. Preclinical studies indicate that substitution of post-transplantation cyclophosphamide with bendamustine (PTB) in a prophylaxis regimen may be associated with an augmented graft-versus-leukemia (GVL) reaction. The aim of this study was to establish the optimal dose of PTB and evaluate the antileukemic effect of HSCT with this type of graft-versus-host disease (GVHD) prophylaxis. In the prospective trial (NCT02799147), PTB was administered in doses of 140, 100, and 70 mg/m2 on days +3 and +4. Myeloablative conditioning with fludarabine and oral busulfan was provided to all patients. The first 12 patients received single-agent PTB, and subsequent patients received combination therapy with tacrolimus and mycophenolate mofetil (MMF). Inclusion criteria were acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and ≥5% clonal blasts in the bone marrow. The study cohort comprised 22 patients with AML and 5 with ALL. Seven patients were enrolled in the 140 mg/m2 group (due to a stopping rule), and 10 each were enrolled in the 100 mg/m2 and 70 mg/m2 groups. Primary refractory disease was documented in 41% of the patients, and secondary refractory was documented in 59%. The median blast count in the bone marrow at the start of the conditioning was 18% (range, 6% to 97%). Transplantation was performed with a matched sibling donor in 5 patients, a matched or mismatched unrelated donor in 15, and a haploidentical donor in 7. Engraftment was documented in 93% of the patients, including 89% with complete remission and 63% without measurable residual disease. After PTB prophylaxis, we observed an unusual complication, a cytokine release syndrome (CRS), in 70% of the patients, including grade 3 to 5 CRS in 44%. The most frequent clinical symptoms included high fever in 67% of patients, abnormal liver function tests in 67%, pancreatitis in 63%, skin vasculitis in 56%, enterocolitis in 48%, inflammation of oral mucosa in 37%, disseminated intravascular coagulation in 37%, and central nervous system toxicity in 26%. The development of CRS was associated with use of an HLA-mismatched donor (75% versus 20%; P=.0043). Classic acute GVHD was documented in 44% of the patients. Grade II-IV acute GVHD was associated with grade 3 to 5 CRS (67% versus 25%; P=.031). Moderate and severe chronic GVHD in the 100-day survivors were more often observed after single-agent PTB than after the combination immunosuppression (100% versus 18%; P=.002). A relatively low relapse rate was observed for this patient population. Three-year overall survival was 28% (95% confidence interval [CI], 13% to 46%), and event-free survival was 29% (95% CI, 13% to 46%). Nonrelapse mortality was 46% (95% CI, 25% to 64%), and the cumulative incidence of relapse was 26% (95% CI, 11% to 44%). No relapses were documented after day +100. There were no statistically significant differences among the dose groups (P=.3481); however, survival was higher in the 100 mg/kg group. Survival was higher in patients with AML compared with those with ALL (35% versus 0%; P=.0157). PTB represents a promising option to augment the GVL effect in refractory AML; however, the high CRS-associated mortality necessitates additional studies to reduce the risk of this complication. Thus, routine clinical application of PTB cannot be currently recommended. Combination immunosuppression with tacrolimus and MMF partially ameliorates these complications, at least in the setting of HLA-matched allografts. Biological mechanisms of CRS and GVL after PTB require further elucidation.

Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including...

Right inguinal metastasis from hepatocellular carcinoma

AbstractInguinal hernias are common diseases, but malignant lesions in groin hernias are rare; metastatic hepatocellular carcinoma (HCC) in the hernia sac is extremely rare. We report a 72‐year‐old man who had advanced stage HCC with portal vein invasion and multiple metastatic lymphadenopathies. He presented a painless palpable mass in the right groin. Computed tomography scan showed a contrast‐enhanced soft tissue mass (2.8 cm in size) at the right herniated inguinal sac. Tumor excision and hernia repair were performed, and the histopathological examination revealed metastatic HCC. After being stabilized from surgery, the patient received combination therapy with sorafenib and nivolumab; however, he still died of rapid tumor progression and liver decompensation 1 month later. This case raises clinical awareness of unusual extrahepatic metastases of HCC, especially for patients at an advanced tumor stage.

Comparative Analysis of Vaginal Microbiota in Women with Breast Cancer in Kazakhstan.

Object:The relevance of the article is that the breast cancer is a leading oncological disease in women in developed countries and has the highest mortality caused by malignant neoplasms in women. The purpose of the study is to evaluate vaginal microbiota in women with various breast cancer subtypes and compared groups. Methods:The study involved 278 women with breast cancer, of whom 174 were patients receiving combination therapy; the control group consisted of 104 patients who had had breast cancer 2-4 years ago. Results:It was found that despite a significant decrease in the total number of Lactobacillus spp., there were no statistically significant changes in the numbers of microorganisms in patients with different subtypes of breast cancer. According to the results of the comparative analysis, the representatives of obligate anaerobic flora Peptostreptococcus spp. prevailed in vaginal microbiota in luminal A and luminal B subtypes, and the representative of the facultative anaerobic organisms Staphylococcus spp. – in unfavourable outcomes in Her2/Neu+ and triple-negative subtypes. Conclusion:The observed features of the vaginal microbiota in women with different subtypes of breast cancer require further studies for preventive purposes.

#39: Streptococcus anginosus Group Infections in Children: A Retrospective Cohort Study, 2015–2019

Abstract Background Infections attributed to the Streptococcus anginosus group (SAG), which includes Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius, have varying clinical presentations. SAG infections are difficult to identify initially, and members of the group may require different management strategies. Methods A retrospective review of SAG-positive cultures from January 2015, to September 2019, was conducted to describe the demographic, clinical, and laboratory features including the site of infection, antibiotic susceptibility, management, and clinical outcome. Results We identified 561 patients [median age 11.3, interquartile range (IQR) 7.1–14.9 years, male:female ratio 3:2, non-Hispanic–non-Latino 454 (81%), White 279 (49%)]. Thirty-nine (7%) had at least one underlying condition. Of these, inflammatory bowel disease 15 (39%), diabetes 7 (18%), immunodeficiency 5 (13%). SAG was found in exudate, fluid, or aspirate (537/561, 96%), blood (11/561, 2%), and tissue (11/561, 2%) samples; 388 (69%) were polymicrobial infections. The most common site of infection was intra-abdominal (175, 31%), followed by neck/odontogenic (114. 20%) and genitourinary tract (66, 12%). The median length of stay was 6 days (IQR 3–10 days) and was statistically significantly longer for patients with blood, central nervous system, and pulmonary infections compared with soft tissue and upper respiratory tract infections (P &amp;lt; 0.001). Beta-lactams were the most commonly used antibiotics (38%), followed by clindamycin (30 %) (see Figure for antibiotic susceptibility results) and 33 (56%) patients received combination therapy. We did not observe any SAG attributed to mortality. Conclusions In our retrospective cohort, SAG infections were more commonly identified in males, were associated with abscess formation, and presented as polymicrobial infections. Children with underlying comorbidities are more likely to present with systemic SAG infections. SAG-associated infections can be variable in presentation site and severity and should be considered as pathogens when managing patients.

A randomized phase IIa study of quantified bone scan response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride alone or in combination with abiraterone acetate/prednisone or enzalutamide

BackgroundIn metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide).Patients and methodsThis randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR.ResultsOverall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline.ConclusionsTechnetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.