Patients Receiving Combination Therapy Research Articles

PB2285: CLINICAL EXPERIENCE WITH CEFTAZIDIME-AVIBACTAM FOR THE TREATMENT OF BACTEREMIA DUE TO CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA IN HEMATOLOGIC PATIENTS

Background: Experience on effectiveness of ceftazidime-avibactam (CAZ-AVI) for bacteremia caused by carbapenem-resistant gram-negative bacteria in hematologic patients is scare. Aims: We conducted this cohort to evaluate the effectiveness and safety of CAZ-AVI for this population, and also, to explore the predictors of clinical outcome. Methods: We performed a retrospective, observational study at a blood diseases hospital in China for patients who received ≥ 72 h of CAZ-AVI for bloodstream infections due to carbapenem-resistant Enterobacteriacea and Pseudomonas aeruginosa between November 2018 and June 2021. Clinical and microbiological characteristics of these patients were collected; clinical and microbiological outcomes, occurrence of adverse effect were assessed. We compared the survival between transplant and nontransplant patients, also between patients who did or did not undergo granulocyte recovery within 14 days. We used Kaplan-Meier survival estimates to generate survival curves. To identify predictors of survival and clinical success, univariate and multivariate analysis was performed. Results: Forty-seven patients were eligible for our study. Forty (85.1%) patients received combination therapy, while seven received CAZ-AVI monotherapy. All patients infected with MBL (metallo-β-lactamase)-CRE (carbapenem-resistant Enterobacteriaceae) (n=23) received combination therapy with aztreonam. The survival at 28 days was 83.0% in 47 patients, and was 91.3% (21/23) in patients with MBL-CRE bacteremia. Clinical success was observed in 35/47 (74.5%) patients. Multivariate analysis revealed the most significant factor of clinical success was the granulocyte recovery within 14 days. Summary/Conclusion: CAZ-AVI-containing regimen is an effective option for the bacteremia due to carbapenem-resistant Gram-negative bacteria among hematologic patients, even in those infected with MBL-CRE bacteremia. Appropriate combination therapy is important after acquiring the information of enzymes and susceptibility to CAZ-AVI in vitro. Granulocyte recovery within 14 days may be a predictor of clinical success.

Abstract 5249: Efficacy and safety of apatinib in treatment of unresectablehepatocellular carcinoma: A real-world study

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Apatinib is a small molecule TKI inhibitor. Its efficacy and safety for unresectable HCC patients have been demonstrated in randomized controlled clinical studies. However, the efficacy and safety of apatinib in real world is lacking. We are aiming to evaluate the efficacy and safety of apatinib in real world.MethodsPatients of older than 18 years with unresectable HCC confirmed by IHC (Immunohistochemistry) or CT and MR Imaging were enrolled in the study. All patients received apatinib monotherapy or combined with other treatments including TACE and chemotherapy. The enrolled patients were treated until disease progression, death, or severe intolerable toxicity, etc. The primary endpoint was overall response rate (ORR), and secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were also recorded.ResultsFrom February, 2019 to May, 2020, a total of 233 patients were enrolled. Among them, 66 (28.33%) patients received apatinib monotherapy and 167 (71.67%) patients received combination therapy. Patients with a history of hepatitis accounted for 70%. 8 patients achieved complete response (CR), 64 patients achieved partial response (PR), 120 patients achieved stable disease (SD), and 41 patients had progressive disease (PD), illustrating an ORR of 30.90% and a DCR of 82.40%. Median PFS and OS were 6.93 months (95% CI, 6.19-7.68 months) and 11.36 months (95% CI, 9.96-12.77 months), respectively. The safety profile indicated that the most common drug-related adverse events were hypertension (37.90%), hand-foot-skin reaction (27.39%), fatigue (19.11%), thrombocytopenia (16.02%). Grade 3/4 treatment related AEs included thrombocytopenia (4.30%), hypertension (3.82%), neutropenia (2.73%). After symptomatic treatment, all the adverse events were treated properly, and no unexpected adverse events were observed. Conclusions In current study, apatininb showed good tolerance with acceptable toxicity and high tumor response rate that translated into promising PFS and OS in unresectable HCC patients. ChiCTR1900021822 Citation Format: Jun Liu, Guangbing Li, Qiang He, Shijun Sun, Chuanlin Zhao, Chuandong Sun, Bo Zhang, Yi Cui, Yongqiang Ye, Xuting Zhi, Shiping Li, Shiping Li, Guozheng Pan, Changlin Ma, Jinhua Hu, Jun Li, Suling Wang, Yuangang Qiao, Wanhua Ren, Qi Meng. Efficacy and safety of apatinib in treatment of unresectablehepatocellular carcinoma: A real-world study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5249.

Mucormycosis in Children With Hematologic Malignancies: A Case Series and Review of the Literature.

Mucormycosis is classified as the third leading cause of invasive fungal disease in immunocompromised patients and is characterized by high morbidity and mortality (33%-56%). The aim of this study is to describe presentation, treatment and outcome of Dutch pediatric hemato-oncology patients recently diagnosed with mucormycosis and to review the literature to gain more insight specifically into contemporary outcome data. Ten cases were diagnosed in the Princess Máxima Center for Pediatric Oncology from 2018 to 2021 and were retrospectively reviewed. In addition, 9 case series (n = 148) were included from literature. In our case series, 5 patients of 10 children (age 2-17 years) had disseminated invasive fungal disease. Four patients had localized pulmonary disease and 1 had a localized renal infection. One diagnosis was made postmortem. The underlying diseases were acute lymphoblastic leukemia (n = 6), acute myeloid leukemia (n = 2) and lymphoma (n=2). Seven patients received combination therapy comprising of a lipid amphotericin B formulation and a triazole, surgery was performed in 67%. All neutropenic patients received granulocyte transfusions and/or granulocyte colony-stimulating factor. Mucormycosis-related mortality was 20%. In the literature review, mucormycosis-related mortality was 36% for all patients and 66% for patients with disseminated disease. Survival rates were similar over the past 2 decades. The most common underlying disorder was acute lymphoblastic leukemia. Liposomal amphotericin B was the mainstay of treatment. Seventy percent of patients underwent surgery. Although survival of mucormycosis improved significantly overtime, it plateaued in the past decades. This series shows that with screening, early diagnostics and early antifungal and if possible surgical treatment, mortality is low and even disseminated disease is salvageable if approached aggressively with a combination of surgery and antifungal treatment. Further research focused on diagnostics, combination antifungal and adjunctive therapy is necessary to enhance the survival of mucormycosis in children.

Myelosuppression Rates with Administration of Nafcillin with and without Rifampin in Pediatric Patients.

Myelosuppression, a potential adverse reaction of nafcillin and rifampin, is rarely documented in pediatric populations. The objective of this study is to describe the incidence of myelosuppression in pediatric patients receiving nafcillin or a combination of nafcillin and rifampin therapy. This retrospective chart review identified patients who received nafcillin alone or in combination with rifampin. The primary endpoint was the incidence of myelosuppression as a composite outcome. The secondary endpoints were the incidence of thrombocytopenia, anemia, and neutropenia individually. Of 199 patients in this study, 98 received nafcillin alone. There was no difference in the rates of myelosuppression between patients receiving nafcillin alone or in combination with rifampin (p = 0.0763), and the use of combination therapy did not affect the development of neutropenia (p = 0.2764) or thrombocytopenia (p = 0.1672). Patients receiving combination therapy were more likely to be anemic at the end of therapy (odds ratio [OR] = 2.333, 95% confidence interval [CI] 0.999, 5.446). Similarly, patients receiving longer durations of nafcillin were more likely to experience anemia (OR 1.774, 95% CI 1.382, 2.370) and neutropenia (OR 1.256, 95% CI 1.024, 1.540). The use of nafcillin does not significantly affect myelosuppression in pediatric patients, although longer durations of therapy may result in increased rates of neutropenia and anemia. Combination therapy with rifampin may result in increased rates of neutropenia.

HGG-34. Upfront Molecular Targeted Therapy for the Treatment of BRAF-mutant Pediatric High-Grade Glioma

Abstract BACKGROUND: The prognosis for pediatric high-grade glioma (pHGG) is poor despite aggressive multi-modal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 10.7 years (range: 1.8–20.3). Histologic diagnoses included HGG (n=6), glioblastoma (n=3), anaplastic ganglioglioma (n=4), diffuse midline glioma (n=3), high-grade neuroepithelial tumor (n=1), anaplastic astrocytoma (n=1), and anaplastic astroblastoma (n=1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range,0.3–6.5), three-year progression-free (PFS) and overall survival (OS) for the cohort were 65% and 82%, respectively, and superior to a historical control cohort treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes observed compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.

Risk Factors for the Development of Colistin Resistance during Colistin Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

ABSTRACTColistin is one of the last-resort options for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections if novel antibiotics are unavailable, where the development of colistin resistance during treatment represents a major challenge for clinicians. We aimed to investigate the risk factors associated with the development of colistin resistance in patients with CRKP infections following colistin treatment. We conducted a retrospective case-control study of patients with CRKP strains available before and after colistin treatment at a medical center in Taiwan, between October 2016 and November 2020. Cases (n = 35) included patients with an initial colistin-susceptible CRKP (ColS-CRKP) strain and a subsequent colistin-resistant CRKP (ColR-CRKP) strain. Controls (n = 18) included patients with ColS-CRKP as both the initial and subsequent strains. The 30-day mortality rate after the subsequent CRKP isolation was not different between cases and controls (12/35 [34%] versus 5/18 [28%] [P = 0.631]). blaKPC (n = 38) and blaOXA-48 (n = 11) accounted for the major mechanisms of carbapenem resistance. Alterations in mgrB were found in 18/35 (51%) ColR-CRKP strains, and mcr-1 was not detected in any of the strains. More patients received combination therapy in the control group than in the case group (17/18 versus 21/35 [P = 0.008]). The logistic regression model indicated that combination therapy with tigecycline was protective against the acquisition of colistin resistance (odds ratio, 0.17; 95% confidence interval, 0.05 to 0.62 [P = 0.008]). We observed that the inclusion of tigecycline in colistin treatment mitigated the risk of acquiring colistin resistance. These results offer insight into using the combination of tigecycline and colistin for the treatment of CRKP infections in antimicrobial stewardship.IMPORTANCE Treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is challenging due to the limited options of antibiotics. Colistin is one of the last-resort antibiotics if novel antimicrobial agents are not available. It is crucial to identify modifiable clinical factors associated with the emergence of resistance during colistin treatment. Here, we found that the addition of tigecycline to colistin treatment prevented the acquisition of colistin resistance. Colistin-tigecycline combination therapy is therefore considered a hopeful option in antimicrobial stewardship to treat CRKP infections.

17-LB: Antihyperglycemic Use in Hemodialysis-Dependent Kidney Failure

Background: At least two-thirds of people with hemodialysis-dependent kidney failure have comorbid diabetes which associates with higher mortality. Some GLP-1 receptor agonists (RA) do not require renal dosing and could uniquely benefit dialysis patients, individuals with tremendous cardiovascular disease burden. Methods: Using data from a national surveillance system for kidney failure in the U.S. that includes Medicare Part D prescription drug claims, we: 1) calculated the quarterly prevalence of antihyperglycemic use among diabetic hemodialysis patients from 2012 to 2017 and 2) characterized antihyperglycemic users in October 2017. Results: Among the 129,865 hemodialysis patients with comorbid diabetes, insulin was the most prescribed agent (33%) , followed by sulfonylureas (SU, 7%) and DPP4 inhibitors (DPP4i, 5%) in October 2017. SU use fell, and DPP4i use rose from 2012 to 2017. Less than 5% of patients received combination therapy (insulin + a 2nd agent; Figure 1) . Disregarding kidney disease as an atherosclerotic cardiovascular disease (ASCVD) risk factor, 64% of patients met American Diabetes Association ASCVD criteria and 98% were at high risk for ASCVD in 2017. GLP-1 RA were prescribed to <1% of patients, 20% of whom had an endocrinology claim in the prior 6 months. Conclusions: GLP-1 RA use by hemodialysis patients is limited. There is compelling need to establish the safety and efficacy of GLP-1 RA in this high-risk population. Disclosure K. Klein: None. V. Pate: None. M. M. Assimon: None. T. Stürmer: Research Support; Novo Nordisk. Stock/Shareholder; Novartis AG, Novo Nordisk, Roche Pharmaceuticals. Other Relationship; AbbVie Inc., Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Takeda Pharmaceutical Company Limited, UCB, Inc. J. B. Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S. Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics. Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics. J. Flythe: Advisory Panel; Fresenius Medical Care. Consultant; AstraZeneca. Research Support; Fresenius Medical Care.

An integrated approach for obesity management: the effectiveness of glucagon-like peptide 1 agonist and life-style interventions for obesity management

Background. The obesity is found in 24.8% (approximately 10 million people) and overweight in 34.3% of the population of Ukraine, mainly in females. Obesity is associated with hereditary factors, overeating as well as a sedentary lifestyle. An integrated approach is applied to treat obesity such as combination of adequate eating behavior, high physical activity and administration of pharmacological correction, including glucagon-like peptide 1 agonist (GLP-1). Currently, the little is known about utility and effectiveness of GLP-1 in combination with adequate physical activity for obesity management among Ukrainian patients. The purpose of this study was to determine and evaluate the role of GLP-1 in combination with high physical activity for weight loss in obese patients and to compare with obese patients receiving treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Materials and methods. A prospective study included 155 obese patients, and follow-up data were available of 49 patients. The study group GLP-1 consisted of 30 patients receiving combination therapy GLP-1 liraglutide in daily doses of 1.2 to 3 mg per day. The control group consisted of 19 patients receiving complex therapy with metformin in daily doses from 500 to 2000 mg, and SGLT2i in daily doses from 10 to 12.5mg. Body mass index (BMI), waist circumference (WC), hip circumference (HC), and WC/HC ratio were evaluated. Number of daily steps was determined using pedometers built into smartphones or smartwatches. Evaluation of the obtained data was performed using non-parametric statistical methods. Results. In study group GLP-1 the mean weight before the treatment was 104.6kg, after treatment 96.36 kg (p=0.000007), the mean weight lost was 7.8% (range 1–23.71%) of initial body weight. Mean BMI before treatment was 37.1 kg/m2, after treatment 34.11kg/m2 (p=0.000006). In the control group, the mean weight before the treatment was 99.4 kg, after treatment 91.74 kg (p=0.000196), the mean weight lost was 7.73% (range 0–16.9%) of initial body weight. Mean BMI before treatment was 35.6kg/m2, after treatment 34.11 kg/m2 (p=0.000196). Analyses of the entrie chorot showed that before treatment, the daily number of steps >5000/day was determined in 25 (51%) patients, after treatment in 48 (98%); the daily number of steps >10,000/day before treatment was determined in 6 (11%) patients, after treatment it was 5 times more frequent in 31 (63%) patients. These results indicate a significant intensification of physical activity, and high motivation for weight loss in both study groups. Conclusions. Our findings suggest that weight loss in obese people is effective in case of administration of GLP-1, metformin, SGLT2i in combination with high physical activities of daily steps >5000, which is part of life style intervention.

The study of the effect of adherence with modern recommendations on antihypertensive therapy on compliance of patients with arterial hypertension

Aim. To study the relationship between the adherence with modern recommendations on antihypertensive therapy using fixed combinations of drugs in a “single” tablet with patients’ compliance and suggest ways to improve compliance in patients with hypertension based on the data obtained. 
 Materials and methods. Compliance of patients was assessed using the compliance scale of Hill-Bone arterial hypertension therapy; the nature of the antihypertensive therapy received was analyzed.
 Results. Compliance of hypertensive patients was 63.64 %. No patients with low compliance and no compliance at all were found among the patients examined. Female patients had 1.32 times more compliance for treating hypertension than male patients. At the same time, only 36.11 % of patients received a fixed combination of drugs in a “single” tablet. It was found that in patients receiving monotherapy with an antihypertensive drug, compliance was 60 %; in patients receiving combination therapy with several drugs compliance was 68.75 %, while compliance of patients receiving fixed combinations of antihypertensives was 71.43 %.
 Conclusions. The results obtained indicate a relatively low level of compliance in patients with hypertension. Also, against the background of insufficient adherence with current recommendations on antihypertensive therapy, a significantly higher compliance of patients treated with fixed combinations of antihypertensive drugs in a “single” tablet has been determined.

Comparative study of the effectiveness of combination therapy of vitiligo with methotrexate in combination with medium-wave narrow-band therapy UVB-311 nm and monotherapy UVB-311 nm

BACKGROUND: Vitiligo, a multifactorial chronic acquired disease with a genetic predisposition, occurs due to the destruction of melanocytes of the skin and is characterized by the appearance of foci of depigmentation. Despite the fact that new therapies are emerging, there are no actual treatment regimens that would guarantee a positive result, including stopping the progression of the process, repigmentation. In this regard, it is advisable to search for drugs that have an immunosuppressive effect.
 AIMS: Clinical evaluation of the effectiveness of methotrexate in combination with UVB-311 nm and UVB-311 nm monotherapy in vitiligo.
 MATERIALS AND METHODS: 77 patients suffering from progressive vitiligo were included in this study. All patients were divided into 2 groups. A course of methotrexate therapy in combination with UV therapy was prescribed to 39 patients, UVB-311 nm monotherapy was performed in 38 patients. The lesion area relative to the body surface area was estimated using the VES index (Vitiligo extent score) on the vitiligo calculator. The effect of the disease on the quality of life was assessed using the Dermatology Life Quality Index (DLQI). The duration of the study was 6 months.
 RESULTS: The patients included in the study were divided into two groups randomly. There were 39 patients in group I, 38 in group II. 76 out of 77 patients completed it: 1 patient was excluded due to increased hepatic transaminases during methotrexate therapy. Among patients receiving combination therapy with methotrexate in combination with medium-wave narrow-band therapy UVB-311 nm, there was a more pronounced decrease in the percentage of depigmentation relative to the body surface area. And also patients of this group demonstrated the most active positive dynamics of the Dermatology Life Quality Index than patients who received only phototherapy.
 CONCLUSIONS: The study demonstrated good clinical efficacy of the drug. Small doses of methotrexate have a positive effect on the tolerability of the drug and prevent the development of side effects, which makes it possible to influence pathogenetic mechanisms for a long time, stabilizing the skin process.

Evaluating potential toxicities of cancer immunotherapies using autoimmune animal models.

Abstract During the past few decades, cancer immunotherapy has recorded breakthroughs involving therapeutic agents that mediate immune response against several tumor types. However, an important consideration with immunotherapy treatment in the clinic has been the emergence of immune related adverse events (irAEs), that could lead to frequent hospitalization, premature therapy cessation and fatalities, thus limiting the efficacy of these therapies. Additionally, despite the clinical benefits of combining therapies, it has been observed that severity of toxicity increases with combination of therapy. Although, these irAEs are commonly seen in patients receiving immunotherapy, such events have been rarely observed in preclinical mouse models due to their nature: inbred, resistant, and short study duration. Here, we report the use of EAE autoimmune mouse model to evaluate potential toxicities of a novel cancer immunotherapy: anti-CD3ɛ mono-Fab, that is effective as a single therapy and could synergize with checkpoint inhibitors for superior anti-metastatic tumor response. EAE model groups treated with combination therapies showed more disease severity recapitulating the higher grade of irAEs seen in patients receiving combination therapies. The data suggest that autoimmune mouse models could serve as an effective tool to study the severity of toxicity associated with immunotherapeutic agents, and to determine optimized combinatorial regimens for best therapeutic performance. Supported by NCI U01CA244314

Assessment of Contributing Factors and Treatment Practices for Therapeutic Efficacy and Drug-Related Problems in Suicidal Psychotic Patients.

Suicide, a deliberate act of self-harm with the intention to die, is an emerging health concern but, unfortunately, the most under-researched subject in Pakistan, especially in Khyber Pukhtunkhwa (KPK). In this study, we aimed to identify risk factors that can be associated with suicidal behavior (SB) and to evaluate the prevailing treatment practices for therapeutic efficacy and drug-related problems (DRPs) in psychotic patients among the local population of KPK. A prospective, multicenter study was conducted for suicidal cases admitted to the study centers by randomized sampling. Socio-demographics and data on suicidal behavior were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), socioeconomic condition by Kuppuswamy socioeconomic scale (KSES) and treatment adherence by Morisky Medication-Taking Adherence Scale (MMAS-4). Drug-related problems and the therapeutic efficacy of prevailing treatment practices were assessed at baseline and follow-up after 3 months of treatment provided. Regarding suicidality (N = 128), females reported more ideations (63.1%), while males witnessed more suicidal behavior (66.6%, p < 0.001). Suicide attempters were mostly married (55.6%, p < 0.002); highly educated (53.9%, p = 0.004); dissatisfied with their life and had a previous history (p < 0.5) of suicide attempt (SA) (20.6%), self-injurious behavior (SIB) (39.7%) and interrupted (IA) or aborted attempts (AA) (22.2%). A greater improvement was observed in patients receiving combination therapy (p = 0.001) than pharmacotherapy (p = 0.006) or psychotherapy (p = 0.183), alone. DRPs were also detected, including drug-selection problems (17.88%), dose-related problems (20.64%), potential drug–drug interactions (24.31%), adverse drug reactions (11.46%) and other problems like inadequate education and counseling (21.55%). Furthermore, it was also found that psychotic patients with suicidal ideations (SI) were significantly (p = 0.01) more adherent to the treatment as compared to those with suicidal attempts. We concluded that suicide attempters differed significantly from patients with suicidal ideations in psychotic patients and presented with peculiar characteristics regarding socio-demographic factors. A combination of therapies and adherence to the treatment provided better outcomes, and targeted interventions are warranted to address drug-related problems.

Curative Analysis of Patients with Hepatocellular Carcinoma Using Transcatheter Arterial Chemoembolization Combined with Radiofrequency Ablation.

BackgroundTranscatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) can improve the survival of patients with hepatocellular carcinoma (HCC). The purpose was to explore the characteristics of high-risk and low-risk groups of HCC patients receiving combination therapy using a decision tree model.Material/MethodsThis retrospective cohort study investigated HCC patients treated with a combination of TACE and RFA at our hospital from 2012 to 2018. Decision tree analysis was used to study the 1-year prognosis of patients, and patients were divided into high-risk and low-risk groups.ResultsWe included a total of 142 patients with HCC, 21.83% female and 78.17% male, with the median age of 60 years old. The median follow-up was 13.5 months; 39.44% of patients had progressive disease or death (high-risk group) and 60.56% of patients did not have progressive disease or survival (low-risk group). The area under the curve (AUC) of the decision tree model was 0.846. There were significant differences in sex (P=0.003), age (P=0.038), tumor number (P=0.043), number of RFAs in the first treatment cycle (P<0.001), alanine transaminase (ALT) (P<0.001), and aspartate transaminase (AST) (P=0.041) between the high-risk and the low-risk groups. Risk of progressive disease or death in the high-risk group was 12.232 times higher than in the low-risk group.ConclusionsTo improve individual survival, clinicians should pay attention to the identification of high-risk HCC patients receiving combination therapy, especially those with less frequent use of RFA during the first treatment and higher ALT and AST levels.

Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.

Inhaled iloprost induces long-term beneficial hemodynamic changes in patients with pulmonary arterial hypertension receiving combination therapy.

Inhaled iloprost is an established treatment for pulmonary arterial hypertension (PAH). However, the long‐term hemodynamic changes that inhaled iloprost induces are unclear. Here, we retrospectively enrolled 18 patients with PAH who received inhaled iloprost as add‐on to oral combination therapy from December 2016 to January 2021 at our institute in Japan. We then examined the changes in hemodynamic parameters induced by iloprost in these patients during right heart catheterization (RHC). To examine the long‐term effects of iloprost, we repeated the RHC examination at follow‐up (median time to follow‐up, 8.5 months). During both catheterization procedures, iloprost was administered by using an I‐neb AAD system (Philips NV). In a comparison of pre‐inhalation values at the first and follow‐up RHCs, inhaled iloprost significantly improved mean pulmonary artery pressure (mPAP; 39.9 ± 7.8 to 32.5 ± 7.2 mmHg, p = 0.016) and pulmonary vascular resistance (PVR; 588.5 ± 191.7 to 464.4 ± 188.5 dyn s cm−5, p = 0.047). During the follow‐up RHC, in a comparison of the pre‐inhalation and best recorded values out to 30 min after the end of iloprost inhalation, iloprost significantly decreased mPAP (32.5 ± 7.2 to 30.0 ± 6.6 mmHg, p = 0.007) and PVR (457.8 ± 181.4 to 386.2 ± 142.8 dyn s cm−5, p = 0.025) and significantly increased cardiac output (4.19 ± 0.91 to 4.64 ± 1.01 L/min, p = 0.035). Iloprost may have not only acute vasodilation effects but also long‐term hemodynamic benefits in PAH patients receiving combination therapy.

Solifenacin and Mirabegron Monotherapies Versus Combination Therapy in Overactive Bladder: A Prospective Observational Study

Overactive bladder (OAB) is a common medical condition, especially in the elderly population, that affects the quality of life. The primary treatment of OAB is a combination of behavioural measures and widely used anti-muscarinic drug therapy like solifenacin, which brings about significant side effects, thereby affecting the quality of life adversely. Mirabegron, a recently approved drug for treatment of OAB is a β3 - adrenergic agonist, which relaxes the detrusor muscle. With this background, the current study was done to compare the efficacy and safety of solifenacin, mirabegron and combination of low doses of solifenacin and mirabegron on various parameters of OAB. A total no. of 70 patients with OAB symptoms coming to urology OPD were included in this study and they were divided into 3 groups - Group 1: 24 patients receiving solifenacin 10mg/day, Group 2: 23 patients receiving solifenacin 5mg/day plus mirabegron 25mg/day, Group 3: 23 patients receiving mirabegron 50 mg/day. Patients were assessed for change in mean numbers of micturition, urgency, incontinence per 24 hour and quality of life using Patient Perception of Bladder Control (PPBC) Questionnaire. They were followed up after 4 weeks and 12 weeks and change in the above parameters from baseline were noted. Patients receiving combination therapy achieved a significant reduction in urgency, frequency, nocturia and urge incontinence and decrease in side effects when compared with solifenacin and mirabegron alone. Combination therapy with solifenacin and mirabegron significantly improved quality of life and reduced side effects like dry mouth, blurred vision, constipation in OAB patients in comparison to solifenacin and mirabegron monotherapy.

Response to SARS-CoV-2 vaccination in systemic autoimmune rheumatic disease depends on immunosuppressive regimen: a matched, prospective cohort study

ObjectiveTo assess the humoral response to messenger RNA (mRNA) vaccine of patients with systemic autoimmune rheumatic disease (SARD) and the effect of immunosuppressive medication in a matched cohort study.MethodsPatients with...

РЕЗУЛЬТАТЫ КОМПЛЕКСНОГО КОНСЕРВАТИВНОГО ЛЕЧЕНИЯ ПАЦИЕНТОВ С ЭНДОКРИННОЙ ОФТАЛЬМОПАТИЕЙ СРЕДНЕЙ СТЕПЕНИ ТЯЖЕСТИ

Background. Pathogenetic therapy of the moderate severity endocrine ophthalmopathy (EOP) is performed by the administration of glucocorticoids (GC), which possess immunosuppressive, anti-inflammatory and anti-edematous effects. Currently, the application of selenium and pentoxifylline medications, as well as treatment with magnetic field over periorbital region are considered as a part of combined therapy for the disease. Purpose of the study. To evaluate the results of combined conservative treatment of patients with moderate severity EOP. Material and methods. The study included 25 patients (50 orbits) with the clinical signs of moderate severity EOP. Depending on the treatment regimen, patients were divided into group A (comparison) and group B (main). Group A (comparison) – 10 patients who received pulse therapy with methylprednisolone. Group B (main) – 15 patients who were prescribed a combination of pulse therapy with methylprednisalone and a new developed treatment regimen additionally: selenium 100 mgq 2 times a day for 6 months, pentoxifylline at a dose of 600 mg 2 times a day for 6 months, a low-frequency pulsed magnetic field generated by the "UniSPOK" apparatus, lasting for 10-20 minutes, up to 8-12 procedures performed daily. Methylprednisolone application in the form of intravenous pulse therapy was prescribed collegially by an endocrinologist and an ophthalmologist individually for each patient and in total did not exceed 4.5 g recommended for the present process intensity (on average, 4.5±0.5 g in both groups). Results. The sequence in decreasing of EOP clinical signs in patients receiving combination therapy was revealed: a decrease in tremor, eyelid edema and palpebral fissure width in comparison with the initial parameters were noted already by the 3rd month of treatment, after 6 months these indicators disappeared. Lacrimation in the studied groups was not recorded by the 6th month, which can be explained by the corticosteroids application. A significant reduction in exophthalmos under developed therapy was found after 6 months, while no reduction was observed in the standard treatment group. Conclusions. The method of EOP complex treatment, including pulse therapy with methylprednisolone in combination with selenium, pentoxifylline and magnetotherapy, was effective in the moderate severity of the disease and led to the reduction of the ophthalmopathy severity symptoms. The positive effect of the combined therapy indicates the necessity for a six-month treatment course.

Effectiveness of first-line therapy in patients with advanced non-clear renal cell carcinoma (nccRCC).

304 Background: Current treatment principles for advanced nccRCC have been largely extrapolated from guidelines for clear cell RCC. Given the emerging randomized data for select nccRCC subtypes, real-world outcomes for these patients are informative particularly in the contemporary checkpoint inhibitor era. Methods: We performed an analysis using the Canadian Kidney Cancer information system (CKCis), a prospective database involving 14 academic centers, on nccRCC patients undergoing first-line systemic therapy between January 2011 – December 2019. Treatment groups were defined as receipt of: vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-TKI), mammalian target of rapamycin inhibitors (mTORi), and PD-1/PD-L1 immune checkpoint inhibitors (ICI, mono- or combination therapy). Primary outcome was 1-yr overall survival (OS) rate. Secondary outcomes were median time to treatment failure ((TTF, months), defined as treatment discontinuation, change or death) and objective response rate (ORR, %). Results: We identified 265 nccRCC patients: 204 (77.0%) received VEGF-TKI, 19 (7.2%) received mTORi and 42 (15.8%) received ICI-based first-line therapy (Table). Overall, median age was 64 years, 75% were male, 84% were classified as IMDC intermediate/poor risk, and 16% underwent prior nephrectomy. Twenty-three percent of patients were enrolled in clinical trials. Patients received primarily sunitinib (81%) or pazopanib (15%) in the VEGF-TKI group (other: 4%), while mTORi-treated patients received temsirolimus (74%) or everolimus (26%). For the ICI-based treatment group, most patients received combination therapy as ipilimumab-nivolumab (71%) or pembrolizumab-axitinib (26%), with 3% receiving ICI monotherapy. 1-yr OS was 65.2% for VEGF-TKI, 57.9% for mTORi and 69.0% for ICI-treated patients. Median TTF was 3.3 for VEGF-TKI, 3.5 for mTORi and 7.1 mos for ICI-treated patients. ORR was 17%, 5%, and 37% respectively for the VEGF-TKI, mTORi and ICI-treated groups. Conclusions: We describe the effectiveness of first-line therapy for patients with nccRCC from a national database. This real-world data suggests an association between first-line ICI-based therapies and improved outcomes, albeit with cabozantinib not available for the indication during this time. Our data supports consensus recommendations for preferred use of ICI-based or VEGF-TKI over mTORi as first-line therapy in nccRCC.[Table: see text]

Prognosis and risk factors for cardiac valve calcification in Chinese end-stage kidney disease patients on combination therapy with hemodialysis and hemodiafiltration

Background Cardiac valve calcification (CVC) is an important risk factor for cardiovascular complications. However, limited data are available concerning the prevalence, clinical features and risk factors for CVC in end-stage kidney disease (ESKD) patients. In this study, we aimed to assess these parameters in Chinese ESKD patients receiving combination therapy with hemodialysis and hemodiafiltration. Methods We conducted a cross-sectional study on 293 ESKD patients undergoing combination therapy of hemodialysis and hemodiafiltration at the First Affiliated Hospital of Chongqing Medical University from October 2014 to December 2015. CVC was evaluated via echocardiography. Results ESKD patients with CVC had a higher prevalence of diabetes mellitus, aortic and/or coronary artery calcification, arrhythmia, heart failure and coronary heart disease; increased systolic, diastolic and pulse pressure; longer duration of hemodialysis and hypertension; reduced hemoglobin, albumin and high-density lipoprotein cholesterol levels; and increased serum calcium and calcium-phosphorus product levels compared with those without CVC. Logistic regression analysis showed that increased dialysis duration (p = 0.006, OR = 2.25), serum calcium levels (p = 0.046, OR = 2.04) and pulse pressure (p < 0.001, OR = 3.22), the presence of diabetes (p = 0.037, OR = 1.81) and decreased serum albumin levels (p = 0.047, OR = 0.54) were risk factors for CVC. The correlation analysis indicated a significantly increased CVCs prevalence with an increase prevalence of heart failure, aortic and coronary artery calcification. Conclusions CVC represents a common complication and a danger signal for cardiovascular events in ESKD patients undergoing combination therapy of hemodialysis and hemodiafiltration. The presence of diabetes, increased pulse pressure, long dialysis duration, hypoalbuminemia and high serum calcium levels were independent risk factors for CVC.